CN105153014B - 用于治疗癌症的作为mdm2抑制剂的哌啶酮衍生物 - Google Patents
用于治疗癌症的作为mdm2抑制剂的哌啶酮衍生物 Download PDFInfo
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- CN105153014B CN105153014B CN201510205985.6A CN201510205985A CN105153014B CN 105153014 B CN105153014 B CN 105153014B CN 201510205985 A CN201510205985 A CN 201510205985A CN 105153014 B CN105153014 B CN 105153014B
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- chlorophenyl
- acetic acid
- methyl
- oxopiperidin
- butan
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- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 71
- 201000011510 cancer Diseases 0.000 title claims abstract description 47
- 238000011282 treatment Methods 0.000 title claims abstract description 30
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical class O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 title claims description 17
- 239000012819 MDM2-Inhibitor Substances 0.000 title abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 272
- 239000003814 drug Substances 0.000 claims abstract description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 357
- -1 2-pyridyl Chemical group 0.000 claims description 211
- 125000002947 alkylene group Chemical group 0.000 claims description 173
- 125000000217 alkyl group Chemical group 0.000 claims description 135
- 125000000623 heterocyclic group Chemical group 0.000 claims description 75
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 69
- 125000001072 heteroaryl group Chemical group 0.000 claims description 53
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 53
- 150000003839 salts Chemical class 0.000 claims description 52
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 39
- 238000000034 method Methods 0.000 claims description 39
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 36
- 125000001188 haloalkyl group Chemical group 0.000 claims description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 35
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 23
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 22
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 18
- 238000006467 substitution reaction Methods 0.000 claims description 18
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 claims description 13
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 13
- 210000004027 cell Anatomy 0.000 claims description 11
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- OMAPWASVHLHIRY-NQSCKRDGSA-N 2-[(3r,5r,6s)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl]acetic acid Chemical compound N1([C@@H]([C@H](C[C@@H](C1=O)CC(=O)O)C=1C=C(Cl)C=CC=1)C=1C=CC(Cl)=CC=1)CC1CC1 OMAPWASVHLHIRY-NQSCKRDGSA-N 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 9
- 125000004076 pyridyl group Chemical group 0.000 claims description 9
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 9
- OMAPWASVHLHIRY-UCNVEGJOSA-N 2-[(3s,5r,6s)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl]acetic acid Chemical compound N1([C@@H]([C@H](C[C@H](C1=O)CC(=O)O)C=1C=C(Cl)C=CC=1)C=1C=CC(Cl)=CC=1)CC1CC1 OMAPWASVHLHIRY-UCNVEGJOSA-N 0.000 claims description 8
- YUALYRLIFVPOHL-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2-hydroxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C1C(C)(CC(O)=O)C(=O)N(C(C(C)O)CC)C(C=2C=CC(Cl)=CC=2)C1C1=CC=CC(Cl)=C1 YUALYRLIFVPOHL-UHFFFAOYSA-N 0.000 claims description 8
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 8
- 150000002367 halogens Chemical group 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- CIDOSHLRBQPHIP-ZDLYWVCESA-N 2-[(3r,5r,6s)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-[(3s)-1,1,1-trifluoro-2-hydroxypentan-3-yl]piperidin-3-yl]acetic acid Chemical compound C1([C@@H]2[C@H](N(C([C@@H](CC(O)=O)C2)=O)[C@H](C(O)C(F)(F)F)CC)C=2C=CC(Cl)=CC=2)=CC=CC(Cl)=C1 CIDOSHLRBQPHIP-ZDLYWVCESA-N 0.000 claims description 7
- LSXWGWIINRYFAI-JMUQELJHSA-N methyl 2-[(3r,5r,6s)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl]acetate Chemical compound N1([C@@H]([C@H](C[C@@H](C1=O)CC(=O)OC)C=1C=C(Cl)C=CC=1)C=1C=CC(Cl)=CC=1)CC1CC1 LSXWGWIINRYFAI-JMUQELJHSA-N 0.000 claims description 7
- AXQMSOFCQLTJGV-UHFFFAOYSA-N 2-[1-(1-tert-butylsulfonylbutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C1C(C)(CC(O)=O)C(=O)N(C(CS(=O)(=O)C(C)(C)C)CC)C(C=2C=CC(Cl)=CC=2)C1C1=CC=CC(Cl)=C1 AXQMSOFCQLTJGV-UHFFFAOYSA-N 0.000 claims description 6
- MHIVCWTYRMHMGG-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-methylsulfonylethyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound O=C1C(C)(CC(O)=O)CC(C=2C=C(Cl)C=CC=2)C(C=2C=CC(Cl)=CC=2)N1C(CS(C)(=O)=O)C1CC1 MHIVCWTYRMHMGG-UHFFFAOYSA-N 0.000 claims description 6
- GNBHDBPUJCJXQG-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[1-cyclopropyl-2-[cyclopropylsulfonyl(methyl)amino]ethyl]-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C1CC1S(=O)(=O)N(C)CC(N1C(C(C)(CC(O)=O)CC(C1C=1C=CC(Cl)=CC=1)C=1C=C(Cl)C=CC=1)=O)C1CC1 GNBHDBPUJCJXQG-UHFFFAOYSA-N 0.000 claims description 6
- 206010039491 Sarcoma Diseases 0.000 claims description 6
- 125000005605 benzo group Chemical group 0.000 claims description 6
- 125000002757 morpholinyl group Chemical group 0.000 claims description 6
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims description 6
- DRLCSJFKKILATL-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(3-methyl-1-propan-2-ylsulfonylbutan-2-yl)-2-oxopiperidin-3-yl]acetic acid Chemical compound C1C(C)(CC(O)=O)C(=O)N(C(CS(=O)(=O)C(C)C)C(C)C)C(C=2C=CC(Cl)=CC=2)C1C1=CC=CC(Cl)=C1 DRLCSJFKKILATL-UHFFFAOYSA-N 0.000 claims description 5
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 5
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 5
- 206010025323 Lymphomas Diseases 0.000 claims description 5
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 5
- 201000001441 melanoma Diseases 0.000 claims description 5
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 5
- VCLKYYIVEHNXSL-XDFGCPGZSA-N 2-[(3r,5r,6s)-1-[(1s)-2-(benzylsulfonylamino)-1-cyclopropylethyl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C([C@@H](N1[C@@H]([C@H](C[C@@](C1=O)(CC(O)=O)C)C=1C=C(Cl)C=CC=1)C=1C=CC(Cl)=CC=1)C1CC1)NS(=O)(=O)CC1=CC=CC=C1 VCLKYYIVEHNXSL-XDFGCPGZSA-N 0.000 claims description 4
- QGKMXIKHMXVVSS-ZJTSJXPUSA-N 2-[(3r,5r,6s)-1-[(2s)-1-(tert-butylsulfonylamino)butan-2-yl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C1([C@@H]2[C@H](N(C([C@@](C)(CC(O)=O)C2)=O)[C@H](CNS(=O)(=O)C(C)(C)C)CC)C=2C=CC(Cl)=CC=2)=CC=CC(Cl)=C1 QGKMXIKHMXVVSS-ZJTSJXPUSA-N 0.000 claims description 4
- DSXCZCSHMQWYGJ-NANZAVOOSA-N 2-[(3r,5r,6s)-1-[(2s)-1-[tert-butylsulfonyl(methyl)amino]butan-2-yl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C1([C@@H]2[C@H](N(C([C@@](C)(CC(O)=O)C2)=O)[C@H](CN(C)S(=O)(=O)C(C)(C)C)CC)C=2C=CC(Cl)=CC=2)=CC=CC(Cl)=C1 DSXCZCSHMQWYGJ-NANZAVOOSA-N 0.000 claims description 4
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- JXPCJNIFNLDWFI-PIBIMKELSA-N 2-[(3r,5r,6s)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(1s)-1-(5-methyl-1,3,4-oxadiazol-2-yl)propyl]-2-oxopiperidin-3-yl]acetic acid Chemical compound C1([C@@H]2[C@H](N(C([C@@H](CC(O)=O)C2)=O)[C@@H](CC)C=2OC(C)=NN=2)C=2C=CC(Cl)=CC=2)=CC=CC(Cl)=C1 JXPCJNIFNLDWFI-PIBIMKELSA-N 0.000 claims description 4
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- ODKVMWAWCVLXJM-DCHZYZNDSA-N 2-[(3r,5r,6s)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(1s,2r)-1-cyclopropyl-2-hydroxypropyl]-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C1([C@@H]([C@H](O)C)N2C([C@@](C)(CC(O)=O)C[C@@H]([C@H]2C=2C=CC(Cl)=CC=2)C=2C=C(Cl)C=CC=2)=O)CC1 ODKVMWAWCVLXJM-DCHZYZNDSA-N 0.000 claims description 4
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- AWWJRXUFVJUAMA-XMXZMMKCSA-N 2-[(3r,5r,6s)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(2r)-1-(ethylamino)-1-oxobutan-2-yl]-2-oxopiperidin-3-yl]acetic acid Chemical compound C1([C@@H]2[C@H](N(C([C@@H](CC(O)=O)C2)=O)[C@H](CC)C(=O)NCC)C=2C=CC(Cl)=CC=2)=CC=CC(Cl)=C1 AWWJRXUFVJUAMA-XMXZMMKCSA-N 0.000 claims description 4
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- 125000000335 thiazolyl group Chemical class 0.000 claims description 3
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- WNQWWOBTWUSPFE-MJFZWJQVSA-N (2s)-2-[(3r,5r,6s)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(2s)-1-[cyclopropylsulfonyl(methyl)amino]butan-2-yl]-3-methyl-2-oxopiperidin-3-yl]propanoic acid Chemical compound C([C@H](CC)N1C([C@@](C)([C@H](C)C(O)=O)C[C@@H]([C@H]1C=1C=CC(Cl)=CC=1)C=1C=C(Cl)C=CC=1)=O)N(C)S(=O)(=O)C1CC1 WNQWWOBTWUSPFE-MJFZWJQVSA-N 0.000 claims description 2
- SDVTVXLQMGTUDI-LHWXFDGDSA-N (3r,5r,6s)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(1s)-1-cyclopropyl-2-ethylsulfonylethyl]-3-(3-hydroxy-2-oxopropyl)-3-methylpiperidin-2-one Chemical compound C1([C@@H](CS(=O)(=O)CC)N2C([C@@](C)(CC(=O)CO)C[C@@H]([C@H]2C=2C=CC(Cl)=CC=2)C=2C=C(Cl)C=CC=2)=O)CC1 SDVTVXLQMGTUDI-LHWXFDGDSA-N 0.000 claims description 2
- LXGSJAGQGNYLQC-MWZYUOISSA-N (3r,5r,6s)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(2s)-1-(1,1-dioxo-1,2-thiazolidin-2-yl)butan-2-yl]-3-[(6-methoxypyridin-2-yl)methyl]piperidin-2-one Chemical compound C([C@H](CC)N1C([C@@H](CC=2N=C(OC)C=CC=2)C[C@@H]([C@H]1C=1C=CC(Cl)=CC=1)C=1C=C(Cl)C=CC=1)=O)N1CCCS1(=O)=O LXGSJAGQGNYLQC-MWZYUOISSA-N 0.000 claims description 2
- JALVLPROXFDZPY-SDSXRCECSA-N (3r,5r,6s)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(2s)-1-(1,1-dioxo-1,2-thiazolidin-2-yl)butan-2-yl]-3-methyl-3-[(6-oxo-1h-pyridin-2-yl)methyl]piperidin-2-one Chemical compound C([C@H](CC)N1C([C@@](C)(CC=2N=C(O)C=CC=2)C[C@@H]([C@H]1C=1C=CC(Cl)=CC=1)C=1C=C(Cl)C=CC=1)=O)N1CCCS1(=O)=O JALVLPROXFDZPY-SDSXRCECSA-N 0.000 claims description 2
- KROAAONPLZABTR-GYFOVIHYSA-N (3r,5r,6s)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-[(2r)-2,3-dihydroxypropyl]-1-[(2s,3s)-2-hydroxypentan-3-yl]-3-methylpiperidin-2-one Chemical compound C1([C@@H]2[C@H](N(C([C@@](C)(C[C@@H](O)CO)C2)=O)[C@H]([C@H](C)O)CC)C=2C=CC(Cl)=CC=2)=CC=CC(Cl)=C1 KROAAONPLZABTR-GYFOVIHYSA-N 0.000 claims description 2
- RGUBNHBOWVYYNU-GZGNHOFSSA-N (3r,5r,6s)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-pentan-3-yl-3-(2h-tetrazol-5-ylmethyl)piperidin-2-one Chemical compound C([C@]1(C[C@@H]([C@H](N(C1=O)C(CC)CC)C=1C=CC(Cl)=CC=1)C=1C=C(Cl)C=CC=1)C)C1=NN=NN1 RGUBNHBOWVYYNU-GZGNHOFSSA-N 0.000 claims description 2
- IJSLZYQQCLYVBA-KJXAQDMKSA-N (3r,5r,6s)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-propan-2-yl-3-(2h-tetrazol-5-ylmethyl)piperidin-2-one Chemical compound C([C@]1(C[C@@H]([C@H](N(C1=O)C(C)C)C=1C=CC(Cl)=CC=1)C=1C=C(Cl)C=CC=1)C)C1=NN=NN1 IJSLZYQQCLYVBA-KJXAQDMKSA-N 0.000 claims description 2
- RIEUVQACKRGVBB-WHSBFGAESA-N (3r,5r,6s)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-3-[(5-oxo-1,2-dihydro-1,2,4-triazol-3-yl)methyl]-1-pentan-3-ylpiperidin-2-one Chemical compound C([C@]1(C[C@@H]([C@H](N(C1=O)C(CC)CC)C=1C=CC(Cl)=CC=1)C=1C=C(Cl)C=CC=1)C)C1=NNC(=O)N1 RIEUVQACKRGVBB-WHSBFGAESA-N 0.000 claims description 2
- TZKWWFDFKYPIMR-HYZYYIOASA-N (3r,5r,6s)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-3-[(5-oxo-1,2-dihydropyrazol-3-yl)methyl]-1-pentan-3-ylpiperidin-2-one Chemical compound C([C@]1(C[C@@H]([C@H](N(C1=O)C(CC)CC)C=1C=CC(Cl)=CC=1)C=1C=C(Cl)C=CC=1)C)C1=CC(O)=NN1 TZKWWFDFKYPIMR-HYZYYIOASA-N 0.000 claims description 2
- SVUVOAAWIIGAGC-QBIAMMSFSA-N (3s,5r,6s)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(2s)-1-(1,1-dioxo-1,2-thiazolidin-2-yl)butan-2-yl]-3-[(6-methoxypyridin-2-yl)methyl]-3-methylpiperidin-2-one Chemical compound C([C@H](CC)N1C([C@](C)(CC=2N=C(OC)C=CC=2)C[C@@H]([C@H]1C=1C=CC(Cl)=CC=1)C=1C=C(Cl)C=CC=1)=O)N1CCCS1(=O)=O SVUVOAAWIIGAGC-QBIAMMSFSA-N 0.000 claims description 2
- LXGSJAGQGNYLQC-WUIMFCPGSA-N (3s,5r,6s)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(2s)-1-(1,1-dioxo-1,2-thiazolidin-2-yl)butan-2-yl]-3-[(6-methoxypyridin-2-yl)methyl]piperidin-2-one Chemical compound C([C@H](CC)N1C([C@H](CC=2N=C(OC)C=CC=2)C[C@@H]([C@H]1C=1C=CC(Cl)=CC=1)C=1C=C(Cl)C=CC=1)=O)N1CCCS1(=O)=O LXGSJAGQGNYLQC-WUIMFCPGSA-N 0.000 claims description 2
- JALVLPROXFDZPY-DGEPZWHSSA-N (3s,5r,6s)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(2s)-1-(1,1-dioxo-1,2-thiazolidin-2-yl)butan-2-yl]-3-methyl-3-[(6-oxo-1h-pyridin-2-yl)methyl]piperidin-2-one Chemical compound C([C@H](CC)N1C([C@](C)(CC=2N=C(O)C=CC=2)C[C@@H]([C@H]1C=1C=CC(Cl)=CC=1)C=1C=C(Cl)C=CC=1)=O)N1CCCS1(=O)=O JALVLPROXFDZPY-DGEPZWHSSA-N 0.000 claims description 2
- LHJSKUIKGQUINB-VDKIKQQVSA-N (3s,5r,6s)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-3-(methylsulfonylmethyl)-1-pentan-3-ylpiperidin-2-one Chemical compound C1([C@@H]2[C@H](N(C([C@@](C)(CS(C)(=O)=O)C2)=O)C(CC)CC)C=2C=CC(Cl)=CC=2)=CC=CC(Cl)=C1 LHJSKUIKGQUINB-VDKIKQQVSA-N 0.000 claims description 2
- NYKRRIQBYZLKHH-PSHWWDCKSA-N (3s,6s,7r)-7-(3-chlorophenyl)-6-(4-chlorophenyl)-5-[(2s)-1-[cyclopropylsulfonyl(methyl)amino]butan-2-yl]-4-oxo-5-azaspiro[2.5]octane-2-carboxylic acid Chemical compound C([C@H](CC)N1C([C@@]2(C(C2)C(O)=O)C[C@@H]([C@H]1C=1C=CC(Cl)=CC=1)C=1C=C(Cl)C=CC=1)=O)N(C)S(=O)(=O)C1CC1 NYKRRIQBYZLKHH-PSHWWDCKSA-N 0.000 claims description 2
- UEIXAPRJBQBMEZ-BLUNXUMHSA-N 1-[(3r,5r)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(1s)-1-cyclopropyl-2-(cyclopropylsulfonylamino)ethyl]-3-methyl-2-oxopiperidin-3-yl]cyclopropane-1-carboxylic acid Chemical compound C([C@@H](N1C([C@H](C[C@](C1=O)(C)C1(CC1)C(O)=O)C=1C=C(Cl)C=CC=1)C=1C=CC(Cl)=CC=1)C1CC1)NS(=O)(=O)C1CC1 UEIXAPRJBQBMEZ-BLUNXUMHSA-N 0.000 claims description 2
- UEIXAPRJBQBMEZ-UHFFFAOYSA-N 1-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[1-cyclopropyl-2-(cyclopropylsulfonylamino)ethyl]-3-methyl-2-oxopiperidin-3-yl]cyclopropane-1-carboxylic acid Chemical compound O=C1C(C)(C2(CC2)C(O)=O)CC(C=2C=C(Cl)C=CC=2)C(C=2C=CC(Cl)=CC=2)N1C(C1CC1)CNS(=O)(=O)C1CC1 UEIXAPRJBQBMEZ-UHFFFAOYSA-N 0.000 claims description 2
- YOGMLZIIOGDDPK-CARYDLSXSA-N 2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(1S)-1-cyclopropyl-2-(2-phenylethylsulfonylamino)ethyl]-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound ClC=1C=C(C=CC1)[C@H]1C[C@](C(N([C@@H]1C1=CC=C(C=C1)Cl)[C@H](CNS(=O)(=O)CCC1=CC=CC=C1)C1CC1)=O)(C)CC(=O)O YOGMLZIIOGDDPK-CARYDLSXSA-N 0.000 claims description 2
- GBEKVRADMZPJFP-QUMLNKAGSA-N 2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(1S)-1-cyclopropyl-2-[(2-fluorophenyl)methylsulfonylamino]ethyl]-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C([C@@H](N1[C@@H]([C@H](C[C@@](C1=O)(CC(O)=O)C)C=1C=C(Cl)C=CC=1)C=1C=CC(Cl)=CC=1)C1CC1)NS(=O)(=O)CC1=CC=CC=C1F GBEKVRADMZPJFP-QUMLNKAGSA-N 0.000 claims description 2
- ULZZPAGEIPSFHM-VAUJZKAJSA-N 2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(1S)-1-cyclopropyl-2-[2-(2-fluorophenyl)ethylsulfonylamino]ethyl]-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound ClC=1C=C(C=CC=1)[C@H]1C[C@](C(N([C@@H]1C1=CC=C(C=C1)Cl)[C@H](CNS(=O)(=O)CCC1=C(C=CC=C1)F)C1CC1)=O)(C)CC(=O)O ULZZPAGEIPSFHM-VAUJZKAJSA-N 0.000 claims description 2
- YKVAZXAMPZEUDL-VIJKIUKESA-N 2-[(3r,5r)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(3s)-5-hydroxy-5-methylhexan-3-yl]-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C1([C@@H]2C(N(C([C@@](C)(CC(O)=O)C2)=O)[C@H](CC(C)(C)O)CC)C=2C=CC(Cl)=CC=2)=CC=CC(Cl)=C1 YKVAZXAMPZEUDL-VIJKIUKESA-N 0.000 claims description 2
- VDBOOIDGCNUDCT-CGMQEPJLSA-N 2-[(3r,5r,6s)-1-[(1r)-1-(6-bromopyridin-2-yl)propyl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C1([C@@H]2[C@H](N(C([C@@](C)(CC(O)=O)C2)=O)[C@H](CC)C=2N=C(Br)C=CC=2)C=2C=CC(Cl)=CC=2)=CC=CC(Cl)=C1 VDBOOIDGCNUDCT-CGMQEPJLSA-N 0.000 claims description 2
- VDBOOIDGCNUDCT-PKZARACNSA-N 2-[(3r,5r,6s)-1-[(1s)-1-(6-bromopyridin-2-yl)propyl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C1([C@@H]2[C@H](N(C([C@@](C)(CC(O)=O)C2)=O)[C@@H](CC)C=2N=C(Br)C=CC=2)C=2C=CC(Cl)=CC=2)=CC=CC(Cl)=C1 VDBOOIDGCNUDCT-PKZARACNSA-N 0.000 claims description 2
- MCONUGXGXLKEIA-OCPJJFGMSA-N 2-[(3r,5r,6s)-1-[(1s)-2-(2-chloro-4-fluorophenyl)sulfonyl-1-cyclopropylethyl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C([C@@H](N1[C@@H]([C@H](C[C@@](C1=O)(CC(O)=O)C)C=1C=C(Cl)C=CC=1)C=1C=CC(Cl)=CC=1)C1CC1)S(=O)(=O)C1=CC=C(F)C=C1Cl MCONUGXGXLKEIA-OCPJJFGMSA-N 0.000 claims description 2
- SXSRMKULCNELMF-YWCVFVGNSA-N 2-[(3r,5r,6s)-1-[(1s)-2-(azetidin-1-ylsulfonyl)-1-cyclopropylethyl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C([C@@H](N1[C@@H]([C@H](C[C@@](C1=O)(CC(O)=O)C)C=1C=C(Cl)C=CC=1)C=1C=CC(Cl)=CC=1)C1CC1)S(=O)(=O)N1CCC1 SXSRMKULCNELMF-YWCVFVGNSA-N 0.000 claims description 2
- NDQUVBHWLSONDD-WNNCOPHBSA-N 2-[(3r,5r,6s)-1-[(1s)-2-(benzenesulfonyl)-1-cyclopropylethyl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C([C@@H](N1[C@@H]([C@H](C[C@@](C1=O)(CC(O)=O)C)C=1C=C(Cl)C=CC=1)C=1C=CC(Cl)=CC=1)C1CC1)S(=O)(=O)C1=CC=CC=C1 NDQUVBHWLSONDD-WNNCOPHBSA-N 0.000 claims description 2
- PBVWWSVQHASKOE-HIJQLYNKSA-N 2-[(3r,5r,6s)-1-[(1s)-2-(tert-butylsulfamoyl)-1-cyclopropylethyl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C1([C@@H](CS(=O)(=O)NC(C)(C)C)N2C([C@@](C)(CC(O)=O)C[C@@H]([C@H]2C=2C=CC(Cl)=CC=2)C=2C=C(Cl)C=CC=2)=O)CC1 PBVWWSVQHASKOE-HIJQLYNKSA-N 0.000 claims description 2
- LWZQFTASTGXTQX-JVUUKAHWSA-N 2-[(3r,5r,6s)-1-[(1s)-2-[tert-butylsulfonyl(difluoromethyl)amino]-1-cyclopropylethyl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C1([C@@H](CN(S(=O)(=O)C(C)(C)C)C(F)F)N2C([C@@](C)(CC(O)=O)C[C@@H]([C@H]2C=2C=CC(Cl)=CC=2)C=2C=C(Cl)C=CC=2)=O)CC1 LWZQFTASTGXTQX-JVUUKAHWSA-N 0.000 claims description 2
- IUMMXLMKPRJWNK-QXMDYEBFSA-N 2-[(3r,5r,6s)-1-[(1s)-2-butylsulfonyl-1-cyclopropylethyl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C1([C@@H](CS(=O)(=O)CCCC)N2C([C@@](CC)(CC(O)=O)C[C@@H]([C@H]2C=2C=CC(Cl)=CC=2)C=2C=C(Cl)C=CC=2)=O)CC1 IUMMXLMKPRJWNK-QXMDYEBFSA-N 0.000 claims description 2
- ACFSPISAHLUOQM-QNYAKKFESA-N 2-[(3r,5r,6s)-1-[(1s)-2-tert-butylsulfonyl-1-cyclopropylethyl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C1([C@@H](CS(=O)(=O)C(C)(C)C)N2[C@@H]([C@H](C[C@@](C2=O)(CC(O)=O)CC)C=2C=C(Cl)C=CC=2)C=2C=CC(Cl)=CC=2)CC1 ACFSPISAHLUOQM-QNYAKKFESA-N 0.000 claims description 2
- HMKAZNCSHAJLSA-HIJQLYNKSA-N 2-[(3r,5r,6s)-1-[(1s)-2-tert-butylsulfonyl-1-cyclopropylethyl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C1([C@@H](CS(=O)(=O)C(C)(C)C)N2C([C@@](C)(CC(O)=O)C[C@@H]([C@H]2C=2C=CC(Cl)=CC=2)C=2C=C(Cl)C=CC=2)=O)CC1 HMKAZNCSHAJLSA-HIJQLYNKSA-N 0.000 claims description 2
- MUIJUEFSZHMBNZ-XLGZKVCWSA-N 2-[(3r,5r,6s)-1-[(2s)-1-(4-acetylpiperazin-1-yl)butan-2-yl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C([C@H](CC)N1C([C@@](C)(CC(O)=O)C[C@@H]([C@H]1C=1C=CC(Cl)=CC=1)C=1C=C(Cl)C=CC=1)=O)N1CCN(C(C)=O)CC1 MUIJUEFSZHMBNZ-XLGZKVCWSA-N 0.000 claims description 2
- WJVROBDDTDOTBX-ATBUFXNFSA-N 2-[(3r,5r,6s)-1-[(2s)-1-(benzenesulfonamido)butan-2-yl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C([C@H](CC)N1C([C@@](C)(CC(O)=O)C[C@@H]([C@H]1C=1C=CC(Cl)=CC=1)C=1C=C(Cl)C=CC=1)=O)NS(=O)(=O)C1=CC=CC=C1 WJVROBDDTDOTBX-ATBUFXNFSA-N 0.000 claims description 2
- ZDMLNNOTTZAABS-ATBUFXNFSA-N 2-[(3r,5r,6s)-1-[(2s)-1-(benzenesulfonyl)butan-2-yl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C([C@H](CC)N1C([C@@](C)(CC(O)=O)C[C@@H]([C@H]1C=1C=CC(Cl)=CC=1)C=1C=C(Cl)C=CC=1)=O)S(=O)(=O)C1=CC=CC=C1 ZDMLNNOTTZAABS-ATBUFXNFSA-N 0.000 claims description 2
- QWLFXRGZTYOFAC-YEPCPMPXSA-N 2-[(3r,5r,6s)-1-[(2s)-1-(tert-butylamino)-1-oxobutan-2-yl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C1([C@@H]2[C@H](N(C([C@@](C)(CC(O)=O)C2)=O)[C@@H](CC)C(=O)NC(C)(C)C)C=2C=CC(Cl)=CC=2)=CC=CC(Cl)=C1 QWLFXRGZTYOFAC-YEPCPMPXSA-N 0.000 claims description 2
- CGHHPXBKIIKZHJ-HIJQLYNKSA-N 2-[(3r,5r,6s)-1-[(2s)-1-tert-butylsulfonyl-3-methylbutan-2-yl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C1([C@@H]2[C@H](N(C([C@@](C)(CC(O)=O)C2)=O)[C@H](CS(=O)(=O)C(C)(C)C)C(C)C)C=2C=CC(Cl)=CC=2)=CC=CC(Cl)=C1 CGHHPXBKIIKZHJ-HIJQLYNKSA-N 0.000 claims description 2
- WIRXUNJQOQVNQG-ZJTSJXPUSA-N 2-[(3r,5r,6s)-1-[(2s)-1-tert-butylsulfonylbutan-2-yl]-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C1([C@@H]2[C@H](N(C([C@@](C)(CC(O)=O)C2)=O)[C@H](CS(=O)(=O)C(C)(C)C)CC)C=2C=CC(Cl)=CC=2)=CC(F)=CC(Cl)=C1 WIRXUNJQOQVNQG-ZJTSJXPUSA-N 0.000 claims description 2
- WUIVTCHXUHALJT-NANZAVOOSA-N 2-[(3r,5r,6s)-1-[(2s)-1-tert-butylsulfonylbutan-2-yl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C1([C@@H]2[C@H](N(C([C@@](CC)(CC(O)=O)C2)=O)[C@H](CS(=O)(=O)C(C)(C)C)CC)C=2C=CC(Cl)=CC=2)=CC=CC(Cl)=C1 WUIVTCHXUHALJT-NANZAVOOSA-N 0.000 claims description 2
- KBQKQQVLEHPVQR-CXTNQITHSA-N 2-[(3r,5r,6s)-1-[(2s)-1-tert-butylsulfonylbutan-2-yl]-6-(4-chlorophenyl)-5-(5-chloropyridin-3-yl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C1([C@@H]2[C@H](N(C([C@@](C)(CC(O)=O)C2)=O)[C@H](CS(=O)(=O)C(C)(C)C)CC)C=2C=CC(Cl)=CC=2)=CN=CC(Cl)=C1 KBQKQQVLEHPVQR-CXTNQITHSA-N 0.000 claims description 2
- NKTUPIRZIZMCIT-ODOSVJCGSA-N 2-[(3r,5r,6s)-5-(3-chloro-4-fluorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-propan-2-ylpiperidin-3-yl]acetic acid Chemical compound C1([C@@H]2[C@H](N(C([C@@](C)(CC(O)=O)C2)=O)C(C)C)C=2C=CC(Cl)=CC=2)=CC=C(F)C(Cl)=C1 NKTUPIRZIZMCIT-ODOSVJCGSA-N 0.000 claims description 2
- RCKXSJGZRPHAKO-SODSZRCFSA-N 2-[(3r,5r,6s)-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-[(2s)-1-(ethylsulfonylamino)butan-2-yl]-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C1([C@@H]2[C@H](N(C([C@@](C)(CC(O)=O)C2)=O)[C@H](CNS(=O)(=O)CC)CC)C=2C=CC(Cl)=CC=2)=CC(F)=CC(Cl)=C1 RCKXSJGZRPHAKO-SODSZRCFSA-N 0.000 claims description 2
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- WWTJWHXDAHKEOA-UHFFFAOYSA-N 2-[1-(1-butan-2-ylsulfonylbutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C1C(C)(CC(O)=O)C(=O)N(C(CC)CS(=O)(=O)C(C)CC)C(C=2C=CC(Cl)=CC=2)C1C1=CC=CC(Cl)=C1 WWTJWHXDAHKEOA-UHFFFAOYSA-N 0.000 claims description 2
- CGHHPXBKIIKZHJ-UHFFFAOYSA-N 2-[1-(1-tert-butylsulfonyl-3-methylbutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C1C(C)(CC(O)=O)C(=O)N(C(CS(=O)(=O)C(C)(C)C)C(C)C)C(C=2C=CC(Cl)=CC=2)C1C1=CC=CC(Cl)=C1 CGHHPXBKIIKZHJ-UHFFFAOYSA-N 0.000 claims description 2
- WIRXUNJQOQVNQG-UHFFFAOYSA-N 2-[1-(1-tert-butylsulfonylbutan-2-yl)-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C1C(C)(CC(O)=O)C(=O)N(C(CS(=O)(=O)C(C)(C)C)CC)C(C=2C=CC(Cl)=CC=2)C1C1=CC(F)=CC(Cl)=C1 WIRXUNJQOQVNQG-UHFFFAOYSA-N 0.000 claims description 2
- WUIVTCHXUHALJT-UHFFFAOYSA-N 2-[1-(1-tert-butylsulfonylbutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C1C(CC)(CC(O)=O)C(=O)N(C(CS(=O)(=O)C(C)(C)C)CC)C(C=2C=CC(Cl)=CC=2)C1C1=CC=CC(Cl)=C1 WUIVTCHXUHALJT-UHFFFAOYSA-N 0.000 claims description 2
- KBQKQQVLEHPVQR-UHFFFAOYSA-N 2-[1-(1-tert-butylsulfonylbutan-2-yl)-6-(4-chlorophenyl)-5-(5-chloropyridin-3-yl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C1C(C)(CC(O)=O)C(=O)N(C(CS(=O)(=O)C(C)(C)C)CC)C(C=2C=CC(Cl)=CC=2)C1C1=CN=CC(Cl)=C1 KBQKQQVLEHPVQR-UHFFFAOYSA-N 0.000 claims description 2
- IUMMXLMKPRJWNK-UHFFFAOYSA-N 2-[1-(2-butylsulfonyl-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(CC)(CC(O)=O)C(=O)N1C(CS(=O)(=O)CCCC)C1CC1 IUMMXLMKPRJWNK-UHFFFAOYSA-N 0.000 claims description 2
- HMKAZNCSHAJLSA-UHFFFAOYSA-N 2-[1-(2-tert-butylsulfonyl-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(C)(CC(O)=O)C(=O)N1C(CS(=O)(=O)C(C)(C)C)C1CC1 HMKAZNCSHAJLSA-UHFFFAOYSA-N 0.000 claims description 2
- MUIJUEFSZHMBNZ-UHFFFAOYSA-N 2-[1-[1-(4-acetylpiperazin-1-yl)butan-2-yl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(C)(CC(O)=O)C(=O)N1C(CC)CN1CCN(C(C)=O)CC1 MUIJUEFSZHMBNZ-UHFFFAOYSA-N 0.000 claims description 2
- VDBOOIDGCNUDCT-UHFFFAOYSA-N 2-[1-[1-(6-bromopyridin-2-yl)propyl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=CC(Br)=NC=1C(CC)N(C(C(C)(CC(O)=O)C1)=O)C(C=2C=CC(Cl)=CC=2)C1C1=CC=CC(Cl)=C1 VDBOOIDGCNUDCT-UHFFFAOYSA-N 0.000 claims description 2
- WJVROBDDTDOTBX-UHFFFAOYSA-N 2-[1-[1-(benzenesulfonamido)butan-2-yl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(C)(CC(O)=O)C(=O)N1C(CC)CNS(=O)(=O)C1=CC=CC=C1 WJVROBDDTDOTBX-UHFFFAOYSA-N 0.000 claims description 2
- ZDMLNNOTTZAABS-UHFFFAOYSA-N 2-[1-[1-(benzenesulfonyl)butan-2-yl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(C)(CC(O)=O)C(=O)N1C(CC)CS(=O)(=O)C1=CC=CC=C1 ZDMLNNOTTZAABS-UHFFFAOYSA-N 0.000 claims description 2
- QWLFXRGZTYOFAC-UHFFFAOYSA-N 2-[1-[1-(tert-butylamino)-1-oxobutan-2-yl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C1C(C)(CC(O)=O)C(=O)N(C(CC)C(=O)NC(C)(C)C)C(C=2C=CC(Cl)=CC=2)C1C1=CC=CC(Cl)=C1 QWLFXRGZTYOFAC-UHFFFAOYSA-N 0.000 claims description 2
- ITFUUZBITGMSIO-UHFFFAOYSA-N 2-[1-[1-[(1-carbamoylcyclopropyl)methoxy]butan-2-yl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(CC(O)=O)C(=O)N1C(CC)COCC1(C(N)=O)CC1 ITFUUZBITGMSIO-UHFFFAOYSA-N 0.000 claims description 2
- MCONUGXGXLKEIA-UHFFFAOYSA-N 2-[1-[2-(2-chloro-4-fluorophenyl)sulfonyl-1-cyclopropylethyl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound O=C1C(C)(CC(O)=O)CC(C=2C=C(Cl)C=CC=2)C(C=2C=CC(Cl)=CC=2)N1C(C1CC1)CS(=O)(=O)C1=CC=C(F)C=C1Cl MCONUGXGXLKEIA-UHFFFAOYSA-N 0.000 claims description 2
- SXSRMKULCNELMF-UHFFFAOYSA-N 2-[1-[2-(azetidin-1-ylsulfonyl)-1-cyclopropylethyl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound O=C1C(C)(CC(O)=O)CC(C=2C=C(Cl)C=CC=2)C(C=2C=CC(Cl)=CC=2)N1C(C1CC1)CS(=O)(=O)N1CCC1 SXSRMKULCNELMF-UHFFFAOYSA-N 0.000 claims description 2
- PFUOTILZZCICAE-UHFFFAOYSA-N 2-[1-[2-(benzenesulfonyl)-1-cyclopropylethyl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-2-oxopiperidin-3-yl]acetic acid Chemical compound O=C1C(CC)(CC(O)=O)CC(C=2C=C(Cl)C=CC=2)C(C=2C=CC(Cl)=CC=2)N1C(C1CC1)CS(=O)(=O)C1=CC=CC=C1 PFUOTILZZCICAE-UHFFFAOYSA-N 0.000 claims description 2
- NDQUVBHWLSONDD-UHFFFAOYSA-N 2-[1-[2-(benzenesulfonyl)-1-cyclopropylethyl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound O=C1C(C)(CC(O)=O)CC(C=2C=C(Cl)C=CC=2)C(C=2C=CC(Cl)=CC=2)N1C(C1CC1)CS(=O)(=O)C1=CC=CC=C1 NDQUVBHWLSONDD-UHFFFAOYSA-N 0.000 claims description 2
- PBVWWSVQHASKOE-UHFFFAOYSA-N 2-[1-[2-(tert-butylsulfamoyl)-1-cyclopropylethyl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(C)(CC(O)=O)C(=O)N1C(CS(=O)(=O)NC(C)(C)C)C1CC1 PBVWWSVQHASKOE-UHFFFAOYSA-N 0.000 claims description 2
- LWZQFTASTGXTQX-UHFFFAOYSA-N 2-[1-[2-[tert-butylsulfonyl(difluoromethyl)amino]-1-cyclopropylethyl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(C)(CC(O)=O)C(=O)N1C(CN(S(=O)(=O)C(C)(C)C)C(F)F)C1CC1 LWZQFTASTGXTQX-UHFFFAOYSA-N 0.000 claims description 2
- CJIWXRJWNIPVBG-UHFFFAOYSA-N 2-[4-(3-chlorophenyl)-3-(4-chlorophenyl)-1,1-dioxo-2-propan-2-ylthiazinan-6-yl]acetic acid Chemical compound C1C(CC(O)=O)S(=O)(=O)N(C(C)C)C(C=2C=CC(Cl)=CC=2)C1C1=CC=CC(Cl)=C1 CJIWXRJWNIPVBG-UHFFFAOYSA-N 0.000 claims description 2
- LNPZPVPDOIVJLZ-UHFFFAOYSA-N 2-[4-(3-chlorophenyl)-3-(4-chlorophenyl)-6-methyl-1,1-dioxo-2-propan-2-ylthiazinan-6-yl]acetic acid Chemical compound C1C(C)(CC(O)=O)S(=O)(=O)N(C(C)C)C(C=2C=CC(Cl)=CC=2)C1C1=CC=CC(Cl)=C1 LNPZPVPDOIVJLZ-UHFFFAOYSA-N 0.000 claims description 2
- NKTUPIRZIZMCIT-UHFFFAOYSA-N 2-[5-(3-chloro-4-fluorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-propan-2-ylpiperidin-3-yl]acetic acid Chemical compound C1C(C)(CC(O)=O)C(=O)N(C(C)C)C(C=2C=CC(Cl)=CC=2)C1C1=CC=C(F)C(Cl)=C1 NKTUPIRZIZMCIT-UHFFFAOYSA-N 0.000 claims description 2
- KJBVQUFEAVNSSV-UHFFFAOYSA-N 2-[5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropylsulfonylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=C(F)C=2)CC(C)(CC(O)=O)C(=O)N1C(CC)CS(=O)(=O)C1CC1 KJBVQUFEAVNSSV-UHFFFAOYSA-N 0.000 claims description 2
- BPTBYDCAPGEQIF-UHFFFAOYSA-N 2-[5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-(1-ethylsulfonylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C1C(C)(CC(O)=O)C(=O)N(C(CS(=O)(=O)CC)CC)C(C=2C=CC(Cl)=CC=2)C1C1=CC(F)=CC(Cl)=C1 BPTBYDCAPGEQIF-UHFFFAOYSA-N 0.000 claims description 2
- RCKXSJGZRPHAKO-UHFFFAOYSA-N 2-[5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-[1-(ethylsulfonylamino)butan-2-yl]-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C1C(C)(CC(O)=O)C(=O)N(C(CNS(=O)(=O)CC)CC)C(C=2C=CC(Cl)=CC=2)C1C1=CC(F)=CC(Cl)=C1 RCKXSJGZRPHAKO-UHFFFAOYSA-N 0.000 claims description 2
- LTUHSZJIRQEHAV-UHFFFAOYSA-N 2-[5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-[1-[ethylsulfonyl(methyl)amino]butan-2-yl]-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C1C(C)(CC(O)=O)C(=O)N(C(CN(C)S(=O)(=O)CC)CC)C(C=2C=CC(Cl)=CC=2)C1C1=CC(F)=CC(Cl)=C1 LTUHSZJIRQEHAV-UHFFFAOYSA-N 0.000 claims description 2
- VTWWVNIKLCSIRM-UHFFFAOYSA-N 2-[5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-methylsulfonylbutan-2-yl)-2-oxopiperidin-3-yl]acetic acid Chemical compound C1C(C)(CC(O)=O)C(=O)N(C(CS(C)(=O)=O)CC)C(C=2C=CC(Cl)=CC=2)C1C1=CC(F)=CC(Cl)=C1 VTWWVNIKLCSIRM-UHFFFAOYSA-N 0.000 claims description 2
- ZMFJOMGQWPWIGR-UHFFFAOYSA-N 2-[5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-propan-2-ylsulfonylbutan-2-yl)piperidin-3-yl]acetic acid Chemical compound C1C(C)(CC(O)=O)C(=O)N(C(CS(=O)(=O)C(C)C)CC)C(C=2C=CC(Cl)=CC=2)C1C1=CC(F)=CC(Cl)=C1 ZMFJOMGQWPWIGR-UHFFFAOYSA-N 0.000 claims description 2
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- COYWEWWEQVRWQE-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1,2-dihydroxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C1C(C)(CC(O)=O)C(=O)N(C(C(O)CO)CC)C(C=2C=CC(Cl)=CC=2)C1C1=CC=CC(Cl)=C1 COYWEWWEQVRWQE-UHFFFAOYSA-N 0.000 claims description 2
- VAONVJODAXHCML-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyanopentan-3-yl)-2-oxopiperidin-3-yl]acetic acid Chemical compound C1C(CC(O)=O)C(=O)N(C(CCC#N)CC)C(C=2C=CC(Cl)=CC=2)C1C1=CC=CC(Cl)=C1 VAONVJODAXHCML-UHFFFAOYSA-N 0.000 claims description 2
- MNBMSRKSYHSWJR-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclobutylsulfonylbutan-2-yl)-3-ethyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(CC)(CC(O)=O)C(=O)N1C(CC)CS(=O)(=O)C1CCC1 MNBMSRKSYHSWJR-UHFFFAOYSA-N 0.000 claims description 2
- DESXNNIXZPJORD-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclobutylsulfonylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(C)(CC(O)=O)C(=O)N1C(CC)CS(=O)(=O)C1CCC1 DESXNNIXZPJORD-UHFFFAOYSA-N 0.000 claims description 2
- MDPNIWLYEOXYTH-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopentylsulfonylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(C)(CC(O)=O)C(=O)N1C(CC)CS(=O)(=O)C1CCCC1 MDPNIWLYEOXYTH-UHFFFAOYSA-N 0.000 claims description 2
- PHSMLYLJCQVUSJ-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-1-hydroxybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(C)(CC(O)=O)C(=O)N1C(CC)C(O)C1CC1 PHSMLYLJCQVUSJ-UHFFFAOYSA-N 0.000 claims description 2
- PYYYIHIPDRYKPU-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-cyclopropylsulfonylethyl)-3-ethyl-2-oxopiperidin-3-yl]acetic acid Chemical compound O=C1C(CC)(CC(O)=O)CC(C=2C=C(Cl)C=CC=2)C(C=2C=CC(Cl)=CC=2)N1C(C1CC1)CS(=O)(=O)C1CC1 PYYYIHIPDRYKPU-UHFFFAOYSA-N 0.000 claims description 2
- LBLHTSZWXGQSFY-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-cyclopropylsulfonylethyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound O=C1C(C)(CC(O)=O)CC(C=2C=C(Cl)C=CC=2)C(C=2C=CC(Cl)=CC=2)N1C(C1CC1)CS(=O)(=O)C1CC1 LBLHTSZWXGQSFY-UHFFFAOYSA-N 0.000 claims description 2
- AJDGYAQTHIKFKN-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-ethoxy-2-oxoethyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(C)(CC(O)=O)C(=O)N1C(C(=O)OCC)C1CC1 AJDGYAQTHIKFKN-UHFFFAOYSA-N 0.000 claims description 2
- YSIPRIZLSBKQLW-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-ethylsulfonylethyl)-3-ethyl-2-oxopiperidin-3-yl]acetic acid Chemical compound O=C1C(CC)(CC(O)=O)CC(C=2C=C(Cl)C=CC=2)C(C=2C=CC(Cl)=CC=2)N1C(CS(=O)(=O)CC)C1CC1 YSIPRIZLSBKQLW-UHFFFAOYSA-N 0.000 claims description 2
- IYCQSZFHARZLMX-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-ethylsulfonylethyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(C)(CC(O)=O)C(=O)N1C(CS(=O)(=O)CC)C1CC1 IYCQSZFHARZLMX-UHFFFAOYSA-N 0.000 claims description 2
- RAAKFYNHMLQZKX-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-hydroxybutyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(C)(CC(O)=O)C(=O)N1C(C(O)CC)C1CC1 RAAKFYNHMLQZKX-UHFFFAOYSA-N 0.000 claims description 2
- VIHNWSJGVAGIAC-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-hydroxyethyl)-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(CC(O)=O)C(=O)N1C(CO)C1CC1 VIHNWSJGVAGIAC-UHFFFAOYSA-N 0.000 claims description 2
- FRUTWROHOSPKNL-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-hydroxyethyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound O=C1C(C)(CC(O)=O)CC(C=2C=C(Cl)C=CC=2)C(C=2C=CC(Cl)=CC=2)N1C(CO)C1CC1 FRUTWROHOSPKNL-UHFFFAOYSA-N 0.000 claims description 2
- NYMRMAMSVZGJIB-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-methylsulfonylethyl)-3-ethyl-2-oxopiperidin-3-yl]acetic acid Chemical compound O=C1C(CC)(CC(O)=O)CC(C=2C=C(Cl)C=CC=2)C(C=2C=CC(Cl)=CC=2)N1C(CS(C)(=O)=O)C1CC1 NYMRMAMSVZGJIB-UHFFFAOYSA-N 0.000 claims description 2
- JSZIUWBZPLMUNE-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-morpholin-4-ylsulfonylethyl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound O=C1C(C)(CC(O)=O)CC(C=2C=C(Cl)C=CC=2)C(C=2C=CC(Cl)=CC=2)N1C(C1CC1)CS(=O)(=O)N1CCOCC1 JSZIUWBZPLMUNE-UHFFFAOYSA-N 0.000 claims description 2
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- UXUFGOIKDTYLPE-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(dimethylamino)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C1C(C)(CC(O)=O)C(=O)N(N(C)C)C(C=2C=CC(Cl)=CC=2)C1C1=CC=CC(Cl)=C1 UXUFGOIKDTYLPE-UHFFFAOYSA-N 0.000 claims description 2
- JOTZPQJNNMYSDU-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(2,2-dimethylcyclopentyl)methyl]-2-oxopiperidin-3-yl]acetic acid Chemical compound CC1(C)CCCC1CN1C(=O)C(CC(O)=O)CC(C=2C=C(Cl)C=CC=2)C1C1=CC=C(Cl)C=C1 JOTZPQJNNMYSDU-UHFFFAOYSA-N 0.000 claims description 2
- DUHSKUROEOZMMD-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[1-(2,2-dimethylmorpholin-4-yl)butan-2-yl]-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(C)(CC(O)=O)C(=O)N1C(CC)CN1CCOC(C)(C)C1 DUHSKUROEOZMMD-UHFFFAOYSA-N 0.000 claims description 2
- SFFVDAVTJUMXOP-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[1-(2,2-dimethylpropylamino)-1-oxobutan-2-yl]-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C1C(C)(CC(O)=O)C(=O)N(C(CC)C(=O)NCC(C)(C)C)C(C=2C=CC(Cl)=CC=2)C1C1=CC=CC(Cl)=C1 SFFVDAVTJUMXOP-UHFFFAOYSA-N 0.000 claims description 2
- CUEWZRUHFCTRNB-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[1-(2,6-dimethylmorpholin-4-yl)butan-2-yl]-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(C)(CC(O)=O)C(=O)N1C(CC)CN1CC(C)OC(C)C1 CUEWZRUHFCTRNB-UHFFFAOYSA-N 0.000 claims description 2
- HXMZKAQCYSAEMJ-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[1-(2-hydroxy-2-methylpropoxy)butan-2-yl]-2-oxopiperidin-3-yl]acetic acid Chemical compound C1C(CC(O)=O)C(=O)N(C(COCC(C)(C)O)CC)C(C=2C=CC(Cl)=CC=2)C1C1=CC=CC(Cl)=C1 HXMZKAQCYSAEMJ-UHFFFAOYSA-N 0.000 claims description 2
- KRRJSOLJXVANJL-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[1-(2-hydroxy-2-methylpropyl)sulfonylbutan-2-yl]-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C1C(C)(CC(O)=O)C(=O)N(C(CS(=O)(=O)CC(C)(C)O)CC)C(C=2C=CC(Cl)=CC=2)C1C1=CC=CC(Cl)=C1 KRRJSOLJXVANJL-UHFFFAOYSA-N 0.000 claims description 2
- WIFPPFDNYOIMPU-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[1-(3,3-difluoroazetidin-1-yl)butan-2-yl]-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(C)(CC(O)=O)C(=O)N1C(CC)CN1CC(F)(F)C1 WIFPPFDNYOIMPU-UHFFFAOYSA-N 0.000 claims description 2
- VACCNGYSQZSMAF-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[1-(3,3-dimethylmorpholin-4-yl)butan-2-yl]-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(C)(CC(O)=O)C(=O)N1C(CC)CN1CCOCC1(C)C VACCNGYSQZSMAF-UHFFFAOYSA-N 0.000 claims description 2
- NCSZELYZOAIKBQ-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)propyl]-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound N=1C(C2CC2)=NOC=1C(CC)N(C(C(C)(CC(O)=O)C1)=O)C(C=2C=CC(Cl)=CC=2)C1C1=CC=CC(Cl)=C1 NCSZELYZOAIKBQ-UHFFFAOYSA-N 0.000 claims description 2
- WHRHCOKAMSKIAC-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[1-(4,4-dimethyl-5h-1,3-oxazol-2-yl)propyl]-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound N=1C(C)(C)COC=1C(CC)N(C(C(C)(CC(O)=O)C1)=O)C(C=2C=CC(Cl)=CC=2)C1C1=CC=CC(Cl)=C1 WHRHCOKAMSKIAC-UHFFFAOYSA-N 0.000 claims description 2
- UIPNLSUAIFATGC-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[1-(4-cyclopropylsulfonylpiperazin-1-yl)butan-2-yl]-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(C)(CC(O)=O)C(=O)N1C(CC)CN(CC1)CCN1S(=O)(=O)C1CC1 UIPNLSUAIFATGC-UHFFFAOYSA-N 0.000 claims description 2
- WKUDRGUJRNXDQX-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[1-(5,5-dimethyl-2-oxo-1,3-oxazolidin-3-yl)butan-2-yl]-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(C)(CC(O)=O)C(=O)N1C(CC)CN1CC(C)(C)OC1=O WKUDRGUJRNXDQX-UHFFFAOYSA-N 0.000 claims description 2
- JXPCJNIFNLDWFI-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[1-(5-methyl-1,3,4-oxadiazol-2-yl)propyl]-2-oxopiperidin-3-yl]acetic acid Chemical compound N=1N=C(C)OC=1C(CC)N(C(C(CC(O)=O)C1)=O)C(C=2C=CC(Cl)=CC=2)C1C1=CC=CC(Cl)=C1 JXPCJNIFNLDWFI-UHFFFAOYSA-N 0.000 claims description 2
- GJFWBOZSLJZUTC-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[1-(6-chloropyridin-2-yl)propyl]-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=CC(Cl)=NC=1C(CC)N(C(C(C)(CC(O)=O)C1)=O)C(C=2C=CC(Cl)=CC=2)C1C1=CC=CC(Cl)=C1 GJFWBOZSLJZUTC-UHFFFAOYSA-N 0.000 claims description 2
- QHQNRLZCHQCYRC-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[1-(6-cyclopropylpyridin-2-yl)propyl]-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=CC(C2CC2)=NC=1C(CC)N(C(C(C)(CC(O)=O)C1)=O)C(C=2C=CC(Cl)=CC=2)C1C1=CC=CC(Cl)=C1 QHQNRLZCHQCYRC-UHFFFAOYSA-N 0.000 claims description 2
- HFUSOLWSOMAFRR-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[1-(cyclobutylmethylsulfonyl)butan-2-yl]-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(C)(CC(O)=O)C(=O)N1C(CC)CS(=O)(=O)CC1CCC1 HFUSOLWSOMAFRR-UHFFFAOYSA-N 0.000 claims description 2
- RLXWAAQIUWFMDL-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[1-(cyclobutylsulfonylamino)butan-2-yl]-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(C)(CC(O)=O)C(=O)N1C(CC)CNS(=O)(=O)C1CCC1 RLXWAAQIUWFMDL-UHFFFAOYSA-N 0.000 claims description 2
- ZGGWLUDQFJLUIH-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[1-(cyclopropylmethoxy)butan-2-yl]-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(C)(CC(O)=O)C(=O)N1C(CC)COCC1CC1 ZGGWLUDQFJLUIH-UHFFFAOYSA-N 0.000 claims description 2
- QOOHSEXSGCVVLW-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[1-(cyclopropylmethylsulfonyl)pentan-3-yl]-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(C)(CC(O)=O)C(=O)N1C(CC)CCS(=O)(=O)CC1CC1 QOOHSEXSGCVVLW-UHFFFAOYSA-N 0.000 claims description 2
- NSARKYGTYPMADG-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[1-(cyclopropylsulfonylamino)-3-methylbutan-2-yl]-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(C)(CC(O)=O)C(=O)N1C(C(C)C)CNS(=O)(=O)C1CC1 NSARKYGTYPMADG-UHFFFAOYSA-N 0.000 claims description 2
- YGHOMOFTRXHIOD-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[1-(cyclopropylsulfonylamino)butan-2-yl]-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(C)(CC(O)=O)C(=O)N1C(CC)CNS(=O)(=O)C1CC1 YGHOMOFTRXHIOD-UHFFFAOYSA-N 0.000 claims description 2
- AWWJRXUFVJUAMA-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[1-(ethylamino)-1-oxobutan-2-yl]-2-oxopiperidin-3-yl]acetic acid Chemical compound C1C(CC(O)=O)C(=O)N(C(CC)C(=O)NCC)C(C=2C=CC(Cl)=CC=2)C1C1=CC=CC(Cl)=C1 AWWJRXUFVJUAMA-UHFFFAOYSA-N 0.000 claims description 2
- IOLZYOWLYYNXHV-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[1-(ethylsulfonylamino)-3-methylbutan-2-yl]-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C1C(C)(CC(O)=O)C(=O)N(C(C(C)C)CNS(=O)(=O)CC)C(C=2C=CC(Cl)=CC=2)C1C1=CC=CC(Cl)=C1 IOLZYOWLYYNXHV-UHFFFAOYSA-N 0.000 claims description 2
- GGDUGFMENDVSEV-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[1-(methanesulfonamido)butan-2-yl]-2-oxopiperidin-3-yl]acetic acid Chemical compound C1C(CC(O)=O)C(=O)N(C(CNS(C)(=O)=O)CC)C(C=2C=CC(Cl)=CC=2)C1C1=CC=CC(Cl)=C1 GGDUGFMENDVSEV-UHFFFAOYSA-N 0.000 claims description 2
- PPSUZWIDVCWPSG-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[1-[(1-cyanocyclopropyl)methoxy]butan-2-yl]-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(CC(O)=O)C(=O)N1C(CC)COCC1(C#N)CC1 PPSUZWIDVCWPSG-UHFFFAOYSA-N 0.000 claims description 2
- GYBCIUZWQRYURZ-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[1-[(2-chlorophenyl)sulfonylamino]butan-2-yl]-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(C)(CC(O)=O)C(=O)N1C(CC)CNS(=O)(=O)C1=CC=CC=C1Cl GYBCIUZWQRYURZ-UHFFFAOYSA-N 0.000 claims description 2
- ZEMLYWMOSZRCQL-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[1-[(2-methylpropan-2-yl)oxy]-1-oxobutan-2-yl]-2-oxopiperidin-3-yl]acetic acid Chemical compound C1C(CC(O)=O)C(=O)N(C(CC)C(=O)OC(C)(C)C)C(C=2C=CC(Cl)=CC=2)C1C1=CC=CC(Cl)=C1 ZEMLYWMOSZRCQL-UHFFFAOYSA-N 0.000 claims description 2
- FEADDVGHVYJEBG-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[1-[(3-cyanophenyl)sulfonylamino]butan-2-yl]-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(C)(CC(O)=O)C(=O)N1C(CC)CNS(=O)(=O)C1=CC=CC(C#N)=C1 FEADDVGHVYJEBG-UHFFFAOYSA-N 0.000 claims description 2
- ODWPBVAUWJMRST-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[1-[(4-chlorophenyl)sulfonylamino]butan-2-yl]-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(C)(CC(O)=O)C(=O)N1C(CC)CNS(=O)(=O)C1=CC=C(Cl)C=C1 ODWPBVAUWJMRST-UHFFFAOYSA-N 0.000 claims description 2
- TWTQHZWQJANKFW-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[1-[(4-cyanophenyl)sulfonylamino]butan-2-yl]-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(C)(CC(O)=O)C(=O)N1C(CC)CNS(=O)(=O)C1=CC=C(C#N)C=C1 TWTQHZWQJANKFW-UHFFFAOYSA-N 0.000 claims description 2
- NUBANIUCNGWQMJ-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[1-[(4-methoxyphenyl)sulfonylamino]butan-2-yl]-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(C)(CC(O)=O)C(=O)N1C(CC)CNS(=O)(=O)C1=CC=C(OC)C=C1 NUBANIUCNGWQMJ-UHFFFAOYSA-N 0.000 claims description 2
- BFZPWTDCNKBAEL-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[1-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]butan-2-yl]-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(C)(CC(O)=O)C(=O)N1C(CC)CN1CC(O)(C(F)(F)F)C1 BFZPWTDCNKBAEL-UHFFFAOYSA-N 0.000 claims description 2
- QKFIOVFYWYWBIS-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[1-[4-(cyclopropanecarbonyl)piperazin-1-yl]butan-2-yl]-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(C)(CC(O)=O)C(=O)N1C(CC)CN(CC1)CCN1C(=O)C1CC1 QKFIOVFYWYWBIS-UHFFFAOYSA-N 0.000 claims description 2
- DMOLKJFTGQANBE-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[1-[6-(2-hydroxypropan-2-yl)pyridin-2-yl]propyl]-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=CC(C(C)(C)O)=NC=1C(CC)N(C(C(C)(CC(O)=O)C1)=O)C(C=2C=CC(Cl)=CC=2)C1C1=CC=CC(Cl)=C1 DMOLKJFTGQANBE-UHFFFAOYSA-N 0.000 claims description 2
- GKWCQQRBHGVIFO-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[1-[cyclobutylsulfonyl(ethyl)amino]butan-2-yl]-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(C)(CC(O)=O)C(=O)N1C(CC)CN(CC)S(=O)(=O)C1CCC1 GKWCQQRBHGVIFO-UHFFFAOYSA-N 0.000 claims description 2
- PCXIPVJPADMFKC-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[1-[cyclopropylsulfonyl(methyl)amino]-1-oxobutan-2-yl]-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C1CC1S(=O)(=O)N(C)C(=O)C(CC)N(C(C(C)(CC(O)=O)C1)=O)C(C=2C=CC(Cl)=CC=2)C1C1=CC=CC(Cl)=C1 PCXIPVJPADMFKC-UHFFFAOYSA-N 0.000 claims description 2
- VXJACAQXCDSPJE-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[1-[cyclopropylsulfonyl(methyl)amino]butan-2-yl]-2-oxo-3-(2-pyrrolidin-1-ylethyl)piperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(CCN2CCCC2)(CC(O)=O)C(=O)N1C(CC)CN(C)S(=O)(=O)C1CC1 VXJACAQXCDSPJE-UHFFFAOYSA-N 0.000 claims description 2
- ZWUXHCHNAJMQDB-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[1-[cyclopropylsulfonyl(methyl)amino]butan-2-yl]-3-(2-morpholin-4-ylethyl)-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(CCN2CCOCC2)(CC(O)=O)C(=O)N1C(CC)CN(C)S(=O)(=O)C1CC1 ZWUXHCHNAJMQDB-UHFFFAOYSA-N 0.000 claims description 2
- HENRQNFBDLDTKL-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[1-[cyclopropylsulfonyl(methyl)amino]butan-2-yl]-3-[2-(dimethylamino)ethyl]-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(CCN(C)C)(CC(O)=O)C(=O)N1C(CC)CN(C)S(=O)(=O)C1CC1 HENRQNFBDLDTKL-UHFFFAOYSA-N 0.000 claims description 2
- LYZBKNYTGQNBNY-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[1-[cyclopropylsulfonyl(methyl)amino]butan-2-yl]-3-ethyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(CC)(CC(O)=O)C(=O)N1C(CC)CN(C)S(=O)(=O)C1CC1 LYZBKNYTGQNBNY-UHFFFAOYSA-N 0.000 claims description 2
- UXZAEZNRJHPRDV-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[1-[cyclopropylsulfonyl(methyl)amino]butan-2-yl]-3-methoxy-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(CC(O)=O)(OC)C(=O)N1C(CC)CN(C)S(=O)(=O)C1CC1 UXZAEZNRJHPRDV-UHFFFAOYSA-N 0.000 claims description 2
- UTMAJFUNDVHBFE-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[1-[cyclopropylsulfonyl(methyl)amino]butan-2-yl]-3-methyl-2-oxopiperidin-3-yl]-n-cyanoacetamide Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(C)(CC(=O)NC#N)C(=O)N1C(CC)CN(C)S(=O)(=O)C1CC1 UTMAJFUNDVHBFE-UHFFFAOYSA-N 0.000 claims description 2
- BSODUXURVJNGGU-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[1-[cyclopropylsulfonyl(methyl)amino]butan-2-yl]-3-methyl-2-oxopiperidin-3-yl]-n-hydroxyacetamide Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(C)(CC(=O)NO)C(=O)N1C(CC)CN(C)S(=O)(=O)C1CC1 BSODUXURVJNGGU-UHFFFAOYSA-N 0.000 claims description 2
- XVDPGLNQEKTOFZ-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[1-[cyclopropylsulfonyl(methyl)amino]butan-2-yl]-3-methyl-2-oxopiperidin-3-yl]-n-methoxyacetamide Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(C)(CC(=O)NOC)C(=O)N1C(CC)CN(C)S(=O)(=O)C1CC1 XVDPGLNQEKTOFZ-UHFFFAOYSA-N 0.000 claims description 2
- VGFHAVBKPIGMLJ-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[1-[cyclopropylsulfonyl(methyl)amino]butan-2-yl]-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(C)(CC(O)=O)C(=O)N1C(CC)CN(C)S(=O)(=O)C1CC1 VGFHAVBKPIGMLJ-UHFFFAOYSA-N 0.000 claims description 2
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- LZEXOIAPHSIXMC-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[1-cyclopropyl-2-[methylsulfonyl(propan-2-yl)amino]ethyl]-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(C)(CC(O)=O)C(=O)N1C(CN(C(C)C)S(C)(=O)=O)C1CC1 LZEXOIAPHSIXMC-UHFFFAOYSA-N 0.000 claims description 2
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- ULNYEPXCVJNUHW-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[2-(2-chlorophenyl)sulfonyl-1-cyclopropylethyl]-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound O=C1C(C)(CC(O)=O)CC(C=2C=C(Cl)C=CC=2)C(C=2C=CC(Cl)=CC=2)N1C(C1CC1)CS(=O)(=O)C1=CC=CC=C1Cl ULNYEPXCVJNUHW-UHFFFAOYSA-N 0.000 claims description 2
- HNGZMZGOKGDRLH-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[2-(4-chlorophenyl)sulfonyl-1-cyclopropylethyl]-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound O=C1C(C)(CC(O)=O)CC(C=2C=C(Cl)C=CC=2)C(C=2C=CC(Cl)=CC=2)N1C(C1CC1)CS(=O)(=O)C1=CC=C(Cl)C=C1 HNGZMZGOKGDRLH-UHFFFAOYSA-N 0.000 claims description 2
- BUXMSOLNFPSNDI-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[2-(cyclobutylsulfonylamino)-1-cyclopropylethyl]-3-ethyl-2-oxopiperidin-3-yl]acetic acid Chemical compound O=C1C(CC)(CC(O)=O)CC(C=2C=C(Cl)C=CC=2)C(C=2C=CC(Cl)=CC=2)N1C(C1CC1)CNS(=O)(=O)C1CCC1 BUXMSOLNFPSNDI-UHFFFAOYSA-N 0.000 claims description 2
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- GTSKFXJADAAIKJ-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[2-(cyclopropylsulfonylamino)pentan-3-yl]-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(C)(CC(O)=O)C(=O)N1C(CC)C(C)NS(=O)(=O)C1CC1 GTSKFXJADAAIKJ-UHFFFAOYSA-N 0.000 claims description 2
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- LJZPRRNMBDNYNV-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-[1-(2-oxo-1,3-oxazolidin-3-yl)butan-2-yl]piperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(C)(CC(O)=O)C(=O)N1C(CC)CN1CCOC1=O LJZPRRNMBDNYNV-UHFFFAOYSA-N 0.000 claims description 2
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- LPEXQNGAPWLFLF-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-[1-(2-oxopyrrolidin-1-yl)butan-2-yl]piperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(C)(CC(O)=O)C(=O)N1C(CC)CN1CCCC1=O LPEXQNGAPWLFLF-UHFFFAOYSA-N 0.000 claims description 2
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- WWKWPSAIEAMHPQ-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-[1-(oxolan-2-yl)propyl]piperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(C)(CC(O)=O)C(=O)N1C(CC)C1CCCO1 WWKWPSAIEAMHPQ-UHFFFAOYSA-N 0.000 claims description 2
- LGIYJPFEWSDRND-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-[1-(propan-2-ylsulfonylamino)butan-2-yl]piperidin-3-yl]acetic acid Chemical compound C1C(C)(CC(O)=O)C(=O)N(C(CNS(=O)(=O)C(C)C)CC)C(C=2C=CC(Cl)=CC=2)C1C1=CC=CC(Cl)=C1 LGIYJPFEWSDRND-UHFFFAOYSA-N 0.000 claims description 2
- YUUDVQJKLSFIQP-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-[1-(pyridin-2-ylsulfonylamino)butan-2-yl]piperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(C)(CC(O)=O)C(=O)N1C(CC)CNS(=O)(=O)C1=CC=CC=N1 YUUDVQJKLSFIQP-UHFFFAOYSA-N 0.000 claims description 2
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- FIKSDWQFRFPTPL-UHFFFAOYSA-N 2-[5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-[1-[2-oxo-5-(trifluoromethyl)pyridin-1-yl]butan-2-yl]piperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=CC=2)CC(C)(CC(O)=O)C(=O)N1C(CC)CN1C=C(C(F)(F)F)C=CC1=O FIKSDWQFRFPTPL-UHFFFAOYSA-N 0.000 claims description 2
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- CYJUAPSVHJWMDW-UHFFFAOYSA-N 2-[6-(4-chlorophenyl)-5-(4-chloropyridin-2-yl)-3-methyl-1-[1-[(2-methylpropan-2-yl)oxy]-1-oxobutan-2-yl]-2-oxopiperidin-3-yl]acetic acid Chemical compound C1C(C)(CC(O)=O)C(=O)N(C(CC)C(=O)OC(C)(C)C)C(C=2C=CC(Cl)=CC=2)C1C1=CC(Cl)=CC=N1 CYJUAPSVHJWMDW-UHFFFAOYSA-N 0.000 claims description 2
- XVYRFRBSGHIKKJ-UHFFFAOYSA-N 2-[6-(4-chlorophenyl)-5-(5-chloropyridin-3-yl)-1-(1-cyclopropylsulfonylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=NC=2)CC(C)(CC(O)=O)C(=O)N1C(CC)CS(=O)(=O)C1CC1 XVYRFRBSGHIKKJ-UHFFFAOYSA-N 0.000 claims description 2
- XRUSLSLCODEKLR-UHFFFAOYSA-N 2-[6-(4-chlorophenyl)-5-(5-chloropyridin-3-yl)-1-[1-(cyclopropylsulfonylamino)butan-2-yl]-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=NC=2)CC(C)(CC(O)=O)C(=O)N1C(CC)CNS(=O)(=O)C1CC1 XRUSLSLCODEKLR-UHFFFAOYSA-N 0.000 claims description 2
- MIUPTLFTXFPAKG-UHFFFAOYSA-N 2-[6-(4-chlorophenyl)-5-(5-chloropyridin-3-yl)-1-[1-[cyclopropylsulfonyl(methyl)amino]butan-2-yl]-3-methyl-2-oxopiperidin-3-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1C1C(C=2C=C(Cl)C=NC=2)CC(C)(CC(O)=O)C(=O)N1C(CC)CN(C)S(=O)(=O)C1CC1 MIUPTLFTXFPAKG-UHFFFAOYSA-N 0.000 claims description 2
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- NTYBAEOVGORHFO-HGAMEBRSSA-N 3-[(3r,5s,6r)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(2s)-1-[cyclopropylsulfonyl(methyl)amino]butan-2-yl]-3-methyl-2-oxopiperidin-3-yl]propanoic acid Chemical compound C([C@H](CC)N1C([C@](C)(CCC(O)=O)C[C@H]([C@@H]1C=1C=CC(Cl)=CC=1)C=1C=C(Cl)C=CC=1)=O)N(C)S(=O)(=O)C1CC1 NTYBAEOVGORHFO-HGAMEBRSSA-N 0.000 claims description 2
- NTYBAEOVGORHFO-ZVFGGPEJSA-N 3-[(3s,5r,6s)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(2s)-1-[cyclopropylsulfonyl(methyl)amino]butan-2-yl]-3-methyl-2-oxopiperidin-3-yl]propanoic acid Chemical compound C([C@H](CC)N1C([C@@](C)(CCC(O)=O)C[C@@H]([C@H]1C=1C=CC(Cl)=CC=1)C=1C=C(Cl)C=CC=1)=O)N(C)S(=O)(=O)C1CC1 NTYBAEOVGORHFO-ZVFGGPEJSA-N 0.000 claims description 2
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- UZLWVHOSWNFONP-NANZAVOOSA-N 3-[[(3r,5r,6s)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-[(2s)-1-morpholin-4-ylbutan-2-yl]-2-oxopiperidin-3-yl]methyl]-2h-1,2,4-oxadiazol-5-one Chemical compound C([C@H](CC)N1C([C@@](C)(CC=2NC(=O)ON=2)C[C@@H]([C@H]1C=1C=CC(Cl)=CC=1)C=1C=C(Cl)C=CC=1)=O)N1CCOCC1 UZLWVHOSWNFONP-NANZAVOOSA-N 0.000 claims description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D211/74—Oxygen atoms
- C07D211/76—Oxygen atoms attached in position 2 or 6
-
- 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
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Abstract
本发明提供了式(I)的MDM2抑制剂化合物,其中变量如本文所定义,所述化合物可用作治疗剂,特别是用于治疗癌症的治疗剂。本发明还涉及含有MDM2抑制剂的药物组合物。
Description
本申请为分案申请,原申请的申请日为2011年6月3日,申请号为201180038476.9(PCT/US2011/039184),发明名称为“用于治疗癌症的作为MDM2抑制剂的哌啶酮衍生物”。
技术领域
本发明涉及作为MDM2抑制剂的化合物,其可用作治疗剂,特别是用于治疗癌症的治疗剂。本发明还涉及含有MDM2抑制剂的药物组合物。
发明背景
p53是通过激活细胞周期阻滞、凋亡、衰老和DNA修复中所涉及的许多基因的转录而响应于细胞应激的肿瘤抑制因子和转录因子。与p53激活是由不常见原因引起的正常细胞不同,肿瘤细胞处于来自包括缺氧和促凋亡癌基因激活在内的各种损害(insult)的恒定细胞应激下。因而,对肿瘤中p53途径的灭活具有强的选择性优势,并且已提出消除p53功能可能是肿瘤存活的前提。为了支持这一观点,三个调查研究组已经使用小鼠模型证明p53功能的缺少是已建立肿瘤的维持的持续要求。当调查研究人员恢复p53灭活的肿瘤的p53功能时,该肿瘤消退。
在50%的实体瘤和10%的液体瘤中,p53通过突变和/或缺失来进行灭活。在癌症中,p53途径的其他主要成员也发生遗传或表观遗传改变。MDM2是一种癌蛋白质,它抑制p53功能并且它以报道高达10%的发生率被基因扩增激活。MDM2继而被另一种肿瘤抑制因子p14ARF抑制。p53下游的改变被认为可能负责至少部分地灭活p53WT肿瘤(p53野生型)中的p53途径。为了支持这一概念,一些p53WT肿瘤似乎显示出降低的凋亡功能,但它们经受细胞周期停滞的能力仍然是完整的。一种癌症治疗策略涉及使用结合MDM2并抵消它与p53的相互作用的小分子。MDM2通过三种机制抑制p53活性:1)用作E3泛蛋白连接酶以促进p53降解;2)结合至p53转录激活结构域并阻断p53转录激活结构域;以及3)从细胞核向细胞质输出p53。这三种机制都将通过抵消MDM2-p53相互作用来进行阻断。特别地,这种治疗策略可以应用于p53WT肿瘤,并且利用小分子MDM2抑制剂进行的研究已经显示出肿瘤生长在体外和体内有希望地减小。进一步地,在患有p53-灭活的肿瘤的患者中,由MDM2抑制引起的正常组织中野生型p53的稳定化可能允许选择性地保护正常组织免受有丝分裂毒的损害。
本发明涉及能够抑制p53和MDM2之间的相互作用并且能够激活p53下游效应基因的化合物。因此,本发明化合物将可用于治疗癌症、细菌感染、病毒感染、溃疡和炎症。特别地,本发明化合物可用于治疗诸如乳腺肿瘤、结肠肿瘤、肺肿瘤和前列腺肿瘤的实体瘤以及诸如淋巴瘤和白血病的液体瘤。如本文使用的,MDM2意指人MDM2蛋白,p53意指人p53蛋白。注意,人MDM2也可以称为HDM2或hMDM2。
发明概要
本发明涉及式I的哌啶酮衍生物:
以及其对映异构体、非对映异构体和药学上可接受的盐,
其中
当n*为1至6的整数时,Q为单键或者可以任选地选自O、NR7和S(O)v,
Z为C=O或S(=O)2
Ra在每次出现时均独立地选自H、(C1-C3)烷基、(卤代)(C1-C3)烷基、(羟基)(C1-C3)烷基、(烷氧基)(C1-C3)烷基,或氰基;
Rb为H、卤代、(C1-C3)烷基、(卤代)(C1-C3)烷基、(羟基)(C1-C3)烷基、(烷氧基)(C1-C3)烷基,或氰基;
Rc和Rd独立地为H、卤代、(C1-C3)烷基、(C1-C3)烷氧基、(卤代)(C1-C3)烷基、(卤代)(C1-C3)烷氧基、(烷氧基)(C1-C3)烷基、(羟基)(C1-C3)烷基;
或者Rc和Rd可以任选地组合从而形成螺-环烷基或杂环基环系统;
Re为(a)H,或卤代;或者
(b)(C1-C8)烷基、(C3-C8)环烷基、(C3-C8)杂环基、氰基、卤代、羟基、-OR5、NR7R8、杂环烷基,其中的任一种在化合价容许的情况下可以任选地被1个或多个Rx基团取代。
或者Re与R’或R”基团中的任一个可以任选地组合从而形成螺-环烷基或杂环基环系统;
或者Rd与R’或R”基团中的任一个可以任选地组合从而形成稠合环烷基或杂环基环系统;
或者Rd和Re可以任选地组合从而形成稠合环烷基或杂环基环系统;
R’和R”在每次出现时均分别独立地为H、卤代、(C1-C3)烷基、(C1-C3)烷氧基、(卤代)(C1-C3)烷基、(卤代)(C1-C3)烷氧基、(烷氧基)(C1-C3)烷基、(羟基)(C1-C3)烷基、-S-(C1-C3)烷基、C(O)(C1-C3)烷基、-NR7R8,或羟基
或者结合至同一碳原子的R’和R”可以任选地组合从而形成=O;
或者结合至同一碳原子的R’和R”可以任选地组合从而形成螺-稠合环烷基或杂环基环系统
R1为
(a)–COOH、–C(O)OR10、–C(O)NHOH、–C(O)NH-NH2、-C(O)NHS(O)2R10、-S(O)2NHC(O)R10、-S(O)2NR7R8、-NR7C(O)R10、–NR7C(O)OR5、-C(O)NR7R8、-NR7S(O)2R10,或-NR7C(O)NR7R8、-S(O)vR10,或CN;
(b)杂芳基或杂环基,其中的任一种在化合价容许的情况下可以任选地独立地被一个或多个Rx基团取代;
R2为
(a)–NR7R8、NR7C(O)OR10、NR7C(O)NR7R10,或–C(Ra)R5R6;
(b)芳基、杂芳基、环烷基,或杂环基,其中的任一种在化合价
容许的情况下可以任选地独立地被一个或多个Rx基团取代;
R3和R4独立地为芳基或杂芳基,其中的任一种在化合价容许的情况下可以任选地独立地被一个或多个Rx基团取代;
或者要么R3和Ra与它们都键接的环碳原子,要么R4和Rb与它们都键接的环碳原子可以任选地组合从而形成选自以下的螺-稠合二环环系统:
其中K为–O-、-NR7-,或–C(=O)NR7-,
R5和R6在每次出现时均分别独立地选自
(a)H和CN;或者
(b)-(亚烷基)t–OH、-(亚烷基)t–OR9、-(亚烷基)t–SR9、-(亚烷基)t–NR10R11、-(亚烷基)t-C(O)R9、-(亚烷基)t–C(O)OR9、-(亚烷基)t–OC(O)R9、-(亚烷基)t–S(O)vR9、-(亚烷基)t-NHS(O)2R10、-(亚烷基)t-N(R11)S(O)2R10、-(亚烷基)t-–NR10C(O)R9、C(O)NR10R11、NR10S(O)2R9、S(O)2NR10,和NR10C(O)NR10R11;或者
(a)卤代烷基、卤代烷氧基、C1-6-烷基、C2-6烯基、C2-6-炔基、C3-8-环烷基、(C3-8-环烷基)(C1-3烷基)、C4-8-环烯基、芳基、芳基(C1-3-烷基)杂芳基、杂芳基(C1-3-烷基)、杂环基和杂环基(C1-3-烷基)m,其中的任一种在化合价容许的情况下可以任选地独立地被一个或多个Rx基团取代;
R7和R8在每次出现时均分别独立地选自H、C1-6-烷基、卤代(C1-6)-烷基、环烷基、C2-6-烯基、C2-6-炔基、芳基、杂芳基、杂环基、芳基烷基、杂芳基烷基、杂环基(C1-10烷基),和(C3-8-环烷基)(C1-3烷基),其中的任一种在化合价容许的情况下可以任选地被一个或多个Rx取代;或者R7和R8可以组合从而形成任选地被一个或多个Rx取代的C4-C8-杂环基环;
R9为
卤代烷基、卤代烷氧基、C1-6-烷基、C2-6烯基、C2-6-炔基、C3-8-环烷基、(C3-8-环烷基)(C1-3烷基)、C4-8-环烯基、芳基、杂芳基,和杂环基,其中的任一种在化合价容许的情况下可以任选地独立地被一个或多个Rx基团取代;
R10和R11在每次出现时均分别独立地选自烷基、卤代烷基、环烷基、烯基、炔基、芳基、杂芳基、杂环基、芳基烷基、杂芳基烷基、杂环烷基,和环烷基烷基,其中的任一种在化合价容许的情况下可以任选地被一个或多个Rx取代;
或者R10和R11可以组合从而形成任选地被一个或多个Rx取代的杂环基环;
Rx在每次出现时均独立地为氘、卤代、氰基、硝基、氧代、烷基、卤代烷基、烯基、炔基、环烷基、环烯基、杂环基、芳基、杂芳基、芳基烷基、杂芳基烷基、环烷基烷基、杂环烷基、-(亚烷基)t-OR*、-(亚烷基)t-S(O)vR*、-(亚烷基)t-NR+R++、-(亚烷基)t-C(=O)R*、-(亚烷基)t-C(=S)R*、-(亚烷基)t-C(=O)OR*、-(亚烷基)t-OC(=O)R*、-(亚烷基)t-C(=S)OR*、─(亚烷基)t-C(=O)NR+R++、-(亚烷基)t-C(=S)NR+R++、-(亚烷基)t-N(R+)C(=O)NR+R++、-(亚烷基)t-N(R+)C(=S)NR+R++、-(亚烷基)t-N(R+)C(=O)R*、-(亚烷基)t-N(R+)C(=S)R*、-(亚烷基)t-OC(=O)NR+R++、-(亚烷基)t-OC(=S)NR+R++、-(亚烷基)t-SO2NR+R++、-(亚烷基)t-N(R+)SO2R*、-(亚烷基)t-N(R+)SO2NR+R++、-(亚烷基)t-N(R+)C(=O)OR*、-(亚烷基)t-N(R+)C(=S)OR*,或-(亚烷基)t-N(R+)SO2R*;
其中所述烷基、卤代烷基、烯基、炔基、环烷基、环烯基、杂环基、芳基、杂芳基、芳基烷基、杂芳基烷基、环烷基烷基,和杂环烷基可以进一步独立地被一个或多个以下基团取代:卤代、氰基、氧代、-(亚烷基)t-OR*、-(亚烷基)t-S(O)vR*、-(亚烷基)t-NR+R++、-(亚烷基)t-C(=O)R*、-(亚烷基)t-C(=S)R*、-(亚烷基)t-C(=O)OR*、-(亚烷基)t-OC(=O)R*、-(亚烷基)t-C(=S)OR*、─(亚烷基)t-C(=O)NR+R++、-(亚烷基)t-C(=S)NR+R++、-(亚烷基)t-N(R+)C(=O)NR+R++、-(亚烷基)t-N(R+)C(=S)NR+R++、-(亚烷基)t-N(R+)C(=O)R*、-(亚烷基)t-N(R+)C(=S)R*、-(亚烷基)t-OC(=O)NR+R++、-(亚烷基)t-OC(=S)NR+R++、-(亚烷基)t-SO2NR+R++、-(亚烷基)t-N(R+)SO2R*、-(亚烷基)t-N(R+)SO2NR+R++、-(亚烷基)t-N(R+)C(=O)OR*、-(亚烷基)t-N(R+)C(=S)OR*,或-(亚烷基)t-N(R+)SO2R*;
R*为
卤代烷基、卤代烷氧基、C1-6-烷基、C2-6烯基、C2-6-炔基、C3-8-环烷基、C4-8-环烯基、芳基、杂芳基,和杂环基
R+和R++独立为H、烷基、卤代烷基、环烷基、烯基、炔基、芳基、杂芳基、杂环基、芳基烷基、杂芳基烷基、杂环烷基,和环烷基烷基,
或者结合至同一氮原子的R+和R++可以任选地组合从而形成杂环基环系统;
m为1、2或3
n和n*各自独立地选自0及1至6的整数;
p为0、1、2或3;
t在每次出现时均独立地为0或1至6的整数;
v在每次出现时均独立地为0、1或2;
在式I范围内的优选化合物包括其中R2为–C(H)R5R6或–NR7R8、苯基或吡啶的化合物,所述苯基或所述吡啶基在化合价容许的情况下可以任选地被一个或多个Rx取代。
在式I范围内的优选化合物包括其中R2选自于以下的化合物:
其中的任一种在化合价容许的情况下可以任选地被一个或多个Rx基团取代。
在式I范围内的优选化合物包括这样的化合物,其中的R1为
在式I范围内的优选化合物包括式IA化合物:
以及其对映异构体、非对映异构体和药学上可接受的盐
其中q和p各自独立地为0、1、2或3。优选的式IA化合物包括含有前面提及的优选R1和R2基团的化合物。
在式I范围内的优选化合物包括式IB化合物:
以及其对映异构体、非对映异构体和药学上可接受的盐
其中q和p各自独立地为0、1、2或3。优选的式IB化合物包括含有前面提及的优选R1和R2基团的化合物。
在式I范围内的优选化合物包括式IC化合物:
以及其对映异构体、非对映异构体和药学上可接受的盐
其中q和p各自独立地为0、1、2或3。优选的式IC化合物包括含有本文提及的优选R1和R2基团的化合物。
在式IA、IB和IC范围内的优选化合物进一步包括其中R2选自于以下的化合物:
其中的任一种在化合价容许的情况下可以任选地被一个或多个Rx基团取代。
在另一方面,即方面A中,本发明提供了式I化合物:
或其药学上可接受的盐,其中:
当n*为1至6的整数时,Q为单键或者可以任选地选自O、NR7或S(O)v;
Z为C=O或S(=O)2;
Ra在每次出现时均独立地选自H、(C1-C3)烷基、(卤代)(C1-C3)烷基、(羟基)(C1-C3)烷基、(烷氧基)(C1-C3)烷基,或氰基;
Rb为H、卤代、(C1-C3)烷基、(卤代)(C1-C3)烷基、(羟基)(C1-C3)烷基、(烷氧基)(C1-C3)烷基,或氰基;
Rc和Rd独立地选自H、卤代、(C1-C3)烷基、(C1-C3)烷氧基、(卤代)(C1-C3)烷基、(卤代)(C1-C3)烷氧基、(烷氧基)(C1-C3)烷基,或(羟基)(C1-C3)烷基,或者Rc和Rd可以任选地组合从而形成螺-环烷基或杂环基环系统;
Re为
(a)H或卤代;或者
(b)(C1-C8)烷基、(C3-C8)环烷基、(C3-C8)杂环基、氰基、卤素、羟基、-OR5、NR7R8,或杂环烷基,其中的任一种在化合价容许的情况下可以任选地被1个或多个Rx基团取代,或者Re与R’或R”基团中的任一个可以任选地组合从而形成螺-环烷基或杂环基环系统,或Rd与R’或R”基团中的任一个可以任选地组合从而形成稠合环烷基或杂环基环系统,或者Rd和Re可以任选地组合从而形成稠合环烷基或杂环基环系统;
R’和R”在每次出现时均分别独立地为H、卤代、(C1-C3)烷基、(C1-C3)烷氧基、(卤代)(C1-C3)烷基、(卤代)(C1-C3)烷氧基、(烷氧基)(C1-C3)烷基、(羟基)(C1-C3)烷基、-S-(C1-C3)烷基、C(O)(C1-C3)烷基、-NR7R8,或羟基,或者结合至同一碳原子的R’和R”可以任选地组合从而形成=O,或者结合至同一碳原子的R’和R”可以任选地组合从而形成螺-稠合环烷基或杂环基环系统;
R1为
(a)–COOH、–C(O)OR10、–C(O)NHOH、–C(O)NH-NH2、-C(O)NHS(O)2R10、-S(O)2NHC(O)R10、-S(O)2NR7R8、-NR7C(O)R10、–NR7C(O)OR5、-C(O)NR7R8、-NR7S(O)2R10、‘-NR7C(O)NR7R8、-S(O)vR10、羟基烷基、-环丙基-COOH,或CN;或者
(b)杂芳基或杂环基,其中的任一种在化合价容许的情况下可以任选地独立地被一个或多个Rx基团取代;
R2为
(a)–NR7R8、NR7C(O)OR10、NR7C(O)NR7R10,或–C(Ra)R5R6;或者
(b)芳基、杂芳基、环烷基,或杂环基,其中的任一种在化合价容许的情况下可以任选地独立地被一个或多个Rx基团取代;
R3和R4独立地为芳基或杂芳基,其中的任一种在化合价容许的情况下可以任选地独立地被一个或多个Rx基团取代,或者要么R3和Ra与它们都键接的环碳原子,要么R4和Rb与它们都键接的环碳原子可以任选地组合从而形成选自以下的螺-稠合二环环系统:
其中K为–O-、-NR7-,或–C(=O)NR7-;
R5和R6在每次出现时均分别独立地选自
(a)H或CN;
(b)-(亚烷基)t–OH、-(亚烷基)t–OR9、-(亚烷基)t–SR9、-(亚烷基)t–NR10R11、-(亚烷基)t-C(O)R9、-(亚烷基)t–C(O)OR9、-(亚烷基)t–OC(O)R9、-(亚烷基)t–S(O)vR9、-(亚烷基)t-NHS(O)2R10、-(亚烷基)t-N(R11)S(O)2R10、-(亚烷基)t-S(O)2NR10R11、–NR10C(O)R9、-C(O)NR10R11、-NR10S(O)2R9、S(O)2NR10,或NR10C(O)NR10R11;或者
(c)卤代烷基、卤代烷氧基、C1-6-烷基、C2-6烯基、C2-6-炔基、C3-8-环烷基、(C3-8-环烷基)(C1-3烷基)、C4-8-环烯基、芳基、芳基(C1-3-烷基)、杂芳基、杂芳基(C1-3-烷基)、杂环基或杂环基(C1-3-烷基),其中的任一种在化合价容许的情况下可以任选地独立地被一个或多个Rx基团取代;
R7和R8在每次出现时均分别独立地选自H、氰基、-O C1-6-烷基、C1-6-烷基、卤代(C1-6)-烷基、环烷基、C2-6-烯基、C2-6-炔基、芳基、杂芳基、杂环基、芳基烷基、杂芳基烷基、杂环基(C1-10烷基),或(C3-8-环烷基)(C1-3烷基),其中的任一种在化合价容许的情况下可以任选地被一个或多个Rx取代,或者R7和R8可以组合从而形成任选地被一个或多个Rx取代的C4-C8-杂环基环;
R9为卤代烷基、卤代烷氧基、C1-6-烷基、C2-6烯基、C2-6-炔基、C3-8-环烷基、(C3-8-环烷基)(C1-3烷基)、C4-8-环烯基、芳基、杂芳基,或杂环基,其中的任一种在化合价容许的情况下可以任选地独立地被一个或多个Rx基团取代;
R10和R11在每次出现时均分别独立地选自H、烷基、卤代烷基、环烷基、烯基、炔基、芳基、杂芳基、杂环基、芳基烷基、杂芳基烷基、杂环烷基,或环烷基烷基,其中的任一种在化合价容许的情况下可以任选地被一个或多个Rx取代,或者R10和R11可以组合从而形成任选地被一个或多个Rx取代的杂环基环;
Rx在每次出现时均独立地为氘、卤代、氰基、硝基、氧代、烷基、卤代烷基、烯基、炔基、环烷基、环烯基、杂环基、芳基、杂芳基、芳基烷基、杂芳基烷基、环烷基烷基、杂环烷基、-(亚烷基)t-OR*、-(亚烷基)t-S(O)vR*、-(亚烷基)t-NR+R++、-(亚烷基)t-C(=O)R*、-(亚烷基)t-C(=S)R*、-(亚烷基)t-C(=O)OR*、-(亚烷基)t-OC(=O)R*、-(亚烷基)t-C(=S)OR*、─(亚烷基)t-C(=O)NR+R++、-(亚烷基)t-C(=S)NR+R++、-(亚烷基)t-N(R+)C(=O)NR+R++、-(亚烷基)t-N(R+)C(=S)NR+R++、-(亚烷基)t-N(R+)C(=O)R*、-(亚烷基)t-N(R+)C(=S)R*、-(亚烷基)t-OC(=O)NR+R++、-(亚烷基)t-OC(=S)NR+R++、-(亚烷基)t-SO2NR+R++、-(亚烷基)t-N(R+)SO2R*、-(亚烷基)t-N(R+)SO2NR+R++、-(亚烷基)t-N(R+)C(=O)OR*、-(亚烷基)t-N(R+)C(=S)OR*,或-(亚烷基)t-N(R+)SO2R*,其中所述烷基、卤代烷基、烯基、炔基、环烷基、环烯基、杂环基、芳基、杂芳基、芳基烷基、杂芳基烷基、环烷基烷基,和杂环烷基可以进一步独立地被一个或多个以下基团取代:卤代、氰基、氧代、-(亚烷基)t-OR*、-(亚烷基)t-S(O)vR*、-(亚烷基)t-NR+R++、-(亚烷基)t-C(=O)R*、-(亚烷基)t-C(=S)R*、-(亚烷基)t-C(=O)OR*、-(亚烷基)t-OC(=O)R*、-(亚烷基)t-C(=S)OR*、─(亚烷基)t-C(=O)NR+R++、-(亚烷基)t-C(=S)NR+R++、-(亚烷基)t-N(R+)C(=O)NR+R++、-(亚烷基)t-N(R+)C(=S)NR+R++、-(亚烷基)t-N(R+)C(=O)R*、-(亚烷基)t-N(R+)C(=S)R*、-(亚烷基)t-OC(=O)NR+R++、-(亚烷基)t-OC(=S)NR+R++、-(亚烷基)t-SO2NR+R++、-(亚烷基)t-N(R+)SO2R*、-(亚烷基)t-N(R+)SO2NR+R++、-(亚烷基)t-N(R+)C(=O)OR*、-(亚烷基)t-N(R+)C(=S)OR*,或-(亚烷基)t-N(R+)SO2R*;
R*为H、卤代烷基、卤代烷氧基、C1-6-烷基、C2-6烯基、C2-6-炔基、C3-8-环烷基、C4-8-环烯基、芳基、杂芳基,或杂环基;
R+和R++独立地为H、烷基、卤代烷基、环烷基、烯基、炔基、芳基、杂芳基、杂环基、芳基烷基、杂芳基烷基、杂环烷基,或环烷基烷基,或者结合至同一氮原子的R+和R++可以任选地组合从而形成杂环基环系统;
m为1、2或3;
n和n*各自独立地选自0或1至6的整数;
p为0、1、2或3;
t在每次出现时均独立地为0或1至6的整数;以及
v在每次出现时均独立地为0、1或2。
在另一方面,即方面AA中,本发明提供了式I化合物:
或其药学上可接受的盐,其中:
当n*为1至6的整数时,Q为单键或者可以任选地选自O、NR7或S(O)v;
Z为C=O或S(=O)2;
Ra在每次出现时均独立地选自H、(C1-C3)烷基、(卤代)(C1-C3)烷基、(羟基)(C1-C3)烷基、(烷氧基)(C1-C3)烷基,或氰基;
Rb为H、卤代、(C1-C3)烷基、(卤代)(C1-C3)烷基、(羟基)(C1-C3)烷基、(烷氧基)(C1-C3)烷基,或氰基;
Rc和Rd独立地选自H、卤代、(C1-C3)烷基、(C1-C3)烷氧基、(卤代)(C1-C3)烷基、(卤代)(C1-C3)烷氧基、(烷氧基)(C1-C3)烷基,或(羟基)(C1-C3)烷基,或者Rc和Rd可以任选地组合从而形成螺-环烷基或杂环基环系统;
Re为
(a)H或卤代;或者
(b)(C1-C8)烷基、(C3-C8)环烷基、(C3-C8)杂环基、氰基、卤代、羟基、-OR5、NR7R8,或杂环烷基,其中的任一种在化合价容许的情况下可以任选地被1个或多个Rx基团取代,或者Re与R’或R”基团中的任一个可以任选地组合从而形成螺-环烷基或杂环基环系统,或Rd与R’或R”基团中的任一个可以任选地组合从而形成稠合环烷基或杂环基环系统,或者Rd和Re可以任选地组合从而形成稠合环烷基或杂环基环系统;
R’和R”在每次出现时均分别独立地为H、卤代、(C1-C3)烷基、(C1-C3)烷氧基、(卤代)(C1-C3)烷基、(卤代)(C1-C3)烷氧基、(烷氧基)(C1-C3)烷基、(羟基)(C1-C3)烷基、-S-(C1-C3)烷基、C(O)(C1-C3)烷基、-NR7R8,或羟基,或者结合至同一碳原子的R’和R”可以任选地组合从而形成=O,或者结合至同一碳原子的R’和R”可以任选地组合从而形成螺-稠合环烷基或杂环基环系统;
R1为
(a)–COOH、–C(O)OR10、–C(O)NHOH、–C(O)NH-NH2、-C(O)NHS(O)2R10、-S(O)2NHC(O)R10、-S(O)2NR7R8、-NR7C(O)R10、–NR7C(O)OR5、-C(O)NR7R8、-NR7S(O)2R10、-NR7C(O)NR7R8、-S(O)vR10、羟基烷基、-环丙基-COOH,或CN;或者
(b)杂芳基或杂环基,其中的任一种在化合价容许的情况下可以任选地独立地被一个或多个Rx基团取代;
R2为
(a)–NR7R8、NR7C(O)OR10、NR7C(O)NR7R10,或–C(Ra)R5R6;或者
(b)芳基、杂芳基、环烷基,或杂环基,其中的任一种在化合价容许的情况下可以任选地独立地被一个或多个Rx基团取代;
R3和R4独立地为芳基或杂芳基,其中的任一种在化合价容许的情况下可以任选地独立地被一个或多个Rx基团取代,或者要么R3和Ra与它们都键接的环碳原子,要么R4和Rb与它们都键接的环碳原子可以任选地组合从而形成选自以下的螺-稠合二环环系统:
其中K为–O-、-NR7-,或–C(=O)NR7-;
R5和R6在每次出现时均分别独立地选自
(a)H或CN;
(b)-(亚烷基)t–OH、-(亚烷基)t–OR9、-(亚烷基)t–SR9、-(亚烷基)t–NR10R11、-(亚烷基)t-C(O)R9、-(亚烷基)t–C(O)OR9、-(亚烷基)t–OC(O)R9、-(亚烷基)t–S(O)vR9、-(亚烷基)t-NHS(O)2R10、-(亚烷基)t-N(R11)S(O)2R10、-(亚烷基)t-S(O)2NR10R11、-(亚烷基)t-N(R11)S(O)2NR10R11 、–NR10C(O)R9、-C(O)NR10R11、-NR10S(O)2R9、S(O)2NR10,或NR10C(O)NR10R11;或者
(c)卤代烷基、卤代烷氧基、C1-6-烷基、C2-6烯基、C2-6-炔基、C3-8-环烷基、(C3-8-环烷基)(C1-3烷基)、C4-8-环烯基、芳基、芳基(C1-3-烷基)、杂芳基、杂芳基(C1-3-烷基)、杂环基或杂环基(C1-3-烷基),其中的任一种在化合价容许的情况下可以任选地独立地被一个或多个Rx基团取代;
R7和R8在每次出现时均分别独立地选自H、氰基、-O C1-6-烷基、C1-6-烷基、卤代(C1-6)-烷基、环烷基、C2-6-烯基、C2-6-炔基、芳基、杂芳基、杂环基、芳基烷基、杂芳基烷基、杂环基(C1-10烷基),或(C3-8-环烷基)(C1-3烷基),其中的任一种在化合价容许的情况下可以任选地被一个或多个Rx取代,或者R7和R8可以组合从而形成任选地被一个或多个Rx取代的C4-C8-杂环基环;
R9为卤代烷基、卤代烷氧基、C1-6-烷基、C2-6烯基、C2-6-炔基、C3-8-环烷基、(C3-8-环烷基)(C1-3烷基)、C4-8-环烯基、芳基、杂芳基、杂环基,或杂环烷基,其中的任一种在化合价容许的情况下可以任选地独立地被一个或多个Rx基团取代;
R10和R11在每次出现时均分别独立地选自H、烷基、卤代烷基、环烷基、烯基、炔基、芳基、杂芳基、杂环基、芳基烷基、杂芳基烷基、杂环烷基,或环烷基烷基,其中的任一种在化合价容许的情况下可以任选地被一个或多个Rx取代,或者R10和R11可以组合从而形成任选地被一个或多个Rx取代的杂环基环;
Rx在每次出现时均独立地为氘、卤代、氰基、硝基、氧代、烷基、卤代烷基、烯基、炔基、环烷基、环烯基、杂环基、芳基、杂芳基、芳基烷基、杂芳基烷基、环烷基烷基、杂环烷基、-(亚烷基)t-OR*、-(亚烷基)t-S(O)vR*、-(亚烷基)t-NR+R++、-(亚烷基)t-C(=O)R*、-(亚烷基)t-C(=S)R*、-(亚烷基)t-C(=O)OR*、-(亚烷基)t-OC(=O)R*、-(亚烷基)t-C(=S)OR*、─(亚烷基)t-C(=O)NR+R++、-(亚烷基)t-C(=S)NR+R++、-(亚烷基)t-N(R+)C(=O)NR+R++、-(亚烷基)t-N(R+)C(=S)NR+R++、-(亚烷基)t-N(R+)C(=O)R*、-(亚烷基)t-N(R+)C(=S)R*、-(亚烷基)t-OC(=O)NR+R++、-(亚烷基)t-OC(=S)NR+R++、-(亚烷基)t-SO2NR+R++、-(亚烷基)t-N(R+)SO2R*、-(亚烷基)t-N(R+)SO2NR+R++、-(亚烷基)t-N(R+)C(=O)OR*、-(亚烷基)t-N(R+)C(=S)OR*,或-(亚烷基)t-N(R+)SO2R*,其中所述烷基、卤代烷基、烯基、炔基、环烷基、环烯基、杂环基、芳基、杂芳基、芳基烷基、杂芳基烷基、环烷基烷基,和杂环烷基可以进一步独立地被一个或多个以下基团取代:卤代、氰基、氧代、-(亚烷基)t-OR*、-(亚烷基)t-S(O)vR*、-(亚烷基)t-NR+R++、-(亚烷基)t-C(=O)R*、-(亚烷基)t-C(=S)R*、-(亚烷基)t-C(=O)OR*、-(亚烷基)t-OC(=O)R*、-(亚烷基)t-C(=S)OR*、─(亚烷基)t-C(=O)NR+R++、-(亚烷基)t-C(=S)NR+R++、-(亚烷基)t-N(R+)C(=O)NR+R++、-(亚烷基)t-N(R+)C(=S)NR+R++、-(亚烷基)t-N(R+)C(=O)R*、-(亚烷基)t-N(R+)C(=S)R*、-(亚烷基)t-OC(=O)NR+R++、-(亚烷基)t-OC(=S)NR+R++、-(亚烷基)t-SO2NR+R++、-(亚烷基)t-N(R+)SO2R*、-(亚烷基)t-N(R+)SO2NR+R++、-(亚烷基)t-N(R+)C(=O)OR*、-(亚烷基)t-N(R+)C(=S)OR*,或-(亚烷基)t-N(R+)SO2R*;
R*为H、卤代烷基、卤代烷氧基、C1-6-烷基、C2-6烯基、C2-6-炔基、C3-8-环烷基、C4-8-环烯基、芳基、杂芳基,或杂环基;
R+和R++独立地为H、烷基、卤代烷基、环烷基、烯基、炔基、芳基、杂芳基、杂环基、芳基烷基、杂芳基烷基、杂环烷基,或环烷基烷基,或者结合至同一氮原子的R+和R++可以任选地组合从而形成杂环基环系统;
m为1、2或3;
n和n*各自独立地选自0或1至6的整数;
p为0、1、2或3;
t在每次出现时均独立地为0或1至6的整数;和
v在每次出现时均独立地为0、1或2。
在方面A或AA的化合物,或其药学上可接受的盐的另一个实施方案(实施方案2)中,R2为–C(H)R5R6、–NR7R8、苯基或吡啶,其中所述苯基或所述吡啶基在化合价容许的情况下可以任选地被一个或多个Rx取代。
在方面A或AA的化合物,或其药学上可接受的盐的另一个实施方案(实施方案3)中,R2选自
在另一个实施方案(实施方案4)中,方面A或AA的化合物具有式IA
或其药学上可接受的盐的结构,其中q和p各自独立地为0、1、2或3。
在另一个实施方案(实施方案5)中,方面A或AA的化合物具有式IB
或其药学上可接受的盐的结构,其中q和p各自独立地为0、1、2或3。
在另一个实施方案(实施方案6)中,方面A或AA的化合物具有式IC
或其药学上可接受的盐的结构,其中q和p各自独立地为0、1、2或3。
在实施方案6的另一方面(实施方案7),或其药学上可接受的盐中,R2选自
在实施例6的另一方面(实施例8)或其药学上可接受的盐中,
R2选自
并且R1为
在实施方案6的另一方面(实施方案9),或其药学上可接受的盐中,
R2选自
R1为
在实施方案6的另一方面(实施方案10),或其药学上可接受的盐中,
R2选自
R1为
在另一个实施方案(实施方案11)中,方面A的化合物具有式ID
或其药学上可接受的盐的结构。
在实施方案11的另一方面(实施方案12),或其药学上可接受的盐中,Re为H或甲基或乙基。
在另一个实施方案(实施方案13)中,方面A的化合物具有式IE
或其药学上可接受的盐的结构。
在实施方案13的另一方面(实施方案14),或其药学上可接受的盐中,Re为H或甲基或乙基。
在实施方案13的另一方面(实施方案15),或其药学上可接受的盐中,其中
R2选自
R1为
在实施13的另一方面(实施方案16),或其药学上可接受的盐中,
R1为
或选自以下的杂芳基或杂环:
R2为
Re为甲基。
在实施方案13的另一方面(实施方案17),或其药学上可接受的盐中:
R2为
R5为环丙基,或C1-6烷基;
R9为卤代烷基、卤代烷氧基、C1-6-烷基、C2-6烯基、C2-6-炔基、C3-8-环烷基、(C3-8-环烷基)(C1-3烷基)、C4-8-环烯基、芳基、杂芳基,或杂环烷基,或者R9为卤代烷基、卤代烷氧基、C1-6-烷基、C2-6烯基、C2-6-炔基、C3-8-环烷基、(C3-8-环烷基)(C1-3烷基)、C4-8-环烯基、芳基、杂芳基,或杂环基,其中的任一种在化合价容许的情况下可以任选地独立地被一个或多个Rx基团取代;以及
R10和R11在每次出现时均分别独立地选自H、烷基、卤代烷基、环烷基、烯基、炔基、芳基、杂芳基、杂环基、芳基烷基、杂芳基烷基、杂环烷基,或环烷基烷基,其中的任一种在化合价容许的情况下可以任选地被一个或多个Rx取代,或者R10和R11可以组合从而形成任选地被1个或多个Rx取代的杂环基环。
在实施方案13的另一方面(实施方案18),或其药学上可接受的盐中,
R1为
R2为
并且Re为甲基。
在另一方面,本发明提供了选自以下的化合物,或其药学上可接受的盐:
2-((3R,5R,6S)-1-((S)-1-叔丁氧基-1-氧代丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-3-基)乙酸;
2-((3S,5R,6S)-1-((S)-1-叔丁氧基-1-氧代丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-乙氧基-1-氧代丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-乙氧基-4-甲基-1-氧代戊烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-乙氧基-1-氧代戊烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3S,5S,6R)-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-1-乙氧基-1-氧代戊烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-2-叔丁氧基-1-环丙基-2-氧代乙基)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-羟基乙基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环丙基甲氧基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-甲氧基丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(2-甲氧基乙氧基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-((1-氰基环丙基)甲氧基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环丙基甲氧基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-甲氧基丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(2-甲氧基乙氧基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-1-((1-氨基甲酰基环丙基)甲氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-3-基)乙酸(异构体1);
2-((3S,5R,6S)-1-((S)-1-((1-氨基甲酰基环丙基)甲氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-3-基)乙酸(异构体2);
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(2-羟基-2-甲基丙氧基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-((3S)-1,1,1-三氟代-2-羟基戊烷-3-基)哌啶-3-基)乙酸(异构体1);
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-((3S)-1,1,1-三氟代-2-羟基戊烷-3-基)哌啶-3-基)乙酸(异构体2);
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-吗啉代丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(乙基氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-((S)-1-(2,2,2-三氟乙基氨基)丁烷-2-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-((S)-1-(吡咯烷-1-基)丁烷-2-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-((S)-1-(2-氧代吡咯烷-1-基)丁烷-2-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二氧化(dioxido)硫代吗啉代)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-((S)-1-(噻唑-2-基氨基)丁烷-2-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-1-乙酰氨基丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(甲基磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-氰基戊烷-3-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(甲基磺酰基)戊烷-3-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-((S)-1-(吡啶-2-基)戊烷-3-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(乙基氨基)-1-氧代丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-1-(乙基氨基)-1-氧代丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(5-甲基-1,3,4-噁二唑-2-基)丙基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-1-(5-甲基-1,3,4-噁二唑-2-基)丙基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丁基甲基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(2-乙基丁基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环戊基甲基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2,2-二甲基环戊基)甲基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环己基甲基)-2-氧代哌啶-3-基)乙酸;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酸;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-丙基哌啶-3-基)乙酸;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丁基甲基)-2-氧代哌啶-3-基)乙酸;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-异丁基-2-氧代哌啶-3-基)乙酸;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环戊基甲基)-2-氧代哌啶-3-基)乙酸;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-(戊烷-3-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酸甲酯;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酰胺;
2-(2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酰氨基)乙酸乙酯;
2-(2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酰氨基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酰肼;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)-N-羟基乙酰胺;
(S)-2-((2S,3R,5R)-3-(3-氯苯基)-2-(4-氯苯基)-5-(2-(甲基磺酰氨基)-2-氧代乙基)-6-氧代哌啶-1-基)丁酸乙酯;
(S)-2-((2S,3R,5R)-3-(3-氯苯基)-2-(4-氯苯基)-5-(2-((3-吗啉代丙基)氨基)-2-氧代乙基)-6-氧代哌啶-1-基)丁酸乙酯;
(3R,5R,6S)-3-((1H-四唑-5-基)甲基)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)哌啶-2-酮;
(3R,5R,6S)-3-((1,3,4-噁二唑-2-基)甲基)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)哌啶-2-酮;
(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-3-((5-甲基-1,3,4-噁二唑-2-基)甲基)哌啶-2-酮;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)-N-(甲基磺酰基)乙酰胺;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酰胺;
(3S,5R,6S)-3-((1H-四唑-5-基)甲基)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)哌啶-2-酮;
(3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-3-((5-甲基异噁唑-3-基)甲基)哌啶-2-酮;
2-((2′S,3′R,5′R)-6-氯代-3′-(3-氯苯基)-1′-(环丙基甲基)-2,6′-二氧代螺[二氢吲哚-3,2′-哌啶-5′-基)乙酸;
2-((2′R,3′S,5′S)-6-氯代-3′-(3-氯苯基)-1′-(环丙基甲基)-2,6′-二氧代螺[二氢吲哚-3,2′-哌啶-5′-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(5-氯噻吩-2-基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酸;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(5-氯噻吩-2-基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-乙氧基-1-氧代丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-1-叔丁氧基-1-氧代丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((R)-1-叔丁氧基-1-氧代丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环丙基甲氧基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代-3-(2-(吡咯烷-1-基)乙基)哌啶-3-基)乙酸;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-3-(2-吗啉代乙基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-异丙基-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-环丁基-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-环戊基-3-甲基-2-氧代哌啶-3-基)乙酸;
(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-3-((5-氧代-4,5-二氢-1H-1,2,4-三唑-3-基)甲基)-1-(戊烷-3-基)哌啶-2-酮;
5-(((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)甲基)-1,3,4-噁二唑-2(3H)-酮;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)-N-(三氟甲基磺酰基)乙酰胺;
(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-((3-羟基-1H-吡唑-5-基)甲基)-3-甲基-1-(戊烷-3-基)哌啶-2-酮;
(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-((3-羟基异噁唑-5-基)甲基)-3-甲基-1-(戊烷-3-基)哌啶-2-酮;
5-(((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)甲基)噁唑烷-2,4-二酮;
3-(((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)甲基)-1,2,4-噁二唑-5(4H)-酮;
3-(((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-异丙基-3-甲基-2-氧代哌啶-3-基)甲基)-1,2,4-噁二唑-5(4H)-酮;
3-(((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)甲基)-1,2,4-噻二唑-5(4H)-酮;
3-(((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-异丙基-3-甲基-2-氧代哌啶-3-基)甲基)-1,2,4-噻二唑-5(4H)-酮;
(3R,5R,6S)-3-((1H-四唑-5-基)甲基)-5-(3-氯苯基)-6-(4-氯苯基)-1-异丙基-3-甲基哌啶-2-酮;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-2-氧代-1-(戊烷-3-基)哌啶-3-基)乙酸;
(3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-3-(甲基磺酰基甲基)-1-(戊烷-3-基)哌啶-2-酮;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(3-环丙基-1,2,4-噁二唑-5-基)丙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-1-(3-环丙基-1,2,4-噁二唑-5-基)丙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-吗啉代丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(2,2,2-三氟乙基氨基)丁烷-2-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(2,2-二甲基吗啉代)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2S)-1-(2,6-二甲基吗啉代)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(4-(环丙基磺酰基)哌嗪-1-基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(4-(甲基磺酰基)哌嗪-1-基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-1-(4-乙酰基哌嗪-1-基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(4-(环丙烷羰基)哌嗪-1-基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
3-(((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-吗啉代丁烷-2-基)-2-氧代哌啶-3-基)甲基)-1,2,4-噁二唑-5(4H)-酮;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(5,5-二甲基-2-氧代噁唑烷-3-基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-1-(叔丁基氨基)-1-氧代丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((1S,2R,3S)-2,3-二羟基环戊基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((1R,2R,3S)-2,3-二羟基环戊基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,3′S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1′-(2,2,2-三氟乙基)-1,3′-联哌啶-3-基)乙酸;
2-((3R,3′R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1′-(2,2,2-三氟乙基)-1,3′-联哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((1S,3S)-3-羟基环戊基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((1S,3R)-3-羟基环戊基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-四氢-2H-吡喃-3-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((R)-四氢-2H-吡喃-3-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(吡嗪-2-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-甲基-1H-吡唑-4-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(嘧啶-4-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(2-氯嘧啶-4-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(嘧啶-2-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(3-甲基吡啶-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(4-甲基吡啶-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(二环丙基甲基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(二环丙基甲基)-3-甲基-2-氧代哌啶-3-基)乙酸;
((3S,4R,6R)-4-(3-氯苯基)-3-(4-氯苯基)-1,1-二氧化-2-(2-丙基)-1,2-噻嗪烷-6-基)乙酸;
((3S,4R,6S)-4-(3-氯苯基)-3-(4-氯苯基)-1,1-二氧化-2-(2-丙基)-1,2-噻嗪烷-6-基)乙酸;
((3S,4R,6R)-4-(3-氯苯基)-3-(4-氯苯基)-6-甲基-1,1-二氧化-2-(2-丙基)-1,2-噻嗪烷-6-基)乙酸;
((3S,4R,6S)-4-(3-氯苯基)-3-(4-氯苯基)-6-甲基-1,1-二氧化-2-(2-丙基)-1,2-噻嗪烷-6-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-3-甲基-1-((S)-1-吗啉代丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)乙酸;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-1-叔丁氧基-1-氧代丁烷-2-基)-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;或
2-((3R,5S,6S)-1-((S)-1-叔丁氧基-1-氧代丁烷-2-基)-6-(4-氯苯基)-5-(4-氯吡啶-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸。
在另一方面,本发明提供了选自以下的化合物,或其药学上可接受的盐:
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)丙酸;
(S)-2-((3R,5R,6S)-3-((1H-四唑-5-基)甲基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁酸叔丁酯;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(甲基磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-5-氧代己烷-3-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-5-羟基-5-甲基己烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((3S,5S)-6,6,6-三氟代-5-羟基-5-甲基己烷-3-基)哌啶-3-基)乙酸(异构体1);
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((3S,5R)-6,6,6-三氟代-5-羟基-5-甲基己烷-3-基)哌啶-3-基)乙酸(异构体2);
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基甲基磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S)-5-环丙基-6,6,6-三氟代-5-羟基己烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-6-羟基-6-甲基庚烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-6,6,6-三氟代-5,5-二羟基己烷-3-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((3S)-7,7,7-三氟代-6-羟基-6-甲基庚烷-3-基)哌啶-3-基)乙酸(异构体1);
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((3S)-7,7,7-三氟代-6-羟基-6-甲基庚烷-3-基)哌啶-3-基)乙酸(异构体2);
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-7-羟基-7-甲基辛烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N-环丙基甲基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((3S)-6,6,6-三氟代-5-羟基己烷-3-基)哌啶-3-基)乙酸(异构体1);
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((3S)-6,6,6-三氟代-5-羟基己烷-3-基)哌啶-3-基)乙酸(异构体2);
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S)-5-羟基己烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸(异构体1);
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S)-5-羟基己烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸(异构体2);
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(N-(2,2,2-三氟乙基)甲基磺酰氨基)丁烷-2-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S,4R)-5-羟基-4,5-二甲基己烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S,4S)-5-羟基-4,5-二甲基己烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-5-氰基-5-甲基己烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-2-氧代戊烷-3-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2S,3S)-2-羟基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2S,3S)-2-甲氧基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2R,3S)-2-羟基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2S,3R)-2-羟基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2R,3R)-2-羟基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-羟基-2-甲基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S,4S)-4-羟基己烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S,4R)-4-羟基己烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-甲氧基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(3S)-1,1,1-三氟代-2-羟基-2-甲基戊烷-3-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酰胺;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-(甲基磺酰基)乙酰胺;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-(3-羟基丙基)乙酰胺;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-(2-羟基乙基)乙酰胺;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-羟基乙酰胺;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-甲氧基乙酰胺;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-((R)-2,3-二羟基丙基)乙酰胺;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-((S)-2,3-二羟基丙基)乙酰胺;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-氰基乙酰胺;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-(2-(二甲基氨基)乙基)乙酰胺;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-(3,4-二羟基丁基)乙酰胺;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环丙烷磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
(S)-2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)丙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(3S)-2-(环丙烷磺酰氨基)戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸(异构体1);
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(3S)-2-(环丙烷磺酰氨基)戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸(异构体2);
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((2R,3S)-2-(1-甲基乙基磺酰氨基)戊烷-3-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)-1-氧代丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(新戊基氨基)-1-氧代丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(4,4-二甲基-4,5-二氢噁唑-2-基)丙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(N-(2,2,2-三氟乙基)乙酰氨基)丁烷-2-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二甲基乙基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N,2-二甲基丙烷-2-基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(1-甲基乙基磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N-乙基丙烷-2-基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(三氟甲基磺酰氨基)丁烷-2-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(4-氯苯基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(4-甲基苯基磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(2-氯苯基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(2-甲基苯基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(4-甲氧基苯基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(苯基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1-甲基环丙烷磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二氧化苯并[d]异噻唑-2(3H)-基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(3,3-二甲基-1,1-二氧化苯并[d]异噻唑-2(3H)-基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(吡啶-3-磺酰氨基)丁烷-2-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(4-氰基苯基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(3-氰基苯基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(吡啶-2-磺酰氨基)丁烷-2-基)哌啶-3-基)乙酸。
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N,1-二甲基环丙烷磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
3-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)丙酸;
3-((3R,5S,6R)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)丙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲氧基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-6-甲基-4-氧代庚烷-3-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(乙基磺酰基)戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(异丙基磺酰基)戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环丙基甲基磺酰基)戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(2-氧代吡咯烷-1-基)丁烷-2-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-1-((1R,4R)-2-氧杂-5-氮杂二环[2.2.1]庚烷-5-基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-((S)-3-甲基吗啉代)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-((R)-3-甲基吗啉代)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(硫代吗啉代-1,1-二氧化物)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(3,3-二氟氮杂环丁烷-1-基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((2S)-1-(8-氧杂-3-氮杂二环[3.2.1]辛烷-3-基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(3,3-二甲基吗啉代)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(3-羟基-3-(三氟甲基)氮杂环丁烷-1-基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(甲基(氧杂环丁烷-3-基)氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(2-氧代噁唑烷-3-基)丁烷-2-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(2-氧代吡啶-1(2H)-基)丁烷-2-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(2-氧代-5-(三氟甲基)吡啶-1(2H)-基)丁烷-2-基)哌啶-3-基)乙酸;
(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(吡啶-3-基氧基)丁烷-2-基)哌啶-2-酮;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((1S)-1-(四氢呋喃-2-基)丙基)哌啶-3-基)乙酸(异构体1);
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((1S)-1-(四氢呋喃-2-基)丙基)哌啶-3-基)乙酸(异构体2);
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((1S)-1-5-氧代四氢呋喃-2-基)丙基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((1S)-1-(四氢-2H-吡喃-2-基)丙基)哌啶-3-基)乙酸(异构体1);
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((1S)-1-(四氢-2H-吡喃-2-基)丙基)哌啶-3-基)乙酸(异构体2);
2-((3R,5R,6S)-1-((R)-1-(苯并[d]噻唑-2-基)丙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-1-(苯并[d]噻唑-2-基)丙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(3-甲基异噁唑-5-基)丙基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((R)-1-(3-甲基异噁唑-5-基)丙基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(6-氯吡啶-2-基)丙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-1-(6-氯吡啶-2-基)丙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(吡啶-2-基)丙基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((R)-1-(吡啶-2-基)丙基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(吡啶-2-基)丁基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((R)-1-(吡啶-2-基)丁基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-环丙基-1-(吡啶-2-基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-2-环丙基-1-(吡啶-2-基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(吡啶-3-基)丙基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((R)-1-(吡啶-3-基)丙基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(吡嗪-2-基)丙基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((R)-1-(吡嗪-2-基)丙基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(嘧啶-2-基)丙基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((R)-1-(嘧啶-2-基)丙基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(6-甲基吡啶-2-基)丙基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((R)-1-(6-甲基吡啶-2-基)丙基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(吡啶-4-基)丙基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((R)-1-(吡啶-4-基)丙基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(6-(三氟甲基)吡啶-2-基)丙基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((R)-1-(6-(三氟甲基)吡啶-2-基)丙基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-1-(6-溴吡啶-2-基)丙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((R)-1-(6-溴吡啶-2-基)丙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(噻唑-2-基)丙基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((R)-1-(噻唑-2-基)丙基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(6-(2-羟基丙烷-2-基)吡啶-2-基)丙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-1-(6-(2-羟基丙烷-2-基)吡啶-2-基)丙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(6-环丙基吡啶-2-基)丙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-1-(6-环丙基吡啶-2-基)丙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-3,3,3-三氟代-1-(吡啶-2-基)丙基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((R)-3,3,3-三氟代-1-(吡啶-2-基)丙基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-2-甲基-1-(吡啶-2-基)丙基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((R)-2-甲基-1-(吡啶-2-基)丙基)-2-氧代哌啶-3-基)乙酸;
(3R,5R,6S)-3-((1H-四唑-5-基)甲基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(戊烷-3-基)哌啶-2-酮;
(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-((R)-2,3-二羟基丙基)-1-((2S,3S)-2-羟基戊烷-3-基)-3-甲基哌啶-2-酮;
(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-((S)-2,3-二羟基丙基)-1-((2S,3S)-2-羟基戊烷-3-基)-3-甲基哌啶-2-酮;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)环丙烷羧酸;
2-((3R,5R,6S)-1-((S)-2-(叔丁氧基)-1-环丙基-2-氧代乙基)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-乙氧基-2-氧代乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-羟基乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((1S,2S)-1-环丙基-2-羟基丁基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((1S,2R)-1-环丙基-2-羟基丁基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-甲基环丙烷磺酰氨基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-(环丙烷磺酰氨基)-1-环丙基乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(乙基磺酰氨基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-甲基环丙烷磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((1S,2R)-1-环丙基-2-羟基丙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((1S,2S)-1-环丙基-2-羟基丙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(1-甲基乙基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-1-环丙基-2-(N-甲基环丙烷磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2S,3S)-2-羟基-4-甲基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-环丙基(吡啶-2-基)甲基)-3-甲基-2-氧代哌啶-3-基)乙酸;或
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-环丙基(吡啶-2-基)甲基)-3-甲基-2-氧代哌啶-3-基)乙酸。
在另一方面,本发明提供了选自以下的化合物,或其药学上可接受的盐:
2-(1-(1-叔丁氧基-1-氧代丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-乙氧基-1-氧代丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-乙氧基-4-甲基-1-氧代戊烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-乙氧基-1-氧代戊烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(1-(2-叔丁氧基-1-环丙基-2-氧代乙基)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-羟基丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-羟基乙基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(环丙基甲氧基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-甲氧基丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(2-甲氧基乙氧基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-((1-氰基环丙基)甲氧基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(环丙基甲氧基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-甲氧基丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(2-甲氧基乙氧基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(1-(1-((1-氨基甲酰基环丙基)甲氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(2-羟基-2-甲基丙氧基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-(1,1,1-三氟代-2-羟基戊烷-3-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-吗啉代丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(乙基氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-(1-(2,2,2-三氟乙基氨基)丁烷-2-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-(1-(吡咯烷-1-基)丁烷-2-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-(1-(2-氧代吡咯烷-1-基)丁烷-2-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(1,1-二氧化硫代吗啉代)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-(1-(噻唑-2-基氨基)丁烷-2-基)哌啶-3-基)乙酸;
2-(1-(1-乙酰氨基丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(甲基磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-氰基戊烷-3-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(甲基磺酰基)戊烷-3-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-(1-(吡啶-2-基)戊烷-3-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(乙基氨基)-1-氧代丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(5-甲基-1,3,4-噁二唑-2-基)丙基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(环丁基甲基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-乙基丁基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(环戊基甲基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-((2,2-二甲基环戊基)甲基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(环己基甲基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-丙基哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(环丁基甲基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-异丁基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(环戊基甲基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-(戊烷-3-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酸甲酯;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酰胺;
2-(2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酰氨基)乙酸乙酯;
2-(2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酰氨基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酰肼;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)-N-羟基乙酰胺;
2-(3-(3-氯苯基)-2-(4-氯苯基)-5-(2-(甲基磺酰氨基)-2-氧代乙基)-6-氧代哌啶-1-基)丁酸乙酯;
2-(3-(3-氯苯基)-2-(4-氯苯基)-5-(2-((3-吗啉代丙基)氨基)-2-氧代乙基)-6-氧代哌啶-1-基)丁酸乙酯;
3-((1H-四唑-5-基)甲基)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)哌啶-2-酮;
3-((1,3,4-噁二唑-2-基)甲基)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)哌啶-2-酮;
5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-3-((5-甲基-1,3,4-噁二唑-2-基)甲基)哌啶-2-酮;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)-N-(甲基磺酰基)乙酰胺;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酰胺。
3-((1H-四唑-5-基)甲基)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)哌啶-2-酮;
5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-3-((5-甲基异噁唑-3-基)甲基)哌啶-2-酮;
2-(6-氯代-3′-(3-氯苯基)-1′-(环丙基甲基)-2,6′-二氧代螺[二氢吲哚-3,2′-哌啶-5′-基)乙酸;
2-(5-(3-氯苯基)-6-(5-氯噻吩-2-基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(5-氯噻吩-2-基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-乙氧基-1-氧代丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(1-(1-叔丁氧基-1-氧代丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(环丙基甲氧基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代-3-(2-(吡咯烷-1-基)乙基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-3-(2-吗啉代乙基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-异丙基-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-环丁基-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-环戊基-3-甲基-2-氧代哌啶-3-基)乙酸;
5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-3-((5-氧代-4,5-二氢-1H-1,2,4-三唑-3-基)甲基)-1-(戊烷-3-基)哌啶-2-酮;
5-((5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)甲基)-1,3,4-噁二唑-2(3H)-酮;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)-N-(三氟甲基磺酰基)乙酰胺;
5-(3-氯苯基)-6-(4-氯苯基)-3-((3-羟基-1H-吡唑-5-基)甲基)-3-甲基-1-(戊烷-3-基)哌啶-2-酮;
5-(3-氯苯基)-6-(4-氯苯基)-3-((3-羟基异噁唑-5-基)甲基)-3-甲基-1-(戊烷-3-基)哌啶-2-酮;
5-((5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)甲基)噁唑烷-2,4-二酮;
3-((5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)甲基)-1,2,4-噁二唑-5(4H)-酮;
3-((5-(3-氯苯基)-6-(4-氯苯基)-1-异丙基-3-甲基-2-氧代哌啶-3-基)甲基)-1,2,4-噁二唑-5(4H)-酮;
3-((5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)甲基)-1,2,4-噻二唑-5(4H)-酮;
3-((5-(3-氯苯基)-6-(4-氯苯基)-1-异丙基-3-甲基-2-氧代哌啶-3-基)甲基)-1,2,4-噻二唑-5(4H)-酮;
3-((1H-四唑-5-基)甲基)-5-(3-氯苯基)-6-(4-氯苯基)-1-异丙基-3-甲基哌啶-2-酮;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-2-氧代-1-(戊烷-3-基)哌啶-3-基)乙酸;
5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-3-(甲基磺酰基甲基)-1-(戊烷-3-基)哌啶-2-酮;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(3-环丙基-1,2,4-噁二唑-5-基)丙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-吗啉代丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1-(2,2,2-三氟乙基氨基)丁烷-2-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(2,2-二甲基吗啉代)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(2,6-二甲基吗啉代)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(4-(环丙基磺酰基)哌嗪-1-基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(4-(甲基磺酰基)哌嗪-1-基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(1-(1-(4-乙酰基哌嗪-1-基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(4-(环丙烷羰基)哌嗪-1-基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
3-((5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-吗啉代丁烷-2-基)-2-氧代哌啶-3-基)甲基)-1,2,4-噁二唑-5(4H)-酮;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(5,5-二甲基-2-氧代噁唑烷-3-基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(1-(1-(叔丁基氨基)-1-氧代丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2,3-二羟基环戊基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1′-(2,2,2-三氟乙基)-1,3′-联哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(3-羟基环戊基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(四氢-2H-吡喃-3-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(吡嗪-2-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-甲基-1H-吡唑-4-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(嘧啶-4-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-氯嘧啶-4-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(嘧啶-2-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(3-甲基吡啶-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(4-甲基吡啶-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(二环丙基甲基)-3-甲基-2-氧代哌啶-3-基)乙酸;
(4-(3-氯苯基)-3-(4-氯苯基)-1,1-二氧化-2-(2-丙基)-1,2-噻嗪烷-6-基)乙酸;
(4-(3-氯苯基)-3-(4-氯苯基)-6-甲基-1,1-二氧化-2-(2-丙基)-1,2-噻嗪烷-6-基)乙酸;
2-(5-(3-氯苯基)-6-(5-氯吡啶-2-基)-3-甲基-1-(1-吗啉代丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(5-氯吡啶-2-基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)乙酸;
2-(1-(1-叔丁氧基-1-氧代丁烷-2-基)-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;或
2-(1-(1-叔丁氧基-1-氧代丁烷-2-基)-6-(4-氯苯基)-5-(4-氯吡啶-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸。
在另一方面,本发明提供了选自以下的化合物,或其药学上可接受的盐:
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)丙酸;
2-(3-((1H-四唑-5-基)甲基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁酸叔丁酯;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(甲基磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(5-氧代己烷-3-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(5-羟基-5-甲基己烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(6,6,6-三氟代-5-羟基-5-甲基己烷-3-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(N-甲基甲基磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(5-环丙基-6,6,6-三氟代-5-羟基己烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(6-羟基-6-甲基庚烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(6,6,6-三氟代-5,5-二羟基己烷-3-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(7,7,7-三氟代-6-羟基-6-甲基庚烷-3-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(7-羟基-7-甲基辛烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(N-环丙基甲基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(6,6,6-三氟代-5-羟基己烷-3-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(5-羟基己烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1-(N-(2,2,2-三氟乙基)甲基磺酰氨基)丁烷-2-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(5-羟基-4,5-二甲基己烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(5-氰基-5-甲基己烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(2-氧代戊烷-3-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-羟基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-甲氧基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-羟基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-羟基-2-甲基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(4-羟基己烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-甲氧基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1,1,1-三氟代-2-羟基-2-甲基戊烷-3-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酰胺;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-(甲基磺酰基)乙酰胺;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-(3-羟基丙基)乙酰胺;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-(2-羟基乙基)乙酰胺;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-羟基乙酰胺;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-甲氧基乙酰胺;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-(2,3-二羟基丙基)乙酰胺;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-(2,3-二羟基丙基)乙酰胺;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-氰基乙酰胺;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-(2-(二甲基氨基)乙基)乙酰胺;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-(3,4-二羟基丁基)乙酰胺;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(环丙烷磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)丙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-(环丙烷磺酰氨基)戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(2-(1-甲基乙基磺酰氨基)戊烷-3-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(N-甲基环丙烷磺酰氨基)-1-氧代丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(新戊基氨基)-1-氧代丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(4,4-二甲基-4,5-二氢噁唑-2-基)丙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1-(N-(2,2,2-三氟乙基)乙酰氨基)丁烷-2-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(1,1-二甲基乙基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(N,2-二甲基丙烷-2-基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(1-甲基乙基磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(N-乙基丙烷-2-基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-羟基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1-(三氟甲基磺酰氨基)丁烷-2-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(4-氯苯基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(4-甲基苯基磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(2-氯苯基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(2-甲基苯基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(4-甲氧基苯基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(苯基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(1-甲基环丙烷磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(1,1-二氧化苯并[d]异噻唑-2(3H)-基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(3,3-二甲基-1,1-二氧化苯并[d]异噻唑-2(3H)-基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1-(吡啶-3-磺酰氨基)丁烷-2-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(4-氰基苯基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(3-氰基苯基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1-(吡啶-2-磺酰氨基)丁烷-2-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(N,1-二甲基环丙烷磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
3-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)丙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲氧基-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(6-甲基-4-氧代庚烷-3-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(乙基磺酰基)戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(异丙基磺酰基)戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(环丙基甲基磺酰基)戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1-(2-氧代吡咯烷-1-基)丁烷-2-基)哌啶-3-基)乙酸;
2-(1-(1-(2-氧杂-5-氮杂二环[2.2.1]庚烷-5-基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(3-甲基吗啉代)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(硫代吗啉代-1,1-二氧化物)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(3,3-二氟氮杂环丁烷-1-基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(1-(1-(8-氧杂-3-氮杂二环[3.2.1]辛烷-3-基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(3,3-二甲基吗啉代)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(3-羟基-3-(三氟甲基)氮杂环丁烷-1-基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(甲基(氧杂环丁烷-3-基)氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1-(2-氧代噁唑烷-3-基)丁烷-2-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1-(2-氧代吡啶-1(2H)-基)丁烷-2-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1-(2-氧代-5-(三氟甲基)吡啶-1(2H)-基)丁烷-2-基)哌啶-3-基)乙酸;
3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(吡啶-3-基氧基)丁烷-2-基)哌啶-2-酮;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1-(四氢呋喃-2-基)丙基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1-(5-氧代四氢呋喃-2-基)丙基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1-(四氢-2H-吡喃-2-基)丙基)哌啶-3-基)乙酸;
2-(1-(1-(苯并[d]噻唑-2-基)丙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(3-甲基异噁唑-5-基)丙基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(6-氯吡啶-2-基)丙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1-(吡啶-2-基)丙基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1-(吡啶-2-基)丁基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-环丙基-1-(吡啶-2-基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1-(吡啶-3-基)丙基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1-(吡嗪-2-基)丙基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1-(嘧啶-2-基)丙基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(6-甲基吡啶-2-基)丙基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1-(吡啶-4-基)丙基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1-(6-(三氟甲基)吡啶-2-基)丙基)哌啶-3-基)乙酸;
2-(1-(1-(6-溴吡啶-2-基)丙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1-(噻唑-2-基)丙基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(6-(2-羟基丙烷-2-基)吡啶-2-基)丙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(6-环丙基吡啶-2-基)丙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(3,3,3-三氟代-1-(吡啶-2-基)丙基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(2-甲基-1-(吡啶-2-基)丙基)-2-氧代哌啶-3-基)乙酸;
3-((1H-四唑-5-基)甲基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(戊烷-3-基)哌啶-2-酮;
5-(3-氯苯基)-6-(4-氯苯基)-3-(2,3-二羟基丙基)-1-(2-羟基戊烷-3-基)-3-甲基哌啶-2-酮;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-羟基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)环丙烷羧酸;
2-(1-(2-(叔丁氧基)-1-环丙基-2-氧代乙基)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-乙氧基-2-氧代乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-羟基乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-羟基丁基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(N-甲基环丙烷磺酰氨基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-(环丙烷磺酰氨基)-1-环丙基乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(乙基磺酰氨基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(N-甲基环丙烷磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-羟基丙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(1-甲基乙基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(N-甲基环丙烷磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-羟基-4-甲基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;或
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基(吡啶-2-基)甲基)-3-甲基-2-氧代哌啶-3-基)乙酸。
在另一方面,本发明提供了选自以下的化合物,或其药学上可接受的盐:
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2S,3S)-2-羟基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2R,3S)-2-羟基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二甲基乙基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N,2-二甲基丙烷-2-基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N,1-二甲基环丙烷磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-甲基环丙烷磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((1S,2R)-1-环丙基-2-羟基丙基)-3-甲基-2-氧代哌啶-3-基)乙酸;或
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((1S,2S)-1-环丙基-2-羟基丙基)-3-甲基-2-氧代哌啶-3-基)乙酸。
在另一方面,本发明提供了选自以下的化合物,或其药学上可接受的盐:
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-羟基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-羟基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(1,1-二甲基乙基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(N,2-二甲基丙烷-2-基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(N,1-二甲基环丙烷磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(N-甲基环丙烷磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;或
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-羟基丙基)-3-甲基-2-氧代哌啶-3-基)乙酸。
在另一方面,本发明提供了选自以下的化合物,或其药学上可接受的盐:
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(噻吩-2-磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-甲基噻吩-2-磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-(5-氯噻吩-2-磺酰氨基)-1-环丙基乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-2-(5-氯代-N-甲基噻吩-2-磺酰氨基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-(二氟甲基)-2-甲基丙烷-2-基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-(二氟甲基)乙基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-(二氟甲基)环丙烷磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
1-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-(环丙烷磺酰氨基)-1-环丙基乙基)-3-甲基-2-氧代哌啶-3-基)环丙烷羧酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-(2-氟苯基)乙基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-(2-氟苯基)甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-苯基环丙烷磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-苯基乙基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(乙基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-(3-氟苯基)乙基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-(N-(2-氰基苯基)甲基磺酰氨基)-1-环丙基乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(丙基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-苯基甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-(N-(3-氰基苯基)甲基磺酰氨基)-1-环丙基乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-(吡啶-3-基)甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-(噻吩-2-基甲基)甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-(3-甲氧基苄基)甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(苯基甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(吡啶-2-基甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(吡啶-3-基甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-(吡啶-2-基)甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-乙基甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-异丙基甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(1-甲基乙基磺酰氨基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-(环丁烷磺酰氨基)-1-环丙基乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-(环戊烷磺酰氨基)-1-环丙基乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-3-甲基-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环丙烷磺酰氨基)-3-甲基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(乙基磺酰氨基)-3-甲基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环丁烷磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N-乙基环丁烷磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(苯基磺酰基)丁烷-2-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(甲基磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(丙基磺酰基)丁烷-2-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(异丁基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-((环丙基甲基)磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-((环丁基甲基)磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环戊基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(氧杂环丁烷-3-基磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(((3-甲基氧杂环丁烷-3-基)甲基)磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-((四氢-2H-吡喃-4-基)磺酰基)丁烷-2-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-((2-羟基-2-甲基丙基)磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-1-((R)-仲丁基磺酰基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-1-((S)-仲丁基磺酰基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-(环戊基磺酰基)-1-环丙基乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(((3-甲基氧杂环丁烷-3-基)甲基)磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(苯基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(邻甲苯基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-((2-氯苯基)磺酰基)-1-环丙基乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-((4-氯苯基)磺酰基)-1-环丙基乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-((4-氟苯基)磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(吡啶-4-基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-2-((2-氯代-4-氟苯基)磺酰基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-((环丙基甲基)磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-((2,2,2-三氟乙基)磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-((三氟甲基)磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(苯基磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-((2-氯苯基)磺酰基)-1-环丙基乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-((2-氟苯基)磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-((3-氟苯基)磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-((4-氟苯基)磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(丙基磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-2-(丁基磺酰基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(异戊基磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-(环戊基磺酰基)-1-环丙基乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-(环己基磺酰基)-1-环丙基乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(甲基磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-3-甲基-1-((2,2,2-三氟乙基)磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-1-(叔丁基磺酰基)-3-甲基丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-3-甲基-1-(甲基磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(乙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环丙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(异丙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-1-(叔丁基磺酰基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环丁基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-1-((S)-1-(乙基磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-1-((S)-1-(异丙基磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-1-(叔丁基磺酰基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环丁基磺酰基)丁烷-2-基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环丙基磺酰基)丁烷-2-基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(乙基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(异丙基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-2-(叔丁基磺酰基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-(环丁基磺酰基)-1-环丙基乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(环丙基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(甲基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(叔戊基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-((2,4-二氟苯基)磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(乙基磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(异丙基磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-2-(叔丁基磺酰基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(环丙基磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(乙基磺酰基)-3-甲基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(异丙基磺酰基)-3-甲基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-3,3-二甲基-1-(甲基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(乙基磺酰基)-3,3-二甲基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(异丙基磺酰基)-3,3-二甲基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(戊烷-3-基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-((S)-异丙基亚磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-((R)-异丙基亚磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;极性较大的异构体;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((2S,3S)-2-(甲基磺酰基)戊烷-3-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((2R,3S)-2-(甲基磺酰基)戊烷-3-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2S,3S)-2-(乙基磺酰基)戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2R,3S)-2-(乙基磺酰基)戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-(氧杂环丁烷-3-基)氨磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-((3-甲基氧杂环丁烷-3-基)甲基)氨磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-(氧杂环丁烷-3-基甲基)氨磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-2-(N-(叔丁基)氨磺酰基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-甲基氨磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N,N-二甲基氨磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-异丙基氨磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(吗啉代磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(哌啶-1-基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(吡咯烷-1-基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-2-(氮杂环丁烷-1-基磺酰基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-((N,N-二甲基氨磺酰基)氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-((N,N-二甲基氨磺酰基)(甲基)氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(3-甲基-2,5-二氧代咪唑烷-1-基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(3,4,4-三甲基-2,5-二氧代咪唑烷-1-基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(4,4-二甲基-2,5-二氧代咪唑烷-1-基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(3-异丙基-2,2-二氧化-4-氧代-3,4-二氢-1H-苯并[c][1,2,6]噻二嗪-1-基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-1-基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯代-4-氟苯基)-6-(4-氯苯基)-1-异丙基-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-异丙基-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3S,5R,6S)-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-异丙基-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-((S)-1-(乙基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基乙基磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(甲基磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-((S)-1-(乙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-((S)-1-(环丙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-1-(叔丁基磺酰基)丁烷-2-基)-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-((S)-1-(异丙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-6-(4-氯苯基)-5-(5-氯吡啶-3-基)-1-((S)-1-(环丙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-1-(叔丁基磺酰基)丁烷-2-基)-6-(4-氯苯基)-5-(5-氯吡啶-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-6-(4-氯苯基)-5-(5-氯吡啶-3-基)-1-((S)-1-(环丙烷磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-6-(4-氯苯基)-5-(5-氯吡啶-3-基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-1-((S)-1-(乙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-((S)-吗啉-2-基)丙基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-((R)-吗啉-2-基)丙基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((R)-1-((S)-吗啉-2-基)丙基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((R)-1-((R)-吗啉-2-基)丙基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((R)-1-((R)-吗啉-2-基)丙基)-2-氧代哌啶-3-基)乙酸;
或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((R)-1-((S)-吗啉-2-基)丙基)-2-氧代哌啶-3-基)乙酸;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-3-(2-吗啉代乙基)-2-氧代哌啶-3-基)乙酸;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-(2-(1,1-二氧化硫代吗啉代)乙基)-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代-3-(2-(吡咯烷-1-基)乙基)哌啶-3-基)乙酸;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-(2-(二甲基氨基)乙基)-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-3-(2-吗啉代乙基)-2-氧代哌啶-3-基)乙酰胺;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-3-(2-吗啉代乙基)-2-氧代哌啶-3-基)乙酰胺;
(1R,3S,6S,7R)-7-(3-氯苯基)-6-(4-氯苯基)-5-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-4-氧代-5-氮杂螺[2.5]辛烷-1-羧酸;
(3S,6S,7R)-7-(3-氯苯基)-6-(4-氯苯基)-5-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-4-氧代-5-氮杂螺[2.5]辛烷-1-羧酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2S,3S)-1,2-二羟基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2R,3S)-1,2-二羟基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2R,3S)-1,2-二羟基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2S,3S)-1,2-二羟基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((1S,2S)-1-环丙基-1-羟基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((1R,2S)-1-环丙基-1-羟基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-异丙基-6-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-异丙基-6-甲基-2-氧代哌啶-3-基)乙酸;
(3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-((6-甲氧基吡啶-2-基)甲基)哌啶-2-酮;
(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-((6-甲氧基吡啶-2-基)甲基)哌啶-2-酮;
(3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-((6-羟基吡啶-2-基)甲基)哌啶-2-酮;
(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-((6-羟基吡啶-2-基)甲基)哌啶-2-酮;
(3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-((6-甲氧基吡啶-2-基)甲基)-3-甲基哌啶-2-酮;
(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-((6-甲氧基吡啶-2-基)甲基)-3-甲基哌啶-2-酮;
(3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-((6-羟基吡啶-2-基)甲基)-3-甲基哌啶-2-酮;
(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-((6-羟基吡啶-2-基)甲基)-3-甲基哌啶-2-酮;
(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(乙基磺酰基)乙基)-3-(3-羟基-2-氧代丙基)-3-甲基哌啶-2-酮;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(二乙基氨基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(二甲基氨基)-3-甲基-2-氧代哌啶-3-基)乙酸;或
(2S,3S,5S,6R,7aR,10aS)-6-(3-氯苯基)-5-(4-氯苯基)-3-乙基-2,7a-二甲基六氢呋喃并[2,3-b]噁唑并[3,2-a]吡啶-9(5H)-酮。
在另一方面,本发明提供了选自以下的化合物,或其药学上可接受的盐:
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(噻吩-2-磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(N-甲基噻吩-2-磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-(5-氯噻吩-2-磺酰氨基)-1-环丙基乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(1-(2-(5-氯代-N-甲基噻吩-2-磺酰氨基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(N-(二氟甲基)-2-甲基丙烷-2-基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(N-(二氟甲基)乙基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(N-(二氟甲基)环丙烷磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
1-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-(环丙烷磺酰氨基)-1-环丙基乙基)-3-甲基-2-氧代哌啶-3-基)环丙烷羧酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(N-(2-氟苯基)乙基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(N-(2-氟苯基)甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(N-苯基环丙烷磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(N-苯基乙基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(乙基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(N-(3-氟苯基)乙基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-(N-(2-氰基苯基)甲基磺酰氨基)-1-环丙基乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(丙基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(N-苯基甲基磺酰氨基乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-(N-(3-氰基苯基)甲基磺酰氨基)-1-环丙基乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(N-(吡啶-3-基)甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(N-(噻吩-2-基甲基)甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(N-(3-甲氧基苄基)甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(苯基甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(吡啶-2-基甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(吡啶-3-基甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(N-(吡啶-2-基)甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(N-乙基甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(N-异丙基甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(1-甲基乙基磺酰氨基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-(环丁烷磺酰氨基)-1-环丙基乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-(环戊烷磺酰氨基)-1-环丙基乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(3-甲基-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(环丙烷磺酰氨基)-3-甲基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(乙基磺酰氨基)-3-甲基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(环丁烷磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(N-乙基环丁烷磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1-(苯基磺酰基)丁烷-2-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(甲基磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1-(丙基磺酰基)丁烷-2-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(异丁基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-((环丙基甲基)磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-((环丁基甲基)磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(环戊基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(氧杂环丁烷-3-基磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(((3-甲基氧杂环丁烷-3-基)甲基)磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1-((四氢-2H-吡喃-4-基)磺酰基)丁烷-2-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-((2-羟基-2-甲基丙基)磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(1-(1-(-仲丁基磺酰基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-(环戊基磺酰基)-1-环丙基乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(((3-甲基氧杂环丁烷-3-基)甲基)磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(苯基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(邻甲苯基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-((2-氯苯基)磺酰基)-1-环丙基乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-((4-氯苯基)磺酰基)-1-环丙基乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-((4-氟苯基)磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(吡啶-4-基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(1-(2-((2-氯代-4-氟苯基)磺酰基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-((环丙基甲基)磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-((2,2,2-三氟乙基)磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-((三氟甲基)磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(苯基磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-((2-氯苯基)磺酰基)-1-环丙基乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-((2-氟苯基)磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-((3-氟苯基)磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-((4-氟苯基)磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(丙基磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-(1-(2-(丁基磺酰基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(异戊基磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-(环戊基磺酰基)-1-环丙基乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-(环己基磺酰基)-1-环丙基乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(甲基磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(3-甲基-1-((2,2,2-三氟乙基)磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(1-(1-(叔丁基磺酰基)-3-甲基丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(3-甲基-1-(甲基磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(乙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(环丙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(异丙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(1-(1-(叔丁基磺酰基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(环丁基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-1-(1-(乙基磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-1-(1-(异丙基磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(1-(1-(叔丁基磺酰基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(环丁基磺酰基)丁烷-2-基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(环丙基磺酰基)丁烷-2-基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(乙基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(异丙基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(1-(2-(叔丁基磺酰基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-(环丁基磺酰基)-1-环丙基乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(环丙基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(甲基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(叔戊基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-((2,4-二氟苯基)磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(乙基磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(异丙基磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-(1-((2-(叔丁基磺酰基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(环丙基磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(乙基磺酰基)-3-甲基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(异丙基磺酰基)-3-甲基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(3,3-二甲基-1-(甲基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(乙基磺酰基)-3,3-二甲基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(异丙基磺酰基)-3,3-二甲基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(戊烷-3-基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(异丙基亚磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(2-(甲基磺酰基)戊烷-3-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-(乙基磺酰基)戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(N-(氧杂环丁烷-3-基)氨磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(N-((3-甲基氧杂环丁烷-3-基)甲基)氨磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(N-(氧杂环丁烷-3-基甲基)氨磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(1-(2-(N-(叔丁基)氨磺酰基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(N-甲基氨磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(N,N-二甲基氨磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(N-异丙基氨磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(吗啉代磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(哌啶-1-基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(吡咯烷-1-基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(1-(2-(氮杂环丁烷-1-基磺酰基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-((N,N-二甲基氨磺酰基)氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-((N,N-二甲基氨磺酰基)(甲基)氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(3-甲基-2,5-二氧代咪唑烷-1-基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(3,4,4-三甲基-2,5-二氧代咪唑烷-1-基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(4,4-二甲基-2,5-二氧代咪唑烷-1-基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(3-异丙基-2,2-二氧化-4-氧代-3,4-二氢-1H-苯并[c][1,2,6]噻二嗪-1-基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-1-基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯代-4-氟苯基)-6-(4-氯苯基)-1-异丙基-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-异丙基-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-(1-(乙基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-3-甲基-1-(1-(N-甲基乙基磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-3-甲基-1-(1-(甲基磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-(1-(乙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-(1-(环丙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(1-(1-(叔丁基磺酰基)丁烷-2-基)-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-(1-(异丙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(6-(4-氯苯基)-5-(5-氯吡啶-3-基)-1-(1-(环丙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(1-(1-(叔丁基磺酰基)丁烷-2-基)-6-(4-氯苯基)-5-(5-氯吡啶-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(6-(4-氯苯基)-5-(5-氯吡啶-3-基)-1-(1-(环丙烷磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(6-(4-氯苯基)-5-(5-氯吡啶-3-基)-3-甲基-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(5-氯吡啶-2-基)-1-(1-(乙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(吗啉-2-基)丙基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-3-(2-吗啉代乙基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-(2-(1,1-二氧化硫代吗啉代)乙基)-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代-3-(2-(吡咯烷-1-基)乙基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-(2-(二甲基氨基)乙基)-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-3-(2-吗啉代乙基)-2-氧代哌啶-3-基)乙酰胺;
7-(3-氯苯基)-6-(4-氯苯基)-5-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-4-氧代-5-氮杂螺[2.5]辛烷-1-羧酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1,2-二羟基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-1-羟基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-异丙基-6-甲基-2-氧代哌啶-3-基)乙酸;
5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-((6-甲氧基吡啶-2-基)甲基)哌啶-2-酮;
5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-((6-羟基吡啶-2-基)甲基)哌啶-2-酮;
5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-((6-甲氧基吡啶-2-基)甲基)-3-甲基哌啶-2-酮;
5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-((6-羟基吡啶-2-基)甲基)-3-甲基哌啶-2-酮;
(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(乙基磺酰基)乙基)-3-(3-羟基-2-氧代丙基)-3-甲基哌啶-2-酮;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(二乙基氨基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(二甲基氨基)-3-甲基-2-氧代哌啶-3-基)乙酸;或
6-(3-氯苯基)-5-(4-氯苯基)-3-乙基-2,7a-二甲基六氢呋喃并[2,3-b]噁唑并[3,2-a]吡啶-9(5H)-酮。
在另一方面,本发明提供了选自以下的化合物,或其药学上可接受的盐:
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(甲基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(异丙基磺酰基)-3-甲基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-1-(叔丁基磺酰基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(异丙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(异丙基磺酰基)-3,3-二甲基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(乙基磺酰基)-3-甲基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(乙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-苯基环丙烷磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;或
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-((环丙基甲基)磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸。
在另一方面,本发明提供了选自以下的化合物,或其药学上可接受的盐:
2-(-5-(3-氯苯基)-6-(4-氯苯基)-1-(-1-环丙基-2-(甲基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(-5-(3-氯苯基)-6-(4-氯苯基)-1-(-1-(异丙基磺酰基)-3-甲基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(-1-(-1-(叔丁基磺酰基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(-5-(3-氯苯基)-6-(4-氯苯基)-1-(-1-(异丙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(-5-(3-氯苯基)-6-(4-氯苯基)-1-(-1-(异丙基磺酰基)-3,3-二甲基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(-5-(3-氯苯基)-6-(4-氯苯基)-1-(-1-(乙基磺酰基)-3-甲基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(-5-(3-氯苯基)-6-(4-氯苯基)-1-(-1-(乙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(-5-(3-氯苯基)-6-(4-氯苯基)-1-(-1-环丙基-2-(N-苯基环丙烷磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(-5-(3-氯苯基)-6-(4-氯苯基)-1-(-1-((环丙基甲基)磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(-5-(3-氯苯基)-6-(4-氯苯基)-1-(-1-环丙基-2-(甲基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(-5-(3-氯苯基)-6-(4-氯苯基)-1-(-1-(异丙基磺酰基)-3-甲基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;或
2-(-1-(-1-(叔丁基磺酰基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸。
本发明提供了药物组合物,其包含以上方面或实施方案中的任一个方面或实施方案的化合物,或其药学上可接受的盐,以及药学上可接受的赋形剂、稀释剂或载体。
本发明还提供了治疗需要所述治疗的受试者的癌症的方法,所述方法包括向所述受试者施用有效剂量的根据以上方面或实施方案中的任一个方面或实施方案的化合物,或其药学上可接受的盐。
附图简述
术语“H”表示单一的氢原子。这种基团可以(例如)与氧原子连接形成羟基。
当术语“烷基”单独或者在其他术语如“卤代烷基”或“烷基氨基”内使用时,它包括具有1至约12个碳原子的直链或支链基团。更优选的烷基是具有1至约6个碳原子的“低级烷基”。此类基团的实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、己基等。甚至更优选具有1个或2个碳原子的低级烷基。术语“亚烷基(alkylenyl)”或“亚烷基(alkylene)”包括桥连二价烷基如亚甲基或亚乙基。术语“被R2取代的低级烷基”不包括缩醛半族。术语“烷基”进一步包括这样的烷基,其中该链中的一个或多个碳原子被选自氧、氮或硫的杂原子取代。
术语“烯基”包括具有至少一个碳-碳双键的2至约12个碳原子的直链或支链基团。更优选的烯基是具有2至约6个碳原子的“低级烯基”。最优选的低级烯基是具有2至约4个碳原子的基团。烯基的实例包括乙烯基、丙烯基、烯丙基、丙烯基、丁烯基和4-甲基丁烯基。术语“烯基”和“低级烯基”包括具有“顺式”和“反式”取向或者“E”和“Z”取向的基团。
术语“炔基”表示具有至少1个碳-碳三键且具有2至约12个碳原子的直链或支链基团。更优选的炔基是具有2至约6个碳原子的“低级炔基”。最优选具有2至约4个碳原子的低级炔基。此类基团的实例包括丙炔基,和丁炔基等。
烷基、亚烷基、烯基和炔基可以任选地被一个或多个官能团如卤代、羟基、硝基、氨基、氰基、卤代烷基、芳基、杂芳基,和杂环基等取代。
术语“卤代(halo)”表示卤素如氟、氯、溴或碘原子。
术语“卤代烷基”包括其中任何一个或多个烷基碳原子被如上所定义的卤代取代的基团。特别包括一卤代烷基、二卤代烷基和包括全卤代烷基在内的多卤代烷基。一卤代烷基在该基团内(例如)可以具有碘、溴、氯或氟原子。二卤代和多卤代烷基可以具有两个或更多个相同的卤原子或不同卤代基团的组合。“低级卤代烷基”包括具有1至6个碳原子的基团。甚至更优选具有1至3个碳原子的低级卤代烷基。卤代烷基的实例包括氟甲基、二氟甲基、三氟甲基、氯甲基、二氯甲基、三氯甲基、五氟乙基、七氟丙基、二氟氯甲基、二氯氟甲基、二氟乙基、二氟丙基、二氯乙基和二氯丙基。
术语“全氟烷基”意指全部氢原子都被氟原子替代的烷基。实例包括三氟甲基和五氟乙基。
术语“羟基烷基”包括具有1至约10个碳原子而其中任何一个碳原子可以被一个或多个羟基取代的直链或支链烷基。更优选的羟基烷基是具有1至6个碳原子和一个或多个羟基的“低级羟基烷基”。此类基团的实例包括羟基甲基、羟基乙基、羟基丙基、羟基丁基和羟基己基。甚至更优选具有1至3个碳原子的低级羟基烷基。
术语“烷氧基”包括直链或支链的含有氧基的基团,该每一个基团具有1至约10个碳原子的烷基部分。更优选的烷氧基是具有1至6个碳原子的“低级烷氧基”。此类基团的实例包括甲氧基、乙氧基、丙氧基、丁氧基和叔丁氧基。甚至更优选具有1至3个碳原子的低级烷氧基。烷氧基可以进一步被一个或多个卤原子例如氟、氯或溴取代从而提供“卤代烷氧基”。甚至更优选具有1至3个碳原子的低级卤代烷氧基。此类基团的实例包括氟甲氧基、氯甲氧基、三氟甲氧基、三氟乙氧基、氟乙氧基和氟丙氧基。
单独或组合使用的术语“芳基”意指含有一个或两个环的碳环芳族系统,其中此类环可以稠合的方式连接在一起。术语“芳基”包括芳族基团如苯基、萘基、茚基、四氢萘基和茚满基。更优选的芳基是苯基。“芳基”可以具有1个或多个取代基如低级烷基、羟基、卤代、卤代烷基、硝基、氰基、烷氧基和低级烷基氨基等。被-O-CH2-O-取代的苯基形成芳基苯并二氧杂环戊烯基取代基。
术语“杂环基(heterocyclyl)”(或“杂环基(heterocyclo)”)包括饱和、部分饱和及不饱和的含有杂原子的环基,其中杂原子可以选自氮、硫和氧。它不包括含有-O-O-、-O-S-或-S-S-部分的环。“杂环基”可以具有1至4个取代基如羟基、Boc、卤代、卤代烷基、氰基、低级烷基、低级芳烷基、氧代、低级烷氧基、氨基和低级烷基氨基。
饱和杂环基的实例包括含有1-4个氮原子的饱和3至6元杂单环基[例如吡咯烷基、咪唑烷基、哌啶基、吡咯啉基、哌嗪基];含有1至2个氧原子和1至3个氮原子的饱和3至6元杂单环基[例如吗啉基];含有1至2个硫原子和1至3个氮原子的饱和3至6元杂单环基[例如噻唑烷基]。部分饱和杂环基的实例包括二氢噻吩基、二氢吡喃基、二氢呋喃基和二氢噻唑基。
也称为“杂芳基”的不饱和杂环基的实例包括含有1至4个氮原子的不饱和5至6元杂单环基,例如吡咯基、咪唑基、吡唑基、2-吡啶基、3-吡咬基、4-吡咬基、嘧啶基、吡嗪基、哒嗪基、三唑基[例如,4H-1,2,4-三唑基、1H-1,2,3-三唑基、2H-1,2,3-三唑基];含有氧原子的不饱和5至6元杂单环基,例如吡喃基、2-呋喃基、3-呋喃基等;含有硫原子的不饱和5至6元杂单环基,例如2-噻吩基、3-噻吩基等;含有1至2个氧原子和1至3个氮原子的不饱和5至6元杂单环基,例如噁唑基、异噁唑基、噁二唑基[例如1,2,4-噁二唑基、1,3,4-噁二唑基、1,2,5-噁二唑基];含有1至2个硫原子和1至3个氮原子的不饱和5至6元杂单环基,例如噻唑基、噻二唑基[例如1,2,4-噻二唑基、1,3,4-噻二唑基、1,2,5-噻二唑基]。
术语杂环基还包括其中杂环基与芳基稠合的(fused/condensed)基团:含有1至5个氮原子的不饱和稠合杂环基,例如吲哚基、异吲哚基、中氮茚基、苯并咪唑基、喹啉基、异喹啉基、吲唑基、苯并三唑基、四唑并哒嗪基[例如四唑并[1,5-b]哒嗪基];含有1至2个氧原子和1至3个氮原子的不饱和稠合杂环基[例如苯并噁唑基、苯并噁二唑基];含有1至2个硫原子和1至3个氮原子的不饱和稠合杂环基[例如苯并噻唑基、苯并噻二唑基];以及含有1至2个氧原子或硫原子的饱和、部分不饱和以及不饱和稠合杂环基[例如苯并呋喃基、苯并噻吩基、2,3-二氢-苯并[1,4]二噁英基和二氢苯并呋喃基]。优选的杂环基包括5至10元稠合或未稠合基团。更优选的杂芳基实例包括喹啉基、异喹啉基、咪唑基、吡啶基、噻吩基、噻唑基、噁唑基、呋喃基和吡嗪基。其他优选的杂芳基是含有一个或两个选自硫、氮和氧的杂原子的5或6元杂芳基,其选自噻吩基、呋喃基、吡咯基、吲唑基、吡唑基、噁唑基、三唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、吡啶基、哌啶基和吡嗪基。
含有非氮的杂芳基的具体实例包括吡喃基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、苯并呋喃基,和苯并噻吩基等。
部分饱和以及饱和杂环基的具体实例包括吡咯烷基、咪唑烷基、哌啶基、吡咯啉基、吡唑烷基、哌嗪基、吗啉基、四氢吡喃基、噻唑烷基、二氢噻吩基、2,3-二氢-苯并[1,4]二噁烷基、二氢吲哚基、异二氢吲哚基、二氢苯并噻吩基、二氢苯并呋喃基、异苯并二氢吡喃基、苯并二氢吡喃基、1,2-二氢喹啉基、1,2,3,4-四氢-异喹啉基、1,2,3,4-四氢-喹啉基、2,3,4,4a,9,9a-六氢-1H-3-氮杂-芴基、5,6,7-三氢-1,2,4-三唑并[3,4-a]异喹啉基、3,4-二氢-2H-苯并[1,4]噁嗪基、苯并[1,4]二噁烷基、2,3-二氢-1H-1λ′-苯并[d]异噻唑-6-基、二氢吡喃基、二氢呋喃基和二氢噻唑基等。
术语“杂环基”因而包括以下环系统:
术语“磺酰基”,无论单独使用还是连接至其他术语(例如烷基磺酰基),都是指二价基团-SO2-。
术语“氨磺酰基”、“氨基磺酰基”和“磺酰氨(sulfonamidyl)”,是指被胺基取代从而形成磺酰胺(-SO2NH2)的磺酰基。
术语“烷基氨基磺酰基”包括“N-烷基氨基磺酰基”,其中氨磺酰基独立地被一个或两个烷基取代。更优选的烷基氨基磺酰基是具有1至6个碳原子的“低级烷基氨基磺酰基”。甚至更优选具有1至3个碳原子的低级烷基氨基磺酰基。此类低级烷基氨基磺酰基的实例包括N-甲基氨基磺酰基和N-乙基氨基磺酰基。
术语“羧基”,无论单独使用还是与其他术语一起使用(例如“羧基烷基”),都是指-CO2H。
术语“羰基”,无论单独使用还是与其他术语一起使用(例如“氨基羰基”),都是指-(C=O)-。
术语“氨基羰基”是指式-C(=O)NH2的酰胺基。
术语“N-烷基氨基羰基”和“N,N-二烷基氨基羰基”分别是指独立地被一个或两个烷基取代的氨基羰基。更优选具有连接到氨基羰基上的如上所述的低级烷基的“低级烷基氨基羰基”。
术语“N-芳基氨基羰基"和“N-烷基-N-芳基氨基羰基”分别是指被一个芳基或者一个烷基和一个芳基取代的氨基羰基。
术语“杂环基亚烷基”和“杂环基烷基”包括被杂环取代的烷基。更优选的杂环基烷基是具有1至6个碳原子的烷基部分和5或6元杂芳基的“5或6元杂芳基烷基”。甚至更优选具有1至3个碳原子的烷基部分的低级杂芳基亚烷基。实例包括诸如吡啶基甲基和噻吩基甲基之类的基团。
术语“芳烷基”包括被芳基取代的烷基。优选的芳烷基是具有连接到具有1至6个碳原子的烷基上的芳基的“低级芳烷基”。甚至更优选连接到具有1至3个碳原子的烷基部分上的“苯基亚烷基”。此类基团的实例包括苄基、二苯基甲基和苯基乙基。所述芳烷基中的芳基可以另外被卤代、烷基、烷氧基、卤代烷基和卤代烷氧基取代。
术语“烷硫基”包括含有连接到二价硫原子上的1至10个碳原子的直链或支链烷基的基团。甚至更优选具有1至3个碳原子的低级烷硫基。“烷硫基”的实例是甲硫基(CH3S-)。
术语“卤代烷硫基”包括含有连接到二价硫原子上的1至10个碳原子的卤代烷基的基团。甚至更优选具有1至3个碳原子的低级卤代烷硫基。“卤代烷硫基”的实例是三氟甲硫基。
术语“烷基氨基”包括“N-烷基氨基”和“N,N-二烷基氨基”,其中氨基分别独立地被一个烷基和两个烷基取代。更优选的烷基氨基是具有一个或两个连接到氮原子上的1至6个碳原子的烷基的“低级烷基氨基”。甚至更优选具有1至3个碳原子的低级烷基氨基。适宜的烷基氨基可以是一或二烷基氨基如N-甲基氨基、N-乙基氨基、N,N-二甲基氨基,和N,N-二乙基氨基等。
术语“芳基氨基”是指被一个或两个芳基取代的氨基,例如N-苯基氨基。芳基氨基可以在该基团的芳基环部分上进一步被取代。
术语“杂芳基氨基”是指被一个或两个杂芳基取代的氨基,例如N-噻吩基氨基。“杂芳基氨基”可以在该基团的杂芳基环部分上进一步被取代。
术语“芳烷基氨基”是指被一个或两个芳烷基取代的氨基。更优选苯基-C1-C3-烷基氨基,例如N-苄基氨基。芳烷基氨基可以在芳基环部分上进一步被取代。
术语“N-烷基-N-芳基氨基”和“N-芳烷基-N-烷基氨基”是指氨基分别独立地被一个芳烷基和一个烷基或者一个芳基和一个烷基取代的氨基。
术语“氨基烷基”包括具有1至约10个碳原子而其中任何一个碳原子可以被一个或多个氨基取代的直链或支链烷基。更优选的氨基烷基是具有1至6个碳原子和一个或多个氨基的“低级氨基烷基”。此类基团的实例包括氨基甲基、氨基乙基、氨基丙基、氨基丁基和氨基己基。甚至更优选具有1至3个碳原子的氨基烷基。
术语“烷基氨基烷基”包括被烷基氨基取代的烷基。更优选的烷基氨基烷基是具有1至6个碳原子的烷基的“低级烷基氨基烷基”。甚至更优选具有1至3个碳原子的烷基的低级烷基氨基烷基。适宜的烷基氨基烷基可以是一或二烷基取代的,例如N-甲基氨基甲基、N,N-二甲基-氨基乙基、N,N-二乙基氨基甲基等。
术语“烷基氨基烷氧基”包括被烷基氨基取代的烷氧基。更优选的烷基氨基烷氧基是具有1至6个碳原子的烷氧基的“低级烷基氨基烷氧基”。甚至更优选具有1至3个碳原子的烷基的低级烷基氨基烷氧基。适宜的烷基氨基烷氧基可以是一或二烷基取代的,例如N-甲基氨基乙氧基、N,N-二甲基氨基乙氧基,和N,N-二乙基氨基乙氧基等。
术语“烷基氨基烷氧基烷氧基”包括被烷基氨基烷氧基取代的烷氧基。更优选的烷基氨基烷氧基烷氧基是具有1至6个碳原子的烷氧基的“低级烷基氨基烷氧基烷氧基”。甚至更优选具有1至3个碳原子的烷基的低级烷基氨基烷氧基烷氧基。适宜的烷基氨基烷氧基烷氧基可以是一或二烷基取代的,例如N-甲基氨基甲氧基乙氧基、N-甲基氨基乙氧基乙氧基、N,N-二甲基氨基乙氧基乙氧基、N,N-二乙基氨基甲氧基甲氧基等。
术语“羧基烷基”包括具有1至约10个碳原子而其中任何一个碳原子可以被一个或多个羧基取代的直链或支链烷基。更优选的羧基烷基是具有1至6个碳原子和一个羧基的“低级羧基烷基”。此类基团的实例包括羧基甲基,和羧基丙基等。甚至更优选具有1至3个CH2基团的低级羧基烷基。
术语“卤代磺酰基”包括被卤素基团取代的磺酰基。此类卤代磺酰基的实例包括氯磺酰基和氟磺酰基。
术语“芳基硫基”包括连接到二价硫原子上的6至10个碳原子的芳基。“芳基硫基”的实例是苯基硫基。
术语“芳烷基硫基”包括连接到二价硫原子上的如上所述的芳烷基。更优选苯基-C1-C3-烷硫基。“芳烷硫基”的实例是苄基硫基。
术语“芳基氧基”包括连接到氧原子上的如上所定义的任选取代的芳基。此类基团的实例包括苯氧基。
术语“芳烷氧基”包括通过氧原子与其他基团连接的含有氧基的芳烷基。更优选的芳烷氧基是具有连接到如上所述的低级烷氧基上的任选取代的苯基的“低级芳烷氧基”。
术语“杂芳基氧基”包括连接到氧原子上的如上所定义的任选取代的杂芳基。
术语“杂芳基烷氧基”包括通过氧原子与其他基团连接的含有氧基的杂芳基烷基。更优选的杂芳基烷氧基是具有连接到如上所述的低级烷氧基上的任选取代的杂芳基的“低级杂芳基烷氧基”。
术语“环烷基”包括饱和碳环基团。优选的环烷基包括C3-C6环。更优选的化合物包括环戊基、环丙基和环己基。
术语“环烷基烷基”包括被环烷基取代的烷基。优选的环烷基烷基是具有连接到具有1至6个碳原子的烷基上的环烷基的“低级环烷基烷基”。甚至更优选连接到具有1至3个碳原子上的烷基部分的“5至6元环烷基烷基”。此类基团的实例包括环己基甲基。所述基团中的环烷基可以另外被卤代、烷基、烷氧基和羟基取代。
术语“环烯基”包括具有一个或多个碳-碳双键的碳环基团,包括“环烷基二烯基”化合物。优选的环烯基包括C3-C6环。更优选的化合物包括(例如)环戊烯基、环戊二烯基、环己烯基和环庚二烯基。
术语“包含”是指开放式的,包括指出的组分但不排除其他成分。
替代氢原子的基团或原子也称为取代基。
任何特定分子或基团可以具有一个或多个取代基,这取决于可被替代的氢原子的数目。
符号“–”代表共价键并且也可以在基团中用来指示与另一个基团的连接点。在化学结构中,该符号常用于表示分子中的甲基。
术语“治疗有效量”是指改善、减轻或消除特定疾病或病状的一个或多个症状,或者预防或延迟特定疾病或病状的一个或多个症状发作的化合物的量。
术语“患者”和“受试者”可以互换地使用,并且意指动物如狗、猫、牛、马、羊和人。具体的患者是哺乳动物。术语患者包括雄性和雌性患者。
术语“药学上可接受的”意指所提及的物质(如式I化合物,或式I化合物的盐,或含有式I化合物或特定赋形剂的制剂)适合于施用予患者。
术语“治疗(treating)”、“治疗(treat)”或“治疗(treatment)”等包括预防性治疗(例如预防疾病的治疗)和姑息性治疗。
术语“赋形剂”意指不同于通常包括的用于配制和/或施用予患者的活性药物成分(API)的任何药学上可接受的添加剂、载体、稀释剂、佐剂,或其他成分。
本发明化合物以治疗有效量施用予患者。该化合物可以单独地施用或作为药学上可接受的组合物或制剂的一部分来施用。另外,该化合物或组合物可以例如通过推注一次性地施用、通过例如系列片剂来多次施用,或者例如施用透皮递送来在一段时间内基本上均一地递送。还要注意,该化合物的剂量可以随时间变化。
另外,本发明化合物可以单独地施用、与本发明其他化合物联合施用,或者与其他药物活性化合物联合施用。所述其他药物活性化合物可旨在治疗与本发明化合物治疗的疾病或病状相同或不同的疾病或病状。如果患者将接受或正接受多种药物活性化合物,则该化合物可以同时或相继施用。例如,在片剂的情况下,该活性化合物可以存在于一个片剂中或存在于分开的片剂中,所述分开的片剂可以一次性施用或以任何顺序相继施用。另外,应认识到该组合物可以为不同形式。例如,一种或多种化合物可以经由片剂递送,而另一种化合物经由注射施用或作为糖浆口服施用。考虑了所有组合、递送方法和施用顺序。
术语“癌症”意指以不受调节的细胞生长为特征的哺乳动物的生理病状。癌症的一般类别包括癌、淋巴瘤、肉瘤,和母细胞瘤。
本发明化合物可以用于治疗癌症。治疗癌症的方法包括向需要它的患者施用治疗有效量的式I、IA、IB、IC、ID或IE化合物,或其药学上可接受的盐。
本发明化合物可以用于治疗肿瘤。治疗肿瘤的方法包括向需要它的患者施用治疗有效量的式I、IA、IB、IC、ID或IE化合物,或其药学上可接受的盐。
本发明还涉及本发明化合物在制造用于治疗诸如癌症的病状的药品中的用途。
可用本发明化合物治疗的癌症包括(而不限于)癌如膀胱癌、乳腺癌、结肠癌、直肠癌、肾癌、肝癌、肺癌(小细胞肺癌和非小细胞肺癌)、食道癌、胆囊癌、卵巢癌、胰腺癌、胃癌、宫颈癌、甲状腺癌、前列腺癌和皮肤癌(包括鳞状细胞癌);淋巴谱系造血系统肿瘤(包括白血病、急性淋巴细胞性白血病、慢性骨髓性白血病、急性成淋巴细胞性白血病、B-细胞淋巴瘤、T-细胞淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、毛细胞淋巴瘤和伯基特淋巴瘤(Burkett′s lymphoma));骨髓谱系造血系统肿瘤(包括急性和慢性骨髓性白血病、骨髓发育不良综合征和前髓细胞白血病);间充质起源的肿瘤(包括纤维肉瘤和横纹肌肉瘤以及其他肉瘤,例如软组织肉瘤和骨肉瘤);中枢和外周神经系统的肿瘤(包括星形细胞瘤、成神经细胞瘤、胶质瘤和神经鞘瘤);以及其他肿瘤(包括黑素瘤、精原细胞瘤、畸胎瘤、骨肉瘤、着色性干皮病(xenoderoma pigmentosum)、角化棘皮瘤(keratoctanthoma)、甲状腺滤泡状癌和卡波西肉瘤)。可用本发明化合物治疗的其他癌症包括子宫内膜癌、头部和颈部癌、胶质母细胞瘤、恶性腹水,和造血系统癌症。
可用本发明化合物治疗的具体癌症包括软组织肉瘤、骨癌(如骨肉瘤)、乳腺肿瘤、膀胱癌、Li-Fraumeni综合征、脑肿瘤、横纹肌肉瘤、肾上腺皮质癌、结肠直肠癌、非小细胞肺癌,和急性骨髓性白血病(AML)。
在涉及癌症治疗的本发明具体实施方案中,该癌症被鉴定为p53野生型(p53WT)。在另一个具体实施方案中,该癌症被鉴定为p53WT和CDKN2A突变体。在另一方面,本发明提供了用于确定哪些患者应施用本发明化合物的诊断。例如,可以获取患者癌细胞样品并进行分析以相对于p53和/或CDKN2A确定该癌细胞的状态。在一方面,在相对于p53突变的癌症的患者中选出患有p53WT癌症的患者用于治疗。在另一方面,将为p53WT并且具有突变体CDNK2A蛋白的癌症的患者从不具有这些特征的患者中选出。分析用癌细胞的获取是本领域技术人员熟知的。术语“p53WT”意指由基因组DNA序列no.NC_000017version 9(7512445..7531642)(GenBank)编码的蛋白质;由cDNA序列no.NM_000546(GenBank)编码的蛋白质;或具有GenBank序列no.NP_000537.3的蛋白质。术语“CDNK2A突变体”意指不属于野生型的CDNK2A蛋白质。术语“CDKN2A野生型”意指由基因组DNA序列no.9:21957751-21984490(EnsemblID)编码的蛋白质;由cDNA序列no.NM_000077(GenBank)或NM_0581959GenBank)编码的蛋白质或;或具有GenBank序列no.NP_000068或NP_478102的蛋白质。
本发明化合物也可用于治疗过度增殖性病症如甲状腺增生症(尤其是Grave病),和囊肿(如卵巢间质血管过多,这是多囊卵巢综合症(Stein-Leventhal综合征)的特征)。
本发明化合物也可用于治疗以下疾病或病状:哮喘、慢性阻塞性肺疾病(COPD)、肺气肿、银屑病、接触性皮炎、结膜炎、变态反应性鼻炎、全身性红斑狼疮(SLE)、溃疡性结肠炎、克罗恩氏病(Crohn’s disease)、多发性硬化症、类风湿性关节炎、炎性肠疾病、阿尔茨海默氏病(Alzheimer’s disease)、动脉粥样硬化和亨廷顿氏病(Huntington’s disease)。
本发明化合物还可用于治疗炎性疾病、缺氧、溃疡、病毒感染、细菌感染,和细菌性败血症。
式I、IA、IB、IC、ID或IE化合物或其药学上可接受的盐也可以与一种或多种另外的药物活性化合物/药物活性剂联合施用。在具体实施方案中,所述另外的药物活性剂是可用于治疗癌症的药剂。例如,另外的药物活性剂可以选自抗肿瘤剂、抗血管生成剂、化疗剂和肽性癌症治疗剂。在又一个实施方案中,抗肿瘤剂选自抗生素型药剂、烷化剂、抗代谢物药剂、激素药剂、免疫学药剂、干扰素-型药剂、激酶抑制剂、混杂(miscellaneous)药剂和它们的组合。注意,另外的药物活性化合物/药物活性剂可以是传统的小有机化学分子或者可以是诸如蛋白质、抗体、肽体、DNA、RNA的大分子或此类大分子的片段。
可用于癌症治疗以及可与本发明的一种或多种化合物联合使用的特定药物活性剂的实例包括:氨甲蝶呤(methotrexate);他莫昔芬(tamoxifen);氟尿嘧啶(fluorouracil);5-氟尿嘧啶(5-fluorouracil);羟基脲(hydroxyurea);巯基嘌呤(mercaptopurine);顺铂(cisplatin);卡铂(carboplatin);柔红霉素(daunorubicin);多柔比星(doxorubicin);依托泊苷(etoposide);长春花碱(vinblastine);长春新碱(vincristine);紫杉醇(pacitaxel);硫鸟嘌呤(thioguanine);伊达比星(idarubicin);更生霉素(dactinomycin);伊马替尼(imatinib);吉西他滨(gemcitabine);六甲蜜胺(altretamine);天门冬酰胺酶(asparaginase);博莱霉素(bleomycin);卡培他滨(capecitabine);卡莫司汀(carmustine);cladisatNaCl水溶液;环磷酰胺(cyclophosphamine);阿糖胞苷(cytarabine);达卡巴嗪(decarazine);多西他赛(docetaxel);伊达比星(idarubicin);异环磷酰胺(ifosfamide);伊立替康(irinotecan);氟达拉滨(fludarabine);丝裂霉素(mitosmycin);米托坦(mitoxane);米托蒽醌(mitoxantrone);拓扑替康(topotecan);长春瑞滨(vinorelbine);阿霉素(adriamycin);米拉霉(mithram);咪喹莫特(imiquimod);阿仑珠单抗(alemtuzmab);依西美坦(exemestane);贝伐珠单抗(bevacizumab);西妥昔单抗(cetuximab);阿扎胞苷(azacitidine);氯法拉滨(clofarabine);地西他滨(decitabine);达沙替尼(desatinib);右丙亚胺(dexrazoxane);多西他赛(docetaxel);表柔比星(epirubicin);奥沙利铂(oxaliplatin);厄洛替尼(erlotinib);雷洛昔芬(raloxifene);氟维司群(fulvestrant);来曲唑(letrozole);吉非替尼(gefitinib);吉妥珠单抗(gemtuzumab);曲妥珠单抗(trastuzumab);吉非替尼(gefitinib);伊沙匹隆(ixabepilone);拉帕替尼(lapatinib);来那度胺(lenalidomide);氨基酮戊酸(aminolevulinic acid);替莫唑胺(temozolomide);奈拉滨(nelarabine);索拉非尼(sorafenib);尼洛替尼(nilotinib);培门冬酶(pegaspargase);培美曲塞(pemetrexed);利妥昔单抗(rituximab);达沙替尼(dasatinib);萨立多胺(thalidomide);蓓萨罗丁(bexarotene);替西罗莫司(temsirolimus);硼替佐米(bortezomib);伏立诺他(vorinostat);卡培他滨(capecitabine);唑来膦酸(zoledronic acid);阿那曲唑(anastrozole);舒尼替尼(sunitinib);阿瑞吡坦(aprepitant)和奈拉滨(nelarabine),或其药学上可接受的盐。
可用于癌症治疗以及可与本发明的一种或多种化合物联合使用的另外的药物活性剂包括:血管内皮生长因子(VEGF)抑制剂、肝细胞生长因子/散射因子(HGF/SF)抑制剂、血管生成素1和/或2抑制剂、肿瘤坏死因子相关细胞凋亡诱导配体(TRAIL)激动剂、重组人apo2配体(TRAIL)、胰岛素样生长因子1类受体(IGFR-1)抑制剂、cFMS抑制剂、HER2抑制剂、c-met抑制剂、极光激酶抑制剂、CDK 4和/或6抑制剂,和B-raf抑制剂。
可用于癌症治疗以及可与本发明的一种或多种化合物联合使用的进一步的另外的药物活性剂包括抗体药物缀合物(ADC),其中结合至蛋白质的抗体(优选在癌细胞上)使用连接体与对癌细胞有害的化学化合物缀合。对癌细胞有害的化学化合物的实例包括类美登素衍生物和奥雷司他汀(auristatin)衍生物。
可用于癌症治疗以及可与本发明的一种或多种化合物联合使用的更进一步的另外的药物活性剂包括:阿法依泊汀(epoetin alfa);阿法达依泊汀(darbepoetin alfa);帕尼单抗(panitumumab);聚乙二醇非格司亭(pegfilgrastim);帕利夫明(palifermin);非格司亭(filgrastim);德尼单抗(denosumab);安西司亭(ancestim);AMG 102;AMG 319;AMG386;AMG 479(盖尼塔单抗(Ganitumab));AMG 511、AMG900、AMG 655(可那木单抗(Conatumumab));AMG 745;AMG 951;以及AMG 706(莫特塞尼(Motesanib)),或其药学上可接受的盐。
在另一方面,本发明涉及本发明化合物与一种或多种作为磷脂酰肌醇3-激酶(PI3K)途径中的蛋白质的抑制剂的药剂的联合使用。本发明化合物与PI3K途径中的蛋白质的抑制剂的联合已经在癌细胞生长测定中显示出协同作用,包括增强细胞凋亡和细胞杀伤。PI3K途径中的蛋白质的实例包括PI3K、mTOR和PKB(也称为Akt)。PI3K蛋白质以包括α、β、δ或γ在内的数种同工型存在。考虑到可与本发明化合物联合使用的PI3K抑制剂可对一种或多种同工型有选择性。选择性意指该化合物相对于其他同工型更强地抑制一种或多种同工型。选择性是本领域人员熟知的概念,并且可以在体外或基于细胞的测定中利用熟知的活性测量。优选的选择性包括相对于其他同工型而言对一种或多种同工型具有高出超过2倍(优选10倍,或更优选100倍)的选择性。在一方面,可与本发明化合物联合使用的PI3K抑制剂是PI3Kα选择性抑制剂。在另一方面,该化合物是PI3K δ选择性抑制剂。
可与本发明的一种或多种化合物联合使用的PI3K抑制剂的实例包括以下文献中公开的那些:PCT申请公布号WO2010/151791、PCT申请公布号WO2010/151737、PCT申请公布号WO2010/151735、PCT申请公布号WO2010151740、PCT申请公布号WO2008/118455、PCT申请公布号WO2008/118454、PCT申请公布号WO2008/118468、美国申请公布号US20100331293、美国申请公布号US20100331306、美国申请公布号US20090023761、美国申请公布号US20090030002、美国申请公布号US20090137581、美国申请公布号US2009/0054405、美国申请公布号U.S.2009/0163489、美国申请公布号US2010/0273764、美国申请公布号U.S.2011/0092504,或PCT申请公布号WO2010/108074。
用于与本发明化合物联合使用的优选PI3K抑制剂包括:
,或其药学上可接受的盐。
还优选下式IIa化合物,或其药学上可接受的盐,
其中X1为氟或氢;Y1为氢或甲基;并且Z1为氢或甲基。
既抑制PI3K,又抑制mTOR的化合物(双重抑制剂)是已知的。在又一方面,本发明提供了PI3K和mTOR双重抑制剂在与本发明化合物的联合使用中的应用。
mTOR是PI3K途径中的蛋白质。本发明的另一方面将mTOR抑制剂与本发明的一种或多种化合物联合使用。可与本发明化合物联合使用的mTOR抑制剂包括在以下文献中公开的那些:PCT申请公布号WO2010/132598或PCT申请公布号WO2010/096314。
PKB(Akt)也是PI3K途径中的蛋白质。本发明的另一方面将mTOR抑制剂与本发明的一种或多种化合物联合使用。可与本发明化合物联合使用的PKB抑制剂包括以下文献中公开的那些:美国专利号7,354,944、美国专利号7,700,636、美国专利号7,919,514、美国专利号7,514,566、美国专利申请公布号US 2009/0270445A1、美国专利号7,919,504、美国专利号7,897,619,或PCT申请公布号WO2010/083246A1。
本发明化合物可与CDK4和/或6抑制剂联合使用。可与本发明化合物联合使用的CDK 4和/或6抑制剂包括以下文献中公开的那些:PCT申请公布号WO 2009/085185或美国专利申请公布号US2011/0097305。
本发明化合物也可以与治疗恶心的药物活性剂联合使用。可用于治疗恶心的药剂的实例包括:屈大麻酚(dronabinol)、格拉司琼(granisetron)、甲氧氯普胺(metoclopramide)、昂丹司琼(ondansetron),和丙氯拉嗪(prochlorperazine),或其药学上可接受的盐。
另外,本发明化合物可以与可用于治疗诸如以下的癌症的其他药剂联合使用:醋孟南(acemannan)、阿柔比星(aclarubicin)、阿地白介素(aldesleukin)、阿利维A酸(alitretinoin)、阿米斯丁(amifostine)、氨柔比星(amrubicin)、安吖啶(amsacrine)、阿那格雷(anagrelide)、阿格拉宾(arglabin)、三氧化二砷(arsenic trioxide)、BAM 002(Novelos)、比卡鲁胺(bicalutamide)、溴尿苷(broxuridine)、西莫白介素(celmoleukin)、西曲瑞克(cetrorelix)、克拉屈滨(cladribine)、克霉唑(clotrimazole)、DA3030(Dong-A)、达利珠单抗(daclizumab)、地尼白介素(denileukin diftitox)、地洛瑞林(deslorelin)、地拉齐普(dilazep)、二十二烷醇(docosanol)、度骨化醇(doxercalciferol)、去氧氟尿苷(doxifluridine)、溴隐亭(bromocriptine)、阿糖胞苷(cytarabine)、HIT双氯芬酸(HIT diclofenac)、干扰素α、维甲酸(tretinoin)、依地福新(edelfosine)、依决可单抗(edrecolomab)、依氟鸟氨酸(eflornithine)、乙嘧替氟(emitefur)、表柔比星(epirubicin)、倍他依泊汀(epoetin beta)、磷酸依托泊苷(etoposide phosphate)、依昔舒林(exisulind)、法倔唑(fadrozole)、非那雄胺(finasteride)、磷酸氟达拉滨(fludarabine phosphate)、福美坦(formestane)、福莫司汀(fotemustine)、硝酸镓(gallium nitrate)、吉妥珠单抗奥佐米星(gemtuzumabzogamicin)、吉美嘧啶(gimeracil)/奥替拉西(oteracil)/替加氟(tegafur)组合、格尼可品(glycopine)、戈舍瑞林(goserelin)、庚铂(heptaplatin)、人绒毛膜促性腺激素、人胎儿α胎蛋白、伊班膦酸(ibandronic acid)、干扰素α、天然干扰素α、干扰素α-2、干扰素α-2a、干扰素α-2b、干扰素α-N1、干扰素α-n3、复合α(alfacon-1)干扰素、天然干扰素α、干扰素β、干扰素β-1a、干扰素β-1b、天然干扰素γ、干扰素γ-1a、干扰素γ-1b、白介素-1β、碘苄胍(iobenguane)、伊索拉定(irsogladine)、兰瑞肽(lanreotide)、LC9018(Yakult)、来氟米特(leflunomide)、来格司亭(lenograstim)、硫酸香菇多糖(lentinan sulfate)、来曲唑(letrozole)、白细胞α干扰素、亮丙瑞林(leuprorelin)、左旋咪唑+氟尿嘧啶(levamisole+fluorouracil)、利阿唑(liarozole)、洛铂(lobaplatin)、氯尼达明(lonidamine)、洛伐他汀(lovastatin)、马索罗酚(masoprocol)、美拉胂醇(melarsoprol)、甲氧氯普胺(metoclopramide)、米非司酮(mifepristone)、米替福新(miltefosine)、米立司亭(mirimostim)、错配双链RNA、米托胍腙(mitoguazone)、二溴卫矛醇(mitolactol)、米托蒽醌(mitoxantrone)、莫拉司亭(molgramostim)、那法瑞林(nafarelin)、钠洛酮+喷他佐辛(naloxone+pentazocine)、那托司亭(nartograstim)、奈达铂(nedaplatin)、尼鲁米特(nilutamide)、诺斯卡品(noscapine)、新红细胞生成刺激蛋白(novel erythropoiesisstimulating protein)、NSC 631570奥曲肽(octreotide)、奥普瑞白介素(oprelvekin)、奥沙特隆(osaterone)、紫杉醇(paclitaxel)、帕米膦酸(pamidronic acid)、聚乙二醇干扰素α-2b、戌聚糖聚硫酸钠(pentosan polysulfate sodium)、喷司他丁(pentostatin)、溶链菌(picibanil)、吡柔比星(pirarubicin)、家兔抗胸腺细胞多克隆抗体、聚乙二醇干扰素α-2a、卟吩姆钠(porfimer sodium)、雷替曲塞(raltitrexed)、拉布立酶(rasburicase)、依替膦酸铼Re 186、RII维甲酰胺(retinamide)、罗莫肽(romurtide)、来昔决南(lexidronam)钐(153Sm)、沙格司亭(sargramostim)、西佐喃(sizofiran)、索布佐生(sobuzoxane)、索纳明(sonermin)、氯化锶-89、苏拉明(suramin)、他索纳明(tasonermin)、他扎罗汀(tazarotene)、替加氟(tegafur)、替莫泊芬(temoporfin)、替尼泊苷(teniposide)、四氯十氧化物(tetrachlorodecaoxide)、胸腺法新(thymalfasin)、促甲状腺素α、托瑞米芬(toremifene)、托西莫单抗(tositumomab)-碘131、曲奥舒凡(treosulfan)、维甲酸(tretinoin)、曲洛司坦(trilostane)、三甲曲沙(trimetrexate)、曲普瑞林(triptorelin)、天然肿瘤坏死因子α、乌苯美司(ubenimex)、膀胱癌疫苗、Maruyama疫苗、黑色素瘤裂解物疫苗、戊柔比星(valrubicin)、维替泊芬(verteporfin)、维鲁利秦(virulizin)、净司他丁斯酯(zinostatin stimalamer)、阿巴瑞克(abarelix)、AE 941(Aeterna)、氨莫司汀(ambamustine)、反义寡核苷酸、bcl-2(Genta)、APC 8015(Dendreon)、右旋氨格鲁米特(dexaminoglutethimide)、地吖醌(diaziquone)、EL 532(Elan)、EM 800(Endorecherche)、恩尿嘧啶(eniluracil)、依他硝唑(etanidazole)、维甲酰酚胺(fenretinide)、非格司亭(filgrastim)SD01(Amgen)、加洛他滨(galocitabine)、促胃液素17免疫原、HLA-B7基因疗法(Vical)、粒细胞巨噬细胞集落刺激因子、二盐酸组胺、替伊莫单抗(ibritumomab tiuxetan)、伊洛马司他(ilomastat)、IM 862(Cytran)、白介素-2、伊丙昔芬(iproxifene)、LDI 200(Milkhaus)、来立司亭(leridistim)、林妥珠单抗(lintuzumab)、CA 125单克隆抗体(MAb)(Biomira)、癌MAb(Japan Pharmaceutical Development)、HER-2和Fc MAb(Medarex)、个体基因型105AD7MAb(CRC Technology)、个体基因型CEAMAb(Trilex)、LYM-1-碘131MAb(Techniclone)、多形态上皮粘蛋白-钇90MAb(Antisoma)、马立马司他(marimastat)、美诺立尔(menogaril)、米妥莫单抗(mitumomab)、莫特沙芬钆(motexafin gadolinium)、MX 6(Galderma)、诺拉曲塞(nolatrexed)、P 30蛋白、培维索孟(pegvisomant)、泊非霉素(porfiromycin)、普啉司他(prinomastat)、RL 0903(Shire)、卢比替康(rubitecan)、沙铂(satraplatin)、苯基乙酸钠(sodium phenylacetate)、膦门冬酸(sparfosic acid)、SRL 172(SRPharma)、SU 5416(Pfizer)、TA 077(Tanabe)、四硫钼酸盐(tetrathiomolybdate)、厚果唐松草碱(thaliblastine)、促血小板生成素、乙基锡初紫红素(tin ethyl etiopurpurin)、替拉扎明(tirapazamine)、癌症疫苗(Biomira)、黑素瘤疫苗(NewYorkUniversity)、黑素瘤疫苗(Sloan Kettering Institute)、黑素瘤溶癌物(oncolysate)疫苗(New York Medical College)、病毒性黑色素瘤细胞裂解物疫苗(RoyalNewcastle Hospital),或伐司朴达(valspodar)。注意,上面列举的药剂在适当的时候也可以作为药学上可接受的盐施用。
本发明化合物也可以与放射治疗、激素治疗、手术治疗和免疫治疗联合使用,所述治疗是本领域技术人员熟知的。
因为本发明的一方面考虑了利用可分开施用的药物活性化合物联合治疗所述疾病/病状,因此本发明进一步涉及将分开的药物组合物以试剂盒形式组合。该试剂盒包含两种分开的药物组合物:本发明化合物和第二药物化合物。该试剂盒包含用于容纳分开的组合物的容器(如分开的瓶或分开的箔包装)。容器的另外的实例包括注射器、盒和袋。通常,该试剂盒包括分开组分的使用说明书。当所述分开的组分优选以不同剂型施用(例如口服和肠胃外施用)、以不同的给药间隔施用,或者当处方医生或兽医需要滴定组合中的各种组分的剂量时,试剂盒形式是特别有利的。
此种试剂盒的实例是所谓的泡罩包装。泡罩包装是包装工业中熟知的,并且被广泛地用于包装药物单位剂型(片剂、胶囊剂等)。泡罩包装一般由覆盖着优选透明的塑料材料箔的相对坚硬的材料的薄片组成。在包装过程中,在塑料箔中形成凹陷。凹陷具有待包装的片剂或胶囊剂的大小和形状。接着,将片剂或胶囊剂置于凹陷中,并在与形成凹陷的方向相反的箔面上用相对坚硬的材料的薄片密封该塑料箔。结果片剂或胶囊剂被密封在塑料箔与薄片之间的凹陷中。优选地,薄片的强度使得通过用手在凹陷上施加压力,由此在薄片的凹陷处形成开口,可将片剂或胶囊剂从泡罩包装中取出。然后可经由所述开口取出片剂或胶囊剂。
可能需要在试剂盒上提供记忆帮助,例如采取紧靠片剂或胶囊剂的数字的形式,借此该数字与所指定的片剂或胶囊剂应当被服用的用药方案的天数一致。此种记忆帮助的另一个实例是在卡片上印刷的日历,例如如下“第一周,星期一、星期二……等等……,第二周,星期一、星期二……”等。记忆帮助的其他变型是显而易见的。“日剂量”可以是在给定日需要服用的一个片剂或胶囊剂或几个丸剂或胶囊剂。此外,本发明化合物的日剂量可以由一个片剂或胶囊剂组成,而第二化合物的日剂量可以由数个片剂或胶囊剂组成,反之亦然。记忆帮助应当反映这一点并且帮助纠正活性剂的施用。
在本发明的另一个具体实施方案中,提供了设计用来以其预期使用顺序一次一个地配送日剂量的配送器。优选给配送器装配记忆帮助,以进一步促进对给药方案的顺应性。此种记忆帮助的实例是指明已配送的日剂量数目的机械计数器。此种记忆帮助的另一个实例是电池供电的微芯片存储器,该存储器与液晶读数或声音提醒信号耦合连接,所述信号(例如)读出上一个日剂量的服用日期和/或在要服用下一个剂量时提醒人们。
需要时,本发明化合物和其他药物活性化合物可以经口服、直肠、肠胃外(例如,静脉内、肌肉内或皮下)、脑池内、阴道内、腹膜内、膀胱内、局部(例如粉剂、膏剂或滴剂),或作为口腔或鼻腔喷雾剂施用给患者。考虑了施用药物活性剂的领域中技术人员使用的所有方法。
适合于肠胃外注射的组合物可以包含生理学上可接受的无菌水溶液或非水溶液、分散体、混悬液或乳液,以及用于重构成无菌可注射溶液或分散体的无菌粉末。适宜的水性和非水性载体、稀释剂、溶剂或溶媒的实例包括:水、乙醇、多元醇(丙二醇、聚乙二醇、甘油等)、其适宜的混合物、植物油(如橄榄油)和可注射的有机酯如油酸乙酯。(例如)通过使用包衣(如卵磷脂),在分散体的情况下通过维持所需粒度,和通过使用表面活性剂,可以维持适当的流动性。
这些组合物也可以含有佐剂,例如防腐剂、湿润剂、乳化剂和分散剂。通过添加多种抗细菌剂和抗真菌剂(例如对羟基苯甲酸酯、氯丁醇、苯酚、山梨酸等)可防止微生物污染。可能还需要引入等渗剂,例如糖类、氯化钠等。通过使用延缓吸收的试剂(如单硬脂酸铝和明胶),可延长可注射药物组合物的吸收。
用于口服施用的固体剂型包括胶囊剂、片剂、粉剂和颗粒剂。在此类固体剂型中,活性化合物与至少一种惰性常规赋形剂(或载体)(如柠檬酸钠或磷酸二钙)或(a)填充剂或增量剂,例如淀粉、乳糖、蔗糖、甘露糖醇和硅酸;(b)粘合剂,例如羧甲基纤维素、藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如甘油;(d)崩解剂,例如琼脂、碳酸钙、马铃薯或木薯淀粉、藻酸、某些复合硅酸盐,和碳酸钠;(a)溶液阻滞剂,例如石蜡;(f)吸收促进剂,例如季铵类化合物;(g)湿润剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如高龄土和膨润土;以及(i)润滑剂,例如滑石、硬脂酸钙、硬脂酸镁、固态聚乙二醇、月桂基硫酸酯钠或它们的混合物混合。在胶囊剂和片剂的情况下,剂型也可以包含缓冲剂。
使用诸如乳糖或奶糖以及高分子量聚乙二醇等赋形剂时,相似类型的固体组合物也可以在软质或硬质填充明胶胶囊中用作填充剂。
固体剂型,如片剂、糖衣丸、胶囊剂、丸剂和颗粒剂可以被制备成带有包衣或外壳,如肠溶衣和本领域熟知的其他包衣。它们还可以含有遮光剂,并且还可以为这样的组合物,其在肠道的一定部位以延缓的方式释放一种或多种活性化合物。可使用的包埋式组合物的实例是聚合物和蜡。在适当的时候,活性化合物也可以为含有一种或多种上述赋形剂的微包囊形式。
用于口服施用的液体剂型包括药物学上可接受的乳剂、溶液剂、混悬剂、糖浆剂和酏剂。除了活性化合物之外,液体剂型还可以含有本领域常用的惰性稀释剂(如水或其他溶剂)、增溶剂和乳化剂,例如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、二甲基甲酰胺、油类,特别是棉籽油、花生油、玉米胚芽油、橄榄油、蓖麻油,和芝麻籽油、甘油、四氢糠醇、聚乙二醇、脱水山梨糖醇的脂肪酸酯,或这些物质的混合物等。
除了此类惰性稀释剂,该组合物还可以包括佐剂,如湿润剂、乳化剂和悬浮剂、甜味剂、调味剂和芳香剂。除了活性化合物之外,混悬剂还可以含有悬浮剂,例如乙氧基化异硬脂醇、聚氧乙烯山梨糖醇和脱水山梨糖醇酯、微晶纤维素、偏氢氧化铝(aluminummetahydroxide)、膨润土、琼脂,和黄芪胶,或这些物质的混合物等。
用于直肠施用的组合物优选为栓剂,其可以通过将本发明化合物与适宜的无剌激性的赋形剂或载体如可可油、聚乙二醇或栓剂用蜡混合来制备,所述适宜的无剌激性的赋形剂或载体在常温下为固态但在体温下为液态,因此在直肠或阴道腔内融化并且释放活性组分。
用于本发明化合物局部施用的剂型包括膏剂、粉剂、喷雾剂和吸入剂。在无菌条件下将活性化合物或适合的(fit)化合物与生理学上可接受的载体和可能需要的任何防腐剂、缓冲剂或抛射剂混合。眼科制剂、眼用膏剂、粉剂和溶液剂也被考虑为在本发明的范围内。
本发明化合物可以以约0.1mg/天至约3,000mg/天范围内的剂量水平施用给患者。对于体重为约70kg的正常成人,约0.01mg/千克体重至约100mg/千克体重的范围内的剂量通常是充足的。可使用的具体剂量和剂量范围取决于许多因素,包括患者的要求、受治疗的病状或疾病的严重性,和所施用化合物的药理活性。对于特定患者的剂量范围和最优剂量的确定在本领域普通技术人员的能力范围之内。
本发明化合物可以作为药学上可接受的盐、酯、酰胺或前药施用。术语“盐”是指本发明化合物的无机和有机盐。该盐可以在化合物的最终的分离和纯化期间原位制得,或者可通过单独地以游离碱或酸形式的纯化化合物与适宜的有机或无机碱或酸反应,并分离出由此形成的盐来制得。代表性的盐包括氢溴酸盐、盐酸盐、硫酸盐、硫酸氢盐、硝酸盐、乙酸盐、草酸盐、棕榈酸盐、硬脂酸盐、月桂酸盐、硼酸盐、苯甲酸盐、乳酸盐、磷酸盐、甲苯磺酸盐、柠檬酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、萘甲酸盐(naphthylate)、甲磺酸盐、葡庚糖酸盐、乳糖酸盐,和月桂基磺酸酯盐(laurylsulphonate salt)等。该盐可以包括基于碱金属和碱土金属的阳离子,例如钠离子、锂离子、钾离子、钙离子、镁离子等,以及无毒的铵、季铵和胺阳离子,包括(但不限于)铵、四甲基铵、四乙基铵、甲基胺、二甲基胺、三甲基胺、三乙基胺、乙基胺等。参见(例如)S.M.Berge,等人,"Pharmaceutical Salts,"JPharmSci,66:1-19(1977)。
本发明化合物的药学上可接受的酯的实例包括C1-C8烷基酯。可接受的酯也包括C5-C7环烷基酯,以及芳基烷基酯(如苄基酯)。经常使用C1-C4烷基酯。本发明化合物的酯可以根据本领域中熟知的方法制备。
本发明化合物的药学上可接受的酰胺的实例包括衍生自氨、C1-C8烷基伯胺,和C1-C8二烷基仲胺的酰胺。在仲胺的情况下,该胺也可以为含有至少一个氮原子的5或6元杂环烷基形式。经常使用衍生自氨、C1-C3烷基伯胺和C1-C2二烷基仲胺的酰胺。本发明化合物的酰胺可以根据本领域技术人员熟知的方法制备。
术语“前药”意指在体内被转化从而产生本发明化合物的化合物。该转化可以通过多种机制发生,如通过在血液中水解发生。前药的使用的讨论提供在Higuchi和W.Stella,"Prodrugs as Novel Delivery Systems,"Vol.14of the A.C.S.Symposium Series,和Bioreversible Carriers in Drug Design,ed.Edward B.Roche,AmericanPharmaceutical Association and Pergamon Press,1987中。
为了说明这一点,如果本发明化合物含有羧酸官能团,则前药可以包含通过用诸如以下的基团替代酸基团的氢原子而形成的酯:(C1-C8)烷基、(C2-C12)烷酰基氧甲基、具有4至9个碳原子的1-(烷酰基氧基)乙基、具有5至10个碳原子的1-甲基-1-(烷酰基氧基)乙基、具有3至6个碳原子的烷氧基羰基氧甲基、具有4至7个碳原子的1-(烷氧基羰基氧基)乙基、具有5至8个碳原子的1-甲基-1-(烷氧基羰基氧基)乙基、具有3至9个碳原子的N-(烷氧基羰基)氨基甲基、具有4至10个碳原子的1-(N-(烷氧基羰基)氨基甲基、3-酞基(phthalidyl)、4-巴豆酸内酯基、γ-丁内酯-4-基、二-N,N-(C1-C2)烷基氨基(C2-C3)烷基(如β-二甲基氨基乙基)、氨基甲酰基-(C1-C2)烷基、N,N-二(C1-C2)烷基氨基甲酰基-(C1-C2)烷基和哌啶子基-(C2-3)烷基、吡咯烷子基-(C2-3)烷基或吗啉代(C2-3)烷基。
类似地,如果本发明化合物包含醇官能团,则前药可以通过用诸如以下的基团替代醇基团的氢原子来形成:(C1-C6)烷酰基氧甲基、1-((C1-C6)烷酰基氧基)乙基、1-甲基-1-((C1-C6)烷酰基氧基)乙基、(C1-C6)烷氧基羰基氧甲基、N-(C1-C6)烷氧基羰基氨基甲基、琥珀酰基、(C1-C6)烷酰基、α-氨基(C1-C4)烷酰基、芳基酰基和α-氨基酰基,或α-氨基酰基-α-氨基酰基,其中每个α-氨基酰基均独立地选自天然存在的L-氨基酸、–P(O)(OH)2、–P(O)(O(C1-C6)烷基)2或糖基(通过将半缩醛形式的碳水化合物的羟基除去而形成的基团)。
本发明化合物可以含有不对称或手性中心,并因此可以以不同的立体异构形式存在。考虑到,该化合物的所有立体异构形式以及它们的混合物(包括外消旋混合物)形成本发明的一部分。另外,本发明考虑了所有几何和位置异构体。例如,如果该化合物含有双键,则考虑顺式和反式形式(分别指定为S和E)以及混合物。
根据它们的物理化学性质差异,通过已知的方法(例如通过色谱法和/或分步结晶法),可将立体异构体混合物(如非对映异构体混合物)分离为其单独的立体化学组分。对映异构体可通过如下方式分离:通过与合适的光学活性化合物(例如醇)反应将对映异构体混合物转化成非对映异构体混合物,分离出非对映异构体并将单独的非对映异构体转化(例如水解)成相应的纯对映异构体。此外,一些化合物可以是阻转异构体(例如取代的联芳基)。
本发明化合物可以以未溶剂化形式以及被药学上可接受的溶剂如水(水合物)、乙醇等溶剂化的形式存在。本发明考虑了并包括溶剂化和未溶剂化形式。
本发明化合物也有可能可以不同的互变异构体形式存在。考虑了本发明化合物的所有互变异构体。例如,四唑半族的所有互变异构形式都包括在本发明内。此外,例如,该化合物的所有酮-烯醇或亚胺-烯胺形式都包括在本发明内。
本领域技术人员将会认识到本文包含的化学名称和结构可以基于化合物的特定互变异构体。虽然可能使用了仅针对特定互变异构体的名称或结构,但是意图所有互变异构体都包括在本发明内,除非另外说明。
还意图本发明包括使用实验室技术(例如合成化学工作者熟知的技术)在体外合成的化合物,或者使用体内技术(例如通过代谢、发酵、消化等)合成的化合物。还考虑到,本发明化合物可以使用体外和体内技术的组合合成。
本发明还包括同位素标记的化合物,它们与本文列举的化合物相同,但是有一个或多个原子被原子质量或质量数不同于通常在自然界中发现的原子质量或质量数的原子替代。可掺入到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,例如2H、3H、13C、14C、15N、16O、17O、18O、31P、32P、35S、18F,和36Cl。在一方面,本发明涉及其中一个或多个氢原子被氘(2H)原子取代的化合物。
含有前述同位素和/或其他原子的其他同位素的本发明化合物在本发明的范围内。本发明的某些同位素标记的化合物,例如掺入放射性同位素(如3H和14C)的化合物可用于药物和/或底物组织分布测定。氚化(即3H)和碳-14(即14C)同位素由于易于制备和检测而是特别优选的。进一步地,用较重的同位素(例如氘,即2H)取代可获得某些由较强的代谢稳定性所带来的治疗方面的优点,例如增加体内半衰期或降低剂量需求,并因此在某些情况下可能是优选的。本发明的同位素标记的化合物一般可以通过用容易获得的同位素标记的试剂替代非同位素标记的试剂来制备。
本发明化合物可以以包括结晶状态在内的多种固体状态形式和作为无定形状态存在。本发明化合物的不同的结晶状态(也称为多晶型),和无定形状态被考虑为本发明的一部分。
在合成本发明化合物时,可能需要使用某些离去基团。术语“离去基团”(“LG”)一般是指可被亲核试剂取代的基团。此类离去基团是本领域中已知的。离去基团的实例包括(但不限于)卤化物(halide)(例如,I、Br、F、Cl)、磺酸酯基(例如甲磺酸酯基、甲苯磺酸酯基)、硫化物(sulfide)(例如SCH3)、N-羟基琥珀酰亚胺、N-羟基苯并三唑等。亲核试剂的实例包括(但不限于)胺类、硫醇类、醇类、格氏试剂、阴离子物质(例如,醇盐、酰胺、负碳离子)等。
本文列举的所有专利、公布的专利申请和其他出版物都以引用的方式并入本文。
下面提供的实施例举例说明了本发明的具体实施方案。这些实施例是代表性实施例,并不意图以任何方式限制权利要求的范围。除非另外说明,否则当本文针对固体使用百分比时,该百分比是针对所提到的固体组合物的重量百分比。当本文针对液体使用百分比时,该百分比是针对所提到的溶液的体积百分比。
通常在以500.13MHz的1H频率运转、装配有带有z-轴梯度的Bruker 5mm PABBI探头的Bruker Avance III 500光谱仪系统(Bruker,Bilerica,MA)上,或者在以400.23MHz的1H频率运转、装配有带有z-轴梯度的Bruker 5mm PABBO探头的Bruker Avance II 400光谱仪上获得1H-NMR谱。通常将样品溶解在500μL DMSO-d6或CD3OD中用于NMR分析。1H化学位移以来自DMSO-d6的在δ2.50处和来自CD3OD的在δ3.30处的残留溶剂信号作为参考。
列出显著峰,且其通常包括:质子数、多重性(s,单峰;d,二重峰;dd,双二重峰;t,三重峰;q,四重峰;m,多重峰;br s,宽单峰)和以Hertz为单位的耦合常数。
通常在Agilent Technologies 6140Quadrupole LC/MS质谱仪上记录电子电离(EI)质谱。质谱结果报道为质量与电荷的比率,其后面有时带有每个离子的相对丰度(在圆括号中)。下面实施例中的原料通常要么从商业来源如Sigma-Aldrich,St.Louis,MO获得,要么经由文献程序获得。
本文中可使用以下缩写:
~ 约
+ve或pos.ion 正离子
Δ 加热
Ac 乙酰基
Ac2O 乙酸酐
aq 含水
AcOH 乙酸
Bn 苄基
Boc 叔丁氧羰基
BSA 牛血清清蛋白
Bu 丁基
Bz 苯甲酰基
Calcd或Calc’d 计算值
Conc. 浓
CSA 樟脑-10-磺酸
d 天
1,8-二氮杂双环[5.4.0]十一碳
DBU
-7-烯
DCE 二氯乙烷
DCM 二氯甲烷
DEA 二乙胺
Dess-Martin过碘烷(periodinane); 1,1,1-三乙酰氧基-1,1-二氢-1,2-
Dess-Martin试剂 苯并碘氧杂戊环-3-(1H)-酮
DIEA或DIPEA 二异丙基乙胺
DMAP 4-二甲基氨基吡啶
DME 1,2-二甲氧基乙烷
DMF N,N-二甲基甲酰胺
DMSO 二甲基亚砜
dr 非对映异构体比率
DTT 二硫代苏糖醇
DVB 二乙烯基苯
N-乙基-N’-(3-二甲基氨基丙基)
EDC
碳二亚胺
eq 当量
ESI或ES 电喷雾电离
Et 乙基
Et2O 乙醚
Et3N 三乙胺
EtOAc 乙酸乙酯
EtOH 乙醇
g 克
h 小时
O-(7-氮杂苯并三唑-1-
HATU 基)-N,N,N’,N’-四甲基脲六氟磷
酸酯
O-苯并三唑-N,N,N′,N′-四甲基
HBTU
脲六氟磷酸酯
Hex 己烷
HMPA 六甲基磷酰胺
HOAt 1-羟基-7-氮杂苯并三唑
HOBt 羟基苯并三唑
HPLC 高压液相色谱
IPA或iPrOH 异丙醇
氧化铬(IV)和硫酸在水中的溶
Jones试剂
液
KHMDS 六甲基二硅烷重氮钾
KOAc 乙酸钾
LCMS、LC-MS或LC/MS 液相色谱质谱
LDA 二异丙基氨基锂
LHMDS或LiHMDS 六甲基二硅烷重氮锂
三仲丁基硼氢化锂
(Sigma-Aldrich,St.Louis)
M 摩尔(mol L-1)
m/z 质量除以电荷
mCPBA 间氯过氧苯甲酸
Me 甲基
MeCN 乙腈
MeI 碘甲烷
MeOH 甲醇
mg 毫克
min 分钟
mL 毫升
M 摩尔
MS 质谱
MsCl 甲烷磺酰氯
MTBE或MtBE 甲基叔丁基醚
m/z 质量与电荷的比率
NaHMDS 六甲基二硅烷重氮钠
NaOtBu 叔丁醇钠
NBS N-溴代琥珀酰亚胺
nBuLi 正丁基锂
NMO N-甲基吗啉-N-氧化物
NMP 1-甲基-2-吡咯烷酮
NMR 核磁共振
三仲丁基硼氢化钠
(Sigma-Aldrich,St.Louis)
PBS 磷酸盐缓冲盐水
PMB 对甲氧基苄基
Pr 丙基
ppm 百万分之...
rac 外消旋
RP-HPLC或RPHPLC 反相高压液相色谱
RT或rt 室温
sat.或sat’d或satd 饱和
SFC 超临界流体色谱
TBAF 四丁基氟化铵
TBDMS 叔丁基二甲基甲硅烷基
TBDMS-Cl 叔丁基二甲基氯甲硅烷
TBDPS 叔丁基二苯基甲硅烷基
(2,2,6,6-四甲基哌啶-1-基)氧化
TEMPO
物
tert或t 叔
TFA 三氟乙酸
THF 四氢呋喃
TIPS 三异丙基甲硅烷基
TLC 薄层色谱
三甲基甲硅烷基或三甲基甲硅
TMS
烷
TPAP 四丙基过钌酸铵
tR 保留时间
tBuOH 叔丁醇
v/v 体积/体积
实施例
一般合成方案
一般可以从商购获得的原料开始,且使用本领域技术人员已知的合成技术制备本发明化合物。下面概述了适合于制备本发明化合物的一些反应方案。进一步的例证在下面提供的具体实施方案中给出。
方案1
如方案1中所示,其中Ra和Rb都为H的本发明化合物可以通过如下方式制备:使适当取代的芳基乙酸1与芳基羧酸2在有机溶剂或溶剂混合物(包括含水混合物)中在碱(如LHMDs或KHMDS)的存在下反应,从而在后处理后得到式3化合物。在碱(如tBuOK)的存在下用丙烯酸甲酯处理3,形成4,5-取代的5-氧代戊酸酯,其可在适宜的溶剂(如THF、乙醚或二甲氧基乙烷)中用还原剂(如NaBH4或LiBEt3H)还原从而产生外消旋化合物4。进而可以从4获得5,其方法是将该醇转化成甲苯磺酸酯、甲烷磺酸酯,或三氟甲烷磺酸酯,接着使该酯与叠氮化钠在适宜的溶剂(如DMF、DME或丙酮)中反应。该叠氮化物可用包括NaBH4、H2在内的许多还原剂和催化剂,三苯基膦和三甲基膦还原成伯胺,该伯胺在用碱(例如在含有适宜有机溶剂如THF的含水混合物中的LiOH、K2CO3或NaHCO3)处理后将进而环化成哌啶-2-酮6。外消旋6的各个对映异构体可以通过手性HPLC使用(例如) OD-H 20mm I.D.×250mm柱(Daicel Chemical Industries LTD,Fort Lee,NJ)用40%异丙醇/己烷作为洗脱剂来进行分离。
方案2
如方案2中所示,哌啶-2-酮6可以例如通过用本领域普通技术人员熟知的方法将氮芳基化或烷基化来进一步修饰。例如,在碱(如氢化钠)的存在下在溶剂(如DME、DMF或THF)中使6与卤代烷反应将实现这种转化。7可以通过如下方式进一步烷基化:在适宜溶剂(如THF)中用碱(如二异丙基氨基锂或六甲基二硅烷重氮锂)处理,接着与烷化剂(如卤代烷、甲烷磺酸烷基酯、三氟甲烷磺酸烷基酯,或甲苯磺酸烷基酯)反应从而得到中间体8。如果需要,可以重复该操作顺序从而得到通式9的化合物。LG为离去基团。
如方案3中所示,连接至氮的基团可以潜在地除去从而得到中间体16。例如用TFA处理2,4-二甲氧基苄基衍生物可实现此种转化。类似的转化有着详细的记载(参见例如P.G.M.Wuts和T.W.Greene,“Greene’s protective groups in organic synthesis”,第4版,John Wiley&Sons,NewYork,(2007))。再次使16经受与上述烷基化条件相似的烷基化条件将得到17。
方案3
如方案3中进一步所示,如果其中一个烷基含有双键,则可以用本领域普通技术人员已知的许多方法将这个双键转化成羧酸11。例如,使10与含有KMnO4或RuCl3的高碘酸盐溶液(参见例如R.U.Lemieux,E.von Rudloff,Can.J.Chem.,38,1703,(1955))反应将实现这种转化。羧酸11可以用本领域普通技术人员熟知的方法进而转化成其他基团(如酰胺或酰肼)。例如,可通过例如使用二环己基碳二亚胺(DCC)或类似碳二亚胺试剂或多种多样的试剂如开发用于形成肽键的试剂使羧酸11与包括羟基苯并三唑(HOBt)和N-羟基琥珀酰亚胺(HOSu)在内的多种偶联试剂缩合来活化羧酸11。此类反应的条件是本领域普通技术人员熟知的。然后可以使活化的中间体(例如HOBt酯或HOSu酯)与多种多样的亲核试剂(如胺或醇)缩合。
方案3示出通过这种操作顺序将式11化合物转化成酰胺12。使用氨作为亲核试剂,获得化合物13。酰胺13脱水成腈14可以通过多种方法实现。五氧化二磷是用于这种反应的常用脱水剂,但许多其他脱水剂是本领域技术人员已知的(参见例如R.C.Larock;Comprehensive Organic Transformations,第2版,John Wiley&Sons,New York,pp.1983,(1999))。该腈可以进而转化成其他基团(如四唑),这通过使该腈与叠氮化物(如叠氮化钠、叠氮化锂或叠氮酸)在溶剂(如DMF或水)中反应来实现。
方案4
如方案4中所示,也可以使用酸11用本领域普通技术人员熟知的方法制备杂环衍生物,例如,[1,3,4]-噁二唑18、[1,2,4]-噁二唑-5(4H)-酮19,和[1,2,4]-噁二唑20。例如,将酸11转化成二酰基酰肼,接着用碱在高温下处理将得到18。在另一个实施例中,如方案3中所述将11转化成腈,用羟胺处理该腈。在碱(如DBU)的存在下与1,1’-羰基二咪唑反应,产生19。在又一个实施例中,使11与N-羟基甲脒衍生物在1,1’-羰基二咪唑的存在下反应,接着用四丁基氟化铵处理从而得到20。
方案5
如方案5中所示,也可以将式16化合物二羟基化从而得到21。在第二氧化剂(如4-甲基吗啉-4-氧化物)的存在下在适宜的溶剂中的四氧化锇将实现此种转化。21可以通过在酸(如甲烷磺酸、对甲苯磺酸或樟脑磺酸)的存在下与丙酮或2,2-二甲氧基丙烷反应而转化成22。然后可以采用本领域普通技术人员熟知的多种方法将22N-芳基化或N-烷基化,例如,在碱(如丁基锂或氢化钠)的存在下在溶剂(如DME、DMF或THF)中用卤代烷、甲烷磺酸烷基酯或甲苯磺酸烷基酯处理化合物22。在水的存在下用酸(如HCl或H2SO4)处理23将产生二醇24,可以用多种氧化剂(如高碘酸或四乙酸铅)将该二醇裂解成醛25(参见,例如,Haines,A.H.Methods for the Oxidation of Organic Compounds,Vol 2.;p 277,AcademicPress,NY,(1988))。可以用包括CrO3或含RuCl3的高碘酸盐溶液在内的强氧化剂将醛25转化成酸26。
方案6
方案6示出用于制备通式结构35的中间化合物的替代方法。这个中间体可用来制备本发明中另外的化合物。在这里,通式28的(4S,5S)-2-烯丙基-2-氯代-3,4-二甲基-5-苯基-1,3,2-氧氮硅杂环戊烷通过使27(如J.Am.Chem.Soc.124,7920,(2002)中所述制备)在Grubbs催化剂的存在下与烯烃反应来制备。与亚胺29的反应将产生化合物30(还可参见J.Am.Chem.Soc.129,14552,(2007)),其中亚胺29通过使用本领域技术人员熟知的条件使2-(氨基甲基)苯酚与醛反应来制备。中间体30可以进而转化成化合物31,这通过使中间体30连续地与乙酸酐在碱(如三乙胺、甲苯磺酸和乙二酰氯)的存在下在丙二醇的存在下反应来实现,如Org.Letters,11,433,(2009)中所描述的。高烯丙基胺31可以任选地进一步修饰,例如通过用本领域普通技术人员熟知的方法将氮芳基化或烷基化来进行。例如,31与酮或醛在还原剂(如硼氢化钠、氰基硼氢化钠或三乙酰氧基硼氢化钠)的存在下在溶剂(如DME、DMF或THF)中的反应将实现这种转化。32可以用本领域普通技术人员熟知的条件酰化或磺酰化从而产生33。33可以通过环合复分解(RCM)反应环化成34。适合于此类转化的催化剂是本领域技术人员已知的(参见,例如,(a)Grubbs,R.H.Handbook of Metathesis;Wiley-VCH:Weinheim,(2003);(b)Angew.Chem.,Int.Ed.,42,1900,(2003)),并包括Grubbs1代催化剂和Grubbs2代催化剂。例如,通过使用(例如)钯、铂或铱催化剂在诸如DCM、THF、甲醇的溶剂,或含有醇或THF作为共溶剂的含水混合物中催化氢化34来还原双键,从而产生化合物35。
方案7
本发明化合物也可以经由方案7中示出的内酯路线制备。可以使芳基苄基酮3(商购获得或者通过Dieckmann缩合或通过使芳基甲基酮41与溴芳基化合物42偶联制备)与包括甲基丙烯酸酯、乙基丙烯酸等在内的丙烯酸酯43缩合从而形成酮酸酯44。利用硼氢化钠在甲醇中进行立体选择性还原从而形成外消旋的45,其为在Re位置上的差向异构体的混合物。或者,可以经由动态动力学拆分进行这种还原(参见,Chen,等人,OrganicProcessResearch&Development,2007,11,616-623和其中包含的参考文献)从而得到对映异构体富集的46,其也为在R”位置上的差向异构体的混合物。在这个过程中,通过酯交换反应产生异丙基酯。水解成羧酸47,接着内酯化,产生外消旋或对映异构体富集的内酯48,其为在Re位置上的非对映异构体的混合物。将该混合物形式的非对映异构体用强碱(如LiHMDS或LDA)烯醇化从而得到常见的烯醇化物,将该烯醇化物用烯丙基溴烷基化从而得到内酯49,为单一对映异构体。(参见实施例261步骤E)。将外消旋内酯49与对映体纯的氨基醇50缩合,产生非对映异构的羟基酰胺51,该羟基酰胺可以转化成噁唑啉52、噁唑啉盐53或羟基内酰胺54。非对映异构体的分离一般可以采用正相硅胶色谱法对这些中间体中的任一中间体进行。或者,对映异构体富集的内酯49与对映异构体富集的氨基醇50的缩合导致所得的51、52、53或54的对映体纯度增加。例如,94%ee的内酯与98%ee的氨基醇的组合形成99.94%ee的主要非对映异构体。
羟基内酰胺54(R5=Et,cPr)已通过替代程序(参见实施例91步骤B;和实施例252步骤A)制备并用作本发明许多化合物的中间体(等效于方案3中的内酰胺10)。使用内酯程序,可以制备另外的实例(R5=iPr[实施例261,步骤H],tBu,等)。另外,可以将含有两个相邻的立体中心(即R6不为H)的氨基醇整合到这个路线中。噁唑啉盐53也是多用途的中间体。它可以被多种亲核试剂(如叠氮化物、硫醇或亚磺酸盐)截断从而形成内酰胺56,导致产生胺、酰胺、磺酰胺和砜。可以将噁唑啉盐53的烯丙基氧化至羧酸氧化态,使得来自连缀在噁唑啉环中的伯醇或仲醇中心的复杂性(complication)最小。由此产生的原酰胺(orthoamide)57在温和的水解条件下释放内酰胺羧酸盐58。因此组合内酯49[R3=pClPh,R4=mClPh,Re=Me]和(2S,3S)-3-氨基戊-2-醇[WO2007/110649A2]。通过利用钼酸铵作为催化剂在Dean-Stark条件下在甲苯中进行脱水来形成相应的噁唑啉52[R3=pClPh,R4=mClPh,Re=Me R5=Et,R6=Me]。于-50℃下在含有二甲基吡啶的二氯甲烷中用三氟甲磺酸酐处理,得到噁唑啉盐53[R3=pClPh,R4=mClPh,Re=Me R5=Et,R6=Me]。用四丁基氯化铵促进的在二氯甲烷/水中的KMnO4进行氧化,在后处理并用在乙酸异丙酯中的碳酸氢钠在70℃下水解后得到化合物58[R3=pClPh,R4=mClPh,Re=Me R5=Et,R6=Me],其与在实施例152中制备的材料相同。
实施例1
2-((3R,5R,6S)-1-((S)-1-叔丁氧基-1-氧代丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-3-基)乙酸
步骤A. 2-(3-氯苯基)-1-(4-氯苯基)乙酮
在-78℃下用超过1h的时间向2-(3-氯苯基)乙酸(10g,58.6mmol)在THF(58ml)中的溶液中缓慢地加入117mL 1M双(三甲基甲硅烷基)氨基钠在THF中的溶液。在-78℃下搅拌40min后,用超过10min的时间加入4-氯苯甲酸甲酯(10g,58.6mmol)在THF(35ml)中的溶液。将反应物在-78℃下搅拌3h,然后让其升温至25℃,并再搅拌2h直至完成。用饱和NH4Cl水溶液淬灭反应物,并在减压下除去大部分THF。用乙酸乙酯(2×100ml)萃取残余物。用NaCl饱和溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并浓缩滤液。将产物从乙醚/戊烷中重结晶从而得到本标题化合物,为白色固体。
步骤B. 4-(3-氯苯基)-5-(4-氯苯基)-5-氧代戊酸甲酯
在0℃下用超过20min的时间向52.1g(197mmol)2-(3-氯苯基)-1-(4-氯苯基)乙酮(实施例1,步骤A)和丙烯酸甲酯(19.5ml,216mmol)在360mL THF中的溶液中缓慢地加入20mL 1M叔丁醇钾在THF中的溶液(保持反应溶液温度<10℃)。让反应物升温至室温。在室温下搅拌1h后,在减压下浓缩反应物,用水稀释并用乙酸乙酯萃取。用NaCl饱和溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并浓缩滤液。通过硅胶快速色谱法(洗脱剂:15%EtOAc/己烷)纯化残余物,得到本标题化合物,为物无色液体。R为CH3。
步骤C. (4S,5S)-4-(3-氯苯基)-5-(4-氯苯基)-5-羟基戊酸甲酯和(4R,5R)-4-(3-氯苯基)-5-(4-氯苯基)-5-羟基戊酸甲酯
在0℃下将硼氢化钠(8058mg,213mmol)分成几个小部分加入到75.1g(213mmol)4-(3-氯苯基)-5-(4-氯苯基)-5-氧代戊酸甲酯(实施例1,步骤B)在MeOH(0.71L,c=0.3M)中的溶液中。在0℃下搅拌30min后,用冰冷的H2O淬灭反应混合物,在减压下浓缩,并用EtOAc萃取。洗涤(NaCl饱和水溶液)组合的有机层,经Na2SO4干燥,过滤,并浓缩滤液。通过硅胶快速色谱法(洗脱剂:20%至30%EtOAc/己烷,梯度洗脱)纯化残余物,得到本标题化合物的外消旋混合物,为无色液体。
步骤D. (4S,5R)-5-叠氮基-4-(3-氯苯基)-5-(4-氯苯基)戊酸甲酯和(4R,5S)-5-叠氮基-4-(3-氯苯基)-5-(4-氯苯基)戊酸甲酯
在0℃下用超过10min的时间向63.1g(179mmol)(4S,5S)-4-(3-氯苯基)-5-(4-氯苯基)-5-羟基戊酸甲酯和(4R,5R)-4-(3-氯苯基)-5-(4-氯苯基)-5-羟基戊酸甲酯(实施例1,步骤C)和三乙胺(49.8ml,357mmol)在DCM(600mL,0.3M)中的溶液中逐滴加入甲烷磺酰氯(18ml,232mmol)。将反应物在0℃下搅拌40min并通过TLC监测反应的完成。然后用冰冷的水淬灭反应物,萃取(3×DCM),并用NaCl饱和水溶液洗涤。干燥(Na2SO4)合并的有机层,并在减压下浓缩。
将上面合成的粗甲磺酸酯溶解在DMF(350mL,0.5M)中,并将叠氮化钠(58g,893mmol)分几个部分加入。将该混合物加热至100℃并且在100℃下搅拌30min后,将反应混合物冷却至室温,用水稀释并用EtOAc萃取。洗涤(NaCl饱和水溶液)合并的有机层,经Na2SO4干燥,过滤,并浓缩滤液。通过硅胶快速色谱法(洗脱剂:5%至20%EtOAc/己烷,梯度洗脱)纯化残余物,得到本标题化合物,为无色液体。
步骤E. (5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)哌啶-2-酮
向45.9g(121mmol)5-叠氮基-4-(3-氯苯基)-5-(4-氯苯基)戊酸甲酯(实施例1,步骤D)在THF/H2O(4:1,375mL)中的溶液中加入152mL 1M三甲基膦在THF(152mmol)中的溶液。在25℃下搅拌1h后,在减压下除去大部分THF。碱化(冰冷的2M LiOH)残余物,并用二氯甲烷萃取产物。用NaCl饱和溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液从而得到白色固体。
将该固体溶解在MeOH/NaHCO3饱和水溶液(4:1,2.4L,c=0.05M)中,并将反应物加热至回流达3h。在减压下除去多余的有机溶剂,用水稀释残余物并对残余物进行萃取(2×10%MeOH/DCM)。用NaCl饱和溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液从而得到反式-5-(3-氯苯基)-6-(4-氯苯基)哌啶-2-酮,为立体异构体的混合物。通过手性HPLC(流速:在 OD-H 20mm I.D.×250mm,5mic柱(Daicel Inc.,Fort Lee,NJ)上18ml/min,使用40%异丙醇/己烷作为洗脱剂)分离单个立体异构体,从而得到本标题化合物(tR=8.2min),为白色固体。
[α]D=+158(T=23.4℃,c=1.12,MeOH);1H NMR(400MHz,氯仿-d)δppm 7.21(2H,d,J=8.2Hz),7.09–7.19(3H,m),7.04–7.01(1H,m),6.97(2H,d,J=8.2Hz),6.80–6.77(1H,m),5.83(1H,s,br),4.51(1H,d,J=9.8Hz),2.94–2.77(1H,m),2.74–2.60(2H,m),2.34–2.20(1H,m),2.17–2.08(1H,m);MS(ESI)320.0[M+H]+。
还通过上述方法获得本标题化合物的对映异构体,(5S,6R)-5-(3-氯苯基)-6-(4-氯苯基)哌啶-2-酮:tR=12.4min;[α]D=–156(T=23.4℃,c=1.13,MeOH)。
步骤F. (2S)-2-((2S,3R)-3-(3-氯苯基)-2-(4-氯苯基)-6-氧代-1-哌啶基)丁酸叔丁酯和(2R)-2-((2S,3R)-3-(3-氯苯基)-2-(4-氯苯基)-6-氧代-1-哌啶基)丁酸叔丁酯
在0℃下向13.5g(42.2mmol)(5R,6S)-5,6-双(4-氯苯基)哌啶-2-酮(实施例1,步骤E)在140mL DMF中的溶液中加入4.22g(105mmol)60%的氢化钠在矿物油中的分散体。在搅拌20min后,在0℃下加入2-溴丁酸叔丁酯(28.2g,126mmol),并将由此产生的溶液在25℃下搅拌1.5h直至反应完成。然后加入NH4Cl饱和水溶液,并用乙酸乙酯萃取该混合物。用水和NaCl饱和溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过硅胶快速色谱法(洗脱剂:20%至50%EtOAc/己烷,梯度洗脱)纯化残余物,得到(2S)-2-((2S,3R)-3-(3-氯苯基)-2-(4-氯苯基)-6-氧代-1-哌啶基)丁酸叔丁酯,为较快地洗脱的次要异构体:
1H NMR(400MHz,氯仿-d)δppm 7.22(2H,d,J=8.2Hz),7.20–7.10(2H,m),7.08(2H,t,J=8.2Hz)6.99–6.96(1H,m),6.77–6.73(1H,m),4.48(1H,d,J=9.4Hz),3.24(1H,t,J=7.0Hz),3.04–2.94(1H,m),2.72–2.58(2H,m),2.25–2.00(3H,m),1.93–1.82(1H,m),1.45(9H,s),0.98(3H,t,J=7.4Hz);MS(ESI)462.1[M+H]+。
进一步洗脱得到
(2R)-2-((2S,3R)-3-(3-氯苯基)-2-(4-氯苯基)-6-氧代-1-哌啶基)丁酸叔丁酯,为较慢地洗脱的主要异构体。
1H NMR(400MHz,氯仿-d)δppm 7.24(2H,d,J=8.2Hz),7.18–7.10(2H,m),7.01(2H,d,J=8,2Hz),7.02–6.98(1H,m),6.82–6.78(1H,m),5.83(1H,s),4.54(1H,d,J=9.8Hz),3.09(1H,dd,J=8.2,4.3Hz),3.05–2.99(1H,m),2.70–2.64(2H,m),2.28–2.18(2H,m),2.08–2.02(1H,m),1.48(9H,s),0.57(3H,t,J=7.4Hz);MS(ESI)462.1[M+H]+。
步骤G. (2S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-1-基)丁酸叔丁酯和(2S)-2-((3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-1-基)丁酸叔丁酯
在-78℃下向1.45g(3.14mmol)(2S)-2-((2S,3R)-3-(3-氯苯基)-2-(4-氯苯基)-6-氧代-1-哌啶基)丁酸叔丁酯(实施例1,步骤F)和烯丙基溴(0.326mL,3.76mmol)在12.5mLTHF中的溶液中逐滴加入3.3mL 1M双(三甲基甲硅烷基)氨基锂的THF(3.3mmol)中的溶液。在-78℃下搅拌3h后,用NH4Cl饱和水溶液淬灭反应物,并用乙酸乙酯萃取。用NaCl饱和溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过硅胶快速色谱法(50gSiO2,洗脱剂:5%至20%EtOAc/己烷,梯度洗脱)纯化残余物,得到(2S)-2-((3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-1-基)丁酸叔丁酯,为较快地洗脱的主要异构体。
1H NMR(400MHz,氯仿-d)δppm 7.27–7.24(2H,m),7.21–7.12(2H,m),7.11–7.00(3H,m),6.93–6.87(1H,m),5.90–5.77(1H,m),5.19–5.09(2H,m),4.64(1H,d,J=8.6Hz),3.21–3.10(2H,m),2.80–2.71(1H,m),2.70–2.63(1H,m),2.56–2.48(1H,m),2.30–2.15(2H,m),2.07–1.99(1H,m),1.60–1.48(1H,m),1.47(9H,s),0.61(3H,t,J=7.6Hz);MS(ESI)446.0[M+H]+。
进一步洗脱得到
(2S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-1-基)丁酸叔丁酯,为较慢地洗脱的次要异构体。
1H NMR(400MHz,氯仿-d)δppm 7.23(2H,d,J=8.2Hz),7.19–7.07(2H,m),7.01–6.95(3H,m),6.77–6.72(1H,m),5.95–5.77(1H,m),5.16–4.99(2H,m),4.51(1H,d,J=10.6Hz),3.13–3.04(1H,m),2.94(1H,dd,J=7.8,4.3Hz),2.87–2.77(1H,m),2.68–2.58(1H,m),2.39–2.27(2H,m),2.16–1.95(2H,m),1.54–1.50(1H,m),1.51(9H,s),0.55(3H,t,J=7.4Hz);MS(ESI)446.0[M+H]+。
步骤H. 2-((3R,5R,6S)-1-((S)-1-叔丁氧基-1-氧代丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-3-基)乙酸
向快速搅拌着的842mg(1.67mmol)(2S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-1-基)丁酸叔丁酯(实施例1,步骤G)在7mL水、5mL乙腈和5mL CCl4的混合物中的溶液中加入高碘酸钠(1.43g,6.70mmol),接着加入氯化钌(III)水合物(37.8mg,0.168mmol)。在剧烈搅拌18h后,酸化(10%柠檬酸)反应物,并用EtOAc稀释。通过硅藻土(celite)过滤反应混合物并用EtOAc萃取滤液。用NaCl饱和溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过反相制备型HPLC(GeminiTM Prep C185μm柱,Phenomenex,Torrance,CA;洗脱剂:60%至80%乙腈+0.1%TFA于水+0.1%TFA中,梯度洗脱)纯化残余物,得到本标题化合物,为白色固体。
1H NMR(400MHz,氯仿-d)δppm 7.35(2H,d,J=8.6Hz),7.27–7.24(3H,m),7.22–7.16(1H,m),7.18(2H,d,J=8.6Hz),4.85(1H,d,J=5.1Hz),3.36(1H,dd,J=8.6,3.5Hz),3.18–3.14(1H,m),2.92–2.80(2H,m),2.79–2.72(1H,m),2.32–2.18(2H,m),2.15–2.06(1H,m),1.63–1.50(1H,m),1.44(9H,s),0.67(3H,t,J=7.4Hz);MS(ESI)520.2[M+H]+,518.0[M–H]–。
实施例2
2-((3S,5R,6S)-1-((S)-1-叔丁氧基-1-氧代丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-3-基)乙酸。按照实施例1,步骤H中描述的程序由(S)-2-((3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-1-基)丁酸叔丁酯(实施例1,步骤G)制备本标题化合物。
1H NMR(500MHz,氯仿-d)δppm 7.27–7.26(2H,m),7.12–7.16(1H,m),7.13–7.10(1H,m),7.02–6.94(3H,m),6.74–6.71(1H,m),4.51(1H,d,J=10.8Hz),3.18–3.08(2H,m),3.06–2.96(2H,m),2.47(1H,dd,J=15.4,3.2Hz),2.35–2.25(1H,m),2.24–2.12(2H,m),1.52–1.57(1H,m),1.51(9H,s),0.56(3H,t,J=7.5Hz);MS(ESI)520.2[M+H]+,518.0[M–H]–。
分别用适量的2-溴丁酸乙酯、2-溴代-3-甲基戊酸乙酯、2-溴戊酸乙酯,和2-溴代-2-环丙基乙酸乙酯替代步骤F中的2-溴丁酸叔丁酯,如实施例1中所述制备下面的实施例3至6。
实施例3
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-乙氧基-1-氧代丁烷-2-基)-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 7.42–7.33(3H,m),7.32–7.28(3H,m),7.27–7.24(2H,m),4.91(1H,d,J=3.5Hz),4.23–4.10(2H,m),3.54(1H,dd,J=8.6,3.5Hz),3.22–3.16(1H,m),2.84–2.73(3H,m),2.38–2.30(2H,m),2.05–1.97(1H,m),1.60–1.50(1H,m),1.27(3H,t,J=7.4Hz),0.70(3H,t,J=7.4Hz);MS(ESI)491.8[M+H]+,489.9[M–H]–。
实施例4
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-乙氧基-4-甲基-1-氧代戊烷-2-基)-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 0.34(d,J=6.7Hz,3H),0.77(d,J=6.7Hz,3H),1.13(m,1H),1.28(t,J=7.1Hz,3H),1.30-1.44(m,1H),1.98(m,1H),2.32-2.47(m,2H),2.75(m,1H),2.79-2.86(m,2H),3.14-3.19(m,1H),3.66(dd,J=9.2,2.4Hz,1H),4.11-4.24(m,2H),4.95(m,1H),7.23-7.34(m,5H),7.36-7.41(m,3H),MS(ESI)520.2[M+H]+。518.0[M-H]-。
实施例5
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-乙氧基-1-氧代戊烷-2-基)-2-氧代哌啶-3-基)乙酸和2-((3S,5S,6R)-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-1-乙氧基-1-氧代戊烷-2-基)-2-氧代哌啶-3-基)乙酸
从实施例1,步骤E中制备的外消旋哌啶酮获得实施例5中描述的化合物。
1H NMR(400MHz,氯仿-d)δppm 7.40–7.37(3H,m),7.31–7.27(3H,m),7.27–7.24(2H,m),4.92(1H,d,J=3.5Hz),4.20–4.10(2H,m),3.60(1H,dd,J=8.6,3.5Hz),3.20–3.15(1H,m),2.83–2.72(3H,m),2.40–2.30(2H,m),2.03–1.97(1H,m),1.44–1.37(1H,m),1.27(3H,t,J=7.2Hz),1.26–1.17(1H,m),0.92–0.80(1H,m),0.54–0.78(3H,t,J=7.4Hz);MS(ESI)506.0[M+H]+,504.0[M–H]–。
实施例6
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-乙氧基-2-氧代乙基)-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 0.08(1H,m),0.34(1H,m),0.47(1H,m),0.58(1H,m),1.06(1H,m),1.13(3H,t,J=7.1Hz),1.83(1H,m),2.19(1H,m),2.50–2.63(2H,m),2.74(1H,dd,J=16,6.8Hz),3.08(1H,m),3.42(1H,d,J=10.8Hz),3.97(2H,m),5.20(1H,s),7.08(1H,m),7.15–7.25(7H,m);MS(ESI)504.1[M+H]+。
实施例7
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)-2-氧代哌啶-3-基)乙酸
在0℃下向300mg(0.61mmol)2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-乙氧基-1-氧代丁烷-2-基)-2-氧代哌啶-3-基)乙酸(实施例3)在12mL Et2O中的溶液中加入四氢硼酸锂(39.8mg,1.83mmol)。搅拌20min后,在0℃下加入甲醇(37.0μl,914μmol),并将由此产生的溶液在25℃下搅拌2h。淬灭(10%柠檬酸)反应物,萃取(2×EtOAc)并洗涤(1×NaCl饱和水溶液)。用NaCl饱和溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过反相制备型HPLC(GeminiTM Prep C18 5μm柱,Phenomenex,Torrance,CA;洗脱剂:35%至75%乙腈+0.1%TFA于水+0.1%TFA中,梯度洗脱)纯化,得到本标题化合物,为白色泡沫状物。
1H NMR(400MHz,氯仿-d)δppm 7.42–7.37(3H,m),7.34–7.27(4H,m),7.18–7.13(1H,m),4.89(1H,d,J=2.7Hz),3.99–3.90(1H,m),3.78(1H,dd,J=11.5,3.3Hz),3.32–3.23(1H,m),3.13–3.07(1H,m),2.88–2.65(3H,m),2.35–2.25(1H,m),2.12–2.03(1H,m),1.95–1.84(1H,m),1.58–1.46(1H,m),0.71(3H,t,J=7.4Hz);MS(ESI)450.1[M+H]+,448.0[M–H]–。
实施例8
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-羟基乙基)-2-氧代哌啶-3-基)乙酸
如实施例7中所述,从2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-乙氧基-2-氧代乙基)-2-氧代哌啶-3-基)乙酸(实施例6)制备本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 0.23(m,1H),0.36(m,1H),0.65–0.69(m,2H),0.95(m,1H),1.90(m,1H),2.40(m,1H),2.68(m,1H),2.80(2H,d,J=5.3Hz),3.13(1H,m),3.48(m,1H),3.60–3.85(m,2H),5.32(s,1H),7.20(m,1H),7.27–7.40(m,3H),7.40–7.43(m,4H);MS(ESI)462.1[M+H]+。
实施例9
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环丙基甲氧基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
步骤A. (S)-2-((2S,3R)-3-(3-氯苯基)-2-(4-氯苯基)-6-氧代哌啶-1-基)丁酸乙酯
在0℃下向15g(46.8mmol)((5R,6S)-5-(3-氯苯基)-6-(4-氯苯基哌啶-2-酮(实施例1,步骤E)在140mL DMF中的溶液中加入3.75g(94mmol)的60%氢化钠在矿物油中的分散体。在搅拌20min后,在0℃下加入2-溴丁酸乙酯(17.2mL,117mmol)并将由此产生的溶液在25℃下搅拌12h直至反应完成。然后加入NH4Cl饱和水溶液并用乙酸乙酯萃取该混合物。用水和NaCl饱和溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过硅胶快速色谱法(洗脱剂:30%EtOAc/己烷,梯度洗脱)纯化残余物,得到本标题化合物,为较快地洗脱的异构体。
步骤B. (S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-1-基)丁酸乙酯
在-78℃下向0.62g(1.4mmol)(S)-2-((2S,3R)-3-(3-氯苯基)-2-(4-氯苯基)-6-氧代哌啶-1-基)丁酸乙酯(实施例9,步骤A)和烯丙基溴(0.14ml,1.7mmol)在THF(6.0mL,0.25M)中的溶液中加入双(三甲基甲硅烷基)氨基锂(1M在THF中的溶液,1.5ml,1.5mmol)。让反应物升温至室温,然后淬灭(NH4Cl饱和水溶液)并用EtOAc萃取。用水和NaCl饱和溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过硅胶快速色谱法(15%至20%EtOAc/Hex,梯度洗脱)纯化残余物,得到本标题化合物,其为较慢地洗脱的异构体,为无色油状物。
步骤C. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)哌啶-2-酮
在0℃下向256mg(0.54mmol)(S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-1-基)丁酸乙酯(实施例9,步骤B)在Et2O(5.5mL)中的溶液中加入90%纯度的硼氢化锂(17.6mg,0.809mmol)。在0℃下搅拌10min后,淬灭(冰冷的10%柠檬酸)反应物,萃取(2×EtOAc)并洗涤(NaCl饱和水溶液)。用NaCl饱和溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过硅胶色谱法(洗脱剂:30%至50%EtOAc/己烷,梯度洗脱)纯化,得到本标题化合物。
步骤D. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环丙基甲氧基)丁烷-2-基)哌啶-2-酮
在0℃下向(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)哌啶-2-酮(98mg,0.227mmol)在DMF(1.10mL)中的溶液中加入在矿物油中的60%氢化钠(27.2mg,0.680mmol)。在0℃下搅拌2min后,加入(溴甲基)环丙烷(47.3μL,0.680mmol)。将该混合物在0℃下搅拌2h,然后升温至室温,然后将反应物在室温下搅拌过夜。淬灭(NH4Cl饱和水溶液)反应物,萃取(2×EtOAc)并洗涤(NaCl饱和水溶液)。干燥(Na2SO4)合并的有机层并在减压下浓缩。通过硅胶色谱法(10%至20%EtOAc/己烷梯度)纯化,得到(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-1-(环丙基甲氧基)丁烷-2-基)哌啶-2-酮(为极性较小的异构体),和本标题化合物(为极性较大的立体异构体)。
步骤E. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环丙基甲氧基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
按照与实施例1,步骤H中描述的程序类似的程序,将(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环丙基甲氧基)丁烷-2-基)哌啶-2-酮转化成羧酸。通过反相制备型HPLC(GeminiTM Prep C18 5μm柱,Phenomenex,Torrance,CA;洗脱剂:50%至80%乙腈+0.1%TFA于水+0.1%TFA中,梯度洗脱)纯化,得到本标题化合物,为白色固体。
1H NMR(400MHz,氯仿-d)δppm 7.39(2H,d,J=8.2Hz),7.38–7.36(1H,m),7.33–7.28(3H,m),7.23(2H,d,J=8.2Hz),5.09(1H,d,J=2.0Hz),4.17–4.07(1H,m),3.47–3.40(2H,m),3.23–3.15(m,2H),3.12–3.08(1H,m),2.85(1H,dd,J=15.8,8.8Hz),2.66–2.55(2H,m),2.22–2.12(1H,m),2.07–1.99(1H,m),1.95–1.85(1H,m),1.62–1.54(1H,m),1.07–1.00(1H,m),0.65(3H,t,J=7.4Hz),0.60–0.52(2H,m),0.24–0.18(2H,m);MS(ESI)504.1[M+H]+,502.1[M–H]–。
按照与实施例9,步骤D和E中描述的程序类似的程序,分别用适量的碘甲烷、2-甲氧基乙基溴和1-(溴甲基)环丙烷甲腈替代步骤D中的(溴甲基)环丙烷,从(3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)哌啶-2-酮(实施例9,步骤C)制备下面的实施例10至12。
实施例10
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-甲氧基丁烷-2-基)-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 7.52–7.48(1H,m),7.40(2H,d,J=8.2Hz),7.31–7.28(2H,m),7.27–7.24(1H,m),7.24–7.27(2H,m),5.05(1H,s),4.08(1H,t,J=9.6Hz),3.39(3H,s),3.34(1H,dd,J=9.8,3.1Hz),3.20–3.10(2H,m),2.88–2.78(1H,m),2.64–2.55(2H,m),2.25–2.16(1H,m),2.10–2.00(1H,m),1.90–1.81(1H,m),1.56–1.50(1H,m),0.65(3H,t,J=7.4Hz);MS(ESI)464.0[M+H]+,462.1[M–H]–。
实施例11
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(2-甲氧基乙氧基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 7.41–7.35(3H,m),7.28–7.26(2H,m),7.25–7.21(3H,m),5.09(1H,d,J=2.7Hz),4.17–4.10(1H,m),3.74–3.65(1H,m),3.60–3.52(3H,m),3.44(1H,dd,J=10.4,3.3Hz),3.35(3H,s),3.25–3.15(1H,m),3.12–3.07(1H,m),2.91–2.80(1H,m),2.71–2.58(2H,m),2.21–2.12(1H,m),2.05–1.89(2H,m),1.61–1.52(1H,m),0.64(3H,t,J=7.6Hz);MS(ESI)508.1[M+H]+,506.0[M–H]–。
实施例12
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-((1-氰基环丙基)甲氧基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 7.43–7.30(3H,m),7.28–7.20(4H,m),7.18–7.10(1H,m),5.04(1H,d,J=3.9Hz),4.13(1H,t,J=9.4Hz),3.52–3.43(2H,m),3.42–3.33(1H,m),3.32–3.24(1H,m),3.13–3.05(1H,m),2.92–2.75(2H,m),2.72–2.60(1H,m),2.20–2.10(1H,m),2.10–1.90(1H,m),1.64–1.49(1H,m),1.35–1.25(2H,m),1.00–0.90(2H,m),0.71–0.57(3H,m);MS(ESI)529.2[M+H]+,527.0[M–H]–。
采用与针对实施例9,步骤D和E描述的工艺类似的工艺,从(3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-羟基乙基)哌啶-2-酮制备实施例13–15。
实施例13
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环丙基甲氧基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 7.25(2H,d,J=8.6Hz),7.22–7.18(1H,m),7.15–7.11(1H,m),7.08–7.04(1H,m),6.96(2H,d,J=8.6Hz),6.77–6.73(1H,m),4.69(1H,d,J=10.2Hz),4.03(1H,t,J=9.8Hz),3.42–3.33(2H,m),3.28–3.22(1H,m),3.10–2.90(4H,m),2.50(1H,dd,J=15.3,3.1Hz),2.20–2.10(1H,m),2.01–2.01(1H,m),1.92–1.80(1H,m),1.65–1.53(1H,m),1.16–1.08(1H,m),0.66–0.60(2H,m),0.53(3H,t,J=7.6Hz),0.28–0.24(2H,m);MS(ESI)504.1[M+H]+,502.1[M–H]–。
实施例14
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-甲氧基丁烷-2-基)-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 0.55(t,J=7.53Hz,3H),1.49-1.60(m,1H),1.77-1.91(m,1H),2.02-2.15(m,2H),2.51(dd,J=15.26,3.33Hz,1H),2.89-2.99(m,1H),2.99-3.09(m,2H),3.09-3.17(m,1H),3.29(dd,J=9.68,4.21Hz,1H),3.34(s,3H),3.90(t,J=9.49Hz,1H),4.57(d,J=9.98Hz,1H),6.75(d,J=7.43Hz,1H),6.97(d,J=8.41Hz,2H),7.00(t,J=1.76Hz,1H),7.14(t,J=7.73Hz,1H),7.17-7.22(m,1H),7.25(d,J=8.41Hz,2H)。
实施例15
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(2-甲氧基乙氧基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 7.24(2H,d,J=8.2Hz),7.21–7.16(1H,m),7.14–7.09(1H,m),7.05–7.03(1H,m),6.97(2H,d,J=8.2Hz),6.75–6.71(1H,m),4.66(1H,d,J=10.6Hz),4.09(1H,t,J=9.8Hz),3.70–3.55(4H,m),3.47(3H,s),3.44(1H,dd,J=9.8,4.3Hz),3.05–2.90(4H,m),2.53(1H,dd,J=15.1,2.5Hz),2.28–2.15(1H,m),2.05–1.97(1H,m),1.92–1.82(1H,m),1.65–1.55(1H,m),0.50(3H,t,J=7.6Hz);MS(ESI)508.1[M+H]+,506.0[M–H]–。
实施例16
2-((3R,5R,6S)-1-((S)-1-((1-氨基甲酰基环丙基)甲氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-3-基)乙酸
将10mg(0.02mmol)2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-((1-氰基环丙基)甲氧基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸(实施例11)和氢氧化钾(3.2mg,0.06mmol)在t-BuOH(189μL)中的溶液在85℃下搅拌24h。酸化(10%柠檬酸)反应物并对反应物进行萃取(2x EtOAc)。用NaCl饱和溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过反相制备型HPLC(GeminiTM Prep C18 5μm柱,Phenomenex,Torrance,CA;洗脱剂:35%至75%乙腈+0.1%TFA于水+0.1%TFA中,梯度洗脱)纯化,得到本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 0.67(m,5H),1.34(m.,2H),1.54(m.,1H),1.87-2.18(m,4H),2.65(m,1H),2.71-2.90(m,2H),3.08(m,1H),3.38-3.64(m,4H),3.94(m,1H),4.84(m,1H),6.35(br.s.,1H),6.91(br.s.,1H)7.13(m,1H)7.21-7.38(m,7H)。MS(ESI)547.2[M+H]+,545.0[M-H]-。
进一步洗脱得到实施例17。
实施例17
2-((3S,5R,6S)-1-((S)-1-((1-氨基甲酰基环丙基)甲氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 7.26–7.21(2H,m),7.17–7.12(2H,m),7.06(1H,br,s),6.95–6.90(2H,m),6.88–6.80(1H,s),6.79–6.76(1H,m),6.74(1H,br,s),4.63(1H,d,J=10.2Hz),4.10–4.00(1H,m),3.33–3.10(3H,m),3.02–2.92(2H,m),2.90–2.78(1H,m),2.70–2.60(1H,m),2.44–2.34(1H,m),2.00–1.90(1H,m),1.85–1.75(1H,m),1.65–1.55(1H,m),1.43–1.35(2H,m),0.85–0.73(2H,m),0.63–0.52(3H,m);MS(ESI)547.2[M+H]+,545.0[M–H]–。
实施例18
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(2-羟基-2-甲基丙氧基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
步骤A. 2-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-1-基)丁氧基)乙酸乙酯
在25℃下向203mg(0.47mmol)(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)哌啶-2-酮(实施例9,步骤B)和乙酸铑(II)二聚体(10.4mg,0.047mmol)在CH2Cl2(1.90mL)中的溶液中逐滴加入重氮基乙酸乙酯(286μL,2.35mmol)。在25℃下搅拌14h后,在减压下浓缩反应物并通过硅胶色谱法(20%至30%EtOAc/己烷,梯度洗脱)纯化从而得到本标题化合物,为无色液体:
步骤B. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(2-羟基-2-甲基丙氧基)丁烷-2-基)哌啶-2-酮
在0℃下向2-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-1-基)丁氧基)乙酸乙酯(69.0mg,0.133mmol)在THF(2.22mL)中的溶液中加入1.4M在甲苯/THF中的甲基溴化镁(0.38mL,0.532mmol)。在25℃下搅拌3h后,淬灭(NH4Cl饱和水溶液)反应物,并用EtOAc萃取。用NaCl饱和溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过硅胶色谱法(20%至50%的EtOAc/己烷,梯度洗脱)纯化,得到本标题化合物,为无色液体。
步骤C. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(2-羟基-2-甲基丙氧基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
向快速搅拌着的(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(2-羟基-2-甲基丙氧基)丁烷-2-基)哌啶-2-酮(51.0mg,0.101mmol)在水(361μL)、乙腈(241μL)和CCl4(241μL)的混合物中的溶液中加入高碘酸钠(86mg,0.404mmol),接着加入氯化钌(III)水合物(2.28mg,10.1μmol)。在剧烈搅拌18h后,酸化(10%柠檬酸)反应物并稀释(EtOAc)。通过(J.T.Baker,Phillipsberg,NJ,J.T.Baker,Phillipsberg,NJ,硅藻土)过滤该混合物,并用EtOAc萃取滤液。用NaCl饱和溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过反相制备型HPLC(GeminiTM Prep C18 5μm柱,Phenomenex,Torrance,CA;洗脱剂:50%至76%乙腈+0.1%TFA于水+0.1%TFA中,梯度洗脱)纯化,得到本标题化合物,为白色固体。
1H NMR(400MHz,氯仿-d)δppm 0.64-0.74(t,J=7.6Hz,3H),1.21(d,J=3.7Hz,6H),1.58(ddd,J=14.0,7.6,4.4Hz,1H),1.84-1.99(m,2H),2.21(m,1H),2.64-2.83(m,3H),3.04-3.15(m,1H),3.19(d,J=9.2Hz,1H),3.29(d,J=9.2Hz,1H),3.38(m,1H),3.41-3.55(m,1H),3.98(t,J=8.6Hz,1H),4.98(d,J=2.9Hz,1H)7.12-7.20(m,1H),7.21-7.34(m,5H),7.34-7.41(m,2H);MS(ESI)522.1[M+H]+。520.2[M-H]-。
实施例19
*绝对立体化学未知
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-((3S)-1,1,1-三氟代-2-羟基戊烷-3-基)哌啶-3-基)乙酸(异构体1)
步骤A. (S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-1-基)丁醛
在N2下向-60℃下的乙二酰二氯(166μL,1.87mmol)在DCM(4.16mL)中的溶液中加入DMSO(222μL,3.12mmol)在DCM(4.16mL)中的溶液。在约20min后,加入540mg(1.25mmol)(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)哌啶-2-酮(实施例9,步骤B)在4.2mL DCM中的溶液,并将由此产生的溶液搅拌15min。然后加入三乙胺(872μL,6.24mmol)。在-60℃下搅拌5min后,让反应物升温至室温,并加入5mL水。萃取(2×DCM)溶液,洗涤(NaCl饱和水溶液),干燥(MgSO4)并在减压下浓缩从而得到粗的本标题化合物,其含有20%原料(SM)。
步骤B. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S)-1,1,1-三氟代-2-羟基戊烷-3-基)哌啶-2-酮
*绝对立体化学未知
在0℃下用1M在THF中的四丁基氟化铵(93μL,0.093mmol)处理(S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-1-基)丁醛(80mg,0.186mmol)和三甲基(三氟甲基)硅烷(82μL,0.558mmol)在THF(929μL)中的溶液。在搅拌1h后,在0℃下向反应物加入另外3个当量的三甲基(三氟甲基)硅烷(82μL,0.558mmol)和1M在THF中的四丁基氟化铵(93μL,0.093mmol),并将反应物搅拌14h。稀释(EtOAc)反应混合物,洗涤(用1×H2O和1×NaCl饱和水溶液),干燥(Na2SO4),并在减压下浓缩。通过反相制备型HPLC(GeminiTM Prep C18 5μm柱,Phenomenex,Torrance,CA;洗脱剂:60%至90%乙腈+0.1%TFA于水+0.1%TFA中,梯度洗脱)纯化,得到两种化合物,它们是在仲醇上的非对映异构体。
步骤C. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-((3S)-1,1,1-三氟代-2-羟基戊烷-3-基)哌啶-3-基)乙酸
按照与实施例18,步骤C中描述的程序类似的程序,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S)-1,1,1-三氟代-2-羟基戊烷-3-基)哌啶-2-酮的单一非对映异构体制备本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 0.53(t,J=7.5Hz,3H),1.66(m,1H),1.97-2.05(m,1H),2.18(m,1H),2.32-2.45(m,1H),2.68-2.83(m,2H),2.94-3.05(m,1H),3.15-3.25(m,1H),4.42(m,1H),4.69(d,J=3.9Hz,1H),6.95-7.02(m,1H),7.12(m,1H),7.22-7.37(m,5H),7.37-7.46(m,2H);MS(ESI)518.0[M+H]+。516.0[M-H]-。
实施例20
*绝对立体化学未知
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-((3S)-1,1,1-三氟代-2-羟基戊烷-3-基)哌啶-3-基)乙酸(异构体2)
向快速搅拌着的6.3mg(0.013mmol)(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S)-1,1,1-三氟代-2-羟基戊烷-3-基)哌啶-2-酮(实施例19,步骤B,未用于实施例19步骤B中的非对映异构体)(6.30mg,0.013mmol)在水(108μL)、乙腈(71.9μL)和CCl4(71.9μL)的混合物中的溶液中加入高碘酸钠(10.7mg,0.050mmol),接着加入氯化钌(III)水合物(0.284mg,1.26μmol)。在剧烈搅拌18h后,酸化(10%柠檬酸)反应物并稀释(EtOAc)。通过(J.T.Baker,Phillipsberg,NJ,J.T.Baker,Phillipsberg,NJ,硅藻土)过滤反应混合物。萃取(2×EtOAc)滤液。用NaCl饱和溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过反相制备型HPLC(GeminiTM Prep C18 5μm柱,Phenomenex,Torrance,CA;洗脱剂:45%至70%乙腈+0.1%TFA于水+0.1%TFA中,梯度洗脱)纯化,得到本标题化合物,为白色固体。
1H NMR(400MHz,氯仿-d)δppm 0.44–0.72(m,3H);1.28–1.46(m,1H),2.15–2.28(m,2H),2.45–2.55(m,1H),2.89–3.05(m,3H),3.10–3.18(m,2H),4.02–4.16(m,1H),4.56(d,J=7.8Hz,1H),6.84–6.93(m,1H),7.01–7.04(m,1H),7.08–7.14(m,2H),7.17–7.20(m,2H),7.32–7.38(m,2H);MS(ESI)518.0[M+H]+。516.0[M–H]–。
实施例21
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-吗啉代丁烷-2-基)-2-氧代哌啶-3-基)乙酸
步骤A. (S)-2-((3R,5R,6S)-3-(2-叔丁氧基-2-氧代乙基)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-1-基)丁酸乙酯
在-78℃下向搅拌着的1.14g(2.3mmol)2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-乙氧基-1-氧代丁烷-2-基)-2-氧代哌啶-3-基)乙酸(实施例3)在DCM(21.0mL)中的溶液中加入硫酸(0.247mL,4.63mmol),接着加入异丁烯(4.42mL,46.3mmol)。密封反应容器,并将混合物温度缓慢地升至室温并剧烈搅拌3天。在冷却至-78℃后,打开管子并用饱和NaHCO3水溶液淬灭反应物至pH为8。在减压下除去有机溶剂,萃取(2x EtOAc)剩余的混合物。用NaCl饱和溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过硅胶色谱法(洗脱剂:20%至35%的EtOAc/己烷)纯化残余物从而得到本标题化合物,为泡沫状物。
步骤B. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)-2-氧代哌啶-3-基)乙酸叔丁酯
在0℃下向(S)-2-((3R,5R,6S)-3-(2-叔丁氧基-2-氧代乙基)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-1-基)丁酸乙酯(1.94g,3.54mmol,实施例21,步骤A)在Et2O(35.4mL)中的溶液中加入90%硼氢化锂(0.154g,7.07mmol)。在0℃下搅拌30min后,淬灭(冰冷的10%柠檬酸)反应物,萃取(2×EtOAc)并洗涤(NaCl饱和水溶液)。用NaCl饱和溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过硅胶色谱法(50%至100%的EtOAc/己烷,梯度洗脱)纯化得到本标题化合物。
步骤C. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-((S)-1-氧代丁烷-2-基)哌啶-3-基)乙酸叔丁酯
在N2下向-60℃下的乙二酰氯(0.261mL,2.99mmol)在DCM(5.87mL)中的溶液中加入DMSO(0.512mL,5.98mmol)在DCM(5.87mL)中的溶液。在搅拌20min后,加入2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)-2-氧代哌啶-3-基)乙酸叔丁酯(1.01g,1.99mmol,实施例21,步骤B)在DCM(5.87mL)中的溶液,并将由此产生的溶液搅拌15min。向该溶液中加入三乙胺(1.39mL,9.97mmol)。在-60℃下搅拌5min后,让反应物升温至室温,并淬灭(H2O)。萃取(3×DCM)该溶液并洗涤(H2O和NaCl饱和水溶液)。用NaCl饱和溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液从而得到本标题化合物。
步骤D. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-吗啉代丁烷-2-基)-2-氧代哌啶-3-基)乙酸叔丁酯
在0℃下向2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-((S)-1-氧代丁烷-2-基)哌啶-3-基)乙酸叔丁酯(0.050g,0.099mmol,实施例21,步骤C)和吗啉(0.013mL,0.149mmol)在DCE(1.0mL)中的溶液中加入三乙酰氧基硼氢化钠(0.063g,0.297mmol)。在25℃下搅拌18h后,通过加入冰冷的饱和NaHCO3水溶液淬灭反应物,萃取(2×DCM)并洗涤(1×NaCl饱和水溶液)合并的有机层并在减压下浓缩。将产物用于下一步骤而无需进一步纯化。
步骤E. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-吗啉代丁烷-2-基)-2-氧代哌啶-3-基)乙酸
在0℃下向含有在DCM(1mL)中的2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-吗啉代丁烷-2-基)-2-氧代哌啶-3-基)乙酸叔丁酯(0.057g,0.099mmol;实施例21;步骤D)的圆底烧瓶中加入TFA(1.129g,9.90mmol)。移开冰浴并将混合物在室温下搅拌3h。除去溶剂。通过反相制备型HPLC(GeminiTM Prep C18 5μm柱,Phenomenex,Torrance,CA;洗脱剂:10%至90%乙腈+0.1%TFA于水+0.1%TFA中,梯度洗脱)纯化,得到本标题化合物,为白色粉末。
1H NMR(400MHz,氯仿-d)δppm 0.99(m,3H),1.60-2.43(m.,4H),2.60-2.86(m,5H),3.11-3.40(m,2H),3.83-4.04(m,5H),4.43(m,2H),4.90(m,1H),7.01(m,1H)7.12(m,1H)7.20-7.36(m,2H)7.46(m.,4H);MS(ESI)519.1[M+H]+。517.2[M-H]-
采用与针对实施例21描述的工艺类似的工艺,用合适的胺替代步骤D中的吗啉来制备实施例22至27。
实施例22
2-((3RS,5RS,6SR)-5-(3-氯苯基)-6-(4-氯苯基)-1-((SR)-1-(乙基氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸(由外消旋中间体制备)
1H NMR(400MHz,氯仿-d)δppm 0.91–1.13(t,J=7.8Hz,3H),1.28(t,J=7.14Hz,3H),1.55–1.65(m,1H),1.76–1.86(m,1H),1.95–2.05(m,1H),2.31–2.59(m,2H),2.73–2.85(m,2H),2.90–3.09(m,5H),4.78–4.82(m,1H),4.88–5.02(m,1H),6.90–6.98(m,1H),7.04–7.12(m,1H),7.20–7.30(m,3H),7.36–7.42(m,2H),7.45–7.56(m,1H);MS(ESI)477.1[M+H]+,475.1[M–H]–。
实施例23
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-((S)-1-(2,2,2-三氟乙基氨基)丁烷-2-基)哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 0.96(t,J=7.3Hz,3H),1.62–1.74(m,1H),1.79–1.98(m,2H),2.41–2.51(m,1H),2.61–2.75(m,2H),3.01–3.21(m,4H),3.74–3.91(m,2H),4.57(m,1H),4.89(d,J=2.9Hz,1H),6.96–7.02(m,1H),7.12(m,1H),7.24–7.31(m,2H),7.36–7.49(m,4H);MS(ESI)531.1[M+H]+,529.0[M–H]–。
实施例24
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-((S)-1-(吡咯烷-1-基)丁烷-2-基)哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 0.93(m.,3H),1.67–1.75(m,2H),2.03–2.39(m.,7H),2.74–2.91(m,6H),3.09–3.17(m,2H),3.86(m,1H),4.05(m,1H),4.86(m,1H),6.82–7.04(m,1H)7.09(m,1H)7.25(m,2H)7.44(m,4H);MS(ESI)503.2[M+H]+,501.1[M–H]–。
实施例25
2-((3RS,5RS,6SR)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-((SR)-1-(2-氧代吡咯烷-1-基)丁烷-2-基)哌啶-3-基)乙酸(由外消旋中间体制备。)
使用4-氨基丁酸乙酯盐酸盐作为胺。在还原胺化后,通过在乙酸和甲苯中加热至120℃来使中间体环化,从而得到本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 0.93(m.,3H),1.67(m,1H),1.82(m,1H),2.07–2.20(m.,5H),2.44–2.46(m,3H),2.71–3.06(m,3H),3.20–3.30(m,2H),3.40–3.55(m,3H),3.69(m,1H),4.70(m,1H),6.99–7.04(m,1H)7.12–7.16(m,3H)7.24–7.27(m,2H)7.35(m,2H);MS(ESI)517.2[M+H]+。
实施例26
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二氧化硫代吗啉代)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 0.85(m.,3H)1.71(m,2H)1.83–1.98(m,1H)2.37(m,1H)2.58(m,1H)2.63–2.83(m,2H)3.04–3.15(m,3H),3.25–3.35(m.,6H)3.43–3.64(m,2H)4.88(m,1H)7.09(m.,1H)7.19(m,1H)7.29(m,2H)7.34–7.50(m,4H);MS(ESI)567.1[M+H]+,565.2[M–H]–。
实施例27
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-((S)-1-(噻唑-2-基氨基)丁烷-2-基)哌啶-3-基)乙酸
1H NMR(500MHz,乙腈-d3)δppm 0.58(t,J=7.2Hz,3H),1.52–1.64(m,1H),1.73–1.89(m,1H),1.98–2.05(m,1H),2.05–2.16(m,1H),2.67–2.81(m,1H),2.81–2.92(m,2H),3.11–3.32(m,2H),3.50(m,1H),3.68(m,1H),4.81(d,J=6.8Hz,1H),6.72–6.79(m,1H),7.04–7.12(m,1H),7.14(s,1H),7.17–7.23(m,2H),7.25(d,J=4.4Hz,1H),7.29–7.41(m,4H);MS(ESI)530.0[M–H]–。
实施例28
2-((3RS,5RS,6SR)-1-((SR)-1-乙酰氨基丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-3-基)乙酸(外消旋)
步骤A. (3SR,5RS,6SR)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((SR)-1-(4-甲氧基苄基氨基)丁烷-2-基)哌啶-2-酮
在0℃下将三乙酰氧基硼氢化钠(117mg,0.551mmol)分成几个部分加入到79mg(0.184mmol)(SR)-2-((3SR,5RS,6SR)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-1-基)丁醛(实施例19,步骤A的外消旋物)和4-甲氧基苄胺(35.7μL,0.275mmol)在1.8mL二氯乙烷中的溶液中。在25℃下搅拌18h后,通过加入冰冷的饱和NaHCO3水溶液淬灭反应物,萃取(2×DCM)并用NaCl饱和溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过硅胶快速色谱法(含有1%NH4OH水溶液的0%至3%的MeOH/DCM)纯化,得到本标题化合物,为黄色膜状物。
步骤B. (3SR,5RS,6SR)-3-烯丙基-1-((SR)-1-氨基丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)哌啶-2-酮
在25℃下向(3SR,5RS,6SR)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((SR)-1-(4-甲氧基苄基氨基)丁烷-2-基)哌啶-2-酮(88mg,0.160mmol)在乙腈(1899μL)和水(380μL)中的溶液中加入硝酸高铈铵(350mg,0.638mmol)。用LCMS和HPLC监测反应,反应一完成就用0.5MNaOH水溶液和EtOAc稀释,并将由此产生的乳液通过(J.T.Baker,Phillipsberg,NJ,J.T.Baker,Phillipsberg,NJ,硅藻土)垫进行过滤。用乙酸乙酯萃取滤液,并用NaCl饱和溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液从而得到粗产物,将粗产物用于后续步骤而无需进一步纯化。
步骤C. N-((SR)-2-((3SR,5RS,6SR)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-1-基)丁基)乙酰胺
在25℃下向53mg(0.123mmol)(3SR,5RS,6SR)-3-烯丙基-1-((RS)-1-氨基丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)哌啶-2-酮(步骤B)在DMF(307μL)中的溶液中加入乙酸酐(116μL,1.229mmol)。在25℃下搅拌14h后,淬灭(H2O)反应物并对反应物进行萃取(2xEtOAc)。用NaCl饱和溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过反相HPLC(50%至80%的AcCN/H2O,25min,2次注射进样,tR=15.683min)分离,得到本标题化合物,为黄色固体。
步骤D. 2-((3RS,5RS,6SR)-1-((SR)-1-乙酰氨基丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-3-基)乙酸
如实施例1,步骤H中所述,进行N-((SR)-2-((3SR,5RS,6SR)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-1-基)丁基)乙酰胺至本标题化合物的氧化,从而得到本标题化合物,为白色固体。
1H NMR(500MHz,氯仿-d)δppm 0.80(t,J=7.4Hz,3H,)1.62–1.75(m,1H),1.84–1.97(m,2H),2.07(s,3H),2.36–2.49(m,1H),2.64–2.80(m,2H),3.02–3.16(m,2H),3.16–3.31(m,1H),3.32–3.40(m,1H),3.74–3.90(m,1H),4.76–4.82(m,1H),7.04–7.08(m,1H),7.16–7.19(m,1H),7.22–7.30(m,2H),7.32–7.38(m,4H);MS(ESI)491.0[M+H]+,489.1[M–H]–。
实施例29
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(甲基磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
步骤A. N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-1-基)丁基)甲烷磺酰胺
在0℃下向69mg(0.16mmol)(3S,5R,6S)-3-烯丙基-1-((S)-1-氨基丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)哌啶-2-酮(实施例28,步骤B,由实施例19,步骤A中描述的非外消旋前体制得)在1.6mL DCM中的溶液中依次加入甲烷磺酰氯(13.7μL,0.175mmol)和吡啶(38.7μL,0.478mmol)。在室温下搅拌14h后,用10%柠檬酸水溶液酸化反应混合物并对其进行萃取(2x DCM)。用NaCl饱和溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过反相HPLC(40%至90%的MeCN/H2O,45min,2次注射进样,tR=25.94min)纯化,得到本标题化合物,为黄色固体。
步骤B. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(甲基磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
如实施例28,步骤D中所述,使用N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-1-基)丁基)甲烷磺酰胺(步骤A)制备本标题化合物。
1H NMR(500MHz,氯仿-d)δppm 0.67(t,J=7.6Hz,3H),1.51–1.61(m,1H),1.88–1.92(m,1H),2.13–2.26(m,2H),2.79–2.89(m,2H),2.89–2.95(m,1H),2.98(s,3H),3.02–3.10(m,1H),3.17–3.21(m,1H),3.42–3.52(m,1H),4.85(d,J=5.4Hz,1H),5.27(br.s.,1H),7.02–7.10(m,1H),7.10–7.15(m,1H),7.18–7.30(m,4H),7.34(d,J=8.6Hz,2H);MS(ESI)527.0[M+H]+,525.1[M–H]–。
实施例30
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-氰基戊烷-3-基)-2-氧代哌啶-3-基)乙酸
步骤A. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-氰基戊-1-烯-3-基)-2-氧代哌啶-3-基)乙酸叔丁酯
在0℃下向氰甲基膦酸二乙酯(62.4μL,0.396mmol)和DMPU(239μL,1.98mmol)在THF(661μL)中的溶液中加入作为悬浮液的在矿物油中的60%氢化钠(11.89mg,0.297mmol)。将混合物搅拌30min,然后用100mg(0.2mmol)2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-((R)-1-氧代丁烷-2-基)哌啶-3-基)乙酸叔丁酯(实施例21,步骤C)在THF(661μL)中的溶液处理。在搅拌12h后,用水淬灭反应物,萃取(2x EtOAc)并用NaCl饱和溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过硅胶快速色谱法(10%至20%的EtOAc/Hex,梯度洗脱)纯化残余物,得到本标题化合物,为E-和Z-异构体的混合物。MS(ESI)527.2[M+H]+。
步骤B. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-氰基戊烷-3-基)-2-氧代哌啶-3-基)乙酸叔丁酯
向56mg(0.106mmol)2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-氰基戊-1-烯-3-基)-2-氧代哌啶-3-基)乙酸叔丁酯(实施例30,步骤A)在3.5mLEtOH中的溶液中加入10%的负载于活性炭上的钯(11.30mg,10.62μmol)。然后用氢气对反应混合物进行常规的氢化。在室温下于氢气气氛下搅拌2h后,使用短硅胶塞过滤催化剂。用EtOAc洗涤该短硅胶塞数次。在减压下浓缩合并的滤液,从而得到粗的本标题化合物,为无色膜状物,将该物质用于后续反应中而无需进一步纯化。MS(ESI)529.2[M+H]+。
步骤C. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-氰基戊烷-3-基)-2-氧代哌啶-3-基)乙酸
在0℃下向57mg(0.11mmol)2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-氰基戊烷-3-基)-2-氧代哌啶-3-基)乙酸叔丁酯(实施例30,步骤B)在DCM(359μL)中的溶液中加入三氟乙酸(415μL,5.38mmol)。在25℃下搅拌2h后,在减压下除去溶剂并通过在减压下用甲苯共沸三次来除去残余的TFA。通过反相HPLC(45%至70%的AcCN/H2O,30min,运行3次,tR=18.52min)分离粗产物,得到本标题化合物,为白色固体。
1H NMR(400MHz,氯仿-d)δppm 7.37(2H,d,J=8.6Hz),7.27–7.25(2H,m),7.21(2H,d,J=8.6Hz),7.15–7.12(1H,m),7.04–6.98(1H,m),4.74(1H,d,J=5.3Hz),3.42–3.32(1H,m),3.13–3.08(1H,m),3.08–3.00(1H,m),2.99–2.92(1H,m),2.85–2.77(1H,m),2.43–2.33(2H,m),2.23–2.15(2H,m),2.13–2.03(1H,m),1.94–1.77(2H,m),1.64–1.54(1H,m),0.64(3H,t,J=7.4Hz);MS(ESI)473.0[M+H]+,471.1[M–H]–。
采用与针对实施例30描述的工艺类似的工艺,在步骤A中使用适当取代的膦酸酯来制备实施例31和32。
实施例31
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(甲基磺酰基)戊烷-3-基)-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 0.71(t,J=8.0Hz,3H),1.58-1.69(m,1H),1.82(m,1H),1.98-2.17(m,3H),2.20-2.34(m,1H),2.83-3.13(m,10H),4.80-4.84(m,1H),7.00-7.07(m,1H),7.13-7.18(m,1H),7.23-7.32(m,4H),7.34-7.41(m,2H);MS(ESI)526.2[M+H]+。
实施例32
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-((S)-1-(吡啶-2-基)戊烷-3-基)哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 0.89(t,J=7.5Hz,3H),1.60-1.79(m,4H),1.90-1.98(m,1H),2.53(m,1H),2.61-2.69(m,1H),2.72-2.79(m,1H),2.90-3.03(m,2H),3.07-3.12(m,1H),3.19-3.28(m,1H),4.15(m,1H),4.80-4.81(m,1H),7.01-7.07(m,1H),7.15(s,1H),7.22-7.35(m,4H),7.40-7.47(m,1H),7.59(d,J=7.82Hz,1H),7.75(t,J=6.75Hz,1H),8.28(t,J=7.92Hz,1H),8.85-8.89(m,1H);MS(ESI)525.1[M+H]+
实施例33
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(乙基氨基)-1-氧代丁烷-2-基)-2-氧代哌啶-3-基)乙酸和2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-1-(乙基氨基)-1-氧代丁烷-2-基)-2-氧代哌啶-3-基)乙酸
步骤A. (R)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-1-基)丁酸
在0℃下向320mg(0.64mmol)(2S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-1-基)丁酸叔丁酯(实施例1,步骤G)在DCM(3184μL)中的溶液中加入三氟乙酸(2453μL,31.8mmol)。在25℃下搅拌3h后,在减压下除去溶剂并通过在减压下用甲苯共沸三次来除去残余的TFA从而得到本标题化合物,为浅黄色泡沫状物,将该物质用于后续反应中而无需进一步纯化。
步骤B. (S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-1-基)-N-乙基丁酰胺
在0℃下依次用N1-((乙基亚氨基)亚甲基)-N3,N3-二甲基丙烷-1,3-二胺盐酸盐(138mg,0.719mmol)、3H-[1,2,3]三唑并[4,5-b]吡啶-3-醇(98mg,0.719mmol),和碳酸氢钠(60.4mg,0.719mmol)处理107mg(0.24mmol)(S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-1-基)丁酸(实施例33,步骤A)和乙胺(31.4μL,0.479mmol)在DCM(539μL)和DMF(59.9μL)中的溶液。然后将反应物在25℃下搅拌12h。稀释(1N HCl水溶液)反应物,萃取(2×EtOAc),用NaCl饱和水溶液和NaHCO3溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过硅胶色谱法(30%至40%的EtOAc/己烷,梯度洗脱)纯化,得到本标题化合物,其为非对映异构体的混合物(dr=5:1),为白色固体:MS(ESI)473.2[M+H]+。
步骤C. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(乙基氨基)-1-氧代丁烷-2-基)-2-氧代哌啶-3-基)乙酸和2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-1-(乙基氨基)-1-氧代丁烷-2-基)-2-氧代哌啶-3-基)乙酸
如实施例1,步骤H中所述,将2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-1-基)-N-乙基丁酰胺(实施例33,步骤B)转化成酸,从而得到本标题化合物,为非对映异构体的混合物(dr=5:1)。
1H NMR(400MHz,氯仿-d)δppm 0.81(t,J=7.8Hz,3H),1.10(t,J=7.2Hz,3H),1.65–1.75(m,1H),1.87(m,1H),2.24–2.41(m,2H),2.57–2.66(m,1H),2.70(dd,J=16.8,5.09Hz,1H),2.98(dd,J=16.9,5.58Hz,1H),3.04–3.26(m,3H),3.97(dd,J=10.37,4.89Hz,1H),5.05–5.10(m,1H),7.06–7.19(m,2H),7.19–7.24(m,1H)7.24–7.38(m,5H);MS(ESI)491.0[M+H]+。489.1[M–H]–。
实施例34
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(5-甲基-1,3,4-噁二唑-2-基)丙基)-2-氧代哌啶-3-基)乙酸和2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-1-(5-甲基-1,3,4-噁二唑-2-基)丙基)-2-氧代哌啶-3-基)乙酸
步骤A. (S)-N′-乙酰基-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-1-基)丁酰肼
依次用在0℃下的N1-((乙基亚氨基)亚甲基)-N3,N3-二甲基丙烷-1,3-二胺盐酸盐(122mg,0.638mmol)、3H-[1,2,3]三唑并[4,5-b]吡啶-3-醇(87mg,0.638mmol),和碳酸氢钠(53.6mg,0.638mmol)在0℃下处理95mg(0.213mmol)(S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-1-基)丁酸(实施例33,步骤A)和乙酰肼(23.65mg,0.319mmol)在DCM(479μL)和DMF(53.2μL)中的溶液。然后将反应物在25℃下搅拌12h。用1NHCl水溶液稀释反应物并对其进行萃取(2×EtOAc)。用NaCl饱和水溶液和NaHCO3溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过硅胶色谱法(60%至80%的EtOAc/己烷,梯度洗脱)纯化,得到本标题化合物,为无色膜状物。MS(ESI)502.1[M+H]+。
步骤B. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(5-甲基-1,3,4-噁二唑-2-基)丙基)哌啶-2-酮
将58mg(0.115mmol)(S)-N′-乙酰基-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-1-基)丁酰肼(实施例34,步骤A)和Burgess试剂(110mg,0.462mmol)在二氯乙烷(1154μL)中的溶液在微波炉中于120℃下加热30min。然后用水稀释反应混合物并用DCM萃取。用NaCl饱和水溶液和NaHCO3溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过反相HPLC(55%至90%的MeCN/H2O,35min,每次注射29mg)分离,得到本标题化合物,为无色膜状物。MS(ESI)484.1[M+H]+。
步骤C. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(5-甲基-1,3,4-噁二唑-2-基)丙基)-2-氧代哌啶-3-基)乙酸
如实施例1,步骤H中所述,将(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(5-甲基-1,3,4-噁二唑-2-基)丙基)哌啶-2-酮(实施例34,步骤B)转化成酸,从而得到本标题化合物,为非对映异构体的混合物(dr=10:1)。
1H NMR(400MHz,氯仿-d)δppm 0.81(t,J=7.8Hz,3H),1.93–2.04(m,2H),2.25(m,1H),2.26(s,3H),2.33–2.44(m,1H),2.83–2.94(m,3H),3.12(d,J=2.3Hz,1H),5.08–5.18(m,1H),5.60(br.s.,1H),7.07(d,J=8.2Hz,2H),7.18–7.23(m,1H),7.26(m,1H),7.28(m,1H),7.30–7.35(m,3H);MS(ESI)502.1[M+H]+,500.0[M–H]–。
实施例35
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酸
步骤A. (5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)哌啶-2-酮
在0℃下向1.5g(4.7mmol)(5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)哌啶-2-酮(实施例1,步骤E)在9.4mL DMF中的溶液中加入氢化钠(60%悬浮液于矿物油中,244mg,6.1mmol)。将反应物在0℃下搅拌20min,然后用环丙基甲基溴(759μl,5621μmol)处理。在25℃下搅拌5h后,淬灭(NH4Cl饱和水溶液)反应物,萃取(2x EtOAc)。用NaCl饱和水溶液和NaHCO3溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过硅胶快速色谱法(30%至50%的EtOAc/己烷,梯度洗脱)纯化残余物,得到本标题化合物,为无色泡沫状物。
步骤B. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)哌啶-2-酮
在-78℃下向(5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)哌啶-2-酮(1481mg,3957μmol;实施例35,步骤A)和烯丙基溴(360μl,4155μmol)在THF(16mL,0.25M)中的溶液中逐滴加入双(三甲基甲硅烷基)氨基锂(1M溶液在THF中,4352μl,4352μmol)。在-78℃下搅拌3h后,淬灭(NH4Cl饱和水溶液)反应物,萃取(2x EtOAc)。用NaCl饱和水溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过快速色谱法(SiO2,20%至30%的EtOAc/Hex,梯度洗脱)纯化残余物,得到本标题化合物,为立体异构体的混合物。
通过HPLC在Chiralcel OD柱(洗脱剂:25%iPA/己烷)上分离各个立体异构体。
步骤C. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酸
如实施例1,步骤H中所述,将(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)哌啶-2-酮(实施例35,步骤B)转化成酸,从而得到本标题化合物,为白色固体。
1H NMR(400MHz,氯仿-d)δppm 7.48–7.46(1H,m),7.40(2H,d,J=8.6Hz),7.31–7.35(2H,m),7.22–7.26(1H,m),7.13(2H,d,J=8.6Hz),5.17(1H,s),4.24(1H,dd,J=14.1,6.7Hz),3.23–3.19(1H,m),2.96–2.78(1H,m),2.64–2.50(2H,m),2.36(1H,dd,J=14.1,7.8Hz),2.17–2.08(1H,m),1.93–1.83(1H,m),1.29–1.17(1H,m),0.77–0.69(1H,m),0.67–0.58(1H,m),0.37–0.25(2H,m);MS(ESI)432.1[M+H]+,429.9[M–H]–。
采用与针对实施例35描述的工艺类似的工艺,用适量的烷基溴和烷基碘替代步骤A中的(溴甲基)环丙烷来制备实施例36至40。
实施例36
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丁基甲基)-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,CDCl3)δppm 1.62-1.74(m,1H),1.75-1.84(m,2H),1.84-2.01(m,2H),2.03-2.17(m,2H),2.18-2.29(m,1H),2.53(dd,J=13.69和7.24Hz,1H),2.57-2.63(m,1H),2.63-2.70(m,1H),2.69-2.76(m,1H),2.76-2.85(m,1H),3.04-3.17(m,1H),4.25(dd,J=13.69和7.63Hz,1H),4.76-4.89(m,1H),7.07-7.17(m,1H),7.22(d,J=8.61Hz,2H),7.27-7.31(m,3H),7.39(d,J=8.61Hz,2H)。MS(ESI)446.2[M+H]+。
实施例37
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(2-乙基丁基)-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 7.37(2H,d,J=8.4Hz),7.27(2H,m),7.18(1H,s),7.15(2H,d,J=8.4Hz),7.03(1H,m),4.67(1H,d,J=7.5Hz),3.29(1H,m),3.09–2.97(3H,m),2.72(1H,dd,J=15.4,3.7Hz),2.20–2.00(2H,m),1.83(1H,m),1.68(1H,m),1.55–1.40(2H,m),0.89(3H,t,J=8.0Hz),0.55(3H,t,J=8Hz);MS(ESI)448.1[M–H]–。
实施例38
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环戊基甲基)-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 7.42(2H,d,J=8.4Hz),7.31(2H,m),7.24(1H,s),7.20(2H,d,J=8.4Hz),7.11(1H,m),4.93(1H,s),3.87(1H,m),3.16(1H,m),2.81(1H,dd,J=16.4,7.8Hz),2.68(1H,dd,J=16.4,3.9Hz),2.57(1H,m),2.12(1H,m),2.00(1H,m),1.90–1.65(6H,m),1.55–1.40(2H,m);MS(ESI)446.0[M–H]–。
实施例39
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2,2-二甲基环戊基)甲基)-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 7.41(2H,d,J=8.2Hz),7.39(1H,m),7.35–7.27(3H,m),7.13(2H,d,J=8.2Hz),4.93(1H,s),4.45(1H,m),3.20(2H,m),3.00(1H,dd,J=16.8,8.0Hz),2.51(1H,dd,J=16.8,3.3Hz),2.10(1H,m),1.90(1H,m),1.65–1.35(5H,m),0.88(3H,s),0.53(3H,s);MS(ESI)474.1[M–H]–。
实施例40
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环己基甲基)-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 7.41(2H,d,J=8.6Hz),7.35–7.27(3H,m),7.18(2H,d,J=8.6Hz),7.14(1H,m),4.95(1H,s),3.08(1H,m),2.90(1H,dd,J=15.8,9.2Hz),2.65(1H,m),2.51(1H,dd,J=15.8,2.7Hz),2.10(1H,m),1.90–1.55(4H,m),1.35–1.20(8H,m);MS(ESI)460.4[M–H]–。
实施例41
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酸
如实施例1,步骤H中所述,将(3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)哌啶-2-酮(实施例35,步骤B)转化成酸从而得到本标题化合物,为白色固体。
1H NMR(400MHz,氯仿-d)δppm 7.24(2H,d,J=8.2Hz),7.23–7.19(1H,m),7.17–7.12(1H,t,J=7.4Hz),7.01(1H,s),6.86(2H,d,J=8.2Hz),6.74(1H,d,J=7.4Hz),4.63(1H,d,J=10.2Hz),3.92(1H,dd,J=14.1,6.3Hz),3.12–2.92(3H,m),2.60(1H,dd,J=15.5,3.3Hz),2.34(1H,dd,J=14.1,7.4Hz),2.29–2.08(2H,m),0.95–0.85(1H,m),0.55–0.47(1H,m),0.46–0.39(1H,m),0.15–(–)0.02(2H,m);MS(ESI)432.0[M+H]+,429.9[M–H]–。
实施例42
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-丙基哌啶-3-基)乙酸
步骤A. (3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)哌啶-2-酮.
在配有磁力搅拌棒的100mL火焰干燥的圆底烧瓶中装入(5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)哌啶-2-酮(1.32g,4.12mmol)(实施例1,步骤E)和无水THF(41.2mL)。在氩气下将该溶液冷却至0℃并加入BuLi(3.30mL,8.24mmol)。在10分钟后,加入烯丙基溴(0.357mL,4.12mmol)。再过45分钟后,通过加入NH4Cl饱和水溶液淬灭反应物并分离各层。用EtOAc萃取水层两次,将有机物汇集在一起,用NaCl饱和水溶液洗涤,干燥(MgSO4),过滤并在真空中浓缩从而得到无色油状物。通过使用Combiflash Companion(快速柱色谱法,Teledyne Isco,Lincoln,NE)用120g SiO2柱,用10%至100%的EtOAc/己烷洗脱来进行纯化,得到本标题化合物。
1H NMR(400MHz,CDCl3)δppm 2.07(m,1H),2.15(m,1H),2.45(m,1H),2.69(m,1H),2.80(m,1H),2.88(m,1H),4.49(d,J=10.3Hz,1H),5.13(m,2H),5.82(br s,1H),5.84(m,1H),6.77(m,1H),6.95(d,J=8.4Hz,2H),7.01(m,1H),7.12(t,J=7.7Hz,1H),7.18(m,1H),7.21(d,J=8.6Hz,2H)。
步骤B. (3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-丙基哌啶-2-酮.
在0℃下向(3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)哌啶-2-酮(实施例42,步骤A)(70mg,0.19mmol)在430μL DMF中的溶液中加入氢化钠(60%悬浮液于矿物油中,20mg,0.51mmol)。将反应物在0℃下搅拌15min,然后用1-溴丙烷(53μL,0.58mmol)处理。在25℃下搅拌4h后,用NaHCO3饱和水溶液淬灭反应物并对其进行萃取(2x EtOAc)。用NaCl饱和水溶液和NaHCO3溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过硅胶制备板(25%EtOAc/己烷)纯化残余物,得到本标题化合物,为无色固体。
步骤C. 2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-丙基哌啶-3-基)乙酸
按照与实施例1,步骤H中描述的程序类似的程序,从(3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-丙基哌啶-2-酮(实施例42,步骤B)获得本标题化合物。通过硅胶制备板(5%MeOH/DCM)纯化,得到本标题化合物,为白色固体。
1H NMR(400MHz,CDCl3)δppm 0.78(t,J=7.34Hz,3H)1.33-1.45(m,1H)1.45-1.57(m,1H)2.05-2.21(m,2H)2.48(ddd,J=13.89,9.39和5.09Hz,1H)2.60(dd,J=15.94和4.79Hz,1H)2.96(dd,J=16.04和7.43Hz,1H)2.97-3.02(m,1H)3.02-3.12(m,1H)3.75(ddd,J=13.69,9.68和6.36Hz,1H)4.41(d,J=10.17Hz,1H)6.66-6.76(m,1H)6.87(d,J=8.41Hz,2H)6.97(t,J=1.66Hz,1H)7.12(t,J=7.83Hz,1H)7.16-7.20(m,1H)7.23(d,J=8.41Hz,2H)。MS(ESI)420.2[M+H]+。
实施例43
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丁基甲基)-2-氧代哌啶-3-基)乙酸
步骤A. (5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丁基甲基)哌啶-2-酮.
在0℃下向(3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)哌啶-2-酮(实施例42,步骤A)(70mg,0.19mmol)在430μL DMF中的溶液中加入氢化钠(60%悬浮液于矿物油中,20mg,0.51mmol)。将反应混合物在0℃下搅拌15min,并且在用(溴甲基)环丁烷(66μL,0.58mmol)处理后,将反应混合物加热70℃并保持15h。将反应混合物冷却至室温,用NaHCO3饱和水溶液淬灭并对其进行萃取(2x EtOAc)。用NaCl饱和水溶液和NaHCO3溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过硅胶制备板(25%EtOAc/己烷)纯化残余物,得到本标题化合物,为无色固体。
步骤B. 2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丁基甲基)-2-氧代哌啶-3-基)乙酸
如实施例1步骤H中所述从(5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丁基甲基)哌啶-2-酮(实施例43,步骤A)制备本标题化合物,并通过反相HPLC在Eclipse柱(45-60%的乙腈/水,梯度洗脱)上纯化,从而得到本标题化合物,为白色固体。
1H NMR(400MHz,CDCl3)δppm 1.52-1.69(m,2H),1.72-1.90(m,2H),1.91-2.09(m,3H),2.14(t,J=12.52Hz,1H),2.42(dd,J=13.50和7.43Hz,1H),2.46-2.57(m,1H),2.62(dd,J=16.43和6.85Hz,1H),2.86-3.01(m,2H),3.01-3.12(m,1H),4.05(dd,J=13.50和7.24Hz,1H),4.38(d,J=9.98Hz,1H),6.70(d,J=7.43Hz,1H),6.84(d,J=8.22Hz,2H),6.97(s,1H),7.12(t,J=7.83Hz,1H),7.16-7.20(m,1H),7.22(d,J=8.22Hz,2H)。MS(ESI)446.2[M+H]+。
实施例44
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-异丁基-2-氧代哌啶-3-基)乙酸.
步骤A. (3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-异丁基哌啶-2-酮
在0℃下向(3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)哌啶-2-酮(实施例42,步骤A)(78mg,0.22mmol)在480μL DMF中的溶液中加入叔丁醇钾(40mg,0.54mmol)。将反应混合物在0℃下搅拌15min,然后用1-溴代-2-甲基丙烷(82μL,0.76mmol)处理。在25℃下搅拌4h后,用NaHCO3饱和水溶液淬灭反应物并对其进行萃取(2x EtOAc)。用NaCl饱和水溶液和NaHCO3溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过硅胶制备板(25%EtOAc/己烷)纯化残余物,得到本标题化合物,为无色固体。
步骤B. 2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-异丁基-2-氧代哌啶-3-基)乙酸。
如实施例1,步骤H中所述从(3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-异丁基哌啶-2-酮(实施例44,步骤A)制备本标题化合物,得到白色固体。
1H NMR(400MHz,CDCl3)δppm 0.83(d,J=6.65Hz,3H),0.85(d,J=6.85Hz,3H),1.93(dq,J=8.39and 6.66Hz,1H),2.06-2.16(m,2H),2.17-2.24(m,1H),2.60(dd,J=15.85and 4.30Hz,1H),2.90-2.97(m,1H),2.97-3.03(m,1H),3.04-3.13(m,1H),3.86(dd,J=13.69and 8.80Hz,1H),4.41(d,J=10.17Hz,1H),6.68-6.76(m,1H),6.84(d,J=8.41Hz,2H),6.96(t,J=1.76Hz,1H),7.14(t,J=7.82Hz,1H),7.18-7.22(m,1H),7.24(m,2H)。MS(ESI)434.2[M+H]+。
实施例45
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环戊基甲基)-2-氧代哌啶-3-基)乙酸
步骤A. (3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-(环戊基甲基)哌啶-2-酮
如实施例44,步骤A中所述从(3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)哌啶-2-酮(实施例42,步骤A)和(溴甲基)环戊烷制备本标题化合物。通过硅胶制备板(25%EtOAc/己烷)纯化残余物,得到本标题化合物,为无色固体。
步骤B. 2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环戊基甲基)-2-氧代哌啶-3-基)乙酸。
如实施例1,步骤H中所述从(3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-(环戊基甲基)哌啶-2-酮(实施例45,步骤A)制备本标题化合物,得到白色固体。
1H NMR(500MHz,CDCl3)δppm 1.02-1.10(m,1H),1.12-1.19(m,1H),1.46-1.57(m,2H),1.59-1.71(m,4H),2.04-2.21(m,3H),2.32(dd,J=13.69和6.85Hz,1H),2.60(dd,J=15.77和4.03Hz,1H),2.92-3.01(m,2H),3.06(dd,J=11.98和7.09Hz,1H),4.02(dd,J=13.69和8.56Hz,1H),4.48(d,J=10.03Hz,1H),6.72(d,J=7.82Hz,1H),6.84(d,J=8.31Hz,2H),6.93-7.00(m,1H),7.14(t,J=7.70Hz,1H),7.18-7.22(m,1H),7.24(m,2H)。MS(ESI)460.2[M+H]+。
实施例46
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-(戊烷-3-基)哌啶-3-基)乙酸
步骤A. (3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-(戊烷-3-基)哌啶-2-酮
在室温下在氮气下向(3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)哌啶-2-酮(实施例42,步骤A)(440mg,1.221mmol)在3-溴戊烷(3196μL,25.6mmol)中的溶液中加入60%氢化钠在矿物油中的分散体(244mg,6.11mmol)。观察到气体逸出。将反应物在室温下搅拌10min,然后在N2下加热至120℃并保持19h。将反应混合物冷却至室温并用饱和NH4Cl淬灭。分离各层,并经Na2SO4干燥有机层并在减压下浓缩。通过硅胶快速色谱法(洗脱剂:0%至25%的EtOAc于己烷中)纯化残余物,以得到本标题化合物(375mg,71%产率),为非对映异构体的混合物。
步骤B. 2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-(戊烷-3-基)哌啶-3-基)乙酸
如实施例1步骤H中所述从(5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-1-(戊烷-3-基)哌啶-2-酮(实施例46,步骤A)制备本标题化合物。通过反相制备型HPLC(洗脱剂:0%至100%MeCN+0.1%TFA于水+0.1%TFA,超过20分钟)纯化,得到本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 0.55(t,J=7.53Hz,3H)0.94(t,J=7.34Hz,3H)1.32-1.54(m,2H)1.85(tt,J=14.38和7.24Hz,2H)2.04-2.12(m,1H)2.18(q,J=12.72Hz,1H)2.66(dd,J=16.14和4.40Hz,1H)2.85-3.01(m,2H)3.01-3.17(m,2H)4.33(d,J=9.98Hz,1H)6.71(d,J=7.63Hz,1H)6.90-7.01(m,3H)7.09-7.22(m,2H)7.23-7.26(m,1H)10.11(br.s.,1H)。质谱(ESI)m/z=448[M+H]+。
实施例47
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酸甲酯
在0℃下向250mg(0.578mmol)2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酸(实施例35)在MeOH(3mL)中的悬浮液中逐滴加入亚硫酰氯(78.0μl,1070μmol)。在25℃下搅拌14h后,稀释(EtOAc)反应物,碱化(饱和NaHCO3),萃取(2x EtOAc)。用NaCl饱和水溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液从而得到本标题化合物,为无色液体。
1H NMR(400MHz,氯仿-d)δppm 7.53–7.49(1H,m),7.39(2H,d,J=8.6Hz),7.31–7.28(2H,m),7.27–7.22(3H,m),5.12(1H,s),4.25–4.18(1H,m),3.69(3H,s),3.20–3.14(1H,m),2.85–2.82(1H,m),2.69–2.63(1H,m),2.60–2.53(1H,m),2.33–2.20(2H,m),1.85–1.77(1H,m),1.20–1.15(1H,m),0.70–0.63(1H,m),0.61–0.53(1H,m),0.30–0.20(2H,m);MS(ESI)445.9[M+H]+。
实施例48
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酰胺
在密封管中,将60mg(134μmol)2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酸甲酯(实施例47)和4.8mL氨在甲醇(7N,3.4mmol)中的溶液在25℃下搅拌5天。然后加入NaCN(3mg)并将由此产生的溶液在50℃下搅拌3天。在减压下除去多余的NH3和MeOH。通过反相HPLC(10%至90%的AcCN/H2O,超过45min)分离,得到本标题化合物,为无色固体。
1H NMR(400MHz,氯仿-d)δppm 7.52–7.45(1H,m),7.37(2H,d,J=8.2Hz),7.33–7.29(2H,m),7.26–7.22(1H,m),7.17(2H,d,J=8.6Hz),6.40(1H,br.s.),5.42(1H,br.s.),5.11(1H,br.s.),4.21(1H,dd,J=14.1,6.3Hz),3.20–3.16(1H,m),2.77–2.70(1H,m),2.60–2.48(2H,m),2.33–2.25(2H,m),1.92–1.85(1H,m),1.22–1.15(1H,m),0.72–0.64(1H,m),0.62–0.54(1H,m),0.32–0.20(2H,m);MS(ESI)430.9[M+H]+。
实施例49
2-(2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酰氨基)乙酸乙酯
在0℃下依次用N1-((乙基亚氨基)亚甲基)-N3,N3-二甲基丙烷-1,3-二胺盐酸盐(27mg,139μmol)、3H-[1,2,3]三唑并[4,5-b]吡啶-3-醇(19mg,139μmol),和碳酸氢钠(23mg,278μmol)处理40mg(93μmol)2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酸(实施例35)和2-氨基乙酸乙酯盐酸盐(14mg,102μmol)在DMF(0.31mL)中的溶液。在25℃下搅拌12h后,用水稀释反应物并用EtOAc萃取。依次用10%柠檬酸水溶液、NaHCO3饱和水溶液和NaCl饱和水溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过快速色谱法(SiO2,40%至60%的EtOAc/己烷,梯度洗脱)纯化残余物,得到本标题化合物,为无色膜状物。
1H NMR(400MHz,氯仿-d)δppm 7.51–7.47(1H,m),7.35(2H,d,J=8.6Hz),7.32–7.28(2H,m),7.26–7.24(1H,m),7.16(2H,d,J=8.2Hz),6.89(1H,br,s),5.11(1H,s),4.27–4.18(3H,m),4.11–3.98(2H,m),3.20–3.15(1H,d,J=1.6Hz),2.83–2.72(1H,m),2.63–2.55(2H,m),2.32–2.16(2H,m),1.95–1.87(1H,m),1.29(3H,t,J=7.0Hz),1.22–1.12(1H,m),0.72–0.62(1H,m),0.60–0.52(1H,m),0.30–0.18(2H,m);MS(ESI)516.8[M+H]+。
实施例50
2-(2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酰氨基)乙酸
在25℃下向38mg(73μmol)2-(2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酰氨基)乙酸乙酯(实施例49)在0.75mL MeOH/THF/H2O(2/2/1)中的溶液中加入2M氢氧化锂水溶液(70μl,141μmol),并将混合物搅拌10h。酸化(1NHCl水溶液)反应物并用DCM(2X)萃取。依次用10%柠檬酸水溶液和NaCl饱和水溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过反相HPLC(10%至90%的含有0.1%TFA的AcCN/H2O,超过45min)纯化残余物,得到本标题化合物,为白色固体。
1H NMR(400MHz,氯仿-d)δppm 7.37–7.34(1H,m),7.35(2H,d,J=8.2Hz),7.27–7.25(1H,m),7.23–7.19(1H,m),7.17–7.14(1H,m),7.08(2H,d,J=8.2Hz),5.00(1H,d,J=3.9Hz),4.18–4.08(2H,m),4.07–3.99(1H,m),3.23–3.18(1H,m),2.83–2.75(2H,m),2.72–2.64(1H,m),2.35–2.23(2H,m),2.05–1.95(1H,m),1.16–1.05(1H,d,J=1.2Hz),0.68–0.60(1H,m),0.58–0.50(1H,m),0.27–0.13(2H,m);MS(ESI)488.8[M+H]+,486.9[M–H]–.
实施例51
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酰肼
向120mg(0.27mmol)2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酸甲酯(实施例47)在EtOH中的溶液中加入肼一水合物(135μl,2688μmol)。在回流14h后,浓缩反应物,稀释(H2O)并萃取(2x EtOAc)。用NaCl饱和水溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过硅胶快速色谱法(5%MeOH/CH2Cl2,梯度洗脱)纯化残余物,得到本标题化合物,为白色固体。
1H NMR(400MHz,氯仿-d)δppm 7.52–7.46(1H,m),7.37(2H,d,J=8.6Hz),7.33–7.28(2H,m),7.26–7.22(1H,m),7.15(2H,d,J=8.6Hz),5.10(1H,s),4.20(1H,dd,J=14.1,6.7Hz),3.20–3.15(1H,m),2.71–2.63(1H,m),2.60–2.48(2H,m),2.31–2.18(1H,m),1.92–1.82(1H,m),1.20–1.10(1H,dt,J=7.9,3.3Hz),0.70–0.63(1H,m),0.59–0.52(1H,m),0.30–0.18(2H,m);MS(ESI)445.9[M+H]+。
实施例52
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)-N-羟基乙酰胺
依次用N1-((乙基亚氨基)亚甲基)-N3,N3-二甲基丙烷-1,3-二胺盐酸盐(0.03g,0.1mmol)、3H-[1,2,3]三唑并[4,5-b]吡啶-3-醇(0.02g,0.1mmol)、羟胺盐酸盐(0.006ml,0.1mmol)和碳酸氢钠(0.02g,0.2mmol)处理30mg(0.07mmol)2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酸(实施例35)在DMF中的溶液(0.5mL,c=0.14M)。在25℃下搅拌12h后,用水稀释反应物并用EtOAc萃取。依次用NaHCO3饱和水溶液和NaCl饱和水溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过反相HPLC(10%至90%的含有0.1%TFA的AcCN/H2O,超过45min)纯化残余物,得到本标题化合物,为白色固体。
1H NMR(400MHz,氯仿-d)δppm 7.45(1H,s),7.41–7.16(5H,m),7.16–6.98(2H,m),5.10(1H,br.s.),4.26–4.13(1H,m),3.25–3.17(1H,m),2.65(3H,br.s.),2.30(2H,dd,J=14.1,7.8Hz),1.91(1H,br.s.),1.15(1H,d,J=2.0Hz),0.77–0.65(1H,m),0.65–0.51(1H,m),0.37–0.14(2H,m)。
实施例53
(S)-2-((2S,3R,5R)-3-(3-氯苯基)-2-(4-氯苯基)-5-(2-(甲基磺酰氨基)-2-氧代乙基)-6-氧代哌啶-1-基)丁酸乙酯
将甲烷磺酰胺(0.02g,0.2mmol)、N-乙基-N-异丙基丙烷-2-胺(0.05ml,0.3mmol)、二(1H-咪唑-1-基)甲酮(0.04g,0.2mmol)和2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-1-乙氧基-1-氧代丁烷-2-基)-2-氧代哌啶-3-基)乙酸(实施例3,0.030g,0.06mmol)合并在2mL THF中。在25℃下搅拌12h后,加入NH4Cl饱和溶液并用EtOAc萃取反应混合物。依次用NaHCO3饱和水溶液和NaCl饱和水溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过反相HPLC(10%至90%的含有0.1%TFA的AcCN/H2O,超过45min)纯化残余物,得到本标题化合物,为白色固体。
1H NMR(400MHz,氯仿-d)δppm 7.45–7.33(3H,m),7.33–7.21(5H,m),4.88(1H,d,J=3.9Hz),4.27–4.10(2H,m),3.48(1H,dd,J=8.8,3.3Hz),3.30(3H,s),3.20(1H,dd,J=4.7,0.8Hz),3.04–2.74(2H,m),2.72–2.59(1H,m),2.48–2.28(2H,m),2.03(1H,s),1.63–1.46(1H,m),1.28(3H,t,J=7.2Hz),0.69(3H,t,J=7.4Hz)。
实施例54
(S)-2-((2S,3R,5R)-3-(3-氯苯基)-2-(4-氯苯基)-5-(2-((3-吗啉代丙基)氨基)-2-氧代乙基)-6-氧代哌啶-1-基)丁酸乙酯
使用2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-1-乙氧基-1-氧代丁烷-2-基)-2-氧代哌啶-3-基)乙酸(实施例3)作为原料,如实施例49中所述制备本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 7.34(2H,d,J=8.6Hz),7.30–7.16(5H,m),7.11–7.03(1H,m),4.73(1H,d,J=5.5Hz),4.14(2H,q,J=7.3Hz),4.09–3.92(4H,m),3.67–3.51(2H,m),3.50–3.40(1H,m),3.39–3.30(2H,m),3.25(1H,dd,J=8.8,3.3Hz),3.22–3.12(2H,m),2.98–2.50(5H,m),2.33–2.03(5H,m),1.52–1.37(0H,m),1.26(3H,t,J=7.2Hz),0.60(3H,t,J=7.4Hz)。
实施例55
(3R,5R,6S)-3-((1H-四唑-5-基)甲基)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)哌啶-2-酮
步骤A. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙腈
在0℃下用三氟乙酸酐(111μl,788μmol)处理136mg(0.315mmmol)2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酰胺(实施例48)和三乙胺(220μl,1576μmol)在5mL THF中的溶液。在0℃下搅拌2h后,淬灭(饱和NH4Cl)反应物,萃取(2×EtOAc)并洗涤(NaCl饱和水溶液)。干燥(Na2SO4)合并的有机层并在减压下浓缩。在0℃下搅拌2h后,加入NH4Cl饱和溶液并用EtOAc萃取反应混合物。用NaCl饱和水溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过快速色谱法(SiO2,20-25%的EtOAc/己烷)纯化残余物,得到本标题化合物,使用该物质而无需进一步纯化。
步骤B. (3R,5R,6S)-3-((1H-四唑-5-基)甲基)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)哌啶-2-酮
向136mg(0.33mmol)2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙腈(实施例55,步骤A)在1.8mL DMF中的溶液中加入氯化铵(176mg,3290μmol)和叠氮化钠(214mg,3290μmol)。将由此产生的混合物在90℃下搅拌4天。然后,酸化(10%柠檬酸水溶液)反应物并对其进行萃取(2x EtOAc)。用NaCl饱和水溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过反相HPLC(60-90%的AcCN/H2O,30min内)分离,得到本标题化合物,为白色固体。
1H NMR(400MHz,氯仿-d)δppm 7.51–7.48(1H,s),7.35(2H,d,J=8.2Hz),7.32–7.28(2H,m),7.25–7.21(1H,m),6.86(2H,d,J=8.2Hz),5.14(1H,s),4.23(1H,dd,J=14.1,6.7Hz),3.40(1H,dd,J=15.3,3.1Hz),3.28–3.20(1H,m),3.15(1H,dd,J=15.1,8.0Hz),2.60–2.52(1H,m),2.33(1H,dd,J=14.1,8.2Hz),2.26–2.18(2H,br.s.),2.04–1.93(1H,m),1.25–1.15(1H,m),0.77–0.70(1H,m),0.68–0.59(1H,m),0.36–0.24(2H,m);MS(ESI)456.0[M+H]+,453.9[M–H]–。
实施例56
(3R,5R,6S)-3-((1,3,4-噁二唑-2-基)甲基)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)哌啶-2-酮
向20mg(45μmol)2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酰肼(实施例51)在0.2mL甲苯中的溶液中加入甲亚氨酸乙酯盐酸盐(6.4mg,58μmol)。将反应混合物加热至回流达14h,然后在减压下浓缩反应物。通过反相HPLC(10%至90%的AcCN/H2O,40min内)分离,得到本标题化合物,为无色膜状物。
1H NMR(400MHz,氯仿-d)δppm 8.35(1H,s),7.50–7.45(1H,m),7.37(2H,d,J=8.6Hz),7.34–7.28(2H,m),7.26–7.22(1H,m),7.13(2H,d,J=8.6Hz),5.13(1H,s),4.22–4.17(1H,m),3.38–3.35(2H,m),3.24–3.18(1H,m),2.80–2.72(1H,m),2.35–2.28(1H,m),2.25–2.18(1H,m),1.96–1.86(1H,m),1.21–1.12(1H,m),0.70–0.62(1H,m),0.61–0.54(1H,m),0.30–0.20(2H,m);MS(ESI)456.0[M+H]+。
实施例57
(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-3-((5-甲基-1,3,4-噁二唑-2-基)甲基)哌啶-2-酮
向40mg(90μmol)2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酰肼(实施例51)在0.2mL甲苯中的溶液中加入乙亚氨酸甲酯盐酸盐(13mg,116μmol)。将反应混合物加热至回流达14h,然后在减压下浓缩反应物。通过反相HPLC(10%至90%的AcCN/H2O,45min内)分离,得到本标题化合物,为无色膜状物。
1H NMR(400MHz,氯仿-d)δppm 7.47–7.45(1H,s),7.38(2H,d,J=8.6Hz),7.33–7.29(2H,m),7.24–7.19(1H,m),7.15(2H,d,J=8.6Hz),5.12–5.10(1H,m),4.18(1H,dd,J=14.1,6.7Hz),3.38–3.23(2H,m),3.22–3.18(1H,m),2.80–2.72(1H,m),2.54(3H,s),2.36–2.22(2H,m),1.94–1.88(1H,m),1.20–1.10(1H,m),0.70–0.63(1H,m),0.60–0.52(1H,m),0.30–0.20(2H,m);MS(ESI)469.9[M+H]+。
实施例58
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)-N-(甲基磺酰基)乙酰胺.
向2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酸(实施例41)(83mg,0.192mmol)、甲烷磺酰胺(22.59mg,0.230mmol)和4-二甲基氨基吡啶(1.057mg,.00865mmol)在DCM(2mL)中的溶液中加入二异丙基乙胺(80μL,0.461mmol)。将反应混合物在室温下搅拌1分钟,然后加入三吡咯烷基溴化鏻六氟磷酸盐(125mg,0.269mmol)。将反应混合物在室温下搅拌3小时。用1N HCl淬灭反应物并用DCM(10mL)萃取水层。用1N HCl、1N NaOH、NaCl饱和水溶液洗涤合并的有机层,并在减压下浓缩。通过反相制备型HPLC(柱:Gemini-NX C185um柱;Phenomonex,Torrance,CA;洗脱剂:0%至100%MeCN+0.1%TFA于水+0.1%TFA中,超过20分钟)纯化残余物,以得到本标题化合物。
1H NMR(400MHz,氯仿-d)δppm-0.06-0.04(m,1H)0.06-0.16(m,1H)0.43(dd,J=8.51和4.60Hz,1H)0.47-0.60(m,1H)0.88(d,J=6.26Hz,1H)2.09-2.18(m,1H)2.29(dt,J=14.04和6.77Hz,2H)2.62(dd,J=15.26和3.52Hz,1H)2.90(dd,J=15.26和7.63Hz,1H)3.02(t,J=2.64Hz,1H)3.14(d,J=3.72Hz,1H)3.32(s,3H)3.93(dd,J=14.28和6.26Hz,2H)4.64(d,J=10.17Hz,1H)6.74(d,J=7.63Hz,1H)6.85-6.91(m,2H)7.00(d,J=1.76Hz,1H)7.10-7.26(m,4H)。质谱(ESI)m/z=509[M+H]+。
实施例59
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酰胺.
步骤A. 2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酸甲酯
向2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酸(实施例41)(500mg,1.156mmol)在含10%MeOH的DCM(10mL)中的溶液中加入(三甲基甲硅烷基)重氮甲烷(2.0M在乙醚中)(1mL)。将黄色反应混合物在室温下搅拌30min。在减压下浓缩反应物,并通过硅胶快速色谱法(洗脱剂:0%至50%的在己烷中的EtOAc)纯化,从而得到本标题化合物,为透明油状物。
步骤B. 2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酰胺.
在密封管中装入2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酸甲酯(实施例59,步骤A)(109mg,0.244mmol)、氨在甲醇中的7N溶液(2ml,14.00mmol)和氰化钠(1.197mg,0.024mmol)。密封该管并将其加热至50℃。在1小时后压力达到35千帕。将反应物在50℃下搅拌18h。将反应物冷却至室温,并于室温下在该溶液中鼓入无水氨(气体)达10分钟。将反应混合物加盖并加热至50℃并保持18h。将反应物冷却至室温,并于室温下在该溶液中鼓入无水氨(气体)20分钟。将反应混合物加盖并加热至50℃并保持2天。在减压下浓缩粗反应物,并通过反相制备型HPLC(柱:Gemini-NX C185um柱;Phenomonex,Torrance,CA;洗脱剂:0%至100%MeCN+0.1%TFA于水+0.1%TFA中,超过20分钟)纯化从而得到本标题化合物。
1H NMR(400MHz,氯仿-d)δppm-0.05-0.04(m,1H)0.06-0.15(m,1H)0.36-0.45(m,1H)0.46-0.56(m,1H)0.79-0.93(m,1H)2.11-2.20(m,1H)2.29(dt,J=13.99,6.90Hz,1H)2.64-2.73(m,1H)2.75-2.83(m,1H)2.96-3.13(m,2H)3.91(dd,J=14.09,6.46Hz,1H)4.63(d,J=9.98Hz,1H)6.41(br.s.,1H)6.75(dt,J=7.58,1.59Hz,2H)6.83-6.90(m,2H)7.01(t,J=1.96Hz,1H)7.10-7.26(m,4H).质谱(ESI)m/z=431[M+H]+。
实施例60
(3S,5R,6S)-3-((1H-四唑-5-基)甲基)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)哌啶-2-酮
步骤A. (3S,5R,6S)-3-((1H-四唑-5-基)甲基)-5-(3-氯苯基)-6-(4-氯苯基)哌啶-2-酮
将100mL圆底烧瓶放置在真空下并用加热枪加热以确保干燥。让该烧瓶冷却至室温,并在氩气下加入500mg(1.56mmol)(5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)哌啶-2-酮(实施例1,步骤E)在THF(12mL)中的溶液,并冷却至0℃。加入丁基锂(1.6M在己烷中,2440μL,3.90mmol),接着加入5-氯甲基-1H-四唑(185mg,1.561mmol),并将反应混合物在0℃下搅拌15分钟。用饱和氯化铵溶液淬灭反应物并用乙酸乙酯萃取。用1M HCl酸化水层。用乙酸乙酯(2x30mL)萃取水层,并用NaCl饱和水溶液洗涤合并的有机层,经硫酸钠干燥,并在减压下浓缩。通过反相制备型HPLC(柱:Gemini-NX C185um柱;Phenomonex,Torrance,CA;洗脱剂:0%至100%MeCN+0.1%TFA于水+0.1%TFA中,超过25分钟)纯化残余物,以得到本标题化合物。
步骤B. (3S,5R,6S)-3-((1H-四唑-5-基)甲基)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)哌啶-2-酮
将(3S,5R,6S)-3-((1H-四唑-5-基)甲基)-5-(3-氯苯基)-6-(4-氯苯基)哌啶-2-酮(实施例60,步骤A)(65mg,0.162mmol)在DMF(1.6mL)中的溶液冷却至0℃并加入叔丁醇钠(31.1mg,0.323mmol)。将反应混合物在0℃下搅拌10分钟,然后加入(溴甲基)环丙烷(78μL,0.808mmol)。将反应混合物升温至室温并搅拌16小时,用饱和氯化铵淬灭,并用水和乙酸乙酯稀释。用乙酸乙酯萃取水层,且合并有机层,用1M LiCl、NaCl饱和水溶液洗涤,经硫酸钠干燥,并在减压下浓缩。通过反相制备型HPLC(柱:Gemini-NX C185um柱;Phenomonex,Torrance,CA;洗脱剂:0%至100%MeCN+0.1%TFA于水+0.1%TFA中,超过20分钟)纯化残余物,以得到本标题化合物。
1H NMR(400MHz,氯仿-d)δppm-0.08-0.02(m,1H)0.11(dt,J=9.44和4.77Hz,1H)0.38-0.46(m,1H)0.50(td,J=8.31和4.50Hz,1H)0.78-0.89(m,1H)2.18-2.28(m,2H)2.31-2.41(m,1H)2.96-3.07(m,2H)3.29(dd,J=14.87和7.82Hz,1H)3.47-3.56(m,1H)3.89(dd,J=14.09和6.46Hz,1H)4.58(d,J=9.98Hz,1H)6.71-6.76(m,1H)6.80-6.87(m,2H)6.98(d,J=1.76Hz,1H)7.12-7.18(m,1H)7.19-7.25(m,3H)。质谱(ESI)m/z=456[M+H]+。
实施例61
(3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-3-((5-甲基异噁唑-3-基)甲基)哌啶-2-酮
如实施例60中所述,从(5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)哌啶-2-酮(实施例1,步骤E)、3-(溴甲基)-5-甲基异噁唑,和(溴甲基)环丙烷制备本标题化合物。
1H NMR(400MHz,氯仿-d)δppm-0.05-0.04(m,1H)0.05-0.14(m,1H)0.32-0.41(m,1H)0.42-0.51(m,1H)0.79-0.94(m,1H)2.04-2.09(m,2H)2.28(dd,J=14.28和7.24Hz,1H)2.37(d,J=0.59Hz,3H)2.86-3.04(m,3H)3.33-3.41(m,1H)3.93(dd,J=14.18和6.55Hz,1H)4.56(d,J=9.98Hz,1H)5.92(d,J=0.78Hz,1H)6.70(dt,J=7.58和1.30Hz,1H)6.80-6.86(m,2H)6.95(t,J=1.76Hz,1H)7.06-7.11(m,1H)7.13-7.17(m,1H)7.17-7.23(m,2H)。质谱(ESI)m/z=469[M+H]+。
实施例62
(外消旋)2-((2′S,3′R,5′R)-6-氯代-3′-(3-氯苯基)-1′-(环丙基甲基)-2,6′-二氧代螺[二氢吲哚-3,2′-哌啶]-5′-基)乙酸.
步骤A. 1-(3-氯苯基)戊-4-烯-1-酮
向3-氯苯甲酰氯(7ml,54.7mmol)在THF(60mL)中的溶液中加入碘化亚铜(I)(0.521g,2.73mmol)。将该浆液冷却至-10℃并用超过30min的时间经由插管逐滴加入3-丁烯基溴化镁(0.5M在THF中)(112ml,55.8mmol)。将反应混合物在-10℃下搅拌1h,然后升温至室温。将反应混合物浓缩至25mL并用100mL DCM和100mL 1M HCl稀释。分离各层并对有机层进行过滤。用饱和NaHCO3洗涤滤液,经Na2SO4干燥并在减压下浓缩。通过硅胶快速色谱法(洗脱剂:0%至50%的在己烷中的DCM)纯化残余物,从而得到本标题化合物。
步骤B. 6-氯代-3-(1-(3-氯苯基)戊-4-烯亚基)二氢吲哚-2-酮
在室温下向1-(3-氯苯基)戊-4-烯-1-酮(实施例62,步骤A)(14.86g,76mmol)和6-氯二氢吲哚-2-酮(12.79g,76mmol)在甲苯(50mL)中的混合物中加入吡咯烷(6.31mL,76mmol)。用Dean-Stark蒸馏器(trap)将该浆液在回流下加热6h。将反应混合物冷却至室温,并在减压下浓缩。通过硅胶快速色谱法(洗脱剂:10%至20%的在己烷中的EtOAc)纯化残余物从而得到本标题化合物。
步骤C. 6-氯代-3-(1-(3-氯苯基)戊-4-烯基)二氢吲哚-2-酮
在室温下向6-氯代-3-(1-(3-氯苯基)戊-4-亚烯基)二氢吲哚-2-酮(实施例62,步骤B)(12.81g,37.2mmol)在MeOH(200mL)中的黄色浆液中缓慢地加入硼氢化钠(1.689g,44.7mmol)。观察到气体逸出。将该黄色反应混合物在室温下搅拌30min。再缓慢地加入硼氢化钠(1.689g,44.7mmol),并将反应混合物在室温下搅拌1h。将反应混合物倒入水(200mL)中。有沉淀形成,将该混合物超声处理15min,然后过滤。在减压下浓缩滤液至36mL,然后用EtOAc萃取两次。合并有机层,经Na2SO4干燥并在减压下浓缩从而得到本标题化合物。
步骤D. 3-溴代-6-氯代-3-(1-(3-氯苯基)戊-4-烯基)二氢吲哚-2-酮
经由添加漏斗在-78℃下在Ar下向6-氯代-3-(1-(3-氯苯基)戊-4-烯基)二氢吲哚-2-酮(实施例62,步骤C(13.0g,37.5mmol)在THF(200mL)(此前用Ar脱气)中的溶液中加入N1,N1,N2,N2-四甲基乙烷-1,2-二胺(11.79mL,79mmol)(此前用Ar脱气)和丁基锂(1.6M在己烷中)(49.3mL,79mmol)(此前用Ar脱气)。将淡棕色反应混合物在-78℃下搅拌30min.,将其包裹在箔中,并经由插管加入在THF(50mL)(此前用Ar脱气)中的重结晶的1-溴吡咯烷-2,5-二酮(6.68g,37.5mmol)。添加后,立即用饱和磷酸二氢钾(potassium phosphate monobasic)淬灭反应物并升温至室温。用EtOAc萃取该混合物两次。合并有机层,经Na2SO4干燥并在减压下浓缩。通过硅胶快速色谱法(洗脱剂:0%至10%EtOAc在己烷中)纯化残余物从而得到本标题化合物,为1:1.7比例的非对映异构体。
步骤E. 4-(3-溴代-6-氯代-2-氧代二氢吲哚-3-基)-4-(3-氯苯基)丁酸
向快速搅拌着的3-溴代-6-氯代-3-(1-(3-氯苯基)戊-4-烯基)二氢吲哚-2-酮(实施例62,步骤D)(7.74g,18.21mmol)在H2O/CCl4/MeCN(1.5/1/1)(80mL/50mL/50mL)中的溶液中加入高碘酸钠(15.58g,72.8mmol)和氯化钌(III)水合物(0.205g,0.910mmol)。将反应混合物剧烈搅拌30min并通过TLC监测反应。酸化(10%柠檬酸)反应混合物并用EtOAc萃取。用NaCl饱和水溶液洗涤有机层,经Na2SO4干燥并在减压下浓缩。通过硅胶快速色谱法(洗脱剂:30%至70%EtOAc在己烷中)纯化残余物从而得到本标题化合物。
步骤F. 4-(3-溴代-6-氯代-2-氧代二氢吲哚-3-基)-4-(3-氯苯基)丁酸甲酯
在室温下向4-(3-溴代-6-氯代-2-氧代二氢吲哚-3-基)-4-(3-氯苯基)丁酸(实施例62,步骤E)(5.38g,12.14mmol)在MeOH(120mL)中的溶液中加入1滴浓硫酸。将反应混合物在室温下搅拌18h,然后在减压下浓缩。通过硅胶快速色谱法(洗脱剂:0%至50%EtOAc在己烷中)纯化残余物从而得到本标题化合物。
步骤G. (外消旋)(S)-4-((S)-6-氯代-3-(环丙基甲基氨基)-2-氧代二氢吲哚-3-基)-4-(3-氯苯基)丁酸甲酯和(外消旋)(R)-4-((S)-6-氯代-3-(环丙基甲基氨基)-2-氧代二氢吲哚-3-基)-4-(3-氯苯基)丁酸甲酯
将4-(3-溴代-6-氯代-2-氧代二氢吲哚-3-基)-4-(3-氯苯基)丁酸甲酯(实施例62,步骤F)(110mg,0.241mmol)在DCE(4mL)中的溶液在回流下加热。一次性加入在DCE(1mL)中的碳酸铯(157mg,0.481mmol)和环丙基甲胺盐酸盐(25.9mg,0.241mmol)。将反应混合物在回流下加热5h,然后将其冷却至室温。通过celite过滤反应混合物并用DCM洗涤。浓缩滤液并通过硅胶快速色谱法(洗脱剂:20%至60%EtOAc在己烷中)分离非对映异构体对从而得到本标题化合物。将极性较大的异构体用于实施例62,步骤H中。
步骤H. (外消旋)(2′S,3′R)-6-氯代-3′-(3-氯苯基)-1′-(环丙基甲基)螺[二氢吲哚-3,2′-哌啶]-2,6′-二酮
用饱和NaHCO3洗涤(外消旋)(R)-4-((S)-6-氯代-3-(环丙基甲基氨基)-2-氧代二氢吲哚-3-基)-4-(3-氯苯基)丁酸甲酯(实施例62,步骤G,极性较大的异构体)在DCM中的溶液,经Na2SO4干燥并在减压下浓缩。将残余物溶解在蒸馏的二甲苯(5mL),并将反应混合物加热至135℃并保持24h。将反应混合物冷却至室温并在减压下浓缩。通过硅胶快速色谱法(洗脱剂:20%至60%EtOAc在己烷中)纯化残余物从而得到本标题化合物。
步骤I. (外消旋)(2′S,3′R)-6-氯代-3′-(3-氯苯基)-1′-(环丙基甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)螺[二氢吲哚-3,2′-哌啶]-2,6′-二酮
向0℃下的(外消旋)(2′S,3′R)-6-氯代-3′-(3-氯苯基)-1′-(环丙基甲基)螺[二氢吲哚-3,2′-哌啶]-2,6′-二酮(实施例62,步骤H)(114mg,0.274mmol)在DMF(2mL)中的溶液中加入60%氢化钠在矿物油中的分散体(10.98mg,0.274mmol),接着加入(2-(氯甲氧基)乙基)三甲基甲硅烷(48.4μL,0.274mmol)。将反应混合物在0℃下搅拌30min,然后升温至室温并在室温下搅拌24h。将反应混合物倒入冰水中并用EtOAc萃取。用1M LiCl、NaCl饱和水溶液洗涤有机层,经Na2SO4干燥并在减压下浓缩。通过硅胶快速色谱法(洗脱剂:0%至50%EtOAc在己烷中)纯化残余物从而得到本标题化合物。
步骤J. (外消旋)(2′S,3′R,5′S)-5′-烯丙基-6-氯代-3′-(3-氯苯基)-1′-(环丙基甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)螺[二氢吲哚-3,2′-哌啶]-2,6′-二酮
在-78℃在Ar下向(外消旋)(2′S,3′R)-6-氯代-3′-(3-氯苯基)-1′-(环丙基甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)螺[二氢吲哚-3,2′-哌啶]-2,6′-二酮(实施例62,步骤I)(97mg,0.178mmol)在THF(1mL)中的溶液中加入新制备的LDA(1.0M在THF中)(178μL,0.178mmol)。反应物颜色变成黄橙色。将反应物在-78℃下搅拌30min,然后加入蒸馏的烯丙基溴(15.39μL,0.178mmol)。将反应物在-78℃下搅拌10min,然后升温至0℃。用饱和NH4Cl淬灭反应物并升温至室温。用EtOAc稀释该混合物并分离各层。经Na2SO4干燥有机层并在减压下浓缩。通过硅胶快速色谱法(洗脱剂:0%至25%EtOAc在己烷中)纯化残余物从而得到本标题化合物。
步骤K. (外消旋)2-((2′S,3′R,5′R)-6-氯代-3′-(3-氯苯基)-1′-(环丙基甲基)-2,6′-二氧代-1-((2-(三甲基甲硅烷基)乙氧基)甲基)螺[二氢吲哚-3,2′-哌啶]-5′-基)乙酸
向快速搅拌着的(外消旋)(2′S,3′R,5′S)-5′-烯丙基-6-氯代-3′-(3-氯苯基)-1′-(环丙基甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)螺[二氢吲哚-3,2′-哌啶]-2,6′-二酮(实施例62,步骤J)(46mg,0.079mmol)在H2O/CCl4/MeCN(0.75ml/.5mL/.5mL)中的溶液中加入高碘酸钠(67.2mg,0.314mmol)和氯化钌(III)水合物(1.771mg,7.85μmol)。将反应混合物剧烈搅拌19h,然后酸化(10%柠檬酸),通过celite塞过滤并用EtOAc洗涤。将滤液转移至分液漏斗并用EtOAc萃取。经Na2SO4干燥有机层,并在减压下浓缩从而得到本标题化合物。
步骤L. (外消旋)2-((2′S,3′R,5′R)-6-氯代-3′-(3-氯苯基)-1′-(环丙基甲基)-1-(羟基甲基)-2,6′-二氧代螺[二氢吲哚-3,2′-哌啶]-5′-基)乙酸
在室温下向(外消旋)2-((2′S,3′R,5′R)-6-氯代-3′-(3-氯苯基)-1′-(环丙基甲基)-2,6′-二氧代-1-((2-(三甲基甲硅烷基)乙氧基)甲基)螺[二氢吲哚-3,2′-哌啶]-5′-基)乙酸(实施例62,步骤K)(47mg,0.078mmol)在DCM(0.8mL)中的溶液中加入0.2mL TFA。将反应混合物在室温下搅拌19h,然后在减压下浓缩。通过硅胶快速色谱法(洗脱剂:50%至100%EtOAc在己烷中)纯化残余物从而得到本标题化合物。
步骤M. (外消旋)2-((2′S,3′R,5′R)-6-氯代-3′-(3-氯苯基)-1′-(环丙基甲基)-2,6′-二氧代螺[二氢吲哚-3,2′-哌啶]-5′-基)乙酸
在室温下向(外消旋)2-((2′S,3′R,5′R)-6-氯代-3′-(3-氯苯基)-1′-(环丙基甲基)-1-(羟基甲基)-2,6′-二氧代螺[二氢吲哚-3,2′-哌啶]-5′-基)乙酸(实施例62,步骤L)(12.6mg,0.025mmol)在MeOH(1mL)中的溶液中加入DIEA(8.74μL,0.050mmol)。将反应混合物在室温下搅拌1h。用10%柠檬酸淬灭反应物并在减压下浓缩。通过反相制备型HPLC(柱:Gemini-NX C185um柱;Phenomonex,Torrance,CA;洗脱剂:0%至100%MeCN+0.1%TFA于水+0.1%TFA中)纯化残余物从而得到本标题化合物。
1H NMR(400MHz,乙腈-d3)δppm-0.25--0.18(1H,m)-0.12--0.04(1H,m)0.20-0.34(2H,m)0.66-0.77(1H,m)1.64-1.73(1H,m)2.68(1H,dd,J=14.3和7.0Hz)2.73-2.81(1H,m)2.86-3.02(1H,m)3.12-3.33(3H,m)3.53-3.65(1H,m)6.61(1H,d,J=1.8Hz)6.79-6.91(2H,m)7.08(1H,t,J=7.8Hz)7.11-7.20(2H,m)7.49(1H,d,J=8.2Hz)8.29(1H,br s)。质谱(ESI)m/z=473[M+H]+。
实施例63
2-((3R,5R,6S)-5-(3-氯苯基)-6-(5-氯噻吩-2-基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酸
步骤A. 2-(3-氯苯基)-1-(5-氯噻吩-2-基)乙酮
向500-mL圆底烧瓶中加入硅胶60(21g,350mmol),并用加热抢将该烧瓶在高真空下加热30min。将该系统冷却至室温,并加入五氧化二磷(8.75mL,148mmol)。将该混合物于110℃(油浴)在高真空下搅拌120min。让该混合物冷却至室温。加入3-氯苯基乙酸(15.6g,91mmol)、2-氯噻吩(33.8mL,366mmol)和DCE(50mL)。将反应混合物在回流下搅拌4小时。LCMS分析显示反应完成。让反应混合物冷却至室温。用乙醚(300mL)稀释反应混合物并过滤。在减压下浓缩该有机溶液。用己烷研磨残余物从而得到本标题化合物,为灰白色固体。浓缩己烷母液并通过快速色谱法(SiO2,0%至30%的EtOAc/Hex,梯度洗脱)纯化,得到另一批的本标题化合物,为淡黄色固体。质谱(ESI)m/z=271(M+1)。
步骤B. 外消旋4-(3-氯苯基)-5-(5-氯噻吩-2-基)-5-氧代戊酸甲酯
在0℃下用超过20min的时间向7.35g(27.1mmol)2-(3-氯苯基)-1-(5-氯噻吩-2-基)乙酮(实施例63,步骤A)和丙烯酸甲酯(2.81mL,31.2mmol)在DCM(60mL)中的溶液中缓慢地加入在DCM(10mL)中的1,8-二氮杂二环[5.4.0]十一碳-7-烯(4.05mL,27.1mmol)。然后让反应物升温至室温。在25℃下搅拌2天后,用DCM稀释反应混合物并用2N HCl、水和NaCl饱和水溶液洗涤。经Na2SO4干燥有机萃取物。过滤该溶液并在真空中浓缩从而得到粗材料,为淡黄色油状物。使该粗材料吸附到硅胶塞上,并采用色谱法通过预装填的硅胶柱(220g),用0%至30%的在己烷中的EtOAc梯度洗脱来进行纯化,从而得到本标题化合物,为淡黄色油状物。质谱(ESI)m/z=357(M+1)。
步骤C. 外消旋(4S,5S)(4R,5R)4-(3-氯苯基)-5-(5-氯噻吩-2-基)-5-羟基戊酸甲酯
在0℃下向8.20g(22.95mmol)4-(3-氯苯基)-5-(5-氯噻吩-2-基)-5-氧代戊酸甲酯(实施例63,步骤B)在MeOH(100mL)中的溶液中分批加入硼氢化钠(0.809mL,22.95mmol)。然后将反应物在0℃下搅拌30min。LCMS分析显示反应完成。加入冰水来淬灭反应物。在减压下浓缩反应混合物从而除去大部分MeOH。用DCM(3X100mL)萃取残余物。用NaCl饱和水溶液洗涤合并的有机层,经Na2SO4干燥,并在减压下浓缩。通过快速色谱法(TLC,SiO2,20%至30%的EtOAc/己烷,梯度洗脱)纯化残余物,得到本标题化合物,为无色油状物。
步骤D. 外消旋(4S,5R)(4R,5S)-5-叠氮基-4-(3-氯苯基)-5-(5-氯噻吩-2-基)戊酸甲酯
在0℃下在搅拌的条件下用超过5min的时间向1.18g(3.28mmol)外消旋(4S,5S)(4R,5R)-4-(3-氯苯基)-5-(5-氯噻吩-2-基)-5-羟基戊酸甲酯(实施例63,步骤C)在甲苯(10mL)中的溶液中加入1,8-二氮杂二环[5.4.0]十一碳-7-烯(0.639mL,4.27mmol)。用超过8min的时间向上述溶液中逐滴加入二苯基磷酰叠氮化物(0.852mL,3.94mmol)。将反应混合物在0℃至室温下搅拌14小时并通过LCMS分析监测。稀释(NH4Cl饱和水溶液)反应混合物,萃取(3x EtOAc),并洗涤(2xNaCl饱和水溶液)。干燥(Na2SO4)合并的有机层并在减压下浓缩。将粗材料溶解在少量DCM中用于色谱分析。通过过滤除去不溶性材料,并使该溶液吸附到硅胶塞上,并采用色谱法通过Redi-Sep预装填的硅胶柱(40g),用0%至60%的在己烷中的EtOAc梯度洗脱来进行纯化,从而得到外消旋的本标题化合物,为无色油状物。
质谱(ESI)m/z=406(M+23)。
步骤E. (5R,6S)-5-(3-氯苯基)-6-(5-氯噻吩-2-基)哌啶-2-酮
向7.8g(20.3mmol)外消旋(4S,5R)(4R,5S)-5-叠氮基-4-(3-氯苯基)-5-(5-氯噻吩-2-基)戊酸甲酯(实施例63,步骤D)在THF/H2O(4/1,75mL)中的溶液中加入三甲基膦在四氢呋喃中的1.0M溶液(24.36mL,24.36mmol)。在23℃下搅拌1h后,LCMS分析显示反应完成。在减压下除去大部分THF,碱化(冰冷的2M LiOH)残余物,并对该产物进行萃取(3×DCM)和洗涤(2×NaCl饱和水溶液)。干燥(Na2SO4)合并的有机层,并在减压下浓缩从而得到粗胺混合物,为黄色固体。
将上面的粗胺溶解在MeOH/NaHCO3饱和水溶液(4/1,60mL,c=0.04M)中,并将反应物回流3h。在LCMS分析显示反应完成之后,在减压下除去多余的溶剂,稀释(水)残余物,萃取(2×10%MeOH/DCM),并洗涤(1×饱和NaCl水溶液)。干燥(Na2SO4)合并的有机层,并在减压下浓缩从而得到粗的本标题化合物。
使该粗材料吸附到硅胶塞上,并采用色谱法通过预装填的硅胶柱(220g),用20%至100%的在CH2Cl2中的EtOAc梯度洗脱来进行纯化,从而得到外消旋的本标题化合物,为白色固体。
通过手性SFC在250x30mm Chiralcel AS-H柱上用50g/min MeOH(+20mM NH3)+50g/min CO2在Thar 350SFC(Thar Technologies,Inc.,Pittsburg,PA)中分离外消旋(5R,6S)(5S,6R)-5-(3-氯苯基)-6-(5-氯噻吩-2-基)哌啶-2-酮的各个对映异构体。出口压力=100bar;Temp.=46℃;波长=245nm。运行时间=20min.;循环时间=17min。所获得的本标题化合物(5R,6S)-5-(3-氯苯基)-6-(5-氯噻吩-2-基)哌啶-2-酮为较快地洗脱的异构体。
1H NMR(400MHz,氯仿-d)δppm 7.18-7.24(2H,m),7.10(1H,m),6.93-6.95(1H,m)6.23(1H,d,J=4Hz),6.42(1H,d,J=4Hz),6.09(1H,s),4.73(1H,d,J=8Hz),2.87-2.94(1H,m),2.60-2.65(2H,m),2.05-2.25(2H,m);质谱(ESI)m/z=326(M+1);[α]D=+165.8(T=24.7℃,c=0.104,CHCl3)
还通过上述方法获得本标题化合物的对映异构体,(5S,6R)-5-(3-氯苯基)-6-(5-氯噻吩-2-基)哌啶-2-酮,为较慢地洗脱的异构体。[α]D=-158(T=24.8℃,c=0.104,CHCl3)
步骤F. 外消旋(5R,6S)(5S,6R)-5-(3-氯苯基)-6-(5-氯噻吩-2-基)-1-(环丙基甲基)哌啶-2-酮
如实施例35,步骤A中所述,从外消旋(5R,6S),(5S,6R)-5-(3-氯苯基)-6-(5-氯噻吩-2-基)哌啶-2-酮(实施例63,步骤E)制备本标题化合物。
1H NMR(400MHz,氯仿-d)αppm 7.34(1H,br s),7.25-7.30(2H,m),7.13–7.17(1H,m),6.74(1H,d,J=4Hz),6.56(1H,d,J=4Hz),5.06(1H,d,J=4Hz),4.13–4.19(1H,m),3.19–3.23(1H,m),2.46–2.60(3H,m),2.23-2.29(1H,m),2.01-2.10(1H,m),1.05–1.13(1H,m),0.59–0.66(1H,m),0.49–0.56(1H,m),0.27–0.33(1H,m),0.18–0.24(1H,m)。质谱(ESI)m/z=380(M+1)。
步骤G. (3R,5R,6S)(3S,5S,6R)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)哌啶-2-酮和(3S,5R,6S)(3R,5S,6R)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)哌啶-2-酮
如实施例1步骤G中所述,从外消旋((5R,6S)(5S,6R)-5-(3-氯苯基)-6-(5-氯噻吩-2-基)-1-(环丙基甲基)哌啶-2-酮(实施例63,步骤F)制备本标题化合物,所获得的本标题化合物为立体异构体的混合物。通过硅胶色谱法分离各个外消旋立体异构体。
所获得的本标题化合物(3R,5R,6S)(3S,5S,6R)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)哌啶-2-酮为通过硅胶色谱法较快地洗脱的异构体(极性较小的异构体)。
1H NMR(400MHz,氯仿-d)δppm 7.16-7.23(2H,m),7.10–7.12(1H,m),6.60(1H,d,J=4Hz),6.32(1H,d,J=4Hz),5.75–5.84(1H,m),5.05–5.12(2H,m),4.76(1h,d,J=8Hz),3.98–4.03(1H,m),3.04–3.10(1H,m),2.75–2.81(1H,m),2.51–2.63(2H,m),2.35-2.42(1H,m),2.05-2.11(1H,m),1.89–1.99(1H,m),0.88–0.98(1H,m),0.49–0.56(1H,m),0.39–0.46(1H,m),0.19–0.25(1H,m),0.07-0.13(1H,m)。质谱(ESI)m/z=420(M+1)。
所获得的本标题化合物(3S,5R,6S)(3R,5S,6R)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)哌啶-2-酮为在硅胶色谱法中较慢地洗脱的异构体。
1H NMR(400MHz,氯仿-d)δppm 7.42(1H,br s)726-7.31(1H,m),7.19-7.23(1H,m),6.79(1H,d,J=4Hz),6.60(1H,d,J=4Hz),5.70–5.80(1H,m),5.06–5.15(3H,m),4.18–4.23(1H,m),3.26–3.29(1H,m),2.62–2.68(1H,m),2.41–2.51(2H,m),2.31-2.38(1H,m),2.15-2.22(1H,m),1.92–1.98(1H,m),1.11–1.21(1H,m),0.63–0.69(1H,m),0.54–0.60(1H,m),0.24–0.34(2H,m)。质谱(ESI)m/z=420(M+1)。
步骤H. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(5-氯噻吩-2-基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酸
如实施例1步骤H中所述,从外消旋(3R,5R,6S)(3S,5S,6R)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)哌啶-2-酮(实施例63,步骤G)制备本标题化合物,并通过手性SFC在OJ柱(Daicel,Fort Lee,NJ)上进行拆分。所获得的本标题化合物为较慢地洗脱的异构体。
1H NMR(400MHz,氯仿-d)δppm 7.45(1H,br s)7.31-7.34(2H,m),7.23-7.35(1H,m),6.84(1H,d,J=4Hz),6.74(1H,d,J=4Hz),5.27(1H,br s),4.22–4.27(1H,m),3.33(1H,br s),2.76–2.84(1H,m),2.52–2.63(3H,m),2.31-2.36(1H,m),1.96–2.02(1H,m),1.15–1.24(1H,m),0.71–0.77(1H,m),0.60–0.67(1H,m),0.34–0.40(1H,m),0.27-0.33(1H,m)。质谱(ESI)m/z=438(M+1)。
实施例64
2-((3S,5R,6S)-5-(3-氯苯基)-6-(5-氯噻吩-2-基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酸
如实施例1步骤H中所述,从外消旋(3R,5R,6S)(3S,5S,6R)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)哌啶-2-酮(实施例63,步骤G)制备本标题化合物,并通过手性SFC在AD柱上进行拆分。所获得的本标题化合物为在(Daicel,Fort Lee,NJ)AD柱上较慢地洗脱的异构体。
1H NMR(400MHz,氯仿-d)δppm 7.17-7.24(2H,m),7.09–7.10(1H,m),6.90–6.92(1H,m),6.62(1H,d,J=4Hz),6.35(1H,d,J=4Hz),4.80(1H,d,J=12Hz),3.94–3.99(1H,m),3.11–3.18(1H,m),2.99–3.16(1H,m),2.54–2.66(2H,m),2.09-2.22(2H,m),0.87–0.98(1H,m),0.50–0.57(1H,m),0.40–0.47(1H,m),0.18–0.24(1H,m),0.07-0.13(1H,m)。质谱(ESI)m/z=438(M+1)。
实施例65
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-乙氧基-1-氧代丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. (S)-2-((3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-1-基)丁酸乙酯和(S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-1-基)丁酸乙酯
在-78℃下向362mg(833μmol)(S)-2-((2S,3R)-3-(3-氯苯基)-2-(4-氯苯基)-6-氧代哌啶-1-基)丁酸乙酯(实施例9,步骤A)和烯丙基溴(87μl,1000μmol)在THF(3.30mL,0.25M)中的溶液中逐滴加入双(三甲基甲硅烷基)氨基锂(1M溶液在THF中;875μl,875μmol)。在-78℃下搅拌3h后,淬灭(NH4Cl饱和水溶液)反应物,并对其进行萃取(2×EtOAc)。用水和NaCl饱和水溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过色谱法(12g SiO2,15%至20%的EtOAc/Hex,梯度洗脱)纯化残余物,得到本标题化合物,为立体异构体的混合物。
步骤B. (2S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁酸乙酯和(2S)-2-((3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁酸乙酯
在室温下向0.66g(1.39mmol)(S)-2-((5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-1-基)丁酸乙酯(实施例65,步骤A;非对映异构体的混合物)和碘甲烷(0.592g,4.17mmol)在15mL THF中的溶液中加入LHMDS(1.0M溶液在THF中;4.17mL,4.17mmol)。在搅拌12h后,淬灭(NH4Cl饱和水溶液)反应物,并对其进行萃取(2×EtOAc)。用水和NaCl饱和水溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过反相制备型HPLC(GeminiTM Prep C18 5μm柱,Phenomenex,Torrance,CA;洗脱剂:10%至90%乙腈+0.1%TFA于水+0.1%TFA中,梯度洗脱)纯化残余物,得到本标题化合物,为立体异构体的混合物。
步骤D. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-乙氧基-1-氧代丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
向快速搅拌着的0.28g(0.573mmol)(2S)-2-((5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁酸乙酯(实施例65,步骤B;非对映异构体的混合物)在H2O/CCl4/MeCN(4.0/2.0/2.0,8.0mL)中的溶液中加入高碘酸钠(0.490g,2.29mmol),接着加入氯化钌(III)水合物(0.013g,0.057mmol)。在剧烈搅拌12h后,酸化(10%柠檬酸)反应物并用EtOAc稀释。通过经由(J.T.Baker,Phillipsberg,NJ,硅藻土)垫过滤来除去不溶性材料。萃取(2×EtOAc)滤液。用水和NaCl饱和水溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过反相制备型HPLC(GeminiTM PrepC18 5μm柱,Phenomenex,Torrance,CA;洗脱剂:10%至90%乙腈+0.1%TFA于水+0.1%TFA中,梯度洗脱)纯化残余物,从而得到本标题化合物,其为第一洗脱异构体,为白色粉末。
1H NMR(400MHz,氯仿-d)δppm 0.59(t,J=7.6Hz,3H),1.28(t,J=7.2Hz,3H),1.44(s,3H),1.50-1.64(m,1H),2.10-2.19(m,1H),2.19-2.37(m,2H),2.86(q,J=14.5Hz,2H),3.19-3.35(m,2H),4.11-4.27(m,2H),4.58(d,J=10.5Hz,1H),6.77(m,1H)6.93-7.05(m,3H)7.05-7.17(m,2H)7.20-7.33(m,2H);MS(ESI)506.2[M+H]+。504.1[M-H]-。
实施例66
2-((3S,5R,6S)-1-((S)-1-叔丁氧基-1-氧代丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸:
步骤A. (S)-2-((2S,3R)-3-(3-氯苯基)-2-(4-氯苯基)-6-氧代哌啶-1-基)丁酸叔丁酯
如实施例9,步骤A中所述,用2-溴丁酸叔丁酯替代2-溴丁酸乙酯来合成本标题化合物。通过硅胶快速色谱法(30%的EtOAc/己烷)纯化,得到本标题化合物,其为较快地洗脱的组分,为白色泡沫状物。
步骤B. (2S)-2-((2S,3R)-3-(3-氯苯基)-2-(4-氯苯基)-5-甲基-6-氧代哌啶-1-基)丁酸叔丁酯
在-78℃下向11.2g(24.2mmol)(S)-2-((2S,3R)-3-(3-氯苯基)-2-(4-氯苯基)-6-氧代哌啶-1-基)丁酸叔丁酯(实施例66,步骤A)和碘甲烷(1.813mL,29.1mmol)在THF(120.0mL)中的溶液中加入双(三甲基甲硅烷基)氨基锂(1M溶液在THF中;26.6mL,26.6mmol)。让反应物升温至室温,然后淬灭(NH4Cl饱和水溶液)并萃取(2×EtOAc)。用水和NaCl饱和水溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。使残余物吸附到硅胶塞上并通过硅胶色谱法,用10%至30%的在己烷中的EtOAc梯度洗脱来进行纯化,从而得到本标题化合物,为立体异构体的混合物。
步骤C. (2S)-2-((5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁酸叔丁酯
在室温下向10.2g(21.4mmol)(2S)-2-((2S,3R)-3-(3-氯苯基)-2-(4-氯苯基)-5-甲基-6-氧代哌啶-1-基)丁酸叔丁酯(实施例66,步骤B,非对映异构体的混合物)和烯丙基溴(7.24mL,86mmol)在THF(210mL)中的溶液中加入LHMDS,(1.0M溶液在THF中;64.2mL,64.2mmol)。让它在室温下搅拌5min。然后将反应混合物在50℃下加热3h。加入NH4Cl饱和水溶液并用CH2Cl2萃取该混合物。用水和NaCl饱和水溶液洗涤合并的有机层,经MgSO4干燥,过滤,并在减压下浓缩滤液。通过色谱法,用0%至20%的在己烷中的EtOAc梯度洗脱来对残余物进行纯化,从而得到本标题化合物,为在C-3上的立体异构体的混合物。
步骤D. 2-((3S,5R,6S)-1-((S)-1-叔丁氧基-1-氧代丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸
按照与实施例65,步骤D中描述的程序类似的程序,将(2S)-2-((5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁酸叔丁酯(实施例66,步骤C,非对映异构体的混合物)转化成酸。通过反相制备型HPLC(GeminiTM Prep C18 5μm柱,Phenomenex,Torrance,CA;洗脱剂:10%至90%乙腈+0.1%TFA于水+0.1%TFA中,梯度洗脱)纯化粗产物,从而得到本标题化合物,为第一洗脱异构体。
1H NMR(400MHz,氯仿-d)δppm 0.54(t,J=7.5Hz,3H),1.41-1.55(m,14H),2.07-2.17(m,1H),2.25(d,J=13.5Hz,1H),2.28-2.42(m,1H),2.81(d,J=15.4Hz,1H),2.93-3.03(m,2H),3.24(ddd,J=13.3,10.5,3.1Hz,1H),4.58(d,J=10.5Hz,1H),6.76(m,1H)6.97-7.06(m,3H)7.08-7.20(m,2H)7.25(s,2H);MS(ESI)534.1[M+H]+。532.0[M-H]-。
进一步洗脱得到实施例67。
实施例67
2-((3R,5R,6S)-1-((S)-1-叔丁氧基-1-氧代丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 1.00(t,J=7.5Hz,3H),1.43(s,9H),1.50(s,3H),1.93-2.27(m,4H),2.79(d,J=15.3Hz,1H),3.04(d,J=15.5Hz,1H),3.15-3.29(m,2H),4.52(d,J=10.4Hz,1H),6.68-6.78(m,1H),6.90-6.98(m,1H),7.05-7.29(m,6H);MS(ESI)534.1[M+H]+。532.0[M-H]-。
实施例68
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环丙基甲氧基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. (5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)哌啶-2-酮
在0℃下向3g(6.9mmol)(S)-2-((2S,3R)-3-(3-氯苯基)-2-(4-氯苯基)-6-氧代哌啶-1-基)丁酸乙酯(实施例9,步骤A)在45mL Et2O中的溶液中加入四氢硼酸锂(0.334g,13.81mmol)。在0℃下搅拌50min后,淬灭(冰冷的10%柠檬酸)反应物并对其进行萃取(2×EtOAc)。用水和NaCl饱和水溶液洗涤合并的有机层,经MgSO4干燥,过滤,并在减压下浓缩滤液。通过硅胶快速色谱法(洗脱剂:30%至60%的EtOAc/己烷,梯度洗脱)纯化,得到本标题化合物。
步骤B. (5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环丙基甲氧基)丁烷-2-基)哌啶-2-酮
在0℃下向1.48g(3.77mmol)(5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)哌啶-2-酮(实施例68,步骤A)和溴甲基环丙烷(0.828mL,7.54mmol)在DMF(20mL)中的溶液中加入叔丁醇钠(0.544g,5.66mmol)。将该混合物在0℃下搅拌2h,然后升温至室温。然后将反应物在室温下搅拌14h。用NH4Cl饱和水溶液淬灭反应物并用EtOAc萃取。用水和NaCl饱和水溶液洗涤合并的有机层,经MgSO4干燥,过滤,并在减压下浓缩滤液。通过硅胶快速色谱法(洗脱剂:20%-40%的EtOAc/己烷,梯度洗脱)纯化,得到本标题化合物,为无色油状物。
步骤C. (5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环丙基甲氧基)丁烷-2-基)-3-甲基哌啶-2-酮
在-78℃下向0.325g(0.73mmol)(5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环丙基甲氧基)丁烷-2-基)哌啶-2-酮(实施例68,步骤B)和碘甲烷(0.055mL,0.874mmol)在THF(7.0mL)中的溶液中加入双(三甲基甲硅烷基)氨基锂(1M溶液在THF中,0.8mL,0.8mmol)。让反应物升温至室温,然后用NH4Cl饱和水溶液淬灭,并用EtOAc萃取。用水和NaCl饱和水溶液洗涤合并的有机层,经MgSO4干燥,过滤,并在减压下浓缩滤液。使该粗材料吸附到硅胶塞上并通过硅胶色谱法,用10%至30%的在己烷中的EtOAc梯度洗脱来进行纯化,从而得到本标题化合物,其为如用*表示的C-3立体异构体的混合物。
步骤D. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环丙基甲氧基)丁烷-2-基)-3-甲基哌啶-2-酮
在室温下向0.2g(0.434mmol)(5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环丙基甲氧基)丁烷-2-基)-3-甲基哌啶-2-酮(实施例68,步骤C,非对映异构体的混合物)和烯丙基溴(0.147mL,1.737mmol)在THF(5mL)中的溶液中加入LHMDS,(1.0M溶液在THF中,1.3mL,1.3mmol)。让它在室温下搅拌5min。然后将反应混合物在50℃下加热3h。用饱和NH4Cl稀释反应混合物,并用CH2Cl2萃取。用水和NaCl饱和水溶液洗涤合并的有机层,经MgSO4干燥,过滤,并在减压下浓缩滤液。粗材料通过色谱法,用0%至20%的在己烷中的EtOAc梯度洗脱来进行纯化,从而得到本标题化合物,为无色油状物。
步骤E. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环丙基甲氧基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
按照与实施例1,步骤H中描述的程序类似的程序,将(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环丙基甲氧基)丁烷-2-基)-3-甲基哌啶-2-酮(实施例68,步骤E)转化成酸,从而得到本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 0.20-0.33(m,2H),0.51(t,J=7.5Hz,3H),0.57-0.70(m,2H),1.05-1.17(m,1H),1.44(s,3H),1.48-1.62(m,1H),1.82-1.95(m,1H),2.01(dd,J=13.9,3.3Hz,1H),2.20(t,J=13.5Hz,1H),2.72(d,J=15.1Hz,1H),2.95-3.12(m,3H),3.24-3.40(m,3H),3.95(t,J=9.8Hz,1H),4.69(d,J=10.0Hz,1H),6.72-6.80(m,1H),6.94-7.07(m,3H),7.07-7.21(m,2H),7.25(d,J=8.61Hz,2H);
实施例69
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代-3-(2-(吡咯烷-1-基)乙基)哌啶-3-基)乙酸
步骤A. (5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-3-(2-(三异丙基甲硅烷基氧基)乙基)哌啶-2-酮
经由注射器用超过6min的时间向3.70g(8.9mmol)(5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)哌啶-2-酮氧代戊酸酯的C-3非对映异构体的混合物(实施例35,步骤B)和20.7g(63mmol)(2-碘乙氧基)三异丙基甲硅烷在干燥脱气的THF(60mL)中的溶液中缓慢地加入54.5mL(54.5mmol)双(三甲基甲硅烷基)氨基锂在THF中的1M溶液。在10min后,将该橙色溶液升温至40℃并再搅拌2.25h。将反应物冷却至室温,用饱和氯化铵水溶液淬灭,并用EtOAc(3X)萃取。经Na2SO4干燥合并的有机层,过滤,并浓缩滤液。通过硅胶快速色谱法(2-25%的EtOAc/己烷,梯度洗脱)纯化残余物,得到本标题化合物(C-3差向异构体的混合物),为淡黄色油状物。
步骤B. 2-((5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代-3-(2-(三异丙基甲硅烷基氧基)乙基)哌啶-3-基)乙醛
向1.28g(2.08mmol)(5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-3-(2-(三异丙基甲硅烷基氧基)乙基)哌啶-2-酮(实施例69,步骤A,非对映异构体的混合物)在THF(50mL)和水(17.5mL)中的溶液中加入催化量的四氧化锇。在25min后,加入1.34g(6.25mmol)高碘酸钠。将由此产生的淡棕色浆液搅拌19h,然后通过烧结漏斗过滤。在减压下部分浓缩滤液,然后用水稀释并用乙酸乙酯(2X)萃取。先后用饱和硫代硫酸钠水溶液和饱和氯化钠水溶液洗涤合并的有机层。经Na2SO4干燥有机层,过滤,并浓缩滤液。该粗的本标题化合物(C-3差向异构体的混合物)直接用于下一步骤。
步骤C. (5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-3-(2-(吡咯烷-1-基)乙基)-3-(2-(三异丙基甲硅烷基氧基)乙基)哌啶-2-酮的合成
将1.02g(1.66mmol)粗2-((5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代-3-(2-(三异丙基甲硅烷基氧基)乙基)哌啶-3-基)乙醛(实施例69,步骤B,非对映异构体的混合物)、0.55mL(6.6mmol)吡咯烷、880mg(4.15mmol)三乙酰氧基硼氢化钠和285μL(4.98mmol)乙酸的混合物悬浮在1,2-二氯乙烷(36mL)和DMF(12mL)的混合物中。在室温下搅拌20h后,用饱和碳酸氢钠水溶液淬灭反应混合物并用DCM(3X)萃取。经Na2SO4干燥合并的有机层,过滤,并浓缩滤液。该粗的本标题化合物(C-3差向异构体的混合物)直接用于下一步骤。
步骤D. (5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-3-(2-羟基乙基)-3-(2-(吡咯烷-1-基)乙基)哌啶-2-酮
向冰冷却的1.12g(1.66mmol)粗(5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-3-(2-(吡咯烷-1-基)乙基)-3-(2-(三异丙基甲硅烷基氧基)乙基)哌啶-2-酮(实施例69,步骤C,非对映异构体的混合物)在THF(55mL)中的溶液中加入8.3mL(8.3mmol)TBAF在THF中的1M溶液。在室温下搅拌1.5h后,用水淬灭反应混合物并用EtOAc(3X)萃取。干燥(Na2SO4)合并的有机层,并在减压下浓缩。通过硅胶快速色谱法(3-30%MeOH/DCM,梯度洗脱)纯化残余物,得到本标题化合物(C-3差向异构体的混合物),为淡黄色油状物。
步骤E. 2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代-3-(2-(吡咯烷-1-基)乙基)哌啶-3-基)乙酸
经由注射器用1.75mL(32.7mmol)硫酸处理2.05g(20.5mmol)氧化铬(VI)在水(4mL)中的冰冷却的溶液。用另外的水(4mL)稀释该混合物并在使用前将其储存在0℃下。在单独的烧瓶中,将105mg(0.21mmol)(5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-3-(2-羟基乙基)-3-(2-(吡咯烷-1-基)乙基)哌啶-2-酮(实施例69,步骤D,非对映异构体的混合物)溶解在丙酮(20mL)中,然后在室温下经由吸移管用琼斯试剂(Jones reagent)(见上文)缓慢地处理。在30min后,将由此产生的暗红色溶液在55℃下再加热17.5h。在减压下浓缩反应物,然后用水稀释并用乙酸乙酯(4X)萃取。经Na2SO4干燥有机层,过滤,并浓缩滤液。通过反相制备型HPLC(Sunfire Prep C18OBD10μm柱(Waters,Milford,MA),用40%的在水中的MeCN至55%的在水中的MeCN梯度洗脱超过35min,其中这两种溶剂都含有0.1%TFA)纯化残余物,得到本标题化合物(单一对映异构体),为白色固体。[注意所需的C-3(3S)差向异构体是极性较小的差向异构体并第二洗脱出]。
1H NMR(400MHz,CDCl3)δppm 11.11(1H,br s),7.18-7.24(2H,m),7.08-7.18(2H,m),6.99(1H,br s),6.77-6.87(3H,m),4.61(1H,dd,J=10.1Hz,4.7Hz),3.72-3.86(3H,m),3.61(1H,br s),3.36(1H,br s),3.13(1H,br s),2.75-2.97(4H,m),2.20-2.35(2H,m),1.99-2.22(7H,m),0.84(1H,br s),0.36-0.54(2H,m),-0.05-0.13(2H,m)。质谱(ESI)m/z=529(M+1)。
实施例70
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-3-(2-吗啉代乙基)-2-氧代哌啶-3-基)乙酸
步骤A. (5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-3-(2-羟基乙基)-3-(2-吗啉代乙基)哌啶-2-酮
将94mg(0.15mmol)粗2-((5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代-3-(2-(三异丙基甲硅烷基氧基)乙基)哌啶-3-基)乙醛(实施例69,步骤B,非对映异构体的混合物)、66μL(0.76mmol)吗啉、97mg(0.46mmol)三乙酰氧基硼氢化钠和30μL(0.53mmol)乙酸的混合物悬浮在1,2-二氯乙烷(6mL)和DMF(2mL)的混合物中。在室温下搅拌20h后,用饱和碳酸氢钠水溶液淬灭反应混合物,并用DCM(3X)萃取。经Na2SO4干燥合并的有机层,过滤,并浓缩滤液。通过反相制备型HPLC(SunFireTMPrep C18OBD 10μm柱(Waters,Milford,MA),用50%的在水中的MeCN至90%的在水中的MeCN梯度洗脱超过30min,其中这两种溶剂都含有0.1%TFA)纯化残余物,得到与相应的TIPS醚(C-3差向异构体的混合物)和相应的三氟乙酸盐(C-3差向异构体的混合物)在一起的本标题化合物(C-3差向异构体的混合物),为无色油状物。
将该混合物溶解在THF(5mL)中,并用0.76mL(0.76mmol)TBAF在THF中的1M溶液处理。在室温下搅拌3.5h后,用水淬灭反应混合物并用EtOAc(3X)萃取。干燥(Na2SO4)合并的有机层,并在减压下浓缩。通过硅胶快速色谱法(8-35%MeOH/DCM,梯度洗脱)纯化残余物,得到本标题化合物(C-3差向异构体的混合物),为白色固体。
步骤B. 2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-3-(2-吗啉代乙基)-2-氧代哌啶-3-基)乙酸
经由注射器用343μL(6.44mmol)硫酸处理403mg(4.03mmol)氧化铬(VI)在水(1mL)中的冰冷却的溶液。用另外的水(1mL)稀释该溶液并在使用前将其储存在0℃下。在单独的烧瓶中,将(5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-3-(2-羟基乙基)-3-(2-吗啉代乙基)哌啶-2-酮(实施例70,步骤A,非对映异构体的混合物)溶解在丙酮(5mL)中,然后在室温下经由吸移管用琼斯试剂(见上文)缓慢地处理。在30min后,将由此产生的暗红色溶液在55℃下再加热17h。在减压下浓缩反应物,然后用水稀释并用乙酸乙酯(3X)萃取。经Na2SO4干燥有机层,过滤,并浓缩滤液。通过反相制备型HPLC(SunFireTMPrep C18OBD10μm柱(Waters,Milford,MA),用40%的在水中的MeCN至60%的在水中的MeCN梯度洗脱超过35min,其中这两种溶剂都含有0.1%TFA)纯化残余物,得到本标题化合物(单一对映异构体),为白色固体。[注意所需的(3S)C-3差向异构体是极性较小的差向异构体并第二洗脱出]。
1H NMR(400MHz,CDCl3)δppm 12.05(1H,br s),6.95-7.26(5H,m),6.76-6.88(3H,m),4.64(1H,d,J=10.0Hz),4.23(1H,br s),3.76-4.10(5H,m),3.43-3.65(2H,m),3.08-3.34(2H,m),2.78-3.01(3H,m),2.41-2.76(2H,m),2.26-2.39(2H,m),2.08-2.24(2H,m),0.85(1H,br s),0.33-0.55(2H,m),-0.10-0.15(2H,m)。质谱(ESI)m/z=545(M+1)。
实施例71
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)乙酸
步骤A. (5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(2,4-二甲氧基苄基)哌啶-2-酮.
在0℃在氮气下用超过1小时的时间在机械搅拌下将亚硫酰氯(116mL,1586mmol)逐滴加入到(2,4-二甲氧基苯基)甲醇(97.00g,577mmol)和吡啶(93mL,1153mmol)在无水Et2O(1153mL)中的混浊溶液中。在1小时后,将反应混合物倒入2L冰水中并分离各层。用Et2O(2x 1L)萃取水层,并将有机物汇集在一起,用冰水(1.2L)、冷的5:1NaCl饱和水溶液/NaHCO3饱和水溶液(1.2L)洗涤,干燥(MgSO4),过滤并于12℃在真空下除去大部分乙醚。加入苯(300mL)并在12℃下浓缩该混合物直至剩余100mL苯从而得到1-(氯甲基)-2,4-二甲氧基苯溶液。
0℃在氮气下用超过20分钟的时间将80g(250mmol)(5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)哌啶-2-酮(实施例1,步骤E)分数个部分加入到在的NaH(19.98g,500mmol)在无水DMF(400mL)中的混合物中。在添加完成后,移开冰浴并将该混合物在室温下搅拌1小时,然后将该溶液冷却至0℃。向冷却的溶液中加入1-(氯甲基)-2,4-二甲氧基苯(107g,575mmol)在苯中的溶液,并让反应混合物升温至室温。在16小时后,将反应混合物倒入冰水(2L)中并用EtOAc(3x1L)萃取。将有机物汇集在一起,用水(3x1L)、NaCl饱和水溶液(1L)洗涤,干燥(MgSO4),过滤并在真空中浓缩从而得到黄色的粘稠油状物。通过在Combiflash XL(快速柱色谱法,Teledyne Isco,Lincoln,NE)上使用四根堆叠的330g柱和1根1.5kg柱,用35-40-45-50-55%EtOAc/己烷洗脱来进行纯化,得到很浅的黄色的油状物。将该物质溶于苯中,在真空中除去该溶剂并在真空下干燥2天从而得到本标题化合物,为白色泡沫状物(105.8g,90%)。
步骤B. (5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(2,4-二甲氧基苄基)-3-甲基哌啶-2-酮.
当(5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(2,4-二甲氧基苄基)哌啶-2-酮(实施例71,步骤A)(140.34g,298mmol)在无水THF(994mL)中的溶液冷却至-78℃时,通过在该溶液中鼓入氩气20分钟来将该溶液脱气。加入碘甲烷(23.32mL,373mmol),接着用超过15分钟的时间加入LHMDS(328mL,328mmol)。将反应混合物在-78℃下搅拌15分钟,然后从冷浴上移开反应物并将其在室温下搅拌12小时。通过加入NH4Cl饱和水溶液淬灭反应物并分离各层。用EtOAc(2x500mL)萃取水层,将有机物汇集在一起,用NaCl饱和水溶液洗涤,干燥(MgSO4),过滤并在真空中浓缩从而得到橙色油状物。通过使用Combiflash Companion XL(快速柱色谱法,Teledyne Isco,Lincoln,NE)用1.5kg SiO2柱,用4L 15-20-25-30-35%EtOAc/己烷中的一种洗脱来进行纯化(用少量的DCM湿法装柱),得到本标题化合物,其为很浅的黄色的粘稠油状物,为C-3非对映异构体的3.7:1混合物。
步骤C. (5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-(2,4-二甲氧基苄基)-3-甲基哌啶-2-酮.
将(5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(2,4-二甲氧基苄基)-3-甲基哌啶-2-酮(实施例71,步骤B,C-3非对映异构体的混合物)(117.0g,242mmol)在无水THF(966mL)中的溶液脱气,这通过在该溶液中鼓入氩气20分钟来进行。加入烯丙基溴(105mL,1208mmol),接着用超过20分钟的时间加入LHMDS(725mL,725mmol)。将反应混合物于40℃在氩气下加热5小时。将反应混合物冷却至室温,并通过加入NH4Cl饱和水溶液(500mL)淬灭反应物并分离各层。用EtOAc(2x1L)萃取水层,将有机物汇集在一起,用NaCl饱和水溶液(1L)洗涤,干燥(MgSO4),过滤并在真空中浓缩从而得到红色油状物(180g)。通过使用Biotage系统(Charlotte,NC)用1.5kg SiO2柱,用10-30%EtOAc/己烷洗脱来进行纯化,得到本标题化合物,其为很浅的黄色的油状物,为(3S):(3R)非对映异构体的3.7:1混合物。
步骤D. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮.
将(5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-(2,4-二甲氧基苄基)-3-甲基哌啶-2-酮(实施例71,步骤C,非对映异构体的混合物)(105.87g,202mmol)在TFA(778mL,1.01E+04mmol)中的溶液在50℃下加热2小时,然后在真空中浓缩反应混合物。通过将残余物用己烷共沸来除去全部TFA。将含有一些残余物的深紫色油状物溶解在最低量的DCM中,过滤并用DCM充分洗涤。在真空中浓缩滤液从而得到暗紫色油状物。通过使用Biotage Isolera(Biotage,Charlotte,NC)用1.5kg柱,用25-40%EtOAc/己烷洗脱来进行纯化(用最低量的DCM湿法装柱),得到本标题化合物,为白色固体。
1H NMR(500MHz,CDCl3)δppm 1.30(s,3H),2.06(m,2H),2.52(dd,J=13.7和7.1Hz,1H),2.60(dd,J=13.7和7.8Hz,1H),3.06(m,1H),4.50(d,J=10.7Hz,1H),5.17(m,2H),5.81(br s,1H),5.86(m,1H),6.77(d,J=7.6Hz,1H),6.96(d,J=8.3Hz,2H),7.00(s,1H),7.12(t,J=7.7Hz,1H),7.17(m,1H),7.20(d,J=8.3Hz,2H)。[]22 D+182.2°(c1.55,CHCl3)。
步骤E. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(戊烷-3-基)哌啶-2-酮
向1.81g(4.8mmol)(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮(实施例71,步骤D)在3-溴戊烷(17.6mL)中的悬浮液中加入967mg(在矿物油中的60wt.%,24.2mmol)氢化钠。将由此产生的乳白色浆液在120℃下加热20h,然后再加入3-溴戊烷(5.1mL)。再在120℃下24h后,将反应物冷却至室温并用饱和氯化铵水溶液淬灭。用乙酸乙酯(3X)萃取该混合物,经Na2SO4干燥合并的有机层,过滤,并浓缩滤液。通过硅胶快速色谱法(2%至26%的EtOAc/己烷,梯度洗脱)纯化残余物,得到本标题化合物,为白色固体。
步骤F. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)乙酸的合成
向725mg(1.63mmol)(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(戊烷-3-基)哌啶-2-酮(实施例3,步骤A)在乙腈(4mL)、四氯化碳(4mL)和水(5.9mL)的混合物中的溶液中加入1.40g(6.53mmol)高碘酸钠,接着加入44mg(0.20mmol)氯化钌(III)水合物。将该暗棕色的两相混合物在室温下剧烈搅拌21h,然后用1N HCl酸化。用EtOAc稀释该混合物并通过(J.T.Baker,Phillipsberg,NJ,硅藻土)垫过滤。在过滤后,分离各层并用EtOAc(1X)萃取水层。用饱和氯化钠水溶液(1X)洗涤合并的有机层,然后经Na2SO4干燥,过滤,并浓缩滤液。通过硅胶快速色谱法(0%至25%的MeOH/DCM,梯度洗脱)纯化残余物,得到本标题化合物,为白色固体。
1H NMR(400MHz,CDCl3)δppm 7.06-7.27(5H,m),6.90-7.01(2H,m),6.68(d,1H,J=7.8Hz),4.34(1H,d,J=10.4Hz),3.00-3.15(2H,m),2.63-2.79(2H,m),2.15-2.27(1H,m),1.85-2.03(3H,m),1.51(s,3H),1.38-1.51(2H,m),0.95(3H,t,J=7.4Hz),0.50(3H,t,J=7.4Hz)。质谱(ESI)m/z=462(M+1)。
采用与针对实施例71描述的工艺类似的工艺,用适量的卤代烷替代步骤E中的3-溴戊烷来制备实施例72–75。
实施例72
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 7.29(2H,d,J=8.6Hz),7.12–7.24(3H,m),6.90(2H,d,J=8.6Hz),6.88–6.82(1H,m),4.80(1H,d,J=8.4Hz),4.02(1H,dd,J=14.1,6.8Hz),3.11–3.03(1H,m),2.98(1H,d,J=15.5Hz),2.68(1H,d,J=15.5Hz),2.37(1H,dd,J=14.1,7.4Hz),2.23–2.14(1H,m),2.13–2.05(1H,m),1.39(3H,s),1.03–0.94(1H,m),0.62–0.46(2H,m),0.23–0.08(1H,m);MS(ESI)446.0[M+H]+,444.1[M–H]–。
实施例73
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-异丙基-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 7.27(2H,d,J=7.8Hz),7.14–7.20(2H,m),7.02(1H,s),6.97(2H,d,J=7.8Hz),6.75(1H,d,J=7.6Hz),4.49(1H,d,J=9.0Hz),3.45(1H,m),3.08(1H,m),2.98(1H,d,J=15.2Hz),2.77(1H,d,J=15.2Hz),2.08(2H,m),1.38(3H,s),1.24(6H,t,J=6.7Hz);MS(ESI)434.0[M+H]+。
实施例74
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-环丁基-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 7.15-7.26(3H,m),7.17(1H,m),7.04(1H,s),6.65-6.79(3H,m),4.65(1H,d,J=8.8Hz),3.85(1H,m),3.05(1H,d,J=15.8Hz),2.85(1H,m),2.60(1H,d,J=15.8Hz),2.45(1H,m),2.20(1H,m),1.90-2.2.20(2H,m),1.65(1H,m),1.42-1.55(3H,m),1.42(3H,s);MS(ESI)446.0[M+H]+。
实施例75
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-环戊基-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 7.28(2H,d,J=8.3Hz),7.14–7.25(2H,m),7.06(1H,s),6.93(2H,d,J=8.3Hz),6.80(1H,d,J=7.6Hz),4.63(1H,d,J=8.1Hz),3.40(1H,m),3.03(1H,d,J=15.7Hz),3.02(1H,m),2.62(1H,d,J=15.7Hz),1.75-2.13(7H,m),1.26-1.45(3H,m),1.33(3H,s);MS(ESI)460.1[M+H]+。
实施例76
(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-3-((5-氧代-4,5-二氢-1H-1,2,4-三唑-3-基)甲基)-1-(戊烷-3-基)哌啶-2-酮
步骤A. 2-(2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)乙酰基)肼甲酰胺
向320mg(0.69mmol)2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)乙酸(实施例71,步骤F)和921mg(2.42mmol)HOBt在DMF(13mL)中的溶液中加入0.58mL(4.15mmol)三乙胺。在室温下搅拌40min后,加入270mg(2.42mmol)盐酸半卡肼(semicarbazide)。将由此产生的暗红色溶液在室温下搅拌2.5h,然后在减压下浓缩。通过反相制备型HPLC(SunfireTMPrep C18OBD 10μm柱(Waters,Milford,MA),用40%的在水中的MeCN至90%的在水中的MeCN梯度洗脱超过30min,其中这两种溶剂都含有0.1%TFA)纯化残余物,得到本标题化合物,为淡黄色固体。
步骤B. (3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-3-((5-氧代-4,5-二氢-1H-1,2,4-三唑-3-基)甲基)-1-(戊烷-3-基)哌啶-2-酮
将259mg(0.50mmol)2-(2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)乙酰基)肼甲酰胺(实施例76,步骤A)悬浮在2N氢氧化钠水溶液(16mL)中并在回流下加热3.25h。在冷却至室温后,用浓HCl酸化该混合物直至强酸性,然后用EtOAc(3X)萃取。经Na2SO4干燥合并的有机层,过滤,并浓缩滤液。通过反相制备型HPLC(SunfireTMPrep C18OBD 10μm柱(Waters,Milford,MA),用40%的在水中的MeCN至75%的在水中的MeCN梯度洗脱超过30min,其中这两种溶剂都含有0.1%TFA)纯化残余物,得到本标题化合物,为白色固体。
1H NMR(400MHz,CDCl3)δppm 10.36(1H,br s),9.35(1H,brs),7.20-7.27(3H,m),7.05-7.17(2H,m),6.86-6.95(2H,m),6.68(1H,d,J=7.8Hz),4.34(1H,d,J=10.5Hz),2.90-3.09(3H,m),2.68-2.76(1H,m),2.21(1H,t,J=13.8Hz),2.05(1H,dd,J=13.9Hz,2.9Hz)1.85-1.99(2H,m),1.37-1.52(2H,m),1.36(3H,s),0.94(3H,t,J=7.4Hz),0.50(3H,t,J=7.5Hz)。质谱(ESI)m/z=501(M+1),523(M+23)。
实施例77
5-(((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)甲基)-1,3,4-噁二唑-2(3H)-酮
将56mg(0.19mmol)三光气在DCM(1mL)中的溶液逐滴加入到62mg(0.13mmol)2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)乙酰肼(作为实施例76步骤B中的副产品获得的)和170μL(0.98mmol)二异丙基乙胺在DCM(4mL)中的溶液中。将由此产生的淡黄色溶液在室温下搅拌18h,然后用饱和碳酸氢钠水溶液淬灭并用EtOAc(3X)萃取。经Na2SO4干燥合并的有机层,过滤,并浓缩滤液。通过反相制备型HPLC(SunfireTMPrep C18OBD10μm柱,(Waters,Milford,MA),用40%的在水中的MeCN至75%的在水中的MeCN梯度洗脱超过30min,其中这两种溶剂都含有0.1%TFA)纯化残余物,得到本标题化合物,为白色固体。
1H NMR(400MHz,CDCl3)δppm 9.68(1H,br s),7.08-7.27(4H,m),6.90-7.01(3H,m),6.70(1H,d,J=7.4Hz),4.35(1H,d,J=10.4Hz),3.01-3.15(3H,m),2.70-2.79(1H,m),2.15(1H,t,J=13.8Hz),2.01(1H,dd,J=13.8Hz,3.1Hz)1.82-1.95(2H,m),1.35-1.57(2H,m),1.43(3H,s),0.93(3H,t,J=7.4Hz),0.51(3H,t,J=7.4Hz)。质谱(ESI)m/z=502(M+1)。
实施例78
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)-N-(三氟甲基磺酰基)乙酰胺
向47mg(0.10mmol)2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)乙酸(实施例71,步骤F)在DMF(4mL)中的溶液中加入64mg(0.34mmol)EDC、48mg(0.36mmol)HOBt,和催化量的DMAP。在30min后,加入45.5mg(0.30mmol)三氟甲烷磺酰胺。将由此产生的淡黄色溶液在室温下搅拌3h,然后在减压下浓缩。通过反相制备型HPLC(SunfireTMPrep C18OBD10μm柱(Waters,Milford,MA),用50%的在水中的MeCN至90%的在水中的MeCN梯度洗脱超过30min,其中这两种溶剂都含有0.1%TFA)纯化残余物,得到本标题化合物,为白色固体。
1H NMR(400MHz,CDCl3)δppm 7.25-7.32(3H,m),7.16-7.20(1H,m),7.11(t,1H,J=7.8Hz),6.92-7.00(2H,m),6.67(d,1H,J=7.6Hz),4.35(1H,d,J=10.4Hz),3.19(d,1H,J=15.7Hz),2.97-3.06(1H,m),2.73-2.83(1H,m),2.68(1H,d,J=15.7Hz),2.26(1H,t,J=13.8Hz),1.86-2.08(3H,m),1.52(3H,s),1.39-1.52(2H,m),0.95(3H,t,J=7.4Hz),0.50(3H,t,J=7.4Hz)。质谱(ESI)m/z=593(M+1),615(M+23)。
实施例79
(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-((3-羟基-1H-吡唑-5-基)甲基)-3-甲基-1-(戊烷-3-基)哌啶-2-酮
步骤A. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)乙醛
向240mg(0.54mmol)(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(戊烷-3-基)哌啶-2-酮(实施例71,步骤E)在THF(8mL)和水(2.8mL)中的溶液中加入催化量的四氧化锇。在1.25h后,加入323mg(1.51mmol)高碘酸钠。将由此产生的淡棕色浆液在室温下搅拌18.5h,然后通过烧结漏斗过滤。在减压下部分浓缩滤液,然后用水稀释并用乙酸乙酯(2X)萃取。先后用饱和硫代硫酸钠水溶液和饱和氯化钠水溶液洗涤合并的有机层。经Na2SO4干燥有机层,过滤,并浓缩滤液。该粗的本标题化合物直接用于下一步骤。
步骤B. 4-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)-3-氧代丁酸乙酯
用超过3min的时间经由注射器向160mg(0.36mmol)2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)乙醛(实施例79,步骤A)和20.4mg(0.11mmol)氯化锡(II)在DCM(6mL)中的悬浮液中加入104μL(1.00mmol)重氮基乙酸乙酯。将由此产生的黄色浆液在室温下搅拌14.25h,然后用1N HCl淬灭并用EtOAc(2X)萃取。用1N HCl(1X)洗涤合并的有机层,然后经Na2SO4干燥,过滤,并浓缩滤液。通过反相制备型HPLC(SunfireTMPrep C18OBD 10μm柱(Waters,Milford,MA),用55%的在水中的MeCN至85%的在水中的MeCN梯度洗脱超过30min,其中这两种溶剂都含有0.1%TFA)纯化残余物,得到本标题化合物,为淡黄色油状物。
步骤C. (3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-((3-羟基-1H-吡唑-5-基)甲基)-3-甲基-1-(戊烷-3-基)哌啶-2-酮
向42mg(0.08mmol)4-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)-3-氧代丁酸乙酯(实施例79,步骤B)在乙醇(4mL)中的溶液中加入36μL(0.48mmol)肼一水合物(64-65%的重量百分比的肼)。将由此产生的无色溶液在65℃下加热3.5h,然后在减压下浓缩。通过反相制备型HPLC(Sunfire Prep C18OBD 10μm柱,用45%的在水中的MeCN至80%的在水中的MeCN梯度洗脱超过30min,其中这两种溶剂都含有0.1%TFA)纯化残余物,得到本标题化合物,为白色固体。
1H NMR(400MHz,CDCl3)δppm 7.23-7.30(3H,m),7.18-7.22(1H,m),7.12(1H,t,J=7.7Hz),6.90-6.96(2H,m),6.67(1H,d,J=7.8Hz),5.66(1H,s),4.34(1H,d,J=10.6Hz),3.42(1H,d,J=15.9Hz),3.02-3.11(1H,m),2.82(1H,d,J=15.9Hz),2.68-2.77(1H,m),2.36(1H,t,J=13.9Hz),1.87-2.03(3H,m),1.40-1.51(2H,m),1.36(3H,s),0.96(3H,t,J=7.4Hz),0.50(3H,t,J=7.5Hz)。质谱(ESI)m/z=500(M+1),522(M+23)。
实施例80
(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-((3-羟基异噁唑-5-基)甲基)-3-甲基-1-(戊烷-3-基)哌啶-2-酮
向冰冷却的65mg(0.12mmol)4-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)-3-氧代丁酸乙酯(实施例79,步骤B)在水(2mL)中的浆液中加入53.5mg(0.77mmol)羟胺盐酸盐和62mg(1.55mmol)氢氧化钠。在5min后,加入THF(1mL)和MeOH(1mL)。将由此产生的混浊的淡黄色溶液在0℃下搅拌20min,然后升温至室温并再搅拌6h。通过逐滴添加浓HCl来酸化反应物直至强酸性,然后用水稀释并用EtOAc(4X)萃取。经Na2SO4干燥合并的有机层,过滤,并浓缩滤液。通过反相制备型HPLC(SunfireTMPrepC18OBD 10μm柱(Waters,Milford,MA),用55%的在水中的MeCN至85%的在水中的MeCN梯度洗脱超过30min,其中这两种溶剂都含有0.1%TFA)纯化残余物,得到本标题化合物,为白色固体。
1H NMR(400MHz,CDCl3)δppm 7.20-7.27(3H,m),7.14-7.20(1H,m),7.11(1H,dt,J=7.8Hz,3.8Hz),6.89-7.01(3H,m),6.70(1H,d,J=7.4Hz),4.33(1H,dd,J=10.5Hz,3.4Hz),3.59-3.78(2H,m),3.13-3.23(1H,m),3.07(1H,dd,J=14.1Hz,3.1Hz),2.66-2.77(2H,m),2.15-2.26(1H,m),1.96-2.04(1H,m),1.78-1.94(2H,m),1.40-1.51(1H,m),1.41(3H,s),0.93(3H,dt,J=7.4Hz,3.5Hz),0.51(3H,dt,J=7.5Hz,3.6Hz)。质谱(ESI)m/z=501(M+1)。
实施例81
5-(((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)甲基)噁唑烷-2,4-二酮
步骤A. (3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-(2,3-二羟基丙基)-3-甲基-1-(戊烷-3-基)哌啶-2-酮
向298mg(0.67mmol)(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(戊烷-3-基)哌啶-2-酮(实施例71,步骤E)在丙酮(11.5mL)和水(4mL)的混合物中的溶液中加入催化量的四氧化锇。在4min后,加入275mg(2.35mmol)N-甲基吗啉-N-氧化物。将由此产生的棕色溶液在室温下搅拌3.5h,然后将其分配在水与DCM(3X)之间。经Na2SO4干燥合并的有机层,过滤,并浓缩滤液。通过硅胶快速色谱法(1%至20%的MeOH/DCM,梯度洗脱)纯化残余物,得到本标题化合物(醇差向异构体的混合物),为黄色油状物。
步骤B. 3-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)-2-羟基丙酸
在35℃下,同时用105mg(1.16mmol)亚氯酸钠在水(1.2mL)中的溶液和106μL(0.07mmol)漂白剂溶液(约0.7N)在水(0.6mL)中的溶液处理142mg(0.30mmol)(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-(2,3-二羟基丙基)-3-甲基-1-(戊烷-3-基)哌啶-2-酮(实施例81,步骤A)和28mg(0.18mmol)TEMPO在乙腈(6mL)和磷酸钠-氢氧化钠缓冲液(pH 6.7,4.5mL)的混合物中的混合物超过10min。将由此产生的暗橙色溶液在35℃下搅拌1.75h,然后将其分配在1N HCl与EtOAc(3X)之间。经Na2SO4干燥合并的有机层,过滤,并浓缩滤液。通过反相制备型HPLC(SunfireTMPrep C18OBD 10μm柱(Waters,Milford,MA),用60%的在水中的MeCN至80%的在水中的MeCN梯度洗脱超过30min,其中这两种溶剂都含有0.1%TFA)纯化残余物,得到本标题化合物(醇差向异构体的混合物),为白色固体。
步骤C. 3-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)-N-(2,4-二甲氧基苄基)-2-羟基丙酰胺
向43mg(0.09mmol)3-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)-2-羟基丙酸(实施例81,步骤B)在DMF(5mL)中的溶液中加入67mg(0.18mmol)HATU、58.5mg(0.35mmol)2,4-二甲氧基苄胺和36μL(0.26mmol)三乙胺。将由此产生的黄色溶液在室温下搅拌1.1h,然后将其分配在饱和碳酸氢钠水溶液和EtOAc(2X)之间。经Na2SO4干燥合并的有机层,过滤,并浓缩滤液。该粗的本标题化合物(醇差向异构体的混合物)直接用于下一步骤。
步骤D. (S)-3-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)-2-羟基丙酰胺和(R)-3-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)-2-羟基丙酰胺
将56mg(0.09mmol)3-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)-N-(2,4-二甲氧基苄基)-2-羟基丙酰胺(实施例81,步骤C)在三氟乙酸(2.3mL)中的溶液在50℃下加热2.5h,然后在减压下浓缩。通过反相制备型HPLC(SunfireTMPrep C18OBD 10μm柱(Waters,Milford,MA),用50%的在水中的MeCN至75%的在水中的MeCN梯度洗脱超过30min,其中这两种溶剂都含有0.1%TFA)纯化残余物,得到两种本标题化合物(在每种情况下,醇立体中心处的立体化学均是任意指定的),均为淡绿色固体。
步骤E. 5-(((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)甲基)噁唑烷-2,4-二酮
向10.3mg(0.02mmol)(S)-3-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)-2-羟基丙酰胺(实施例81,步骤D)在MeOH(2.5mL)中的溶液中加入0.50mL(1.22mmol)乙醇钠(21wt.%的在乙醇中的溶液)和1.20mL(9.90mmol)碳酸二乙酯。将由此产生的混合物在回流下加热15min,然后在减压下浓缩。将残余物分配在0.5M HCl与EtOAc(3X)之间。经Na2SO4干燥合并的有机层,过滤,并浓缩滤液。通过反相制备型HPLC(SunfireTMPrep C18OBD 10μm柱(Waters,Milford,MA),用60的在水中的MeCN至80的在水中的MeCN梯度洗脱超过30min,其中这两种溶剂都含有0.1%TFA)纯化残余物,得到本标题化合物(醚差向异构体的混合物),为白色固体。
1H NMR(400MHz,CDCl3,差向异构体的混合物)δppm 8.90(1H,br s,主要差向异构体),8.83(1H,br s,次要差向异构体),7.20-7.27(3H,m),7.15-7.20(1H,m),7.11(1H,dt,J=7.7Hz,1.9Hz),6.94-7.02(2H,m),6.71(1H,d,J=7.6Hz),5.37(1H,t,J=10.0Hz),4.33(1H,d,J=10.4Hz),2.67-2.79(1H,m),2.67-2.79(1H,m,主要差向异构体)2.41(1H,dd,J=15.2Hz,8.6Hz,次要差向异构体),1.82-2.31(6H,m),1.48-1.61(1H,m),1.35-1.45(1H,m),1.45(3H,s,次要差向异构体),1.44(s,3H,主要差向异构体),0.94(3H,t,J=7.4Hz),0.52(3H,t,J=7.5Hz)。质谱(ESI)m/z=517(M+1),539(M+23)。
实施例82
3-(((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)甲基)-1,2,4-噁二唑-5(4H)-酮
步骤A. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)乙酰胺
向1.15g(2.49mmol)2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)乙酸(实施例71,步骤F)在THF(12.5mL)中的冰冷却的溶液中加入383μL(3.48mmol)N-甲基吗啉和392μL(2.98mmol)氯甲酸异丁酯。将由此产生的灰白色浆液在0℃下搅拌2h,然后加入336μL(28%的在水中的氨,4.97mmol)氢氧化铵。再在0℃下3h后,用饱和氯化铵水溶液淬灭反应物并用EtOAc(3X)萃取。经Na2SO4干燥合并的有机层,过滤,并浓缩滤液。该粗的本标题化合物直接用于下一步骤。
步骤B. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)乙腈
向1.15g(2.49mmol)2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)乙酰胺(实施例82,步骤A)在THF(21mL)中的冰冷却的溶液中加入1.73mL(12.4mmol)三乙胺和865μL(6.22mmol)TFA。将由此产生的棕褐色溶液在0℃下搅拌2.75h,然后升温至室温并再搅拌2h。将反应物再冷却至0℃,用1N柠檬酸淬灭,然后用EtOAc(3X)萃取。经Na2SO4干燥合并的有机层,过滤,并浓缩滤液。用饱和氯化钠水溶液(1X)洗涤合并的有机层,然后经Na2SO4干燥,过滤,并浓缩滤液。通过硅胶快速色谱法(5%至35%的EtOAc/己烷,梯度洗脱)纯化残余物,得到本标题化合物,为白色固体。
步骤C. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)-N′-羟基乙脒
向1.49g(20.6mmol)羟胺盐酸盐在DMSO(10mL)中的悬浮液中加入2.88mL(20.6mmol)三乙胺。将该浆液搅拌5min,然后通过过滤棉(cotton)过滤两次,用THF冲洗,以除去固体。将滤液在减压下部分浓缩以除去THF,然后加入到含有915mg(2.06mmol)2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)乙腈(实施例82,步骤B)的烧瓶中。将由此产生的黄色溶液在75℃下加热22h,然后将其分配在水与EtOAc之间。经Na2SO4干燥有机层,过滤,并浓缩滤液。通过硅胶快速色谱法(1%至7%的MeOH/DCM,梯度洗脱)纯化残余物,得到本标题化合物,为白色固体。
步骤D. 3-(((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)甲基)-1,2,4-噁二唑-5(4H)-酮
向385mg(0.81mmol)2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)-N′-羟基乙脒(实施例82,步骤C)在二噁烷(12.5mL)中的溶液中加入211μL(1.41mmol)DBU和262mg(1.62mmol)1,1’-羰基二咪唑。将由此产生的无色溶液在100℃下加热25min,然后用水淬灭并用EtOAc萃取。用饱和氯化钠水溶液洗涤有机层,然后经Na2SO4干燥,过滤,并浓缩滤液。通过反相制备型HPLC(SunfireTMPrep C18OBD 10μm柱(Waters,Mlford,MA),用55%的在水中的MeCN至80%的在水中的MeCN梯度洗脱超过35min,其中这两种溶剂都含有0.1%TFA)纯化残余物,得到本标题化合物,为白色固体。
1H NMR(400MHz,CDCl3)δppm 10.39(1H,br s),7.22-7.27(3H,m),7.18(1H,d,J=8.1Hz),7.12(1H,t,J=7.8Hz),6.87-6.98(2H,m),6.68(1H,d,J=7.6Hz),4.35(1H,d,J=10.3Hz),3.19(1H,d,J=15.4Hz),3.05(1H,ddd,J=13.3Hz,10.5Hz,2.6Hz),2.82(1H,d,J=15.4Hz),2.69-2.78(1H,m),2.31(1H,t,J=13.8Hz),2.06(1H,dd,J=13.9Hz,2.7Hz),1.84-2.00(2H,m),1.39-1.51(2H,m),1.38(3H,s),0.95(3H,t,J=7.5Hz),0.50(3H,t,J=7.5Hz)。质谱(ESI)m/z=502(M+1),524(M+23)。
实施例83
3-(((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-异丙基-3-甲基-2-氧代哌啶-3-基)甲基)-1,2,4-噁二唑-5(4H)-酮
按照与实施例82中描述的方法类似的方法制备本标题化合物。1H NMR(400MHz,CDCl3)δppm 10.38(1H,br s),7.24-7.32(2H,m),7.18-7.23(m,1H),7.15(1H,dt,J=7.8Hz,3.6Hz),7.04(1H,br s),6.90(2H,d,J=5.4Hz),6.76(1H,d,J=7.1Hz),4.52(1H,dd,J=8.6Hz,3.2Hz),3.40-3.50(1H,m),3.09(1H,dd,J=15.3Hz,2.8Hz),2.99-3.06(1H,m),2.78(1H,dd,J=15.3Hz,3.1Hz),2.18(1H,dt,J=11.9Hz,3.2Hz),2.05-2.13(1H,m),1.22-1.27(m,9H)。质谱(ESI)m/z=474(M+1)。
实施例84
3-(((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)甲基)-1,2,4-噻二唑-5(4H)-酮
向83mg(0.17mmol)2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)-N′-羟基乙脒(实施例82,步骤C)在THF(4mL)中的溶液中加入50mg(0.28mmol)1,1’-硫代羰基二咪唑。将由此产生的黄色溶液在室温下搅拌1h,然后用水淬灭并用EtOAc萃取。经Na2SO4干燥有机层,过滤,并浓缩滤液。将残余物溶解在THF(4.5mL)中,并经由注射器加入69μL(0.56mmol)三氟化硼醚化物。将由此产生的淡黄色溶液在室温下搅拌2.5h,然后用水淬灭并用EtOAc萃取。经Na2SO4干燥有机层,过滤,并浓缩滤液。通过反相制备型HPLC(Sunfire Prep C18OBD 10μm柱,用55%的在水中的MeCN至85%的在水中的MeCN梯度洗脱超过35min,其中这两种溶剂都含有0.1%TFA)纯化残余物,得到本标题化合物,为白色固体。
1H NMR(400MHz,CDCl3)δppm 10.94(1H,br s),7.20-7.27(3H,m),7.13-7.18(1H,m),7.09(1H,t,J=7.7Hz),6.85-6.95(2H,m),6.66(1H,d,J=7.6Hz),4.34(1H,d,J=10.2Hz),3.09(1H,d,J=14.8Hz),2.87-3.01(2H,m),2.68-2.77(1H,m),2.25(1H,t,J=13.5Hz),2.04-2.13(1H,m),1.87-2.04(2H,m),1.39-1.51(2H,m),1.38(3H,s),0.95(3H,t,J=7.4Hz),0.50(3H,t,J=7.4Hz)。质谱(ESI)m/z=518(M+1),540(M+23)。
实施例85
3-(((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-异丙基-3-甲基-2-氧代哌啶-3-基)甲基)-1,2,4-噻二唑-5(4H)-酮
按照与实施例84中描述的方法类似的方法制备本标题化合物。1H NMR(400MHz,CDCl3)δppm 10.89(1H,br s),7.24-7.30(2H,m),7.18-7.22(m,1H),7.15(1H,t,J=7.8Hz),7.04(1H,br s),6.86(2H,d,J=8.3Hz),6.77(1H,d,J=7.8Hz),4.53(1H,d,J=8.3Hz),3.41-3.50(1H,m),2.90-3.04(3H,m),2.05-2.19(2H,m),1.27(6H,dd,J=6.6Hz,6.6Hz),1.23(s,3H)。质谱(ESI)m/z=490(M+1),512(M+23)。
实施例86
(3R,5R,6S)-3-((1H-四唑-5-基)甲基)-5-(3-氯苯基)-6-(4-氯苯基)-1-异丙基-3-甲基哌啶-2-酮
如实施例51中所述从2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-异丙基-3-甲基-2-氧代哌啶-3-基)乙酸(实施例73)制备本标题化合物。
1H NMR(400MHz,CDCl3)δppm 1.20(s,3H),1.27(d,J=6.9Hz,3H),1.29(d,J=6.8Hz,3H),2.20(m,2H),3.08(m,1H),3.41(d,J=15.7Hz,1H),3.47(m,1H),3.50(d,J=15.6Hz,1H),4.52(d,J=8.8Hz,1H),6.78(m,3H),7.06(m,1H),7.16(m,1H),7.23(m,3H)。质谱(ESI)m/z 458.0[M+H]+。
实施例87
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-2-氧代-1-(戊烷-3-基)哌啶-3-基)乙酸
步骤A. (5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-1-(戊烷-3-基)哌啶-2-酮.
在室温下在氮气下向(3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)哌啶-2-酮(实施例42,步骤A)(440mg,1.221mmol)在3-溴戊烷(3196μL,25.6mmol)中的溶液中加入60%氢化钠在矿物油中的分散体(244mg,6.11mmol)。观察到气体逸出。将反应物在室温下搅拌10min,然后在N2下加热至120℃并保持19h。将反应混合物冷却至室温并用饱和NH4Cl淬灭。分离各层,经Na2SO4干燥有机层并在减压下浓缩。通过硅胶快速色谱法(洗脱剂:0%至25%的在己烷中的EtOAc)纯化残余物,得到本标题化合物,为非对映异构体的混合物。
步骤B. (5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-1-(戊烷-3-基)哌啶-2-酮.
向(5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-(戊烷-3-基)哌啶-2-酮(实施例87,步骤A)(125mg,0.290mmol)中加入甲苯(15mL),并在减压下浓缩该混合物。将这个步骤重复三次。加入不含抑制剂的THF(1mL)并将该混合物冷却至-78℃。加入新制备的LDA(1.0M在THF中)(290μL,0.290mmol),反应物颜色变成金黄色。将反应物升温至0℃并保持30min,反应物颜色变成橙色。将反应物冷却至-78℃并加入碘乙烷(281μL,3.49mmol)。将反应混合物升温至0℃并搅拌30min。用饱和NH4Cl淬灭反应物,升温至室温,用EtOAc稀释并分离各层。经Na2SO4干燥有机层,并在减压下浓缩。通过硅胶快速色谱法(洗脱剂:0%至10%的在己烷中的EtOAc)纯化残余物,得到本标题化合物,为非对映异构体的1:1混合物。
步骤C. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-2-氧代-1-(戊烷-3-基)哌啶-3-基)乙酸
如实施例42,步骤C中所述从(5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-1-(戊烷-3-基)哌啶-2-酮(实施例87,步骤B)制备本标题化合物。通过反相制备型HPLC(洗脱剂:0%至100%MeCN+0.1%TFA于水+0.1%TFA中)纯化,得到本标题化合物,为第一洗脱非对映异构体。
1H NMR(500MHz,氯仿-d)δppm 0.50(3H,t,J=7.5Hz)0.95(3H,t,J=7.5Hz)1.00(3H,t,J=7.5Hz)1.29-1.45(2H,m)1.45-1.53(1H,m)1.84-2.01(4H,m)2.30(1H,t,J=13.8Hz)2.72-2.80(2H,m)3.03-3.11(2H,m)4.34(1H,d,J=10.3Hz)6.69(1H,d,J=7.6Hz)6.95(2H,br s)7.05-7.20(2H,m)7.08-7.17(2H,m)7.22-7.25(1H,m)。质谱(ESI)m/z=476[M+H]+。
实施例88
(3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-3-(甲基磺酰基甲基)-1-(戊烷-3-基)哌啶-2-酮
步骤A. (5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(2,4-二甲氧基苄基)-3-甲基-2-氧代哌啶-3-羧酸甲酯.
在室温在氩气下将LHMDS(5.42mL,5.42mmol)加入到(5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(2,4-二甲氧基苄基)-3-甲基哌啶-2-酮(实施例71,步骤B)(1.75g,3.61mmol)在无水THF(14.45mL)中的溶液中。在5分钟后,加入二碳酸二甲酯(1.159mL,10.84mmol)。在4小时后,TLC指示已经有大量产物形成,但是仍存在一些原料。再加入LHMDS(5.42mL,5.42mmol),接着加入二碳酸二甲酯(1.159mL,10.84mmol)。在2.5小时后,通过加入NH4Cl饱和水溶液淬灭反应物并分离各层。用EtOAc萃取水层两次,将有机物汇集在一起,用NaCl饱和水溶液洗涤,干燥(MgSO4),过滤并在真空中浓缩从而得到黄色油状物。通过使用120g SiO2柱,用25%至40%的EtOAc/己烷洗脱来进行纯化,得到本标题化合物,其为无色油状物,为异构体混合物。
步骤B. (5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(2,4-二甲氧基苄基)-3-(羟基甲基)-3-甲基哌啶-2-酮
在0℃在氮气下将2M硼氢化锂(1.078mL,2.157mmol)加入到(5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(2,4-二甲氧基苄基)-3-甲基-2-氧代哌啶-3-羧酸甲酯(实施例88,步骤A)(1.17g,2.157mmol)在无水THF(21.57mL)和无水乙醚(20mL)中的溶液中。在58小时后通过加入NH4Cl饱和水溶液淬灭反应物,并分离各层。用EtOAc萃取水层两次,将有机物汇集在一起,用NaCl饱和水溶液洗涤,干燥(MgSO4),过滤并在真空中浓缩从而得到无色油状物。通过使用80g SiO2柱,用35%至65%的EtOAc/己烷洗脱来进行纯化,得到本标题化合物,为异构体的~30:1混合物。
步骤C. ((5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(2,4-二甲氧基苄基)-3-甲基-2-氧代哌啶-3-基)甲基4-甲基苯磺酸酯
在室温下将DMAP(0.015g,0.120mmol)加入到(5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(2,4-二甲氧基苄基)-3-(羟基甲基)-3-甲基哌啶-2-酮(实施例88,步骤B)(0.616g,1.197mmol)和对甲苯磺酰氯(0.457g,2.395mmol)在吡啶(5.99mL)中的溶液中。将反应混合物加热至100℃并保持5小时,然后在真空中除去该溶剂从而得到米色油状物。通过使用80gSiO2柱,用25%至55%的EtOAc/己烷洗脱来进行纯化,得到本标题化合物,其为无色油状物,为异构体的33:1混合物。
步骤D. (3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(2,4-二甲氧基苄基)-3-甲基-3-(甲基硫代甲基)哌啶-2-酮
在室温在氮气下将硫代甲醇钠(0.193g,2.76mmol)加入到((5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(2,4-二甲氧基苄基)-3-甲基-2-氧代哌啶-3-基)甲基4-甲基苯磺酸酯(实施例88,步骤C)(0.738g,1.104mmol)在无水DMF(5.52mL)中的溶液中。将反应混合物在50℃下加热8小时,然后冷却至室温,用水稀释并用乙醚萃取三次。将有机物汇集在一起,用水洗涤三次,用NaCl饱和水溶液洗涤,干燥(MgSO4),过滤并在真空中浓缩从而得到无色油状物。通过使用40gSiO2柱,用15%至40%的EtOAc/己烷洗脱来进行纯化,得到本标题化合物,为无色泡沫状物。
步骤E. (3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-3-(甲基硫代甲基)哌啶-2-酮
将(3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(2,4-二甲氧基苄基)-3-甲基-3-(甲基硫代甲基)哌啶-2-酮(实施例88,步骤D)(0.406g,0.746mmol)在TFA(6.00mL)中的溶液于50℃在氮气下加热2小时。在真空中浓缩反应混合物从而得到紫色油状物。通过使用40g SiO2柱,用35%至60%的EtOAc/己烷洗脱来进行纯化,得到本标题化合物,为白色固体。
步骤F. (3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-3-(甲基硫代甲基)-1-(戊烷-3-基)哌啶-2-酮
在室温在氮气下将NaH(0.076g,1.900mmol)加入到(3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-3-(甲基硫代甲基)哌啶-2-酮(实施例88,步骤E)(0.150g,0.380mmol)在3-溴戊烷(1.42mL,11.41mmol)中的溶液中。将反应混合物在120℃下加热24小时,冷却至室温,用水稀释并用DCM萃取三次。将有机物汇集在一起,用NaCl饱和水溶液洗涤,干燥(MgSO4),过滤并在真空中浓缩从而得到黄色油状物。通过使用24g SiO2柱,用15%的EtOAc/己烷洗脱来进行纯化,得到本标题化合物,为无色浆液。
步骤G. (3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-3-(甲基磺酰基甲基)-1-(戊烷-3-基)哌啶-2-酮
在0℃下将3-氯过苯甲酸(0.054g,0.242mmol)加入到(3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-3-(甲基硫代甲基)-1-(戊烷-3-基)哌啶-2-酮(实施例88,步骤F)(0.045g,0.097mmol)在DCM(0.969mL)中的溶液中。将反应混合物在室温下搅拌1小时,用NaHCO3饱和溶液、NaCl饱和水溶液洗涤,干燥(MgSO4),过滤并在真空中浓缩从而得到无色油状物。通过使用4g SiO2ISCO柱,用25%至75%的EtOAc/己烷洗脱来进行纯化,得到本标题化合物,为无色玻璃状物。
1H NMR(500MHz,CDCl3)δppm 0.49(t,J=7.6Hz,3H),0.95(t,J=7.5Hz,3H),1.39(m,1H),1.54(s,3H),1.56(m,1H),1.89(m,2H),2.10(m,1H),2.57(dd,J=14.4和3.1Hz,1H),2.72(m,1H),3.05(s,3H),3.24(d,J=13.9Hz,1H),3.63(m,1H),3.82(d,J=13.9Hz,1H),4.40(d,J=10.7Hz,1H),6.78(m,1H),7.02(br s,1H),7.06(m,2H),7.10(m,2H),7.20(m,2H)。质谱(ESI)m/z 496.2[M+H]+。
实施例89
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(3-环丙基-1,2,4-噁二唑-5-基)丙基)-3-甲基-2-氧代哌啶-3-基)乙酸.
步骤A. 2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁酸.
在室温下将在水(2.6mL)中的LiOH(0.267g,11.13mmol)加入到2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁酸甲酯(实施例65,步骤B)(0.528g,1.113mmol)在MeOH(7.5mL)中的溶液中。将反应混合物在80℃下加热14小时,冷却至室温并用3M HCl酸化至pH=1。用EtOAc萃取该混合物三次,将有机物汇集在一起,用NaCl饱和水溶液洗涤,干燥(MgSO4),过滤并在真空中浓缩从而得到白色固体。通过使用40gSiO2柱,用35-60%的EtOAc/己烷洗脱来进行纯化,得到本标题化合物,为异构体的混合物。
步骤B. N′-(2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁酰基氧基)环丙烷甲脒
在室温下将1,1’-羰基二咪唑(0.104g,0.639mmol)加入到2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁酸(实施例89,步骤A)(0.196g,0.426mmol)在二氯甲烷(1.703mL)中的溶液中,并搅拌22小时,然后加入n-羟基环丙烷甲脒(0.064g,0.639mmol)。在6小时后,使反应混合物吸附到二氧化硅上,并通过使用12g SiO2ISCO柱,用35%至60%的EtOAc/己烷洗脱来进行纯化,得到异构体的2:1混合物。
步骤C. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(3-环丙基-1,2,4-噁二唑-5-基)丙基)-3-甲基哌啶-2-酮和(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-1-(3-环丙基-1,2,4-噁二唑-5-基)丙基)-3-甲基哌啶-2-酮
在室温下将四丁基氟化铵溶液(1.0M在THF中,1.880mL,1.880mmol)加入到N′-(2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁酰基氧基)环丙烷甲脒(实施例89,步骤B)(0.204g,0.376mmol)在THF(3.76mL)中的溶液中。在2小时后,在真空中浓缩反应混合物,并通过使用24g SiO2柱,用25%Et2O/己烷洗脱来进行纯化,从而得到(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(3-环丙基-1,2,4-噁二唑-5-基)丙基)-3-甲基哌啶-2-酮。
进一步洗脱得到(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-1-(3-环丙基-1,2,4-噁二唑-5-基)丙基)-3-甲基哌啶-2-酮。
步骤D. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(3-环丙基-1,2,4-噁二唑-5-基)丙基)-3-甲基-2-氧代哌啶-3-基)乙酸
如实施例42步骤C中所述,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(3-环丙基-1,2,4-噁二唑-5-基)丙基)-3-甲基哌啶-2-酮(实施例89,步骤C)制备本标题化合物。通过使用4g SiO2柱,用35%至100%的EtOAc/己烷洗脱来进行纯化,得到本标题化合物,为无色膜状物。
1H NMR(500MHz,CDCl3)δppm 0.84(t,J=7.5Hz,3H),0.89(m,2H),1.01(m,2H),1.25(m,1H),1.43(s,3H),1.95(m,1H),1.98(m,1H),2.20(m,2H),2.37(m,1H),2.90(m,2H),3.26(m,1H),4.60(t,J=6.9Hz,1H),4.63(d,J=10.3Hz,1H),6.76(m,1H),6.90(m,2H),7.00(br s,1H),7.10(t,J=7.9Hz,1H),7.16(m,3H)。质谱(ESI)m/z 542.2[M+H]+。
实施例90
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-1-(3-环丙基-1,2,4-噁二唑-5-基)丙基)-3-甲基-2-氧代哌啶-3-基)乙酸.
如实施例42步骤C中所述从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-1-(3-环丙基-1,2,4-噁二唑-5-基)丙基)-3-甲基哌啶-2-酮(实施例89,步骤C)制备本标题化合物。
1H NMR(400MHz,CDCl3)δppm 0.85-1.05(m,3H)1.09(t,J=7.6Hz,3H),1.44(s,3H),2.01(m,1H),2.19(m,1H),2.26(m,3H),2.83(d,J=14.7Hz,1H),2.91(d,J=14.7Hz,2H),3.32(m,1H),3.95(t,J=7.2Hz,1H),4.57(d,J=10.4Hz,1H),6.73(m,1H),6.98(m,1H),7.09(t,J=7.8Hz,1H),7.16(m,2H),7.20(m,3H)。质谱(ESI)m/z 542.2[M+H]+。
实施例91
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-吗啉代丁烷-2-基)-2-氧代哌啶-3-基)乙酸
步骤A. (S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁酸甲酯
在0℃下向(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮(实施例71,步骤D)(4.00g,10.7mmol)在45mL DMF中的溶液中加入60%氢化钠在矿物油中的分散体(1.71g,42.7mmol)。在搅拌20min后,在0℃下加入2-溴丁酸甲酯(6.15mL,53.4mmol),并将由此产生的溶液在25℃下搅拌12h直至反应完成。然后加入NH4Cl饱和水溶液,并用乙酸乙酯萃取该混合物。用水和NaCl饱和水溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过硅胶快速色谱法(洗脱剂:0%至100%的MTBE/己烷,梯度洗脱)纯化残余物,接着通过手性SFC(流速:在 AD-H柱(Diacel Inc.,FortLee,NJ)上65mL/min,使用3:1的庚烷/IPA(0.1%DEA)/CO2作为洗脱剂)分离各个立体异构体,得到本标题化合物,为较快地洗脱的异构体。
1H NMR(400MHz,氯仿-d)δppm 7.23(2H,d,J=8.4Hz),7.06-7.17(2H,m),7.00(3H,t,J=1.8Hz),6.77(1H,d,J=7.6Hz),5.79-5.94(1H,m),5.20(1H,d,J=4.7Hz),5.17(1H,s),4.56(1H,d,J=10.8Hz),3.73(3H,s),3.25-3.37(1H,m),3.18(1H,dd,J=7.6Hz,4.9Hz),2.61(2H,d,J=7.4Hz),2.20-2.34(1H,m),2.09-2.19(1H,m),1.99(1H,d,J=3.1Hz),1.57-1.72(1H,m),1.24(3H,s),0.61(3H,t,J=7.5Hz);质谱(ESI)m/z=474.1[M+H]+。
进一步洗脱得到:
(R)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁酸甲酯
其为较慢地洗脱的异构体。
1H NMR(400MHz,氯仿-d)δppm 7.22(2H,d,J=8.0Hz),6.99-7.19(4H,m),6.95(1H,t,J=1.8Hz),6.71(1H,d,J=7.6Hz),5.81-5.95(1H,m),5.19(1H,d,J=2.7Hz),5.16(1H,d,J=1.0Hz),4.48(1H,d,J=10.6Hz),3.67(3H,s),3.24-3.32(1H,m),3.20(1H,dd,J=7.8Hz,6.1Hz),2.61-2.72(1H,m),2.49-2.60(1H,m),1.91-2.21(4H,m),1.27(3H,s),1.00(3H,t,J=7.5Hz);MS(ESI)m/z=474.1[M+H]+。
步骤B. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-1-羟基丁烷-2-基)-3-甲基哌啶-2-酮
在0℃下向(S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁酸甲酯和(R)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁酸甲酯(1.73g,3.64mmol)(实施例91,步骤A中的立体异构体混合物)在27mL Et2O和9mL THF中的溶液中加入四氢硼酸锂在THF中的溶液(0.238mL,7.28mmol)。将由此产生的溶液在25℃下搅拌2h。淬灭(10%柠檬酸)反应物,萃取(2×EtOAc)并洗涤(1×NaCl饱和水溶液)。用NaCl饱和水溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过硅胶快速色谱法(洗脱剂:0-60%的在己烷中的EtOAc)纯化残余物,从而得到本标题化合物,为较快地洗脱的异构体。
1H NMR(400MHz,氯仿-d)δppm 0.99(t,J=7.4Hz,3H),1.29(s,3H),1.79-2.03(m,4H),2.62(d,J=7.4Hz,2H),2.80–2.85(m,1H),3.05-3.16(m,1H),3.40–3.49(m,2H),4.33(d,J=10.4Hz,1H),5.13-5.22(m,2H),5.79-5.95(m,1H),6.7(d,J=7.6Hz,1H),6.85-6.97(m,3H),7.08-7.15(m,1H),7.17–7.19(m,1H),7.23(d,J=8.6Hz,2H);质谱(ESI)m/z=446(M+1)。
进一步洗脱得到:
(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)-3-甲基哌啶-2-酮
其为较慢地洗脱的异构体。
1H NMR(400MHz,氯仿-d)δppm 0.68(t,J=7.5Hz,3H),1.27(s,3H),1.38-1.52(m,1H),1.90-2.08(m,4H),2.61(d,J=7.4Hz,2H),3.10-3.25(m,2H),3.59–3.68(m,2H),4.46(d,J=10.2Hz,1H),5.18(dd,J=13.7,1.8Hz,2H),5.79-5.93(m,1H),6.72(d,J=7.6Hz,1H),6.93-7.04(m,2H),7.09–7.13(m,1H),7.15-7.20(m,1H),7.24(d,J=8.6Hz,2H);质谱(ESI)m/z=446(M+1)。
步骤C. (S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁醛
在室温下向218mg(0.49mmol)(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)-3-甲基哌啶-2-酮(实施例91,步骤B)在水(13.20μL,0.733mmol)和DCM(4883μL)的混合物中的溶液中加入1,1,1,-三(乙酰氧基)-1,1-二氢-1,2-苯并碘氧杂戊环-3-(1H)酮(“Dess Martin过碘烷”)(311mg,0.733mmol)。通过LCMS监测反应,并将另外的过碘烷分成几个小部分加入直至反应完成。淬灭(2mL,1M Na2S2O3)反应物,萃取(2x DCM),并用NaHCO3饱和溶液(2X)、NaCl饱和溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过硅胶快速色谱法(洗脱剂:20%至35%的EtOAc/己烷,梯度洗脱)纯化残余物,得到本标题化合物。
步骤D. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-吗啉代丁烷-2-基)哌啶-2-酮.
向100mg(0.225mmol)(S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁醛(实施例91,步骤C)在DCE(2420μL)中的溶液中加入吗啉(200μL,2.297mmol)、乙酸(1.288μL,0.023mmol)和三乙酰氧基硼氢化钠(95mg,0.450mmol)。将反应混合物在室温下搅拌18小时。用碳酸氢钠饱和溶液淬灭反应物,并用DCM(2x10mL)萃取。用NaCl饱和溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液从而得到粗的本标题化合物,为油状物。
步骤E. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-吗啉代丁烷-2-基)-2-氧代哌啶-3-基)乙醛.
向装有(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-吗啉代丁烷-2-基)哌啶-2-酮(实施例91,步骤D)(125mg,0.242mmol)的圆底烧瓶中加入THF(2mL)。逐滴加入大约1mL水直至溶液变得混浊并且在轻轻搅拌的情况下仍然是混浊的。逐滴加入t-BuOH(0.350mL),直至溶液变得均匀。加入NMO(42.6mg,0.364mmol),接着加入4wt.%的在水中的四氧化锇(玻璃巴氏(Pasteur)吸管的1滴)。将反应混合物在室温下搅拌16小时。再加入1滴4wt.%的在水中的四氧化锇。在5小时后,再加入2滴4wt.%的在水中的四氧化锇,并将反应混合物再在室温下搅拌16小时。加入高碘酸钠(145mg,0.679mmol),并将反应混合物在室温下搅拌2小时。用乙酸乙酯(10mL)和水(10mL)稀释反应混合物并过滤。用另外的乙酸乙酯(10mL)萃取滤液的水层,并用NaCl饱和水溶液洗涤合并的有机层,经硫酸钠干燥,过滤,并在减压下浓缩滤液从而得到本标题化合物。
步骤F. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-吗啉代丁烷-2-基)-2-氧代哌啶-3-基)乙酸
向2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-吗啉代丁烷-2-基)-2-氧代哌啶-3-基)乙醛(实施例91,步骤E)(125mg,0.242mmol)在丙酮(2mL)中的溶液中加入3mL CrO3在水(2mL)中的混合物和浓H2SO4(1ml)。将反应混合物在室温下搅拌2小时,然后用水(10mL)和乙酸乙酯(10mL)稀释,并分离各层。用另外的乙酸乙酯(10mL)萃取水层。在减压下浓缩合并的有机层。通过反相制备型HPLC(柱:Gemini-NX C185um柱;Phenomonex,Torrance,CA;洗脱剂:0%至100%MeCN+0.1%TFA于水+0.1%TFA中)纯化残余物,得到本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 0.57(t,J=7.53Hz,1H)1.26(s,1H)1.39(s,3H)1.54-1.70(m,1H)1.72-1.89(m,1H)2.02-2.27(m,3H)2.49(br.s.,2H)2.69(br.s.,2H)2.82(m,2H)3.02(br.s.,2H)3.13-3.30(m,2H)3.74-3.93(m,4H)4.47-4.72(m,1H)6.75(d,J=7.82Hz,1H)6.96(t,J=1.86Hz,1H)7.01(br.s.,1H)7.04-7.17(m,3H)7.22(d,J=8.41Hz,2H)。质谱(ESI)m/z=533[M+H]+。
按照与实施例91中描述的程序类似的程序,用适量的胺代替步骤D中的吗啉来从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-羟基乙基)哌啶-2-酮制备实施例92–94。
实施例92
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(2,2,2-三氟乙基氨基)丁烷-2-基)哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 0.56(t,J=7.43Hz,3H)1.23-1.35(m,1H)1.44(s,3H)1.48-1.65(m,2H)1.77-1.91(m,1H)2.02-2.11(m,1H)2.13-2.25(m,1H)2.59-2.71(m,1H)2.73-2.84(m,1H)2.90-3.24(m,5H)4.60(d,J=10.17Hz,1H)6.69-6.77(m,1H)6.91-7.05(m,3H)7.06-7.13(m,1H)7.13-7.18(m,1H)7.23(d,J=8.22Hz,2H)。质谱(ESI)m/z=545[M+H]+。
实施例93
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(2,2-二甲基吗啉代)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸.
1H NMR(400MHz,氯仿-d)δppm 0.49(t,J=7.34Hz,3H)1.21-1.30(m,4H)1.34(s,3H)1.37(s,3H)1.42(s,3H)1.51-1.68(m,1H)1.86(dd,J=14.48和7.24Hz,1H)2.08-2.22(m,2H)2.30(br.s.,1H)2.35-2.48(m,2H)2.74-2.84(m,1H)2.86-2.94(m,1H)3.00-3.22(m,2H)3.68-3.91(m,2H)4.57(d,J=10.37Hz,1H)6.68(d,J=7.63Hz,1H)6.91-7.00(m,2H)7.03-7.11(m,1H)7.14(d,J=7.24Hz,2H)7.23(d,J=7.43Hz,2H)。质谱(ESI)m/z=561[M+H]+。
实施例94
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2S)-1-(2,6-二甲基吗啉代)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
通过反相制备型HPLC(柱:Gemini-NX C185um柱;Phenomonex,Torrance,CA;洗脱剂:0%至100%MeCN+0.1%TFA于水+0.1%TFA中)纯化粗产物,从而得到4:1比例的在用*表示的位置上的构型未被确定的非对映异构体。
1H NMR(400MHz,氯仿-d)δppm 1.02(br.s.,1H)1.24(d,J=6.06Hz,6H)1.35-1.49(m,4H)2.02-2.44(m,4H)2.68(s,1H)2.79-2.89(m,2H)3.20-3.32(m,2H)3.37-3.49(m,1H)3.80-4.00(m,2H)4.10(br.s.,3H)4.23-4.34(m,1H)4.41-4.58(m,1H)4.91-5.10(m,1H)6.89-6.98(m,2H)6.99-7.15(m,4H)7.20–7.30(m,2H)。质谱(ESI)m/z=561[M+H]+。
实施例95
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(4-(环丙基磺酰基)哌嗪-1-基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. 4-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁基)哌嗪-1-羧酸叔丁酯.
根据实施例91步骤D中描述的程序,从(S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁醛(实施例91,步骤C)和哌嗪-1-羧酸叔丁酯制备本标题化合物。
步骤B. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(哌嗪-1-基)丁烷-2-基)哌啶-2-酮
向4-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁基)哌嗪-1-羧酸叔丁酯(实施例95,步骤A)(187mg,0.304mmol)在DCM(2.4mL)中的溶液中加入TFA(600μL,7.79mmol)。将反应混合物在室温下搅拌16小时,然后在减压下浓缩。将残余物溶解在DCM(15mL)中并用碳酸氢钠饱和溶液(10mL)和饱和氯化钠溶液(10mL)洗涤。经硫酸钠干燥有机层,过滤,并在减压下浓缩滤液从而得到本标题化合物,为白色泡沫状物。
步骤C. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(4-(环丙基磺酰基)哌嗪-1-基)丁烷-2-基)-3-甲基哌啶-2-酮
向(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(哌嗪-1-基)丁烷-2-基)哌啶-2-酮(实施例95,步骤B)(60mg,0.117mmol)在DCE(1.2mL)中的溶液中加入环丙烷磺酰氯(23.76μL,0.233mmol),接着加入二异丙基乙胺(40.6μL,0.233mmol)。将反应混合物在室温下搅拌16小时,用水(10mL)稀释并分离各层。用DCM(2x10mL)萃取水层。用饱和NaCl溶液(10mL)洗涤合并的有机层,经硫酸钠干燥,过滤,并在减压下浓缩滤液从而得到本标题化合物,为固体。
步骤D. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(4-(环丙基磺酰基)哌嗪-1-基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
向装有(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(4-(环丙基磺酰基)哌嗪-1-基)丁烷-2-基)-3-甲基哌啶-2-酮(实施例23,步骤C)(85.1mg,0.138mmol)的10mL圆底烧瓶中加入THF(~800uL),接着加入水(~600uL,直至反应物在轻轻搅拌的情况下仍然是混浊的),接着加入tBuOH(~200uL,直至反应物变得半透明)。加入NMO(24.17mg,0.206mmol),接着经由巴氏吸管加入5滴4wt.%的在水中的四氧化锇(33.6μL,0.138mmol)。将反应物在室温下搅拌过夜,然后加入琼斯试剂(0.154mL)。将反应物在室温下搅拌2小时,用水(15mL)稀释并用乙酸乙酯(3x15mL)萃取。用水(3x20mL)、饱和氯化钠溶液(20mL)洗涤合并的有机层,经硫酸钠干燥,过滤,并在减压下浓缩滤液。通过反相制备型HPLC(柱:Gemini-NX C185um柱;Phenomonex,Torrance,CA;洗脱剂:0%至100%MeCN+0.1%TFA于水+0.1%TFA中,超过20分钟)纯化残余物,从而得到本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 0.92-1.25(m,10H)1.43(s,3H)1.85(br.s.,1H)2.08(d,J=13.50Hz,1H)2.16-2.30(m,1H)2.40(d,J=5.87Hz,2H)2.52(br.s.,2H)2.69-2.79(m,2H)2.79-2.92(m,2H)3.21-3.34(m,2H)3.83(br.s.,3H)4.51(br.s.,1H)6.67(br.s.,1H)6.91-7.01(m,2H)7.03-7.09(m,2H)7.11-7.18(m,3H)。质谱(ESI)m/z=636[M+H]+。
实施例96
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(4-(甲基磺酰基)哌嗪-1-基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
如实施例95,步骤C和D中所述从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(哌嗪-1-基)丁烷-2-基)哌啶-2-酮(实施例95,步骤B)和甲烷磺酰氯制备本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 1.04(br.s.,3H)1.42(s,3H)1.85(br.s.,2H)2.00-2.13(m,1H)2.14-2.28(m,1H)2.56(br.s.,3H)2.66-2.77(m,3H)2.85(d,J=14.48Hz,2H)2.90-2.99(m,3H)3.27(t,J=10.27Hz,3H)3.80(br.s.,3H)4.51(br.s.,1H)6.63-6.71(m,1H)6.97(s,2H)7.03-7.10(m,2H)7.11-7.17(m,3H)。质谱(ESI)m/z=610[M+H]+。
实施例97
2-((3R,5R,6S)-1-((S)-1-(4-乙酰基哌嗪-1-基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. (3S,5R,6S)-1-((S)-1-(4-乙酰基哌嗪-1-基)丁烷-2-基)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮.
向(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(哌嗪-1-基)丁烷-2-基)哌啶-2-酮(实施例95,步骤B)(80mg,0.155mmol)在DCE(1.5mL)中的溶液中加入乙酰氯(22.1μL,0.31mmol),接着加入二异丙基乙胺(54.1μL,0.311mmol)。将反应混合物在室温下搅拌16小时,然后在减压下浓缩从而得到本标题化合物。
步骤B. 2-((3R,5R,6S)-1-((S)-1-(4-乙酰基哌嗪-1-基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸
如实施例95,步骤D中所述从(3S,5R,6S)-1-((S)-1-(4-乙酰基哌嗪-1-基)丁烷-2-基)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮(实施例97,步骤A)制备本标题化合物。通过反相制备型HPLC(柱:Gemini-NX C185um柱;Phenomonex,Torrance,CA;洗脱剂:0%至100%MeCN+0.1%TFA于水+0.1%TFA中,超过20分钟)纯化残余物,从而得到本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 0.94-1.18(m,3H)1.42(s,3H)1.77-1.98(m,1H)2.12(s,4H)2.23(s,2H)2.48-2.63(m,3H)2.67(s,3H)2.84(br.s.,3H)3.16-3.35(m,2H)3.83-4.05(m,3H)4.43-4.61(m,1H)6.62-6.75(m,1H)6.97(s,2H)7.07(d,J=7.83Hz,2H)7.10-7.17(m,3H)。质谱(ESI)m/z=574[M+H]+。
实施例98
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(4-(环丙烷羰基)哌嗪-1-基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
如实施例97中所述,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(哌嗪-1-基)丁烷-2-基)哌啶-2-酮(实施例95,步骤B)和环丙烷甲酰氯制备本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 0.79-0.91(m,6H)1.02(br.s.,6H)1.43(s,3H)1.65-1.75(m,2H)2.11(br.s.,2H)2.17-2.30(m,2H)2.51(br.s.,3H)2.65(s,2H)2.80-2.88(m,2H)3.29(t,J=11.44Hz,2H)6.98(s,2H)7.06(t,J=7.83Hz,2H)7.10-7.16(m,2H)7.19-7.26(m,2H)。质谱(ESI)m/z=600[M+H]+。
实施例99
3-(((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-吗啉代丁烷-2-基)-2-氧代哌啶-3-基)甲基)-1,2,4-噁二唑-5(4H)-酮.
使用与针对实施例82描述的程序类似的程序,从2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-吗啉代丁烷-2-基)-2-氧代哌啶-3-基)乙酸(实施例91)制备本标题化合物。通过硅胶快速色谱法(洗脱剂:0%至10%的在DCM中的MeOH)纯化该粗产物从而得到本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 0.56(t,J=7.34Hz,3H)1.29(br.s.,1H)1.30-1.38(m,3H)1.57(ddd,J=13.99,7.53和3.91Hz,1H)1.81(dt,J=14.48和7.43Hz,1H)2.09(dd,J=13.99和3.03Hz,1H)2.18(d,J=9.98Hz,1H)2.22-2.32(m,1H)2.46(d,J=3.72Hz,2H)2.66(br.s.,2H)2.90(d,J=15.06Hz,1H)2.95-3.21(m,4H)3.74-3.89(m,4H)4.59(d,J=10.17Hz,1H)6.72(d,J=7.63Hz,1H)6.84-6.99(m,3H)7.08-7.13(m,1H)7.14-7.18(m,1H)7.23(d,J=8.22Hz,2H)。质谱(ESI)m/z=573[M+H]+。
实施例100
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(5,5-二甲基-2-氧代噁唑烷-3-基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸.
步骤A. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(2-羟基-2-甲基丙基氨基)丁烷-2-基)-3-甲基哌啶-2-酮.
如实施例91,步骤D中所述并使用1-氨基-2-甲基丙烷-2-醇(Tyger Scientific,Inc.,Ewing,NJ)制备本标题化合物。
步骤B. 3-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁基)-5,5-二甲基噁唑烷-2-酮.
向42mg(0.081mmol)(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(2-羟基-2-甲基丙基氨基)丁烷-2-基)-3-甲基哌啶-2-酮(实施例100,步骤A)在二噁烷(2705μL)中的溶液中加入羰基二咪唑(132mg,0.812mmol)。将反应物加热至100°并保持6h。通过反相HPLC(SunfireTMPrep C18OBD 10μm柱(Waters,Milford,MA)(洗脱剂:60%至85%的MeCN/水(0.1%TFA),梯度洗脱)纯化残余物,得到本标题化合物。
步骤C. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(5,5-二甲基-2-氧代噁唑烷-3-基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸.
向快速搅拌着的20mg(0.037mmol)3-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁基)-5,5-二甲基噁唑烷-2-酮(实施例100,步骤B)在CCl4(210μL)、MeCN(210μL)和水(315μL)的混合物中的溶液中加入高碘酸钠(31.5mg,0.147mmol),接着加入催化的氯化钌(III)水合物(4.15mg,0.018mmol)。当根据LCMS监测确定完成时,用柠檬酸酸化反应物并用氯仿稀释。通过经由celite过滤来除去不溶性材料。萃取到乙酸乙酯中,并用饱和NaCl洗涤合并的有机层,经Na2SO4干燥,过滤并在真空中浓缩滤液。通过反相HPLC(SunfireTMPrep C18OBD 10μm柱(Waters,Milford,MA)(洗脱剂:60%至80%的MeCN/水(0.1%TFA),梯度洗脱)纯化残余物,得到本标题化合物,为白色粉末。
1H NMR(500MHz,氯仿-d)δppm 0.55(t,J=7.21Hz,2H)0.94(br.s.,2H)1.27(d,J=2.93Hz,1H)1.33(d,J=2.69Hz,1H)1.52(t,7H)1.88-1.99(m,2H)2.34(t,J=13.82Hz,1H)2.71(d,J=14.92Hz,2H)2.95-3.12(m,4H)3.29-3.39(m,2H)4.44(d,J=10.27Hz,1H)6.73(d,J=7.58Hz,1H)6.95(s,2H)7.11(t,J=7.70Hz,1H)7.13-7.20(m,1H)。质谱(ESI)m/z=561(M+1)。
实施例101
2-((3R,5R,6S)-1-((S)-1-(叔丁基氨基)-1-氧代丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸.
步骤A. 2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁酸
向15-mL圆底烧瓶中加入(S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁酸叔丁酯(420mg,0.813mmol)(实施例1,步骤F)和茴香醚(444μL,4.07mmol),接着加入已预先冷却到0℃的TFA(4066μL)。将反应混合物在0℃下搅拌1h,用50ml乙醚稀释,并且用20ml水、NaHCO3/饱和NaCl溶液洗涤合并的有机层直至中性,然后经Na2SO4干燥,过滤,并浓缩滤液。通过硅胶快速色谱法(洗脱剂:0%至20%的EtOAc/己烷,梯度洗脱)纯化残余物,得到本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 7.25(1H,s),7.07-7.19(2H,m),7.00(3H,br.s.),6.76(1H,d,J=7.4Hz),5.77-5.93(1H,m),5.15-5.25(2H,m),4.58(1H,d,J=10.8Hz),3.35(1H,br.s.),3.23-3.33(1H,m),2.62(2H,d,J=7.2Hz),2.27(1H,dquin,J=14.6,7.5,7.5,7.5,7.5Hz),2.14(1H,t,J=13.5Hz),1.99(1H,dd,J=13.7,2.9Hz),1.50-1.64(1H,m),1.29(3H,s),0.66(3H,t,J=7.4Hz)。
步骤B. 2-((5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-N-叔丁基丁酰胺
向在0°下的2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁酸(81mg,0.176mmol)(实施例101,步骤A)在含有3当量TEA(73.6μL,0.528mmol)的干DMF(880μL)中的溶液中加入2当量HATU(134mg,0.352mmol)。将反应物在0°下搅拌5min,接着加入叔丁基胺(25.7mg,0.352mmol)。将它在0°下搅拌30min,用饱和NaHCO3淬灭,并萃取到EtOAc中。用饱和NaCl溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并浓缩滤液。通过硅胶快速色谱法(洗脱剂:0-30%的EtOAc/己烷,梯度洗脱)纯化残余物,得到本标题化合物,为立体异构体的混合物。
步骤C. 2-((3R,5R,6S)-1-((S)-1-(叔丁基氨基)-1-氧代丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸.
如实施例1,步骤H中所述,从(5R,6S)-5-(3-氯苯基)-6-(5-氯吡啶-2-基)哌啶-2-酮(实施例101,步骤B)制备本标题化合物。通过反相制备型HPLC(SunfireTMPrep C18OBD 10μm柱(Waters,Milford,MA)(洗脱剂:55%乙腈、水、0.1%TFA,梯度洗脱)纯化该粗产物。
1H NMR(500MHz,氯仿-d)δppm 0.71(t,J=7.46Hz,3H),1.32(s,9H),1.40(s,3H),1.60-1.71(m,1H),2.07-2.25(m,3H),2.86(d,J=2.20Hz,2H),3.16(ddd,J=12.65,9.60,3.42Hz,1H),3.67(dd,J=8.80,5.62Hz,1H),4.70(d,J=9.78Hz,1H),6.78(d,J=7.58Hz,1H),6.97(s,1H),6.98-7.05(m,3H),7.11(t,J=7.83Hz,1H),7.14-7.19(m,1H),7.21(d,J=8.56Hz,2H)。质谱(ESI)m/z=533(M+1)。
实施例102
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((1S,2S,3R)-2,3-二羟基环戊基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. (3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-(2,3-二羟基丙基)-3-甲基哌啶-2-酮.
向4g(10.69mmol)(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮(实施例71,步骤D)在100mL THF中的溶液中加入水(60mL),接着加入4-甲基吗啉4-氧化物(1.878g,16.03mmol)。该混浊的反应混合物在5min内变得澄清,加入氧化锇(VIII)(4%水溶液)(0.340mL,0.053mmol),反应混合物仍然是澄清的。将反应混合物在室温下搅拌18h。加入氧化锇(VIII)(4%水溶液)(0.1mL),并将反应混合物在室温下搅拌24h。加入饱和NaCl溶液并用EtOAc萃取该混合物。合并有机层,经Na2SO4干燥,过滤,并浓缩滤液从而得到本标题化合物,为1:1比例的非对映异构体。
步骤B. (3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-3-甲基哌啶-2-酮
在室温下向(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-(2,3-二羟基丙基)-3-甲基哌啶-2-酮(实施例102,步骤A)(4.900g,12.00mmol)和2,2-二甲氧基丙烷(14.76mL,120mmol)在N,N-二甲基甲酰胺(34mL)中的溶液中加入CSA(0.279g,1.200mmol),并让反应混合物在室温下搅拌1hr。用碳酸氢钠(100mL)和EtOAc(100mL)淬灭反应物。分离各层并用饱和碳酸钠(100mL)洗涤有机层三次。合并水层并用EtOAc(200mL)萃取。合并有机层,用NaCl饱和水溶液洗涤,经硫酸钠干燥,过滤,并在减压下浓缩从而得到本标题化合物。
步骤C. (3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环戊-2-烯基)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-3-甲基哌啶-2-酮
向(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-3-甲基哌啶-2-酮(实施例102,步骤B)(0.909g,2.027mmol)中加入甲苯(15mL),并在减压下浓缩该该混合物。将这个步骤重复三次。加入不含抑制剂的THF(20mL),并将该溶液冷却至-78℃。逐滴加入在戊烷中的丁基锂(2.0M)(1.014mL,2.027mmol),反应混合物仍然是无色的。将反应混合物升温至0℃,反应物颜色变成很淡的黄色。逐滴加入在戊烷中的nBuLi(2.0M)直至反应混合物保持为亮黄色。将反应混合物冷却至-78℃并逐滴加入新制备的在THF(2mL)中的3-溴环戊-1-烯(0.4g,2.72mmol)。将反应混合物包裹在箔中并升温至0℃。将反应混合物在0℃下搅拌1h,然后在室温下搅拌2天。用饱和NH4Cl淬灭反应物并用EtOAc萃取。经Na2SO4干燥有机层并在减压下浓缩。通过硅胶快速色谱法(洗脱剂:0%至100%的在己烷中的EtOAc)纯化残余物,从而得到本标题化合物,为无色膜状物。
步骤D. (3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环戊-2-烯基)-3-(2,3-二羟基丙基)-3-甲基哌啶-2-酮
向在室温下的(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环戊-2-烯基)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-3-甲基哌啶-2-酮(实施例28,步骤C)(310mg,0.603mmol)在THF(3mL)中的溶液中加入HCl水溶液(1M)(3013μL,3.01mmol)。将反应混合物在室温下搅拌19h。用EtOAc稀释反应混合物并分离各层。用饱和NaHCO3、NaCl饱和水溶液洗涤有机层,经Na2SO4干燥并在减压下浓缩从而得到本标题化合物。
步骤E. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环戊-2-烯基)-3-甲基-2-氧代哌啶-3-基)乙醛
在室温下向(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环戊-2-烯基)-3-(2,3-二羟基丙基)-3-甲基哌啶-2-酮(实施例102,步骤D)(286mg,0.603mmol)在THF(3mL)和水(3mL)中的溶液中加入高碘酸钠(258mg,1.206mmol)。将浆液在室温下搅拌1h,然后用EtOAc稀释并分离各层。用饱和Na2S2O3和NaCl饱和水溶液洗涤有机层,经Na2SO4干燥并在减压下浓缩从而得到本标题化合物。
步骤F. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环戊-2-烯基)-3-甲基-2-氧代哌啶-3-基)乙酸
在室温下向在丙酮(4mL)中的2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环戊-2-烯基)-3-甲基-2-氧代哌啶-3-基)乙醛(实施例102,步骤E)(267mg,0.604mmol)中加入新制备的琼斯试剂(0.5mL)。将反应混合物在室温下搅拌15min,然后用EtOAc稀释该混合物并用水和NaCl饱和水溶液洗涤。经Na2SO4干燥有机层并在减压下浓缩。通过硅胶快速色谱法(洗脱剂:50%至100%的在己烷中的EtOAc)纯化残余物从而得到本标题化合物,其为无色膜状物,为非对映异构体的3.6:1混合物。
步骤G. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((1S,2S,3R)-2,3-二羟基环戊基)-3-甲基-2-氧代哌啶-3-基)乙酸
在室温下向2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环戊-2-烯基)-3-甲基-2-氧代哌啶-3-基)乙酸(实施例102,步骤F)(94mg,0.205mmol)在THF(1.0mL)中的溶液中加入水(0.25mL)和tBuOH(0.2mL)。加入NMO(36.0mg,0.308mmol),接着加入四氧化锇(4%水溶液)(1.303μL,0.205μmol)。将反应混合物在室温下搅拌24h。加入水(10mL),并用DCM萃取该混合物两次。合并有机层,经Na2SO4干燥并在减压下浓缩。通过反相制备型HPLC(柱:Gemini-NX C185um柱;Phenomonex,Torrance,CA;洗脱剂:30%至50%MeCN+0.1%TFA于水+0.1%TFA中,超过20分钟)纯化含有三种立体异构体的混合物的残余物,从而得到本标题化合物,为第一洗脱异构体。
1H NMR(400MHz,氯仿-d)δppm 1.21-1.36(3H,m),1.38(3H,s),1.53-1.56(2H,m),2.20-2.02(3H,m),2.22(1H,t,J=13.2Hz),2.62-2.78(1H,m),2.85-3.00(1H,m),3.00-3.13(1H,m),4.06-4.17(1H,m),4.35(1H,br s),4.70(1H,d,J=8.8Hz),6.76-6.88(1H,m),6.93-7.12(4H,m),7.12-7.25(3H,m)。质谱(ESI)m/z=492[M+H]+。
进一步洗脱得到最后洗脱的异构体,实施例103。
实施例103
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((1R,2R,3S)-2,3-二羟基环戊基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 1.19-1.38(1H,m)1.38-1.50(3H,m)1.38-1.50(1H,m)1.71-1.98(2H,m)2.06-2.27(3H,m)2.33(1H,d,J=8.2Hz)2.70-2.79(1H,m)2.79-2.90(1H,m)3.20-3.37(2H,m)3.40(1H,d,J=5.1Hz)3.86(1H,br.s.)4.50(1H,d,J=10.2Hz)6.67-6.77(1H,m)6.93-7.07(1H,m)7.06-7.19(3H,m)7.23(3H,d,J=8.6Hz)。质谱(ESI)m/z=492[M+H]+。
实施例104
2-((3R,3′S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1′-(2,2,2-三氟乙基)-1,3′-联哌啶-3-基)乙酸或2-((3R,3′R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1′-(2,2,2-三氟乙基)-1,3′-联哌啶-3-基)乙酸
步骤A. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(1,5-二氧代戊烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸.
在室温下向2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(2,3-二羟基环戊基)-3-甲基-2-氧代哌啶-3-基)乙酸(实施例102,步骤F)(110mg,0.223mmol)在THF(3mL)和水(3mL)中的溶液中加入高碘酸钠(134mg,0.626mmol)。将反应混合物在室温下搅拌45min,且用EtOAc稀释并分离各层。用Na2S2O3饱和水溶液、NaCl饱和水溶液洗涤有机层,经Na2SO4干燥并在减压下浓缩从而得到本标题化合物。
步骤B.
2-((3R,3′S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1′-(2,2,2-三氟乙基)-1,3′-联哌啶-3-基)乙酸或2-((3R,3′R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1′-(2,2,2-三氟乙基)-1,3′-联哌啶-3-基)乙酸(异构体1)
在室温下向2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(1,5-二氧代戊烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸(实施例104,步骤A)(55mg,0.112mmol)在DCE(1mL)中的溶液中加入2,2,2-三氟乙胺(9.24μL,0.118mmol)和三乙酰氧基硼氢化钠(76mg,0.359mmol)。将该混浊的反应混合物在室温下搅拌2h。在减压下浓缩反应混合物,用DCM稀释,并用NaHCO3饱和水溶液和NaCl饱和水溶液洗涤。分离各层并用DCM萃取水层三次。合并有机层,经Na2SO4干燥并在减压下浓缩。通过反相制备型HPLC(柱:Gemini-NX C185um柱;Phenomonex,Torrance,CA;洗脱剂:40%MeCN+0.1%TFA于水+0.1%TFA中,超过20分钟)纯化残余物,并在真空中浓缩从而得到第一洗脱非对映异构体。将残余物溶解在DCM(1mL)中,并加入在乙醚中的HCl(1M)(1mL),并在减压下除去溶剂从而得到本标题化合物中的一种的盐酸盐,为第一洗脱异构体。
1H NMR(400MHz,氯仿-d)δppm 0.73-1.00(4H,m),1.13-1.53(6H,m),1.58-1.84(2H,m),1.98-2.13(1H,m),2.24-2.44(1H,m),2.67-2.99(3H,m),3.17-3.32(1H,m),4.22(2H,t,J=6.0Hz),6.65-6.91(1H,m),7.00(1H,d,J=0.6Hz),7.05-7.24(4H,m),7.48-7.59(1H,m),7.63-7.79(1H,m)。质谱(ESI)m/z=557[M+H]+。
进一步洗脱和在真空中浓缩得到实施例105。
实施例105
2-((3R,3′S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1′-(2,2,2-三氟乙基)-1,3′-联哌啶-3-基)乙酸或2-((3R,3′R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1′-(2,2,2-三氟乙基)-1,3′-联哌啶-3-基)乙酸(异构体2)
将残余物溶解在DCM(1mL),并加入在乙醚中的(1M)(1mL),并在减压下除去溶剂从而得到本标题化合物中的一种的盐酸盐,为第二洗脱异构体。
1H NMR(400MHz,氯仿-d)δppm 0.73-1.08(7H,m),1.13-1.50(7H,m),1.69(6H,d,J=6.1Hz),7.54(4H,dd,J=5.7和3.3Hz),7.72(4H,dd,J=5.7和3.3Hz)。质谱(ESI)m/z=557[M+H]+。
实施例106
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((1S,3S)-3-羟基环戊基)-3-甲基-2-氧代哌啶-3-基)乙酸或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((1S,3R)-3-羟基环戊基)-3-甲基-2-氧代哌啶-3-基)乙酸
*立体化学未知
步骤A. (5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环戊-2-烯基)哌啶-2-酮.
在0℃下向3.25g(10.16mmol)(5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)哌啶-2-酮(实施例1,步骤E)在DMF(150mL)中的溶液中加入60%氢化钠在矿物油中的分散体(1.016g,25.4mmol)。观察到气体逸出。将该混浊的反应混合物在0℃下搅拌20min,然后加入3-溴环戊-1-烯(4.48g,30.5mmol)。将该混浊的反应混合物升温至室温并在室温下搅拌18h。用NH4Cl饱和水溶液淬灭反应物,用EtOAc稀释并分离各层。用1M LiCl、NaCl饱和水溶液洗涤有机层,经Na2SO4干燥并在减压下浓缩。通过硅胶快速色谱法(洗脱剂:25%至100%的在己烷中的EtOAc)纯化残余物从而得到本标题化合物,为非对映异构体的5:2混合物。
步骤B. (5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(3-羟基环戊基)哌啶-2-酮
向(5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环戊-2-烯基)哌啶-2-酮(实施例106,步骤A)(394mg,1.020mmol)在THF(10mL)中的溶液中加入硼烷四氢呋喃络合物(1.0m在THF中)(1020μL,1.020mmol)。观察到气体逸出。将反应物在室温下搅拌30min,然后加入NaOH水溶液(6M)(1.25mL)和30%H2O2(1.25mL)。反应混合物变混浊,将其在室温下搅拌1h。用EtOAc萃取反应混合物。用NaCl饱和水溶液洗涤有机层并经Na2SO4干燥。通过硅胶快速色谱法(洗脱剂:40%至100%的在己烷中的EtOAc)纯化残余物,从而得到本标题化合物,为非对映异构体的混合物。
步骤C. (5R,6S)-1-((1S,3S)-3-((叔丁基二甲基甲硅烷基)氧基)环戊基)-5-(3-氯苯基)-6-(4-氯苯基)哌啶-2-酮或(2S,3R)-1-((1S,3R)-3-((叔丁基二甲基甲硅烷基)氧基)环戊基)-3-(3-氯苯基)-2-(4-氯苯基)哌啶
*立体化学未知
在室温下向(5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(3-羟基环戊基)哌啶-2-酮(实施例106,步骤B)(175mg,0.433mmol)在DMF(4mL)中的溶液中加入TBDMS-Cl(71.8mg,0.476mmol)和咪唑(29.5mg,0.433mmol)。将反应混合物在室温下搅拌18h。再加入咪唑(29.5mg,0.433mmol)和TBDMS-Cl(71.8mg,0.476mmol)。将反应混合物在室温下搅拌18h,然后用EtOAc稀释,用1M LiCl水溶液、1M HCl和Na2CO.饱和水溶液洗涤。经Na2SO4干燥有机层并在减压下浓缩。通过硅胶快速色谱法(洗脱剂:0%至100%的在己烷中的EtOAc)纯化残余物从而得到本标题化合物,为主要的单一异构体。
步骤D. (5R,6S)-1-((1S,3S)-3-(叔丁基二甲基甲硅烷基氧基)环戊基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮或(2S,3R)-1-((1S,3R)-3-((叔丁基二甲基甲硅烷基)氧基)环戊基)-3-(3-氯苯基)-2-(4-氯苯基)-5-甲基哌啶
*立体化学未知
向得自上面(实施例106,步骤C)的(5R,6S)-1-((1S,3S)-3-((叔丁基二甲基甲硅烷基)氧基)环戊基)-5-(3-氯苯基)-6-(4-氯苯基)哌啶-2-酮或(2S,3R)-1-((1S,3R)-3-((叔丁基二甲基甲硅烷基)氧基)环戊基)-3-(3-氯苯基)-2-(4-氯苯基)哌啶(104mg,0.201mmol)中加入甲苯(15mL),并在减压下浓缩该混合物。将这个步骤重复三次。将残余物溶解在此前用Ar脱气的不含抑制剂的THF(2mL)中,并将该混合物在Ar下冷却至0℃。加入碘甲烷(13.79μL,0.221mmol),接着加入LHMDS(此前用Ar脱气)(1.0M在THF中)(221μL,0.221mmol)。将反应混合物升温至室温并在Ar下搅拌24h。再加入LHMDS(1.0M在THF中)(221μL,0.221mmol),并将反应混合物在室温下搅拌1h。用NH4Cl饱和水溶液淬灭反应物并用EtOAc萃取。经Na2SO4干燥有机层,过滤并在真空中浓缩滤液从而得到本标题化合物。
步骤E. (5R,6S)-3-烯丙基-1-((1S,3S)-3-((叔丁基二甲基甲硅烷基)氧基)环戊基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮或(2S,3R)-5-烯丙基-1-((1S,3R)-3-((叔丁基二甲基甲硅烷基)氧基)环戊基)-3-(3-氯苯基)-2-(4-氯苯基)-5-甲基哌啶
*立体化学未知
向得自上面(实施例106,步骤D)的(5R,6S)-1-((1S,3S)-3-(叔丁基二甲基甲硅烷基氧基)环戊基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮或(2S,3R)-1-((1S,3R)-3-((叔丁基二甲基甲硅烷基)氧基)环戊基)-3-(3-氯苯基)-2-(4-氯苯基)-5-甲基哌啶(107mg,0.201mmol)中加入甲苯(15mL),并在减压下浓缩该混合物。将这个步骤重复三次。将残余物溶解在此前用Ar脱气的不含抑制剂的THF(2mL)中,并将该混合物在Ar下冷却至0℃。加入蒸馏的烯丙基溴(87μL,1.004mmol)和LHMDS(1M在THF中)(502μL,0.502mmol),并将反应混合物升温至室温并在室温下搅拌1h,然后将反应混合物于50℃在Ar下加热过夜。将反应混合物冷却至室温,并再加入烯丙基溴(87μL,1.004mmol)和LHMDS(1.0M在THF中)(502μL,0.502mmol),并将反应混合物在Ar下加热至60℃并保持6h。将反应混合物冷却至室温,用NH4Cl饱和溶液淬灭反应物并用EtOAc萃取。经Na2SO4干燥有机层并在减压下浓缩。通过硅胶快速色谱法(洗脱剂:0%至20%的在己烷中的MTBE)纯化残余物从而得到本标题化合物,为非对映异构体的混合物。
步骤F. 2-((5R,6S)-1-((1S,3S)-3-(叔丁基二甲基甲硅烷基氧基)环戊基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸或2-((5R,6S)-1-((1S,3R)-3-((叔丁基二甲基甲硅烷基)氧基)环戊基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-3-基)乙酸
*立体化学未知
如实施例95步骤D中所述,从上面(如实施例106步骤E所述)的(5R,6S)-3-烯丙基-1-((1S,3S)-3-((叔丁基二甲基甲硅烷基)氧基)环戊基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮或(2S,3R)-5-烯丙基-1-((1S,3R)-3-((叔丁基二甲基甲硅烷基)氧基)环戊基)-3-(3-氯苯基)-2-(4-氯苯基)-5-甲基哌啶制备本标题化合物。
步骤G. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((1S,3S)-3-羟基环戊基)-3-甲基-2-氧代哌啶-3-基)乙酸或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((1S,3R)-3-羟基环戊基)-3-甲基-2-氧代哌啶-3-基)乙酸
在室温下向上面(如实施例106步骤F所述)的2-((5R,6S)-1-((1S,3S)-3-(叔丁基二甲基甲硅烷基氧基)环戊基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸或2-((5R,6S)-1-((1S,3R)-3-((叔丁基二甲基甲硅烷基)氧基)环戊基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-3-基)乙酸(31mg,0.052mmol)在THF(1.0mL)中的溶液中加入1.0M在THF中的TBAF(262μL,0.262mmol)。将反应混合物在室温下搅拌19h,然后在减压下浓缩。通过反相制备型HPLC(柱:Gemini-NX C185um柱;Phenomonex,Torrance,CA;洗脱剂:45%至75%MeCN+0.1%TFA于水+0.1%TFA中)纯化残余物,从而得到本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 1.31(3H,s),1.49-1.65(3H,m),1.65-1.90(3H,m),2.06-2.19(3H,m),2.68-2.78(1H,m),3.05-3.18(1H,m),2.88(1H,d,J=15.1Hz),3.35-3.54(1H,m),4.41-4.49(1H,m),4.68(1H,d,J=8.0Hz),6.85(1H,dt,J=7.4和1.7Hz),6.95-7.00(2H,m),7.09(1H,t,J=1.9Hz),7.15-7.26(2H,m),7.30(2H,d,J=8.6Hz)。质谱(ESI)m/z=476[M+H]+。
实施例107
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-四氢-2H-吡喃-3-基)哌啶-3-基)乙酸或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((R)-四氢-2H-吡喃-3-基)哌啶-3-基)乙酸
*立体化学未确定
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-四氢-2H-吡喃-3-基)哌啶-3-基)乙酸或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((R)-四氢-2H-吡喃-3-基)哌啶-3-基)乙酸
*立体化学未确定
步骤A. 2-((2S,3R)-3-(3-氯苯基)-2-(4-氯苯基)-6-氧代哌啶-1-基)戊二醛
向454mg(1.175mmol)(5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环戊-2-烯基)哌啶-2-酮(实施例104,步骤A)在THF(6mL)中的溶液中逐滴加入水(3.5mL)和tBuOH(0.2mL)。加入4-甲基吗啉4-氧化物(207mg,1.763mmol),接着加入4%氧化锇(VIII)水溶液(37.3μL,5.88μmol)。将反应混合物在室温下搅拌18h。加入高碘酸钠(704mg,3.29mmol)并将该混浊的反应混合物在室温下搅拌90min。加入水(4mL),过滤该混合物并用EtOAc洗涤。用EtOAc稀释滤液并分离各层。用饱和Na2S2O3、NaCl饱和水溶液洗涤合并的有机层,经Na2SO4干燥并在真空中浓缩从而得到本标题化合物。
步骤B. (5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(1,5-二羟基戊烷-2-基)哌啶-2-酮
在室温下向2-((2S,3R)-3-(3-氯苯基)-2-(4-氯苯基)-6-氧代哌啶-1-基)戊二醛(实施例107,步骤A)(492mg,1.176mmol)在MeOH(11mL)中的溶液中加入硼氢化钠(89mg,2.352mmol)。观察到气体逸出。将反应混合物在室温下搅拌15min,然后在减压下浓缩。通过硅胶柱色谱法(洗脱剂:先用50%至100%的在己烷中的EtOAc,然后用10%的在DCM中的MeOH)纯化残余物,从而得到本标题化合物。
步骤C. (5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(四氢-2H-吡喃-3-基)哌啶-2-酮
向在室温下的(5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(1,5-二羟基戊烷-2-基)哌啶-2-酮(实施例107,步骤B)(192mg,0.455mmol)在THF(5mL)中的溶液中加入三苯基膦(119mg,0.455mmol),接着逐滴加入偶氮二甲酸二异丙酯(89μL,0.455mmol)。在添加期间反应混合物颜色变成淡黄色,然后在5min内变成无色。将反应混合物在室温下搅拌1h。用EtOAc稀释反应混合物并用NaCl饱和水溶液洗涤。经Na2SO4干燥有机层并在真空中浓缩。通过硅胶快速色谱法(洗脱剂:0%至100%的在己烷中的EtOAc)纯化残余物从而得到本标题化合物,为非对映异构体的混合物。
步骤D. (5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(四氢-2H-吡喃-3-基)哌啶-2-酮
如实施例71步骤B中所述从(5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(四氢-2H-吡喃-3-基)哌啶-2-酮(实施例107,步骤C)制备本标题化合物。
步骤E. (5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(四氢-2H-吡喃-3-基)哌啶-2-酮
如实施例71步骤C中所述,从(5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(四氢-2H-吡喃-3-基)哌啶-2-酮(实施例107,步骤D)制备本标题化合物,为立体异构体的混合物。
步骤F. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-四氢-2H-吡喃-3-基)哌啶-3-基)乙酸或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((R)-四氢-2H-吡喃-3-基)哌啶-3-基)乙酸
如先前在实施例42步骤C中所述,从(5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(四氢-2H-吡喃-3-基)哌啶-2-酮(实施例107,步骤E)制备本标题化合物。通过反相制备型HPLC(柱:Gemini-NX C185um柱;Phenomonex,Torrance,CA;洗脱剂:0%至100%MeCN+0.1%TFA于水+0.1%TFA中)纯化残余物从而得到本标题化合物,为单一的但未确定的立体异构体。
1H NMR(400MHz,氯仿-d)δppm 1.40(3H,s),1.49-1.84(3H,m),2.01-2.16(3H,m),2.39(1H,dd,J=12.3和4.3Hz),2.66-2.77(1H,m),2.90-3.10(2H,m),3.22-3.33(1H,m),3.48(1H,br.s.),3.69-3.79(1H,m),4.24(1H,t,J=10.5Hz),4.42(1H,d,J=9.4Hz),6.72(1H,d,J=7.6Hz),6.89-7.04(3H,m),7.06-7.26(4H,m)。质谱(ESI)m/z=476[M+H]+。
实施例108
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(吡嗪-2-基)哌啶-3-基)乙酸
步骤A. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(吡嗪-2-基)哌啶-2-酮
将(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮(实施例71,步骤D)(100mg,0.27mmol)、2-碘吡嗪(170μL,0.80mmol)和碳酸铯(220mg,0.67mmol)溶解在2.7mL 1,4-二噁烷中。用氩气吹扫反应容器,加入碘化亚铜(I)(5.1mg,27μmol)和TMEDA(11μL,80μmol),并让反应混合物在110℃下搅拌15小时。将反应混合物冷却至室温,用水淬灭并萃取(2x EtOAc)。用NaCl饱和水溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过硅胶快速色谱法(0%至50%的EtOAc/己烷)纯化残余物,得到本标题化合物,为无色固体。
步骤B. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(吡嗪-2-基)哌啶-3-基)乙酸.
如实施例42步骤C中所述,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(吡嗪-2-基)哌啶-2-酮(实施例108,步骤A)制备本标题化合物,得到白色固体。
1H NMR(400MHz,MeOD)δppm 1.42(s,3H),2.30-2.39(m,1H),2.39-2.49(m,1H),2.60(d,J=14.67Hz,1H),3.07(d,J=12.52Hz,1H),3.71-3.81(m,1H),5.50(d,J=10.76Hz,1H),6.96-7.03(m,2H),7.04-7.11(m,3H),7.12-7.17(m,2H),7.19(br.s.,1H),8.16(br.s.,1H),8.30(s,1H),8.62(br.s.,1H)。MS(ESI)470.2[M+H]+。
实施例109
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-甲基-1H-吡唑-4-基)-2-氧代哌啶-3-基)乙酸.
步骤A. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-甲基-1H-吡唑-4-基)哌啶-2-酮.
将(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮(实施例71,步骤D)(90mg,0.24mmol)、1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吡唑(125mg,0.60mmol)、二乙酰氧基铜(44mg,0.24mmol)和N,N-二甲基吡啶-4-胺(88mg,0.72mmol)溶解在1.2mL甲苯中。加入双(三甲基甲硅烷基)氨基钠(480μL,0.48mmol),并给反应容器装配回流冷凝器,并让该反应容器在115℃下搅拌13小时。将反应混合物冷却至室温,用水淬灭并萃取(2x EtOAc)。用NaCl饱和水溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过快速色谱法(0%至60%的EtOAc/己烷)纯化残余物,得到本标题化合物,为无色固体。
步骤B. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-甲基-1H-吡唑-4-基)-2-氧代哌啶-3-基)乙酸.
如实施例42步骤C中所述,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-甲基-1H-吡唑-4-基)哌啶-2-酮(实施例108,步骤A)制备本标题化合物,得到白色固体。
1H NMR(400MHz,MeOD)δppm 1.42(s,3H),2.25-2.33(m,1H),2.31-2.44(m,1H),2.60(d,J=12.91Hz,1H),3.01(d,J=13.30Hz,1H),3.47-3.59(m,1H),3.68(s,3H),5.06(d,J=10.37Hz,1H),6.95-7.05(m,3H),7.09(d,J=8.41Hz,2H),7.12-7.20(m,3H),7.24(s,1H),7.49(s,1H)。MS(ESI)472.2[M+H]+。
实施例110
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(嘧啶-4-基)哌啶-3-基)乙酸.
步骤A. 1-(嘧啶-4-基氧基)-1H-苯并[d][1,2,3]三唑
在室温下向嘧啶-4-醇(350mg,3.6mmol)和(1H-苯并[d][1,2,3]三唑-1-基氧基)三(二甲基氨基)鏻六氟磷(V)酸盐(1.9g,4.4mmol)在24mL乙腈中的溶液中逐滴加入2,3,4,6,7,8,9,10-八氢嘧啶并[1,2-a]吖庚因(820μL,5.5mmol)。在将反应混合物搅拌1小时后,在减压下除去反应溶剂。通过快速色谱法(0%至70%的EtOAc/己烷)纯化残余物,得到本标题化合物,为淡黄色固体。
步骤B. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(嘧啶-4-基)哌啶-2-酮
在室温下向(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮(实施例71,步骤D)(100mg,0.27mmol)在1.3mL DMSO中的溶液中加入氢化钠(60%的在矿物油中的分散体,13mg,0.32mmol)。将反应混合物搅拌5分钟,并用1-(嘧啶-4-基氧基)-1H-苯并[d][1,2,3]三唑(实施例110,步骤A)(170mg,0.80mmol)处理。将反应混合物在110℃下搅拌13小时。将反应混合物冷却至室温,用水淬灭并萃取(2x EtOAc)。用NaCl饱和水溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过快速色谱法(0%至45%的EtOAc/己烷)纯化残余物,得到本标题化合物,为为无色固体。
步骤C. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(嘧啶-4-基)哌啶-3-基)乙醛
向(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(嘧啶-4-基)哌啶-2-酮(实施例110,步骤B)(60mg,0.13mmol)在四氢呋喃(2.7mL)和水(880μL)的混合物中的溶液中加入四氧化锇(1.7mg,6.6μmol)。在5分钟后,加入高碘酸钠(89mg,0.46mmol),并将反应混合物搅拌14小时。通过(J.T.Baker,Phillipsberg,NJ,硅藻土)过滤反应混合物并用EtOAc和水洗涤。用NaCl饱和水溶液洗涤有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过快速色谱法(0%至75%的EtOAc/己烷,梯度洗脱)纯化残余物,得到本标题化合物,为无色固体。
步骤D. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(嘧啶-4-基)哌啶-3-基)乙酸.
在室温下向2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(嘧啶-4-基)哌啶-3-基)乙醛(实施例110,步骤C)(25mg,55μmol)在2-甲基丙烷-2-醇(1.0mL)和2-甲基-2-丁烯(55μL,2.0M溶液在THF中,0.11mmol)的混合物中的溶液中加入亚氯酸纳(37mg,0.55mmol)和磷酸二氢钠(4.8mg,50μmol)在550μL水中的溶液。将反应混合物搅拌1小时,然后用水淬灭该混合物并对其进行萃取(2x EtOAc)。用NaCl饱和水溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过硅胶制备板(10%MeOH/DCM)纯化残余物,得到本标题化合物,为无色固体。
1H NMR(500MHz,CDCl3)δppm 1.43(s,3H),2.21-2.27(m,1H),2.29-2.36(m,1H),2.84-2.95(m,2H),3.34-3.42(m,1H),5.71(d,J=9.78Hz,1H),6.85-6.92(m,3H),7.01(d,J=8.31Hz,2H),7.10-7.16(m,2H),7.18-7.22(m,1H),7.63(d,J=5.38Hz,1H),8.49(d,J=5.38Hz,1H),8.82(s,1H)。MS(ESI)470.2[M+H]+。
实施例111
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(2-氯嘧啶-4-基)-3-甲基-2-氧代哌啶-3-基)乙酸.
步骤A. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-(2-氯嘧啶-4-基)-3-甲基哌啶-2-酮.
在室温下向(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮(实施例71,步骤D)(100mg,0.27mmol)在1.1mL DMSO中的溶液中加入氢化钠(60%的在矿物油中的悬浮液,32mg,0.80mmol)。将反应混合物搅拌15分钟,并用2,4-二氯嘧啶(200mg,1.3mmol)处理。将反应混合物在60℃下搅拌5小时。将反应混合物冷却至室温,用水淬灭并萃取(2x EtOAc)。用NaCl饱和水溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过硅胶制备板(50%EtOAc/己烷)纯化残余物,得到本标题化合物,为无色固体。
步骤B. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(2-氯嘧啶-4-基)-3-甲基-2-氧代哌啶-3-基)乙醛
如实施例110步骤C中所述,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-(2-氯嘧啶-4-基)-3-甲基哌啶-2-酮(实施例111,步骤A)制备本标题化合物,得到白色固体。
步骤C. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(2-氯嘧啶-4-基)-3-甲基-2-氧代哌啶-3-基)乙酸.
如实施例110步骤D中所述,从2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(2-氯嘧啶-4-基)-3-甲基-2-氧代哌啶-3-基)乙醛(实施例111,步骤B)制备本标题化合物,得到白色泡沫状物。
1H NMR(400MHz,CDCl3)δppm 1.48(s,3H),2.29(d,J=3.91Hz,1H),2.33(d,J=12.52Hz,1H),2.86(d,J=14.87Hz,1H),3.06(d,J=14.67Hz,1H),3.31-3.41(m,1H),5.65(d,J=10.37Hz,1H),6.83-6.87(m,1H),6.88-6.93(m,2H),7.04-7.07(m,1H),7.07-7.10(m,2H),7.15(m,1H),7.18-7.23(m,1H),7.70(d,J=5.67Hz,1H),8.39(d,J=5.7Hz,1H)。MS(ESI)504.0[M+H]+。
实施例112
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(嘧啶-2-基)哌啶-3-基)乙酸.
如实施例111中所述从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮(实施例71,步骤D)和2-氯嘧啶制备,接着如实施例71步骤F中所述转化成该酸来制得本标题化合物。
1H NMR(500MHz,CDCl3)δppm 1.49(s,3H),2.34-2.40(m,2H),2.94(d,J=14.18Hz,1H),3.10(d,J=13.45Hz,1H),3.50(td,J=10.88和3.91Hz,1H),5.46(d,J=10.27Hz,1H),6.89(d,J=7.34Hz,1H),6.93-7.01(m,5H),7.11(t,J=8.19Hz,1H),7.14-7.18(m,2H),8.56(d,J=4.9Hz,2H)。MS(ESI)470.2[M+H]+。
实施例113
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(3-甲基吡啶-2-基)-2-氧代哌啶-3-基)乙酸.
步骤A. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(3-甲基-5-硝基吡啶-2-基)哌啶-2-酮
如实施例111步骤A中所述,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮(实施例71,步骤D)和2-氯代-3-甲基-5-硝基吡啶制备本标题化合物,得到淡黄色固体。
步骤B. (3S,5R,6S)-3-烯丙基-1-(5-氨基-3-甲基吡啶-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮
将(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(3-甲基-5-硝基吡啶-2-基)哌啶-2-酮(实施例113,步骤A)(120mg,0.23mmol)和氯化锡(II)二水合物(260mg,1.1mmol)溶解在2.3mL乙酸乙酯中。给反应器具装配回流冷凝器并将反应器具在90℃下搅拌4小时。将反应混合物冷却至室温,用1MNaOH淬灭并萃取(2x EtOAc)。用NaCl饱和水溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过快速色谱法(0%至90%的EtOAc/Hex,梯度洗脱)纯化残余物,得到本标题化合物,为无色固体。
步骤C. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(3-甲基吡啶-2-基)哌啶-2-酮
在0℃下向(3S,5R,6S)-3-烯丙基-1-(5-氨基-3-甲基吡啶-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮(实施例113,步骤B)(89mg,0.185mmol)在1,4-二噁烷(4.0mL)和乙酸(0.50mL)中的溶液中加入3.0M HCl(730μL,2.2mmol)。在将反应物搅拌5分钟后,逐滴加入过氧化氢(6%wt水溶液,95μL,0.185mmol),接着加入亚硝酸钠(46mg,0.74mmol)。将反应混合物在0℃下搅拌2小时。将反应混合物升温至室温,用1MNaOH淬灭并萃取(2x EtOAc)。用NaCl饱和水溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过快速色谱法(0%至55%的EtOAc/Hex,梯度洗脱)纯化残余物,得到本标题化合物,为无色固体。
步骤D. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(3-甲基吡啶-2-基)-2-氧代哌啶-3-基)乙醛
如实施例110步骤C中所述,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(3-甲基吡啶-2-基)哌啶-2-酮(实施例113,步骤C)制备本标题化合物,得到白色固体。
步骤E. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(3-甲基吡啶-2-基)-2-氧代哌啶-3-基)乙酸
如实施例110步骤D中所述,从2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(3-甲基吡啶-2-基)-2-氧代哌啶-3-基)乙醛(实施例113,步骤D)制备本标题化合物,得到白色泡沫状物。
1H NMR(500MHz,CDCl3)δppm 1.54(s,3H),2.12(s,3H),2.29(dd,J=14.31和3.06Hz,1H),2.50(t,J=13.82Hz,1H),2.92-3.01(m,1H),3.07-3.17(m,1H),3.56-3.67(m,1H),5.51(d,J=11.00Hz,1H),6.90-7.02(m,5H),7.05-7.15(m,4H),7.45(d,J=7.09Hz,1H),8.30(d,J=3.67Hz,1H)。MS(ESI)483.2[M+H]+。
实施例114
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(4-甲基吡啶-2-基)-2-氧代哌啶-3-基)乙酸.
步骤A. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(4-甲基吡啶-2-基)哌啶-2-酮
如实施例113步骤A-C中所述,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮(实施例71,步骤D)和2-氯代-4-甲基-5-硝基吡啶制备本标题化合物,得到白色固体。
步骤B. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(4-甲基吡啶-2-基)-2-氧代哌啶-3-基)乙酸.
在室温下向(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(4-甲基吡啶-2-基)哌啶-2-酮(实施例114,步骤A)(73mg,0.16mmol)在780μL四氢呋喃中的溶液中加入水(1.0mL),接着加入2-甲基丙烷-2-醇(100μL)。用4-甲基吗啉4-氧化物(28mg,0.24mmol),接着用四氧化锇(2.0mg,7.8μmol)处理反应混合物,并将其在室温下搅拌2小时。在室温下用1.25M琼斯试剂溶液(190μL,0.24mmol)处理反应混合物,并将其在室温下搅拌1小时。用水淬灭反应物并对其进行萃取(3x EtOAc)。用NaCl饱和水溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过HPLC在Eclipse柱(AgilentTechnologies,Santa,Clara,CA)(20%至80%的乙腈/水,梯度稀释)上纯化残余物,得到本标题化合物,为无色固体。
1H NMR(500MHz,CDCl3)δppm 1.49(s,3H),2.23(s,3H),2.28(dd,J=14.2和3.2Hz,1H),2.42(t,J=13.45Hz,1H),2.96(m,1H),3.04(m,1H),3.39(ddd,J=12.9,10.2和3.1Hz,1H),5.57(d,J=10.3Hz,1H),6.81(d,J=5.1Hz,1H),6.86-6.92(m,3H),6.99(d,J=8.1Hz,2H),7.08-7.13(m,2H),7.13-7.18(m,2H),8.13(d,J=5.1Hz,1H)。MS(ESI)483.2[M+H]+。
实施例115
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(二环丙基甲基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. (Z)-2-((4-氯亚苄基氨基)甲基)苯酚
向搅拌着的2-(氨基甲基)苯酚(4.0g,32.5mmol)在乙醇(65mL)中的悬浮液中加入4-氯苯甲醛(3.86mL,32.8mmol)。将由此产生的反应混合物在室温下搅拌3h。除去该溶剂,加入100ml甲苯并在真空中浓缩两次。将由此产生的亚胺在真空下干燥过夜,并将用于下一步骤而无需进一步纯化。
1H NMR(500MHz,DMSO-d6)δppm 9.47(1H,br.s.),8.44(1H,s),7.79(2H,d,J=8.6Hz),7.51(2H,d,J=8.6Hz),7.16(1H,dd,J=7.3,1.6Hz),7.08(1H,td,J=7.6,1.6Hz),6.72-6.87(2H,m),4.71(2H,s)。
步骤B. 2-(((1S,2R)-2-(3-氯苯基)-1-(4-氯苯基)丁-3-烯基氨基)甲基)苯酚
向1.42g(5.3mmol)(4S,5S)-2-烯丙基-2-氯代-3,4-二甲基-5-苯基-[1,3,2]-氧氮硅杂环戊烷(根据J.Am.Chem.Soc.124,7920,2002制备)和1-氯代-3-乙烯基苯(1.69g,12.21mmol)在DCM(12mL)和DCE(12mL)中的溶液中加入0.173g(0.2mmol)1,3-双-(2,4,6-三甲基苯基)-2-(咪唑烷亚基)(二氯苯基亚甲基)(三环己基膦)钌(“Grubbs 2代催化剂”)。将由此产生的混合物脱气两次,然后将其加热至回流并保持8h。将反应混合物冷却至室温。加入上面(步骤A)的亚胺(1.0g,4.07mmol)。将反应混合物加热至回流并保持14h,然后将其冷却至室温并通过加入8ml乙醇淬灭。用乙酸乙酯(120ml)稀释反应混合物,并用水(30ml)和NaCl饱和溶液(30ml)洗涤。经MgSO4干燥合并的有机层,过滤,并浓缩滤液。通过硅胶色谱法(洗脱剂:己烷/乙酸乙酯90/10-65/35)纯化残余物,得到本标题化合物。
1H NMR(500MHz,乙腈-d3)δppm 7.52(2H,d,J=8.3Hz),7.23-7.37(3H,m),7.10-7.17(3H,m),7.06(1H,d,J=8.1Hz),6.92-7.03(2H,m),6.88(1H,td,J=7.5,1.0Hz),6.14(1H,dt,J=16.4,9.8Hz),5.72(1H,d,J=16.4Hz),5.47(1H,dd,J=9.8,1.2Hz),4.35-4.47(1H,m),4.25-4.35(1H,m),4.05(1H,d,J=13.4Hz),3.78(1H,d,J=13.4Hz)。MS(ESI)[M+H]+,398.0.
步骤C. 2-((N-((1S,2R)-2-(3-氯苯基)-1-(4-氯苯基)丁-3-烯基)乙酰氨基)甲基)苯基乙酸酯
在0℃下向1.1g(2.76mmol)2-(((1S,2R)-2-(3-氯苯基)-1-(4-氯苯基)丁-3-烯基氨基)甲基)苯酚(实施例115,步骤B)和三乙胺(0.85mL,6.08mmol)在THF(5.0mL)和DCM(5.0mL)的混合物中的溶液中加入乙酸酐(0.55mL,5.80mmol)。让反应物的温度缓慢地升至室温,并将该混合物在室温下搅拌过夜。当LCMS指示反应完成时,加入100ml乙酸乙酯,并连续地用水(30ml)、柠檬酸(30ml,1M)、NaHCO3溶液(30ml)和NaCl饱和溶液(30ml)洗涤合并的有机物,经MgSO4干燥,过滤,并浓缩滤液从而得到本标题化合物。使用该粗产物而无需进一步纯化。
1H NMR(400MHz,氯仿-d)δppm 7.05-7.14(4H,m),6.91-7.05(6H,m),6.88(1H,d,J=7.4,Hz),6.81(1H,t,J=7.5Hz),6.42(1H,m),5.95(1H,dt,J=16.8,9.6Hz),4.97-5.18(2H,m),4.24-4.45(2H,m),4.05(1H,q,J=7.0Hz),2.31(3H,s),1.91(3H,s)。MS(ESI)[M+H]+,482.0.
步骤D. N-((1S,2R)-2-(3-氯苯基)-1-(4-氯苯基)丁-3-烯基)乙酰胺
将1.05g(2.18mmol)2-((N-((1S,2R)-2-(3-氯苯基)-1-(4-氯苯基)丁-3-烯基)乙酰氨基)甲基)苯基乙酸酯(实施例115,步骤C)和甲苯磺酸一水合物(1.66g,8.71mmol)在甲苯(15.0mL)中的溶液加热至回流并保持约2h。加入120ml乙酸乙酯,并连续地用NaHCO3溶液和NaCl饱和溶液洗涤合并的有机物,经MgSO4干燥,过滤,并浓缩滤液。通过制备型HPLC纯化粗混合物从而得到本标题化合物。
1H NMR(500MHz,氯仿-d)δppm 7.08-7.15(2H,m),7.02-7.08(2H,m),6.92(3H,t,J=8.6,Hz),6.81(1H,dd,J=3.5,2.1Hz),5.83-6.07(2H,m),5.04-5.21(3H,m),3.48(1H,t,J=9.3Hz),1.97(3H,s)。MS(ESI)[M+H]+,334.0。
步骤E. (1S,2R)-2-(3-氯苯基)-1-(4-氯苯基)丁-3-烯-1-胺
在0℃下向4.1g(12.27mmol)N-((1S,2R)-2-(3-氯苯基)-1-(4-氯苯基)丁-3-烯基)乙酰胺(实施例115,步骤D)和吡啶(1.20mL,14.72mmol)在THF(35.0mL)中的混合物中加入1.2mL(13.5mmol)乙二酰氯。将由此产生的淡黄色浆液在0℃下搅拌1.5h。一次性加入1,2-二羟基丙烷(1.80mL,24.53mmol),并将反应物升温至室温。用乙醇(16.0ml),接着用6NHCl(16.0ml)处理该混合物。将反应混合物在55℃下加热10min,然后冷却至室温。当LCMS指示大部分SM已消耗时,加入200ml乙酸乙酯,并连续地用NaHCO3溶液和饱和NaCl溶液洗涤有机物,经MgSO4干燥,过滤,并浓缩滤液。通过硅胶快速色谱法纯化粗混合物从而得到本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 7.21(3H,d,J=8.4Hz),7.03-7.17(3H,m),6.96(1H,s),6.79(1H,ddd,J=6.2,2.2,2.0Hz),5.98(1H,dt,J=16.8,9.8Hz),5.39(1H,d,J=16.8Hz),5.24(1H,d,J=10.2Hz),4.14(1H,d,J=11.2Hz),3.76(1H,t,J=10.2Hz)。MS(ESI)[M+H]+,292.1。
步骤F. (1S,2R)-2-(3-氯苯基)-1-(4-氯苯基)-N-(二环丙基甲基)丁-3-烯-1-胺
在室温下向2.0g(6.84mmol)(1S,2R)-2-(3-氯苯基)-1-(4-氯苯基)丁-3-烯-1-胺(实施例115,步骤E)、二环丙基酮(7.54mL,68.4mmol),和乙酸(1.96mL,34.2mmol)在甲醇(25.0mL)中的溶液中加入氰基硼氢化钠(1.44mL,27.4mmol)。将由此产生的混合物在50℃下搅拌2天。再次加入乙酸(1.5ml)和氰基硼氢化钠(0.6g)并继续加热过夜。加入200ml乙酸乙酯,并连续地用K2CO3溶液和NaCl饱和溶液洗涤有机层,经K2CO3干燥,过滤并于60℃在减压下浓缩滤液。通过硅胶快速色谱法(洗脱剂:DCM/MeOH,95/5)纯化该混合物从而得到本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 7.20-7.41(4H,m),7.04-7.20(2H,m),6.92-7.04(1H,m),6.80(1H,dt,J=7.0,1.6Hz),6.11(1H,ddd,J=16.8,10.0,9.8Hz),5.63(1H,d,J=16.8Hz),5.52(1H,d,J=10.0Hz),4.47(1H,d,J=10.8Hz),4.06(1H,t,J=10.0Hz),1.79(1H,t,J=9.4Hz),1.08-1.24(1H,m),0.91-1.08(2H,m),0.50-0.78(3H,m),0.29-0.50(2H,m),0.24(1H,dq,J=9.9,5.0Hz),0.09(1H,ddd,J=9.9,5.2,5.0Hz)。MS(ESI)[M+H]+,386.0。
步骤G. N-((1S,2R)-2-(3-氯苯基)-1-(4-氯苯基)丁-3-烯基)-N-(二环丙基甲基)丙烯酰胺
在0℃下向2.1g(5.44mmol)(1S,2R)-2-(3-氯苯基)-1-(4-氯苯基)-N-(二环丙基甲基)丁-3-烯-1-胺(实施例115,步骤F)和三乙胺(1.89mL,13.59mmol)在THF(30.0mL)中的溶液中加入丙烯酰氯(0.66mL,8.15mmol)。将由此产生的反应混合物在室温下搅拌2h。当LCMS指示反应完成时,加入100ml乙酸乙酯,并连续地用水(10ml)、柠檬酸(10ml,1M)、NaHCO3溶液(10ml)和NaCl饱和溶液(30ml)洗涤合并的有机层,经MgSO4干燥,过滤,并浓缩滤液。通过硅胶快速色谱法(洗脱剂:己烷/乙酸乙酯,90/10至20/80)纯化粗产物从而得到本标题化合物。
1H NMR(500MHz,氯仿-d)δppm 7.28(3H,br.s.),6.94-7.17(5H,m),6.87(1H,br.s.),6.42(1H,m.),6.20(2H,ddd,J=16.9,9.8,9.5Hz),5.58(1H,d,J=10.3Hz),5.18(1H,d,J=16.9Hz),5.06(2H,dd,J=10.3,1.3Hz),2.72(1H,br.s.),1.19-1.41(1H,m),0.77-1.00(2H,m),0.63(3H,d,J=5.6Hz),0.50(1H,br.s.),0.43(1H,d,J=4.6Hz),0.20(1H,br.s.),-0.28(1H,br.s.)。MS(ESI)[M+H]+,440.0。
步骤H. (5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(二环丙基甲基)-5,6-二氢吡啶-2(1H)-酮
向2.1g(4.77mmol)N-((1S,2R)-2-(3-氯苯基)-1-(4-氯苯基)丁-3-烯基)-N-(二环丙基甲基)丙烯酰胺(实施例115,步骤G)在50mL DCE中的溶液中加入160mg 1,3-双-(2,4,6-三甲基苯基)-2-(咪唑烷亚基)(二氯苯基亚甲基)(三环己基膦)钌(“Grubbs 2代催化剂”)。将由此产生的混合物脱气两次,然后将其加热至70℃并保持18h。在此时加入另一份160mg Grubbs 2代催化剂,并再继续加热18h。将反应混合物冷却至室温。除去溶剂并通过硅胶色谱法(洗脱剂:己烷/乙酸乙酯,90/10至20/80)纯化残余物,从而得到本标题化合物。
1H NMR(500MHz,氯仿-d)δppm 7.13-7.36(8H,m),6.42(1H,d,J=9.8Hz),6.27(1H,ddd,J=9.8,6.1,1.3Hz),4.91(1H,s),3.67(1H,d,J=6.1Hz),3.28-3.44(1H,m),0.42(1H,ddd,J=8.9,4.6,4.5Hz),0.26-0.37(3H,m),0.12-0.26(3H,m),-0.07-0.02(1H,m),-0.24--0.12(1H,m),-0.34--0.24(1H,m)。MS(ESI)[M+H]+,412.1。
步骤I. (5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(二环丙基甲基)哌啶-2-酮
将(5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(二环丙基甲基)-5,6-二氢吡啶-2(1H)-酮(实施例115,步骤H;0.826g,2.003mmol)和(1,5-环辛二烯)(吡啶)(三环己基膦)铱(i)六氟磷酸盐(0.129g,0.160mmol)在DCM(60.0ml)中的溶液用氢气饱和。将由此产生的混合物于室温下在氢气气氛下搅拌2h,然后加入另一份66.0mg(1,5-环辛二烯)(吡啶)(三环己基膦)铱(i)六氟磷酸盐。继续在氢气气氛下搅拌直至LCMS指示双键完全饱和。除去溶剂并通过硅胶色谱法(用乙酸乙酯:己烷,10:90洗脱)纯化粗混合物从而得到本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 7.11-7.32(7H,m),6.98-7.11(1H,m),4.96(1H,d,J=4.7Hz),3.26(1H,m.),2.92-3.15(1H,m),2.60(2H,t,J=6.9Hz),2.09(1H,dddd,J=14.1,7.3,7.1,4.9Hz),1.83-2.01(1H,m),0.80-0.94(1H,m),0.45-0.61(1H,m),0.12-0.41(6H,m),0.05(1H,dt,J=9.7,4.8,Hz),-0.19--0.04(1H,m)。MS(ESI)[M+H]+,414.0。
步骤J. (5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(二环丙基甲基)-3(R,S)-甲基哌啶-2-酮
如实施例68步骤C中所述,从(5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(二环丙基甲基)哌啶-2-酮(实施例115,步骤I)制备本标题化合物。通过硅胶色谱法(洗脱剂:乙酸乙酯:己烷,10:90)纯化粗产物从而得到本标题化合物,为无色油状物。
1H NMR(500MHz,氯仿-d)δppm 7.16(2H,d,J=8.6Hz),7.00-7.14(6H,m),4.95(1H,d,J=2.2Hz),3.21(1H,br.s.),2.85-2.99(1H,m),2.40(1H,dt,J=10.3,7.1Hz),1.68-1.87(2H,m),1.21(3H,s),1.04-1.17(1H,m),0.86(1H,d,J=4.2Hz),0.35-0.51(1H,m),0.12-0.28(4H,m),-0.04-0.12(2H,m),-0.34--0.15(1H,m)。
步骤K. (3S/3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-(二环丙基甲基)-3-甲基哌啶-2-酮
采用与实施例68步骤D中描述的程序类似的程序获得本标题化合物,为立体异构体的混合物。
1H NMR(400MHz,氯仿-d)δppm 7.06-7.23(4H,m),6.91-7.06(3H,m),6.69-6.86(1H,m),5.79-5.98(1H,m),5.03-5.26(2H,m),4.81(1H,d,J=9.6Hz),3.03-3.22(1H,m),2.49-2.78(2H,m),1.88-2.01(2H,m),1.46(1H,s),1.21(2H,s),0.98-1.16(1H,m),0.44-0.71(3H,m),0.19-0.44(3H,m),-0.11-0.19(3H,m)。MS(ESI)[M+H]+,468.2。
步骤L. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(二环丙基甲基)-3-甲基-2-氧代哌啶-3-基)乙酸
按照与实施例71步骤F中描述的程序类似的程序,将(3S/3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-(二环丙基甲基)-3-甲基哌啶-2-酮的非对映异构体混合物(实施例115,步骤K)转化成该酸的非对映异构体混合物。通过反相制备型HPLC(SunfireTMPrep C18OBD 10μm柱(Waters,Milford,MA),40%的在水中的MeCN至80%的在水中的MeCN梯度洗脱超过30min,其中这两种溶剂都含有0.1%TFA)分离单一立体异构体从而得到本标题化合物,为较快地洗脱的异构体。
1H NMR(400MHz,氯仿-d)δppm 7.98(1H,dd,J=7.6,6.5Hz),7.00-7.29(7H,m),6.86(1H,d,J=7.4Hz),4.93(1H,d,J=8.2Hz),4.33(1H,d,J=5.1Hz),3.09-3.15(1H,m),3.03(1H,d,J=15.1Hz),2.69-2.80(1H,m),2.08-2.17(2H,m),1.35(3H,s),1.14-1.21(1H,m),0.53-0.73(2H,m),0.41-0.51(2H,m),0.27-0.40(2H,m),0.02-0.21(3H,m)。MS(ESI)[M+H]+,486.2。
进一步洗脱并在真空中浓缩得到实施例116。
实施例116
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(二环丙基甲基)-3-甲基-2-氧代哌啶-3-基)乙酸
根据程序115获得本标题化合物,为较慢地洗脱的异构体。
1H NMR(500MHz,氯仿-d)δppm 7.10-7.33(6H,m),6.95-7.03(2H,m),6.73-6.83(1H,m),4.80(1H,d,J=9.8Hz),3.18-3.23(1H,m),2.84(1H,t,J=13.4Hz),2.72-2.79(1H,m),2.63-2.72(1H,m),2.32-2.39(1H,m),1.77(1H,dd,J=13.2,3.4Hz),1.64-1.68(3H,m),1.14(1H,m),0.64-0.70(1H,m),0.52-0.58(1H,m),0.44-0.49(2H,m),0.27-0.33(2H,m),0.13-0.18(2H,m),-0.01(1H,m)。MS(ESI)[M-H],484.0。
实施例117
((3S,4R,6R)-4-(3-氯苯基)-3-(4-氯苯基)-1,1-二氧化-2-(2-丙基)-1,2-噻嗪烷-6-基)乙酸
步骤A. (E)-N-((1S,2R)-2-(3-氯苯基)-1-(4-氯苯基)丁-3-烯基)-2-苯乙烯磺酰胺
向5.33g(18.24mmol)(1S,2R)-2-(3-氯苯基)-1-(4-氯苯基)丁-3-烯-1-胺(实施例115,步骤E)在DCM(45.0mL)中的溶液中加入N,N-二异丙基乙胺(4.8mL,27.5mmol),接着加入反式-β-苯乙烯磺酰氯(4.17g,20.58mmol)。将由此产生的溶液于室温下在N2气氛下搅拌。在搅拌3.25小时后,用水稀释反应物并用DCM萃取。用NaCl饱和水溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并浓缩滤液。通过硅胶快速色谱法(用0%至40%的在己烷中的EtOAc梯度洗脱)纯化,得到本标题化合物,为黄色固体。
1H NMR(500MHz,氯仿-d)δ7.30-7.41(m,3H),7.12-7.17(m,2H),7.05-7.11(m,5H),6.97-7.03(m,3H),6.82-6.89(m,1H),6.17(d,J=15.41Hz,1H),6.06-6.15(m,1H),5.21-5.40(m,2H),5.13(d,J=5.62Hz,1H),4.60(dd,J=5.87,9.29Hz,1H),3.54(t,J=9.17Hz,1H)。MS(ESI)480.0[M+Na]+。
步骤B. (3S,4R)-4-(3-氯苯基)-3-(4-氯苯基)-3,4-二氢-2H-1,2-噻嗪
向脱气的7.29g(15.90mmol)(E)-N-((1S,2R)-2-(3-氯苯基)-1-(4-氯苯基)丁-3-烯基)-2-苯乙烯磺酰胺(实施例117,步骤A)在DCM(350mL)和DCE(350mL)的1:1混合物中的溶液中加入Grubbs 1代催化剂(1.20g,1.434mmol)。将由此产生的溶液在70℃下搅拌20小时。在冷却至室温后,在减压下浓缩反应物。通过硅胶快速色谱法(用0%至2%的在DCM中的MeOH梯度洗脱)纯化,得到本标题化合物。
1H NMR(500MHz,氯仿-d)δ7.20-7.29(m,J=8.80Hz,3H),7.11-7.19(m,1H),7.02(d,J=8.31Hz,2H),6.99(t,J=/.71Hz,1H),6.86(dd,J=2.69,10.76Hz,1H),6.79(d,J=7.58Hz,1H),6.44(dd,J=2.20,11.00Hz,1H),5.14(d,J=11.00Hz,1H),4.86(t,J=10.76Hz,1H),3.76(td,J=2.35,10.70Hz,1H)。MS(ESI)376.0[M+Na]+。
步骤C. (3S,4R)-4-(3-氯苯基)-3-(4-氯苯基)-1,2-噻嗪烷
将4.14g(11.69mmol)(3S,4R)-4-(3-氯苯基)-3-(4-氯苯基)-3,4-二氢-2H-1,2-噻嗪(实施例117,步骤B)在二氯甲烷(63.0mL)中的溶液用氩气吹扫三次,然后向反应混合物中加入Crabtree催化剂(835.2mg,1.027mmol)。再次用氩气吹扫反应物,然后在反应物上布置氢气气氛。将该溶液在室温下搅拌15小时,在这一时刻将反应物浓缩成油状物。通过硅胶快速色谱法(用0%至4%的在DCM中的MeOH梯度洗脱)纯化,得到本标题化合物,为棕褐色固体。
1H NMR(500MHz,氯仿-d)δ7.16-7.22(m,2H),7.08-7.14(m,2H),6.99-7.07(m,3H),6.82-6.88(m,1H),4.67(dd,J=5.01,10.88Hz,1H),4.55(d,J=4.65Hz,1H),3.25-3.39(m,2H),2.89-3.04(m,1H),2.67(dddd,J=6.60,10.39,12.50,14.52Hz,1H),2.39(qd,J=3.67,14.43Hz,1H)。MS(ESI)378.0[M+Na]+。
步骤D. (3S,4R)-4-(3-氯苯基)-3-(4-氯苯基)-2-(2-丙基)-1,2-噻嗪烷
向1.21g(3.40mmol)(3S,4R)-4-(3-氯苯基)-3-(4-氯苯基)-1,2-噻嗪烷(实施例117,步骤C)在DMF(8.5mL)中的溶液中加入碳酸铯(4.31g,13.23mmol),接着加入2-碘丙烷(2.9mL,29.0mmol)。将由此产生的混合物在85℃下加热23小时。在冷却至室温后,用水稀释反应混合物并用乙酸乙酯萃取。用NaCl饱和溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并浓缩滤液。通过硅胶快速色谱法(0%至2%的在DCM中的MeOH梯度洗脱)纯化,得到本标题化合物,为白色固体。
1H NMR(500MHz,氯仿-d)δ7.13-7.19(m,3H),7.04-7.12(m,3H),7.00(t,J=1.83Hz,1H),6.75(d,J=7.58Hz,1H),4.51(d,J=10.76Hz,1H),3.81(td,J=6.94,13.75Hz,1H),3.40-3.49(m,1H),3.25-3.39(m,2H),2.53(ddt,J=6.85,11.49,13.45Hz,1H),2.23(tdd,J=2.96,6.54,13.94Hz,1H),1.36(d,J=6.85Hz,3H),1.07(d,J=7.09Hz,3H)。MS(ESI)420.0[M+Na]+。
步骤E. (3S,4R,6R/6S)-4-(3-氯苯基)-3-(4-氯苯基)-2-(2-丙基)-6-(2-丙烯-1-基)-1,2-噻嗪烷
向脱气的211.7mg(0.531mmol)(3S,4R)-4-(3-氯苯基)-3-(4-氯苯基)-2-(2-丙基)-1,2-噻嗪烷(实施例117,步骤D)在THF(2.5mL)中的溶液中加入烯丙基碘(0.25mL,2.74mmol)。将由此产生的溶液加热至50℃。在10分钟后,用超过1分钟的时间逐滴加入1M双(三甲基甲硅烷基)-氨基锂的THF溶液(0.86mL,0.860mmol)。在50℃下加热20小时后,将反应物冷却至室温,用水(2mL)淬灭,然后在减压下浓缩。通过硅胶快速色谱法(用0%至100%的在己烷中的DCM梯度洗脱)纯化,得到本标题化合物,为白色固体。1H NMR显示为R/S烯丙基差向异构体的91:9混合物。
将脱气的98.6mg(0.225mmol)该差向异构体混合物在THF(5mL)中的溶液加热至60℃。在10分钟后,加入双(三甲基甲硅烷基)-氨基锂在THF中的1M溶液(1.0mL,1.00mmol)。将由此产生的溶液在60℃下搅拌45分钟,然后在此时刻加入甲醇(275.0μL,6.80mmol)。将该溶液再在60℃下加热45分钟。在冷却至室温后,用甲醇(5mL)淬灭反应物,然后在减压下浓缩。通过反相制备型HPLC使用Agilent Eclipse Plus C18柱(Agilent Technologies,Santa,Clara,CA),用30%至95%的含有0.1%TFA的MeN/H2O梯度洗脱超过25分钟来对该材料进行纯化,从而得到本标题化合物,为白色固体。1H NMR显示为差向异构体的~2:1混合物。通过SFC(AD-H柱(Diacel,Fort Lee NJ),30mm I.D.×250mm,使用12g/min20mM NH3的异丙醇溶液和68g/min的CO2作为洗脱剂)分离各个立体异构体,从而得到(3S,4R,6S)-4-(3-氯苯基)-3-(4-氯苯基)-2-(2-丙基)-6-(2-丙烯-1-基)-1,2-噻嗪烷(tR=1.62min),为白色固体。
1H NMR(500MHz,氯仿-d)δppm 7.16-7.21(m,1H),7.06-7.15(m,5H),7.00(t,J=1.59Hz,1H),6.72(d,J=7.58Hz,1H),5.71-5.88(m,1H),5.11-5.24(m,2H),4.34(d,J=11.00Hz,1H),3.99-4.11(m,1H),3.46(ddd,J=13.33,10.76,3.06Hz,1H),3.32-3.43(m,1H),2.85-2.96(m,1H),2.43-2.61(m,2H),2.00(dt,J=13.94,2.45Hz,1H),1.35(d,J=6.85Hz,3H),1.00(d,J=7.09Hz,3H)。MS(ESI)460.0[M+Na]+。
还获得(3S,4R,6R)-4-(3-氯苯基)-3-(4-氯苯基)-2-(2-丙基)-6-(2-丙烯-1-基)-1,2-噻嗪烷(tR=1.87min),为白色固体。
1H NMR(500MHz,氯仿-d)δppm 7.16(d,J=8.31Hz,2H),7.10-7.14(m,1H),7.04-7.10(m,3H),6.99(t,J=1.59Hz,1H),6.74(d,J=7.58Hz,1H),5.76(dddd,J=16.84,10.24,8.13,6.11Hz,1H),5.10-5.22(m,2H),4.57(d,J=11.00Hz,1H),3.59(dt,J=13.94,6.97Hz,1H),3.30-3.41(m,J=11.49,9.66,4.71,4.71Hz,1H),3.26(ddd,J=12.65,10.82,3.42Hz,1H),2.84-2.98(m,1H),2.21-2.33(m,2H),2.04-2.19(m,1H),1.36(d,J=6.85Hz,3H),1.13(d,J=6.85Hz,3H)。MS(ESI)460.0[M+Na]+。
步骤F. ((3S,4R,6R)-4-(3-氯苯基)-3-(4-氯苯基)-1,1-二氧化-2-(2-丙基)-1,2-噻嗪烷-6-基)乙酸
按照与实施例71步骤F中所描述的程序类似的程序,从(3S,4R,6S)-4-(3-氯苯基)-3-(4-氯苯基)-2-(2-丙基)-6-(2-丙烯-1-基)-1,2-噻嗪烷(实施例117,步骤E)获得本标题化合物。通过反相制备型HPLC使用Agilent Eclipse Plus C18柱(AgilentTechnologies,Santa,Clara,CA),用30%至95%的含有0.1%TFA的MeCN/H2O梯度洗脱超过25分钟来进行纯化,得到本标题化合物,为白色固体。
1H NMR(500MHz,氯仿-d)δppm 7.12-7.19(m,3H),7.04-7.12(m,3H),6.99(br.s.,1H),6.73(d,J=7.58Hz,1H),4.38(d,J=11.00Hz,1H),3.91-4.05(m,1H),3.84(br.s.,1H),3.39-3.49(m,1H),3.24(d,J=17.12Hz,1H),2.88(dd,J=17.12,10.27Hz,1H),2.66-2.79(m,1H),2.02(d,J=12.72Hz,1H),1.32-1.40(m,3H),1.03(d,J=6.85Hz,3H)。MS(ESI)478.0[M+Na]+。
实施例118
((3S,4R,6S)-4-(3-氯苯基)-3-(4-氯苯基)-1,1-二氧化-2-(2-丙基)-1,2-噻嗪烷-6-基)乙酸
如实施例117步骤F中所述,从(3S,4R,6R)-4-(3-氯苯基)-3-(4-氯苯基)-2-(2-丙基)-6-(2-丙烯-1-基)-1,2-噻嗪烷(实施例117,步骤E)制备本标题化合物。
1H NMR(500MHz,氯仿-d)δppm 7.07(d,J=6.85Hz,2H),6.94-7.05(m,4H),6.90(br.s.,1H),6.65(d,J=7.34Hz,1H),4.48(d,J=11.00Hz,1H),3.70-3.79(m,1H),3.48-3.57(m,1H),3.22-3.32(m,1H),3.10(dd,J=17.12,4.65Hz,1H),2.46(dd,J=17.12,8.80Hz,1H),2.22-2.34(m,1H),2.07(d,J=12.47Hz,1H),1.25(d,J=6.60Hz,3H),1.01(d,J=6.60Hz,3H)。MS(ESI)478.0[M+Na]+。
实施例119
((3S,4R,6R)-4-(3-氯苯基)-3-(4-氯苯基)-6-甲基-1,1-二氧化-2-(2-丙基)-1,2-噻嗪烷-6-基)乙酸
步骤A. (3S,4R,6S)-4-(3-氯苯基)-3-(4-氯苯基)-6-甲基-2-(2-丙基)-6-(2-丙烯-1-基)-1,2-噻嗪烷的合成
在-78℃下向脱气的二异丙胺(300μL,2.123mmol)在THF(1.0ml)中的溶液中逐滴加入2.5M在己烷中的正丁基锂(800μL,2.000mmol)。在将该溶液在-78℃搅拌10min后,将反应物升温至室温。在单独的烧瓶中,将脱气的111.9mg(0.255mmol)(3S,4R,6R)-4-(3-氯苯基)-3-(4-氯苯基)-2-(2-丙基)-6-(2-丙烯-1-基)-1,2-噻嗪烷(实施例117,步骤E)和碘甲烷(0.6ml,9.62mmol)在THF(1.0ml)中的溶液加热至50℃。在5分钟后,将LDA溶液逐滴加入到另一个烧瓶中,并继续在50℃下搅拌14小时。在冷却至室温后,用水(3mL)淬灭反应物,然后在减压下浓缩。通过反相制备型HPLC使用Agilent Eclipse Plus C18柱(AgilentTechnologies,Santa,Clara,CA),用60%至80%的含有0.1%TFA的CH3CN/H2O梯度洗脱超过25分钟来进行纯化,得到本标题化合物,为白色固体。
1H NMR(500MHz,氯仿-d)δppm 7.18(br.s.,2H),7.03-7.14(m,4H),6.96(d,J=1.71Hz,1H),6.72(d,J=7.34Hz,1H),5.64-5.93(m,1H),5.18-5.28(m,2H),4.45(d,J=10.76Hz,1H),3.61-3.75(m,1H),3.30-3.44(m,1H),2.82-2.90(m,1H),2.74-2.82(m,1H),2.17-2.32(m,1H),2.02(dd,J=13.94,3.18Hz,1H),1.42(s,3H),1.34(d,J=6.85Hz,3H),1.11(d,J=6.85Hz,3H)。MS(ESI)474.1[M+Na]+。
步骤B. ((3S,4R,6R)-4-(3-氯苯基)-3-(4-氯苯基)-6-甲基-1,1-二氧化-2-(2-丙基)-1,2-噻嗪烷-6-基)乙酸
如实施例1步骤F中所述,从(3S,4R,6S)-4-(3-氯苯基)-3-(4-氯苯基)-6-甲基-2-(2-丙基)-6-(2-丙烯-1-基)-1,2-噻嗪烷(实施例119,步骤A)制备本标题化合物。
1H NMR(500MHz,氯仿-d)δppm 7.08(d,J=7.34Hz,2H),6.92-7.03(m,4H),6.87(br.s.,1H),6.63(d,J=7.34Hz,1H),4.41(d,J=11.00Hz,1H),3.41-3.52(m,1H),3.29-3.36(m,1H),3.25(d,J=14.92Hz,1H),2.93(d,J=15.16Hz,1H),2.21-2.36(m,2H),1.51(s,3H),1.23(d,J=6.60Hz,3H),1.05(d,J=6.60Hz,3H)。MS(ESI)492.1[M+Na]+。
实施例120
((3S,4R,6S)-4-(3-氯苯基)-3-(4-氯苯基)-6-甲基-1,1-二氧化-2-(2-丙基)-1,2-噻嗪烷-6-基)乙酸
步骤A. (3S,4R,6R)-4-(3-氯苯基)-3-(4-氯苯基)-6-甲基-2-(2-丙基)-1,2-噻嗪烷
向脱气的239.9mg(0.602mmol)(3S,4R)-4-(3-氯苯基)-3-(4-氯苯基)-2-(2-丙基)-1,2-噻嗪烷(实施例117,步骤D)在THF(2.0mL)中的溶液中加入碘甲烷(60.0μl,0.960mmol),接着逐滴加入双(三甲基甲硅烷基)-氨基锂在THF中的1M溶液(640.0μl,0.640mmol)。在室温下搅拌17小时后,用MeOH(3mL)淬灭反应物,然后在减压下浓缩。通过硅胶快速色谱法(用0%至70%的在己烷中的DCM梯度洗脱)纯化,得到本标题化合物,为白色固体。1H NMR显示还分离出6%的6S差向异构体。
1H NMR(500MHz,氯仿-d)δppm 7.14-7.18(m,2H),7.04-7.13(m,4H),6.95-7.01(m,1H),6.71-6.77(m,1H),4.57(d,J=10.76Hz,1H),3.54-3.63(m,1H),3.39-3.51(m,1H),3.23-3.39(m,1H),2.14-2.27(m,2H),1.42(d,J=6.85Hz,3H),1.34-1.38(m,3H),1.13(d,J=6.85Hz,3H)。MS(ESI)434.0[M+Na]+。
步骤B. (3S,4R,6R)-4-(3-氯苯基)-3-(4-氯苯基)-6-甲基-2-(2-丙基)-6-(2-丙烯-1-基)-1,2-噻嗪烷
向脱气的174.7mg(0.424mmol)(3S,4R,6R)-4-(3-氯苯基)-3-(4-氯苯基)-6-甲基-2-(2-丙基)-1,2-噻嗪烷(实施例120,步骤A)在THF(1.5mL)中的溶液中加入烯丙基碘(0.55mL,6.02mmol)。将由此产生的溶液加热至60℃并保持10分钟,然后用超过1分钟的时间逐滴加入双(三甲基甲硅烷基)-氨基锂在THF中的1M溶液(2.0mL,2.00mmol)。在60℃下搅拌17小时后,将反应物冷却至室温,用水(2mL)淬灭,然后在减压下浓缩。通过反相制备型HPLC使用Agilent Eclipse Plus C18柱(Agilent Technologies,Santa,Clara,CA),用40%至95%的含有0.1%TFA的MeCN/H2O梯度洗脱超过25分钟来进行纯化,得到本标题化合物,为白色固体。
1H NMR(500MHz,氯仿-d)δppm 7.15-7.20(m,2H),7.03-7.13(m,4H),6.97(s,1H),6.73(d,J=7.34Hz,1H),5.72-5.89(m,1H),5.22(d,J=4.65Hz,1H),5.19(s,1H),4.47(d,J=10.76Hz,1H),3.56-3.69(m,1H),3.31-3.42(m,1H),2.69(dd,J=13.82,7.21Hz,1H),2.55(dd,J=13.82,7.70Hz,1H),2.38(t,J=13.45Hz,1H),1.87(dd,J=13.94,3.18Hz,1H),1.61(s,3H),1.33(d,J=6.85Hz,3H),1.12(d,J=6.85Hz,3H)。MS(ESI)474.1[M+Na]+。
步骤C. ((3S,4R,6S)-4-(3-氯苯基)-3-(4-氯苯基)-6-甲基-1,1-二氧化-2-(2-丙基)-1,2-噻嗪烷-6-基)乙酸
如实施例1步骤F中所述,从(3S,4R,6R)-4-(3-氯苯基)-3-(4-氯苯基)-6-甲基-2-(2-丙基)-6-(2-丙烯-1-基)-1,2-噻嗪烷(实施例120,步骤B)制备本标题化合物。
1H NMR(500MHz,氯仿-d)δppm 7.15-7.23(m,2H),7.03-7.14(m,4H),6.97(br.s.,1H),6.73(d,J=6.60Hz,1H),4.47(d,J=10.52Hz,1H),3.59-3.73(m,1H),3.42(t,J=11.74Hz,1H),2.95-3.03(m,1H),2.84-2.93(m,1H),2.47(t,J=13.08Hz,1H),2.28(d,J=13.94Hz,1H),1.79(br.s.,3H),1.30-1.39(m,3H),1.02-1.14(m,3H)。MS(ESI)492.1[M+Na]+。
实施例121
2-((3R,5R,6S)-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-3-甲基-1-((S)-1-吗啉代丁烷-2-基)-2-氧代哌啶-3-基)乙酸
步骤A. 5-氯吡啶甲酸甲酯
在室温下向5-氯吡啶-2-羧酸(309g,1.96mol)在无水MeOH(2L)中的溶液中缓慢地加入亚硫酰氯(299.7mL,4.12mol,2.1当量)(在亚硫酰氯添加期间混浊的溶液变成澄清的棕色溶液)。在添加完成后,将反应混合物加热至50℃并在这个温度下搅拌过夜。在减压下除去该溶剂和过量的亚硫酰氯,并将粗产物用甲苯共沸两次。将由此产生的固体转移至过滤漏斗中,并用饱和NaHCO3水溶液洗涤直至滤液为碱性。将由此产生的固体溶解在二氯甲烷(2L)中并用饱和NaHCO3水溶液洗涤。经硫酸钠干燥有机物,过滤,并浓缩滤液从而得到本标题化合物,为灰白色固体。
步骤B. 2-(3-氯苯基)-1-(5-氯吡啶-2-基)乙酮.
在-78℃下用超过2h 45min的时间向3-氯苯乙酸(326.5g,1.91mol,0.95当量)在THF(1.82L)中的溶液中缓慢地加入NaHMDS(1M溶液在THF中,3.82L,3.82mol,2当量),同时保持温度低于-65℃。在添加完成后,将反应混合物在-78℃下搅拌30min。用超过30min的时间将5-氯吡啶甲酸甲酯(326.5g,1.91mol,实施例121,步骤A)在THF(0.9L)中的溶液加入到在-78℃下的上述溶液中。将反应物再搅拌1小时,然后让其升温至室温过夜。将反应混合物缓慢地转移到氯化铵饱和水溶液(4L)中,用乙酸乙酯(2x8L)萃取,然后经Na2SO4干燥合并的有机层,过滤,并浓缩滤液。通过硅胶快速色谱法(洗脱剂:DCM)纯化残余物,得到本标题化合物,为白色固体。
步骤C. 4-(3-氯苯基)-5-(5-氯吡啶-2-基)-5-氧代戊酸甲酯
向在80℃下的368.5g(1.39mol)2-(3-氯苯基)-1-(5-氯吡啶-2-基)乙酮(实施例121,步骤B)在二噁烷(1.5L)中的溶液中加入DBU(207mL,1.39mole,1当量),接着在80℃下逐滴加入丙烯酸甲酯(124.7mL,1.39mol,1当量)。将反应物在80℃下搅拌1h 30min,然后让其冷却至室温。用2M HCl水溶液(56.5当量)将它淬灭,然后用饱和NaHCO3水溶液将它碱化至pH为7。用EtOAc(2X4L)萃取水层。经Na2SO4干燥合并的有机层,过滤并蒸发滤液。通过硅胶快速色谱法(洗脱剂:40%至100%的DCM/己烷)纯化,得到本标题化合物,为黄色液体。
步骤D. (4R,5R)4-(3-氯苯基)-5-(5-氯吡啶-2-基)-5-羟基戊酸甲酯和(4S,5S)-4-(3-氯苯基)-5-(5-氯吡啶-2-基)-5-羟基戊酸甲酯
在0-5℃下向2-(3-氯苯基)-1-(5-氯吡啶-2-基)乙酮(459.5g,1.3mol,实施例121,步骤C)在无水MeOH(1.5L)中的溶液中分批加入硼氢化钠(14.8g,0.392mol,0.3当量)。将反应物在相同温度下搅拌30min,然后用冰水淬灭。在减压下除去甲醇。将残余物溶解在乙酸乙酯中并用水洗涤。用乙酸乙酯(3X2L)萃取水层。用NaCl饱和溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过硅胶快速色谱法(洗脱剂:10%至70%的EtOAc/己烷,梯度洗脱)纯化残余物,得到本标题化合物,为黄色液体。
步骤E. (4R,5S)5-叠氮基-4-(3-氯苯基)-5-(5-氯吡啶-2-基)戊酸甲酯和(4S,5R)-5-叠氮基-4-(3-氯苯基)-5-(5-氯吡啶-2-基)戊酸甲酯
在0–5℃下向(4R,5R)-4-(3-氯苯基)-5-(5-氯吡啶-2-基)-5-羟基戊酸甲酯(432g,1.22mol,实施例121,步骤D)和三乙胺(340mL,2.4mol,2当量)在DCM(2.4L)中的溶液中逐滴加入甲烷磺酰氯(123.21mL,1.59mol,1.3当量)。将反应物在0–5℃下搅拌30min,然后缓慢地用冰水淬灭并用DCM(2X2L)萃取。用NaCl饱和水溶液洗涤合并的有机层,经MgSO4干燥,过滤,并在减压下浓缩滤液。
将如此获得的粗甲磺酸酯溶解在DMF(1.5L)中并向其中加入叠氮化钠(300g,4.6mol,3.8当量)。将反应混合物加热至90℃(内部温度)并保持2h。让它冷却至室温。用水(2L)稀释反应混合物并用乙酸乙酯(2X4L)萃取。用NaCl饱和溶液(2L)洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。将粗叠氮化物直接用于下一步骤而无需进一步纯化。
步骤F. (5R,6S)-5-(3-氯苯基)-6-(5-氯吡啶-2-基)哌啶-2-酮
将粗(4R,5S)-5-叠氮基-4-(3-氯苯基)-5-(5-氯吡啶-2-基)戊酸甲酯(463g,1.22mol,实施例121,步骤E)溶解在2.5L THF/水(4:1)中。在0–5℃下缓慢地加入三甲基膦(1M在THF中,1.46L,1.46mol,1.2当量)。将反应物搅拌30min,然后用2.0M LiOH水溶液碱化至pH为12。将反应混合物再搅拌30min,并将其萃取到乙酸乙酯(2X5L)中。用饱和NaCl溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。
通过硅胶快速色谱法(洗脱剂:20-90%的EtOAc/己烷,梯度洗脱)纯化残余物,接着从EtOAc/己烷中重结晶,得到反式5-(3-氯苯基)-6-(5-氯吡啶-2-基)哌啶-2-酮,为立体异构体的混合物。通过手性HPLC(流速:在 OD-H 10cm I.D.×50cm,20mic柱(Daicel Chemical Industries LTD)上100ml/min,使用25%异丙醇/己烷为洗脱剂)分离各个立体异构体。从而得到本标题化合物(tR=17-25min,较早洗脱的峰),为白色固体。
1H NMR(300MHz,CDCl3)δ8.49(d,J=2.34Hz,1H),7.52(dd,J=2.35和8.21Hz,1H),7.20-7.17(m,2H),7.07(s,1H),6.93-6.88(m,2H),6.11(s,1H),4.70(d,J=9.37Hz,1H),3.20-3.13(m,1H),2.61(q,J=5.27和8.2Hz,2H),2.26-2.04(m,2H)。质谱(ESI)m/z=321(M+1)。
步骤G. (S)-2-((2S,3R)-3-(3-氯苯基)-2-(5-氯吡啶-2-基)-6-氧代哌啶-1-基)丁酸乙酯
向9.93g(30.9mmol)(5R,6S)-5-(3-氯苯基)-6-(5-氯吡啶-2-基)哌啶-2-酮(实施例121,步骤F)在DMF(65mL)中的冰冷却的溶液中加入2.47g(在矿物油中的60wt.%,61.8mmol)氢化钠。将由此产生的黄色浆液在0℃下搅拌5min,然后升温至室温并再搅拌12min。将反应物再冷却至0℃,并经由注射器用超过10min的时间缓慢地加入11.4mL(77mmol)2-溴丁酸乙酯。将由此产生的橙色浆液升温至室温并搅拌4.75h,然后用饱和氯化铵水溶液淬灭。用乙酸乙酯(3X)萃取该混合物,并用水(2X)和NaCl溶饱和水液(1X)洗涤合并的有机层。经Na2SO4干燥有机层,过滤,并浓缩滤液。通过硅胶快速色谱法(38%至40%的EtOAc/己烷,梯度洗脱)纯化残余物,得到本标题化合物,为淡黄色固体。
步骤H. (5R,6S)-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-1-((S)-1-羟基丁烷-2-基)哌啶-2-酮
向3.95g(10.0mmol)(S)-2-((2S,3R)-3-(3-氯苯基)-2-(5-氯吡啶-2-基)-6-氧代哌啶-1-基)丁酸乙酯(实施例121,步骤G)在乙醚(100mL)中的冰冷却的溶液中加入486mg(90%,20.1mmol)硼氢化锂。将由此产生的淡黄色浆液在0℃下搅拌3h,然后升温至室温并再搅拌3h。将反应物再冷却至0℃,并通过小心地加入1N HCl直至停止冒气泡来淬灭。用EtOAc(3X)萃取该混合物,并用饱和氯化钠水溶液(1X)洗涤合并的有机层。经Na2SO4干燥有机层,过滤,并浓缩滤液。通过硅胶快速色谱法(1%至7%的MeOH/DCM,梯度洗脱)纯化残余物,得到本标题化合物,为白色固体。
步骤I. (5R,6S)-1-((S)-1-(叔丁基二苯基甲硅烷基氧基)丁烷-2-基)-5-(3-氯苯基)-6-(5-氯吡啶-2-基)哌啶-2-酮
向2.03g(5.2mmol)(5R,6S)-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-1-((S)-1-羟基丁烷-2-基)哌啶-2-酮(实施例121,步骤H)和877mg(12.9mmol)咪唑在DMF(32mL)中的溶液中加入1.9mL(7.3mmol)叔丁基二苯基氯甲硅烷。将由此产生的淡黄色溶液在室温下搅拌4.5h。将反应物分配在水与EtOAc(2X)之间,然后经Na2SO4干燥合并的有机层,过滤,并浓缩滤液。通过硅胶快速色谱法(0%至4%的MeOH/DCM,梯度洗脱)纯化残余物,得到本标题化合物,为白色固体。
步骤J. (5R,6S)-1-((S)-1-(叔丁基二苯基甲硅烷基氧基)丁烷-2-基)-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-3-甲基哌啶-2-酮
经由注射器用超过2min的时间向-78℃的3.19g(5.05mmol)(5R,6S)-1-((S)-1-(叔丁基二苯基甲硅烷基氧基)丁烷-2-基)-5-(3-氯苯基)-6-(5-氯吡啶-2-基)哌啶-2-酮(实施例121,步骤I)和347μL(5.55mmol)碘甲烷在脱气的干THF(40mL)中的溶液中缓慢地加入6.82mL(6.82mmol)双(三甲基甲硅烷基)氨基锂在THF中的1M溶液。将黄色溶液升温至0℃并搅拌1.5h,然后升温至室温并再搅拌15min。用饱和氯化铵水溶液淬灭反应物,并用EtOAc(3X)萃取。经Na2SO4干燥合并的有机层,过滤,并浓缩滤液。通过硅胶快速色谱法(0-15%MeOH/DCM,梯度洗脱)纯化残余物,得到本标题化合物(C-3差向异构体的混合物),为白色固体。
步骤K. (5R,6S)-3-烯丙基-1-((S)-1-((叔丁基二苯基甲硅烷基)氧基)丁烷-2-基)-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-3-甲基哌啶-2-酮
在室温下经由注射器用超过6min的时间向2.95g(4.57mmol)(5R,6S)-1-((S)-1-(叔丁基二苯基甲硅烷基氧基)丁烷-2-基)-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-3-甲基哌啶-2-酮(实施例121,步骤J)和7.91mL(91.0mmol)烯丙基溴在脱气的干THF(22mL)中的溶液中缓慢地加入68.6mL(68.6mmol)双(三甲基甲硅烷基)氨基锂在THF中的1M溶液。在10min后,将橙色溶液升温至50℃并搅拌24h。在此时,加入11.4mL(11.4mmol)双(三甲基甲硅烷基)氨基锂在THF中的1M溶液和790μL(0.79mmol)烯丙基溴。将反应物再在50℃下搅拌6.25h,然后将其冷却至室温并用饱和氯化铵水溶液淬灭。用EtOAc(3X)萃取该混合物,经Na2SO4干燥合并的有机层,过滤,并浓缩滤液。通过硅胶快速色谱法(2%至25%的EtOAc/己烷,梯度洗脱)纯化残余物,得到本标题化合物(C-3差向异构体的混合物),为淡黄色固体。
步骤L. (5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-1-((S)-1-羟基丁烷-2-基)-3-甲基哌啶-2-酮
向1.30g(1.90mmol)(5R,6S)-3-烯丙基-1-((S)-1-(叔丁基二苯基甲硅烷基氧基)丁烷-2-基)-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-3-甲基哌啶-2-酮(实施例121,步骤K)在THF(55mL)中的冰冷却的溶液中加入11.37mL(11.37mmol)TBAF在THF中的1M溶液。将橙色溶液升温至室温并搅拌3.75h。将反应物分配在1M HCl与EtOAc(2X)之间,然后用水(2X)洗涤合并的有机层。经Na2SO4干燥有机层,过滤,并浓缩滤液。通过硅胶快速色谱法(0%至10%的MeOH/DCM,梯度洗脱)纯化残余物,得到本标题化合物,为淡黄色固体。
步骤M. (S)-2-((5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-3-甲基-2-氧代哌啶-1-基)丁醛
向197mg(0.44mmol)(5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-1-((S)-1-羟基丁烷-2-基)-3-甲基哌啶-2-酮(实施例121,步骤L)在DCM(6mL)中的溶液中加入12μL(0.66mmol)水和280mg(0.66mmol)Dess-Martin过碘烷。将由此产生的淡黄色浆液升温至室温并搅拌50min。用饱和硫代硫酸钠水溶液淬灭反应物,用水稀释,并用DCM(2X)萃取。用饱和碳酸氢钠水溶液(1X)和饱和氯化钠水溶液(1X)洗涤合并的有机层,然后经Na2SO4干燥,过滤,并浓缩滤液。通过硅胶快速色谱法(0%至7%的MeOH/DCM,梯度洗脱)纯化残余物,得到本标题化合物,为淡黄色固体。
步骤N. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-3-甲基-1-((S)-1-吗啉代丁烷-2-基)哌啶-2-酮
如实施例91步骤A中所述,从(S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-3-甲基-2-氧代哌啶-1-基)丁醛(实施例121,步骤M)制备本标题化合物。通过硅胶快速色谱法(3%至10%的MeOH/DCM,梯度洗脱)纯化粗产物,得到本标题化合物,为白色固体。
步骤O. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-3-甲基-1-((S)-1-吗啉代丁烷-2-基)-2-氧代哌啶-3-基)乙醛
向42mg(0.08mmol)(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-3-甲基-1-((S)-1-吗啉代丁烷-2-基)哌啶-2-酮(实施例121,步骤N)在THF(6mL)和水(2mL)中的溶液中加入催化量的四氧化锇。在3min后,加入87mg(0.41mmol)高碘酸钠。将由此产生的白色浆液在室温下搅拌4.25h,然后通过烧结漏斗过滤。在减压下部分浓缩滤液,然后用水和饱和氯化钠水溶液的混合物稀释并用乙酸乙酯(2X)萃取。先后用饱和硫代硫酸钠水溶液和饱和氯化钠水溶液洗涤合并的有机层。经Na2SO4干燥有机层,过滤,并浓缩滤液。通过反相制备型HPLC(SunfireTMPrep C18OBD 10μm柱(Waters,Milford,MA),用35%的在水中的MeCN至75%的在水中的MeCN梯度洗脱超过35min,其中这两种溶剂都含有0.1%TFA纯化残余物,得到本标题化合物,为白色固体。
步骤P. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-3-甲基-1-((S)-1-吗啉代丁烷-2-基)-2-氧代哌啶-3-基)乙酸
向16mg(0.03mmol)2-((3R,5R,6S)-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-3-甲基-1-((S)-1-吗啉代丁烷-2-基)-2-氧代哌啶-3-基)乙醛(实施例121,步骤O)和1.0mL(9.4mmol)2-甲基-2-丁烯在t-BuOH(3mL)中的溶液中加入28mg(0.31mmol)亚氯酸钠和4.6mg(0.03mmol)磷酸二氢钠二水合物在水(1.6mL)中的溶液。将由此产生的混合物在室温下搅拌2h,然后用1M HCl淬灭并用EtOAc(3X)萃取。经Na2SO4干燥合并的有机层,过滤,并浓缩滤液。通过反相制备型HPLC(SunfireTMPrep C18OBD 10μm柱(Waters,Milford,MA),用35%的在水中的MeCN至60%的在水中的MeCN梯度洗脱超过35min,其中这两种溶剂都含有0.1%TFA纯化残余物,得到本标题化合物,为白色固体。
1H NMR(400MHz,CD3OD)δppm 8.69(1H,d,J=2.4Hz),7.65(1H,dd,J=8.3Hz,2.5Hz),7.14-7.22(2H,m),7.01-7.08(2H,m),6.88-6.95(1H,m),4.85-4.90(1H,埋藏的d),3.94-4.09(4H,m),3.42-3.53(1H,m),3.07-3.24(2H,m),2.88-3.01(2H,m),2.73(1H,d,J=13.7Hz),2.38(1H,t,J=13.9Hz),2.10(1H,dd,J=13.9Hz.3.5Hz),1.80-1.92(1H,m),1.41(3H,s),1.39-1.47(2H,m),1.13(3H,dd,J=6.5Hz,4.9Hz),0.93-1.05(3H,br s)。质谱(ESI)m/z=534(M+1)。
实施例122
2-((3R,5R,6S)-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)乙酸
步骤A. (5R,6S)-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-1-(戊烷-3-基)哌啶-2-酮
在0℃下向脱气的(5R,6S)-5-(3-氯苯基)-6-(5-氯吡啶-2-基)哌啶-2-酮(1.00g,3.11mmol,实施例121,步骤F)、3-溴戊烷(6.0ml,48.1mmol)和四丁基碘化铵(3.45g,9.34mmol)在干DMF(5.2ml)中的溶液中加入1.25g(31mmol)60%氢化钠在矿物油中的分散体。将反应物加热至90°并保持8h。加入NaHCO3饱和水溶液/NaCl溶液并用乙酸乙酯萃取该混合物。用水和NaCl饱和溶液洗涤有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过硅胶快速色谱法(洗脱剂:25%至50%的已通入NH3气体的EtOAc/己烷,梯度洗脱)纯化残余物,得到本标题化合物。
步骤B. (5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-3-甲基-1-(戊烷-3-基)哌啶-2-酮
按照与实施例121,步骤J和K中描述的程序类似的程序,从(5R,6S)-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-1-(戊烷-3-基)哌啶-2-酮(实施例122,步骤A)制备本标题化合物,所获得的本标题化合物为在C-3上的差向异构体的混合物。
步骤C. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)乙酸
按照与实施例71步骤F中描述的程序类似的程序,从(5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-3-甲基-1-(戊烷-3-基)哌啶-2-酮(149mg,0.335mmol,在C-3位置上的立体异构体的混合物,实施例122,步骤B)制备本标题化合物。通过反相制备型HPLC(洗脱剂:50%MeCN/水(0.1%TFA),等度洗脱)使用SunfireTMC18 OBD柱,10uM,(30x150mm),Waters Corp(Milford,MA)纯化,得到本标题化合物,为极性较大的主要异构体。
1H NMR(500MHz,氯仿-d)δppm 0.53(t,J=7.46Hz,3H),0.93(t,J=7.46Hz,3H),1.20-1.34(m,1H),1.34-1.46(m,1H),1.49(s,3H),1.62-1.78(m,1H),1.83(ddd,J=14.61,7.58,7.40Hz,1H),1.99(dd,J=13.69,3.18Hz,1H),2.22(t,J=13.57Hz,1H),2.72(d,J=15.89Hz,1H),2.88-2.99(m,1H),3.35(d,J=15.89Hz,1H),3.43(ddd,J=13.14,9.72,3.06Hz,1H),4.50(d,J=9.78Hz,1H),6.76(dt,J=7.58,1.22Hz,1H),6.84(d,J=8.07Hz,1H),6.98(t,J=1.83Hz,1H),7.14(t,J=7.70Hz,1H),7.53(dd,J=8.07,2.45Hz,1H),8.60(d,J=2.20Hz,1H)。质谱(ESI)m/z=463(M+1)。
实施例123
2-((3S,5R,6S)-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)乙酸.
本标题化合物为在实施例122步骤C中获得的极性较小的次要异构体。
1H NMR(500MHz,氯仿-d)δppm 0.51(t,J=7.46Hz,3H),0.94(t,J=7.46Hz,3H),1.33-1.55(m,3H),1.73(s,3H),1.73-1.82(m,3H),2.24(t,J=13.69Hz,1H),2.49(d,J=15.16Hz,1H),2.88(d,J=14.92Hz,1H),3.62(ddd,J=13.88,10.21,3.55Hz,1H),4.42(d,J=10.03Hz,1H),6.70-6.82(m,2H),6.96(t,J=1.83Hz,1H),7.09-7.24(m,2H),7.52(dd,J=8.07,2.45Hz,1H),8.62(d,J=2.45Hz,1H)。质谱(ESI)m/z=463(M+1)。
实施例124
2-((3R,5R,6S)-1-((S)-1-叔丁氧基-1-氧代丁烷-2-基)-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. (5R,6S)-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-1-(2,4-二甲氧基苄基)哌啶-2-酮
向在0℃下的6.72g(20.92mmol)(5R,6S)-5-(3-氯苯基)-6-(5-氯吡啶-2-基)哌啶-2-酮(实施例121,步骤F)在DMF(~0.5M)中的溶液中缓慢地加入60%氢化钠在矿物油中的分散体(2.51g,62.8mmol)。将反应物在0℃下搅拌30min,接着加入1-(氯甲基)-2,4-二甲氧基苯(7.81g,41.8mmol)。在完成后,在0℃下用稍过量的乙酸(4.79mL,84mmol)淬灭反应物。用NaHCO3饱和水溶液中和反应物并用乙酸乙酯萃取。经Na2SO4干燥有机层,过滤,并在减压下浓缩滤液从而得到微红色油状物。通过硅胶快速色谱法(洗脱剂:0%至30%的乙酸乙酯/DCM,梯度洗脱)纯化,得到本标题化合物,为浅黄色油状物。
1H NMR(500MHz,氯仿-d)δppm 1.81-1.93(m,1H),2.00-2.11(m,1H),2.38-2.50(m,1H),2.50-2.61(m,1H),3.30(dt,J=6.60,4.16Hz,1H),3.63(s,3H),3.74(d,J=14.43Hz,1H),3.80(s,3H),4.86(d,J=4.40Hz,1H),5.23(d,J=14.43Hz,1H),6.37(d,J=2.20Hz,1H),6.44(dd,J=8.31,2.45Hz,1H),6.84(d,J=7.58Hz,1H),6.90-7.00(m,2H),7.08(t,J=7.83Hz,1H),7.11-7.16(m,1H),7.18(d,J=8.31Hz,1H),7.61(dd,J=8.31,2.45Hz,1H),8.56(d,J=2.45Hz,1H)。质谱(ESI)m/z=471(M+1)。
步骤B. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-1-(2,4-二甲氧基苄基)-3-甲基哌啶-2-酮和(3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-1-(2,4-二甲氧基苄基)-3-甲基哌啶-2-酮
按照与实施例121,步骤J和K中描述的程序类似的程序,从(5R,6S)-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-1-(2,4-二甲氧基苄基)哌啶-2-酮(实施例124,步骤A)制备本标题化合物,所获得的本标题化合物为在C-3上的差向异构体的混合物。
步骤C. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-3-甲基哌啶-2-酮
将(5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-1-(2,4-二甲氧基苄基)-3-甲基哌啶-2-酮(3.6g,6.85mmol,C-3差向异构体的混合物,实施例124,步骤B)溶解在TFA(26.4mL,343mmol)中,并将反应物加热至70°并保持1.5h。然后将反应物冷却至室温,并通过在减压下浓缩除去TFA。将产物用庚烷共沸,将其溶解在DCM中并用NaHCO3饱和水溶液和NaCl饱和溶液洗涤有机层。通过硅胶快速色谱法(洗脱剂:35%至45%的已通入NH3的EtOAc/己烷,梯度洗脱)纯化,得到本标题化合物,其为极性较大的异构体,为白色固体:(在75%EtOAc/己烷中的Rf=0.44)。
1H NMR(500MHz,氯仿-d)δppm 0.67-0.84(m,1H),1.10-1.25(m,3H),1.60(br.s.,1H),1.85-2.04(m,2H),2.32-2.50(m,1H),2.56(d,J=8.31Hz,1H),3.19-3.33(m,1H),4.56-4.66(m,1H),4.99-5.14(m,2H),5.68-5.84(m,1H),5.89(br.s.,1H),6.72-6.84(m,2H),6.92-7.01(m,1H),7.01-7.12(m,2H),7.12-7.23(m,1H),7.35-7.48(m,1H),8.31-8.48(m,1H)。质谱(ESI)m/z=375(M+1)。
步骤D. (S)2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-3-甲基-2-氧代哌啶-1-基)丁酸叔丁酯
向(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-3-甲基哌啶-2-酮(77mg,0.205mmol,实施例124,步骤C)在DMF(0.3mL)中的溶液中缓慢地加入9.5mg(0.24mmol)60%氢化钠在矿物油中的分散体,接着加入2-溴丁酸叔丁酯(92mg,0.410mmol)。将反应物在室温下搅拌过夜,用MeOH/HOAc猝灭,用EtOAc和水稀释并萃取到EtOAc中。经Na2SO4干燥有机物,过滤,并浓缩滤液。通过反相制备型HPLC(SunfireTMPrepC18 OBD 10μm柱(Waters,Milford,MA)(洗脱剂:70%乙腈、水、0.1%TFA)纯化,得到本标题化合物,以及其立体异构体,(R)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-3-甲基-2-氧代哌啶-1-基)丁酸叔丁酯。
步骤E. (S)-2-((3R,5R,6S)-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-3-甲基-2-氧代-3-(2-氧代乙基)哌啶-1-基)丁酸叔丁酯
如实施例121步骤O中所述,从(S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-3-甲基-2-氧代哌啶-1-基)丁酸叔丁酯(实施例124,步骤D)制备本实施例。通过反相制备型HPLC(SunfireTMPrep C18 OBD 10μm柱(Waters,Milford,MA)(洗脱剂:55%至75%的乙腈、水、0.1%TFA,梯度洗脱)纯化残余物,得到本标题化合物,其在冻干后为白色固体。
步骤F. 2-((3R,5R,6S)-1-((S)-1-叔丁氧基-1-氧代丁烷-2-基)-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
如实施例121步骤P中所述,从(S)-2-((3R,5R,6S)-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-3-甲基-2-氧代-3-(2-氧代乙基)哌啶-1-基)丁酸叔丁酯(实施例124,步骤E)制备本标题化合物。
1H NMR(500MHz,氯仿-d)δppm 0.46(t,J=7.46Hz,2H),1.09-1.28(m,2H),1.28-1.42(m,2H),1.42-1.46(m,2H),1.49(s,7H),1.71-1.90(m,3H),1.93-2.04(m,1H),2.12-2.29(m,2H),2.89-2.97(m,1H),2.99(dd,J=7.70,4.28Hz,1H),3.01-3.09(m,1H),3.61(ddd,J=13.02,9.84,3.55Hz,1H),4.73(d,J=10.27Hz,1H),6.83(d,J=7.58Hz,1H),6.94(d,J=8.31Hz,1H),7.03(s,1H),7.11(t,J=7.70Hz,1H),7.14-7.18(m,1H),7.56(dd,J=8.31,2.45Hz,1H),8.61(d,J=2.45Hz,1H)。质谱(ESI)m/z=535(M+1)。
实施例125
2-((3R,5S,6S)-1-((S)-1-叔丁氧基-1-氧代丁烷-2-基)-6-(4-氯苯基)-5-(4-氯吡啶-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. 1-(4-氯苯基)-2-(4-氯吡啶-2-基)乙酮
在0℃下经由滴液漏斗向4-氯代-2-甲基吡啶(23.07g,181mmol)和4-氯苯甲酸甲酯(30.8g,181mmol)在干THF(500mL)中的溶液中缓慢地加入在THF中的1M LiHMDS(63.5g,380mmol)。当完成时,用NaHCO3溶液淬灭反应物,在减压下浓缩并用乙酸乙酯萃取。经Na2SO4干燥合并的有机层,过滤,并在减压下浓缩滤液从而得到本标题化合物。
步骤B. (4R,5R)-5-(4-氯苯基)-4-(4-氯吡啶-2-基)-5-羟基戊酸甲酯和(4S,5S)-5-(4-氯苯基)-4-(4-氯吡啶-2-基)-5-羟基戊酸甲酯
向在80℃下的1-(4-氯苯基)-2-(4-氯吡啶-2-基)乙酮(42.0g,158mmol)和DBU(28.5mL,189mmol,实施例125,步骤A)在二噁烷(316mL)中的溶液中逐滴加入丙烯酸甲酯(15.73mL,174mmol)。将反应物在80℃下搅拌30min,在此时再加入丙烯酸甲酯(2.86mL,31mmol)。当反应完成时,将它冷却至0℃。缓慢地加入甲醇(500mL),将反应物冷却至0℃并缓慢地加入NaBH4(5.97g,158mmol)。在减压下浓缩该溶液,并将其分配在乙酸乙酯和1NNaOH之间。在减压下浓缩有机层。通过硅胶快速色谱法(洗脱剂:已通入NH3的EtOAc/己烷,梯度洗脱)纯化,得到本标题化合物。
步骤C. (4S,5S)-5-叠氮基-5-(4-氯苯基)-4-(4-氯吡啶-2-基)戊酸甲酯和(4R,5R)-5-叠氮基-5-(4-氯苯基)-4-(4-氯吡啶-2-基)
在100℃下使用2.0当量NaN3,如实施例121步骤E中所述从5-(4-氯苯基)-4-(4-氯吡啶-2-基)-5-羟基戊酸甲酯(实施例125,步骤B)制备本标题化合物。通过硅胶快速色谱法(洗脱剂:15%至45%的乙酸乙酯/己烷,梯度洗脱)纯化残余物。
步骤D. (5S,6S)-6-(4-氯苯基)-5-(4-氯吡啶-2-基)哌啶-2-酮
如实施例121步骤F中所述,从(4S,5S)-5-叠氮基-5-(4-氯苯基)-4-(4-氯吡啶-2-基)戊酸甲酯(外消旋化合物混合物)(实施例125,步骤C)制备本标题化合物。首先通过硅胶快速色谱法(洗脱剂:5%至40%的乙酸乙酯/DCM,梯度洗脱)纯化该粗产物,然后通过手性HPLC(250x30mmAS-H柱,用50g/min IPA(0.2%DEA)+50g/min CO2在Thar 350SFC(TharTechnologies,Pittsburg,PA)上)分离各个立体异构体,从而得到本标题化合物,为较快地洗脱的立体异构体。
1H NMR(500MHz,氯仿-d)δppm 1.60(br.s.,3H),2.07(dddd,J=13.60,5.84,2.93,2.81Hz,2H),2.30-2.46(m,2H),2.54-2.72(m,4H),2.96(ddd,J=12.10,9.54,2.81Hz,2H),3.50(s,1H),4.98(d,J=10.03Hz,2H),5.78(br.s.,2H),6.81(d,J=1.71Hz,2H),7.03(d,J=8.31Hz,4H),7.09-7.17(m,2H),7.21(d,J=8.07Hz,4H),8.46(d,J=5.38Hz,2H),质谱(ESI)m/z=321(M+1),(tR=7.1min在40%iPrOH/己烷上在Chiracel OD分析柱上)
步骤E. (5S,6S)-6-(4-氯苯基)-5-(4-氯吡啶-2-基)-1-(2,4-二甲氧基苄基)哌啶-2-酮或(5R,6R)-6-(4-氯苯基)-5-(4-氯吡啶-2-基)-1-(2,4-二甲氧基苄基)哌啶-2-酮
使用与实施例124步骤A中描述的程序类似的程序,从(5S,6S)-6-(4-氯苯基)-5-(4-氯吡啶-2-基)哌啶-2-酮或(5R,6R)-6-(4-氯苯基)-5-(4-氯吡啶-2-基)哌啶-2-酮(实施例125,步骤D)和1-(氯甲基)-2,4-二甲氧基苯制备本标题化合物。
步骤F. (3S,5S,6S)-3-烯丙基-6-(4-氯苯基)-5-(4-氯吡啶-2-基)-1-(2,4-二甲氧基苄基)-3-甲基哌啶-2-酮和(3R,5S,6S)-3-烯丙基-6-(4-氯苯基)-5-(4-氯吡啶-2-基)-1-(2,4-二甲氧基苄基)-3-甲基哌啶-2-酮
使用与实施例121步骤J和K中描述的程序类似的程序,从(5S,6S)-6-(4-氯苯基)-5-(4-氯吡啶-2-基)-1-(2,4-二甲氧基苄基)-3-甲基哌啶-2-酮(实施例125,步骤E)制备本标题化合物,为立体异构体的混合物。
步骤G. (5R,6S)-5-(3-氯苯基)-6-(5-氯吡啶-2-基)哌啶-2-酮
采用与实施例124步骤C中描述的程序类似的程序以及随后通过在硅胶上纯化来从(5S,6S)-6-(4-氯苯基)-5-(4-氯吡啶-2-基)-1-(2,4-二甲氧基苄基)-3-甲基哌啶-2-酮(实施例125,步骤F)制备本标题化合物(其为在C3位置上的立体异构体的混合物),但是将反应物加热至室温而不是70°并且洗脱剂为0%至3%的MeOH/DCM。
步骤H. 2-((3S,5S,6S)-3-烯丙基-6-(4-氯苯基)-5-(4-氯吡啶-2-基)-3-甲基-2-氧代哌啶-1-基)丁酸叔丁酯和2-((3R,5S,6S)-3-烯丙基-6-(4-氯苯基)-5-(4-氯吡啶-2-基)-3-甲基-2-氧代哌啶-1-基)丁酸叔丁酯
在室温下向100mg,(0.266mmol)(5S,6S)-3-烯丙基-6-(4-氯苯基)-5-(4-氯吡啶-2-基)-3-甲基哌啶-2-酮(实施例125,步骤G;立体异构体混合物)在干DMF(533μL)中的溶液中加入60%氢化钠在矿物油中的分散体(15.99mg,0.400mmol)。将该混合物在40℃下超声处理10min,接着加入2-溴丁酸叔丁酯(119mg,0.533mmol)。在室温下搅拌24h,然后再加入2当量NaH,并搅拌过夜。用少量10%的在MeOH中的HOAc淬灭反应物,用EtOAc和水稀释,并将其萃取到EtOAc x3中。经Na2SO4干燥合并的有机层,过滤,并在减压下浓缩滤液。通过制备型RP-HPLC(SunfireTMPrep C18 OBD 10μm柱(Waters,Milford,MA,用55%的在水中的MeCN至75%的在水中的MeCN梯度洗脱超过35min,其中这两种溶剂都含有0.1%TFA)纯化残余物,得到包括本标题化合物和其他3个差向异构体在内的4个差向异构体的混合物。在HPLC之后,在减压下浓缩含有产物的级分,并将其萃取到乙酸乙酯中。经Na2SO4干燥合并的有机物,过滤,并浓缩滤液。
步骤I. 2-((3R,5S,6S)-1-((S)-1-叔丁氧基-1-氧代丁烷-2-基)-6-(4-氯苯基)-5-(4-氯吡啶-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
如实施例121步骤O和P中所述,从(5R,6S)-5-(3-氯苯基)-6-(5-氯吡啶-2-基)哌啶-2-酮(实施例125,步骤H)制备本标题化合物。通过反相HPLC(SunfireTMPrep C18 OBD 10μm柱(Waters,Milford,MA)(洗脱剂:55%MeCN/水(0.1%TFA)纯化残余物,得到本标题化合物,为白色固体。
1H NMR(500MHz,氯仿-d)δppm 0.56(t,J=7.46Hz,3H),1.43(s,3H),1.45-1.57(m,11H),2.17-2.35(m,3H),2.78-2.92(m,2H),3.09(dd,J=7.70,3.79Hz,1H),3.57-3.66(m,1H),5.00(d,J=10.51Hz,1H),7.02(d,J=1.71Hz,1H),7.11(d,J=7.34Hz,2H),7.20(dd,J=5.50,1.83Hz,1H),7.24(d,J=8.56Hz,2H),8.41(d,J=5.38Hz,1H)。质谱(ESI)m/z=535(M+1)。
实施例126
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
步骤A. (S)-2-((3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-1-基)丁酸甲酯
在0℃下向1.3g(3.61mmol)(3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)哌啶-2-酮(实施例42,步骤A)在DMF(14.43mL)中的溶液中加入60%氢化钠在矿物油中的分散体(0.361g,9.02mmol)。将灰色浆液在0℃下搅拌30分钟。然后加入2-溴丁酸甲酯(1.246mL,10.83mmol)。将该混合物升温至室温并在室温下搅拌1h。用饱和NH4Cl淬灭该混合物。用乙酸乙酯萃取该混合物。用水、1MLiCl(2x),和NaCl饱和水溶液洗涤有机层。经Na2SO4干燥有机层,过滤,并在减压下浓缩滤液。通过硅胶快速色谱法(80g柱;洗脱剂:10%至35%的在己烷中的EtOAc)纯化残余物,从而得到本标题化合物,为极性较小的主要非对映异构体。
步骤B. (3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)哌啶-2-酮
在0℃下向710mg(1.542mmol)(S)-2-((3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-1-基)丁酸甲酯(实施例126,步骤A)在Et2O(15mL)中的溶液中加入硼氢化锂(67.2mg,3.08mmol)。观察到气体逸出。将由此产生的白色浆液在0℃下搅拌60min。用冰冷的1M HCl淬灭该混合物。观察到气体逸出。将该混合物升温至室温并用EtOAc萃取。用NaCl饱和水溶液洗涤有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过硅胶快速色谱法(24g柱;洗脱剂:20%至40%的在己烷中的EtOAc)纯化残余物,从而得到本标题化合物。
步骤C. (S)-2-((3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-1-基)丁醛
在室温下向2.00g(4.63mmol)(3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)哌啶-2-酮(实施例126,步骤B)在水(0.125g,6.94mmol)和DCM(50mL)中的混合物中加入Dess-Martin过碘烷(2.94g,6.94mmol)。在搅拌1h(TLC未检测到SM)后,通过加入10mL 0.5M Na2S2O3淬灭反应物,用DCM萃取反应物,并用NaHCO3饱和水溶液和NaCl饱和水溶液洗涤。经Na2SO4干燥合并的有机层,过滤,并在减压下浓缩滤液。通过硅胶色谱法(80g SiO2,5%至20%的EtOAc/己烷)纯化残余物,得到本标题化合物,为白色泡沫状物。
步骤D. (3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(甲基氨基)丁烷-2-基)哌啶-2-酮
在室温下向1.67g(3.88mmol)(S)-2-((3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-1-基)丁醛(实施例126,步骤C)和乙酸(6.60mL,116mmol)在DCE(40mL)中的溶液中加入2M在THF中的甲胺(19.40mL,38.8mmol)和三乙酰氧基硼氢化钠(3.29g,15.52mmol)。将反应物搅拌2天。用NaHCO3饱和水溶液淬灭反应物,用EtOAc萃取,并用1N NaOH和NaCl饱和水溶液洗涤合并的有机层,经Na2SO4干燥并在减压下浓缩从而得到本标题化合物,为浅黄色油状物,其不加进一步纯化而用于下一步骤。
步骤E. N-(2-((3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-1-基)丁基)-N-甲基环丙烷磺酰胺
在40℃下向实施例126步骤D中制得的游离胺(1.67g,3.75mmol)在DCE(15mL)中的溶液中依次加入吡啶(6.06mL,75.0mmol)和环丙烷磺酰氯(3.85mL,37.5mmol)。将反应物在40℃下搅拌14h。此后,再加入10当量吡啶和10当量环丙烷磺酰氯。将反应物在40℃下搅拌14h。用10%柠檬酸酸化反应物并用EtOAc萃取。用NaHCO3饱和水溶液和NaCl饱和水溶液洗涤合并的有机层,经Na2SO4干燥,并在减压下浓缩。通过硅胶色谱法(SiO2,25g;洗脱剂:20%至40%的EtOAc/己烷)纯化,得到本标题化合物,为白色泡沫状物。
步骤F. 2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
按照与实施例1步骤H中描述的程序类似的程序,将N-(2-((3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-1-基)丁基)-N-甲基环丙烷磺酰胺(实施例126,步骤D)转化成酸,从而得到粗的本标题化合物。使该粗材料吸附到硅胶塞上,并通过色谱法用60%至80%的在己烷中的EtOAc洗脱来进行纯化,从而得到无色油状物。通过反相制备型HPLC(洗脱剂:10%至90%的乙腈、水、0.1%TFA,梯度洗脱)纯化该油状物从而得到本标题化合物,其为反相HPLC的第二洗脱峰,其在冻干后为白色固体。
1H NMR(400MHz,氯仿-d)δppm 0.51(t,J=7.53Hz,3H),0.96-1.11(m,2H),1.17-1.32(m,2H),1.61(ddd,J=14.28,7.83,3.91Hz,1H),1.88-2.02(m,2H),2.31-2.47(m,3H),2.68-2.77(m,1H),2.81(br.s.,1H),2.86-3.10(m,2H),2.92(s,3H),3.23(dd,J=15.45,10.17Hz,1H),4.67(d,J=10.56Hz,1H),6.86(m,1H),6.94(m,3H),7.11-7.20(m,2H),7.23-7.32(m,2H);质谱(ESI)m/z=567.2(M+1)。
实施例127
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)丙酸
*立体化学未知
步骤A. (3R,5R,6S)-3-烯丙基-1-((S)-1-((叔丁基二苯基甲硅烷基)氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)哌啶-2-酮
在0℃下向615mg(1.422mmol)(3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)哌啶-2-酮(实施例126,步骤B)在DMF(4741μL)中的溶液中加入1H-咪唑(97mg,1.422mmol),接着加入叔丁基氯二苯基甲硅烷(473μL,1.849mmol)。将该混合物在0℃下搅拌15min,然后升温至室温。将该混合物在室温下搅拌30min,然后用饱和NH4Cl淬灭。用EtOAc萃取该混合物,并用水、1MLiCl和NaCl饱和水溶液洗涤有机层。经Na2SO4干燥该混合物并在减压下浓缩。通过硅胶快速色谱法(24g柱;洗脱剂:0%至30%的在己烷中的EtOAc)纯化残余物,从而得到本标题化合物。
步骤B. 2-((3S,5R,6S)-1-((S)-1-((叔丁基二苯基甲硅烷基)氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-3-基)乙酸
在室温下向(3R,5R,6S)-3-烯丙基-1-((S)-1-(叔丁基二苯基甲硅烷基氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)哌啶-2-酮(816mg,1.216mmol;实施例127,步骤A)在水/乙腈/CCl4(7mL/5mL/5mL)中的溶液中加入高碘酸钠(1041mg,4.87mmol)和氯化钌水合物(27.4mg,0.122mmol)。将该混合物在室温下剧烈搅拌3h。用EtOAc稀释该混合物并用1MHCl酸化。加入NaCl饱和水溶液并过滤该混合物以除去乳液。分离滤液层。经Na2SO4干燥有机层,并在减压下浓缩。通过硅胶快速色谱法(24g柱;洗脱剂:0%至50%的在己烷中的EtOAc)纯化残余物从而得到本标题化合物。
步骤C. 2-((3S,5R,6S)-1-((S)-1-((叔丁基二苯基甲硅烷基)氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-3-基)乙酸甲酯
在室温下向2-((3S,5R,6S)-1-((S)-1-(叔丁基二苯基甲硅烷基氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-3-基)乙酸(741mg,1.076mmol;实施例127,步骤B)在10mL 10%MeOH的DCM溶液中的溶液中加入TMS-重氮甲烷(2.0M在乙醚中)(807μL,1.614mmol)。观察到气体逸出,并将黄色混合物在室温下搅拌45min。再加入TMS-重氮甲烷(2.0M在乙醚中)(807μL,1.614mmol),并将反应物在室温下搅拌45min。在减压下浓缩该混合物。通过硅胶快速色谱法(24g柱;洗脱剂:0%至30%的在己烷中的EtOAc)纯化残余物,从而得到本标题化合物。
步骤D. 2-((3S,5R,6S)-1-((S)-1-((叔丁基二苯基甲硅烷基)氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-3-基)丙酸甲酯
*立体化学未知
将2-((3S,5R,6S)-1-((S)-1-((叔丁基二苯基甲硅烷基)氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-3-基)乙酸甲酯(实施例127,步骤C)用甲苯3x共沸,然后将其在Ar下溶解于THF(14mL)中,并将该混合物冷却至-78℃。于-78℃在Ar下加入HMPA(236μL,1.356mmol)和LHMDS(1.0M在THF中)(1356μL,1.356mmol)。将该混合物在-78℃下搅拌30min。该混合物颜色变成淡黄色。然后加入碘甲烷(110μL,1.763mmol),并让反应混合物温度缓慢地升至室温。用饱和NH4Cl淬灭该混合物并分离各层。经Na2SO4干燥合并的有机层并在减压下浓缩。通过硅胶快速色谱法(2x50g堆叠的VersaPak I-style,Spherical,Supelco,Bellenfonte,PA;洗脱剂:20%至30%的在己烷中的MtBE)纯化残余物,从而得到本标题化合物,为极性较小的主要非对映异构体。该极性较小的非对映异构体的保留时间为0.871min(80-100%MeCN+0.1%TFA于水+0.1%TFA中,超过1分钟)。极性较大的非对映异构体的保留时间为0.841min(80%至100%MeCN+0.1%TFA于水+0.1%TFA中,超过1分钟)。
步骤E. 2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)-2-氧代哌啶-3-基)丙酸甲酯
*立体化学未知
向2-((3S,5R,6S)-1-((S)-1-((叔丁基二苯基甲硅烷基)氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-3-基)丙酸甲酯(285mg,0.398mmol)(步骤D中的极性较小的异构体)在THF(1988μL)中的溶液中加入TBAF(1.0M在THF中)(1590μL,1.590mmol)。将该混合物在室温下搅拌16h。用1M HCl淬灭该混合物并用EtOAc稀释。用NaCl饱和水溶液洗涤有机层,经Na2SO4干燥并在减压下浓缩。通过硅胶快速色谱法(11g VersaPak I-style,Spherical,Supelco,Bellenfonte,PA;洗脱剂:50%至75%的在己烷中的MtBE)纯化残余物从而得到本标题化合物。
步骤F. 2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)丙酸甲酯
*立体化学未知
将含有2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)-2-氧代哌啶-3-基)丙酸甲酯(195mg,0.408mmol;实施例127,步骤E)和N-甲基环丙烷磺酰胺(165mg,1.223mmol)在甲苯(2038μL)中的溶液的烧瓶抽成真空并回填Ar(5x)。然后加入氰基亚甲基三丁基正膦(321μL,1.223mmol)。将淡棕橙色混合物加热至70℃并保持2h。再加入N-甲基环丙烷磺酰胺(134mg,0.991mmol),并将该混合物加热至70℃并保持2h。将该混合物加热至回流过夜并然后冷却至室温。用EtOAc和NaCl饱和水溶液稀释该混合物。分离各层。经Na2SO4干燥有机层并在减压下浓缩。通过硅胶快速色谱法(4g柱,洗脱剂:0%至100%的在己烷中的EtOAc)纯化残余物从而得到本标题化合物。
步骤G. 2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)丙酸
在室温下向2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)丙酸甲酯(56mg,0.094mmol;实施例127,步骤F)在MeOH/THF/H2O(1mL/1mL/2mL)中的溶液中加入LiOH(3M在水中)(157μL,0.470mmol)。将浆液加热至~100℃并保持3h。将该混合物冷却至室温,用1M HCl酸化并用EtOAc(2x)萃取。合并有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过反相制备型HPLC(柱:Gemini-NX C185um柱;Phenomonex,Torrance,CA;洗脱剂:0%至100%MeCN+0.1%TFA于水+0.1%TFA中,超过20分钟)纯化无色膜状物从而得到本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 0.50(t,J=6.65Hz,3H),0.95-1.07(m,2H),1.20-1.26(m,5H),1.40(dd,J=10.96,7.24Hz,1H),1.52-1.66(m,1H),1.85-1.93(m,1H),1.96-2.00(m,1H),2.22-2.36(m,2H),2.70-2.79(m,1H),2.88-3.07(m,6H),3.13(quin,J=7.19Hz,1H),4.67(d,J=10.56Hz,1H),6.89-6.92(m,1H),6.94-7.01(m,3H),7.14-7.18(m,2H),7.25(d,J=8.41Hz,2H);质谱(ESI)m/z=603(M+23),581(M+1)。
实施例128
(S)-2-((3R,5R,6S)-3-((1H-四唑-5-基)甲基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁酸叔丁酯
步骤A. (S)-2-((3R,5R,6S)-3-(2-氨基-2-氧代乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁酸叔丁酯
依次用N-(3-二甲基氨基丙基)-N’-乙基碳二亚胺盐酸盐(165mg,0.86mmol)、1-羟基-7-氮杂苯并三唑(117mg,0.86mmol)和NaHCO3(72.3mg,0.861mmol)处理2-((3R,5R,6S)-1-((S)-1-叔丁氧基-1-氧代丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸(230mg,0.430mmol;实施例67)在DMF(4.3mL)中的溶液。在室温下搅拌0.5h后,逐滴加入7M在甲醇中的氨(6.2mL,4.30mmol),并将反应物搅拌过夜。然后,稀释(水)反应物,萃取(2×EtOAc),并洗涤(1×饱和NaHCO3,和2×NaCl饱和水溶液)。干燥(Na2SO4)合并的有机层并在减压下浓缩。通过RP-HPLC(45%至70%的MeCN/H2O(0.1%TFA),梯度洗脱)纯化,得到本标题化合物,为白色固体。
步骤B. (S)-2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-(氰基甲基)-3-甲基-2-氧代哌啶-1-基)丁酸叔丁酯
在0℃下用2,2,2-三氟乙酸酐(69.8μL,0.492mmol)处理(S)-2-((3R,5R,6S)-3-(2-氨基-2-氧代乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁酸叔丁酯(105mg,0.197mmol;实施例128,步骤A)和三乙胺(137μL,0.984mmol)在THF(3.3mL)中的溶液。在0℃下搅拌3h后,淬灭(10%柠檬酸)反应物、萃取(2×EtOAc)并洗涤(溶液NaCl饱和水溶液)。干燥(Na2SO4)合并的有机层并在减压下浓缩。通过硅胶色谱法(12g SiO2,20%至50%的EtOAc/Hex,梯度洗脱)纯化残余物,得到本标题化合物,为无色泡沫状物。
步骤C. (S)-2-((3R,5R,6S)-3-((1H-四唑-5-基)甲基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁酸叔丁酯
向(S)-2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-(氰基甲基)-3-甲基-2-氧代哌啶-1-基)丁酸叔丁酯(101mg,0.196mmol;实施例128,步骤B)在DMF(0.50mL)中的溶液中加入叠氮化钠(127mg,1.96mmol)和NH4Cl(105mg,1.96mmol)。将由此产生的混合物在90℃下搅拌5天。然后,淬灭(10%柠檬酸水溶液)反应物,萃取(2×EtOAc),并洗涤(3×NaCl饱和水溶液)。干燥(Na2SO4)合并的有机层并在减压下浓缩。通过RP-HPLC(60%至85%的AcCN/H2O,梯度洗脱)纯化,得到本标题化合物,为白色固体。
1H NMR(400MHz,氯仿-d)δppm 7.23-7.26(2H,m),7.09-7.19(2H,m),7.01(1H,t,J=1.9Hz),6.92(2H,d,J=8.6Hz),6.75-6.80(1H,m),4.60(1H,d,J=10.8Hz),3.44-3.63(2H,m),3.27(1H,br.s.),3.15(1H,dd,J=8.3,3.4Hz),2.29-2.42(2H,m),2.24(1H,d,J=3.3Hz),1.49-1.52(8H,m),1.34-1.40(1H,m),1.32(3H,s),0.55(3H,t,J=7.4Hz);MS(ESI)558.1[M+H]+,556.2[M-H]-。
实施例129
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(甲基磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
步骤A. (3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-((4-甲氧基苄基)氨基)丁烷-2-基)-3-甲基哌啶-2-酮
在0℃下将三乙酰氧基硼氢化钠(429mg,2.03mmol)分成几个部分加入到(S)-2-((3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁醛(300mg,0.675mmol;实施例91,步骤C)和(4-甲氧基苯基)甲胺(131μL,1.01mmol)在DCE(4.5mL)中的溶液中。在25℃下搅拌18h后,通过加入冰冷的饱和NaHCO3水溶液淬灭反应物并对其进行萃取(2×DCM)。洗涤(1×NaCl饱和水溶液)合并的有机层,并在减压下浓缩从而得到本标题化合物,为黄色膜状物。将该产物用于下一步骤而无需进一步纯化。
步骤B. (S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁烷-1-铵2,2,2-三氟乙酸盐
在25℃下向(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(4-甲氧基苄基氨基)丁烷-2-基)-3-甲基哌啶-2-酮(370mg,0.654mmol;实施例129,步骤A)在乙腈(8.0mL)和水(1.6mL)中的溶液中加入硝酸高铈铵(2.87g,5.23mmol)。在室温下搅拌2天后,淬灭(NaCl饱和水溶液)反应物,萃取(3×EtOAc),并洗涤(1×NaCl饱和水溶液)。干燥(Na2SO4)合并的有机层并在减压下浓缩。通过RP-HPLC(35%至70%MeCN/H2O(0.1%TFA),梯度洗脱)纯化,得到本标题化合物,为浅黄色粉末。
步骤C. N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁基)甲烷磺酰胺
在0℃下将(S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁烷-1-铵2,2,2-三氟乙酸盐(74mg,0.14mmol;实施例129,步骤B)溶解在DCM中,并加入2N氢氧化锂(0.34mL,0.68mmol),并将由此产生的溶液在0℃下搅拌5min。萃取(2×DCM)该溶液,洗涤(NaCl饱和水溶液),干燥(Na2SO4),并在减压下浓缩从而得到游离胺。在0℃下向上述的游离胺在DMF(0.34mL)中的溶液中依次加入甲烷磺酰氯(53μL,0.68mmol)和吡啶(66μL,0.820mmol)。在25℃下搅拌过夜后,酸化(10%柠檬酸)反应物,萃取(2×EtOAc)并洗涤(NaCl饱和水溶液)。干燥(Na2SO4)合并的有机层,并在减压下浓缩。通过RP-HPLC(45%至80%的MeCN/H2O(0.1%TFA),梯度洗脱)纯化,得到本标题化合物,为白色粉末。
步骤D. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(甲基磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
向快速搅拌着的N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁基)甲烷磺酰胺(34mg,0.064mmol;实施例91,步骤C)在水(0.55mL)、乙腈(0.37mL)和CCl4(0.37mL)的混合物中的溶液中加入高碘酸钠(55mg,0.26mmol)和氯化钌(III)水合物(1.5mg,6.5μmol)。在剧烈搅拌20h后,酸化(10%柠檬酸)反应物并用EtOAc稀释。通过经由(J.T.Baker,Phillipsberg,NJ,硅藻土)垫过滤除去不溶性材料。萃取(2×EtOAc)滤液并洗涤(NaCl饱和水溶液)。干燥(Na2SO4)合并的有机层并在减压下浓缩。通过RP-HPLC(40%至70%的MeCN/H2O(0.1%TFA),梯度洗脱)纯化,得到本标题化合物,为白色泡沫状物。
1H NMR(400MHz,氯仿-d)δppm 7.25(2H,d,J=8.2Hz),7.10-7.18(2H,m),7.00-7.10(2H,m),6.97(1H,s),6.83(1H,d,J=7.2Hz),4.99-5.20(1H,m),4.87-4.97(1H,m),4.74(1H,d,J=10.4Hz),3.44-3.65(1H,m),3.10-3.33(2H,m),3.02-3.09(1H,m),2.99(3H,s),2.96(1H,s),2.77(1H,s),2.36(1H,s),1.94-2.05(1H,m),1.77-1.92(1H,m),1.52-1.59(1H,m),1.50(3H,s),0.58(3H,t,J=7.3Hz);MS(ESI)541.0[M+H]+,539.0[M-H]-。
实施例130
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-5-氧代己烷-3-基)哌啶-3-基)乙酸
步骤A. (S)-3-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)戊醛
将(甲氧基甲基)三苯基氯化鏻于80℃在真空下干燥3h。在-78℃下向干燥的(甲氧基甲基)三苯基氯化鏻(1.96g,5.71mmol)在THF(10mL)中的溶液中加入0.5M在甲苯中的KHMDS(10.2mL,5.08mmol)。溶液颜色变成血红色。在0℃下搅拌30min.后,在0℃下逐滴加入(S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁醛(实施例91,步骤C;564mg,1.27mmol)在THF(10.1mL)中的溶液。在室温下搅拌过夜后,淬灭(NH4Cl饱和溶液)反应物,萃取(2×EtOAc),并洗涤(NaCl饱和水溶液)。干燥(Na2SO4)合并的有机层并在减压下浓缩。通过硅胶色谱法(SiO2,40g,15%和20%的EtOAc/己烷)纯化,得到乙烯基醚(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S,E)-1-甲氧基戊-1-烯-3-基)-3-甲基哌啶-2-酮。向上面制备的(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S,E)-1-甲氧基戊-1-烯-3-基)-3-甲基哌啶-2-酮在乙腈(7.8mL)中的溶液中加入3N盐酸(4.4mL,13mmol),并将由此产生的溶液在室温下搅拌1.5h。然后,萃取(2×EtOAc)反应物,并洗涤(NaCl饱和水溶液)。干燥(Na2SO4)合并的有机层并在减压下浓缩从而得到本标题化合物,为浅黄色膜状物。
步骤B. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S)-5-羟基己烷-3-基)-3-甲基哌啶-2-酮
在0℃下向(S)-3-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)戊醛(540mg,1.18mmol;实施例130,步骤A)在THF(12mL)中的溶液中加入1.4M在甲苯和THF(75:25)中的溴化甲基镁(2.52mL,3.53mmol)。然后让反应物升温至室温并搅拌3h。淬灭(NH4Cl饱和溶液)反应物,萃取(2×EtOAc),并洗涤(NaCl饱和水溶液)。干燥(Na2SO4)合并的有机层并在减压下浓缩从而得到粗的本标题化合物,为非对映异构体的混合物。
步骤C. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-5-氧代己烷-3-基)哌啶-3-基)乙酸
如实施例71步骤F中所述,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-5-羟基己烷-3-基)-3-甲基哌啶-2-酮(90mg,0.19mmol;实施例130步骤B)制备本标题化合物,为白色泡沫状物。
1H NMR(400MHz,氯仿-d)δppm 7.23-7.27(2H,m),7.06-7.17(4H,m),7.00(1H,t,J=1.8Hz),6.81(1H,s),4.92(1H,d,J=10.8Hz),3.54-3.63(1H,m),3.07(3H,d,J=15.7Hz),2.67(1H,d,J=15.8Hz),2.50-2.60(1H,m),2.19(3H,s),2.12(1H,s),1.97-2.07(1H,m),1.88-1.96(1H,m),1.39(3H,s),1.21-1.32(1H,m),0.37(3H,t,J=7.5Hz);MS(ESI)490.0[M+H]+,488.0[M-H]-。
实施例131
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-5-羟基-5-甲基己烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-5-氧代己烷-3-基)哌啶-2-酮
按照与实施例129步骤C中描述的程序类似的程序,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-5-羟基己烷-3-基)-3-甲基哌啶-2-酮(100mg,0.21mmol;实施例130,步骤B)制备本标题化合物。
步骤B. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-5-羟基-5-甲基己烷-3-基)-3-甲基哌啶-2-酮
在0℃下向(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-5-氧代己烷-3-基)哌啶-2-酮(90mg,0.19mmol;实施例131,步骤A)在THF(1.9mL)中的溶液中加入1.4M在甲苯和THF(75:25)中的溴化甲基镁(408μL,0.571mmol)。然后让反应物升温至室温并搅拌4h。淬灭(NH4Cl饱和溶液)反应物,萃取(2×EtOAc),并洗涤(NaCl饱和水溶液)。干燥(Na2SO4)合并的有机层并在减压下浓缩,并通过硅胶色谱法(12g SiO2,30%和35%EtOAc/Hex)纯化残余物,得到本标题化合物,为无色泡沫状物。
步骤C. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-5-羟基-5-甲基己烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸
按照与实施例71步骤F中描述的程序类似的程序,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-5-羟基-5-甲基己烷-3-基)-3-甲基哌啶-2-酮(73mg,0.15mmol;实施例131,步骤B)获得本标题化合物,为白色泡沫状物。
1H NMR(400MHz,氯仿-d)δppm 7.25(2H,d,J=7.8Hz),6.98-7.18(4H,m),6.95(1H,t,J=1.8Hz),6.70(1H,d,J=7.6Hz),4.90-5.38(2H,m),4.67-4.81(1H,m),3.51(1H,s),2.98-3.13(2H,m),2.70(1H,d,J=15.1Hz),2.19(1H,t,J=13.8Hz),1.93(2H,d,J=13.3Hz),1.48(4H,s),1.16-1.28(7H,m),0.53(3H,br.s.);MS(ESI)506.0[M+H]+,504.0[M-H]-。
实施例132
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((3S)-6,6,6-三氟代-5-羟基-5-甲基己烷-3-基)哌啶-3-基)乙酸(异构体1)
*立体化学未知
步骤A. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((3S,5S)-6,6,6-三氟代-5-羟基-5-甲基己烷-3-基)哌啶-2-酮和(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((3S,5R)-6,6,6-三氟代-5-羟基-5-甲基己烷-3-基)哌啶-2-酮
在0℃下向(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-5-氧代己烷-3-基)哌啶-2-酮(120mg,0.254mmol;实施例131,步骤A)在THF(2.5mL)中的溶液中加入三甲基(三氟甲基)甲硅烷(113μL,0.762mmol),并将反应物搅拌5min。然后在0℃下缓慢地加入1M在THF中的TBAF(381μL,0.381mmol)。在0℃下搅拌20min后,让反应物升温至室温。在室温下搅拌40min后,淬灭(NH4Cl饱和水溶液)反应物,萃取(2×DCM),并洗涤(2×饱和NaHCO3和1×NaCl饱和水溶液)。干燥(Na2SO4)合并的有机层并在减压下浓缩。通过硅胶色谱法(12g SiO2,13%和24%EtOAc/Hex)纯化残余物,得到极性较小的异构体和极性较大的异构体。
(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((3S)-6,6,6-三氟代-5-羟基-5-甲基己烷-3-基)哌啶-2-酮(极性较小的异构体).
1H NMR(400MHz,氯仿-d)δppm 7.24(2H,d,J=8.2Hz),7.15-7.20(1H,m),7.07-7.14(1H,m),6.88-7.06(3H,m),6.69(1H,d,J=7.4Hz),5.77-5.92(1H,m),5.09-5.23(2H,m),4.44-4.59(1H,m),3.13(1H,br.s.),2.62(2H,d,J=7.4Hz),1.84-2.05(3H,m),1.64-1.82(2H,m),1.33(3H,s),1.25-1.31(5H,m),0.72-0.94(3H,m);MS(ESI)542.0[M+H]+。
(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((3S)-6,6,6-三氟代-5-羟基-5-甲基己烷-3-基)哌啶-2-酮(极性较大的异构体).
1H NMR(400MHz,氯仿-d)δppm 7.22-7.27(2H,m),7.14-7.20(1H,m),7.09-7.14(1H,m),6.90-7.08(3H,m),6.70(1H,d,J=7.4Hz),5.86(1H,dd,J=17.4,9.6Hz),5.12-5.22(2H,m),4.44-4.56(1H,m),3.06-3.21(1H,m),1.83-2.03(2H,m),1.53-1.82(3H,m),1.37-1.49(1H,m),1.29(3H,s),1.23(3H,d,J=14.5Hz),0.62-0.94(3H,m);MS(ESI)542.0[M+H]+。
步骤B. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((3S)-6,6,6-三氟代-5-羟基-5-甲基己烷-3-基)哌啶-3-基)乙酸(异构体1)
按照与实施例71步骤F中描述的程序类似的程序,从步骤A中制备的(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((3S)-6,6,6-三氟代-5-羟基-5-甲基己烷-3-基)哌啶-2-酮的极性较小的异构体获得本标题化合物,为白色泡沫状物。
1H NMR(400MHz,氯仿-d)δppm 7.24-7.27(2H,m),7.14-7.19(1H,m),6.96-7.12(3H,m),6.93(1H,t,J=1.7Hz),6.68(1H,d,J=7.6Hz),4.58-4.67(1H,m),2.98-3.14(2H,m),2.71-2.81(1H,m),2.17(1H,s),2.02(2H,s),1.52-1.70(1H,m),1.48(3H,s),1.34(5H,s),0.19-0.93(3H,m);MS(ESI)558.0[M+H]+,560.0[M-H]-。
实施例133
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((3S)-6,6,6-三氟代-5-羟基-5-甲基己烷-3-基)哌啶-3-基)乙酸(异构体2)
*立体化学未知
按照与实施例71步骤F中描述的程序类似的程序,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((3S)-6,6,6-三氟代-5-羟基-5-甲基己烷-3-基)哌啶-2-酮的极性较大的异构体(48mg,0.088mmol;实施例132,步骤A)获得本标题化合物,为白色泡沫状物。
1H NMR(400MHz,氯仿-d)δppm 7.25(2H,br.s.),6.96-7.19(4H,m),6.93(1H,t,J=1.8Hz),6.69(1H,d,J=7.6Hz),4.60-4.70(1H,m),3.01(2H,s),2.75(1H,d,J=15.1Hz),2.11-2.21(1H,m),2.02(2H,s),1.77-1.93(1H,m),1.48(6H,s),1.35(3H,br.s.),0.39-0.71(3H,m);MS(ESI)560.0[M+H]+,558.0[M-H]-。
实施例134
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基甲基磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
步骤A. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(甲基氨基)丁烷-2-基)哌啶-2-酮
在室温下向(S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁醛(70mg,0.16mmol;实施例91,步骤C)和乙酸(271μL,4.73mmol)在ClCH2CH2Cl(2.6mL)中的溶液中加入2M在THF中的甲胺(788μL,1.58mmol)和三乙酰氧基硼氢化钠(100mg,0.47mmol)。在室温下搅拌3h后,淬灭(NaHCO3饱和水溶液)反应物,萃取(2×EtOAc),并洗涤(NaCl饱和水溶液)。干燥(Na2SO4)合并的有机层并在减压下浓缩从而得到粗的本标题化合物,为浅黄色膜状物。将该产物用于下一步骤而无需进一步纯化。
步骤B. N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁基)-N-甲基甲烷磺酰胺
在0℃下向(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(甲基氨基)丁烷-2-基)哌啶-2-酮(72mg,0.16mmol;实施例134步骤A)在DMF(0.40mL)中的溶液中依次加入甲烷磺酰氯(61μL,0.79mmol)和吡啶(76μL,0.95mmol)。在25℃下搅拌过夜后,酸化(10%柠檬酸)反应物并对其进行萃取(2×EtOAc)。洗涤(NaCl饱和水溶液)合并的有机层,干燥(Na2SO4),并在减压下浓缩。通过RP-HPLC(50%至85%MeCN/H2O(0.1%TFA),梯度洗脱)分离,得到本标题化合物,为浅黄色膜状物。
步骤C. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基甲基磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
从实施例AB步骤G中描述的N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁基)-N-甲基甲烷磺酰胺(实施例134,步骤B)制备本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 7.21-7.27(2H,m),7.10-7.17(2H,m),6.92-7.07(3H,m),6.87(1H,dd,J=6.5,1.8Hz),4.78(1H,d,J=10.6Hz),4.12-4.27(1H,m),2.97-3.15(2H,m),2.84-2.90(1H,m),2.85(3H,s),2.84(3H,s),2.63-2.77(2H,m),2.43(1H,t,J=13.9Hz),1.88-1.97(2H,m),1.55-1.68(1H,m),1.51(3H,s),0.50(3H,t,J=7.5Hz);MS(ESI)555.1[M+H]+,553.0[M-H]-。
实施例135
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S)-5-环丙基-6,6,6-三氟代-5-羟基己烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸
*立体化学未知
步骤A. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S)-1-环丙基-1-羟基戊烷-3-基)-3-甲基哌啶-2-酮
在0℃下向(S)-3-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)戊醛(160mg,0.349mmol;实施例130,步骤A)在THF(3.5mL)中的溶液中加入0.5M在THF中的环丙基溴化镁(2.09mL,1.05mmol)。然后让反应物升温至室温并搅拌3.5h。淬灭(NH4Cl饱和溶液)反应物,萃取(2×EtOAc),并洗涤(NaCl饱和水溶液)。干燥(Na2SO4)合并的有机层并在减压下浓缩从而得到本标题化合物,为两个非对映异构体的混合物。将该粗产物用于下一步骤而无需进一步纯化。
步骤B. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-1-氧代戊烷-3-基)-3-甲基哌啶-2-酮
在室温下向上面步骤A中制备的(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-1-羟基戊烷-3-基)-3-甲基哌啶-2-酮(175mg,0.350mmol)和水(9.5μL,0.52mmol)在DCM(3.9mL)中的溶液中加入Dess-Martin过碘烷(222mg,0.524mmol)。在室温下搅拌40min后,淬灭(1M Na2S2O3水溶液)反应物,萃取(2×DCM),并洗涤(2×NaHCO3饱和溶液和1×NaCl饱和水溶液)。干燥(Na2SO4)合并的有机层并在减压下浓缩。通过硅胶色谱法(12g SiO2,15%和25%EtOAc/Hex)纯化残余物,得到本标题化合物,为无色膜状物。
步骤C. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S,5S)-5-环丙基-6,6,6-三氟代-5-羟基己烷-3-基)-3-甲基哌啶-2-酮和(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S,5R)-5-环丙基-6,6,6-三氟代-5-羟基己烷-3-基)-3-甲基哌啶-2-酮
在0℃下向上述步骤B中制备的(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-1-氧代戊烷-3-基)-3-甲基哌啶-2-酮(132mg,0.265mmol)在THF(2.6mL)中的溶液中加入三甲基(三氟甲基)甲硅烷(117μL,0.794mmol),并将反应物搅拌5min。然后在0℃下缓慢地加入1M在THF中的四丁基氟化铵(397μL,0.397mmol)。然后让反应物升温至室温。在搅拌3h后,在0℃下再加入三甲基(三氟甲基)甲硅烷(234μL,1.59mmol)和1M在THF中的四丁基氟化铵(794μL,0.794mmol),并让反应物升温至室温。在室温下搅拌15h后,淬灭(NaCl饱和水溶液)反应物,萃取(2×EtOAc),并洗涤(NaCl饱和水溶液)。干燥(Na2SO4)合并的有机层并在减压下浓缩。通过硅胶色谱法(12g SiO2,6%和13%EtOAc/Hex)纯化残余物,相继得到本标题化合物中的一种(为极性较小的异构体)和本标题化合物中的另一种(为极性较大的异构体)。
(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S)-5-环丙基-6,6,6-三氟代-5-羟基己烷-3-基)-3-甲基哌啶-2-酮(极性较小的异构体)
1H NMR(400MHz,氯仿-d)δppm 7.24(2H,d,J=8.2Hz),7.15-7.20(1H,m),7.07-7.14(1H,m),6.88-7.06(3H,m),6.69(1H,d,J=7.4Hz),5.77-5.92(1H,m),5.09-5.23(2H,m),4.44-4.59(1H,m),3.13(1H,br.s.),2.62(2H,d,J=7.4Hz),1.84-2.05(3H,m),1.64-1.82(2H,m),1.33(3H,s),1.25-1.31(5H,m),0.72-0.94(3H,m);MS(ESI)568.2[M+H]+。
(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S)-5-环丙基-6,6,6-三氟代-5-羟基己烷-3-基)-3-甲基哌啶-2-酮(极性较大的异构体)
1H NMR(400MHz,氯仿-d)δppm 7.22-7.27(2H,m),7.14-7.20(1H,m),7.09-7.14(1H,m),6.90-7.08(3H,m),6.70(1H,d,J=7.4Hz),5.86(1H,dd,J=17.4,9.6Hz),5.12-5.22(2H,m),4.44-4.56(1H,m),3.06-3.21(1H,m),1.83-2.03(2H,m),1.53-1.82(3H,m),1.37-1.49(1H,m),1.29(3H,s),1.23(3H,d,J=14.5Hz),0.62-0.94(3H,m);MS(ESI)568.2[M+H]+。
步骤D. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S)-5-环丙基-6,6,6-三氟代-5-羟基己烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸
按照与实施例71步骤F中描述的程序类似的程序,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S)-5-环丙基-6,6,6-三氟代-5-羟基己烷-3-基)-3-甲基哌啶-2-酮(实施例135,步骤C,极性较大的产物)制备本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 7.00-7.04(2H,m),6.91-6.96(1H,m),6.84-6.90(1H,m),6.67-6.84(3H,m),6.46(1H,d,J=7.6Hz),4.29-4.45(1H,m),2.76-2.91(2H,m),2.51(1H,d,J=15.1Hz),1.84-1.96(1H,m),1.69-1.79(1H,m),1.48-1.67(1H,m),1.12-1.35(6H,m),0.62-0.81(1H,m),0.01-0.51(8H,m);MS(ESI)586.2[M+H]+,584.0[M-H]-。
实施例136
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-6-羟基-6-甲基庚烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. (S)-4-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)己醛
按照与实施例130步骤A中描述的程序类似的程序,从(S)-3-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)戊醛(106mg,0.231mmol;实施例130,步骤A)制备本标题化合物。
步骤B. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S)-6-羟基庚烷-3-基)-3-甲基哌啶-2-酮
按照与实施例130步骤B中描述的程序类似的程序,从(S)-4-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)己醛(84mg,0.18mmol;实施例136,步骤A)制备本标题化合物,为无色膜状物。将该粗产物用于下一步骤而无需进一步纯化。
步骤C. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-6-氧代庚烷-3-基)哌啶-2-酮
按照与实施例129步骤C中描述的程序类似的程序,从上面步骤B中制得的(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-6-羟基庚烷-3-基)-3-甲基哌啶-2-酮的混合物制备本标题化合物。
步骤D. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-6-羟基-6-甲基庚烷-3-基)-3-甲基哌啶-2-酮
在0℃下向上面步骤C中制备的(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-6-氧代庚烷-3-基)哌啶-2-酮(78mg,0.16mmol)在THF(1.6mL)中的溶液中加入1.4M在甲苯和THF(75:25)中的溴化甲基镁(344μL,0.481mmol)。然后让反应物升温至室温并搅拌2h。淬灭(NH4Cl饱和溶液)反应物,萃取(2×EtOAc),并洗涤(NaCl饱和水溶液)。干燥(Na2SO4)合并的有机层并在减压下浓缩。通过硅胶色谱法(12g SiO2,33%和43%EtOAc/Hex)纯化残余物,得到本标题化合物,为无色泡沫状物。
步骤E. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-6-羟基-6-甲基庚烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸
按照与实施例71步骤F中描述的程序类似的程序,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-6-羟基-6-甲基庚烷-3-基)-3-甲基哌啶-2-酮(实施例136,步骤D)制备本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 7.25(2H,d,J=8.4Hz),7.16(1H,dd,J=1.9,1.1Hz),7.11(1H,d,J=7.6Hz),6.94(3H,t,J=1.8Hz),6.70(1H,d,J=7.6Hz),5.01-5.25(2H,m),4.37(1H,d,J=10.4Hz),3.06(2H,d,J=15.3Hz),2.93-3.03(1H,m),2.71(1H,d,J=15.3Hz),2.20(1H,s),2.02(1H,s),1.78-1.97(2H,m),1.37-1.56(7H,m),1.22(6H,d,J=5.5Hz),0.55(3H,t,J=7.5Hz);MS(ESI)520.2[M+H]+,518.0[M-H]-。
实施例137
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-6,6,6-三氟代-5,5-二羟基己烷-3-基)哌啶-3-基)乙酸
步骤A. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((3S)-6,6,6-三氟代-5-羟基己烷-3-基)哌啶-2-酮
在0℃下向(S)-3-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)戊醛(100mg,0.218mmol;实施例130,步骤A)在THF(2.2mL)中的溶液中加入三甲基(三氟甲基)甲硅烷(97μL,0.66mmol),并将反应物搅拌5min。然后在0℃下缓慢地加入1M在THF中的TBAF(327μL,0.327mmol)。在0℃下搅拌40min后,淬灭(NaCl饱和水溶液)反应物,萃取(2×EtOAc),并洗涤(NaCl饱和水溶液)。干燥(Na2SO4)合并的有机层并在减压下浓缩。通过硅胶色谱法(12g SiO2,13%和23%EtOAc/Hex)纯化残余物,得到本标题化合物,为两个非对映异构体的混合物。
步骤B. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-6,6,6-三氟代-5,5-二羟基己烷-3-基)哌啶-2-酮
在室温下向上面步骤A中制备的(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-6,6,6-三氟代-5-羟基己烷-3-基)哌啶-2-酮(100mg,0.189mmol)在DCM(2.1mL)中的溶液中加入水(17μL,0.95mmol)和Dess-Martin过碘烷(161mg,0.378mmol),并将由此产生的溶液搅拌过夜。淬灭(1MNa2S2O3水溶液)反应物,萃取(2×DCM),并洗涤(2×饱和NaHCO3和1×NaCl饱和水溶液)。干燥(Na2SO4)合并的有机层并在减压下浓缩从而得到本标题化合物,为无色膜状物。将该产物用于下一步骤而无需进一步纯化。
步骤C. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-6,6,6-三氟代-5,5-二羟基己烷-3-基)哌啶-3-基)乙酸
按照与实施例71步骤F中描述的程序类似的程序,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-6,6,6-三氟代-5,5-二羟基己烷-3-基)哌啶-2-酮(实施例137,步骤B)制备本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 7.29(2H,br.s.),7.06-7.20(4H,m),6.97(1H,s),6.76-6.82(1H,m),4.74(1H,d,J=10.6Hz),3.88-3.98(1H,m),3.09-3.19(2H,m),2.96(1H,s),2.78(2H,s),2.08(3H,s),1.38(4H,s),0.42(3H,t,J=7.5Hz);MS(ESI)562.1[M+H]+,560.0[M-H]-。
实施例138
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((3S)-7,7,7-三氟代-6-羟基-6-甲基庚烷-3-基)哌啶-3-基)乙酸(异构体1)
*立体化学未知
步骤A. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((3S,6R)-7,7,7-三氟代-6-羟基-6-甲基庚烷-3-基)哌啶-2-酮和(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((3S,6S)-7,7,7-三氟代-6-羟基-6-甲基庚烷-3-基)哌啶-2-酮
在0℃下向(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-6-氧代庚烷-3-基)哌啶-2-酮(169mg,0.347mmol;实施例136,步骤C)在THF(3.5mL)中的溶液中加入三甲基(三氟甲基)甲硅烷(154μL,1.04mmol),并将反应物搅拌5min。然后在0℃下缓慢地加入1M在THF中的TBAF(521μL,0.521mmol)。然后让反应物升温至室温。在室温下搅拌1.5h后,淬灭(水)反应物,萃取(2×EtOAc),并洗涤(水和NaCl饱和水溶液)。干燥(Na2SO4)合并的有机层并在减压下浓缩。通过硅胶色谱法(40g SiO2,13%,23%和33%EtOAc/Hex)纯化残余物,相继得到本标题化合物中的一种(为极性较小的异构体)和本标题化合物中的另一种(为极性较大的异构体)。
(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((3S)-7,7,7-三氟代-6-羟基-6-甲基庚烷-3-基)哌啶-2-酮(极性较小的异构体)
1H NMR(400MHz,氯仿-d)δppm 7.22(2H,d,J=8.2Hz),7.07-7.20(2H,m),6.91(3H,t,J=1.8Hz),6.65-6.74(1H,m),5.82-5.97(1H,m),5.13-5.24(2H,m),4.33(1H,d,J=10.6Hz),3.78-3.99(1H,m),3.10-3.26(1H,m),2.64(2H,dd,J=7.4,4.5Hz),1.91-2.04(2H,m),1.68-1.78(1H,m),1.62(3H,t,J=7.3Hz),1.33-1.46(1H,m),1.29(4H,s),1.25(3H,s),0.94-1.13(1H,m),0.84(3H,t,J=7.3Hz);MS(ESI)556.2[M+H]+。
(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((3S)-7,7,7-三氟代-6-羟基-6-甲基庚烷-3-基)哌啶-2-酮(极性较大的异构体)
1H NMR(400MHz,氯仿-d)δppm 7.23(2H,d,J=8.4Hz),7.08-7.20(2H,m),6.89-7.01(3H,m),6.68-6.75(1H,m),5.84(1H,s),5.13-5.23(2H,m),4.28(1H,d,J=10.4Hz),3.09-3.22(2H,m),2.62(2H,d,J=7.2Hz),1.90-2.05(2H,m),1.73-1.84(2H,m),1.53-1.66(3H,m),1.35-1.48(1H,m),1.31(3H,s),1.24-1.29(4H,m),0.66(3H,t,J=7.4Hz);MS(ESI)556.2[M+H]+。
步骤B. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((3S)-7,7,7-三氟代-6-羟基-6-甲基庚烷-3-基)哌啶-3-基)乙酸(异构体1)
按照与实施例71步骤F中描述的程序类似的程序,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((3S)-7,7,7-三氟代-6-羟基-6-甲基庚烷-3-基)哌啶-2-酮(实施例138,步骤A,极性较小的产物)制备本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 7.23(2H,d,J=8.0Hz),7.14-7.19(1H,m),7.07-7.13(1H,m),7.01(2H,br.s.),6.92(1H,t,J=1.7Hz),6.69(1H,d,J=7.6Hz),5.57-5.68(1H,m),4.38(1H,d,J=10.4Hz),3.52(1H,s),3.17(1H,br.s.),2.77-3.02(2H,m),2.05-2.24(2H,m),1.75(2H,dd,J=11.8,6.6Hz),1.53-1.65(1H,m),1.48(3H,s),1.34-1.45(3H,m),1.29(3H,s),0.71(3H,t,J=7.3Hz);MS(ESI)574.2[M+H]+,572.0[M-H]-。
实施例139
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((3S)-7,7,7-三氟代-6-羟基-6-甲基庚烷-3-基)哌啶-3-基)乙酸(异构体2)
*立体化学未知
按照与实施例71步骤F中描述的程序类似的程序,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((3S)-7,7,7-三氟代-6-羟基-6-甲基庚烷-3-基)哌啶-2-酮(实施例138,步骤A,极性较大的产物)制备本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 7.25(2H,s),7.16-7.21(1H,m),7.09-7.15(1H,m),7.01(2H,d,J=4.1Hz),6.93(1H,t,J=1.7Hz),6.72(1H,d,J=7.6Hz),5.66-5.74(1H,m),4.34(1H,d,J=10.2Hz),3.09-3.27(2H,m),2.98(1H,d,J=14.5Hz),2.74(1H,d,J=14.5Hz),2.14-2.24(1H,m),2.02-2.08(1H,m),1.81(2H,dd,J=14.3,7.2Hz),1.52-1.70(3H,m),1.50(3H,s),1.29-1.38(1H,m),1.27(3H,s),0.64(3H,t,J=7.3Hz);MS(ESI)574.2[M+H]+,572.0[M-H]-。
实施例140
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-7-羟基-7-甲基辛烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. (S)-5-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)庚醛
按照与实施例130步骤A中描述的程序类似的程序,从(S)-4-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)己醛(147mg,0.311mmol;实施例136,步骤A)制备本标题化合物。
步骤B. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S)-7-羟基辛烷-3-基)-3-甲基哌啶-2-酮
在0℃下向上面步骤A中制备的(S)-5-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)庚醛(138mg,0.284mmol)在THF(2.8mL)中的溶液中加入1.4M在甲苯和THF(75:25)中的溴化甲基镁(608μL,0.851mmol)。然后让反应物升温至室温并搅拌2h。淬灭(NH4Cl饱和溶液)反应物,萃取(2×EtOAc),并洗涤(NaCl饱和水溶液)。干燥(Na2SO4)合并的有机层,并在减压下浓缩从而得到本标题化合物,为无色膜状物。
步骤C. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-7-氧代辛烷-3-基)哌啶-2-酮
按照与实施例131步骤A中描述的程序类似的程序,从上面步骤B中制备的(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-7-羟基辛烷-3-基)-3-甲基哌啶-2-酮(143mg,0.285mmol)制备本标题化合物,为白色固体。
步骤D. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-7-羟基-7-甲基辛烷-3-基)-3-甲基哌啶-2-酮
在0℃下向上面步骤C中制备的(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-7-氧代辛烷-3-基)哌啶-2-酮(122mg,0.244mmol)在THF(2.4mL)中的溶液中加入1.4M在甲苯和THF(75:25)中的溴化甲基镁(522μL,0.731mmol)。然后让反应物升温至室温并搅拌2h。淬灭(NH4Cl饱和溶液)反应物,萃取(2×EtOAc),并洗涤(NaCl饱和水溶液)。干燥(Na2SO4)合并的有机层并在减压下浓缩,并通过硅胶色谱法(12g SiO2,30%和40%EtOAc/Hex)纯化残余物,得到本标题化合物,为无色泡沫状物。
步骤E. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-7-羟基-7-甲基辛烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸
按照与实施例71步骤F中描述的程序类似的程序,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-7-羟基-7-甲基辛烷-3-基)-3-甲基哌啶-2-酮(实施例140,步骤D)制备本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 7.23(2H,d,J=8.0Hz),7.05-7.18(2H,m),6.92-7.05(3H,m),6.70(1H,d,J=7.6Hz),4.42(1H,d,J=10.4Hz),3.05-3.18(2H,m),3.00(1H,d,J=15.1Hz),2.72(1H,d,J=15.1Hz),2.11-2.26(1H,m),1.97-2.08(1H,m),1.79-1.92(1H,m),1.64-1.79(1H,m),1.50-1.59(2H,m),1.48(3H,s),1.34-1.45(3H,m),1.28-1.33(1H,m),1.27(3H,s),1.25(3H,s),0.56(3H,t,J=7.4Hz);MS(ESI)534.1[M+H]+,532.2[M-H]-。
实施例141
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
按照与实施例134步骤B和C中描述的程序类似的程序,用适量的环丙基磺酰氯替代步骤B中的甲烷磺酰氯,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(甲基氨基)丁烷-2-基)哌啶-2-酮(实施例134,步骤A)制备本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 7.24(2H,br.s.),7.10-7.17(2H,m),6.80-7.09(4H,m),4.79(1H,d,J=10.8Hz),4.13-4.30(1H,m),2.99-3.12(2H,m),2.89(4H,s),2.64-2.81(2H,m),2.45(1H,t,J=13.8Hz),2.33(1H,s),1.88(2H,dd,J=13.9,2.7Hz),1.54-1.66(1H,m),1.50-1.54(3H,m),1.22(2H,d,J=4.5Hz),1.02(2H,dd,J=8.0,3.9Hz),0.51(3H,t,J=7.4Hz);MS(ESI)581.0[M+H]+,579.0[M-H]-。
实施例142
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N-环丙基甲基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
按照与实施例134步骤A–C中描述的程序类似的程序,用适量的环丙胺替代步骤A中的甲胺,从(S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁醛(实施例91,步骤C)制备本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 7.22-7.27(2H,m),7.11-7.18(2H,m),6.81-7.06(4H,m),4.81(1H,d,J=10.6Hz),4.25-4.41(1H,m),3.08(2H,d,J=15.5Hz),2.95(3H,s),2.81-2.90(1H,m),2.73-2.80(1H,m),2.67(1H,d,J=15.5Hz),2.52(2H,s),1.95-2.14(1H,m),1.77-1.88(1H,m),1.53(4H,s),0.70-0.92(3H,m),0.59-0.69(1H,m),0.50(3H,t,J=7.5Hz);MS(ESI)581.0[M+H]+,579.0[M-H]-。
实施例143
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((3S)-6,6,6-三氟代-5-羟基己烷-3-基)哌啶-3-基)乙酸(异构体1)
*立体化学未知
步骤A. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((3S,5S)-6,6,6-三氟代-5-羟基己烷-3-基)哌啶-2-酮和(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((3S,5R)-6,6,6-三氟代-5-羟基己烷-3-基)哌啶-2-酮
在0℃下向(S)-3-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)戊醛(139mg,0.303mmol;实施例130,步骤A)在THF(3.0mL)中的溶液中加入三甲基(三氟甲基)甲硅烷(134μL,0.910mmol),并将反应物搅拌5min。然后在0℃下缓慢地加入1M在THF中的TBAF(455μL,0.455mmol)。然后,让反应物升温至室温。在室温下搅拌1.5h后,淬灭(NaCl饱和水溶液)反应物,萃取(2×EtOAc),并洗涤(NaCl饱和水溶液)。干燥(Na2SO4)合并的有机层并在减压下浓缩。通过硅胶色谱法(24g SiO2,6%和16%EtOAc/Hex)纯化残余物,相继得到本标题化合物中的一种(为极性较小的异构体)和本标题化合物中的另一种(为极性较大的异构体)。
(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((3S)-6,6,6-三氟代-5-羟基己烷-3-基)哌啶-2-酮(极性较小的异构体)
1H NMR(400MHz,氯仿-d)δppm 7.15-7.26(3H,m),7.11(1H,t,J=7.7Hz),6.93(3H,t,J=1.9Hz),6.68(1H,dt,J=7.6,1.5Hz),5.83-5.95(1H,m),5.17-5.26(2H,m),4.38(1H,d,J=10.4Hz),3.69-3.81(1H,m),3.11-3.22(1H,m),2.66(2H,d,J=7.6Hz),1.92-2.12(3H,m),1.72-1.89(1H,m),1.49-1.60(1H,m),1.25-1.37(5H,m),1.00(1H,无),0.92-1.07(3H,m);MS(ESI)528.1[M+H]+。
(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((3S)-6,6,6-三氟代-5-羟基己烷-3-基)哌啶-2-酮(极性较大的异构体)
1H NMR(400MHz,氯仿-d)δppm 7.24(2H,dd,J=7.4,1.4Hz),7.15-7.20(1H,m),7.11(1H,t,J=7.8Hz),6.90-7.05(3H,m),6.70(1H,dt,J=7.5,1.5Hz),5.79-5.92(1H,m),5.13-5.22(2H,m),4.43(1H,d,J=10.4Hz),3.90(1H,ddd,J=11.1,6.6,2.2Hz),3.09-3.22(1H,m),2.53-2.71(2H,m),1.90-2.05(2H,m),1.56-1.86(4H,m),1.22-1.32(4H,m),0.79(3H,t,J=7.4Hz);MS(ESI)528.1[M+H]+。
步骤B. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((3S,5S)-6,6,6-三氟代-5-羟基己烷-3-基)哌啶-3-基)乙酸(异构体1)
按照与实施例71步骤F中描述的程序类似的程序,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((3S)-6,6,6-三氟代-5-羟基己烷-3-基)哌啶-2-酮(步骤A,极性较小的产物)制备本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 7.06-7.27(6H,m),6.94(1H,t,J=1.7Hz),6.68(1H,d,J=7.6Hz),4.58-5.15(3H,m),4.42(2H,d,J=10.4Hz),3.88-4.01(1H,m),3.19-3.28(1H,m),2.86(2H,d,J=12.7Hz),2.03-2.24(2H,m),1.71-1.89(1H,m),1.54-1.66(1H,m),1.50(3H,s),1.26-1.40(1H,m),0.97(3H,br.s.);MS(ESI)546.0[M+H]+,544.0[M-H]-。
实施例144
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((3S)-6,6,6-三氟代-5-羟基己烷-3-基)哌啶-3-基)乙酸(异构体2)
按照与实施例71步骤F中描述的程序类似的程序,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((3S)-6,6,6-三氟代-5-羟基己烷-3-基)哌啶-2-酮(实施例143,步骤A;极性较大的产物)制备本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 7.23-7.27(2H,m),7.08-7.20(2H,m),6.93-7.08(3H,m),6.70(1H,dt,J=7.7,1.4Hz),4.49(1H,d,J=10.4Hz),3.88-4.01(1H,m),3.51(1H,s),3.10-3.22(1H,m),2.95(1H,d,J=14.5Hz),2.75(1H,d,J=14.5Hz),2.20(1H,t,J=13.8Hz),1.99-2.08(1H,m),1.95(1H,d,J=2.3Hz),1.77(1H,dd,J=14.3,7.2Hz),1.52-1.70(2H,m),1.48(3H,s),0.72(3H,t,J=7.5Hz);MS(ESI)546.0[M+H]+,544.0[M-H]-。
实施例145
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S)-5-羟基己烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸(异构体1)
在0℃下向2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-5-氧代己烷-3-基)哌啶-3-基)乙酸(24mg,0.049mmol;实施例130)在乙醚(0.40mL)和MeOH(0.10mL)中的溶液中加入硼氢化钠(9.26mg,0.245mmol)。然后让反应物升温至室温。在室温下搅拌1h后,淬灭(10%柠檬酸)反应物并对其进行萃取(2×EtOAc)。洗涤(NaCl饱和水溶液)合并的有机层,干燥(Na2SO4),并在减压下浓缩。通过RP-HPLC(30%至70%MeCN/H2O(0.1%TFA),梯度洗脱)纯化,得到本标题化合物,为极性较大的异构体。
1H NMR(400MHz,氯仿-d)δppm 7.22-7.27(2H,m),7.07-7.19(2H,m),6.95-7.06(3H,m),6.71(1H,dt,J=7.6,1.6Hz),4.57(1H,d,J=10.2Hz),3.77-3.89(1H,m),2.99-3.15(2H,m),2.69(1H,d,J=14.9Hz),2.23(1H,t,J=13.6Hz),1.81-1.99(2H,m),1.52-1.64(1H,m),1.47(3H,s),1.39(1H,d,J=2.0Hz),1.19(3H,d,J=6.3Hz),0.60(3H,t,J=7.4Hz);MS(ESI)492.1[M+H]+,490.0[M-H]-。
实施例146
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S)-5-羟基己烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸(异构体2)
从实施例145进一步洗脱得到本标题化合物,为极性较小的异构体。
1H NMR(400MHz,氯仿-d)δppm 7.04-7.27(5H,m),6.91-7.04(2H,m),6.70(1H,dt,J=7.7,1.5Hz),4.47(1H,d,J=10.4Hz),3.75(1H,ddd,J=12.4,6.1,0.7Hz),3.15-3.27(1H,m),2.96(1H,d,J=14.5Hz),2.76(1H,d,J=14.7Hz),2.18(1H,t,J=13.8Hz),2.02-2.09(1H,m),1.59-1.71(2H,m),1.50(3H,s),1.26(1H,dd,J=16.8,6.8Hz),1.08-1.21(2H,m),0.99-1.07(3H,m),0.89(3H,br.s.);MS(ESI)492.1[M+H]+,490.0[M-H]-。
实施例147
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(N-(2,2,2-三氟乙基)甲基磺酰氨基)丁烷-2-基)哌啶-3-基)乙酸
步骤A. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-((2,2,2-三氟乙基)氨基)丁烷-2-基)哌啶-2-酮
在室温下向(S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁醛(104mg,0.234mmol;实施例130,步骤A)在ClCH2CH2Cl(3.9mL)中的溶液中加入2,2,2-三氟乙胺(74μL,0.94mmol)和三乙酰氧基硼氢化钠(248mg,1.17mmol)。在室温下搅拌过夜后,淬灭(NaHCO3饱和水溶液)反应物,萃取(2×EtOAc),并洗涤(NaCl饱和水溶液)。干燥(Na2SO4)合并的有机层并在减压下浓缩从而得到本标题化合物,为白色固体。将该产物用于下一步骤而无需进一步纯化。
步骤B. N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁基)-N-(2,2,2-三氟乙基)甲烷磺酰胺
在室温下向上面步骤A中制备的(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(2,2,2-三氟乙基氨基)丁烷-2-基)哌啶-2-酮(60.9mg,0.115mmol)在DCE(770μL)中的溶液中依次加入DMAP(70.5mg,0.577mmol)和甲烷磺酰氯(35.9μL,0.462mmol)。在室温下搅拌3h后,加入吡啶(46.7μL,0.577mmol)、甲烷磺酰氯(35.9μL,0.462mmol),和DCE(0.77mL),并将由此产生的溶液搅拌15h。淬灭(饱和NH4Cl)反应物,并对其进行萃取(3×DCM)。洗涤(水和NaCl饱和水溶液)合并的有机层,干燥(Na2SO4),并在减压下浓缩。通过RP-HPLC(10%至90%的MeCN/H2O(0.1%TFA),梯度洗脱)分离,得到本标题化合物,为黄色固体。
步骤C. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(N-(2,2,2-三氟乙基)甲基磺酰氨基)丁烷-2-基)哌啶-3-基)乙酸
按照与实施例71步骤F中描述的程序类似的程序,从N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁基)-N-(2,2,2-三氟乙基)甲烷磺酰胺(步骤B)制备本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 7.21-7.28(2H,m),7.11-7.20(2H,m),6.74-7.10(4H,m),4.65(1H,d,J=10.8Hz),4.32-4.50(1H,m),4.11(1H,d,J=7.8Hz),3.48-3.65(1H,m),2.94-3.19(6H,m),2.79-2.92(1H,m),2.75(1H,d,J=14.7Hz),2.42(1H,t,J=13.9Hz),1.85-2.12(2H,m),1.50(4H,s),0.48(3H,t,J=7.4Hz);MS(ESI)623.0[M+H]+,621.0[M-H]-。
实施例148
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁基)-3-氯丙烷-1-磺酰胺
将(3S,5R,6S)-3-烯丙基-1-((S)-1-氨基丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮2,2,2-三氟乙酸盐(76mg,0.14mmol;实施例129,步骤B)溶解在DCM中,碱化(1N LiOH),萃取(3×DCM),并洗涤(NaCl饱和水溶液)。干燥(Na2SO4)合并的有机层并在减压下浓缩从而得到游离胺。在室温下向该游离胺在DCE(0.68mL)中的溶液中依次加入吡啶(55μL,0.68mmol)和3-氯丙烷-1-磺酰氯(96mg,0.54mmol)。将反应物在室温下搅拌5h。然后再加入吡啶(55μL,0.68mmol)和3-氯丙烷-1-磺酰氯(96mg,0.54mmol)。在搅拌过夜后,淬灭(10%柠檬酸)反应物,萃取(3×EtOAc),并洗涤(NaHCO3饱和水溶液和NaCl饱和水溶液)。干燥(Na2SO4)合并的有机层,并在减压下浓缩。通过RP-HPLC(10%至90%的MeCN/H2O(0.1%TFA),梯度洗脱)分离,得到本标题化合物,为黄色固体。
步骤B. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-甲基哌啶-2-酮
在室温下向上面步骤A中制备的N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁基)-3-氯丙烷-1-磺酰胺(36.1mg,0.062mmol)在DMF(1.2mL)中的溶液中加入DBU(46.4μL,0.308mmol)。在室温下搅拌过夜后,淬灭(10%柠檬酸)反应物,萃取(3×EtOAc),并洗涤(NaHCO3饱和水溶液和NaCl饱和水溶液)。干燥(Na2SO4)合并的有机层并在减压下浓缩从而得到本标题化合物,为浅棕色膜状物。
步骤C. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
按照与实施例71步骤F中描述的程序类似的程序,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-甲基哌啶-2-酮(步骤B)制备本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 7.27(2H,d,J=8.0Hz),7.10-7.19(2H,m),6.97-7.10(3H,m),6.83(1H,d,J=7.4Hz),4.87(1H,d,J=0.6Hz),3.33(2H,t,J=6.6Hz),3.24(2H,t,J=7.5Hz),3.09(2H,d,J=15.3Hz),2.96(2H,d,J=2.3Hz),2.74(1H,d,J=15.3Hz),2.37-2.51(3H,m),1.90-2.02(2H,m),1.53(4H,s),0.49(3H,t,J=7.5Hz);MS(ESI)567.1[M+H]+,565.0[M-H]-。
实施例149
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S,4R)-5-羟基-4,5-二甲基己烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S,4S)-5-羟基-4,5-二甲基己烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-2-氧代戊烷-3-基)哌啶-2-酮
在N2下在-60℃下向乙二酰二氯(78μL,0.87mmol)在DCM(1.5mL)中的溶液中加入DMSO(93μL,1.30mmol)在DCM(1.5mL)中的溶液。在搅拌2min后,加入实施例151步骤C中制备的(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S)-2-羟基戊烷-3-基)-3-甲基哌啶-2-酮(200mg,0.434mmol)在DCM(1.5mL)中的溶液,并将由此产生的溶液在-60℃下搅拌15min。然后,向该反应溶液中加入三乙胺(305μL,2.17mmol)。在室温下搅拌20min后,淬灭(水)反应物,萃取(2×EtOAc),并洗涤(2×NaCl饱和水溶液)。干燥(Na2SO4)合并的有机层并在减压下浓缩。通过combi flash(SiO2,24g,20%和30%的EtOAc/己烷)纯化,得到本标题化合物,为无色泡沫状物。
步骤B. ((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-甲氧基-2-甲基戊-1-烯-3-基)-3-甲基哌啶-2-酮
将(甲氧基甲基)三苯基氯化鏻于80℃在真空下干燥2h。在-78℃下向干燥的(甲氧基甲基)三苯基氯化鏻(673mg,1.96mmol)在THF(3.5mL)中的溶液中加入0.5M在甲苯中的KHMDS(3.49mL,1.75mmol)。该溶液产生血红色。在添加后,将反应物在0℃下搅拌30min,并在0℃下逐滴加入上面步骤B中制备的(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-2-氧代戊烷-3-基)哌啶-2-酮(200mg,0.436mmol)在THF(3.5mL)中的溶液。让反应物升温至室温并搅拌1.5h。然后淬灭(饱和NH4Cl溶液)反应物,萃取(2×EtOAc),并洗涤(盐水)。干燥(Na2SO4)合并的有机层并在减压下浓缩。通过combiflash(SiO2,24g,15%和20%的EtOAc/己烷)纯化,得到本标题化合物,为无色膜状物。
步骤C. (2S,3S)-3-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-2-甲基戊醛和(2R,3S)-3-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-2-甲基戊醛
在室温下向上面步骤B中制备的(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-甲氧基-2-甲基戊-1-烯-3-基)-3-甲基哌啶-2-酮(179mg,0.368mmol)在乙腈(3.7mL)中的溶液中加入3N盐酸(1.5mL,4.5mmol)。在室温下搅拌1.5h后,萃取(2×EtOAc)反应物,并洗涤(2×盐水)。干燥(Na2SO4)合并的有机层并在减压下浓缩,得到本标题化合物,其为立体异构体的混合物(dr=7:3),为浅黄色膜状物。
步骤D. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((3S,4R)-4-甲基-5-氧代己烷-3-基)哌啶-2-酮和(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((3S,4S)-4-甲基-5-氧代己烷-3-基)哌啶-2-酮
在0℃下向上面步骤C中制备的(2S,3S)-3-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-2-甲基戊醛和(2R,3S)-3-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-2-甲基戊醛(177mg,0.375mmol)在THF(3.076ml)中的溶液中加入1.4M在甲苯和THF(75:25)中的甲基溴化镁(0.803ml,1.12mmol)。然后让反应物升温至室温并搅拌2h。淬灭(饱和NH4Cl溶液)反应物,萃取(2×EtOAc),并洗涤(盐水)。干燥(Na2SO4)合并的有机层,并在减压下浓缩从而得到粗仲醇产物。向粗仲醇产物(183mg,0.375mmol)在DCM(4.2mL)中的溶液中依次加入水(14μL,0.75mmol)和dess-martin过碘烷(196mg,0.462mmol)。在室温下搅拌过夜后,淬灭(1MNa2S2O3水溶液)反应物,萃取(2×DCM),并洗涤(2×饱和NaHCO3和1×盐水)。干燥(Na2SO4)合并的有机层并在减压下浓缩。通过硅胶色谱法(24g SiO2,13%、27%和37%EtOAc/Hex)纯化残余物,相继得到极性较小的异构体和极性较大的异构体。
极性较小的异构体:1H NMR(400MHz,氯仿-d)δppm 7.25(2H,d,J=8.0Hz),7.03-7.17(4H,m),6.94-6.99(1H,m),6.81-6.87(1H,m),5.12-5.23(2H,m),4.58(1H,d,J=10.8Hz),3.14(1H,s),2.66(1H,s),2.58(2H,d,J=7.4Hz),2.22(3H,s),1.81(1H,d,J=4.3Hz),1.75(1H,d,J=7.2Hz),1.51-1.65(2H,m),1.19(3H,s),1.00(3H,d,J=7.2Hz),0.30(3H,t,J=7.7Hz);MS(ESI)486.1[M+H]+。
极性较大的异构体:1H NMR(400MHz,氯仿-d)δppm 7.22-7.27(2H,m),7.01-7.17(4H,m),6.89-6.95(1H,m),6.71(1H,dt,J=7.5,1.3Hz),5.81-5.93(1H,m),5.17-5.25(2H,m),4.32(1H,d,J=10.8Hz),3.50(1H,br.s.),3.23-3.32(1H,m),3.06(1H,br.s.),2.60-2.66(2H,m),2.13-2.20(3H,m),1.91-2.01(2H,m),1.64-1.70(2H,m),1.28-1.32(3H,m),1.13(3H,d,J=7.0Hz),0.34(3H,t,J=7.5Hz);MS(ESI)486.1[M+H]+。
步骤E. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S,4R)-5-羟基-4,5-二甲基己烷-3-基)-3-甲基哌啶-2-酮或(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S,4S)-5-羟基-4,5-二甲基己烷-3-基)-3-甲基哌啶-2-酮
在0℃下向上面实施例149步骤D中制备的极性较小的异构体(96mg,0.20mmol)在THF(2.0mL)中的溶液中加入1.4M在甲苯和THF(75:25)中的溴化甲基镁(423μL,0.592mmol)。然后让反应物升温至室温并搅拌过夜。淬灭(饱和NH4Cl溶液)反应物,萃取(2×EtOAc),并洗涤(盐水)。干燥(Na2SO4)合并的有机层并在减压下浓缩。通过combi-flash(12g SiO2,30%EtOAc/Hex)纯化残余物,得到本标题化合物,为单一异构体。
步骤F. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S,4R)-5-羟基-4,5-二甲基己烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S,4S)-5-羟基-4,5-二甲基己烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸
按照与实施例129步骤D中描述的程序类似的程序,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S,4R)-5-羟基-4,5-二甲基己烷-3-基)-3-甲基哌啶-2-酮或(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S,4S)-5-羟基-4,5-二甲基己烷-3-基)-3-甲基哌啶-2-酮(实施例149,步骤E)制备本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 7.01-7.27(6H,m),6.96(1H,t,J=1.7Hz),6.70(3H,d,J=7.6Hz),4.59(1H,d,J=9.8Hz),3.63-3.91(1H,m),3.14(1H,s),2.98(1H,d,J=14.5Hz),2.72(1H,d,J=14.5Hz),1.98-2.21(2H,m),1.84-1.96(1H,m),1.56-1.69(2H,m),1.48(3H,s),1.15(3H,s),1.06(3H,s),0.75(3H,br.s.),0.28(3H,br.s.);MS(ESI)520.2[M+H]+,518.2[M-H]-。
实施例150
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-5-氰基-5-甲基己烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. (2S)-2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-(2,3-二羟基丙基)-3-甲基-2-氧代哌啶-1-基)丁酸甲酯
向(S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁酸甲酯(1.06g,2.23mmol;实施例91,步骤A)和4-甲基吗啉4-氧化物(393mg,3.35mmol)在DCM(15.800mL)中的溶液中加入聚合物结合的氧化锇(VIII),1%DVB(56.8mg,2.234μmol)。在室温下剧烈搅拌2天后,再加入聚合物结合的氧化锇(VIII),1%DVB(56.8mg,2.234μmol),并将由此产生的溶液在室温下剧烈搅拌2天。过滤该树脂并洗涤(DCM)。洗涤(NaCl饱和水溶液)合并的有机层,干燥(Na2SO4),并在减压下浓缩。通过硅胶色谱法(SiO2,40g,53%和63%EtOAc/己烷)纯化,得到本标题化合物。
步骤B. (2S)-2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-3-甲基-2-氧代哌啶-1-基)丁酸甲酯
向上面步骤A中制备的(S)-2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-(2,3-二羟基丙基)-3-甲基-2-氧代哌啶-1-基)丁酸甲酯(749mg,1.47mmol)在DCM(8.2mL)中的溶液中加入对甲苯磺酸一水合物(14.0mg,0.074mmol)和2,2-二甲氧基丙烷(8.15mL,66.3mmol)。在室温下搅拌3h后,在减压下浓缩反应混合物,溶解(EtOAc和NaHCO3饱和水溶液)残余物并对其进行萃取(3×EtOAc)。洗涤(NaCl饱和水溶液)合并的有机层,干燥(Na2SO4),并在减压下浓缩。通过硅胶色谱法(SiO2,40g,27%和37%EtOAc/己烷)纯化,得到本标题化合物,为无色膜状物。
步骤C. (3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-1-((S)-1-羟基丁烷-2-基)-3-甲基哌啶-2-酮
在0℃下向上面步骤B中制备的(2S)-2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-3-甲基-2-氧代哌啶-1-基)丁酸甲酯(734mg,1.34mmol)在乙醚(12.2mL)中的溶液中加入硼氢化锂(58.3mg,2.68mmol)。在0℃下搅拌30min后,淬灭(冰冷的10%柠檬酸)反应物,萃取(2×EtOAc)并洗涤(NaCl饱和水溶液)。干燥(Na2SO4)合并的有机层并在减压下浓缩,得到本标题化合物,为无色膜状物。将该产物用于下一步骤而无需进一步纯化。
步骤D. (2S)-2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-3-甲基-2-氧代哌啶-1-基)丁醛
按照与实施例91步骤C中描述的程序类似的程序,从(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-1-((S)-1-羟基丁烷-2-基)-3-甲基哌啶-2-酮(实施例150,步骤C)制备本标题化合物。
步骤E. (4S)-4-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-3-甲基-2-氧代哌啶-1-基)已-2-烯腈
在0℃下向氰甲基膦酸二乙酯(126μL,0.799mmol)和DMPU(481μL,3.99mmol)在THF(1.33mL)中的溶液中加入在矿物油中的60%氢化钠(24.0mg,0.599mmol)。将该混合物搅拌30min,然后用上面步骤D中制备的(2S)-2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-3-甲基-2-氧代哌啶-1-基)丁醛(207mg,0.399mmol)在THF(1.33mL)中的溶液处理。在搅拌4h后,淬灭(水)反应物,萃取(2×EtOAc),并洗涤(NaCl饱和水溶液)。干燥(Na2SO4)合并的有机层并在减压下浓缩。通过硅胶色谱法(24g SiO2,30%至40%EtOAc/Hex,梯度洗脱)纯化残余物,得到本标题化合物,为无色液体。
步骤F. (4S)-4-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-3-甲基-2-氧代哌啶-1-基)己腈
向上面步骤E中制备的(4S)-4-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-3-甲基-2-氧代哌啶-1-基)己-2-烯腈(208mg,0.384mmol)在EtOH(12.8mL)中的溶液中加入10%的负载于活性炭上的钯(40.9mg,0.038mmol)。然后用氢气(0.774mg,0.384mmol)对反应混合物进行常规的氢化。在室温下搅拌1.5h后,使用短硅胶塞过滤该催化剂并洗涤(EtOAc)。在减压下浓缩合并的有机溶液。通过combi flash(快速柱色谱法,Teledyne Isco,Lincoln,NE)(SiO2,24g,35%和40%EtOAc/己烷)纯化,得到本标题化合物,为无色膜状物。
步骤G. (4S)-4-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-3-甲基-2-氧代哌啶-1-基)-2,2-二甲基己腈
在-78℃下向上面步骤F中制备的(4S)-4-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-3-甲基-2-氧代哌啶-1-基)己腈(120mg,0.221mmol)在THF(1.10mL)中的溶液中加入2M二异丙基氨基锂(552μL,1.10mmol)。在-78℃下搅拌5min后,加入碘甲烷(94μL,1.51mmol)并将由此产生的溶液在-78℃下搅拌30min。然后让反应物升温至室温并搅拌过夜。淬灭(NH4Cl饱和水溶液)反应物并对其进行萃取(2×EtOAc),洗涤(NaCl饱和水溶液)合并的有机层,干燥(Na2SO4),并在减压下浓缩。通过硅胶色谱法(SiO2,30%和40%EtOAc/hex)纯化,得到二甲基化产物和单甲基化产物的混合物,使该混合物再经受下面描述的甲基化条件。
在-78℃下向来自前面反应的粗产物在THF(1.10mL)中的溶液中加入2M在庚烷/THF/乙苯中的二异丙基氨基锂(552μL,1.10mmol)。在-78℃下搅拌5min后,加入碘甲烷(94μL,1.51mmol)并将由此产生的溶液在-78℃下搅拌30min。然后让反应物升温至室温并搅拌过夜。淬灭(NH4Cl饱和水溶液)反应物并对其进行萃取(2×EtOAc),洗涤(NaCl饱和水溶液)合并的有机层,干燥(Na2SO4),并在减压下浓缩。通过RP-HPLC纯化(60%至90%的MeCN/H2O(0.1%TFA),梯度洗脱)来进行纯化,得到本标题化合物。
步骤H. (4S)-4-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-(2,3-二羟基丙基)-3-甲基-2-氧代哌啶-1-基)-2,2-二甲基己腈
在室温下向上面步骤G中制备的(4S)-4-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-3-甲基-2-氧代哌啶-1-基)-2,2-二甲基己腈(77mg,0.135mmol)在THF(2.69mL)中的溶液中加入3N在水中的盐酸(1.35μL,4.04mmol)。在室温下搅拌4h后,稀释(NaCl饱和水溶液)反应物并对其进行萃取(2×EtOAc)。洗涤(NaCl饱和水溶液)合并的有机层,干燥(Na2SO4),并在减压下浓缩从而得到本标题化合物,为无色泡沫状物。
步骤I. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-5-氰基-5-甲基己烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸
按照与实施例71步骤F中描述的程序类似的程序,从上面步骤H中制备的(4S)-4-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-(2,3-二羟基丙基)-3-甲基-2-氧代哌啶-1-基)-2,2-二甲基己腈制备本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 7.27(2H,s),7.00-7.20(4H,m),6.97(1H,t,J=1.7Hz),6.82(1H,dt,J=7.4,1.4Hz),4.82(1H,d,J=10.6Hz),3.12(1H,s),3.01(1H,d,J=15.1Hz),2.75(3H,d,J=15.1Hz),2.54(1H,s),2.03-2.12(1H,m),2.01(1H,s),1.90(1H,dd,J=14.0,2.6Hz),1.52(3H,s),1.43(3H,s),1.35-1.41(1H,m),1.31(3H,s),1.23(1H,d,J=13.9Hz),0.33(3H,t,J=7.3Hz);MS(ESI)515.0[M+H]+,513.0[M-H]-。
实施例151
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-2-氧代戊烷-3-基)哌啶-3-基)乙酸
步骤A. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)-3-甲基哌啶-2-酮
用超过10min的时间向1004g(1.47mol)(3S,5R,6S)-3-烯丙基-1-((S)-1-((叔丁基二苯基甲硅烷基)氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮(实施例185,步骤E)在THF(3.0L)中的溶液中加入2.50L(2.50mol)TBAF在THF中的1M溶液。将该橙色溶液在室温下搅拌4h。用1N HCl(3L)淬灭反应物并用EtOAc(3X)萃取。先后用水与饱和氯化钠水溶液的3:1混合物(4X)和饱和氯化钠水溶液(1X)洗涤合并的有机层。经Na2SO4干燥有机层,过滤,并浓缩滤液。通过色谱法(( SnapTM柱;Biotage,LLC,Charlotte,NC),10%至50%的EtOAc/己烷,其中EtOAc含有2%MeCN,梯度洗脱)纯化残余物,得到本标题化合物,为白色泡沫状物。
步骤B. (S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁醛
向428g(959mmol)(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)-3-甲基哌啶-2-酮(实施例151,步骤A)在二氯甲烷(4.55L)中的溶液中加入25.9mL(1.44mol)水。用超过25min的时间缓慢地加入610g(1.44mol)Dess-Martin过碘烷在二氯甲烷(4.55L)中的溶液以便维持内部反应温度不超过25℃。将白色浆液搅拌2.5h,然后通过小心缓慢地加入饱和硫代硫酸钠水溶液(5.2L)来进行淬灭以便维持内部反应温度低于30℃。加入水并用二氯甲烷(3X)萃取该混合物。先后用饱和碳酸氢钠水溶液(4X)和饱和氯化钠水溶液(1X)洗涤合并的有机层,经Na2SO4干燥,过滤,并浓缩滤液从而得到黄色油状固体。加入乙醚和DCM的混合物,并滤掉沉淀的固体。重复沉淀/过滤过程。浓缩滤液从而得到本标题化合物,为白色固体。将该粗产物直接用于下一步骤。
步骤C. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S)-2-羟基戊烷-3-基)-3-甲基哌啶-2-酮
用超过30min的时间向0℃的399g(899mmol)(S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁醛(实施例151,步骤B)在THF(9L)中的溶液中缓慢地加入1.93L(2.70mol)1.4M在75:25的甲苯/四氢呋喃中的溴化甲基镁溶液以便维持内部反应温度低于6℃。将该黄色溶液升温至室温并搅拌1.5h。在此时将反应物冷却至0℃并通过小心缓慢地加入饱和氯化铵水溶液(4.6L)来进行淬灭以便维持内部反应温度低于15℃。将该混合物升温至室温,加入乙酸乙酯,并分离各层。用EtOAc(2X)萃取水层。先后用水(1X)和饱和氯化钠水溶液(1X)洗涤合并的有机层,经Na2SO4干燥,过滤,并浓缩滤液从而得到黄色油状物。通过硅胶色谱法( SnapTM柱;Biotage,LLC,Charlotte,NC),5%丙酮/5%EtOAc/90%己烷逐渐到5%丙酮/29%EtOAc/66%己烷)纯化残余物,得到本标题化合物,为白色固体。
步骤D. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-2-氧代戊烷-3-基)哌啶-3-基)乙酸
在18℃下将氯化钌(III)水合物(1.404g,6.23mmol)加入到(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S)-2-羟基戊烷-3-基)-3-甲基哌啶-2-酮(实施例151,步骤C)(130.30g,283mmol)和NaIO4(61.5g)在EtOAc(630mL)、CH3CN(630mL)和水(935mL)中的溶液中。将剩余的NaIO4(307.5g)分5个部分用超过2.5小时的时间加入,同时保持温度低于26℃。在加入最后一部分NaIO4后15分钟,移开冷却浴并将反应混合物在室温下搅拌50分钟。使用Büchner漏斗过滤棕褐色反应混合物并用EtOAc(500mL)和CH3CN(500mL)洗涤。分离各层并用EtOAc萃取水层两次。将有机物汇集在一起,用10%NaHSO3水溶液(3x1L)、盐水(1L)洗涤,干燥(Na2SO4),轻轻倒出并在真空中浓缩从而得到绿色油状物。将该材料溶解在最低量的DCM中,并通过使用两根1.5kg SnapTM柱(Biotage,LLC,Charlotte,NC),用10-50%(15%MeOH/丙酮)/己烷洗脱来进行纯化从而得到淡粉红色泡沫状物(109.67g)。
1H NMR(400MHz,氯仿-d)δppm 7.25(2H,d,J=8.2Hz),6.93-7.18(5H,m),6.73-6.80(1H,m),4.47(1H,d,J=10.6Hz),3.28(1H,ddd,J=13.4,10.5,3.0Hz),3.16(1H,dd,J=7.0,5.5Hz),2.73-3.00(2H,m),2.28-2.40(1H,m),2.18-2.25(1H,m),2.16(3H,s),2.11-2.15(1H,m),1.83(1H,ddd,J=14.3,7.8,5.7Hz),1.47(3H,s),0.64(3H,t,J=7.5Hz);MS(ESI)476.2[M+H]+。
实施例152
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2S,3S)-2-羟基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸
在-78℃下用超过5min的时间向3.86g(8.13mmol)2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-2-氧代戊烷-3-基)哌啶-3-基)乙酸(实施例151)在THF(102mL)中的溶液中逐滴加入三仲丁基硼氢化钠(Aldrich,St.Louis,MO)在THF中的1M溶液(16.26mL,16.26mmol)。在-78℃下搅拌30min后,让反应物升温至室温。将反应物在室温下搅拌2h,淬灭(NH4Cl饱和溶液)反应物,萃取(3×EtOAc)并洗涤(3×冰冷的1N HCl水溶液和3×饱和氯化钠水溶液)。经Na2SO4干燥合并的有机层,过滤,并在减压下浓缩滤液。通过色谱法在Biotage Isolera flash purification system(Biotage,Charlotte,NC)(2x1500g柱,使用10-30%在己烷中的(15%MeOH/丙酮)梯度洗脱来纯化粗材料。然后将纯化的粗材料从3:1己烷/丙酮(8mL/g)中重结晶从而得到本标题化合物。
1H NMR(500MHz,DMSO-d6)δppm 0.30(t,J=7.6Hz,3H),1.00(d,J=6.3Hz,3H),1.26(s,3H),1.41-1.49(m,1H),1.55-1.64(m,1H),2.04-2.15(m,2H),2.29-2.33(m,1H),2.48(d,J=13.7Hz,1H),2.87(d,J=13.7Hz,1H),3.35-3.40(m,1H),4.01-4.06(m,1H),4.77(d,J=10.9Hz,1H),4.80(br.s,1H),6.93-6.95(m,1H),7.08-7.10(m,1H),7.17-7.27(m,4H),7.33(d,J=8.4Hz,2H),12.42(br s,1H);MS(ESI)478.2[M+H]+,476.2[M-H]-.[α]D=+110°(T=23℃,MeOH,c=0.51)。
替代地,从如实施例261步骤F中制备的(3S,5R,6R)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基四氢-2H-吡喃-2-酮制备本标题化合物。
向10mL圆底反应烧瓶中加入(3S,5R,6R)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基四氢-2H-吡喃-2-酮(750mg,1.998mmol)、(2S,3S)-3-氨基戊烷-2-醇盐酸盐(837mg,6.00mmol,参考:J.OrgChem.,2003,68(26),9948),和三乙胺(1966μl,13.99mmol)。给该容器装配回流冷凝器并将该容器加热到85℃至95℃并保持2天。将反应物冷却至室温,用乙酸乙酯稀释并用1N HCl(2X20mL)和盐水洗涤。经MgSO4干燥有机层,过滤并浓缩。通过柱色谱法使用40%至50%的在己烷中的乙酸乙酯纯化,得到(S)-2-((2R,3R)-2-(3-氯苯基)-3-(4-氯苯基)-3-羟基丙基)-N-((2S,3S)-2-羟基戊烷-3-基)-2-甲基戊-4-烯酰胺。
1H NMR(500MHz,DMSO-d6)δ7.17(m,2H),7.16(m,1H),7.14-7.08(系列m,2H),6.97(m,2H),6.88(br d,J=6.9Hz,1H),5.96(d,J=8.3Hz,1H),5.65(ddt,J=17.4,10.2,7.2Hz,1H),5.07(dd J=10.3,1.0Hz,1H),5.02(d,J=17.6,1H),4.75(t,J=4.2Hz,1H),3.79(m,1H),3.66(ddd,J=8.8,5.9,4.2Hz,1H),3.30(d,J=3.4Hz,1H),3.03(dt,J=6.9,5.4Hz,1H),2.37(dd,J=13.9,7.3Hz,1H),2.32(dd,J=14.7,5.6Hz,1H),2.12(dd,J=13.7,7.1Hz,1H),2.01(d,J=4.7Hz,1H),1.83(dd,J=14.7,7.3Hz,1H),1.58(m,1H),1.42(ddq,J=14.9,8.6,7.3Hz),1.14(s,3H),1.14(d,J=6.4Hz,3H),0.90(t,J=7.3Hz,3H)ppm.LC/MS(M+H)=478.2。
向(S)-2-((2R,3R)-2-(3-氯苯基)-3-(4-氯苯基)-3-羟基丙基)-N-((2S,3S)-2-羟基戊烷-3-基)-2-甲基戊-4-烯酰胺(127mg,0.265mmol)在甲苯(5309μl)中的溶液中加入钼酸铵((NH4)2MoO4)(5.20mg,0.027mmol),并在Dean-Stark条件下加热至回流过夜。将反应物冷却至室温,用乙酸乙酯稀释并用饱和NaHCO3和盐水洗涤。经MgSO4干燥有机物,过滤并浓缩。通过柱色谱法使用20%至40%的在己烷中的乙酸乙酯纯化,得到(1R,2R,4S)-2-(3-氯苯基)-1-(4-氯苯基)-4-((4S,5S)-4-乙基-5-甲基-4,5-二氢噁唑-2-基)-4-甲基庚-6-烯-1-醇。
1H NMR(500MHz,DMSO-d6)δ7.25(m,2H),7.12(m,2H),7.07(br s,1H),7.05(m,2H),6.96(br d,J=6.8Hz,1H),5.53(ddt,J=17.4,10.3,7.4Hz,1H),5.42(d,J=4.2Hz,1H),4.95(m,2H),4.66(t,J=4.9Hz,1H),3.56(dq,J=7.6,6.1Hz,1H),3.12(q,J=7.1Hz,1H),2.90(ddd,(9.5,5.1,2.3Hz,1H),2.20(m,2H),1.93(dd,J=13.7,7.8Hz,1H),1.75(dd,J=14.3,2.2Hz,1H),1.11(m,1H),1.10(d,J=6.4Hz,3H),0.98(m,1H),0.97(s,3H),0.75(t,J=7.6Hz,3H)ppm.LC/MS(M+H)=460.2。
向在-50℃下的(1R,2R,4S)-2-(3-氯苯基)-1-(4-氯苯基)-4-((4S,5S)-4-乙基-5-甲基-4,5-二氢噁唑-2-基)-4-甲基庚-6-烯-1-醇(80mg,0.174mmol)在CH2Cl2(1737μl)中的溶液中加入2,6-二甲基吡啶(46.4μl,0.400mmol),接着加入1M在二氯甲烷中的三氟甲烷磺酸酐溶液(191μl,0.191mmol)。将反应物在-50℃下搅拌30min,然后先后用用另外的25uL1M在二氯甲烷中的三氟甲烷磺酸酐溶液,和2mL饱和CuSO4处理。将反应物升温至室温并用二氯甲烷萃取。经MgSO4干燥有机相,过滤并浓缩。通过柱色谱法使用40%至80%的在己烷中的丙酮纯化,得到(2S,3S,5S,6R,8S)-8-烯丙基-6-(3-氯苯基)-5-(4-氯苯基)-3-乙基-2,8-二甲基-2,3,5,6,7,8-六氢噁唑并[3,2-a]吡啶-4-鎓三氟甲磺酸盐。
1H NMR(500MHz,DMSO-d6)δ7.55-7.05(系列m,8H),5.88(ddt,J=17.3,10.0,7.8Hz,1H),5.36(dd,J=17.1,2.0Hz,1H),5.31(d,J=10.8Hz,1H),5.28(dd,J=10.0,2.0Hz,1H),5.18(五重峰,J=6.1Hz,1H),4.10(td,J=6.6,2.7Hz,1H),3.98(ddd,J=13.7,11.2,3.4Hz,1H),2.80(ABX,JAB=13.7Hz,JAX=7.3Hz,1H),2.73(ABX JAB=13.7Hz,JBX=7.8Hz,1H),2.49(m,1H),2.41(t,J=13.7Hz,1H),2.00(dd,J=13.9,3.7Hz,1H),1.55(d,J=6.1Hz,1H),1.31(s,3H),0.95(dqd,J=14.2,7.8,3.0Hz,1H),0.58(t,J=7.3Hz,1H),0.47(ddq,J=13.7,6.3,6.3Hz,1H)ppm.LC/MS(M+=442.2)。
向在0℃下的(2S,3S,5S,6R,8S)-8-烯丙基-6-(3-氯苯基)-5-(4-氯苯基)-3-乙基-2,8-二甲基-2,3,5,6,7,8-六氢噁唑并[3,2-a]吡啶-4-鎓三氟甲磺酸盐(60mg,0.101mmol)在1mL二氯甲烷中的溶液中加入四正丁基氯化铵(2.81mg,10.13μmol)和乙酸(116μl,2.025mmol)。向其中加入在1mL水中的KMnO4(32.0mg,0.203mmol),接着用1mL水冲洗。再加入10当量乙酸,接着再加入在1mL水中的16mg KMnO4。再次重复该操作。总共加入4当量KMnO4和40当量乙酸。
用1mL Na2S2O3饱和溶液淬灭反应物并用乙酸乙酯稀释。分离各层并用盐水洗涤有机相一次,经MgSO4干燥,过滤并浓缩从而得到粗(2S,3S,5S,6R,7aR)-6-(3-氯苯基)-5-(4-氯苯基)-3-乙基-2,7a-二甲基六氢呋喃并[2,3-b]噁唑并[3,2-a]吡啶-9(5H)-酮。将该粗残余物再溶解于2mL乙酸异丙酯中,用2mL饱和NaHCO3处理并将其加热至70℃。在2h后,将反应物冷却至0℃并用10%乙酸处理以使其pH约为3。用乙酸乙酯稀释反应物并用10%乙酸溶液洗涤一次,经MgSO4干燥,过滤并浓缩。通过柱色谱法使用10%至50%的在己烷中的(15%MeOH/丙酮)纯化,得到2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2S,3S)-2-羟基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸。
实施例153
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2S,3S)-2-甲氧基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2S,3S)-2-羟基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸甲酯
在0℃下向260mg(0.543mmol)2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2S,3S)-2-羟基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸(实施例152)在5mL THF中的溶液中加入60%氢化钠(217mg,5.43mmol)。在0℃下搅拌20min后,加入碘甲烷(271uL,4.35mmol)。让反应物升温至室温,并再搅拌3h直至完成。用饱和NH4Cl水溶液淬灭反应物,并用EtOAc(2x25mL)萃取。用饱和NaCl洗涤合并的有机层,经MgSO4干燥,过滤,并浓缩滤液从而得到本标题化合物。
步骤B. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2S,3S)-2-甲氧基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸甲酯
在25℃下向50mg(0.102mmol)2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2S,3S)-2-羟基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸甲酯(实施例153,步骤A)在0.3mL DMF中的溶液中加入60%氢化钠(20.31mg,0.508mmol)。在25℃下搅拌20min后,加入碘甲烷(25.4uL,0.406mmol)。将反应物再搅拌30min并用饱和NH4Cl水溶液淬灭,用EtOAc(2x25mL)萃取。用饱和NaCl洗涤合并的有机层,经MgSO4干燥,过滤,并浓缩滤液。通过硅胶快速色谱法(洗脱剂:20%至60%的EtOAc/己烷)纯化残余物,得到本标题化合物。
步骤C. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2S,3S)-2-甲氧基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸
在室温下向2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2S,3S)-2-甲氧基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸甲酯(34mg,0.067mmol;实施例153,步骤B)在THF/MeOH/H2O(1/1/1,0.48mL)中的溶液中加入2M氢氧化锂(67uL,0.134mmol)。在室温下搅拌4h后,用饱和NH4Cl水溶液淬灭反应物并对反应物进行萃取(2×DCM),洗涤(1×NaCl饱和水溶液)合并的有机层并在减压下浓缩。通过硅胶快速色谱法(洗脱剂:70%至100%的EtOAc/己烷)纯化残余物,得到本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 0.38(t,J=8.0Hz,3H),1.05(d,J=4.0Hz,1H),1.48(s,3H),1.65(m,1H),1.75(m,1H),2.00(dd,J=12.0,4Hz,1H),2.21(m,1H),2.48(m,1H),2.70(d,J=16.0Hz,1H),3.06-3.15(m,2H),3.41(s,3H),3.94(m,1H),4.63(d,J=12.0Hz,1H),6.75(d,J=8.0Hz,1H),6.90–7.05(m,3H),7.05-7.15(m,2H),7.25(d,J=8.0Hz,2H);MS(ESI)492.1[M+H]+。
实施例154
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2R,3S)-2-羟基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸
向2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-氧代丁烷-2-基)哌啶-3-基)乙酸(71mg,0.154mmol)(实施例210,步骤A)在THF(2mL)中的溶液中通入氩气5分钟。将该混合物冷却至0℃,并以使得内部温度不超过4℃的速率加入3.0M甲基氯化镁的四氢呋喃溶液(0.113ml,0.339mmol)。将该混合物在0℃下搅拌45分钟。用NH4Cl饱和水溶液淬灭该混合物并用EtOAc萃取。经Na2SO4干燥合并的有机层,过滤,并浓缩滤液。通过硅胶快速色谱法(2x4g堆叠的柱,洗脱剂:5%至15%的异丙醇/己烷)纯化残余物,从而得到本标题化合物,为极性较大的非对映异构体。
1H NMR(400MHz,氯仿-d)δppm 0.55(t,J=7.63Hz,3H),1.18(d,J=6.65Hz,3H),1.44(s,3H),1.63-1.77(m,1H),1.99-2.18(m,3H),2.61-2.71(m,1H),2.81(d,J=14.28Hz,1H),2.92(d,J=14.48Hz,1H),3.24(td,J=10.22,5.77Hz,1H),4.11-4.22(m,1H),4.45(d,J=10.17Hz,1H),6.74(dt,J=7.53,1.61Hz,1H),6.93-7.05(m,3H),7.07-7.14(m,1H),7.15-7.20(m,1H),7.24-7.31(m,2H)。质谱(ESI)m/e=478.1(M+1)。
实施例155
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2S,3R)-2-羟基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸(异构体1)
*立体化学未确认
步骤A. (R)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁醛
按照与实施例91步骤B中描述的程序类似的程序,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-1-羟基丁烷-2-基)-3-甲基哌啶-2-酮制备本标题化合物。将该产物用于下一步骤而无需进一步纯化。
步骤B. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((3R)-2-羟基戊烷-3-基)-3-甲基哌啶-2-酮
如实施例149步骤A中所述,从(R)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁醛(实施例155,步骤A)制备本标题化合物。通过快速色谱法(SiO2,40g,10%至25%EtOAc/己烷)纯化,得到本标题化合物,其为在新形成的立体中心上的两个非对映异构体的混合物。
步骤C. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((R)-2-氧代戊烷-3-基)哌啶-3-基)乙酸
按照与实施例71步骤F中描述的程序类似的程序,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((3R)-2-羟基戊烷-3-基)-3-甲基哌啶-2-酮(0.210g,0.456mmol;实施例155,步骤B)制备本标题化合物。
步骤D. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2S,3R)-2-羟基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸
在室温下向2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((R)-2-氧代戊烷-3-基)哌啶-3-基)乙酸(0.150g,0.315mmol,实施例155,步骤C)在THF/MeOH(3/1,4mL)中的溶液中加入硼氢化钠(0.060g,1.574mmol)。在室温下搅拌1h后,用NH4Cl饱和水溶液酸化反应物并用EtOAc萃取。用NaCl饱和水溶液洗涤合并的有机层,经MgSO4干燥,过滤并在减压下浓缩滤液。通过反相制备型HPLC(洗脱剂:10-90%乙腈、水、0.1%TFA,梯度洗脱)纯化粗材料,从而得到两个异构体的混合物(dr=93:7)。通过手性HPLC(250x30mm IC柱(CHIRAL TECHNOLOGIES,INC.,West Chester,PA,USA),用46g/min异丙胺+(20μM NH3)+84g/min CO2在Thar350 SFC(Thar Technologies,Inc.,Pittsburg,PA)上)分离各个立体异构体,从而得到本标题化合物,为较快地洗脱的立体异构体。
1H NMR(400MHz,氯仿-d)δppm 0.61(d,J=6.65Hz,3H),0.99–1.08(t,J=7.34Hz,3H),1.18–1.37(m,1H),1.45–1.60(m,4H),1.99–2.21(m,3H),2.69(dd,J=11.15,3.72Hz,1H),2.82–2.90(m,1H),3.18–3.30(m,1H),3.69–3.79(m,1H),4.34(d,J=10.56Hz,1H),6.71(d,J=7.63Hz,1H),6.88–7.04(m,2H),7.04–7.20(m,3H),7.20–7.32(m,2H)。MS(ESI)478.0[M+H]+。
进一步洗脱得到实施例156。
实施例156
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2R,3R)-2-羟基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸
*立体化学未确认
实施例155,步骤D;从手性HPLC较慢地洗脱的异构体。
1H NMR(400MHz,氯仿-d)δppm 0.81(d,J=6.46Hz,3H),1.01(t,J=7.43Hz,3H),1.47(s,3H),1.64(m,1H),1.82-1.95(m,1H),2.13-2.25(m,2H),2.73-2.84(m,2H),2.93(d,J=14.87Hz,1H),3.37(m,1H),3.93(m,1H),4.45(d,J=10.56Hz,1H),6.72(d,J=7.43Hz,1H),6.96(m,1H),7.02-7.17(m,4H),7.21(m,2H);质谱(ESI)m/z=478.0(M+1)。
实施例157
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-羟基-2-甲基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-羟基-2-甲基戊烷-3-基)-3-甲基哌啶-2-酮
在0℃下向(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-2-氧代戊烷-3-基)哌啶-2-酮(0.100g,0.218mmol;实施例149,步骤B)在THF(4mL)中的溶液中加入1.4M在甲苯中的甲基溴化镁溶液(0.104g,0.873mmol)。让反应物升温至室温。在室温下搅拌4h后,再加入1当量MeMgBr并再搅拌2h。用NH4Cl饱和溶液淬灭反应物,并用EtOAc萃取。用NaCl饱和水溶液洗涤合并的有机层,经MgSO4干燥,过滤,并在减压下浓缩滤液。使粗材料吸附到硅胶塞上,并通过硅胶色谱法用40%EtOAc/己烷洗脱来进行纯化,从而得到本标题化合物,为淡黄色油状物。
步骤B. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-羟基-2-甲基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸
按照与实施例71步骤F中描述的程序类似的程序,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-羟基-2-甲基戊烷-3-基)-3-甲基哌啶-2-酮(实施例157,步骤A)制备本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 0.37(t,J=7.63Hz,3H)1.10(s,3H)1.35(s,3H)1.50(s,3H)1.68(ddd,J=15.21,7.78,4.01Hz,1H)2.10-2.31(m,3H)2.44-2.55(m,1H)2.78-2.95(m,2H)3.24-3.37(m,1H)4.40(d,J=10.56Hz,1H)6.73(dt,J=7.53,1.52Hz,1H)6.95(m,1H)7.01-7.21(m,4H)7.21-7.38(m,2H)。MS(ESI)492.2[M+H]+。
实施例158
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S,4S)-4-羟基己烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S,4R)-4-羟基己烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-4-羟基己烷-3-基)-3-甲基哌啶-2-酮
如实施例149步骤A中所述,从(S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁醛(实施例91,步骤C)和乙基溴化镁制备本标题化合物。将该粗材料用于下一步骤而无需进一步纯化。
步骤B. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-4-氧代己烷-3-基)哌啶-3-基)乙酸
如实施例71步骤F中所述,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-4-羟基己烷-3-基)-3-甲基哌啶-2-酮(实施例158,步骤A)制备本标题化合物。
步骤C. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S)-4-羟基己烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸
在0℃下向2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-4-氧代己烷-3-基)哌啶-3-基)乙酸(0.038g,0.077mmol;实施例158,步骤B)在THF和甲醇的混合物(4:1,5mL)中的溶液中加入硼氢化钠(9mg,0.24mmol)。然后让反应物升温至室温。在室温下搅拌1.5h后,再加入2当量硼氢化钠并再搅拌0.5h。酸化(10%柠檬酸)反应物并对其进行萃取(2×EtOAc)。洗涤(NaCl饱和水溶液)合并的有机层,干燥(MgSO4),并在减压下浓缩。通过反相制备型HPLC(洗脱剂:10%至90%的乙腈、水、0.1%TFA,梯度洗脱)纯化残余物,从而得到本标题化合物,其为第一洗脱级分,其在冻干后为白色固体。
1H NMR(400MHz,氯仿-d)δppm 0.55(t,J=7.53Hz,3H)0.91(t,J=7.34Hz,3H)1.38(m,1H)1.44(s,3H)1.54(m,1H)1.72(m,1H)2.00-2.25(m,3H)2.73-2.79(m,1H)2.82(d,J=14.48Hz,1H)2.92(d,J=14.48Hz,1H)3.26(m,1H)3.87-3.93(m,1H)4.43(d,J=10.17Hz,1H)6.75(dt,J=7.53,1.52Hz,1H)6.95-7.07(m,3H)7.12(t,J=7.73Hz,1H)7.17(m,1H)7.25-7.35(m,2H)。MS(ESI)492.2[M+H]+。
实施例159
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-甲氧基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-甲氧基丁烷-2-基)-3-甲基哌啶-2-酮
在0℃下向50mg(0.112mmol)(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)-3-甲基哌啶-2-酮(实施例91,步骤B)在0.5mL THF中的溶液中加入60%氢化钠(8.96mg,0.244mmol)。在0℃下搅拌30min后,加入碘甲烷(14.01uL,0.244mmol)。让反应物升温至25℃,并再搅拌2h直至完成。用饱和NH4Cl水溶液淬灭反应物,用EtOAc(2x25mL)萃取。用饱和NaCl溶液洗涤合并的有机层,经MgSO4干燥,过滤,并浓缩滤液从而得到本标题化合物。
步骤B. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-甲氧基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
按照与实施例71步骤F中描述的程序类似的程序,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-甲氧基丁烷-2-基)-3-甲基哌啶-2-酮(实施例159,步骤A)制备本标题化合物。通过反相制备型HPLC(在含有0.1%TFA的水中的MeCN,梯度洗脱)纯化残余物,从而得到本标题化合物,为白色固体。
1H NMR(400MHz,氯仿-d)δppm 0.50(t,J=8.0Hz,3H),1.42(s,3H),1.50(m,1H),1.93(m,1H),2.02(dd,J=12.0,4.0Hz,1H),2.18(dd,J=12.0,12.0Hz,1H),2.71(d,J=16.0Hz,1H),3.05(d,J=12.0Hz,1H),2.90-3.10(m,2H),3.31(dd,J=8.0,4.0Hz,1H),3.38(s,3H),3.93(t,J=12.0Hz,1H),4.61(d,J=8.0Hz,1H),6.78(d,J=8.0Hz,1H),7.01(d,J=8.0Hz,2H),7.05(s,1H),7.12(t,J=8.0Hz,1H),7.17(d,J=8.0Hz,1H),7.26(d,J=8.0Hz,2H);MS(ESI)478.0[M+H]+。
实施例160
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((3S)-1,1,1-三氟代-2-羟基-2-甲基戊烷-3-基)哌啶-3-基)乙酸
*立体化学未知
步骤A. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((3S)-1,1,1-三氟代-2-羟基-2-甲基戊烷-3-基)哌啶-2-酮
*立体化学未知
在0℃下用四丁基氟化铵在THF中的1M溶液(196μL,0.196mmol)处理(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-2-氧代戊烷-3-基)哌啶-2-酮(30mg,0.065mmo;实施例149,步骤B)和三甲基(三氟甲基)甲硅烷(48.5μL,0.327mmol)在THF(0.5mL)中的溶液。在搅拌2h后,用EtOAc萃取反应混合物。用水和饱和NaCl溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并浓缩滤液。通过硅胶快速色谱法(洗脱剂:10%至20%的EtOAc/己烷,梯度洗脱)纯化残余物,从而得到本标题化合物,为主要产物。
步骤B. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((3S)-1,1,1-三氟代-2-羟基-2-甲基戊烷-3-基)哌啶-3-基)乙酸
按照与实施例71步骤F中描述的程序类似的程序,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((3S)-1,1,1-三氟代-2-羟基-2-甲基戊烷-3-基)哌啶-2-酮(实施例160,步骤A)制备本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 0.33(t,J=8.0Hz,3H),1.47(s,3H),1.52(s,3H),1.70(m,1H),2.10-2.25(m,3H),2.89(d,J=8.0Hz,2H),2.95(t,J=8.0,1H),3.43(m,1H),4.40(d,J=12.0Hz,1H),6.75(d,J=8.0Hz,1H),6.95(m,1H),7.08-7.20(m,3H),7.26-7.40(m,3H);MS(ESI)545.2[M+H]+。
实施例161
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酰胺
依次用HBTU(0.072g,0.189mmol)、N1-((乙基亚氨基)亚甲基)-N3,N3-二甲基丙烷-1,3-二胺盐酸盐(0.036g,0.189mmol)和碳酸氢钠(0.016g,0.189mmol)处理2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸(0.055g,0.095mmol;实施例141)在DMF(2.0mL)中的溶液。让它搅拌0.5h。逐滴加入7.0M在甲醇中的氨(0.135mL,0.946mmol)。在室温下搅拌18h后,用水稀释反应物,萃取(2×EtOAc),并洗涤(1×饱和NaHCO3,和2×NaCl饱和水溶液)。经Na2SO4干燥合并的有机层,过滤,并在减压下浓缩滤液。通过反相制备型HPLC(洗脱剂:10%至90%的乙腈、水、0.1%TFA,梯度洗脱)纯化残余物,从而得到本标题化合物,其在冻干后为白色固体。
1H NMR(400MHz,氯仿-d)δppm 0.52(t,J=7.53Hz,3H)0.97-1.07(m,2H)1.18-1.25(m,2H)1.47(s,3H)1.59-1.62(m,1H)1.84-2.06(m,2H)2.33(ddd,J=8.02,4.79,3.23Hz,1H)2.43(t,J=13.8Hz,1H)2.65-2.80(m,2H)2.81-2.95(m,5H)3.17(ddd,J=13.74,10.91,2.93Hz,1H)4.80(d,J=10.76Hz,1H)6.78(br.s.,1H)6.86-6.90(m,1H)6.97-7.01(m,1H)7.10-7.15(m,2H)7.24(d,J=7.82Hz,4H)7.42(br.s.,1H);质谱(ESI)m/z=580.2(M+1)。
实施例162
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-(甲基磺酰基)乙酰胺
依次用甲烷磺酰胺(0.029g,0.310mmol)、N-乙基-N-异丙基丙烷-2-胺(0.050g,0.387mmol)和1,1′-羰基二咪唑(0.050g,0.310mmol)处理2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸(0.045g,0.077mmol)(实施例141)在THF(2.0mL)中的溶液。将该混合物加热至回流48h,用NH4Cl饱和溶液淬灭并用EtOAc萃取。经MgSO4干燥合并的有机层,过滤,并在减压下浓缩滤液。通过反相制备型HPLC(洗脱剂:10%至90%的乙腈、水、0.1%TFA,梯度洗脱)纯化残余物,从而得到本标题化合物,其在冻干后为白色固体。
1H NMR(400MHz,氯仿-d)δppm 0.52(t,J=7.53Hz,3H)0.96-1.08(m,2H)1.15-1.28(m,2H)1.50(s,3H)1.61(ddd,J=14.33,7.68,3.62Hz,1H)1.92(dd,J=13.69,2.93Hz,1H)1.96-2.10(m,1H)2.34(tt,J=8.02,4.79Hz,1H)2.49(t,J=13.89Hz,1H)2.65(d,J=14.87Hz,1H)2.73(dd,J=14.48,2.35Hz,1H)2.87(s,3H)2.98-3.08(m,2H)3.32(s,3H)4.79(d,J=10.56Hz,1H)6.84-6.90(m,1H)6.94-7.07(m,1H)7.08-7.16(m,2H)7.19-7.32(m,4H)
除非另外注解,否则采用下面的一般程序使用合适的胺,从2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸(实施例141)制备实施例163–170。
将2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸(0.020g,0.034mmol;实施例141)、相应的胺(1.2当量)、N-乙基-N-异丙基丙烷-2-胺(3.3当量)和(1H-苯并[d][1,2,3]三唑-1-基氧基)三吡咯烷-1-基鏻六氟磷(V)酸盐(1.05当量)在2ml DCM中的混合物在室温下搅拌5h。在减压下除去溶剂,并通过反相HPLC(用40-90%的含有0.1%TFA的水/乙腈梯度洗脱)纯化残余物。然后收集所需级分并浓缩从而得到纯产物。
实施例163
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-(3-羟基丙基)乙酰胺
1H NMR(400MHz,MeOH-d4)δppm 0.54(t,J=7.63Hz,3H),1.00-1.19(m,4H),1.39(s,3H),1.65-2.13(m,5H),2.25-2.36(m,1H),2.48-2.61(m,2H),2.81-2.95(m,6H),3.25-3.43(m,3H),3.61(t,J=6.26Hz,1H),4.13-4.26(br,1H),4.44(s,1H),4.82(d,J=10.76Hz,1H),6.97-7.07(m,2H),7.11-7.22(m,4H),7.27-7.347(m,2H)。质谱(ESI)m/z=638.2(M+1)。
实施例164
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-(2-羟基乙基)乙酰胺
1H NMR(400MHz,MeOH-d4)δppm 0.51(t,J=7.53Hz,3H),0.95-1.15(m,4H),1.38(s,3H),1.60-1.74(m,1H),1.79-1.92(m,1H),2.02–2.11(m,1H),2.22-2.33(m,1H),2.49-2.58(m,2H),2.78-2.93(m,6H),3.37-3.39(m,2H),3.53-3.64(m,2H),4.10-4.24(m,1H),4.39-4.49(m,1H),4.79(d,J=10.76Hz,1H),6.95-7.05(m,2H),7.10-7.21(m,4H),7.24-7.32(m,2H)。质谱(ESI)m/z=624.4(M+1)。
实施例165
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-羟基乙酰胺
1H NMR(400MHz,MeOH-d4)δppm 0.53(t,J=7.53Hz,3H),1.00-1.16(m,4H),1.38(s,3H),1.70(ddd,J=14.23,7.78,4.21Hz,1H),1.88(ddd,J=14.28,8.51,7.34Hz,1H),2.09-2.16(m,1H),2.17-2.22(m,1H),2.24-2.39(m,2H),2.52-2.60(m,1H),2.77-2.88(m,2H),2.92(s,3H),3.37-3.44(m,1H),4.20(br 1H),4.82(d,J=10.76Hz,1H),7.01-7.09(m,2H),7.13-7.22(m,4H),7.30(d,J=8.02Hz,2H)。质谱(ESI)m/z=618(M+1)。
实施例166
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-甲氧基乙酰胺
1H NMR(400MHz,氯仿-d)δppm 0.50(t,J=7.53Hz,3H),0.96-1.07(m,2H),1.17-1.28(m,2H),1.43(s,3H),1.55-1.65(m,1H),1.87-2.00(m,1H),2.07-2.13(dd,J=13.79,2.64Hz,1H),2.28-2.42(m,2H),2.63-2.77(m,3H),2.88(br,4H),3.26(ddd,J=13.89,10.66,3.03Hz,1H),3.82(s,3H),4.25(br,1H),4.77(d,J=10.76Hz,1H),6.88-6.92(m,1H),6.99-7.05(m,2H),7.10-7.14(m,2H),7.18-7.30(m,3H)。质谱(ESI)m/z=632(M+1)。
实施例167
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-((R)-2,3-二羟基丙基)乙酰胺
1H NMR(500MHz,氯仿-d)δppm 0.51(t,J=6.6Hz,3H),1.01(t,J=8.3Hz,2H),1.21(br.s.,2H),1.40-1.48(m,3H),1.58(dd,J=7.8,3.9Hz,1H),1.81-1.99(m,2H),2.28-2.36(m,1H),2.37-2.49(m,1H),2.52-2.64(m,1H,),2.67-2.77(m,1H),2.84(br.s.,2H),2.88(s,4H),2.90-3.05(m,7H),3.11-3.23(m,2H),3.47(br.s.,2H),3.55-3.72(m,2H),3.89(br.s.,1H),4.25(br.s.,1H),4.76(d,J=10.3Hz,1H),6.85-6.92(m,1H)6.98(br.s.,2H),7.00-7.06(m,1H),7.13(br.s.,3H),7.20-7.26(m,2H)。
实施例168
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-((S)-2,3-二羟基丙基)乙酰胺
1H NMR(500MHz,氯仿-d)δppm 0.43-0.58(m,3H),1.01(t,J=7.6Hz,2H),1.16-1.24(m,2H),1.41-1.45(m,1H),1.45-1.49(m,2H),1.49(s,1H),1.54-1.66(m,1H),1.79-1.95(m,2H),2.28-2.36(m,1H),2.38-2.49(m,1H),2.55(d,J=13.7Hz,1H),2.72(s,5H),2.74(s,4H,),2.84(d,J=13.2Hz,2H),2.88(s,3H),3.11-3.25(m,2H),3.28-3.39(m,1H),3.51-3.59(m,1H),3.59-3.76(m,2H),3.92(br.s.,1H),4.18-4.31(m,1H),4.70-4.81(m,1H),6.90(d,J=5.1Hz,1H)6.92-7.01(m,2H,),7.10-7.16(m,2H),7.20-7.26(m,2H)。
实施例169
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-氰基乙酰胺
搅拌2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸(0.030g,0.052mmol;实施例141)、N,N′-二环己基碳二亚胺(10.64mg,0.052mmol)和N-羟基琥珀酰亚胺(5.94mg,0.052mmol)在3mL THF中的混合物,同时用冰浴冷却3h。过滤反应混合物,并将滤液逐滴加入到在冰浴温度下的氰胺一钠(10.90mg,0.170mmol)在2mL水中的溶液中。将反应混合物在室温下搅拌12h。除去溶剂并通过反相HPLC(用40%至90%的含有0.1%TFA的水/乙腈梯度洗脱)纯化残余物。然后收集所需级分并浓缩从而得到本标题化合物。
1H NMR(500MHz,氯仿-d)δppm 0.52(t,J=7.6Hz,3H),0.98-1.10(m,2H),1.17-1.30(m,2H),1.49-1.53(m,3H),1.54-1.61(m,1H),1.91-2.03(m,1H),2.35(tt,J=8.0,4.7Hz,1H),2.56(t,J=13.8Hz,1H),2.60-2.66(m,1H),2.71-2.77(m,1H),2.80-2.87(m,1H),2.87-2.91(m,3H),2.91-3.01(m,1H),3.18(d,J=16.1Hz,1H),4.19-4.32(m,1H),4.79(d,J=10.8Hz,1H),6.84(dt,J=7.1,1.6Hz,1H),6.92-6.96(m,1H),7.11-7.18(m,2H),11.77(br.s.,1H)。
实施例170
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-(2-(二甲基氨基)乙基)乙酰胺
1H NMR(400MHz,MeOH-d4)δppm 0.52(t,J=7.53Hz,3H),1.01-1.21(m,4H),1.47(s,3H)1.62-1.85(m,2H),1.90(dd,J=13.50,3.13Hz,1H),2.42(t,J=13.69Hz,1H),2.51-2.62(m,2H),2.80-2.91(m,3H,2.93(s,3H),3.03(s,6H),3.38-3.50(m,2H),3.29–3.39(m,2H),3.84(ddd,J=15.01,7.38,4.79Hz,1H),4.21(dd,J=13.89,10.56Hz,1H),4.80(d,J=10.76Hz,1H),7.00-7.12(m,2H)7.15-7.25(m,4H)7.33(d,J=6.85Hz,2H)。质谱(ESI)m/z=651.2(M+1)。
实施例171
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-(3,4-二羟基丁基)乙酰胺
向N-(丁-3-烯基)-2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酰胺(0.030g,0.047mmol;实施例170)在1mL THF/H2O(4:1)中的溶液中加入氧化锇(VIII)(0.030mL,2.363μmol),接着加入4-甲基吗啉-4-氧化物(8.31mg,0.071mmol)。将反应混合物在室温下搅拌12h。除去溶剂并通过反相HPLC(用40%至90%的含有0.1%TFA的水/乙腈梯度洗脱)纯化残余物。然后收集所需级分并浓缩从而得到本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 0.51(t,3H),1.00(t,J=7.24Hz,2H),1.21(d,J=4.11Hz,2H),1.42(br.s.,3H),1.61(br.s.,2H),1.75-2.10(m,2H)2.26-2.44(m,2H)2.52-2.80(m,7H)2.88(s,3H),3.21(br.s.,2H),3.45-3.85(m,4H),4.23(br.s.,1H),4.76(d,J=10.56Hz,1H),6.90(br.s.,1H),6.95-7.04(m,2H),7.07-7.15(m,3H)7.23(d,J=7.04Hz,2H)。质谱(ESI)m/z=668(M+1)。
实施例172
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环丙烷磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
按照与实施例129中描述的程序类似的程序,使用等效量的环丙烷磺酰氯替代步骤C中的甲烷磺酰氯来制备本标题化合物。通过反相制备型HPLC(洗脱剂:10%至90%的乙腈、水、0.1%TFA,梯度洗脱)纯化残余物,在冻干所收集的级分后得到为白色固体的本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 0.54(t,J=7.53Hz,3H)0.92-1.08(m,2H)1.08-1.23(m,2H)1.39-1.64(m,4H)1.77-1.92(m,1H)1.96-2.07(m,1H)2.28-2.49(m,2H)2.77(d,J=14.28Hz,1H)2.92(d,J=14.09Hz,1H)3.01-3.28(m,3H)3.61(m,1H)4.76(d,J=10.56Hz,1H)6.78-6.90(m,1H)6.90-7.18(m,5H)7.23(m,2H)。
实施例173
(S)-2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)丙酸
*立体化学未确定
步骤A. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸甲酯
在0℃下向2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸(0.055g,0.095mmol;实施例141)在1mL MeOH和4mL苯中的溶液中加入(三甲基甲硅烷基)重氮甲烷在乙醚中的2.0M溶液(0.095mL,0.189mmol)。将反应混合物在0℃下搅拌0.5h,然后进行浓缩。通过反相制备型HPLC(洗脱剂:10%至90%的乙腈、水、0.1%TFA,梯度洗脱)纯化粗材料,从而在冻干汇集的所收集级分后得到为白色粉末的本标题化合物。
步骤B. (S)-2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)丙酸甲酯
*立体化学未确定
在-78℃下向上面步骤A的2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸甲酯(0.040g,0.067mmol)和HMPA(0.012mL,0.067mmol)在无水THF(1mL)中的溶液中加入2.0M在THF中的LDA(0.037mL,0.074mmol)。让它在-78℃下搅拌0.5h。然后加入碘甲烷(0.057mL,0.913mmol)。在搅拌1h后,用NH4Cl饱和水溶液淬灭反应物并用EtOAc萃取。将有机物汇集在一起,用NaCl饱和水溶液洗涤,干燥(MgSO4),过滤,并在减压下浓缩滤液从而得到黄色油状物。将该黄色油状物用于下一步骤而无需进一步纯化。
步骤C. S)-2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)丙酸
向上面步骤B的(S)-2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)丙酸甲酯(0.041g,0.067mmol)在MeOH/THF/H2O(1mL/1mL/2mL)中的溶液中加入氢氧化锂(8.02mg,0.335mmol)。将该混合物加热至60℃并保持14h。用1N HCl酸化反应混合物并用EtOAc(×2)萃取。将有机物汇集在一起,用NaCl饱和水溶液洗涤,干燥(MgSO4),过滤,并在减压下浓缩滤液从而得到无色膜状物。通过反相制备型HPLC(洗脱剂:10%至90%的乙腈、水、0.1%TFA,梯度洗脱)纯化该粗材料从而得到本标题化合物,为第一洗脱峰。
1H NMR(400MHz,氯仿-d)δppm 0.52(t,J=7.53Hz,3H)0.97-1.06(m,2H)1.20-1.26(m,2H)1.41(s,3H)1.43-1.51(m,3H)1.57-1.70(m,1H)1.88-2.04(m,2H)2.26-2.38(m,2H)2.78-2.97(m,5H)3.13(q,J=7.11Hz,1H)3.32(ddd,J=13.55,10.51,3.13Hz,1H)4.86(d,J=10.56Hz,1H)6.88-7.03(m,3H)7.10-7.16(m,2H)7.24(m,3H)。
实施例174
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S)-2-(环丙烷磺酰氨基)戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸(异构体1)
*立体化学未确定
步骤A. N-((2S,3S)-3-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)戊烷-2-基)环丙烷磺酰胺和N-((2R,3S)-3-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)戊烷-2-基)环丙烷磺酰胺
于室温下在氩气气氛下向(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S)-2-羟基戊烷-3-基)-3-甲基哌啶-2-酮(0.053g,0.115mmol;立体异构体混合物;实施例149,步骤A)和环丙烷磺酰胺(0.042g,0.345mmol)在甲苯(2mL)中的溶液中加入氰基亚甲基三正丁基正膦(0.093mL,0.345mmol),然后将该溶液在110℃下搅拌2天。然后淬灭(饱和NH4Cl)反应物,对反应物进行萃取(3×EtOAc),并洗涤(2×水和1×NaCl饱和水溶液)合并的萃取物。干燥(Na2SO4)合并的有机层并在减压下浓缩。通过反相制备型HPLC(洗脱剂:10%至90%的乙腈、水、0.1%TFA,梯度稀释)纯化粗材料从而得到本标题化合物,其为两种分开的级分。
步骤B. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2S,3S)-2-(环丙烷磺酰氨基)戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸
按照与实施例71步骤F中描述的程序类似的程序,从N-((S)-3-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)戊烷-2-基)环丙烷磺酰胺(实施例174,步骤A,较快地洗脱的异构体)制备本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 0.67(t,J=7.43Hz,3H)0.92-1.04(m,2H)1.04-1.19(m,2H)1.22(d,J=6.85Hz,3H)1.50(s,3H)1.79-1.93(m,1H)1.96-2.09(m,2H)2.28-2.42(m,2H)2.77(d,J=13.89Hz,1H)2.92-2.96(m,2H)3.14-3.31(m,1H)4.54(d,J=10.37Hz,1H)6.80(m,1H)6.91-7.19(m,5H)7.21-7.27(m,2H)
实施例175
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S)-2-(环丙烷磺酰氨基)戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸(异构体2)
*立体化学未确定
按照与实施例71步骤F中描述的程序类似的程序,从N-((3S)-3-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)戊烷-2-基)环丙烷磺酰胺(实施例174,步骤A,较慢地洗脱的异构体)制备本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 0.45-0.53(m,3H)0.97-1.12(m,2H)1.18(m,1H)1.23-1.32(m,5H)1.52(s,3H)1.70(m,1H)1.92(m,2H)2.40-2.54(m,2H)2.74(d,J=15.06Hz,1H)3.02(d,J=15.06Hz,1H)3.14(m,1H)4.85(d,J=10.56Hz,1H)6.84(m,1H)6.99(m,1H)7.08-7.17(m,2H)7.25(m,4H)
实施例176
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((3S)-2-(1-甲基乙基磺酰氨基)戊烷-3-基)-2-氧代哌啶-3-基)乙酸
*立体化学未确定
按照与实施例174中描述的程序类似的程序,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S)-2-羟基戊烷-3-基)-3-甲基哌啶-2-酮(立体异构体混合物;实施例149,步骤A)和丙烷-2-磺酰胺制备本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 0.47(t,J=7.83Hz,3H)1.20(d,J=6.85Hz,3H)1.41(dd,J=14.87,6.85Hz,6H)1.51-1.60(s,3H)1.60-1.73(m,1H)1.80-2.00(m,2H)2.50(t,J=13.89Hz,1H)2.72-2.81(d,J=14.67Hz,1H)2.97(d,J=14.67Hz,1H)3.07-3.23(m,2H)4.85(d,J=10.96Hz,1H)6.87(m,1H)6.97-7.07(m,1H)7.07-7.19(m,2H)7.19-7.33(m,4H)。
实施例177
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)-1-氧代丁烷-2-基)-2-氧代哌啶-3-基)乙酸
*立体化学未确认
步骤A. 2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁酸
向搅拌着的2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁酸甲酯(200mg,0.42mmol;实施例91,步骤A)在THF(5mL)中的溶液中加入在水(5mL)中的氢氧化钠(506mg,12.65mmol),并将反应物在回流下加热大约12h。在此时间后,将反应物冷却至室温并将其分配在EtOAc(80mL)和1.0M HCl(20mL)之间。用EtOAc(30mL)萃取分离的水层,经MgSO4干燥合并的有机层,过滤,并在真空中蒸发滤液从而得到本标题化合物,为白色固体。质谱(ESI)m/z=460.0(M+1)。
步骤B. (S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-N-(环丙基磺酰基)丁酰胺
*立体化学未确认
向搅拌着的2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁酸(140mg,0.304mmol;实施例177,步骤A)在DMF(2mL)中的溶液中加入三吡咯烷-1基溴化鏻六氟磷酸盐(V)(354mg,0.76mmol)和N,N-二异丙基乙胺(0.11mL,0.61mmol),并将反应物在室温下搅拌3小时。在此时间后,将反应物分配在EtOAc(60mL)和1.0M LiCl水溶液(20mL)之间。经MgSO4干燥分离的有机层,过滤,并在真空中蒸发。柱色谱分离(SiO2,己烷:EtOAc,1:0至1:1)得到本标题化合物。质谱(ESI)m/z=563.0(M+1)。
步骤C. (S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-N-(环丙基磺酰基)-N-甲基丁酰胺
*立体化学未确认
在室温下向搅拌着的(S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-N-(环丙基磺酰基)丁酰胺(8mg,0.014mmol;实施例177,步骤B)在DMF(1.0mL)中的溶液中加入碳酸钾(2.9mg,0.021mmol)和碘甲烷(1.1μL,0.017mmol)。将反应物搅拌1小时。在此时间后,再加入碘甲烷(1.1μL,0.017mmol)和碳酸钾(2.9mg,0.021mmol),并将反应物在室温下搅拌60小时。在此时间后,将反应物分配在EtOAc(20mL)和1.0M LiCl(5mL)之间。用1.0M LiCl(5mL)洗涤分离的有机层,经MgSO4干燥,过滤,并在真空中蒸发从而得到本标题化合物。质谱(ESI)m/z=577.0(M+1)。
步骤D. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)-1-氧代丁烷-2-基)-2-氧代哌啶-3-基)乙酸
按照与实施例71步骤F中描述的程序类似的程序,从2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-N-(环丙基磺酰基)-N-甲基丁酰胺(实施例177,步骤C)制备本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 7.30(2H,d,J=8.4Hz),7.15-7.25(4H,m),6.94(2H,d,J=7.6Hz),4.79-4.93(2H,m),3.31(3H,s),3.08-3.17(1H,m),2.92(1H,d,J=15.1Hz),2.70(1H,d,J=14.7Hz),2.08-2.19(2H,m),1.72(2H,t,J=7.5Hz),0.92-1.39(8H,m),0.84-0.91(3H,m)。质谱(ESI)m/z=595.0(M+1)。
实施例178
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(新戊基氨基)-1-氧代丁烷-2-基)-2-氧代哌啶-3-基)乙酸
*立体化学未确认
步骤A. 2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁酸
*立体异构体混合物
向在0℃下的搅拌着的2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁酸(110mg,0.24mmol;实施例177,步骤A或实施例1,步骤F)和DIEA(0.050ml,0.287mmol)在干DMF(1195μL)中的溶液中加入HATU(109mg,0.287mmol)。将反应物在0°下搅拌5min,接着加入2当量新戊胺(55.9μL,0.478mmol;TCI America)。将反应溶液在0℃下搅拌10min直至根据LCMS确定完成,然后过滤。通过反相制备型HPLC(SunfireTMPrep C18 OBD10μm柱(Waters,Milford,MA),用70%至100%的在水中的MeCN梯度洗脱超过35min,这两种溶剂都含有0.1%TFA)纯化该溶液,得到本标题化合物,为差向异构体混合物。
步骤B. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(新戊基氨基)-1-氧代丁烷-2-基)-2-氧代哌啶-3-基)乙酸
按照与实施例71步骤F中描述的程序类似的程序并随后通过反相HPLC(洗脱剂:55%MeCN/水(0.1%TFA),等度洗脱)使用Sunfire C18 OBD柱,10uM,(30x150mm),WatersCorp(Milford,MA)纯化残余物,来从2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-N-新戊基丁酰胺(88mg,0.166mmol)(实施例178,步骤A)获得本标题化合物。
1H NMR(500MHz,氯仿-d)δppm 0.79(t,J=7.46Hz,3H),0.93(s,9H),1.26(s,2H),1.43(s,3H),1.78(dquin,J=14.38,7.29,7.29,7.29,7.29Hz,1H),2.08-2.23(m,3H),2.81(dd,J=13.20,5.14Hz,1H),2.88(s,2H),3.09(dd,J=13.20,6.60Hz,1H),3.17(ddd,J=12.78,9.72,3.67Hz,1H),3.92(t,J=7.34Hz,1H),4.63(d,J=9.78Hz,1H),6.75(d,J=7.58Hz,1H),6.94-7.00(m,3H),7.10(t,J=7.70Hz,2H),7.13-7.24(m,3H)。质谱(ESI)m/z=547(M+1)。
实施例179
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(4,4-二甲基-4,5-二氢噁唑-2-基)丙基)-3-甲基-2-氧代哌啶-3-基)乙酸
*立体化学未确认
步骤A. 2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-N-(1-羟基-2-甲基丙烷-2-基)丁酰胺
*立体异构体混合物
在0℃下向2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-N-(1-羟基-2-甲基丙烷-2-基)丁酰胺(实施例177,步骤A)和5当量2-氨基-2-甲基丙烷-1-醇(80μL,0.836mmol;Sigma-Aldrich)在DMF(1672μL)中的溶液中加入1.2当量HATU(76mg,0.201mmol)。将反应溶液搅拌1小时,此时根据LCMS判断反应已完成。用EtOAc(50mL)稀释反应混合物并用NaHCO3(20mL)、1N HCl,和水洗涤。经Na2SO4干燥合并的有机层,过滤,并浓缩滤液从而得到粗材料,其为澄清的溶液(存在残余DMF)。将该产物用于下一步骤而无需进一步纯化。
步骤B. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(4,4-二甲基-4,5-二氢噁唑-2-基)丙基)-3-甲基哌啶-2-酮
*立体化学未确认
向冷(-78℃)的2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-N-(1-羟基-2-甲基丙烷-2-基)丁酰胺(89mg,0.167mmol;实施例179,步骤A:差向异构体混合物)在DCM(1674μL)中的溶液中逐滴加入3当量二乙基胺基三氟化硫(26.5μL,0.201mmol)。将反应混合物在-78℃下搅拌20min。然后一次性加入无水K2CO3(1.5当量),并让该混合物升温至室温。将反应物倒入饱和NaHCO3水溶液中,并用EtOAc x2萃取该两相混合物。经MgSO4干燥合并的有机萃取物,过滤,并在减压下浓缩滤液。通过硅胶快速色谱法(洗脱剂:0%至20%的乙酸乙酯/己烷)纯化残余物,得到本标题化合物。
1H NMR(500MHz,氯仿-d)δppm 0.76(t,J=7.46Hz,3H),1.08(s,3H),1.15(s,3H),1.24(s,3H),1.67(s,1H),1.82(dt,J=14.43,7.21Hz,1H),1.89-1.96(m,1H),2.00-2.11(m,1H),2.21(dt,J=14.31,7.27Hz,1H),2.61(d,J=7.58Hz,2H),3.21(ddd,J=13.14,10.09,3.18Hz,1H),3.64(d,J=7.83Hz,1H),3.90(d,J=7.83Hz,1H),4.12(t,J=6.85Hz,1H),4.54(d,J=10.27Hz,1H),5.16(s,1H),5.18(d,J=3.18Hz,1H),5.81-5.93(m,1H),6.75(d,J=7.58Hz,1H),7.00(s,3H),7.10(t,J=7.70Hz,1H),7.15(d,J=8.07Hz,1H),7.20(d,J=8.31Hz,2H)。质谱(ESI)m/z=513(M+1)。
进一步洗脱得到另一个差向异构体:(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-1-(4,4-二甲基-4,5-二氢噁唑-2-基)丙基)-3-甲基哌啶-2-酮。
1H NMR(500MHz,氯仿-d)δppm 0.96(t,J=7.46Hz,3H),1.19(s,3H),1.27(s,3H),1.30(s,3H),1.65(br.s.,1H),1.86-2.06(m,4H),2.60(qd,J=14.06,7.70Hz,2H),3.20(ddd,J=13.27,10.09,3.30Hz,1H),3.79-3.89(m,2H),3.89-3.95(m,1H),4.49(d,J=10.03Hz,1H),5.15(s,1H),5.18(d,J=3.91Hz,1H),5.82-5.95(m,1H),6.72(d,J=7.58Hz,1H),6.97(t,J=1.83Hz,1H),7.08-7.13(m,1H),7.13-7.23(m,3H)。质谱(ESI)m/z=513(M+1)。
步骤C. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(4,4-二甲基-4,5-二氢噁唑-2-基)丙基)-3-甲基-2-氧代哌啶-3-基)乙酸
按照与实施例71步骤F中描述的程序类似的程序,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(4,4-二甲基-4,5-二氢噁唑-2-基)丙基)-3-甲基哌啶-2-酮(53mg,0.103mmol;实施例179,步骤B)获得本标题化合物。
1H NMR(500MHz,氯仿-d)δppm 0.74(t,J=7.46Hz,3H)1.08(s,3H)1.14(s,3H)1.41(s,3H)1.74(dt,J=14.31,7.03Hz,1H)2.04-2.12(m,1H)2.12-2.30(m,2H)2.76(d,J=14.43Hz,1H)2.88(d,J=14.18Hz,1H)3.24(ddd,J=12.59,9.66,3.18Hz,1H)3.66(d,J=8.07Hz,1H)3.88(d,J=8.07Hz,1H)4.16(t,J=6.72Hz,1H)4.60(d,J=9.78Hz,1H)6.78(d,J=7.58Hz,1H)6.99-7.06(m,2H)7.10(t,J=7.82Hz,2H)7.14-7.18(m,1H)7.22(d,J=8.31Hz,2H)。质谱(ESI)m/z=531(M+1)。
实施例180
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(N-(2,2,2-三氟乙基)乙酰氨基)丁烷-2-基)哌啶-3-基)乙酸
步骤A. N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁基)-N-(2,2,2-三氟乙基)乙酰胺
按照与实施例28步骤C中描述的程序类似的程序,通过乙酰化(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-((2,2,2-三氟乙基)氨基)丁烷-2-基)哌啶-2-酮(实施例147,步骤A)获得本标题化合物。
步骤B. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(N-(2,2,2-三氟乙基)乙酰氨基)丁烷-2-基)哌啶-3-基)乙酸
按照与实施例71步骤F中描述的程序类似的程序,从N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁基)-N-(2,2,2-三氟乙基)乙酰胺(实施例180,步骤A)获得本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 0.52(t,J=8.0Hz,3H),1.50(s,3H),1.61(m,1H),1.87(m,1H),1.90-2.40(m,3H),2.27(s,3H),2.77(d,J=16.0Hz,1H),3.00(d,J=16.0Hz,1H),3.10-3.30(m,2H),3.43(m,1H),3.85-4.05(m,3H),4.40(d,J=8.0Hz,1H),6.71(d,J=8.0Hz,1H),6.92(s,1H),7.01(m,2H),7.05-7.20(m,2H),7.25(d,J=8.0Hz,2H)。
实施例181
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二甲基乙基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁基)-2-甲基丙烷-2-磺酰胺
将202.6mg(0.454mmol)(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)-3-甲基哌啶-2-酮(实施例91,步骤B)和2-甲基丙烷-2-磺酰胺(130mg,0.948mmol,Oakwood)溶解在无水甲苯(4.5mL)中。经由注射器将421mg氰基亚甲基三丁基正膦转移至反应容器中。在第一次添加后2分钟,再加入约30mg该正膦试剂。在预先加热的油浴中于34-41℃下搅拌反应混合物。通过LCMS监测反应。在2h 15min后再加入133mg叔丁基磺酰胺,并将反应混合物在35℃下加热过夜。
在第二天,在26h,15min的总反应时间后,再加入133mg叔丁基磺酰胺。30分钟后,再加入421mg氰基亚甲基三丁基正膦。继续在35℃至40℃下加热过夜。
在第三天,根据LCMS,反应似乎完成。在53h总反应时间后,将该混合物分配在乙酸乙酯和饱和氯化铵之间。将水相用EtOAc反萃2X,用NaCl饱和水溶液洗涤,经硫酸钠干燥,过滤,并在真空中浓缩滤液从而得到残余物,通过在24g硅胶柱上用0%至30%的在己烷中的EtOAc梯度洗脱来对该残余物进行色谱分离。合并含有所需产物的级分并浓缩从而得到本标题化合物,为灰白色固体,在高真空下干燥该固体。MS(ESI)m/z=565[M+H]+。
步骤B. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二甲基乙基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
将N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁基)-2-甲基丙烷-2-磺酰胺(100mg,0.177mmol;实施例181,步骤A)转移到含有搅拌棒的圆底烧瓶中,接着将四氯化碳(1.100mL)、乙腈(1.1mL),和水(1.6mL)转移到该烧瓶中。然后在该烧瓶中装入高碘酸钠(190mg,0.888mmol)和氯化钌(III)水合物(6mg,0.023mmol),并将由此产生的红棕色悬浮液在室温下剧烈搅拌。在18h反应时间后,再加入200mg高碘酸钠,和2mg氯化钌(III)水合物。继续在室温下搅拌。在4h后,通过加入1.3M HCl水溶液来淬灭反应物并用乙酸乙酯稀释反应物。过滤由此产生的混合物。向水相中加入NaCl饱和水溶液以促进相分离。用NaCl饱和水溶液洗涤合并的有机物,经硫酸钠干燥,过滤,并在真空中浓缩滤液。由此产生的残余物通过在SunfireTM反相制备型HPLC柱(Waters,Milford,MA)上,用50%至95%的在水中的MeCN(这两种溶剂都含有0.1%TFA)梯度洗脱超过35分钟来进行色谱分离。合并经HPLC获得的含有高纯度的所需产物的级分,在旋转蒸发器上除去挥发物,并冻干从而得到本标题化合物,为灰白色固体。
1H NMR(500MHz,CD3OD)δ0.46(t,J=7.58Hz,3H),1.30-1.42(m,9H),1.45(s,3H),1.52-1.66(m,1H),1.75-1.89(m,1H),1.96-2.10(m,1H),2.33-2.49(m,1H),2.64(d,J=13.45Hz,1H),2.72-2.83(m,1H),2.88-2.97(m,1H),2.97-3.07(m,1H),3.32-3.40(m,1H),3.86-4.05(m,1H),4.94-5.05(m,1H),6.79-7.45(m,8H)。MS(ESI)m/z=583[M+H]+。
实施例182
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N,2-二甲基丙烷-2-基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁基)-N,2-二甲基丙烷-2-磺酰胺
将N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁基)-2-甲基丙烷-2-磺酰胺(100mg,0.177mmol;实施例181,步骤A)溶解在DMF(2.5mL)中,并一次性加入氢化钠(60%的在矿物油中的分散体,19mg,0.45mmol)。在25分钟后,将该混合物在冰水浴中冷却至0℃,并通过注射器逐滴加入碘甲烷(0.04mL,0.643mmol)。让该混合物温度逐渐升至室温,逐渐变成浅黄色悬浮液。在2h后,非常小心地加入水(2mL)。将由此产生的混合物分配在乙酸乙酯和NH4Cl饱和水溶液之间。反萃(2X)水相,用NaCl饱和水溶液(2X)洗涤合并的有机物,经硫酸钠干燥,过滤,并在真空中浓缩滤液至油状残余物,通过在12g硅胶柱上用0%至35%的在己烷中的EtOAc梯度洗脱来对该油状残余物进行色谱分离。汇集含有磺酰胺产物的级分并浓缩从而得到本标题化合物。MS(ESI)m/z=579[M+H]+。
步骤B. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N,2-二甲基丙烷-2-基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
按照与实施例181步骤B中描述的程序类似的程序,从N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁基)-N,2-二甲基丙烷-2-磺酰胺(实施例182,步骤A)制备该化合物。将获得的粗材料溶解在甲醇中,过滤,并通过反相HPLC在SunfireTM反相制备型HPLC柱(Waters,Milford,MA)上,用50%至100%的在水中的MeCN(这两种溶剂都含有0.1%TFA)梯度洗脱来进行纯化。除去挥发物,用最少的MeCN重新溶解悬浮物,冷冻,并冻干从而得到本标题化合物,为灰白色固体。
1H NMR(500MHz,CD3OD)δ0.51(t,J=7.21Hz,3H),1.32-1.48(m,12H),1.58-1.71(m,1H),1.78-1.92(m,1H),1.94-2.06(m,1H),2.43(t,J=13.69Hz,1H),2.63(d,J=13.20Hz,1H),2.71-2.88(m,2H),2.88-3.01(m,4H),3.28(d,J=2.93Hz,0H),3.32-3.35(m,1H),4.40(br.s.,1H),4.79(d,J=10.76Hz,1H),6.96-7.09(m,3H),7.10-7.40(m,5H)。MS(ESI)m/z=597[M+H]+。
实施例183
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(1-甲基乙基磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
步骤A. N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁基)丙烷-2-磺酰胺
如实施例181步骤A中所述,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)-3-甲基哌啶-2-酮(实施例91,步骤B)和丙烷-2-磺酰胺制备本标题化合物。MS(ESI)m/z=551[M+H]+。
步骤B. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(1-甲基乙基磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
按照与实施例181步骤B中描述的程序类似的程序,从N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁基)丙烷-2-磺酰胺(实施例183,步骤A)获得本标题化合物。通过反相HPLC在SunfireTM反相制备型HPLC柱(Waters,Milford,MA)上,用50%至100%的在水中的MeCN(这两种溶剂都含有0.1%TFA)梯度洗脱来纯化残余物。合并色谱分离的级分并在真空中浓缩。通过加入最少的MeCN来使由此产生的悬浮液变成均匀的,将该悬浮液冷冻,并冻干从而得到本标题化合物。
1H NMR(500MHz,CD3OD)δ0.45(t,J=7.58Hz,3H),1.35(dd,J=8.56,6.85Hz,6H),1.41(br.s.,3H),1.51-1.64(m,1H),1.83(ddd,J=14.43,8.56,7.34Hz,1H),2.05(dd,J=13.69,2.93Hz,1H),2.39(t,J=13.69Hz,1H),2.64(d,J=13.45Hz,1H),2.80(t,J=9.29Hz,1H),2.87-3.04(m,2H),3.23(dt,J=13.51,6.82Hz,1H),3.33-3.40(m,1H),3.85(dd,J=14.06,10.15Hz,1H),4.96(d,J=11.00Hz,1H),6.36-7.71(m,8H)。MS(ESI)m/z=569[M+H]+。
实施例184
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N-乙基丙烷-2-基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁基)-N-乙基丙烷-2-磺酰胺
按照与实施例182步骤A中描述的程序类似的程序,用碘乙烷代替碘甲烷来从N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁基)丙烷-2-磺酰胺(实施例183,步骤A)制备本标题化合物。MS(ESI)m/z=579[M+H]+。
步骤B. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N-乙基丙烷-2-基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
按照与实施例71步骤F中描述的程序类似的程序,从N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁基)-N-乙基丙烷-2-磺酰胺(实施例184,步骤A)制备本标题化合物。通过在SunfireTMC18反相制备型HPLC柱(Waters,Milford,MA)上,用50%至100%的在水中的MeCN(这两种溶剂都含有0.1%TFA)梯度洗脱来对残余物进行色谱分离。合并经HPLC获得的含有高纯度的产物的级分,并在旋转蒸发器上除去挥发物。将悬浮液重新溶解在最少的MeCN中,冷冻,并冻干过夜从而得到本标题化合物,为白色泡沫状物。
1H NMR(500MHz,CD3OD)δ0.52(t,J=7.21Hz,3H),1.09-1.20(m,3H),1.30(d,J=6.85Hz,3H),1.38(d,J=6.85Hz,3H),1.43(s,3H),1.56-1.69(m,1H),1.82-1.97(m,1H),2.01(dd,J=13.69,2.93Hz,1H),2.41(t,J=13.69Hz,1H),2.64(d,J=13.20Hz,1H),2.82(br.s.,1H),2.88-3.02(m,2H),3.15-3.25(m,1H),3.28(d,J=3.18Hz,1H),3.33-3.36(m,1H),3.40-3.55(m,1H),4.29(d,J=6.36Hz,1H),4.84(br.d,J=1.00Hz,1H),6.81-7.55(m,8H)。MS(ESI)m/z=597[M+H]+。
实施例185
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. (S)-2-((2S,3R)-3-(3-氯苯基)-2-(4-氯苯基)-6-氧代哌啶-1-基)丁酸甲酯
用超过45min的时间向50℃的33.8g(60%在矿物油中,845mmol)氢化钠在2-甲基四氢呋喃(550mL)中的溶液中加入240g(750mmol)(5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)哌啶-2-酮(实施例1,步骤E)在2-甲基四氢呋喃(550mL)中的溶液。再在50℃下1.25h后,用超过20min的时间加入105mL(912mmol)2-溴丁酸甲酯。将由此产生的浆液在50℃下搅拌3.5h,然后冷却至室温并用NH4Cl饱和水溶液淬灭。加入水溶解沉淀,并用乙酸乙酯(4X)萃取由此产生的混合物。用NaCl饱和水溶液(1X)洗涤合并的有机层,经Na2SO4干燥,过滤并浓缩滤液。通过硅胶色谱法( SnapTM柱(Biotage,LLC,Charlotte,NC),0%至35%的EtOAc/DCM,梯度洗脱)纯化残余物,得到本标题化合物,为白色油状固体。
步骤B. (5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)哌啶-2-酮
向冰冷却的48.5g(115mmol)(S)-2-((2S,3R)-3-(3-氯苯基)-2-(4-氯苯基)-6-氧代哌啶-1-基)丁酸甲酯(实施例185,步骤A)在乙醚(850mL)中的溶液中加入5.96g(90%,246mmol)硼氢化锂。将由此产生的浅黄色溶液在0℃下搅拌3h,然后加入MeOH(2.5mL)并再加入乙醚(100mL)。在加入MeOH后观察到气体逸出。在40min后,通过小心地加入1N HCl直至停止冒气泡来淬灭反应物。用EtOAc(2X)萃取该混合物,并用饱和氯化钠水溶液(1X)洗涤合并的有机层。经Na2SO4干燥有机层,过滤,并浓缩滤液从而得到本标题化合物,为白色泡沫状物。将该粗产物直接用于下一步骤而无需进一步纯化。
步骤C. (5R,6S)-1-((S)-1-(叔丁基二苯基甲硅烷基氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)哌啶-2-酮
向44.7g(114mmol)(5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)哌啶-2-酮(实施例185,步骤B)和19.4g(285mmol)咪唑在DMF(350mL)中的溶液中加入39.4mL(154mmol)叔丁基二苯基氯甲硅烷。将该无色溶液在室温下搅拌17h。将反应物分配在水和乙醚(3X)之间,然后用饱和氯化钠水溶液(1X)洗涤合并的有机层,经Na2SO4干燥,过滤,并浓缩滤液。通过硅胶色谱法( SnapTM柱(Biotage,LLC,Charlotte,NC),0%至60%的EtOAc/己烷,梯度洗脱)纯化残余物,得到本标题化合物,为白色泡沫状物。
步骤D. (5R,6S)-1-((S)-1-(叔丁基二苯基甲硅烷基氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮
用超过20min的时间向-78℃的98.2g(156mmol)(5R,6S)-1-((S)-1-(叔丁基二苯基甲硅烷基氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)哌啶-2-酮(实施例185,步骤C)和10.0mL(160mmol)碘甲烷在脱气的干THF(400mL)中的溶液中缓慢地加入200mL(200mmol)脱气的双(三甲基甲硅烷基)氨基锂在THF中的1M溶液。将该橙色溶液在-78℃下搅拌1.5h,然后升温至0℃并再搅拌1.5h。用饱和氯化铵水溶液淬灭反应物,并用EtOAc(3X)萃取。经Na2SO4干燥合并的有机层,过滤,并浓缩滤液。通过硅胶色谱法( SnapTM柱;Biotage,LLC,Charlotte,NC),5-55%EtOAc/己烷,梯度洗脱)纯化残余物,得到本标题化合物,为淡黄色泡沫状物。
步骤E. (3S,5R,6S)-3-烯丙基-1-((S)-1-(叔丁基二苯基甲硅烷基氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮
经由插管向-78℃的37.3mL(266mmol)二异丙胺在脱气的干THF(150mL)中的溶液中缓慢地加入100mL(250mmol)脱气的正丁基锂在己烷中的2.5M溶液。将该淡黄色溶液在-78℃下搅拌15min,然后升温至0℃并再搅拌5min。用超过15min的时间经由插管向冰冷却的LDA溶液中加入85.7g(133mmol)(5R,6S)-1-((S)-1-(叔丁基二苯基甲硅烷基氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮(实施例185,步骤D)在脱气的干THF(210mL)中的溶液。将该暗橙色溶液在0℃下搅拌30min,然后经由注射器快速地加入34.5mL(399mmol)烯丙基溴。在20sec后,移开冰浴,将反应物置于室温水浴中并再搅拌15min。用氯化铵饱和水溶液淬灭反应物,并用EtOAc(3X)萃取。经Na2SO4干燥合并的有机层,过滤,并浓缩滤液。通过硅胶色谱法( SnapTM柱;Biotage,LLC,Charlotte,NC),用6-14%EtOAc/己烷梯度洗脱)纯化残余物,得到本标题化合物,为白色泡沫状物。
步骤F. 2-((3R,5R,6S)-1-((S)-1-(叔丁基二苯基甲硅烷基氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸
按照与实施例71步骤F中描述的程序类似的程序,从(3S,5R,6S)-3-烯丙基-1-((S)-1-(叔丁基二苯基甲硅烷基氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮(实施例185,步骤E)制备本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 0.30(t,J=7.53Hz,3H)1.17(s,9H)1.34-1.48(m,1H)1.53(s,3H)1.74-1.88(m,1H)1.93-2.03(m,1H)2.29(t,J=13.69Hz,1H)2.69(d,J=15.85Hz,1H)2.81-2.93(m,1H)2.98-3.08(m,1H)3.12(d,J=15.65Hz,1H)3.52(dd,J=10.66,4.21Hz,1H)4.32(t,J=10.27Hz,1H)4.71(d,J=10.76Hz,1H)6.56-6.66(m,1H)6.91-6.97(m,1H)7.02-7.09(m,1H)7.12-7.18(m,1H)7.20-7.30(m,4H)7.33-7.51(m,6H)7.64(td,J=7.83,1.57Hz,4H)。
步骤G. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
向370g(0.53mmol)2-((3R,5R,6S)-1-((S)-1-(叔丁基二苯基甲硅烷基氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸(实施例185,步骤F)在THF(15mL)中的冰冷却的溶液中加入2.60mL(2.60mmol)TBAF在THF中的1M溶液。将该黄色溶液升温至室温并搅拌5h。在此时加入2.60mL(2.60mmol)TBAF在THF中的1M溶液,并将反应物再搅拌20h。将反应物分配在1N HCl和EtOAc(4X)之间。经Na2SO4干燥合并的有机层,过滤,并浓缩滤液。通过反相制备型HPLC(SunfireTMPrep C18OBD 10μm柱(Waters,Milford,MA),用40%的在水中的MeCN至80%的在水中的MeCN梯度洗脱超过30min,其中这两种溶剂都含有0.1%TFA)纯化残余物,得到本标题化合物,为白色固体。
1H NMR(400MHz,CDCl3)δppm 7.23-7.28(2H,m),7.15-7.20(1H,m),7.07-7.14(1H,m),6.98-7.06(3H,m),6.74(1H,d,J=7.1Hz),4.55(1H,dd J=9.8Hz,2.9Hz),3.71-3.79(1H,m),3.58-3.66(1H,m),3.19-3.28(1H,m),3.07-3.16(1H,m),2.96-3.03(1H,m),2.75(1H,dd,J=14.9Hz,2.9Hz),2.16-2.25(1H,m),2.03-2.10(1H,m),1.87-1.98(1H,m),1.46(3H,s),1.41-1.54(m,1H),0.63(3H,dd,J=7.3Hz,3.3Hz)。质谱(ESI)m/z=464.1(M+1)。
实施例186
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(三氟甲基磺酰氨基)丁烷-2-基)哌啶-3-基)乙酸
步骤A. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸甲酯
将2-((3R,5R,6S)-1-((S)-1-(叔丁基二苯基甲硅烷基氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸(实施例185)在MeOH(2mL)和苯(8mL)中的溶液与2.0M在乙醚中的(三甲基甲硅烷基)重氮甲烷(2.02mL,4.04mmol)一起在室温下搅拌0.5h。在此时间后,浓缩该混合物从而得到粗甲酯,在室温下用在THF中的TBAF处理该粗甲酯30h。浓缩该混合物并通过硅胶色谱法(0%至100%的在己烷中的EtOAc)纯化从而得到本标题化合物。质谱(ESI)m/z=478(M+1)。
步骤B. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(三氟甲基磺酰氨基)丁烷-2-基)哌啶-3-基)乙酸
在氩气下的反应瓶中装入在甲苯(0.5mL)中的2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸甲酯(0.048g,0.1mmol;实施例186,步骤A)、2-(三丁基正膦亚基)乙腈(0.036g,0.15mmol)和三氟甲烷磺酰胺(0.022g,0.15mmol)。将反应瓶中的反应混合物密封,并在110℃下搅拌1h。硅胶柱色谱分离得到2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(三氟甲基磺酰氨基)丁烷-2-基)哌啶-3-基)乙酸甲酯与未知杂质的混合物。将该混合物在室温下用在乙醇(0.5mL)中的LiOH(1N水溶液,0.3mL)水解3h。HPLC纯化(C18柱,用10%至95%的含有0.1%TFA的在水中的CH3CN洗脱),得到本标题化合物。
1H NMR(500MHz,氯仿-d)δppm 7.26(2H,br.s.),7.15-7.20(1H,m),7.12(1H,t,J=7.8Hz),7.05(1H,d,J=9.3Hz),6.95(1H,t,J=1.7Hz),6.75(1H,d,J=7.6Hz),6.49(1H,br.s.),4.53(1H,d,J=10.3Hz),3.13-3.27(3H,m),2.80-2.93(3H,m),2.24(1H,t,J=13.8Hz),2.10(1H,dd,J=14.1,3.1Hz),1.83(1H,br.s.),1.55-1.66(1H,m),1.49(3H,s),0.71(3H,br.s.)。质谱(ESI)m/z=595(M+1)。
除非另外注解,否则按照与实施例186步骤B中描述的程序类似的程序,用合适的试剂替代三氟甲烷磺酰胺来从2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸甲酯(实施例186,步骤A)制备实施例187-195。
实施例187
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(4-氯苯基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(500MHz,氯仿-d)δppm 7.77(2H,m,J=8.6Hz),7.48-7.54(2H,m),7.23(2H,d,J=8.1Hz),7.11-7.19(2H,m),7.05(2H,d,J=5.9Hz),6.98(1H,s),6.86(1H,d,J=7.3Hz),5.31(2H,br.s.),5.26(3H,br.s.),4.78(1H,d,J=10.3Hz),3.43(1H,br.s.),3.17(2H,ddd,J=13.5,10.7,2.9Hz),2.97(1H,d,J=14.4Hz),2.79(1H,d,J=14.4Hz),2.74(1H,d,J=13.7Hz),2.38(1H,t,J=13.8Hz),2.05(1H,dd,J=13.9,2.9Hz),1.80(1H,dt,J=14.6,7.5Hz),1.52(3H,s),1.43-1.50(1H,m),0.51(3H,t,J=7.1Hz)。质谱(ESI)m/z=637(M+1)。
实施例188
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(4-甲基苯基磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
1H NMR(500MHz,氯仿-d)δppm 7.72(2H,m,J=8.3Hz),7.33(2H,m,J=8.1Hz),7.23(2H,d,J=8.1Hz),7.11-7.19(2H,m),7.05(2H,d,J=6.6Hz),6.96-6.99(1H,m),6.85-6.91(1H,m),4.95(1H,br.s.),4.83(1H,d,J=10.5Hz),3.49(1H,br.s.),3.14(2H,ddd,J=13.4,10.6,2.8Hz),3.02(1H,d,J=14.9Hz),2.70-2.81(2H,m),2.45(3H,s),2.36-2.44(1H,m),2.01(1H,dd,J=13.9,2.9Hz),1.81(1H,dd,J=15.3,7.5Hz),1.53(3H,s),1.47(1H,ddd,J=14.2,7.6,4.3Hz),0.47(3H,t,J=7.5Hz)。质谱(ESI)m/z=617(M+1)。
实施例189
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(2-氯苯基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(500MHz,氯仿-d)δppm 7.77(2H,m,J=8.6Hz),7.48-7.54(2H,m),7.23(2H,d,J=8.1Hz),7.11-7.19(2H,m),7.05(2H,d,J=5.9Hz),6.98(1H,s),6.86(1H,d,J=7.3Hz),5.31(2H,br.s.),5.26(3H,br.s.),4.78(1H,d,J=10.3Hz),3.43(1H,br.s.),3.17(2H,ddd,J=13.5,10.7,2.9Hz),2.97(1H,d,J=14.4Hz),2.79(1H,d,J=14.4Hz),2.74(1H,d,J=13.7Hz),2.38(1H,t,J=13.8Hz),2.05(1H,dd,J=13.9,2.9Hz),1.80(1H,dt,J=14.6,7.5Hz),1.52(3H,s),1.43-1.50(1H,m),0.51(3H,t,J=7.1Hz)。质谱(ESI)m/z=651(M+1)。
实施例190
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(2-甲基苯基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(500MHz,氯仿-d)δppm 7.89(1H,d,J=7.8Hz),7.46-7.52(1H,m),7.31-7.38(2H,m),7.23(2H,d,J=7.8Hz),7.12-7.18(2H,m),7.06(2H,br.s.),6.99(1H,s),6.88(1H,d,J=7.1Hz),5.16(1H,br.s.),4.85(1H,d,J=10.5Hz),4.46(3H,br.s.),3.44(1H,br.s.),3.11-3.22(2H,m),2.99(1H,d,J=14.9Hz),2.73-2.84(2H,m),2.67(3H,s),2.36-2.47(1H,m),2.04(1H,dd,J=13.9,2.9Hz),1.80(1H,dt,J=14.7,7.7Hz),1.53(3H,s),1.45(1H,ddd,J=14.1,7.6,4.4Hz),0.46(3H,t,J=7.5Hz)。质谱(ESI)m/z=617(M+1)。
实施例191
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(4-甲氧基苯基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(500MHz,氯仿-d)δppm 7.76(2H,d,J=8.8Hz),7.24(2H,d,J=7.8Hz),7.11-7.19(2H,m),7.04(1H,br.s.),7.01(1H,s),6.98(2H,d,J=4.4Hz),6.88(1H,d,J=6.8Hz),4.92(1H,br.s.),4.83(1H,d,J=10.5Hz),4.03(3H,br.s.),3.89(3H,s),3.49(1H,br.s.),3.14(2H,t,J=10.8Hz),3.02(1H,d,J=14.9Hz),2.69-2.80(2H,m),2.42(1H,t,J=13.8Hz),1.97-2.05(1H,m),1.82(1H,dt,J=14.6,7.5Hz),1.53(3H,s),1.41-1.50(1H,m),0.47(3H,t,J=7.3Hz)。质谱(ESI)m/z=633(M+1)。
实施例192
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(苯基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(500MHz,氯仿-d)δppm 7.84(2H,d,J=7.3Hz),7.62(1H,t,J=7.3Hz),7.55(2H,t,J=7.7Hz),7.24(2H,d,J=8.1Hz),7.12-7.19(2H,m),7.05(2H,d,J=6.6Hz),6.98(1H,s),6.87(1H,d,J=6.8Hz),5.03(1H,br.s.),4.82(1H,d,J=10.5Hz),4.01(2H,br.s.),3.49(1H,br.s.),3.09-3.21(2H,m),3.02(1H,d,J=14.9Hz),2.77(2H,d,J=14.7Hz),2.41(1H,t,J=13.8Hz),2.02(1H,dd,J=13.9,2.7Hz),1.82(1H,dt,J=14.9,7.6Hz),1.53(3H,s),1.48(1H,ddd,J=14.2,7.7,4.5Hz),0.49(3H,t,J=7.5Hz)。质谱(ESI)m/z=603(M+1)。
实施例193
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1-甲基环丙烷磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(500MHz,氯仿-d)δppm 7.24(2H,d,J=7.8Hz),7.10-7.17(2H,m),7.03(1H,s),7.06(1H,s),6.95-6.97(1H,m),6.84-6.89(1H,m),4.88(2H,br.s.),4.81(2H,d,J=10.5Hz),4.71(1H,br.s.),3.71(1H,br.s.),3.03-3.18(3H,m),2.96-3.02(1H,m),2.76(1H,d,J=14.7Hz),2.40(1H,t,J=13.8Hz),1.98(1H,dd,J=13.9,2.9Hz),1.88(1H,dt,J=15.0,7.5Hz),1.52(3H,s),1.50(3H,s),1.45-1.49(1H,m),1.33-1.43(2H,m),0.77-0.86(2H,m),0.52(3H,t,J=7.5Hz)。质谱(ESI)m/z=581(M+1)。
实施例194
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二氧化苯并[d]异噻唑-2(3H)-基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(500MHz,氯仿-d)δppm 7.91(1H,d,J=7.6Hz),7.66-7.72(1H,m),7.60-7.65(1H,m),7.43(1H,d,J=7.6Hz),7.25(1H,br.s.),7.06-7.11(1H,m),6.95-7.06(3H,m),6.87(1H,s),6.71(1H,d,J=7.6Hz),4.86(1H,d,J=10.3Hz),4.36-4.47(2H,m),4.20(1H,dd,J=14.2,10.5Hz),4.03(5H,br.s.),3.24(1H,dd,J=14.7,3.4Hz),3.01-3.15(3H,m),2.74(1H,d,J=14.9Hz),2.32(1H,t,J=13.8Hz),1.95-2.07(1H,m),1.90(1H,dd,J=13.8,2.8Hz),1.53(1H,ddd,J=10.7,7.4,3.9Hz),1.49(3H,s),0.53(3H,t,J=7.5Hz)。质谱(ESI)m/z=615(M+1)。
实施例195
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(3,3-二甲基-1,1-二氧化苯并[d]异噻唑-2(3H)-基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(500MHz,氯仿-d)δppm 7.88(1H,d,J=7.6Hz),7.68-7.74(1H,m),7.58-7.64(1H,m),7.45(1H,d,J=7.8Hz),7.25(1H,br.s.),7.02-7.12(3H,m),6.99(1H,t,J=7.8Hz),6.94(1H,s),6.75(1H,d,J=7.6Hz),5.02(1H,d,J=10.0Hz),4.24(1H,dd,J=14.8,10.6Hz),3.15(2H,d,J=13.0Hz),3.03-3.13(3H,m),2.92(8H,br.s.),2.71(1H,d,J=15.4Hz),2.36(1H,t,J=13.6Hz),2.06-2.19(1H,m),1.90(1H,dd,J=13.8,3.1Hz),1.57(3H,s),1.48-1.52(4H,m),1.47(3H,s),0.51(3H,t,J=7.5Hz)。质谱(ESI)m/z=643(M+1)。
实施例196
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(吡啶-3-磺酰氨基)丁烷-2-基)哌啶-3-基)乙酸,为2,2,2-三氟乙酸盐
步骤A. 2-((3R,5R,6S)-1-((S)-1-(双(叔丁氧基羰基)氨基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸甲酯
将2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸甲酯(282mg,0.589mmol;实施例186,步骤A)、2-(三丁基正膦亚基)乙腈(171mg,0.707mmol)和亚胺二羧酸二叔丁酯(256mg,1.179mmol)在甲苯(3mL)中的溶液在氩气下于110℃搅拌2h。硅胶快速柱纯化(0%至60%的在己烷中的EtOAc)得到本标题化合物。质谱(ESI)m/z=677(M+1)。
步骤B. 2-((3R,5R,6S)-1-((S)-1-氨基丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸甲酯
将上面步骤A中制备的2-((3R,5R,6S)-1-((S)-1-(双(叔丁氧基羰基)氨基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸甲酯(167mg,0.246mmol)在二噁烷中的溶液与HCl(4M,0.6mL)一起在室温下搅拌2h。硅胶色谱分离(0%至20%的MeOH/DCM)得到本标题化合物。质谱(ESI)m/z=477(M+1)。
步骤C. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(吡啶-3-磺酰氨基)丁烷-2-基)哌啶-3-基)乙酸
将2-((3R,5R,6S)-1-((S)-1-氨基丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸甲酯(13mg,0.027mmol;实施例196,步骤A)和吡啶-3-磺酰氯(4.84mg,0.027mmol)在吡啶(0.3mL)中的溶液在110℃下搅拌4h。硅胶色谱分离(0%至60%的在己烷中的EtOAc)得到2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(吡啶-3-磺酰氨基)丁烷-2-基)哌啶-3-基)乙酸甲酯。将其在室温下用在乙醇(0.5mL)中的LiOH(1N水溶液,0.3mL)水解3h。HPLC纯化(C18柱,用10%至95%的含有0.1%TFA的在水中的CH3CN洗脱)得到本标题化合物,其为与2,2,2-三氟乙酸1:1络合的络合物。
1H NMR(500MHz,氯仿-d)δppm 9.29(1H,br.s.),8.90(1H,d,J=4.4Hz),8.32(1H,d,J=8.1Hz),7.66-7.76(1H,m),7.15(1H,d,J=8.1Hz),7.10(1H,t,J=7.8Hz),7.02(2H,s),7.06(1H,s),6.94(1H,s),6.74(1H,d,J=7.3Hz),4.60(1H,d,J=9.0Hz),3.18(1H,ddd,J=13.4,10.4,2.8Hz),2.86(4H,br.s.),2.27-2.35(3H,m),2.03(2H,dd,J=14.1,3.1Hz),1.66(1H,br.s.),1.54-1.64(1H,m),1.48(3H,s),0.72(3H,br.s.)。质谱(ESI)m/z=604(M+1)。
按照与实施例196步骤C中描述的程序类似的程序,用合适的试剂替代吡啶-3-磺酰氯来从2-((3R,5R,6S)-1-((S)-1-氨基丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸甲酯(实施例196,步骤B)制备实施例197–199。
实施例197
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(4-氰基苯基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(500MHz,氯仿-d)δppm 7.95(2H,m,J=8.6Hz),7.81-7.87(2H,m),7.22(2H,d,J=8.1Hz),7.16-7.20(1H,m),7.11-7.16(1H,m),7.06(1H,s),6.98(1H,t,J=1.7Hz),6.80(1H,d,J=7.6Hz),5.41(1H,br.s.),4.68(1H,d,J=10.0Hz),3.38(1H,br.s.),3.17(1H,ddd,J=13.5,10.5,2.7Hz),2.98(1H,d,J=14.7Hz),2.78(1H,d,J=14.7Hz),2.69-2.76(1H,m),2.35(1H,t,J=13.8Hz),2.00-2.08(2H,m),1.55(1H,d,J=7.6Hz),1.52(4H,s),0.59(3H,br.s.)。质谱(ESI)m/z=628(M+1)。
实施例198
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(3-氰基苯基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(500MHz,氯仿-d)δppm 8.15(1H,t,J=1.5Hz),8.07(1H,d,J=7.8Hz),7.89(1H,dt,J=7.8,1.2Hz),7.70(1H,t,J=7.9Hz),7.20(2H,d,J=7.8Hz),7.17(1H,dt,J=8.3,1.5Hz),7.13(1H,t,J=7.7Hz),7.06(1H,s),6.97(1H,s),6.80(1H,d,J=7.3Hz),5.49(1H,br.s.),4.68(1H,d,J=10.0Hz),3.40(1H,br.s.),3.27(1H,br.s.),3.17(1H,ddd,J=13.4,10.5,2.9Hz),2.97(1H,d,J=14.9Hz),2.80(1H,d,J=14.7Hz),2.76(1H,br.s.),2.35(1H,t,J=13.7Hz),2.04(1H,dd,J=13.9,2.9Hz),1.56(1H,d,J=7.1Hz),1.52(3H,s),0.61(3H,br.s.)。质谱(ESI)m/z=628(M+1)。
实施例199
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(吡啶-2-磺酰氨基)丁烷-2-基)哌啶-3-基)乙酸.所获得的化合物为2,2,2-三氟乙酸盐。
1H NMR(500MHz,氯仿-d)δppm 8.73(1H,d,J=4.2Hz),7.93-8.04(2H,m),7.53-7.60(1H,m),7.18-7.24(2H,m),7.11-7.18(2H,m),7.00-7.09(2H,m),6.98(1H,s),6.87(1H,d,J=6.8Hz),5.54(1H,br.s.),4.82(1H,d,J=10.5Hz),3.51(1H,br.s.),3.22(1H,br.s.),3.10-3.18(1H,m),3.03(1H,d,J=14.9Hz),2.94(1H,dt,J=14.0,4.1Hz),2.75(1H,d,J=14.9Hz),2.44(1H,t,J=13.7Hz),1.99(4H,dd,J=14.1,2.8Hz),1.78-1.83(3H,m),1.54(3H,s),1.43-1.53(2H,m),0.51(3H,t,J=7.3Hz)。质谱(ESI)m/z=604(M+1)。
实施例200
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N,1-二甲基环丙烷磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
将2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(1-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸甲酯(21.7mg,0.036mmol;实施例193)、2-(三丁基正膦亚基)乙腈(8.8mg,0.036mmol)和1滴MeOH在甲苯(0.5mL)中的溶液于110℃下搅拌1h。硅胶快速柱纯化(0%至60%的在己烷中的EtOAc)得到2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N,1-二甲基环丙烷磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸甲酯。将其在室温下用在乙醇(0.5mL)中的LiOH(1N水溶液,0.3mL)水解3h。HPLC纯化(C18柱,用10%至95%的含有0.1%TFA的在水中的CH3CN洗脱)得到本标题化合物。
1H 1H NMR(500MHz,氯仿-d)δppm 7.26(2H,br.s.),7.13(2H,d,J=3.7Hz),6.94(2H,br.s.),6.88(1H,br.s.),4.80(1H,d,J=9.5Hz),4.36(1H,br.s.),2.96-3.12(3H,m),2.86-2.93(4H,m),2.79(3H,d,J=14.2Hz),2.69(3H,d,J=15.4Hz),2.41-2.64(15H,m),1.96(1H,dd,J=14.4,7.3Hz),1.84(1H,d,J=13.7Hz),1.55-1.64(2H,m),1.53(3H,br.s.),1.38-1.48(6H,m),0.81(2H,br.s.),0.51(3H,t,J=6.2Hz)。质谱(ESI)m/z=595(M+1)。
实施例201
3-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)丙酸或3-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)丙酸
*立体化学未确定
步骤A. (5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)哌啶-2-酮
在室温下向(5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)哌啶-2-酮(20.00g,51.0mmol;实施例185,步骤B)和N-甲基环丙烷磺酰胺(10.34g,76mmol)在100mL甲苯中的混合物中加入氰基亚甲基三丁基正膦(20.51mL,76mmol)。将由此产生的混合物加热至130℃并保持12h,然后冷却至室温并直接将其上样到硅胶柱上用于纯化,用0%至10%的在DCM中的MeOH洗脱从而得到本标题化合物。质谱(ESI)m/z=509(M+1)。
步骤B. N-((2S)-2-((2S,3R)-3-(3-氯苯基)-2-(4-氯苯基)-5-甲基-6-氧代哌啶-1-基)丁基)-N-甲基环丙烷磺酰胺
使用与实施例185步骤D中描述的程序类似的程序,从N-((S)-2-((2S,3R)-3-(3-氯苯基)-2-(4-氯苯基)-6-氧代哌啶-1-基)丁基)-N-甲基环丙烷磺酰胺(实施例201,步骤A)获得本标题化合物,为非对映异构体混合物。质谱(ESI)m/z=523(M+1)。
步骤C. N-((S)-2-((5R,6S)-3-(丁-3-烯基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁基)-N-甲基环丙烷磺酰胺(异构体1)
*立体化学未确定
在-15℃下向N-((2S)-2-((2S,3R)-3-(3-氯苯基)-2-(4-氯苯基)-5-甲基-6-氧代哌啶-1-基)丁基)-N-甲基环丙烷磺酰胺(2618mg,5.0mmol;实施例201,步骤B)在脱气的THF(10mL)中的溶液中加入二异丙基氨基锂(5.00mL,10.00mmol)。在-15℃下搅拌30min后,将反应混合物冷却至-74℃。缓慢地加入4-溴丁-1-烯(1.066mL,10.50mmol)。将反应混合物在-74℃下搅拌3h,然后升温至室温并然后在室温下搅拌66h。过滤并通过HPLC(C18柱,用10%至95%的含有0.1%TFA的在水中的CH3CN洗脱)纯化,从而得到本标题化合物,为第一洗脱异构体。所获得的它的立体异构体是较晚洗脱的异构体。
1H NMR(500MHz,氯仿-d)δppm 7.22(2H,d,J=7.6Hz),7.10-7.17(2H,m),6.96(2H,s),6.90-6.95(1H,m),5.90(1H,ddt,J=17.0,10.3,6.4,6.4Hz),5.10(1H,dd,J=17.1,1.5Hz),5.03(1H,dd,J=10.0,1.5Hz),4.77(1H,d,J=10.5Hz),4.24(1H,br.s.),3.07(1H,ddd,J=13.7,10.6,3.1Hz),2.90(3H,s),2.74-2.87(2H,m),2.24-2.37(2H,m),2.11-2.21(2H,m),2.00(1H,ddd,J=13.6,10.1,6.6Hz),1.78-1.93(3H,m),1.60-1.70(1H,m),1.58(2H,br.s.),1.28-1.32(3H,m),1.22(2H,d,J=3.2Hz),0.95-1.04(2H,m),0.53(3H,t,J=7.5Hz).质谱(ESI)m/z=577(M+1)。
步骤D. 3-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)丙酸或3-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)丙酸
按照与实施例71步骤F中描述的程序类似的程序,从N-((S)-2-((5R,6S)-3-(丁-3-烯基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁基)-N-甲基环丙烷磺酰胺(异构体1,604mg,1.046mmol;实施例201,步骤C)获得本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 7.23(2H,d,J=7.4Hz),7.11-7.17(3H,m),6.98(2H,m),6.89-6.94(1H,m),4.75(1H,d,J=11.3Hz),4.24(1H,br.s.),3.17(1H,ddd,J=13.8,10.8,3.1Hz),2.89(3H,s),2.63-2.82(3H,m),2.55(1H,dd,J=8.5,6.2Hz),2.39-2.52(2H,m),2.27-2.39(2H,m),1.82-1.94(2H,m),1.73(1H,dd,J=13.7,3.1Hz),1.48-1.65(2H,m),1.28-1.33(4H,m),1.17-1.25(2H,m),0.95-1.04(2H,m),0.46-0.55(3H,m)。质谱(ESI)m/z=595(M+1)。
实施例202
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
步骤A. (5R,6S)-1-((S)-1-(叔丁基二苯基甲硅烷基氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基哌啶-2-酮
在氩气下向-78℃的(5R,6S)-1-((S)-1-(叔丁基二苯基甲硅烷基氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)哌啶-2-酮(764mg,1.211mmol;实施例185,步骤C)在THF(6mL)中的溶液中加入二异丙基氨基锂在THF中的1.0M溶液(1.211mL,1.211mmol)。将该混合物温度升至0℃并保持30分钟。将该混合物冷却至-78℃并加入碘乙烷(0.117mL,1.454mmol)。将由此产生的溶液在0℃下搅拌1小时。用NH4Cl饱和水溶液淬灭该混合物。用乙酸乙酯萃取该混合物。用NaCl饱和水溶液洗涤合并的有机层,经Na2SO4干燥并浓缩。通过硅胶快速色谱法(洗脱剂:5%至25%的乙酸乙酯/己烷)纯化残余物从而得到本标题化合物,为非对映异构体的混合物。
步骤B. (5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-1-((S)-1-羟基丁烷-2-基)哌啶-2-酮
将(5R,6S)-1-((S)-1-(叔丁基二苯基甲硅烷基氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基哌啶-2-酮(421mg,0.639mmol;实施例202,步骤A)用甲苯(3X)共沸。加入THF(1.6mL)。向该混合物中通入氩气5分钟,然后将其冷却至0℃。逐滴加入二异丙基氨基锂在THF中的1.0M溶液(1.246mL,1.246mmol)。在25分钟后,逐滴加入烯丙基溴(0.166mL,1.917mmol)。在20分钟后,用NH4Cl饱和水溶液淬灭该混合物。用乙酸乙酯萃取该混合物。用NaCl饱和水溶液洗涤有机层,经Na2SO4干燥,并浓缩。将残余物溶解在THF(3mL)中,并加入四丁基氟化铵在THF中的1.0M溶液(2.335mL,2.335mmol)。在搅拌过夜后,将该混合物分配在5%HCl水溶液和乙酸乙酯之间。用NaCl饱和水溶液洗涤有机层,经Na2SO4干燥,并浓缩。通过硅胶快速色谱法(洗脱剂:20%至50%的乙酸乙酯/己烷)纯化残余物从而得到本标题化合物,为极性较大的主要非对映异构体。
步骤C. N-((2S)-2-((5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-2-氧代哌啶-1-基)丁基)-N-甲基环丙烷磺酰胺
将(5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-1-((S)-1-羟基丁烷-2-基)哌啶-2-酮(147mg,0.319mmol;实施例202,步骤B)和N-甲基环丙烷磺酰胺(129mg,0.958mmol)溶解在甲苯(2mL)中。将该混合物抽真空并回填氩气(5X)。加入氰基亚甲基三丁基正膦(0.251mL,0.958mmol)。将该混合物抽真空并回填氩气(5X)。将该混合物在70℃下加热2小时。将该混合物上样到硅胶上并用5%至75%的乙酸乙酯/己烷洗脱产物从而得到本标题化合物。
步骤D. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
按照与实施例71步骤F中描述的程序类似的程序,从N-((2S)-2-((5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-2-氧代哌啶-1-基)丁基)-N-甲基环丙烷磺酰胺(实施例202,步骤C)获得本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 0.54(t,J=7.53Hz,3H)0.85-1.10(m,7H)1.15-1.23(m,2H)1.51-1.65(m,1H)1.84-2.04(m,4H)2.15-2.25(m,1H)2.25-2.38(m,2H)2.69-2.82(m,1H)2.87(s,3H)2.93-3.10(m,2H)4.76(d,J=10.37Hz,1H)6.84(d,J=6.65Hz,1H)6.91-6.97(m,1H)7.08-7.17(m,2H)7.20-7.29(m,4H)。质谱(ESI)m/z=595.2(M+1)。
实施例203
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲氧基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
步骤A. (5R,6S)-1-((S)-1-(叔丁基二苯基甲硅烷基氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-羟基哌啶-2-酮
将(5R,6S)-1-((S)-1-(叔丁基二苯基甲硅烷基氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)哌啶-2-酮(1.100g,1.744mmol;实施例185,步骤C)溶解在THF(8.72mL)中,并向其中通入氩气5分钟。将该混合物冷却至-78℃,并逐滴加入双(三甲基甲硅烷基)氨基锂在THF中的1.0M溶液(2.093mL,2.093mmol)。在30分钟后,逐滴加入双(三甲基甲硅烷)过氧化物(0.413mL,1.918mmol)。在1小时后,移开冷却浴。在搅拌过夜后,用NH4Cl饱和水溶液淬灭该混合物并用乙酸乙酯萃取。用NaCl饱和水溶液洗涤有机层,经Na2SO4干燥,并浓缩。将残余物溶解在EtOH(14mL)中并加入吡啶对甲苯磺酸盐(131mg,0.523mmol)。在1小时后,用NaHCO3饱和水溶液碱化该混合物。将该混合物分配在乙酸乙酯和水之间。用NaCl饱和水溶液洗涤有机层,经Na2SO4干燥,并浓缩。通过硅胶快速色谱法(40g柱,洗脱剂:5%至50%的乙酸乙酯/己烷)纯化残余物从而得到本标题化合物。
步骤B. (5R,6S)-1-((S)-1-(叔丁基二苯基甲硅烷基氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲氧基哌啶-2-酮
向0℃的(5R,6S)-1-((S)-1-(叔丁基二苯基甲硅烷基氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-羟基哌啶-2-酮(476mg,0.736mmol;实施例203,步骤A)在THF(7.360mL)中的溶液中加入氢化钠(58.9mg,1.472mmol)。在30分钟后,加入碘甲烷(0.092mL,1.472mmol)。在5分钟后,移开冷却浴。在2小时后,用NH4Cl饱和水溶液淬灭该混合物。将该混合物分配在乙酸乙酯和水之间。用NaCl饱和水溶液洗涤有机层,经Na2SO4干燥,并浓缩从而得到本标题化合物。
步骤C. (3R,5R,6S)-3-烯丙基-1-((S)-1-((叔丁基二苯基甲硅烷基)氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲氧基哌啶-2-酮
向(5R,6S)-1-((S)-1-((叔丁基二苯基甲硅烷基)氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲氧基哌啶-2-酮(495mg,0.749mmol;实施例203,步骤B)在THF(7.49mL)中的溶液中通入氩气5分钟,并将其冷却至0℃。逐滴加入在THF中的1.0M二异丙基氨基锂溶液(1.461mL,1.461mmol)。该内部温度上升不超过2℃。在30分钟后,加入烯丙基溴(0.194mL,2.247mmol)。将冷却浴替换为室温水浴。在70分钟后,用NH4Cl饱和水溶液淬灭该混合物并用乙酸乙酯萃取。用NaCl饱和水溶液洗涤有机层,经Na2SO4干燥并浓缩。通过硅胶快速色谱法(40g柱,洗脱剂:5%至30%的乙酸乙酯/己烷)纯化残余物从而得到本标题化合物,为极性较大的非对映异构体。
步骤D. (3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)-3-甲氧基哌啶-2-酮
向(3R,5R,6S)-3-烯丙基-1-((S)-1-((叔丁基二苯基甲硅烷基)氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲氧基哌啶-2-酮(260mg,0.371mmol;实施例203,步骤C)在THF(1mL)中的溶液中加入在THF中的1.0M四丁基氟化铵溶液(1.484mL,1.484mmol)。在搅拌过夜后,将该混合物分配在水和乙酸乙酯之间。加入NH4Cl饱和水溶液以分散乳液。用NaCl饱和水溶液洗涤有机层,经Na2SO4干燥,并浓缩。通过硅胶快速色谱法(12g柱,洗脱剂:35%至100%的乙酸乙酯/己烷)纯化残余物从而得到本标题化合物。
步骤E. N-((S)-2-((3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲氧基-2-氧代哌啶-1-基)丁基)-N-甲基环丙烷磺酰胺
向(3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)-3-甲氧基哌啶-2-酮(124mg,0.268mmol;实施例203,步骤D)在甲苯(1.3mL)中的溶液中加入N-甲基环丙烷磺酰胺(109mg,0.804mmol)。将该混合物抽真空并回填氩气(5X)。加入氰基亚甲基三丁基正膦(0.211mL,0.804mmol)。将该混合物抽真空并回填氩气(5X)。将该混合物在70℃油浴中加热12小时,然后将其冷却至室温并在室温下搅拌2天。将该混合物上样到硅胶上并用20-60%乙酸乙酯/己烷洗脱产物。再一次通过硅胶快速色谱法(12g柱,洗脱剂:10%至60%的乙酸乙酯/己烷)纯化残余物从而得到本标题化合物。
步骤F. 2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲氧基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
按照与实施例71步骤F中描述的程序类似的程序,从N-((S)-2-((3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲氧基-2-氧代哌啶-1-基)丁基)-N-甲基环丙烷磺酰胺(实施例203,步骤E)获得本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 0.59(t,J=7.53Hz,3H)1.02-1.05(m,2H)1.16-1.27(m,2H)1.59-1.77(m,1H)1.85–1.99(m,2H)2.22-2.40(m,1H)2.75(d,J=13.30Hz,1H)2.84–2.98(m,6H)3.03-3.16(m,2H)3.26(d,J=15.65Hz,1H)3.52(s,3H)4.99(d,J=10.76Hz,1H)6.91–6.97(m,2H)7.02(s,1H)7.10-7.20(m,2H)7.22-7.31(m,3H)。质谱(ESI)m/z=597.1(M+1)。
实施例204
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-6-甲基-4-氧代庚烷-3-基)-2-氧代哌啶-3-基)乙酸
步骤A. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S)-4-羟基-6-甲基庚烷-3-基)-3-甲基哌啶-2-酮
在N2下向在0℃下的(S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁醛(1.755mmol)(实施例91,步骤C)在THF(5mL)中的溶液中加入2M异丁基溴化镁(878μL,1.742mmol)。让反应物温度升至室温。在室温下搅拌2h后,用饱和NH4Cl溶液淬灭反应物并用EtOAc萃取。洗涤(NaCl饱和水溶液)合并的有机层,经MgSO4干燥,过滤,并在减压下浓缩滤液。通过硅胶快速色谱法(洗脱剂:15%至35%的EtOAc/己烷,梯度洗脱)纯化残余物从而得到本标题化合物,为两个非对映异构体的混合物。
步骤B. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-6-甲基-4-氧代庚烷-3-基)-2-氧代哌啶-3-基)乙酸
向快速搅拌着的120mg(0.239mmol)(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S)-4-羟基-6-甲基庚烷-3-基)-3-甲基哌啶-2-酮(实施例204,步骤A)在1.5mL水、1.0mL乙腈和1.0mLCCl4的混合物中的溶液中加入高碘酸钠(204mg,0.995mmol),接着加入氯化钌(III)水合物(5.38mg,0.024mmol)。在剧烈搅拌2h后,酸化(10%柠檬酸)反应物并用EtOAc稀释。通过(J.T.Baker,Phillipsberg,NJ,硅藻土)过滤反应混合物,并用EtOAc萃取滤液。用NaCl饱和溶液洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过硅胶快速色谱法(洗脱剂:10%至20%的iPrOH/己烷,梯度洗脱)纯化残余物从而得到本标题化合物,为白色固体。
1H NMR(400MHz,氯仿-d)δppm 0.64(t,J=8.0Hz,3H),0.89(d,J=8.0Hz,3H),0.92(d,J=8.0Hz,3H),1.21(m,1H),1.39(s,3H),1.82(m,1H),210-2.45(m,7H),2.87(dd,J=16.0,12Hz,2H),3.09(t,J=8.0Hz,1H),3.26(m,1H),4.44(d,J=8.0Hz,1H),6.76(d,J=8.0Hz,1H),6.90–7.02(m,3H),7.08(t,J=8.0Hz,1H),7.12(d,J=8.0Hz,1H),7.23(d,J=8.0Hz,2H);MS(ESI)531.1[M+H]+。
实施例205
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(乙基磺酰基)戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. 乙基磺酰基甲基膦酸二乙酯
向在0℃下的搅拌着的乙基硫代甲基膦酸二乙酯(Aldrich,St.Louis,MO)(0.912mL,4.71mmol)在二氯甲烷(47.1mL)中的溶液中加入间氯过氧苯甲酸(2.63g,15.2mmol)。将反应混合物在25℃下搅拌24小时。在真空中除去反应溶剂,用乙醚稀释粗材料,然后用饱和碳酸氢钠(3X)洗涤。经Na2SO4干燥有机层,过滤,并在减压下浓缩滤液从而得到本标题化合物,为灰白色固体。
步骤B. (3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-1-((S,E)-1-(乙基磺酰基)戊-1-烯-3-基)-3-甲基哌啶-2-酮
向在-78℃下的搅拌着的乙基磺酰基甲基膦酸二乙酯(153mg,0.625mmol;实施例202,步骤A)在THF(2.60mL)中的溶液中加入丁基锂(177μL,0.443mmol)。在30分钟后,加入(2S)-2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-3-甲基-2-氧代哌啶-1-基)丁醛(135mg,0.260mmol;实施例150,步骤D)在THF(0.50mL)中的溶液。将反应物在-78℃下搅拌15分钟,然后在25℃下搅拌3小时。将反应物分配在饱和氯化铵和EtOAc(2X)之间,然后经Na2SO4干燥合并的有机层,过滤,并在减压下浓缩滤液。通过硅胶快速色谱法(4g柱,洗脱剂:0%至40%的EtOAc/己烷)纯化残余物,得到本标题化合物,为灰白色固体。
步骤C. (3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-1-((S)-1-(乙基磺酰基)戊烷-3-基)-3-甲基哌啶-2-酮
向在25℃下的(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-1-((S,E)-1-(乙基磺酰基)戊-1-烯-3-基)-3-甲基哌啶-2-酮(65.0mg,0.107mmol;实施例205,步骤B)在1,2-二氯乙烷(1.07mL)中的溶液中加入Crabtree催化剂(7.74mg,9.61μmol)。将反应系统(加氢反应釜)用氢气吹扫3次,用在3447.38千帕下的氢气加压,并将反应物在25℃下搅拌24小时。通过硅藻土过滤反应混合物,用DCM洗涤,并在减压下浓缩从而得到本标题化合物,为灰白色固体。
步骤D. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(乙基磺酰基)戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸
向在25℃下的搅拌着的(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-1-((S)-1-(乙基磺酰基)戊烷-3-基)-3-甲基哌啶-2-酮(70.0mg,0.115mmol;实施例202,步骤C)在THF(1.15mL)中的溶液中加入琼斯试剂(氧化铬(VI))(138μL,0.172mmol),并将反应混合物搅拌1小时。将反应混合物分配在水和EtOAc(2X)之间,然后经Na2SO4干燥合并的有机层,过滤,并在减压下浓缩滤液。通过反相高压液相色谱法(Eclipse柱(Agilient Technologies,Santa Clara,CA),洗脱剂:30-75%乙腈/水)纯化残余物,得到本标题化合物,为灰白色固体。
1H NMR(500MHz,CDCl3)δppm 0.58(t,J=7.34Hz,3H),1.43(t,J=7.46Hz,3H),1.49(s,3H),1.51-1.57(m,1H),1.86(dt,J=14.55,7.40Hz,1H),1.98(dd,J=12.84,5.75Hz,1H),2.04(dd,J=13.94,2.45Hz,1H),2.16-2.23(m,2H),2.76(d,J=15.16Hz,1H),2.97-3.04(m,5H),3.11-3.20(m,1H),3.24-3.38(m,1H),4.58(d,J=10.51Hz,1H),6.75(d,J=7.58Hz,1H),6.95(s,1H),7.05(d,J=4.89Hz,2H),7.09-7.14(m,1H),7.14-7.18(m,1H),7.23-7.27(m,2H);MS(ESI)554.2[M+H]+。
实施例206
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(异丙基磺酰基)戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. S-(二异丙氧基磷酰基)甲基乙酸酯
向搅拌着的溴甲基膦酸二异丙酯(5.00g,19.3mmol)在N,N-二甲基甲酰胺(15.4mL)中的溶液中加入硫代乙酸钾(3.75g,32.8mmol),接着加入四丁基碘化铵(0.36g,0.97mmol)。将反应混合物在85℃下搅拌2.5小时。冷却反应混合物,将其分配在水和EtOAc(3X)之间,并分离各层。经Na2SO4干燥合并的有机层,过滤,并在减压下浓缩滤液。通过硅胶快速色谱法(24g柱,洗脱剂:0%至90%的EtOAc/己烷)纯化残余物,得到本标题化合物,为灰白色固体。
步骤B. 异丙基硫代甲基膦酸二异丙酯
向在0℃下的搅拌着的S-(二异丙氧基磷酰基)甲基乙酸酯(1.00g,3.93mmol;实施例206,步骤A)在甲醇(39.3mL)中的溶液中加入甲醇钠(7.87mL,3.93mmol),接着加入2-溴丙烷(0.44mL,4.72mmol)。将反应物在25℃下搅拌16小时。在真空中除去反应溶剂,将粗材料分配在水和EtOAc(2X)之间,并分离各层。用EtOAc萃取水层,并经Na2SO4干燥合并的有机层,过滤,并在减压下浓缩滤液。通过硅胶快速色谱法(40g柱,洗脱剂:0%至75%的DCM/己烷)纯化残余物,得到本标题化合物,为灰白色固体。
步骤C. 异丙基磺酰基甲基膦酸二异丙酯
按照实施例205步骤A中描述的程序将异丙基硫代甲基膦酸二异丙酯转化为本标题化合物,并加以分离,为灰白色固体。
步骤D. (3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-1-((S,E)-1-(异丙基磺酰基)戊-1-烯-3-基)-3-甲基哌啶-2-酮
如实施例205步骤B中所述将(2S)-2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-3-甲基-2-氧代哌啶-1-基)丁醛(实施例150,步骤D)转化为本标题化合物并加以分离,为灰白色固体。
步骤E. (3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-1-((S)-1-(异丙基磺酰基)戊烷-3-基)-3-甲基哌啶-2-酮
如实施例205步骤C中所述将(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-1-((S,E)-1-(异丙基磺酰基)戊-1-烯-3-基)-3-甲基哌啶-2-酮转化为本标题化合物,并加以分离,为灰白色固体。
步骤F. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(异丙基磺酰基)戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸
如实施例205步骤D中所述将(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-1-((S)-1-(异丙基磺酰基)戊烷-3-基)-3-甲基哌啶-2-酮转化为本标题化合物,并加以分离,为灰白色固体。
1H NMR(400MHz,CDCl3)δppm 0.55(t,J=6.55Hz,3H),1.43(d,J=6.26Hz,6H),1.49(br.s.,3H),1.81-1.96(m,1H),1.98-2.10(m,2H),2.14-2.25(m,1H),2.27-2.41(m,1H),2.77(d,J=15.85Hz,2H),2.95-3.07(m,3H),3.09-3.19(m,2H),3.19-3.31(m,1H),4.65(d,J=10.56Hz,1H),6.75(d,J=7.24Hz,1H),6.96(s,1H),7.01-7.10(m,2H),7.12(d,J=7.63Hz,1H),7.14-7.19(m,1H),7.23-7.27(m,2H);MS(ESI)568.2[M+H]+。
实施例207
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环丙基甲基磺酰基)戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸
按照如实施例205中描述的程序,用(环丙基甲基磺酰基)甲基膦酸二异丙酯(用类似于实施例206步骤A和B的程序制备,为灰白色固体)将(2S)-2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-((2,2-二甲基-1,3-二氧环戊烷-4-基)甲基)-3-甲基-2-氧代哌啶-1-基)丁醛(实施例150,步骤D)转化为本标题化合物。本标题化合物为灰白色固体。.
1H NMR(400MHz,CDCl3)δppm 0.39-0.48(m,2H),0.56(t,J=7.10Hz,3H),0.74-0.86(m,2H),1.13-1.25(m,1H),1.48(br.s.,3H),1.51-1.59(m,1H),1.79-1.94(m,1H),1.97-2.11(m,2H),2.13-2.24(m,1H),2.24-2.42(m,1H),2.78(d,J=14.87Hz,1H),2.92(d,J=5.28Hz,2H),2.97-3.11(m,3H),3.16(t,J=11.54Hz,1H),3.21-3.33(m,1H),4.62(d,J=10.37Hz,1H),6.75(d,J=7.04Hz,1H),6.96(br.s.,1H),7.01-7.20(m,4H),7.21-7.27(m,2H);MS(ESI)580.2[M+H]+。
实施例208
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(2-氧代吡咯烷-1-基)丁烷-2-基)哌啶-3-基)乙酸
步骤A. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(2-氧代吡咯烷-1-基)丁烷-2-基)哌啶-2-酮
在25℃下向(S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁醛(84mg,0.189mmol;实施例91,步骤C)、4-氨基丁酸乙酯盐酸盐(127mg,0.756mmol)和乙酸(3滴)在DCE/MeOH(3/1,4.0mL)中的溶液中加入三乙酰氧基硼氢化钠(200mg,0.945mmol)。在25℃下搅拌18h后,通过加入冰冷的饱和NaHCO3水溶液来淬灭反应物并用DCM萃取。洗涤(1×NaCl饱和水溶液)合并的有机层并在减压下浓缩。通过反相制备型HPLC(含有0.1%TFA的在水中的乙腈,梯度洗脱)纯化残余物从而得到本标题化合物,为白色固体。
步骤B. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(2-氧代吡咯烷-1-基)丁烷-2-基)哌啶-3-基)乙酸
按照与实施例71步骤F中描述的程序类似的程序,从((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(2-氧代吡咯烷-1-基)丁烷-2-基)哌啶-2-酮(实施例208,步骤A)获得本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 0.55(t,J=8.0Hz,3H),1.52(s,3H),1.65(m,1H),1.90-2.28(m,5H),2.58(m,2H),2.75(d,J=12.0Hz,1H),3.02(d,J=12.0Hz,1H),3.08(m,3H),3.47(m,2H),3.99(m,1H),4.37(d,J=12.0Hz,1H),6.72(d,J=8.0Hz,1H),6.89–7.00(m,3H),71.0(t,J=8.0Hz,1H),7.16(m,1H),7.26(d,J=4.0Hz,2H);MS(ESI)531.1[M+H]+。
实施例209
2-((3R,5R,6S)-1-((S)-1-((1R,4R)-2-氧杂-5-氮杂二环[2.2.1]庚烷-5-基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸-TFA盐
步骤A. (3S,5R,6S)-1-((S)-1-((1R,4R)-2-氧杂-5-氮杂二环[2.2.1]庚烷-5-基)丁烷-2-基)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮
向(S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁醛(100mg,0.224mmol;实施例91,步骤C)在DCE(2mL)中的溶液中加入(1R,4R)-2-氧杂-5-氮杂二环[2.2.1]庚烷(Butora,G.;Goble,S.;Pastemak,A.;Yang,L.;Zhou,C.;Moyes,C.U.S.专利公布号2008/0081803)(50mg,0.504mmol),接着加入三乙酰氧基硼氢化钠(95mg,0.448mmol)和乙酸(1.2μL,0.022mmol)。在搅拌过夜后,用NaHCO3饱和水溶液淬灭该混合物。用乙酸乙酯(2X)萃取该混合物。用NaCl饱和水溶液洗涤合并的有机层,经Na2SO4干燥,并浓缩。通过硅胶快速色谱法(洗脱剂:1%至5%的甲醇/二氯甲烷)纯化残余物从而得到本标题化合物。
步骤B. 2-((3R,5R,6S)-1-((S)-1-((1R,4R)-2-氧杂-5-氮杂二环[2.2.1]庚烷-5-基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸-TFA盐
向(3S,5R,6S)-1-((S)-1-((1R,4R)-2-氧杂-5-氮杂二环[2.2.1]庚烷-5-基)丁烷-2-基)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮(87mg,0.17mmol;实施例209,步骤A)在THF(0.8mL)、水(0.4mL)和叔丁醇(0.4mL)中的溶液中加入4-甲基吗啉N-氧化物(29mg,0.25mmol)和5滴4%OsO4水溶液。在18小时后,加入琼斯试剂(0.20mL)。在24小时后,将50mL水加入到该混合物中,然后用乙酸乙酯(3X)萃取该混合物。用水洗涤合并的有机层,经Na2SO4干燥并浓缩。通过反相制备型HPLC(柱:Gemini-NX C185um柱;Phenomonex,Torrance,CA;洗脱剂:0%至100%MeCN+0.1%TFA于水+0.1%TFA中,超过20分钟)纯化残余物从而得到本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 0.95-1.17(m,3H)1.30-1.53(m,5H)1.75-1.95(m,1H)2.03-2.17(m,2H)2.18-2.32(m,2H)2.37-2.54(m,1H)2.59-2.79(m,2H)2.80-2.94(m,1H)3.17-3.32(m,1H)3.73-3.93(m,2H)3.95-4.14(m,1H)4.40-4.55(m,2H)4.56-4.65(m,1H)4.90-5.23(m,1H)6.58-6.73(m,1H)6.93-7.02(m,1H)7.04–7.09(m,1H)7.14(d,J=7.43Hz,2H)7.23-7.36(m,3H)。质谱(ESI)m/z=545.2(M+1)。
实施例210
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-((S)-3-甲基吗啉代)丁烷-2-基)-2-氧代哌啶-3-基)乙酸或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-((R)-3-甲基吗啉代)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
*立体化学未确定
步骤A. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((2S)-1-氧代丁烷-2-基)哌啶-3-基)乙酸
向-78℃的乙二酰氯(0.166mL,0.332mmol)在二氯甲烷(2mL)中的溶液中逐滴加入二甲亚砜(0.047mL,0.663mmol)。在10分钟后,逐滴加入在二氯甲烷(2mL)中的2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸(140mg,0.301mmol;实施例185)。在15分钟后,逐滴加入三乙胺(0.210mL,1.507mmol)。将该混合物温度升至0℃并保持10分钟,然后用10%柠檬酸水溶液淬灭。用水稀释该混合物并用二氯甲烷(2X)萃取。用NaCl饱和水溶液洗涤合并的有机层,经无水Na2SO4干燥,并浓缩从而得到本标题化合物。
步骤B. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((2S)-1-(3-甲基吗啉代)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
向2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-氧代丁烷-2-基)哌啶-3-基)乙酸(960mg,2.076mmol;实施例210,步骤A)在1,2-二氯乙烷(15mL)中的溶液中加入3-甲基吗啉(Enamine Ltd,Kiev,Ukraine)(0.471mL,4.15mmol)和三乙酰氧基硼氢化钠(880mg,4.15mmol)。在搅拌过夜后,用NH4Cl饱和水溶液淬灭该混合物。用二氯甲烷(2X)萃取该混合物。用NaCl饱和水溶液洗涤合并的有机层,经无水Na2SO4干燥,并浓缩。通过硅胶快速色谱法(洗脱剂:1%至10%的甲醇/二氯甲烷)纯化残余物从而得到本标题化合物,为主要非对映异构体。3-吗啉立体中心的立体化学未知。
1H NMR(400MHz,氯仿-d)δppm 0.50(t,J=7.53Hz,3H)1.02(d,J=6.26Hz,3H)1.46(s,3H)1.54-1.68(m,1H)1.85-1.98(m,2H)2.01–2.06(m,1H)2.15-2.28(m,2H)2.58-2.89(m,4H)2.97-3.13(m,2H)3.26-3.37(m,1H)3.55-3.71(m,2H)3.77-3.85(m,1H)3.90(d,J=10.96Hz,1H)4.78(d,J=10.17Hz,1H)6.77(dt,J=7.48,1.54Hz,1H)6.82-6.96(m,2H)6.97-7.02(m,1H)7.08-7.30(m,4H)。质谱(ESI)m/z=547.2(M+1)。
实施例211
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(硫代吗啉代-1,1-二氧化物)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
向2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-氧代丁烷-2-基)哌啶-3-基)乙酸(0.101g,0.219mmol;实施例210,步骤A)在1,2-二氯乙烷(3mL)中的溶液中加入硫代吗啉1,1-二氧化物(0.128g,0.947mmol)、三乙酰氧基硼氢化钠(0.093g,0.438mmol),和2滴乙酸。在搅拌2天后,用水淬灭该混合物。用乙酸乙酯(2X)萃取该混合物。用NaCl饱和水溶液洗涤合并的有机层,经无水Na2SO4干燥,并浓缩。通过反相制备型HPLC(柱:Gemini-NX C185um柱;Phenomonex,Torrance,CA;洗脱剂:0%至100%MeCN+0.1%TFA于水+0.1%TFA中,超过20分钟)纯化无色膜状物。将含有产物的级分转移到分液漏斗中,并加入NaHCO3饱和水溶液和二氯甲烷。将水层用二氯甲烷反萃。用NaCl饱和水溶液洗涤合并的有机层,经无水Na2SO4干燥,并浓缩从而得到本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 0.66(t,J=7.14Hz,3H)1.46(s,4H)1.53-1.64(m,1H)1.78-1.91(m,1H)1.99-2.26(m,5H)2.77(d,J=15.06Hz,1H)2.91-3.17(m,9H)4.41(d,J=9.98Hz,1H)6.73(d,J=7.43Hz,1H)6.90–6.91(m 1H)7.09-7.22(m,2H)7.23-7.30(m,4H)。质谱(ESI)m/z=581.2(M+1)。
实施例212
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(3,3-二氟氮杂环丁烷-1-基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
向2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-氧代丁烷-2-基)哌啶-3-基)乙酸(99mg,0.215mmol;实施例210,步骤A)在1,2-二氯乙烷(3mL)中的溶液中加入3,3-二氟氮杂环丁烷盐酸盐(55.7mg,0.430mmol),接着加入三乙酰氧基硼氢化钠(91mg,0.430mmol)。在搅拌过夜后,用水淬灭该混合物。用乙酸乙酯(2X)萃取该混合物。用NaCl饱和水溶液洗涤合并的有机层,经无水Na2SO4干燥并浓缩。通过反相制备型HPLC(柱:Gemini-NX C185um柱;Phenomonex,Torrance,CA;洗脱剂:0%至100%MeCN+0.1%TFA于水+0.1%TFA中,超过20分钟)纯化残余物。将含有产物的级分转移到分液漏斗中,并加入NaHCO3饱和水溶液和二氯甲烷。将水层用二氯甲烷反萃。用NaCl饱和水溶液洗涤合并的有机层,经无水Na2SO4干燥,过滤并浓缩滤液从而得到本标题化合物。
1H NMR(400MHz,乙腈-d3)δppm 0.48(t,J=7.53Hz,3H)1.32(s,3H)1.46-1.62(m,1H)1.68-1.82(m,1H)1.90-1.98(m,2H)2.01–2.05(m 1H)2.13-2.23(m,1H)2.40(dd,J=12.42,4.99Hz,1H)2.67-2.78(m,1H)2.82-2.92(m,1H)3.16-3.29(m,1H)3.43-3.70(m,4H)4.55(d,J=10.37Hz,1H)6.96(td,J=4.35,1.66Hz,1H)7.03-7.10(m,1H)7.12-7.21(m,4H)7.23-7.31(m,2H)。质谱(ESI)m/z=539.0(M+1)。
实施例213
2-((3R,5R,6S)-1-((2S)-1-(8-氧杂-3-氮杂二环[3.2.1]辛烷-3-基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸
向2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-氧代丁烷-2-基)哌啶-3-基)乙酸(99mg,0.215mmol;实施例210,步骤A)在DCE(3mL)中的溶液中加入48.7mg(0.43mmol)8-氧杂-3-氮杂二环[3.2.1]辛烷(Connolly,T.;Considine,J.;Ding,Z.;Forsatz,B.;Jennings,M.;MacEwan,M.;McCoy,K.;Place,D.;Sharma,A.;Sutherland,K.Organic Process Research&Development.2010,14(2),459-465.注意:参考文献是针对HCl盐的)。加入三乙酰氧基硼氢化钠(91mg,0.430mmol),接着加入乙酸(1.2μL,0.022mmol)。在搅拌过夜后,将该混合物分配在5%HCl水溶液和乙酸乙酯之间。用NaCl饱和水溶液洗涤有机层,经Na2SO4干燥,并浓缩。通过反相制备型HPLC(洗脱剂:0-100%MeCN+0.1%TFA于水+0.1%TFA中,超过20分钟)纯化残余物。将含有产物的级分转移到分液漏斗中,并加入NaHCO3饱和水溶液和二氯甲烷。将水层用二氯甲烷反萃。用NaCl饱和水溶液洗涤合并的有机层,经无水Na2SO4干燥,过滤,并浓缩滤液从而得到本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 0.37-0.53(m,3H)1.48-1.58(m,4H)1.83-2.15(m,7H)2.18-2.31(m,2H)2.50(s,2H)2.60(d,J=10.76Hz,1H)2.70(d,J=15.65Hz,1H)2.96-3.17(m,4H)4.29-4.42(m,2H)4.55(d,J=10.56Hz,1H)6.65(dt,J=7.68,1.44Hz,1H)6.94-7.02(m,1H)7.06-7.13(m,1H)7.14-7.21(m,1H)7.21-7.33(m,4H)。质谱(ESI)m/z=559.2(M+1)。
实施例214
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(3,3-二甲基吗啉代)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
向2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-氧代丁烷-2-基)哌啶-3-基)乙酸(70mg,0.151mmol;实施例210,步骤A)在DCE(3mL)中的溶液中加入45.9mg(0.303mmol)3,3-二甲基吗啉盐酸盐(Cottle,D.;Jeltsch,A.;Stoudt,T.;Walters,D.Journal of Organic Chemistry.1946,11(3),286-91.;注意:参考文献是针对游离碱的)和三乙酰氧基硼氢化钠(64.2mg,0.303mmol)。在搅拌过夜后,用NH4Cl饱和水溶液稀释该混合物。用DCM(2X)萃取该混合物。用NaCl饱和水溶液洗涤合并的有机层,经无水Na2SO4干燥,过滤,并浓缩滤液。通过制备型硅胶薄层色谱法(洗脱剂:50%乙酸乙酯/己烷)纯化残余物。将含有产物的级分汇集在一起,浓缩并通过制备型硅胶薄层色谱法(洗脱剂:10%MeOH/DCM)再纯化从而得到本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 0.47–0.51(m 3H)0.92-1.07(m,6H)1.26(s,3H)1.44–1.48(m 6H)1.83-1.98(m,2H)1.99-2.08(m,1H)2.14-2.52(m,3H)3.34–3.37(m 1H)3.42-3.52(m,1H)3.57-3.69(m,1H)3.87(d,J=10.96Hz,1H)4.86(d,J=11.15Hz,1H)6.77(d,J=7.43Hz,1H)6.94-7.05(m,1H)7.08-7.30(m,6H)。质谱(ESI)m/z=561.3(M+1)。
实施例215
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(3-羟基-3-(三氟甲基)氮杂环丁烷-1-基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
向2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-氧代丁烷-2-基)哌啶-3-基)乙酸(70mg,0.151mmol;实施例210,步骤A)在DCE(3mL)中的溶液中加入53.8mg(0.303mmol)3-(三氟甲基)氮杂环丁烷-3-醇盐酸盐(美国专利公布号2007/0275930)和三乙酰氧基硼氢化钠(64.2mg,0.303mmol)。在搅拌18小时后,将该混合物分配在水和DCM之间。用DCM洗涤水层。用NaCl饱和水溶液洗涤合并的有机层,经无水Na2SO4干燥,过滤,并浓缩滤液。通过制备型硅胶薄层色谱法(洗脱剂:50%乙酸乙酯/己烷)纯化残余物从而得到本标题化合物。
1H NMR(400MHz,MeOH)δppm 0.51(t,J=7.43Hz,3H)1.36(s,3H)1.50-1.66(m,1H)1.71-1.86(m,1H)2.09-2.26(m,2H)2.38(dd,J=12.52,3.91Hz,1H)2.52-2.64(m,1H)2.75(br.s.,1H)2.93(d,J=14.87Hz,1H)3.11-3.27(m,2H)3.28-3.43(m,3H)3.66-3.79(m,2H)4.62(d,J=10.56Hz,1H)6.86-6.98(m,1H)7.03(s,1H)7.09-7.22(m,4H)7.27(d,J=7.24Hz,2H)。质谱(ESI)m/z=587.2(M+1)。
实施例216
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(甲基(氧杂环丁烷-3-基)氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
步骤A. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(甲基氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸-铵盐
向2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-氧代丁烷-2-基)哌啶-3-基)乙酸(201mg,0.434mmol;实施例210步骤A)在DCE(3mL)中的溶液中加入甲胺盐酸盐(117mg,1.736mmol),接着加入三乙酰氧基硼氢化钠(184mg,0.868mmol)。在4小时后,用甲醇和DCM稀释该混合物,过滤,并浓缩。通过硅胶快速色谱法(洗脱剂:先用20-100%乙酸乙酯/己烷,然后用6:1:0.1DCM:MeOH:NH4OH)纯化残余物从而得到本标题化合物。
步骤B. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(甲基(氧杂环丁烷-3-基)氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
向氧杂环丁烷-3-酮(17.78mg,0.247mmol)在DCE(3mL)中的溶液中加入步骤A中获得的2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(甲基氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸铵盐(61mg,0.123mmol),接着加入三乙酰氧基硼氢化钠(78mg,0.370mmol)和3滴AcOH。在45分钟后,加入3ml MeOH和氧杂环丁烷-3-酮(12mg,0.17mmol)。在搅拌过夜后,加入氧杂环丁烷-3-酮(12mg,0.17mol)和三乙酰氧基硼氢化钠(60mg,0.32mmol)。在24小时后,用甲醇稀释该混合物并使其蒸发到硅胶上。通过硅胶快速色谱法(洗脱剂:0%至100%的在DCM中的[6:1:0.1DCM/MeOH/NH4OH])纯化固体。将含有产物的级分汇集在一起,浓缩,并通过制备型硅胶薄层色谱法(洗脱剂:10%MeOH/DCM)纯化从而得到本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 0.51(t,J=7.53Hz,3H)0.78-0.93(m,1H)1.14-1.32(m,3H)1.87–1.95(m 1H)2.04(d,J=13.30Hz,1H)2.12(s,3H)2.19-2.38(m,2H)2.71(d,J=15.65Hz,1H)2.99-3.15(m,3H)3.44-3.60(m,1H)4.44-4.81(m,6H)6.81(d,J=7.24Hz,1H)6.94-7.04(m,2H)7.09-7.21(m,2H)7.23-7.31(m,3H)。质谱(ESI)m/z=533.2(M+1)。
实施例217
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(2-氧代噁唑烷-3-基)丁烷-2-基)哌啶-3-基)乙酸
步骤A. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-((2-羟基乙基)氨基)丁烷-2-基)-3-甲基哌啶-2-酮和(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-1-((2-羟基乙基)氨基)丁烷-2-基)-3-甲基哌啶-2-酮
将在ClCH2CH2Cl(1mL)中的(S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁醛(180mg,0.405mmol;实施例91,步骤C)与三乙酰氧基硼氢化钠(172mg,0.81mmol)、乙醇胺(0.04mL,0.73mmol)和乙酸(0.06mL,1.013mmol)一起在室温下搅拌18h,此时的LC-MS分析指示存在所需的产物。将该混合物分配在饱和NaHCO3和CH2Cl2之间。浓缩有机层,并通过色谱法(硅胶,先用己烷/EtOAc,然后用EtOAc/MeOH,多达15%)纯化残余物从而得到本标题化合物,为两个非对映异构体的1:1混合物。MS(ESI)m/z=489(M+1)。
步骤B. 3-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁基)噁唑烷-2-酮和3-((R)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁基)噁唑烷-2-酮
将(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-((2-羟基乙基)氨基)丁烷-2-基)-3-甲基哌啶-2-酮和(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-1-((2-羟基乙基)氨基)丁烷-2-基)-3-甲基哌啶-2-酮(60mg,0.123mmol;实施例217,步骤A)的混合物与1,1′-羰基二咪唑(99mg,0.61mmol)和1,8-二氮杂二环[5.4.0]十一碳-7-烯(37mg,0.245mmol)混合在1,4-二噁烷(1mL)中。将该混合物在油浴中加热至100℃并保持18h。让该混合物冷却至室温,用EtOAc稀释并用水洗涤三次。通过由硅胶和Na2SO4构成的垫过滤粗产物从而得到本标题化合物,使用该化合物无需进一步纯化。MS(ESI)m/z=515(M+1)。
步骤C. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((2S)-1-(5-甲基-2-氧代噁唑烷-3-基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
按照与实施例71步骤F中描述的程序类似的程序,从实施例217步骤B中获得的混合物制备本标题化合物。将两个非对映异构体的混合物分离,然后通过手性分离进一步纯化从而得到本标题化合物(250x30mm IC柱(Chiral Technologies,Inc.,West Chester,PA,USA),用32g/min MeOH(20mM NH3))。
1H NMR(CDCl3,500MHz)δppm 0.57(t,3H),1.50(s,3H),1.70(m,1H),1.90(m,1H),2.00(m,1H),2.25(t,1H),2.78(br,1H),2.98(br,1H),3.13(m,3H),3.62(m,2H),3.85(br,1H),4.40(m,3H),6.67(m,1H),6.93(s,1H),6.99(br,2H),7.14(m,2H),7.24(m,2H)。MS(ESI)m/z=533(M+1)。
实施例218
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(2-氧代吡啶-1(2H)-基)丁烷-2-基)哌啶-3-基)乙酸
步骤A. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)-3-甲基哌啶-2-酮
在烘干的3-颈圆底烧瓶中将(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)-3-甲基哌啶-2-酮(60mg,0.134mmol;实施例91,步骤C)与三苯基膦(42mg,0.161mmol)、2-羟基吡啶(14.1mg.0.148mmol)和偶氮二甲酸二异丙酯(0.029mL,0.148mmol)混合在甲苯中。将该混合物于室温在氮气下搅拌18h。蒸发溶剂。通过色谱法(硅胶,己烷/EtOAc,1:0至2:3)纯化残余物从而得到本标题化合物,为无色油状物。
步骤B. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(2-氧代吡啶-1(2H)-基)丁烷-2-基)哌啶-3-基)乙酸
向装有(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)-3-甲基哌啶-2-酮(35mg,0.067mmol;实施例218,步骤A)的25mL圆底烧瓶中加入THF、水(直至反应物变得混浊并且在轻轻搅拌情况下仍然混浊),和tBuOH(直至混浊反应物变得半透明)。加入4-甲基吗啉4-氧化物一水合物(13.6mg,0.10mmol),接着加入4wt.%在水中的四氧化锇(0.016mL,0.067mmol)。让反应物在室温下搅拌16h以完成二醇的形成。在室温下向由此产生的混合物中加入琼斯试剂(70μL),并继续搅拌18h。用水淬灭反应物,用EtOAc稀释,并用另外的EtOAc(3x8mL)萃取。用水洗涤合并的有机层,经MgSO4干燥,过滤,并浓缩滤液。通过制备型HPLC纯化淡绿色残余物从而得到本标题化合物。
1H NMR(CDCl3,400MHz)δppm 0.53(t,3H),1.43(s,3H),1.68(m,1H),1.85(t,1H),2.03(m,2H),2.65(m,1H),2.91(m,1H),3.30(m,2H),3.72(m,1H),4.25(m,1H),4.42(m,1H),6.71(m,4H),7.70(m,4H),7.26(m,2H),7.51(m,1H),7.77(m,1H)。质谱(ESI)m/z=541(M+1)。
实施例219
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(2-氧代-5-(三氟甲基)吡啶-1(2H)-基)丁烷-2-基)哌啶-3-基)乙酸
采用针对实施例218描述的程序,通过在步骤A中使用2-羟基-5-(三氟甲基)吡啶,和三正丁基膦、偶氮二甲酸二哌啶(azodicarboxylic dipiperidine)来制备2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(2-氧代-5-(三氟甲基)吡啶-1(2H)-基)丁烷-2-基)哌啶-3-基)乙酸。
1H NMR(CDCl3,500MHz)δppm 0.54(t,3H),1.42(s,3H),1.60(m,1H),1.78(m,1H),2.01(m,2H),2.77-2.93(m,2H),3.13(m,1H),3.42(m,1H),3.81(m,1H),4.32(m,2H),6,50(m,1H),6.71(m,1H),6.77(m,1H),6.91(br,2H),7.03(m,1H),7.11(m,1H),7.23(m,2H),7.69(m,2H)。质谱(ESI)m/z=609(M+1)。
实施例220
(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(吡啶-3-基氧基)丁烷-2-基)哌啶-2-酮
用3-羟基吡啶代替2-羟基吡啶,如针对实施例218所述制备(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(吡啶-2-基氧基)丁烷-2-基)哌啶-2-酮(10mg)。
1H NMR(MeOH-d4,500MHz)δppm 0.62(m,3H),1.27(s,3H),1.70(m,1H),1.97(m,1H),2.18(m,2H),2.59(m,1H),2.96(m,1H),3.44(m,2H),4.11(m,1H),4.58(m,1H),4.70(m,1H),6.97(m,1H),7.06(m,1H),7.15-7.28(m,6H),7.81(m,1H),7.98(m,1H),8.37(m,1H),8.56(s,1H)。质谱(ESI)m/z=541(M+1)。
实施例221
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((1S)-1-(四氢呋喃-2-基)丙基)哌啶-3-基)乙酸(异构体1)
*立体化学未确定
步骤A. (3S,5R,6S)-3-烯丙基-1-((3S)-7-((叔丁基二甲基甲硅烷基)氧基)-4-羟基庚烷-3-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮
*立体化学未确定
根据Minguez等人Biorg.Med.Chem 11,3335,2003在1.8mmol规模上制备由(3-溴丙氧基)(叔丁基)二甲基甲硅烷衍生的格氏试剂,为在THF(~3mL)中的灰色溶液。将约1.5mL格氏试剂缓慢地加入到在室温下的(S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁醛(100mg,0.22mmol;实施例91,步骤C)在THF(1mL)中的溶液中。在2h后,将反应物稀释在乙酸乙酯中,并先后用饱和氯化铵溶液和NaCl饱和水溶液洗涤。经硫酸钠干燥有机层并浓缩。通过硅胶色谱法用乙酸乙酯/己烷洗脱来进行纯化,得到本标题化合物,为非对映异构体混合物。
1H NMR(400MHz,氯仿-d)代表信号:
主要非对映异构体δppm 1.17(s,3H),4.25(d J=10.6Hz,1H)。
次要非对映异构体δppm 1.21(s,3H),4.37(d,J=10.6Hz,1H)。
质谱(ESI)m/z=618.4(M+1)。
步骤B. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S)-4,7-二羟基庚烷-3-基)-3-甲基哌啶-2-酮
在室温下用四丁基氟化铵(0.62mL 1M在THF中,0.62mmol)处理(3S,5R,6S)-3-烯丙基-1-((3S)-7-(叔丁基二甲基甲硅烷基氧基)-4-羟基庚烷-3-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮(127mg,0.21mmol;实施例221,步骤A)在THF(1.5mL)中的溶液1.5小时。在真空下除去溶剂。通过硅胶色谱法用乙酸乙酯/己烷洗脱来进行纯化,得到本标题化合物,为非对映异构体混合物。
1H NMR(400MHz,氯仿-d)代表信号:
主要非对映异构体δppm 1.15(s,3H),4.26(d J=10.6Hz,1H),
次要非对映异构体δppm 1.20(s,3H),4.31(d,J=10.6Hz,1H)。
质谱(ESI)m/z=504.3(M+1)。
步骤C. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-((S)-四氢呋喃-2-基)丙基)哌啶-2-酮和(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-((R)-四氢呋喃-2-基)丙基)哌啶-2-酮
在室温下用(E)-二氮烯-1,2-二甲酸二乙酯(0.033ml,0.22mmol)处理(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S)-4,7-二羟基庚烷-3-基)-3-甲基哌啶-2-酮(55mg,0.11mmol;实施例221,步骤B)和三苯基膦(57.2mg,0.22mmol)在二氯甲烷(2mL)中的溶液2小时。通过硅胶色谱法用乙酸乙酯/己烷洗脱来进行纯化,得到本标题化合物中的一种,其为主要非对映异构体,为第一洗脱化合物,接着得到次要非对映异构体。
(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((1S)-1-(四氢呋喃-2-基)丙基)哌啶-2-酮(主要非对映异构体;第一洗脱化合物)
1H NMR(400MHz,氯仿-d)δppm 0.65(t,J=7.43Hz,3H)1.20(s,3H)1.51-1.58(m,3H),1.71(m,3H),1.83-1.97(m,4H),2.54-2.57(dd,J=7.53,3.62Hz,2H),3.08-3.14(ddd,J=13.01,10.47,3.72Hz,1H),3.53-3.58(m,2H),3.73-3.77(m,1H),4.30(d,J=10.56Hz,1H),5.08(s,1H),5.11(d,J=4Hz,1H),5.74-5.84(m,1H),6.62-6.64(d,J=8Hz,1H),6.86(s,3H),7.02(t,J=8Hz,1H),7.04-7.09(s,1H),7.15(d,J=4Hz,2H)。质谱(ESI)m/z=486.3(M+1)。
(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((1S)-1-(四氢呋喃-2-基)丙基)哌啶-2-酮(次要非对映异构体;第二洗脱化合物)
1H NMR(400MHz,氯仿-d)δppm 0.47(t,J=7.53Hz,3H),1.10-1.21(m,4H),1.36-1.46(m,1H),1.51(s,1H),1.73-2.06(m,5H),2.45-2.59(m,3H),3.07-3.14(ddd,J=13.60,10.56,3.23Hz,1H)3.70-3.80(m,2H)4.37(d,J=0.59Hz,1H)4.69(d,J=10.76Hz,1H)5.14-5.23(m,2H)5.75-5.85(m,J=17.17,9.83,7.43,7.43Hz,1H)6.68(dt,J=7.38,1.59Hz,1H)6.90–6.94(m,3H)7.04(m,2H),7.12(d,J=8Hz,2H)。质谱(ESI)m/z=486.3(M+1)
步骤D. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((1S)-1-(四氢呋喃-2-基)丙基)哌啶-3-基)乙酸(异构体1)
按照与实施例71步骤F中描述的程序类似的程序,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((1S)-1-(四氢呋喃-2-基)丙基)哌啶-2-酮(主要非对映异构体;第一洗脱化合物;实施例121,步骤C)制备本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 0.61(t,J=7.63Hz,3H)1.34(s,3H)1.46-1.56(m,2H)1.72(s,br,3H)1.82-1.89(m,2H)2.00-2.14(m,2H)2.61(d,J=13.89Hz,2H)2.76-2.84(m,2H)3.20(dd,J=13.30,7.24Hz,2H)3.29(br.s.,1H)3.73(td,J=7.87,5.18Hz,1H)4.34(d,J=10.37Hz,1H)6.68(dd,J=7.43,1.56Hz,1H)6.87(s,1H)7.00-7.15(m,4H)7.14(dd,J=8.12,0.5Hz,2H)。质谱(ESI)m/z=504.3(M+1)
实施例222
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((1S)-1-(四氢呋喃-2-基)丙基)哌啶-3-基)乙酸(异构体2)
*立体化学未确定
按照与实施例71步骤F中描述的程序类似的程序,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((1S)-1-(四氢呋喃-2-基)丙基)哌啶-2-酮(次要非对映异构体;第二洗脱化合物;实施例121,步骤C)制备本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 0.46(t,J=7.63Hz,3H)1.15-1.26(m,3H)1.36(s,br.3H),1.46-1.50(m,1H),1.79-1.85(m,4H),2.05-2.09(dd,J=12,4Hz,1H),2.17(t,J=12Hz,1H),2.51(s,br,1H),2.66(d,J=12Hz,1H),2.77(d,J=12Hz,1H),3.76(m,2H),4.68(d,J=8nHz,1H),6.76(d,J=8Hz,1H),6.92-7.03(m,3H),7.06(d,J=2.2Hz,2H),7.16(d,J=8.8Hz,2H)。质谱(ESI)m/z=504.3(M+1)
实施例223
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((1S)-1-(5-氧代四氢呋喃-2-基)丙基)哌啶-3-基)乙酸
*立体化学未确定
使用实施例221的氧化程序,但使用过量较多的高碘酸钠(7当量)并且反应较长时间(18h)来制备本标题化合物。
1H NMR(400MHz,CD3OD)δppm 0.7(s,be,3H),1.42(s,br,3H),1.68-1.75(m,1H),1.96(m,1H),2.21-2.24(m,3H),2.33(m,1H),2.49-2.67(m,3H),2.97(d,J=12Hz,1H),3.37(m,2H),3.51(m,1H),4.60(d,J=8Hz,1H),6.96(m,1H),7.10(s,1H)7.13-7.19(m,2H),7.31(s,br,4H)。质谱(ESI)m/z=518.2(M+1)。
实施例224
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((1S)-1-(四氢-2H-吡喃-2-基)丙基)哌啶-3-基)乙酸(异构体1)
*立体化学未确定
步骤A. (3S,5R,6S)-3-烯丙基-1-((3S)-8-((叔丁基二甲基甲硅烷基)氧基)-4-羟基辛烷-3-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮
按照与实施例221步骤A中描述的程序类似的程序,在格氏试剂制备期间用(4-氯丁氧基)(叔丁基)二甲基甲硅烷替代(3-溴丙氧基)(叔丁基)二甲基甲硅烷来制备本标题化合物,为非对映异构体混合物。质谱(ESI)m/z=632.2(M+1)。
步骤B. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S)-4,8-二羟基辛烷-3-基)-3-甲基哌啶-2-酮
通过使用与实施例221步骤B中描述的程序类似的程序,从(3S,5R,6S)-3-烯丙基-1-((3S)-8-((叔丁基二甲基甲硅烷基)氧基)-4-羟基辛烷-3-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮(实施例224,步骤B)获得本标题化合物。经NMR观察到非对映异构体比率为约2:1。
1H NMR(400MHz,d4-甲醇)代表信号:
主要非对映异构体δppm 0.45(t,J=7.6Hz,3H),4.76(d,J=12Hz,1H)。
次要非对映异构体:δppm 0.54(t,J=7.6Hz,3H),4.53(d,J=12Hz,1H)。
m/z=518.2(M+1)。
步骤C. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((1S)-1-(四氢-2H-吡喃-2-基)丙基)哌啶-2-酮
*立体化学未确定
在室温下用(E)-二氮烯-1,2-二甲酸二乙酯(0.02ml,0.12mmol)处理(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S)-4,8-二羟基辛烷-3-基)-3-甲基哌啶-2-酮(31mg,0.060mmol;非对映异构体混合物;实施例224,步骤B)和三苯基膦(31.4mg,0.12mmol)在二氯甲烷(1.5mL)中的溶液2小时。通过硅胶色谱法用乙酸乙酯/己烷洗脱来进行纯化,得到本标题化合物,为非对映异构体混合物。
1H NMR(400MHz,d4-甲醇)代表信号:
主要非对映异构体δppm 0.46(t,J=8Hz,3H),4.75(d,J=12Hz,1H)。
次要非对映异构体δppm 0.55(t,J=8Hz,3H),4.53(d,J=12Hz,1H)。
质谱(ESI)m/z=500.2(M+1)
步骤D. (3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-(2,3-二羟基丙基)-3-甲基-1-((1S)-1-(四氢-2H-吡喃-2-基)丙基)哌啶-2-酮
*立体化学未确定
在室温下用4-甲基吗啉N-氧化物(2.45mg,0.021mmol)和2.5%在t-BuOH中的四氧化锇(2μL,0.15μmol)处理(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((1S)-1-(四氢-2H-吡喃-2-基)丙基)哌啶-2-酮(3mg,5.99μmol;实施例224,步骤C)在THF(37.5μL)、H2O(25μL)和叔丁醇(21μL)中的溶液18h。用乙酸乙酯稀释该混合物,先后用水和NaCl饱和水溶液洗涤,并经硫酸钠干燥。在浓缩后,将非对映异构体混合物用于下一步骤而无需进一步纯化。质谱(ESI)m/z=534.1(M+1)
步骤E. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((1S)-1-(四氢-2H-吡喃-2-基)丙基)哌啶-3-基)乙醛
*立体化学未确定
用高碘酸钠(3.60mg,0.02mmol)处理(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-(2,3-二羟基丙基)-3-甲基-1-((1S)-1-(四氢-2H-吡喃-2-基)丙基)哌啶-2-酮(3mg,5.61μmol;实施例224,步骤D)在水(20.0μL)和THF(40.0μL)中的溶液。在沉淀形成后,加入甲醇(40μL)以形成乳液,将该乳液在室温下搅拌1小时。用NaCl饱和水溶液稀释反应物,并用乙酸乙酯萃取。经硫酸钠干燥合并的有机层,过滤,并浓缩滤液从而得到两个非对映异构体的混合物,将其用于下一步骤。质谱(ESI)m/z=502.1(M+1)
步骤F. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((1S)-1-(四氢-2H-吡喃-2-基)丙基)哌啶-3-基)乙酸(异构体1)
将2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((1S)-1-(四氢-2H-吡喃-2-基)丙基)哌啶-3-基)乙醛(3mg,5.97μmoL;立体异构体混合物,实施例224,步骤E)在1.25M磷酸二氢钾水溶液(0.050mL)、叔丁醇(0.050mL)和2-甲基丁-2-烯在THF中的2.0M溶液(0.15mL,0.30mmol)中的溶液用亚氯酸钠(2.16mg,0.024mmol)在室温下处理3h。用1M硫代硫酸钠溶液(0.03mL)淬灭反应物。在10min后,用1M硫酸氢钾溶液(0.03mL)酸化该混合物并用乙酸乙酯萃取。用NaCl饱和水溶液洗涤有机层并经无水硫酸钠干燥。通过反相制备型HPLC(洗脱剂:0%至100%MeCN+0.1%TFA于水+0.1%TFA中,超过20分钟)纯化,得到本标题化合物,为第一洗脱异构体。
1H NMR(400MHz,MeOH-D4)δppm 0.51(t,J=8Hz,3H),1.03(m,1H),1.32(s,br,1H),1.39(s,3H),1.50(m,2H),1.67(m,1H),1.85(m,1H),1.96(m,3H),2.19-2.22(m,2H),2.60(d,J=12Hz,1H),2.99(d,J=12Hz,1H),3.16(m,1H),3.44(m,1H),3.51(m.1H),3.85(m,1H),4.57(d,J=12hZ,1H),6.97-6.99(m,1H),7.06(s,br,1H),7.15-7.21(m,3H),7.29-7.31(d,J=8Hz,2H)。质谱(ESI)m/z=518.2(M+1)。
进一步洗脱得到实施例225,为第二洗脱异构体。
实施例225
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((1S)-1-(四氢-2H-吡喃-2-基)丙基)哌啶-3-基)乙酸(异构体2)
*立体化学未确定
1H NMR(400MHz,MeOH-d4)δppm 0.39(t,J=8Hz,3H),1.00-1.07(m,1H),1.18-1.20(m,1H),1.32(s,br,1H),1.37(s,br,3H),1.50-1.68(m,4H),1.86(m,2H),2.15-2.19(m,2H),2.58(d,J=16Hz,1H),2.96(d,J=16Hz,1H),3.41(m,1H),3.52(m,1H),3.89-3.94(m,1H),4.11(m,1H),3.71(d,J=8HZ,1H),6.94(m,1H),7.03(s,br,1H),7.14-7.20(m,4H),7.28-7.30(d,J=8HZ,2H)。质谱(ESI)m/z=518.2(M+1)
实施例226
2-((3R,5R,6S)-1-((R)-1-(苯并[d]噻唑-2-基)丙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸或2-((3R,5R,6S)-1-((S)-1-(苯并[d]噻唑-2-基)丙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸(异构体1)
步骤A. 1-(苯并[d]噻唑-2-基)丙烷-1-醇
用超过15分钟的时间向1,3-苯并噻唑-2-甲醛(0.96g,5.88mmol)在THF(15.0mL)中的溶液中缓慢地加入乙基溴化镁(1.0M溶液在THF中,12.0mL,12.0mmol,2当量)(观察放热情况)。将由此产生的暗红色溶液在室温下搅拌55分钟,然后用饱和氯化铵水溶液(4mL)淬灭。在减压下浓缩该混合物。通过硅胶快速色谱法(用0-70%的在己烷中的EtOAc梯度洗脱)纯化,得到本标题化合物,为红色油状物。
步骤B. 2-(1-溴丙基)苯并[d]噻唑
向0℃的891.4mg(4.61mmol)1-(苯并[d]噻唑-2-基)丙烷-1-醇(实施例1,步骤A)在THF(12.0mL)中的溶液中加入三苯基膦(1.8g,6.86mmol,1.5当量),接着加入四溴化碳(2.22g,6.69mmol,1.5当量)。将由此产生的混合物在0℃下搅拌35分钟,然后让其温度升至室温过夜。然后在减压下浓缩反应混合物。通过硅胶快速色谱法(用0-50%的在己烷中的EtOAc梯度洗脱)纯化,得到本标题化合物,为深色油状物。
步骤C. (3S,5R,6S)-3-烯丙基-1-((R)-1-(苯并[d]噻唑-2-基)丙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮和(3S,5R,6S)-3-烯丙基-1-((S)-1-(苯并[d]噻唑-2-基)丙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮
用超过1分钟的时间向在0℃下的氢化钠(在油中的60%分散体,100.0mg,2.500mmol,3.1当量)在DMF(1mL)中的悬浮液中加入300mg(0.801mmol)(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮(实施例71,步骤D)在DMF(1mL)中的溶液。在5分钟后,逐滴加入576.7mg(2.25mmol,2.8当量)2-(1-溴丙基)苯并[d]噻唑(实施例226,步骤B)在DMF(1mL)中的溶液。让由此产生的混合物温度升至室温过夜。用水淬灭反应物,然后在减压下浓缩。通过反相制备型HPLC(Agilent Eclipse Plus C18柱(AgilentTechnologies,Santa Clara,CA),用70%至90%的含有0.1%TFA的CH3CN/H2O梯度洗脱,超过25分钟)纯化,得到本标题化合物的混合物,为白色固体。
步骤D. 2-((3R,5R,6S)-1-((R)-1-(苯并[d]噻唑-2-基)丙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸或2-((3R,5R,6S)-1-((S)-1-(苯并[d]噻唑-2-基)丙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸(异构体1)
向97.5mg(0.177mmol)(3S,5R,6S)-3-烯丙基-1-((R)-1-(苯并[d]噻唑-2-基)丙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮(实施例226,步骤C)在乙腈(1mL)、水(1.5mL)和四氯化碳(1mL)中的溶液中加入高碘酸钠(154.2mg,0.721mmol,4.1当量),接着加入氯化钌(III)水合物(11.0mg,0.049mmol,0.27当量)。将由此产生的混合物在室温下搅拌2.75小时,然后通过0.45μm过滤器过滤从而除去残余固体,并然后在减压下浓缩。通过反相制备型HPLC(Agilent Eclipse Plus C18柱(Agilent Technologies,Santa Clara,CA),用40%至80%的含有0.1%TFA的CH3CN/H2O梯度洗脱,超过25分钟)纯化,得到本标题化合物中的一种,其为第一洗脱异构体,为白色固体。
1H NMR(500MHz,氯仿-d)δppm 1.05(t,J=7.46Hz,3H)1.55(s,3H)2.10-2.32(m,3H)2.41-2.54(m,1H)2.87-2.98(m,2H)3.16-3.25(m,1H)4.62(d,J=10.27Hz,1H)4.81(dd,J=8.56,6.85Hz,1H)6.71(d,J=7.58Hz,1H)6.80(d,J=8.07Hz,2H)6.88(d,J=8.31Hz,2H)6.96(s,1H)7.03-7.10(m,1H)7.16(dd,J=7.95,0.86Hz,1H)7.42-7.47(m,1H)7.48-7.54(m,1H)7.85(t,J=8.19Hz,2H)。质谱(ESI)m/z=567(M+1)。
实施例227
2-((3R,5R,6S)-1-((R)-1-(苯并[d]噻唑-2-基)丙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸或2-((3R,5R,6S)-1-((S)-1-(苯并[d]噻唑-2-基)丙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸(异构体2)
如实施例226步骤D中所述从(3S,5R,6S)-3-烯丙基-1-((S)-1-(苯并[d]噻唑-2-基)丙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮(实施例226,步骤C)制备本标题化合物中的一种(异构体2),为第二洗脱异构体。
1H NMR(500MHz,氯仿-d)δppm 0.77(t,J=7.34Hz,3H)1.39(s,3H)2.03-2.16(m,2H)2.16-2.24(m,1H)2.58(dt,J=14.61,7.49Hz,1H)2.82-2.98(m,2H)3.20-3.29(m,1H)4.75-4.84(m,2H)6.75(d,J=7.58Hz,1H)6.94(s,1H)7.00(d,J=8.31Hz,2H)7.05-7.11(m,3H)7.13-7.17(m,1H)7.44-7.49(m,1H)7.53(t,J=7.46Hz,1H)7.87(d,J=8.07Hz,1H)8.01(d,J=8.07Hz,1H)。质谱(ESI)m/z=567(M+1)。
还用等效量的合适的卤代烷替代实施例226步骤C中的2-(1-溴丙基)苯并[d]噻唑,如实施例226中所述从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮(实施例71,步骤D)制备了实施例228至240。所需要的卤代烷基(试剂)如个别实施例中所述制备。
实施例228
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(3-甲基异噁唑-5-基)丙基)-2-氧代哌啶-3-基)乙酸或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((R)-1-(3-甲基异噁唑-5-基)丙基)-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 0.74(t,J=7.43Hz,3H)1.33(s,3H)1.90-2.11(m,2H)2.14-2.29(m,5H)2.90(q,J=7.24Hz,2H)3.37-3.47(m,1H)4.47(t,J=7.14Hz,1H)4.60(d,J=10.37Hz,1H)5.70(s,1H)6.80(dt,J=7.48,1.54Hz,1H)6.90-7.02(m,3H)7.04-7.19(m,4H)。质谱(ESI)m/z=515(M+1)。
5-(1-溴丙基)-3-甲基异噁唑的合成:
步骤A. 1-(3-甲基异噁唑-5-基)丙烷-1-醇
在-78℃下向3-甲基异噁唑-5-甲醛(0.801g,7.21mmol)在10mL THF中的溶液中缓慢地加入乙基溴化镁(3.60mL,10.81mmol)。将反应混合物在-78℃下搅拌2h,然后用NH4Cl饱和水溶液淬灭,并用乙醚(3x80mL)萃取。经Na2SO4干燥合并的有机层,过滤,并蒸发滤液从而得到粗产物。通过硅胶色谱法用10%至60%的EtOAc/己烷洗脱纯化粗产物从而得到本标题化合物。质谱(ESI)m/z=142.2(M+1)。
步骤B. 5-(1-溴丙基)-3-甲基异噁唑
向1-(3-甲基异噁唑-5-基)丙烷-1-醇(0.589g,4.17mmol)在15mL THF中的溶液中加入CBr4(1.730g,5.22mmol)和三苯基膦(1.423g,5.42mmol)。将反应混合物在室温下搅拌3h。滤去固体,并用THF洗涤。浓缩滤液并通过硅胶色谱法用5%至30%的EtOAc/己烷洗脱来纯化残余物从而得到本标题化合物。质谱(ESI)m/z=204.2(M+1)。
实施例229
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(6-氯吡啶-2-基)丙基)-3-甲基-2-氧代哌啶-3-基)乙酸或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-1-(6-氯吡啶-2-基)丙基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 0.77(t,J=7.43Hz,3H)1.30(s,3H)1.99-2.13(m,2H)2.15-2.37(m,2H)2.70–2.90(m,2H)3.20(ddd,J=12.96,9.73,3.33Hz,1H)4.56(t,J=7.24Hz,1H)4.84(d,J=9.98Hz,1H)6.82(dt,J=7.43,1.56Hz,1H)6.88(d,J=8.22Hz,2H)6.99–7.24(m,7H)7.47(t,J=7.73Hz,1H)。质谱(ESI)m/z=545(M+1)。
2-(1-溴丙基)-6-氯吡啶的合成:
步骤A. 1-(6-氯吡啶-2-基)丙烷-1-醇
在-78℃下向6-氯代吡啶甲醛(1.00g,7.06mmol)在20mL THF中的溶液中缓慢地加入乙基溴化镁在乙醚中的3.0M溶液(3.53mL,10.60mmol)。将反应混合物在-78℃下搅拌2h。用NH4Cl饱和水溶液淬灭反应混合物,并用乙醚(3x100mL)萃取。经Na2SO4干燥合并的有机层并蒸发从而得到粗产物。通过硅胶色谱法,用10%至60%的EtOAc/己烷洗脱来纯化粗产物从而得到本标题化合物。质谱(ESI)m/z=172(M+1)。
步骤B. 2-(1-溴丙基)-6-氯吡啶
将1-(6-氯吡啶-2-基)丙烷-1-醇(0.497g,2.90mmol)、CBr4(1.2g,3.62mmol)和三苯基膦(0.987g,3.76mmol)在25mL THF中的混合物在室温下搅拌2h。滤去固体并用THF洗涤。浓缩滤液并通过硅胶色谱法,用10%至50%的EtOAc/己烷洗脱来纯化残余物从而得到本标题化合物。质谱(ESI)m/z=236(M+1)。
实施例230
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(吡啶-2-基)丙基)哌啶-3-基)乙酸或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((R)-1-(吡啶-2-基)丙基)哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 0.75(t,J=7.43Hz,3H),1.21-1.31(m,3H),1.93-2.10(m,2H),2.10-2.23(m,1H),2.50(dt,J=14.77,7.48Hz,1H),2.75(d,J=13.89Hz,1H),2.97(d,J=14.28Hz,1H),3.09-3.25(m,1H),4.65(dd,J=8.22,6.06Hz,1H),4.95(d,J=9.00Hz,1H),6.80(d,J=7.63Hz,1H),6.89(d,J=8.22Hz,2H),7.02-7.21(m,6H),7.34(d,J=7.83Hz,1H),7.54(td,J=7.68,1.66Hz,1H),8.42(d,J=4.30Hz,1H)。质谱(ESI)m/z=511.1(M+1)。
2-(1-溴丙基)吡啶的合成:
在室温下向2-丙基吡啶(2.5g,20.63mmol,购自Sigma-Aldrich,St.Louis,MO)和(E)-2,2′-(二氮烯-1,2-二基)双(2-甲基丙烷腈)(1.253g,7.63mmol,购自Sigma-Aldrich)在CCl4(60mL)中的混合物中加入n-溴琥珀酰亚胺(1.93mL,22.7mmol,购自Sigma-Aldrich)。将混合物在荧光灯下于室温搅拌12hr。通过经由(J.T.Baker,Phillipsberg,NJ,硅藻土)垫过滤该混合物来除去沉淀,用CCl4(10mL)洗涤该沉淀。在减压下浓缩滤液。通过硅胶快速色谱法(洗脱剂:20%EtOAc/己烷)纯化残余物,得到本标题化合物,为黄色液体。质谱(ESI)m/z=199.9和201.9(M+1)。
实施例231
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(吡啶-2-基)丁基)哌啶-3-基)乙酸或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((R)-1-(吡啶-2-基)丁基)哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 1.04(m,3H),1.41-1.71(m,5H),2.03(br.s.,1H),2.18(d,J=13.69Hz,1H),2.30(t,J=13.69Hz,1H),2.44-2.74(m,2H),3.08(d,J=15.26Hz,1H),3.47(t,J=10.56Hz,1H),4.31(br.s.,1H),4.59(d,J=10.37Hz,1H),6.77(d,J=6.46Hz,1H),6.89-7.20(m,8H),7.79(br.s.,1H),8.17(br.s.,1H),8.72-9.01(m,1H),11.51(br.s.,1H)。质谱(ESI)m/z=525.1(M+1)。
2-(1-溴丁基)-6-氯吡啶的合成:
步骤A. 1-(吡啶-2-基)丁烷-1-醇
用超过10min的时间在-78℃在N2下向2-溴吡啶(1.1g,6.96mmol,购自Sigma-Aldrich)在乙醚(8mL)中的溶液中加入丁基锂(3.1mL×2.5M)。将反应溶液在-78℃下搅拌1.0hr。用超过10min的时间向该混合物中逐滴加入丁醛(0.602g,8.35mmol,购自Sigma-Aldrich)。在-78℃下搅拌15min后,让该混合物温度升至室温并在室温下搅拌1.5hr。将反应混合物倒入饱和NH4Cl水溶液(10mL)中,用水(15mL)稀释,并用EtOAc(20mL×3)萃取。合并有机层,用水、NaCl饱和水溶液洗涤,并经MgSO4干燥。在减压下除去有机溶剂后,通过硅胶快速色谱法用20-80%的EtOAc/己烷纯化残余物,得到本标题化合物,为白色固体。质谱(ESI)m/z=152.1(M+1)。
步骤B. 2-(1-溴丁基)吡啶
在0℃在N2气氛下向1-(吡啶-2-基)丁烷-1-醇(0.35g,2.3mmol;实施例231,步骤A)和三苯基膦(1.1g,4.2mmol)在THF(15mL)中的混合物中加入CBr4(1.2g,3.5mmol)。将该混合物在0℃下搅拌2min,然后让其温度升至室温并搅拌25min。经由(J.T.Baker,Phillipsberg,NJ,硅藻土)垫滤去沉淀,并用冷THF(10mL)洗涤该固体。在减压下浓缩滤液。通过硅胶快速色谱法用0-5-15%EtOAc/己烷纯化残余物,得到本标题化合物,为无色油状物。质谱(ESI)m/z=214.0和216.0(M+1)。
实施例232
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-环丙基-1-(吡啶-2-基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-2-环丙基-1-(吡啶-2-基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm-0.45--0.34(m,1H),-0.06(dq,J=9.19,4.63Hz,1H),0.16-0.39(m,2H),0.46(dd,J=7.43,5.28Hz,1H),1.16-1.31(m,3H),1.63(dt,J=13.60,6.90Hz,1H),2.00-2.17(m,2H),2.50-2.65(m,1H),2.77(br.s.,1H),2.88(d,J=9.59Hz,1H),3.19(t,J=8.80Hz,1H),4.84(br.s.,1H),4.97(d,J=9.19Hz,1H),6.78(d,J=7.43Hz,1H),6.93(d,J=7.83Hz,2H),7.00-7.17(m,7H),7.34(d,J=7.43Hz,1H),7.48-7.57(m,1H),8.34-8.56(m,1H)。质谱(ESI)m/z=537.2(M+1)。
2-(1-溴代-2-环丙基乙基)吡啶的合成:
步骤A. 2-环丙基-1-(吡啶-2-基)乙醇
用超过15min的时间在0℃在N2下向2-环丙基乙醛(1.00g,11.89mmol,购自BetaPharma,Inc.,Branford,CT)在THF(15mL)中的溶液中逐滴加入2-吡啶基溴化镁(47.6mL×0.25M,购自RiekeMetals,Inc.,Lincoln,NE)。在0℃下搅拌该混合物,在30min后,让其温度升至室温,并在室温下搅拌3.5hr。向反应混合物中加入饱和NH4Cl水溶液(5mL),接着加入水(15mL)。用EtOAc(2×10mL)萃取该混合物。经Na2SO4干燥合并的有机层。在除去有机溶剂之后,通过硅胶快速色谱法用40-70%EtOAc/己烷纯化残余物,获得本标题化合物,为白色固体。质谱(ESI)m/z=164.1(M+1)。
步骤B. 2-(1-溴代-2-环丙基乙基)吡啶
使用与实施例231步骤B中描述的程序类似的程序,从2-环丙基-1-(吡啶-2-基)乙醇(实施例232,步骤A)制备本标题化合物。质谱(ESI)m/z=226.0和228.0(M+1)。
实施例233
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(吡啶-3-基)丙基)哌啶-3-基)乙酸或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((R)-1-(吡啶-3-基)丙基)哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 0.97-1.10(d,J=8.6Hz,3H),1.44(s,3H),1.95-2.09(m,1H),2.09-2.23(m,2H),2.28(s,1H),2.62(d,J=13.89Hz,1H),2.87(d,J=13.89Hz,1H),3.33(ddd,J=13.40,10.47,3.13Hz,1H),4.37(d,J=10.37Hz,1H),5.93(t,J=7.92Hz,1H),6.54-6.61(m,1H),6.62-6.79(m,3H),6.83-6.90(m,1H),6.91-7.00(m,1H),7.00-7.07(m,1H),7.07-7.15(m,1H),7.15-7.23(m,1H),7.26(dd,J=8.02,5.67Hz,1H),7.36(d,J=8.02Hz,1H),8.35(d,J=5.48Hz,1H),8.80(s,1H)。质谱(ESI)m/z=511.1(M+1)。
3-(1-溴丙基)吡啶的合成:
步骤A. 1-(吡啶-3-基)丙烷-1-醇
在室温在N2气氛下向1-(吡啶-3-基)丙烷-1-酮(2.46g,18.20mmol,购自Lancaster Synthesis Ltd.)在MeOH(15mL)中的溶液中加入硼氢化钠粉末(0.690g,18.20mmol)。在室温下搅拌1.5hr后,向反应溶液中加入水(20ml)。将由此产生的混合物搅拌4min,用EtOAc(20mL×3)萃取。合并有机层,用水、NaCl饱和水溶液洗涤,并经MgSO4干燥。除去溶剂得到粗的本标题化合物,为白色固体。质谱(ESI)m/z=138.0(M+1)。
步骤B. 3-(1-溴丙基)吡啶
按照实施例231,步骤B中描述的程序,从1-(吡啶-3-基)丙烷-1-醇(实施例233,步骤A)制备本标题化合物。质谱(ESI)m/z=199.9和201.9(M+1)。
实施例234
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(吡嗪-2-基)丙基)哌啶-3-基)乙酸或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((R)-1-(吡嗪-2-基)丙基)哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 0.95(t,J=7.14Hz,3H),1.39(s,3H),1.94-2.24(m,4H),2.71(s,2H),3.39-3.54(m,1H),4.46(d,J=9.98Hz,1H),5.71(t,J=7.43Hz,1H),6.61(d,J=7.82Hz,1H),6.77(br.s.,4H),6.86-7.00(m,2H),7.04(d,J=8.80Hz,1H),8.03-8.16(m,1H),8.25(br.s.,1H),8.34(s,1H)。质谱(ESI)m/z=512.1(M+1)。
2-(1-溴丙基)吡嗪的合成:
按照与实施例230中描述的程序类似的程序,从2-丙基吡嗪(购自MatrixScientific)制备本标题化合物。质谱(ESI)m/z=200.8和202.9(M+1)。
实施例235
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(嘧啶-2-基)丙基)哌啶-3-基)乙酸或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((R)-1-(嘧啶-2-基)丙基)哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 0.78(t,J=7.43Hz,3H),1.34(s,3H),1.90-2.07(m,1H),2.08-2.19(m,1H),2.20-2.34(m,1H),2.52(dt,J=14.33,7.21Hz,1H),2.80(br.s.,1H),2.93(qd,J=7.27,2.05Hz,1H),3.29-3.49(m,1H),4.50(br.s.,1H),4.80(d,J=10.17Hz,1H),6.79(d,J=7.63Hz,1H),6.90-7.19(m,8H),8.60(d,J=4.69Hz,2H)。质谱(ESI)m/z=512.2(M+1)。
2-(1-溴丙基)嘧啶的合成:
步骤A. 2-丙基嘧啶
用超过5min的时间向在N2气氛下的0℃的三苯基膦(2.290g,8.73mmol)、乙酰丙酮镍(II)(0.464mL,2.62mmol)和2-氯嘧啶(5.00g,43.7mmol,购自Sigma-Aldrich)在THF(45mL)中的溶液中加入丙基氯化镁(21.83mL,43.7mmol)。让该混合物温度升至室温并在室温下搅拌3hr。向反应混合物中加入饱和NH4Cl水溶液(5mL),接着加入水(12mL)。用EtOAc(2×10mL)萃取该混合物。经Na2SO4干燥合并的有机层,过滤,并浓缩。通过硅胶快速色谱法(洗脱剂:0%至50%的EtOAc/己烷)纯化残余物从而得到本标题化合物,为无色液体。
步骤B. 2-(1-溴丙基)嘧啶
按照与实施例230中描述的程序类似的程序,从2-丙基嘧啶(实施例235,步骤A)制备本标题化合物。质谱(ESI)m/z=201.0和203.0(M+1)。
实施例236
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(6-甲基吡啶-2-基)丙基)-2-氧代哌啶-3-基)乙酸或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((R)-1-(6-甲基吡啶-2-基)丙基)-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 0.99(br.s.,3H),1.39(s,3H),1.90-2.06(m,1H),2.11(d,J=12.72Hz,1H),2.16-2.37(m,2H),2.68(d,J=15.06Hz,1H),2.89(s,3H),3.03(d,J=15.06Hz,1H),3.34(t,J=10.76Hz,1H),4.78(d,J=9.59Hz,1H),5.61(br.s.,1H),6.76(d,J=7.04Hz,1H),6.96(br.s.,6H),6.99-7.20(m,2H),7.50(d,J=7.43Hz,1H),7.90(t,J=7.63Hz,1H),8.60(br.s.,1H)。质谱(ESI)m/z=525.1(M+1)。
2-(1-溴丙基)-6-甲基吡啶的合成:
步骤A. 1-(6-甲基吡啶-2-基)丙烷-1-醇
使用与上面针对2-环丙基-1-(吡啶-2-基)乙醇(实施例232,步骤A)的合成描述的程序类似的程序,从6-甲基-2-吡啶甲醛(购自Tokyo Chemical Industry Co.Ltd.)制备本标题化合物。质谱(ESI)m/z=151.4(M+1)。
步骤B. 2-(1-溴丙基)-6-甲基吡啶
按照与实施例231步骤B中描述的程序类似的程序,从1-(6-甲基吡啶-2-基)丙烷-1-醇(实施例236,步骤A)制备本标题化合物。质谱(ESI)m/z=214.0和216.0(M+1)。
实施例237
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(吡啶-4-基)丙基)哌啶-3-基)乙酸或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((R)-1-(吡啶-4-基)丙基)哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 1.14(t,J=7.14Hz,3H),1.48-1.54(m,3H),1.94-2.09(m,1H),2.09-2.32(m,2H),2.64(d,J=16.24Hz,1H),2.96-3.11(m,1H),3.26(d,J=16.24Hz,1H),3.52-3.69(m,1H),4.39(d,J=10.37Hz,1H),6.02(br.s.,1H),6.61(d,J=7.63Hz,3H),6.77(br.s.,2H),6.89-7.09(m,5H),7.13(d,J=7.43Hz,1H),8.33(br.s.,1H)。质谱(ESI)m/z=511.1(M+1)。
4-(1-溴丙基)吡啶的合成:
步骤A. 1-(吡啶-4-基)丙烷-1-醇
按照与针对1-(吡啶-3-基)丙烷-1-醇(实施例233,步骤A)的合成描述的程序类似的程序,从1-(吡啶-4-基)丙烷-1-酮(购自Waterstonestone Technology)制备本标题化合物。质谱(ESI)m/z=138.0(M+1)。
步骤B. 4-(1-溴丙基)吡啶
按照与实施例231步骤B中描述的程序类似的程序,从1-(吡啶-4-基)丙烷-1-醇(实施例237,步骤A)制备本标题化合物。质谱(ESI)m/z=199.9和201.9(M+1)。
实施例238
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(6-(三氟甲基)吡啶-2-基)丙基)哌啶-3-基)乙酸或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((R)-1-(6-(三氟甲基)吡啶-2-基)丙基)哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 0.75(t,J=7.43Hz,3H),1.21-1.30(m,3H),1.98-2.19(m,2H),2.29(t,J=13.50Hz,1H),2.47(dt,J=14.62,7.46Hz,1H),2.78(d,J=14.87Hz,1H),2.98(d,J=14.87Hz,1H),3.14-3.28(m,1H),4.23-4.33(m,1H),5.05(d,J=9.98Hz,1H),6.84(d,J=7.24Hz,1H),6.91-7.06(m,3H),7.10-7.22(m,4H),7.54(d,J=7.63Hz,2H),7.80(t,J=7.83Hz,1H)。质谱(ESI)m/z=579.0(M+1)。
2-(1-溴丙基)-6-(三氟甲基)吡啶的合成:
步骤A. 1-(6-(三氟甲基)吡啶-2-基)丙烷-1-醇
按照上面针对1-(吡啶-2-基)丁烷-1-醇(实施例231,步骤A)的合成描述的程序,从2-溴代-6-(三氟甲基)吡啶(购自Oakwood Products Inc.,West Columbia,SouthCarolina)和丙醛制备本标题化合物。质谱(ESI)m/z=206.1(M+1)。
步骤B. 2-(1-溴丙基)-6-(三氟甲基)吡啶
按照与针对2-(1-溴丁基)吡啶(实施例231,步骤B)的合成描述的程序类似的程序,从1-(6-(三氟甲基)吡啶-2-基)丙烷-1-醇(实施例238,步骤A)制备本标题化合物。质谱(ESI)m/z=268.0(M+1)和269.9(M+1)。
实施例239
2-((3R,5R,6S)-1-((S)-1-(6-溴吡啶-2-基)丙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸或2-((3R,5R,6S)-1-((R)-1-(6-溴吡啶-2-基)丙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 0.66(t,J=7.43Hz,3H),1.23(s,3H),1.90-2.10(m,2H),2.15-2.34(m,2H),2.69-2.88(m,2H),3.05-3.22(m,1H),4.29(t,J=7.04Hz,1H),4.84(d,J=9.78Hz,1H),6.77(d,J=7.43Hz,1H),6.85(d,J=8.02Hz,2H),6.97(s,1H),6.99-7.14(m,4H),7.16-7.27(m,2H),7.29-7.40(m,1H),8.16(br.s.,1H)。质谱(ESI)m/z=589.0,591.0,593.0(M+1)。
2-溴代-6-(1-溴丙基)吡啶的合成:
步骤A. 1-(6-溴吡啶-2-基)丙烷-1-醇
按照与上面针对1-(吡啶-2-基)丁烷-1-醇(实施例231,步骤A)的合成描述的程序类似的程序,从2,6-二溴吡啶(购自Sigma-Aldrich,St.Louis,MO)和丙醛制备本标题化合物。质谱(ESI)m/z=219.9和217.9(M+1)。
步骤B. 2-溴代-6-(1-溴丙基)吡啶
按照上面针对2-(1-溴丁基)吡啶(实施例231,步骤B)的合成描述的程序,从1-(6-溴吡啶-2-基)丙烷-1-醇(实施例239,步骤A)制备本标题化合物。质谱(ESI)m/z=277.7、279.7和281.7(M+1)。
实施例240
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(噻唑-2-基)丙基)哌啶-3-基)乙酸或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((R)-1-(噻唑-2-基)丙基)哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 0.66(t,J=7.43Hz,3H),1.19-1.41(m,3H),1.90-2.06(m,1H),2.06-2.25(m,2H),2.54(dt,J=15.11,7.60Hz,1H),2.77-2.98(m,2H),3.14-3.37(m,1H),4.57(dd,J=8.41,4.70Hz,1H),4.85(d,J=9.78Hz,1H),6.79(d,J=7.43Hz,1H),6.95(s,1H),6.99-7.24(m,6H),7.40(d,J=3.33Hz,1H),7.83(d,J=3.13Hz,1H),8.60(br.s.,1H)。质谱(ESI)m/z=517.0(M+1)。
2-(1-溴丙基)噻唑的合成:
按照与上面针对2-(1-溴丙基)吡啶(实施例230)的合成描述的程序类似的程序,从2-丙基噻唑(购自Waterstone Technologies,Inc.,Carmel,IN)制备本标题化合物。质谱(ESI)m/z=205.8和207.8(M+1)。
实施例241
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(6-(2-羟基丙烷-2-基)吡啶-2-基)丙基)-3-甲基-2-氧代哌啶-3-基)乙酸或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-1-(6-(2-羟基丙烷-2-基)吡啶-2-基)丙基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. 6-丙基吡啶甲酸乙酯
在0℃下向6-溴吡啶甲酸乙酯(8g,34.8mmol,购自AK Scientific,Inc.,UnionCity,CA)在THF(200mL)中的溶液中通入N220min。用超过30min的时间向在N2气氛下的该混合物中逐滴加入Pd(PPh3)4(3.21g,2.78mmol)和丙基溴化锌溶液(100mL,0.5M在THF中,50.0mmol)。将该混合物从冰浴上移开并将其加热至回流18h。在此时间后,将该溶液冷却至室温,倒入饱和NH4Cl水溶液(18mL)中,用水(30mL)稀释,并用EtOAc(3×30mL)萃取。用水和NaCl饱和水溶液洗涤合并的有机层,并经Na2SO4干燥。在减压下除去有机溶剂后,通过硅胶快速色谱法用0%至50%的EtOAc/己烷纯化残余物,得到本标题化合物。质谱(ESI)m/z=194.0(M+1)。
步骤B. 6-(1-溴丙基)吡啶甲酸乙酯
按照与针对2-(1-溴丙基)吡啶(实施例230)的合成描述的程序类似的程序,从实施例241,步骤A制备本标题化合物。质谱(ESI)m/z=272.0和274.0(M+1)。
步骤C. 6-((R)-1-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丙基)吡啶甲酸乙酯和6-((S)-1-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丙基)吡啶甲酸乙酯
按照与实施例226,步骤C中描述的程序类似的程序,从6-(1-溴丙基)吡啶甲酸乙酯(实施例241,步骤B)制备本标题化合物,为混合物。质谱(ESI)m/z=566.2(M+1)。
步骤D. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-1-(6-(2-羟基丙烷-2-基)吡啶-2-基)丙基)-3-甲基哌啶-2-酮和(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(6-(2-羟基丙烷-2-基)吡啶-2-基)丙基)-3-甲基哌啶-2-酮
向在N2下的0℃的6-((R)-1-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丙基)吡啶甲酸乙酯和6-((S)-1-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丙基)吡啶甲酸乙酯(160mg,0.283mmol,实施例241,步骤C)在THF(3mL)中的溶液中加入CH3MgBr(在乙醚中的3.0M溶液,0.377mL,1.132mmol)。将该混合物从冰浴上移开,并在室温下搅拌30min。再向该反应混合物中加入CH3MgBr(在乙醚中的3.0M溶液,0.24mL,0.78mmol)。在室温下搅拌2.0hr后,向反应混合物中加入饱和NH4Cl水溶液(3mL)和水(4mL)。用EtOAc(3×8mL)萃取该混合物。用水、NaCl饱和水溶液洗涤合并的有机层,并经Na2SO4干燥。在减压下除去有机溶剂后,通过硅胶快速色谱法用20-80%EtOAc/己烷纯化残余物,得到本标题化合物,为立体异构体的混合物。质谱(ESI)m/z=551.1(M+1)。
步骤E. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(6-(2-羟基丙烷-2-基)吡啶-2-基)丙基)-3-甲基-2-氧代哌啶-3-基)乙酸或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-1-(6-(2-羟基丙烷-2-基)吡啶-2-基)丙基)-3-甲基-2-氧代哌啶-3-基)乙酸
按照与上面在实施例230,步骤C中描述的程序类似的程序,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-1-(6-(2-羟基丙烷-2-基)吡啶-2-基)丙基)-3-甲基哌啶-2-酮和(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(6-(2-羟基丙烷-2-基)吡啶-2-基)丙基)-3-甲基哌啶-2-酮(实施例241,步骤D)的混合物制备本标题化合物。如所述纯化粗混合物,得到本标题化合物中的一种,为单一异构体,为白色固体。
1H NMR(400MHz,氯仿-d)δppm 1.08-1.17(m,3H),1.32-1.50(m,9H),1.87-1.97(m,1H),1.97-2.08(m,1H),2.08-2.18(m,1H),2.27-2.48(m,1H),2.70(br.s.,2H),3.23(br.s.,1H),4.63-4.74(m,2H),6.76(m,3H),6.84(br.s.,1H),6.93(d,J=5.87Hz,2H),6.99-7.11(m,3H),7.13-7.24(m,2H),7.48(br.s.,1H)。质谱(ESI)m/z=569.1(M+1)。
实施例242
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(6-环丙基吡啶-2-基)丙基)-3-甲基-2-氧代哌啶-3-基)乙酸或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-1-(6-环丙基吡啶-2-基)丙基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(6-环丙基吡啶-2-基)丙基)-3-甲基哌啶-2-酮或(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-1-(6-环丙基吡啶-2-基)丙基)-3-甲基哌啶-2-酮
向室温下的((3S,5R,6S)-3-烯丙基-1-(1-(6-溴吡啶-2-基)丙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮的混合物(165mg,0.288mmol;实施例239在DMF(3mL)中的溶液中加入三环己基膦(11.32mg,0.04mmol)、磷酸钾(214mg,1.009mmol)、环丙基硼酸(49.5mg,0.577mmol)和二乙酰氧基钯(4.53mg,0.020mmol)。向该混合物中通入N25min,然后将其加热至80℃并保持5hr。将由此产生的溶液冷却至室温,用水(6mL)稀释,并用EtOAc(8mL×2)萃取。合并有机层,用水、NaCl饱和水溶液洗涤,并经MgSO4干燥。在减压下除去有机溶剂后,通过硅胶快速色谱法用0%至70%的EtOAc/己烷纯化残余物,得到本标题化合物,为无色浆液。
步骤B. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(6-环丙基吡啶-2-基)丙基)-3-甲基-2-氧代哌啶-3-基)乙酸
按照与实施例71步骤F)中描述的程序类似的程序,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(6-环丙基吡啶-2-基)丙基)-3-甲基哌啶-2-酮(实施例242,步骤A)制备本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 0.95-1.08(m,3H),1.08-1.23(m,2H),1.36-1.44(m,3H),1.44-1.54(m,1H),1.54-1.66(m,1H),1.99-2.29(m,4H),2.49-2.60(m,1H),2.72(d,J=15.26Hz,1H),3.04(d,J=15.26Hz,1H),3.30-3.43(m,1H),4.71(d,J=10.17Hz,1H),5.52(br.s.,1H),6.74(d,J=7.63Hz,2H),6.90-7.01(m,5H),7.01-7.08(m,1H),7.10(d,J=8.02Hz,2H),7.75(t,J=8.02Hz,1H)。质谱(ESI)m/z=551.2(M+1)。
实施例243
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-3,3,3-三氟代-1-(吡啶-2-基)丙基)哌啶-3-基)乙酸,2,2,2-三氟乙酸盐(1:1)或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((R)-3,3,3-三氟代-1-(吡啶-2-基)丙基)哌啶-3-基)乙酸,2,2,2-三氟乙酸盐(1:1)
步骤A. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(吡啶-2-基甲基)哌啶-2-酮
向(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮(2.246g,6mmol;实施例71D)在DMF(25mL)中的溶液中加入氢化钠(在矿物油中的60%分散体)(0.504g,12.60mmol),并将该混合物在0℃下搅拌5分钟。在0℃下向其中加入2-(溴甲基)吡啶氢溴酸盐(1.593g,6.30mmol)。将由此产生的混合物在0℃下搅拌10min并用饱和NH4Cl溶液淬灭,用EtOAc萃取,用NaCl饱和水溶液洗涤,经MgSO4干燥,过滤,并浓缩滤液。通过硅胶快速色谱法(洗脱剂:0%至100%的在己烷中的EtOAc)纯化残余物从而得到本标题化合物。质谱(ESI)m/z=465(M+1)。
步骤B. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-3,3,3-三氟代-1-(吡啶-2-基)丙基)哌啶-2-酮或(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((R)-3,3,3-三氟代-1-(吡啶-2-基)丙基)哌啶-2-酮
向在N2在-78℃下的(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(吡啶-2-基甲基)哌啶-2-酮(660mg,1.418mmol;实施例243,步骤A)在不含抑制剂的THF(7mL)中的溶液中加入二异丙基氨基锂(1.418mL,2.84mmol),并将该混合物搅拌30min。加入1,1,1-三氟代-2-碘乙烷(744mg,3.55mmol;Sigma,St.Louis,MO),并将橙色反应物在-78℃下搅拌1h。然后将反应物温度升至室温并搅拌过夜。用0.2mL MeOH淬灭该混合物,过滤,浓缩,并通过HPLC(C18柱,用10-95%的含有0.1%TFA的在水中的CH3CN洗脱)纯化残余物从而得到本标题化合物,为较慢地洗脱的非对映异构体。质谱(ESI)m/z=547(M+1)。
步骤C. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-3,3,3-三氟代-1-(吡啶-2-基)丙基)哌啶-3-基)乙酸/2,2,2-三氟乙酸(1:1)
按照与实施例71步骤F中描述的程序类似的程序,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-3,3,3-三氟代-1-(吡啶-2-基)丙基)哌啶-2-酮(61.2mg,0.112mmol;实施例243,步骤B)获得本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 8.96(1H,d,J=4.7Hz),8.09(1H,t,J=7.8Hz),7.86(1H,d,J=8.2Hz),7.56-7.68(1H,m),7.22(4H,s),7.08-7.17(3H,m),6.94(1H,s),6.90(1H,d,J=6.7Hz),5.27-5.38(1H,m),4.95(1H,d,J=6.5Hz),3.63(1H,dt,J=16.1,9.8Hz),3.28-3.40(1H,m),2.88(1H,d,J=15.1Hz),2.74(1H,d,J=15.1Hz),2.59-2.71(1H,m),2.12-2.25(1H,m),1.98-2.09(1H,m),1.15(3H,s)。质谱(ESI)m/z=565(M+1)。
实施例244
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-3,3,3-三氟代-1-(吡啶-2-基)丙基)哌啶-3-基)乙酸,为2,2,2-三氟乙酸(1:1)盐
步骤A. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-3,3-二氟代-1-(吡啶-2-基)丙基)-3-甲基哌啶-2-酮
在N2在-78℃下向(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(吡啶-2-基甲基)哌啶-2-酮(705mg,1.515mmol;实施例71,步骤D)在不含抑制剂的THF(7mL)中的溶液中加入二异丙基氨基锂(1.515mL,3.03mmol),并将该混合物搅拌30min。加入1,1-二氟代-2-碘乙烷(727mg,3.79mmol;Oakwood),并将橙色反应混合物在-78℃下搅拌1h。将反应物温度升至室温过夜,并用0.2mL MeOH淬灭,过滤并浓缩。通过HPLC(C18柱,用10-95%的含有0.1%TFA的在水中的CH3CN洗脱)纯化残余物,从而得到(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-3,3-二氟代-1-(吡啶-2-基)丙基)-3-甲基哌啶-2-酮(HPLC保留时间7.38min,Agilent Eclipse Plus C18柱,用70%-90%的含有0.1%TFA的CH3CN/H2O梯度洗脱超过25分钟)和(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-3,3-二氟代-1-(吡啶-2-基)丙基)-3-甲基哌啶-2-酮(HPLC保留时间7.94min,Agilent Eclipse Plus C18柱(Agilent Technologies,Santa Clara,CA),用70%-90%的含有0.1%TFA的CH3CN/H2O梯度洗脱超过25分钟)。质谱(ESI)m/z=529(M+1)。
步骤B. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-3,3,3-三氟代-1-(吡啶-2-基)丙基)哌啶-3-基)乙酸/2,2,2-三氟乙酸(1:1)
按照与实施例71步骤F中描述的程序类似的程序,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-3,3-二氟代-1-(吡啶-2-基)丙基)-3-甲基哌啶-2-酮(50mg,0.095mmol;实施例244,步骤A)获得本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 9.03(1H,d,J=4.3Hz),8.17(1H,t,J=7.8Hz),7.79(1H,d,J=8.2Hz),7.72(1H,t,J=6.3Hz),7.18-7.25(4H,m),7.08-7.16(2H,m),6.95(1H,s),6.88-6.93(1H,m),5.44(1H,br.s.),5.31(2H,d,J=10.4Hz),5.21(6H,br.s.),5.10(2H,br.s.),3.30-3.42(1H,m),3.18(1H,br.s.),2.90(1H,d,J=15.1Hz),2.72(1H,d,J=15.1Hz),2.44(1H,d,J=16.4Hz),2.27(1H,t,J=13.8Hz),1.98-2.08(1H,m),1.21(3H,s)。质谱(ESI)m/z=547(M+1)。
实施例245
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-2-甲基-1-(吡啶-2-基)丙基)-2-氧代哌啶-3-基)乙酸或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((R)-2-甲基-1-(吡啶-2-基)丙基)-2-氧代哌啶-3-基)乙酸
步骤A: 2-(1-溴代-2-甲基丙基)吡啶
按照与实施例230中描述的程序类似的程序,从2-异丁基吡啶(5.17g,38.2mmol;Alfa Aesar,Ward Hill,MA)制备本标题化合物。将反应混合物冷却至室温并过滤,用DCM充分洗涤滤饼。在真空中浓缩滤液,并通过硅胶色谱法用0%至25%的在己烷中的EtOAc梯度洗脱来进行纯化。浓缩含有所需产物的级分从而得到本标题化合物。
步骤B. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-2-甲基-1-(吡啶-2-基)丙基)哌啶-2-酮或(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-2-甲基-1-(吡啶-2-基)丙基)哌啶-2-酮.
根据与实施例226步骤C中描述的程序类似的程序合并2-(1-溴代-2-甲基丙基)吡啶(实施例245,步骤A)和(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮(实施例71,步骤D),在分离后得到本标题化合物,为低丰度的非对映异构体。MS(ESI)507[M+H]+。
步骤C.
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-2-甲基-1-(吡啶-2-基)丙基)-2-氧代哌啶-3-基)乙酸或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((R)-2-甲基-1-(吡啶-2-基)丙基)-2-氧代哌啶-3-基)乙酸
通过按照如实施例71步骤F中描述的程序对实施例245步骤B的化合物进行处理而获得本标题化合物。
1H NMR(500MHz,二氯甲烷-d2)δ0.87(d,J=6.11Hz,3H),1.18(br.s.,3H),1.33-1.47(m,3H),1.96-2.10(m,1H),2.10-2.27(m,1H),2.70-2.88(m,3H),3.19-3.30(m,1H),4.66(d,J=9.54Hz,1H),6.73(d,J=7.58Hz,1H),6.84(br.s.,2H),6.97(br.s.,3H),7.05-7.23(m,3H),7.55(t,J=6.60Hz,1H),7.82(t,J=8.31Hz,1H),8.79(d,J=4.89Hz,1H)。MS(ESI)525[M+H]+。
实施例246
(3R,5R,6S)-3-((1H-四唑-5-基)甲基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(戊烷-3-基)哌啶-2-酮
如实施例86中所述从2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)乙酸(实施例71)制备本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 0.49(t,J=7.53Hz,3H)0.97(t,J=7.43Hz,3H)1.33(s,3H)1.37-1.58(m,2H)1.84-2.05(m,2H)2.17-2.35(m,2H)2.77(dt,J=9.00,4.50Hz,1H)3.05-3.21(m,1H)3.42-3.64(m,2H)4.36(d,J=10.37Hz,1H)6.71(d,J=7.63Hz,1H)6.82(d,J=7.63Hz,2H)6.98(t,J=1.66Hz,1H)7.06-7.25(m,4H)。质谱(ESI)m/z 486.3[M+H]+。
实施例247
(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-((R)-2,3-二羟基丙基)-1-((2S,3S)-2-羟基戊烷-3-基)-3-甲基哌啶-2-酮和(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-((S)-2,3-二羟基丙基)-1-((2S,3S)-2-羟基戊烷-3-基)-3-甲基哌啶-2-酮
步骤A. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((2S,3S)-2-羟基戊烷-3-基)-3-甲基哌啶-2-酮
向在-8℃(内部温度)在氮气气氛下的搅拌着的(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-2-氧代戊烷-3-基)哌啶-2-酮(185mg,0.40mmol;实施例149,步骤B)在THF(4mL)中的溶液中逐滴加入(Aldrich,St.Louis,MO)(0.48mL,0.48mmol,1M溶液在THF中),该添加用超过2分钟的时间完成(内部温度达到-5℃)。在10分钟后,用MeOH(0.1mL)淬灭反应物并用在水(30mL)中的(2KHSO5·KHSO4·K2SO4,DuPont,Wilmington,DE)(992mg,1.61mmol)处理,然后将它在室温下搅拌2小时。在此时间后,将反应物分配在EtOAc(50mL)和Na2S2O3(30mL,饱和水溶液)之间。用盐水(20mL)洗涤分离的有机层,然后经MgSO4干燥该有机层,过滤,并在真空中蒸发从而得到本标题化合物。质谱(ESI)m/z=460.0(M+1)。
步骤B:(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-((R)-2,3-二羟基丙基)-1-((2S,3S)-2-羟基戊烷-3-基)-3-甲基哌啶-2-酮和(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-((S)-2,3-二羟基丙基)-1-((2S,3S)-2-羟基戊烷-3-基)-3-甲基哌啶-2-酮
向搅拌着的(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((2S,3S)-2-羟基戊烷-3-基)-3-甲基哌啶-2-酮(75mg,0.163mmol,实施例247,步骤A)在t-BuOH(2mL)中的溶液中加入4-甲基吗啉4-氧化物(76mg,0.652mmol)和四氧化锇(2.1mg,8.14μmol),并将反应物在室温下搅拌过夜。在此时间后,将反应物分配在EtOAc(100mL)和Na2S2O3(40mL,饱和水溶液)之间。用NaHCO3(40mL,饱和水溶液)洗涤分离的有机层,经MgSO4干燥,过滤,并在真空中蒸发。由此产生的残余物通过反相HPLC(SunfireTMPrep C18OBD10μm柱(Waters,Milford,MA),用20%的在水中的MeCN至80%的在水中的MeCN梯度洗脱超过30min,其中这两种溶剂都含有0.1%TFA)纯化,从而得到本标题化合物,为可分离的非对映异构体混合物。
第一洗脱异构体:1H NMR(400MHz,氯仿-d)δppm 6.96-7.28(8H,m),6.73(1H,dt,J=7.6,1.6Hz),4.39(1H,d,J=10.6Hz),3.96-4.06(1H,m),3.71(1H,dd,J=11.0,3.5Hz),3.56(1H,dd,J=11.1,7.3Hz),3.26-3.38(1H,m),1.78-2.15(6H,m),1.44(3H,s),1.19-1.39(4H,m),0.50-0.67(3H,m)。质谱(ESI)m/z=494.0(M+1)。
第二洗脱异构体:1H NMR(400MHz,氯仿-d)δppm 6.96-7.28(8H,m),6.70(1H,dd,J=6.2,1.5Hz),4.38(1H,d,J=10.4Hz),4.31(1H,br.s.),3.66-3.76(1H,m),3.53-3.63(1H,m),3.22-3.33(1H,m),1.80-2.32(4H,m),1.45(3H,s),1.16-1.45(6H,m),0.40-0.55(3H,br.s.)。质谱(ESI)m/z=494.0(M+1)。
实施例248
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)环丙烷羧酸
步骤A. (3S,5R,6S)-1-((S)-1-(叔丁基二苯基甲硅烷基氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-羧酸甲酯
将搅拌着的(5R,6S)-1-((S)-1-(叔丁基二苯基甲硅烷基氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮(1.3g,2.016mmol;实施例185,步骤D)在不含抑制剂的THF(10mL)中的溶液用氩气脱气30分钟。经由插管用超过5分钟的时间将反应物转移到-78℃下的新制备的LDA溶液中(该LDA溶液通过如下方式制备:将在-20℃在氩气气氛下的在不含抑制剂的THF(2mL)中的N,N-二异丙基胺(0.72mL,5.04mmol)用丁基锂(2.02mL,5.04mmol,2.5M在己烷中)处理超过1分钟,并将该混合物在-15℃下搅拌30分钟)。搅拌由此产生的反应混合物,同时用超过30分钟的时间升温至0℃。将反应物冷却至-78℃并用逐滴的氯甲酸甲酯(0.47mL,6.05mmol)处理超过2分钟。将反应物在-78℃下搅拌2小时又30分钟,然后用30mL饱和NH4Cl水溶液淬灭,并让反应物温度升至室温。将该混合物分配在乙酸乙酯(150mL)和水(50mL)之间。经MgSO4干燥分离的有机层,过滤,并在真空中蒸发。柱色谱分离(SiO2,己烷:EtOAc,1:0至4:1)得到本标题化合物。质谱(ESI)m/z=702.1(M+1)。
步骤B. (3R,5R,6S)-1-((S)-1-(叔丁基二苯基甲硅烷基氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-(羟基甲基)-3-甲基哌啶-2-酮
向在0℃在氮气气氛下的搅拌着的(3S,5R,6S)-1-((S)-1-(叔丁基二苯基甲硅烷基氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-羧酸甲酯(450mg,0.640mmol;实施例248,步骤A)在THF(4mL)中的溶液中逐滴加入三乙基硼氢化锂(1.60mL,1.60mmol,1M溶液在THF中)。将反应物在0℃下搅拌1小时,然后用甲醇(0.2mL)淬灭反应物,并用在水(50mL)中的(2KHSO5·KHSO4·K2SO4,DuPont,Wilmington,DE)(1.18g,1.92mmol)处理。将该混合物搅拌1小时,然后用乙酸乙酯(100mL)萃取。用Na2S2O3(50mL,饱和水溶液)洗涤分离的有机层,然后经MgSO4干燥,过滤,并在真空中蒸发。柱色谱分离(SiO2,己烷:EtOAc,1:0至7:3)得到本标题化合物。质谱(ESI)m/z=674.2(M+1)。
步骤C. (3R,5R,6S)-1-((S)-1-(叔丁基二苯基甲硅烷基氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-甲醛
向在0℃下的搅拌着的(3R,5R,6S)-1-((S)-1-(叔丁基二苯基甲硅烷基氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-(羟基甲基)-3-甲基哌啶-2-酮(210mg,0.311mmol;实施例248,步骤B)在CH2Cl2(8mL)中的溶液中一次性加入NaHCO3(131mg,1.56mmol)和Dess Martin过碘烷(158mg,0.373mmol)。将反应物在室温下搅拌2小时。用CH2Cl2(30mL)稀释反应物并用Na2S2O3(15mL,饱和水溶液)和NaHCO3(15mL,饱和水溶液)在室温下处理2小时。用CH2Cl2(2x50mL)萃取分离的水层,并经MgSO4干燥合并的有机萃取物,过滤,并在真空中蒸发从而得到本标题化合物。质谱(ESI)m/z=672.2(M+1)。
步骤D. (E)-3-((3R,5R,6S)-1-((S)-1-(叔丁基二苯基甲硅烷基氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)丙烯酸甲酯
用超过30秒的时间向在0℃在氮气气氛下的搅拌着的THF(4mL)和氢化钠(16mg,0.40mmol,60%分散体在油中)的溶液中逐滴加入磷酰基乙酸三甲酯(61μL,0.43mmol)。让该混合物温度升至室温并保持30分钟。加入(3R,5R,6S)-1-((S)-1-(叔丁基二苯基甲硅烷基氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-甲醛(205mg,0.305mmol;实施例248,步骤C)在THF(3mL)中的溶液。将由此产生的混合物在室温下搅拌2小时。将反应物分配在EtOAc(80mL)和水(40mL)之间。经MgSO4干燥分离的有机层,过滤,并在真空中蒸发。柱色谱分析(SiO2,己烷:EtOAc,1:0至8:2)得到本标题化合物。质谱(ESI)m/z=728.2(M+1)。
步骤E. 2-((3R,5R,6S)-1-((S)-1-((叔丁基二苯基甲硅烷基)氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)环丙烷羧酸甲酯
用超过1分钟的时间向在氩气气氛下的搅拌着的氢化钠(12mg,0.30mmol,60%的在油中的分散体)在THF(1.0mL)中的溶液中分批加入三甲基碘化亚砜(72mg,0.33mmol)。将反应物在室温下搅拌1小时。用超过1分钟的时间逐滴加入(E)-3-((3R,5R,6S)-1-((S)-1-(叔丁基二苯基甲硅烷基氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)丙烯酸甲酯(120mg,0.165mmol;实施例248,步骤D)在DMSO(1.0mL)中的溶液。将反应物在室温下搅拌过夜。在此时间后,再通过如下方式合成硫叶立德(sulfur ylide):将三甲基碘化亚砜(140mg)悬浮在氮气气氛下的DMSO(0.5mL)中,并用NaH(24mg,60%的在油中的分散体)处理该混合物并搅拌30分钟。然后将硫叶立德加入到该反应物中,并将该混合物在室温下搅拌16小时。在此时间后,再通过如下方式合成硫叶立德:将三甲基碘化亚砜(140mg)悬浮在氮气气氛下的DMSO(0.5mL)中,并用NaH(24mg,60%的在油中的分散体)处理该混合物并搅拌30分钟。然后将硫叶立德加入到该反应物中,并将该混合物在室温下搅拌16小时。将反应物分配在乙酸乙酯(70mL)和NH4Cl(30mL,饱和水溶液)之间。经MgSO4干燥分离的有机层,过滤,并在真空中蒸发。通过反相HPLC(Sunfire Prep C18OBD 10μm柱,用40%的在水中的MeCN至100%的在水中的MeCN梯度洗脱超过40min,其中这两种溶剂都含有0.1%TFA)纯化,得到本标题化合物,为第一洗脱的主要非对映异构体。在环丙烷上的立体化学是单一的但未确定的非对映异构体。质谱(ESI)m/z=742.2(M+1)。
步骤F. 2-((3R,5R,6S)-1-((S)-1-(叔丁基二苯基甲硅烷基氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)环丙烷羧酸
向搅拌着的实施例248步骤E的酯(10mg,0.013mmol)在THF(1.0mL)中的溶液中加入氢氧化钠(404μL,0.404mmol,1M水溶液)。将反应物在室温下搅拌24小时。在此时间后,将反应物分配在EtOAc(30mL)和1.0M HCl(5mL)之间。经MgSO4干燥分离的有机层,过滤,并在真空中蒸发从而得到本标题化合物,为单一非对映异构体。质谱(ESI)m/z=728.2(M+1)。
步骤G. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)环丙烷羧酸
向搅拌着的实施例248步骤F的酸(10mg,0.014mmol)在THF(0.2mL)中的溶液中加入TBAF(0.1mL,1.0M溶液在THF中)。在30分钟后,再加入TBAF(0.1mL,1.0M溶液在THF中),并将反应物在室温下搅拌3小时。在此时间后,将反应物分配在EtOAc(30mL)和1M HCl水溶液(5mL)之间。经MgSO4干燥分离的有机层,过滤,并在真空中蒸发。由此产生的残余物通过反相HPLC(Sunfire Prep C18OBD 10μm柱,用20%的在水中的MeCN至80%的在水中的MeCN梯度洗脱超过30min,其中这两种溶剂都含有0.1%TFA)纯化从而得到本标题化合物。
1H NMR(400MHz,CD3OD)δppm 7.29-7.34(2H,m),7.06-7.21(5H,m),6.87-6.98(1H,m),4.70(1H,d,J=11.0Hz),4.06(1H,dd,J=11.1,9.3Hz),3.45-3.56(2H,m),2.89(1H,dt,J=8.9,4.5Hz),2.48(1H,t,J=13.5Hz),1.92-2.04(1H,m),1.78-1.88(1H,m),1.61-1.72(1H,m),1.43-1.53(2H,m),1.22-1.36(6H,m),0.41-0.52(3H,m)。质谱(ESI)m/z=490.0(M+1)。
实施例249
2-((3R,5R,6S)-1-((S)-2-(叔丁氧基)-1-环丙基-2-氧代乙基)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-3-基)乙酸
步骤A. 2-溴代-2-环丙基乙酸乙酯.
在25℃下用5分钟向2-环丙基乙酸(24.7g,247mmol)在无水DCE(250mL)中的溶液中逐滴加入亚硫酰氯(22mL,302mmol)。在回流2h后,将反应物冷却至室温,在25℃下依次加入N-溴琥珀酰亚胺(53.6g,301mmol)和溴化氢(48%水溶液)(0.195mL,1.727mmol)。将所得到的混合物加热至回流96h。在将反应混合物冷却至室温后,加入绝对EtOH(200mL)并将由此产生的暗棕色溶液在室温下搅拌1小时。在减压(35℃,4.0千帕)下浓缩反应混合物,并将残余物悬浮在四氯化碳(300mL)中并使其通过玻璃过滤器。在减压(35℃,4.0千帕)下浓缩滤液。通过色谱法(硅胶,330g×2,5%乙酸乙酯/己烷)纯化粗产物,并在减压(35℃,4.0千帕)下浓缩所需的合并的级分,得到本标题化合物,为浅黄色液体。
1H NMR(400MHz,氯仿-d)δppm 4.20-4.32(2H,m),3.59(1H,d,J=10.4Hz),1.53-1.66(1H,m),1.29-1.36(3H,m),0.76-0.93(2H,m),0.51-0.61(1H,m),0.40-0.47(1H,m)。
步骤B. (S)-2-((2S,3R)-3-(3-氯苯基)-2-(4-氯苯基)-6-氧代哌啶-1-基)-2-环丙基乙酸乙酯
在0℃下向(3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-哌啶-2-酮(8.01g,25mmol;实施例1,步骤E)在DMF(60mL)中的溶液中加入在矿物油中的60%氢化钠(2.0g,50mmol),并将由此获得的混合物在相同温度下搅拌30min。向该混合物中逐滴加入在DMF(10mL)中的2-溴代-2-环丙基乙酸乙酯(12.18g,50mmol),并将该混合物在室温下搅拌2h,然后用氯化铵饱和溶液淬灭反应物并用乙酸乙酯稀释。用10%柠檬酸水溶液、5%NaHCO3水溶液、水、NaCl饱和水溶液洗涤有机层,然后经MgSO4干燥。在减压下蒸发溶剂,并通过硅胶色谱法用20%至50%的在己烷中的乙酸乙酯洗脱来纯化残余物,从而得到本标题化合物,为第一洗脱非对映异构体,为白色固体。
1H NMR(400MHz,氯仿-d)δppm-0.34(m,1H),0.23(m,1H),0.38(m,1H),0.62(m,1H),1.26(t,J=8Hz,3H),1.39(m,1H),2.13(m,2H),2.63(m,2H),3.09(m,1H),3.20(d,J=12Hz,1H),4.07(m,2H),4.81(d,J=8Hz,1H),6.90(dt,J=7.1,1.7Hz,1H),7.11-7.19(m,5H),7.28(m,2H)。质谱(ESI)m/z=446.2(M+1)。
步骤C. (S)-2-((2S,3R)-3-(3-氯苯基)-2-(4-氯苯基)-6-氧代哌啶-1-基)-2-环丙基乙酸叔丁酯
在室温下向(S)-2-((2S,3R)-3-(3-氯苯基)-2-(4-氯苯基)-6-氧代哌啶-1-基)-2-环丙基乙酸乙酯(500mg,1.12mmol)(实施例249,步骤B)在THF/MeOH/H2O(5/5/5,15mL)中的溶液中加入氢氧化锂(1.68mL,3.36mmol),然后将反应物加热至60℃。在60℃下搅拌1.5h后,用饱和NH4Cl水溶液淬灭反应物,并萃取(2×DCM)。洗涤(1×NaCl饱和水溶液)合并的有机层,经Na2SO4干燥,过滤,浓缩并在减压下浓缩滤液。
将上面合成的粗酸(450mg,1.076mmol)溶解在DCM(10mL)中,并在-78℃下加入硫酸(115uL,2.151mmol),接着加入2-甲基丙-1-烯(1.207g,21.51mmol)。将反应容器密封并将该混合物温度缓慢地升至室温。在剧烈搅拌4天后,用NH4Cl饱和水溶液淬灭反应物并用乙酸乙酯萃取。用NaCl饱和水溶液洗涤合并的有机层,经硫酸钠干燥,过滤,并在减压下浓缩滤液。通过硅胶快速色谱法(洗脱剂:40%EtOAc/己烷)纯化残余物,得到本标题化合物。
步骤D. (S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-1-基)-2-环丙基乙酸叔丁酯
将双(三甲基甲硅烷基)氨基锂溶液(1M溶液在THF中,0.165mL,0.165mmol)在-78℃下逐滴加入到(S)-2-((2S,3R)-3-(3-氯苯基)-2-(4氯苯基)-6-氧代哌啶-1-基)-2-环丙基乙酸叔丁酯(实施例249,步骤C,71mg,0.15mmol)和烯丙基溴(15.54uL,0.165mmol)在0.5mL THF中的溶液中。让反应物温度升至室温。在搅拌2h后,用氯化铵饱和水溶液淬灭反应物并用乙酸乙酯萃取。用NaCl饱和水溶液洗涤合并的有机层,经硫酸钠干燥,然后过滤并在减压下浓缩滤液。通过硅胶快速色谱法用乙酸乙酯/己烷洗脱来进行纯化,得到本标题化合物。
步骤E. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N-环丙基乙酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
按照实施例71步骤F的程序,从(S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-1-基)-2-环丙基乙酸叔丁酯(实施例249,步骤D)获得本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 0.08(m,1H),0.49(m,1H),0.58(m,1H),0.66(m,1H),1.02(m,1H),1.44(s,9H),1.99(m,1H),2.19(m,1H),2.58(dd,J=16.0,4.0Hz,1H),2.66(m,1H),2.93(dd,J=12.0,12.0HZ,1H),3.20(s,1H),3.34(d,J=12HZ,1H),5.37(s,1H),7.14(m,1H),7.25–7.33(m,3H),7.37–7.45(m,4H)。质谱(ESI)m/z=532.2(M+1)。
实施例250
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-乙氧基-2-氧代乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. 2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-2-环丙基乙酸乙酯
采用如实施例9步骤A中描述的程序,使(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮(实施例71,步骤D)与2-溴代-2-环丙基乙酸乙酯(实施例249,步骤A)偶联,得到本标题化合物,为两个非对映异构体的混合物。
步骤B. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-乙氧基-2-氧代乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
采用实施例71,步骤F中描述的氧化程序,从非对映异构的2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-2-环丙基乙酸乙酯(实施例250,步骤A)获得本标题化合物。通过手性HPLC(150x30mm IC柱(CHIRALTECHNOLOGIES,INC.,West Chester,PA,USA),使用20%IPA(0.1%DEA)/CO2,50mL/min,在Thar 350SFC(Thar Technologies,Inc.,Pittsburg,PA)上)分离各个立体异构体从而得到本标题化合物,为较快地洗脱的立体异构体。
1H NMR(400MHz,氯仿-d)δppm-0.49--0.40(m,1H)0.12-0.21(m,1H)0.36-0.46(m,1H)0.64(m,1H)1.28(t,J=7.14Hz,3H)1.37(s,3H)1.40-1.56(m,1H)2.14-2.27(m,2H)2.83(d,J=14.48Hz,1H)2.95(d,J=14.48Hz,1H)3.02(d,J=9.78Hz,1H)3.22-3.36(m,1H)4.06-4.22(m,2H)4.75(d,J=9.39Hz,1H)6.81(m,1H)7.00-7.21(m,5H)7.21-7.35(m,2H)。质谱(ESI)m/z=518.0(M+1)。
实施例251
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-羟基乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. (5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-羟基乙基)哌啶-2-酮
将硼氢化锂溶液(2M溶液在THF中,15.46mL,30.9mmol)加入到0℃的(S)-2-((2S,3R)-3-(3-氯苯基)-2-(4-氯苯基)-6-氧代哌啶-1-基)-2-环丙基乙酸乙酯(实施例249,步骤B,2.3g,5.15mmol)在乙醚(40mL)中的溶液中。在室温下搅拌20小时后,用NH4Cl饱和水溶液淬灭反应物并将其萃取到EtOAc中。用NaCl饱和水溶液洗涤有机层,经硫酸钠干燥,并浓缩从而得到本标题化合物,为固体,使用该化合物而无需进一步纯化。
1H NMR(400MHz,氯仿-d)δppm 0.00(m,1H),0.23(m,1H),0.48-0.57(m,2H),0.85(m,1H),1.99(m,1H),2.07(m,1H),2.61(m,2H),2.64(m,1H),3.22(dd,J=11.2,9.8Hz,1H),3.42(td,J=10.1,4.3Hz,1H),3.60(m,1H),4.93(d,J=6.5Hz,1H),6.89(m,1H),7.09(m,4H),7.18(m,2H),7.27(m,1H)。质谱(ESI)m/z=404.0(M+1)。
步骤B. (5R,6S)-1-((S)-2-((叔丁基二苯基甲硅烷基)氧基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)哌啶-2-酮
按照与实施例185步骤C中描述的程序类似的程序,将实施例251步骤A的产物转化为本标题化合物。
1H NMR(400MHz,氯仿-d)δppm-0.70(m,1H),-0.40(m,1H),0.02(m,1H),0.13(m,1H),0.91(s,9H),1.09(m,1H),1.92-1.91(m,2H),2.47-2.50(m,2H),2.78(s,br,1H),2.80(m,1H),3.31(m,1H),3.98(m,1H),4.62(d,J=7.8Hz,1H),6.60(m,1H),6.82-6.91(m,4H),6.91-7.03(m,3H),7.18-7.26(6H),7.37-7.45(m,4H)。质谱(ESI)m/z=642.3(M+1)。
步骤C. (5R,6S)-1-((S)-2-((叔丁基二苯基甲硅烷基)氧基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮
按照实施例185步骤D的方法,将(5R,6S)-1-((S)-2-((叔丁基二苯基甲硅烷基)氧基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)哌啶-2-酮(实施例251步骤B,7.9g,12.29mmol)转化为本标题化合物,为非对映异构体混合物。
1H NMR(400MHz,氯仿-d)δppm-0.15(m,1H),0.00(m,1H),0.41-0.52(m,2H),1.26(s,9H),1.41(m,1H),1.62(d,J=7.2Hz,3H),2.09(m,1H),2.30(m,1H),2.87(m,1H),3.28(m,2H),3.68(m,1H),4.23(m,1H),5.11(d,J=6.1Hz,1H),7.16-7.34(m,4H),7.37-7.46(m,4H),7.51-7.65(m,6H),7.74-7.78(m,4H)。
步骤D. (5R,6S)-3-烯丙基-1-((S)-2-((叔丁基二苯基甲硅烷基)氧基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮
按照针对实施例185步骤E描述的程序,将(5R,6S)-1-((S)-2-(叔丁基二苯基甲硅烷基氧基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮(5.02g,7.64mmol,实施例251,步骤C)转化为本标题化合物。在后处理后,所获得的未纯化产物直接被使用。
步骤E. 2-((3R,5R,6S)-1-((S)-2-((叔丁基二苯基甲硅烷基)氧基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸
根据实施例185步骤F的程序对(5R,6S)-3-烯丙基-1-((S)-2-((叔丁基二苯基甲硅烷基)氧基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮(实施例251,步骤D,106mg,0.15mmol)进行处理,从而得到2-((3R,5R,6S)-1-((S)-2-((叔丁基二苯基甲硅烷基)氧基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸。质谱(ESI)m/z=714.3(M+1)。
步骤F. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-羟基乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
将四丁基氟化铵溶液(1.0M溶液在THF中,0.453mL,0.453mmol)加入到2-((3R,5R,6S)-1-((S)-2-(叔丁基二苯基甲硅烷基氧基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸(实施例251,步骤E,108mg,0.151mmol)在THF(4ml)中的溶液中,并将反应物在室温下搅拌20小时。LC-MS分析显示反应未完成,所以再加入0.225ml四丁基氟化铵溶液,并将反应物再搅拌26小时。将该混合物稀释在乙酸乙酯中,然后用水和NaCl饱和水溶液洗涤。经硫酸钠干燥有机层并浓缩。通过RP-HPLC(Sunfire PrepC18OBD 10μm柱,用10%的在水中的MeCN至80%的在水中的MeCN梯度洗脱超过30min,其中这两种溶剂都含有0.1%TFA)纯化,得到本标题化合物,为固体。
1H NMR(400MHz,氯仿-d)δppm-0.30(s,m,1H),0.00(s,m,1H),0.37(m,2H),0.79(m,1H),1.22(s,3H),2.00(m,2H),2.52(d,J=14.1Hz,1H),2.70(d,J=13.9Hz,1H),3.00(m,2H),3.20(s,br,3H),3.29(m,1H),4.65(d,J=10.o Hz,1H),6.61(m,1H),6.84(s,br,2H),6.97(m,3H),7.04(m,2H)。质谱(ESI)m/z=476.2(M+1)。
实施例252
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((1S,2S)-1-环丙基-2-羟基丁基)-3-甲基-2-氧代哌啶-3-基)乙酸或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((1S,2R)-1-环丙基-2-羟基丁基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-羟基乙基)-3-甲基哌啶-2-酮
将四丁基氟化铵在THF中的溶液(1M,2.10mL,2.10mmol)加入到非对映异构体(5R,6S)-3-烯丙基-1-((S)-2-(叔丁基二苯基甲硅烷基氧基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮(实施例251,步骤D,488mg,0.700mmol)在THF(10ml)中的溶液中。将反应物在室温下搅拌2小时。将该混合物稀释在乙酸乙酯中,并用水和NaCl饱和水溶液洗涤。经硫酸钠干燥有机层。通过用乙酸乙酯/己烷洗脱来进行硅胶色谱分离,得到本标题化合物,为单一非对映异构体。
质谱(ESI)m/z=458.0(M+1)
步骤B. (S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-2-环丙基乙醛
按照实施例91步骤C中描述的程序,将(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-羟基乙基)-3-甲基哌啶-2-酮(实施例252,步骤A,80mg,0.17mmol)转化为本标题化合物,为白色泡沫状物。质谱(ESI)m/z=456.1(M+1)
步骤C. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((1S,2S)-1-环丙基-2-羟基丁基)-3-甲基哌啶-2-酮或(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((1S,2R)-1-环丙基-2-羟基丁基)-3-甲基哌啶-2-酮
按照实施例149步骤A的程序,用乙基溴化镁替代甲基溴化镁,将(S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-2-环丙基乙醛(实施例252,步骤B,90mg,0.20mmol)转化为本标题化合物,其在色谱分离后获得,为第二洗脱非对映异构体。
1H NMR(400MHz,氯仿-d)δppm-0.43(m,1H),-0.16(m,1H),0.32(m,1H),0.51(m,1H),0.78(t,J=.3Hz,3H),1.18(s,3H),1.21-1.35(m,1H),2.54(m,2H),1.57(s,br,1H),1.87-2.0(m,2H),2.21(s,br,1H),2.50-2.62(m,2H),3.22(ddd,J=12.8,10.2,4.0Hz,1H),3.68(s,br,1H),4.34(d,J=10.0Hz,1H),5.12(s,1H),5.14(d,J=8Hz,1H),5.79(m,1H),6.65(dt,J=7.6,1.6Hz,1H),6.87-6.91(m,3H),7.01-7.07(m,2H),7.16-7.18(m,2H)。质谱(ESI)m/z=486.3(M+1)
步骤D. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((1S,2S)-1-环丙基-2-羟基丁基)-3-甲基-2-氧代哌啶-3-基)乙酸或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((1S,2R)-1-环丙基-2-羟基丁基)-3-甲基-2-氧代哌啶-3-基)乙酸
通过按照实施例71,步骤F中描述的方法对实施例252步骤C的化合物进行处理而获得本标题化合物。
1H NMR(400MHz,甲醇-d4)δppm-0.16(s,br,1H),0.26(s,br,1H),0.55(s,br,1H),0.67(s,br,1H),0.86(m,3H),1.32(m,4H),1.41(s,3H),1.68(m,1H),1.92(m,2H),2.64(d,J=12Hz,1H),2.99(d,J=12Hz,1H),3.51(m,1H),4.97(m,1H),6.97(m,1H),7.06(m,1H),7.17(m,4H),7.28(m,2H)。质谱(ESI)m/z=504.1(M+1)。
实施例253
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-甲基环丙烷磺酰氨基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸
步骤A. (5R,6S)-1-((S)-2-((叔丁基二苯基甲硅烷基)氧基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基哌啶-2-酮
采用针对实施例185步骤D描述的程序,用碘乙烷替代碘甲烷,将(5R,6S)-1-((S)-2-(叔丁基二苯基甲硅烷基氧基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)哌啶-2-酮(实施例251,步骤B,2.6g,4.05mmol)转化为本标题化合物,为泡沫状物。
1H NMR(400MHz,甲醇-d4)δppm-0.39(m,1H),-0.22(m,1H),0.20-0.24(m,1H),0.35-0.38(m,1H),1.03-1.19(m,14),1.26(t,J=4Hz,1H),1.78-1.84(m,1H),1.94-1.99(m,1H),2.13-2.19(m,2H),2.46-2.51(m,1H),3.24-3.26(m,1H),3.52-3.53(m,1H),5.0(d,J=8Hz,1H),7.06(m,1H),7.17-7.24(m,5H),7.30-7.32(m,2H),7.37-7.50(m,6H),7.58-7.62(m,4H)。质谱(ESI)m/z=670.2(M+1)
步骤B. (5R,6S)-3-烯丙基-1-((S)-2-((叔丁基二苯基甲硅烷基)氧基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基哌啶-2-酮
采用针对实施例185步骤E描述的程序,将(5R,6S)-1-((S)-2-(叔丁基二苯基甲硅烷基氧基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮(实施例253,步骤A,1.6g,2.38mmol)转化为本标题化合物,使用该化合物而无需进一步纯化。
步骤C. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-羟基乙基)-3-乙基哌啶-2-酮
采用与实施例202步骤A中的程序类似的程序制备本标题化合物。在用乙酸乙酯/己烷洗脱的硅胶色谱分析后分离出该化合物,为第二洗脱非对映异构体。
1H NMR(400MHz,甲醇-d4)δppm-0.48(m,1H),-0.01(m,1H),0.40(m,1H),0.48(m,1H),0.97-1.01(m,3H),1.37(m,1H),1.49-1.58(m,1H),1.75-1.78(d,J=12Hz,1H),1.97(m,1H),2.38(t,J=16Hz,1H),2.65(m,2H),2.76(m,1H),3.94(t,J=12Hz,1H),4.79(d,J=12Hz,1H),5.20-5.28(m,2H),5.94-6.03(m,1H),6.96(s,br,1H),7.09(s,2H),3.01(s,br,3H),7.29(s,br,2H)。质谱(ESI)m/z=472.1(M+1)。
步骤D. N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-2-氧代哌啶-1-基)-2-环丙基乙基)-N-甲基环丙烷磺酰胺
按照实施例202步骤C中描述的程序,将(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-羟基乙基)-3-乙基哌啶-2-酮(实施例253,步骤C,125mg,0.265mmol)转化为本标题化合物。
1H NMR(400MHz,甲醇-d4)δppm-0.46(s,br,1H),-0.24(s,br,1H),0.48(s,br,2H),0.96(t,J=7.5Hz,3H),0.99(m,6H),1.71-1.79(m,2H),1.88(m,1H),2.35(t,J=16Hz,1H),2.51(s,br,1H),2.69(m,2H),3.43(m,2H),4.89(m,1H),5.17-5.28(m,2H),5.94-6.05(m,1H),7.0(m,1H),7.05(m,1H),7.17-7.19(m,4H),7.30(m,2H)。质谱(ESI)m/z=589.2(M+1)。
步骤E. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-甲基环丙烷磺酰氨基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸
按照实施例71步骤F中描述的程序,从N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-2-氧代哌啶-1-基)-2-环丙基乙基)-N-甲基环丙烷磺酰胺(实施例253,步骤D)获得本标题化合物。
1H NMR(400MHz,氯仿-d)δppm-0.71(s,br,1H),-0.29(s,br,1H),0.31-0.41(d,br,2H),0.88(m,6H),1.10(s,br,2H),1.19(m,2H),1.82-1.87(m,2H),2.20-2.27(m,2H),2.69-2.73(d,J=16Hz,1H),2.82(s,br,4H),2.97-3.03(m,3H),4.72(d,J=12Hz,1H),6.77(m,1H),6.88(s,br,2H),7.06(m,3H),7.16(s,br,2H)。质谱(ESI)m/z=607.2(M+1)。
实施例254
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-(环丙烷磺酰氨基)-1-环丙基乙基)-3-乙基-2-氧代哌啶-3-基)乙酸
步骤A. N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-2-氧代哌啶-1-基)-2-环丙基乙基)环丙烷磺酰胺
按照实施例202步骤C中描述的程序,使(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-羟基乙基)-3-乙基哌啶-2-酮(实施例253,步骤C)与环丙烷磺酰胺偶联,从而得到本标题化合物,为白色泡沫状物。
1H NMR(400MHz,氯仿-d)δppm-0.28(s,br,1H),0.00(s,br,1H),0.36(d,br,2H),0.66(m,7H),0.89(m,2H),1.50(m,1H),1.53(dd,J=13.7,3.1Hz,1H),1.98(t,J=13.7Hz,1H),2.15(m,1H),2.35(m,1H),2.44(m,1H),2.71(s,br,1H),2.85(m,1H),2.97(ddd,J=13.6,10.6,3.0Hz,1H),3.13(s,br,1H),4.54(d,J=10.4Hz,1H),4.91-4.96(m,2H),5.63-5.73(m,1H),6.49(dt,J=7.5,1.5Hz,1H),6.72(t,J=1.9Hz,2H),6.85-6.91(m,3H),6.94(s,br,2H)。质谱(ESI)m/z=575.2(M+1)。
步骤B. N-((2S)-2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-(2,3-二羟基丙基)-3-乙基-2-氧代哌啶-1-基)-2-环丙基乙基)环丙烷磺酰胺
先后用4-甲基吗啉N-氧化物(57.0mg,0.486mmol)和2.5%在叔丁醇中的四氧化锇(45.6μL,3.47μmol)处理N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-2-氧代哌啶-1-基)-2-环丙基乙基)环丙烷磺酰胺(实施例254,步骤A,80mg,0.139mmol)在THF(375μL)、水(250μL)和叔丁醇(208μL)中的溶液。在室温下搅拌16h后,用乙酸乙酯稀释该混合物,并用水和NaCl饱和水溶液洗涤。经硫酸钠干燥有机层,并浓缩从而得到本标题化合物,为非对映异构体混合物(85mg),其直接用于下一步骤。质谱(ESI)m/z=609.1(M+1)
步骤C. N-((S)-2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-2-氧代-3-(2-氧代乙基)哌啶-1-基)-2-环丙基乙基)环丙烷磺酰胺
将高碘酸钠(89mg,0.418mmol)加入到N-((2S)-2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-(2,3-二羟基丙基)-3-乙基-2-氧代哌啶-1-基)-2-环丙基乙基)环丙烷磺酰胺(实施例254,步骤B,85mg,0.14mmol)在水(0.5mL)和THF(1mL)中的澄清溶液中。在数分钟后,形成固体。加入甲醇(1ml),并将由此产生的乳液搅拌30min。用NaCl饱和水溶液稀释反应物并用乙酸乙酯萃取两次。用NaCl饱和水溶液洗涤合并的有机层,经硫酸钠干燥,并在减压下浓缩从而得到本标题化合物(94mg),将其用于下一步骤而无需纯化。质谱(ESI)m/z=577.0(M+1)
步骤D. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-(环丙烷磺酰氨基)-1-环丙基乙基)-3-乙基-2-氧代哌啶-3-基)乙酸
将亚氯酸钠(58.9mg,0.651mmol)在0.25×1.25M磷酸二氢钾水溶液(1mL)中的溶液在0℃下加入到N-((S)-2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-2-氧代-3-(2-氧代乙基)哌啶-1-基)-2-环丙基乙基)环丙烷磺酰胺(实施例254,步骤C,94mg,0.163mmol)在1.25M磷酸二氢钾水溶液(1mL)+叔丁醇(1mL)+2M 2-甲基丁-2-烯的THF溶液(4.07mL,8.14mmol)中的澄清溶液中。在室温下搅拌4小时后,用0.6mL 1M硫代硫酸钠溶液淬灭反应物。在室温下搅拌10min后,用1.2mL 1M硫酸氢钾溶液酸化该混合物。用乙酸乙酯萃取该混合物。先后用水和NaCl饱和水溶液洗涤有机层,并经硫酸钠干燥。通过反相HPLC(Sunfire Prep C18OBD 10μm柱,用20%的在水中的MeCN至80%的在水中的MeCN梯度洗脱超过30min,其中这两种溶剂都含有0.1%TFA)纯化,得到本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 0.00(s,br,1H),0.30(s,br,1H),0.64(d,br,2H),0.96(m,7H),1.12(m,3H),1.75-1.82(m,1H),1.92(dd,J=13.8,3.03Hz,1H),2.02(m,1H),2.34(t,J=13.8Hz,1H),2.47(m,1H),2.84(s,br,3H),3.05(dd,J=13.0,5.18Hz,1H),3.24(ddd,J=13.5,10.3,2.74Hz,1H),3.53(s,br,1H),4.84(d,J=10.4Hz,1H),6.78(dt,J=7.63,1.37Hz,1H)7.02(t,J=1.86Hz,2H)7.10-7.20(m,5H)。质谱(ESI)m/z=593.0(M+1)。
实施例255
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(乙基磺酰氨基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸
步骤A. N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-2-氧代哌啶-1-基)-2-环丙基乙基)乙烷磺酰胺
根据实施例202步骤D的程序,使(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-羟基乙基)-3-乙基哌啶-2-酮(实施例253,步骤C)与乙基磺酰胺偶联,得到本标题化合物。
1H NMR(400MHz,氯仿-d)δppm-0.29(s,br,1H),0.00(s,br,1H),0.37(d,br,2H),0.69(t,J=7.3Hz,3H),1.14(t,J=8Hz,3H),1.30(m,1H),1.56(dd,J=13.7,3.1Hz,1H),1.69(m,1H),2.01(t,J=13.7Hz,1H),2.38-2.40(m,1H),2.44-2.48(m,1H),2.77(m,4H),2.99-3.12(m,2H),4.58(d,J=10.6Hz,1H),4.96(s,1H),4.98(dd,J=7.0,2.0Hz,1H),5.43(s,br,1H),5.67-5.76(m,1H),6.54(dt,J=7.4,1.6Hz,1H),6.75(s,br,2H),63.87-6.93(m,3H),6.94(s,br,2H)。质谱(ESI)m/z=563.2(M+1)。
步骤B. N-((2S)-2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-(2,3-二羟基丙基)-3-乙基-2-氧代哌啶-1-基)-2-环丙基乙基)乙烷磺酰胺
采用与实施例254步骤B中描述的程序类似的程序制备本标题化合物,为非对映异构体混合物。
步骤C. N-((S)-2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-2-氧代-3-(2-氧代乙基)哌啶-1-基)-2-环丙基乙基)乙烷磺酰胺
采用与针对实施例254步骤C描述的程序类似的程序制备本标题化合物。质谱(ESI)m/z=565.2(M+1)。
步骤D. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(乙基磺酰氨基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸
采用与针对实施例254步骤D描述的程序类似的程序获得本标题化合物。
1H NMR(400MHz,氯仿-d)δppm-0.51(s,br,1H),0.00(s,br,1H),0.39(s,br,1H),0.47(s,br,1H),0.97(t,J=7.4Hz,4H),1.32(t,J=7.4Hz,5H),1.74-1.81(m,1H),1.93-2.02(m,2H),2.37(t,J=12Hz,1H),2.64(d,J=13.7Hz,1H),2.91(d,J=13.5Hz,1H),3.04(m,3H),3.40(m,1H),4.90(d,J=10.8Hz,1H),6.99(m,1H),7.05(m,2H),7.14-7.19(m,5H)。质谱(ESI)m/z=581.2(M+1)。
实施例256
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-甲基环丙烷磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-2-环丙基乙基)-N-甲基环丙烷磺酰胺
采用与针对实施例202步骤D描述的程序类似的程序制备本标题化合物。
1H NMR(400MHz,氯仿-d)δppm-0.71(s,br,1H),-0.31(s,br,1H),0.31(s,br,1H),0.40(s,br,1H),1.01(m,2H),1.25(m,3H),1.29(s,3H),1.59(s,br,1H),1.85-1.89(dd,J=13.6,3.4Hz,2H),2.22(m,1H),2.35(s,br,1H),2.67(d,J=8Hz,2H),2.94(s,3H),3.11(m,1H),3.19(m,1H),4.78(d,J=8Hz,1H),5.19(m,2H),5.25(s,1H),5.85-5.95(m,1H),6.93(m,2H),7.06(m,2H),7.14(m,2H),7.23(m,2H)。质谱(ESI)m/z=575.2(M+1)。
步骤B. N-((2S)-2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-(2,3-二羟基丙基)-3-甲基-2-氧代哌啶-1-基)-2-环丙基乙基)-N-甲基环丙烷磺酰胺
采用与实施例254步骤B中描述的程序类似的程序制备本标题化合物,为非对映异构体混合物。质谱(ESI)m/z=609.1(M+1)。
步骤C. N-((S)-2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-3-(2-氧代乙基)哌啶-1-基)-2-环丙基乙基)-N-甲基环丙烷磺酰胺
采用与针对实施例254步骤C描述的程序类似的程序制备本标题化合物。质谱(ESI)m/z=577.2(M+1)。
步骤D. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-甲基环丙烷磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
采用与针对实施例254步骤D描述的程序类似的程序制备本标题化合物。
1H NMR(400MHz,甲醇-d4)δppm-0.71(s,br,1H),-0.28(s,br,1H),0.29(s,br,1H),0.40(s,br,1H),1.06(d,br,4H),1.44(s,3H),1.73(s,br,1H),2.08(m,1H),2.20(s,br,1H),2.35(t,J=8Hz,1H),2.57(s,br,1H),2.70(d,J=12Hz,1H),2.94(s,3H),2.99(d,J=12Hz,1H),3.07(m,1H),3.42(m,1H),4.40(s,br,1H),4.82(d,J=8Hz,1H),7.02-7.05(m,3H),7.11(m,3H),7.31(s,br,2H)。质谱(ESI)m/z=593.2(M+1)。
实施例257
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((1S,2R)-1-环丙基-2-羟基丙基)-3-甲基-2-氧代哌啶-3-基)乙酸.
步骤A. (3S,5R,6S)-3-烯丙基-1-((S)-2-(叔丁基二苯基甲硅烷基氧基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮
按照实施例251步骤D的方法从(5R,6S)-1-((S)-2-(叔丁基二苯基甲硅烷基氧基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮(4.34g,6.61mmol)制得的非对映异构体混合物采用硅胶色谱法用乙酸乙酯/己烷洗脱来进行纯化。合并含有所需差向异构体的级分并浓缩从而得到(3S,5R,6S)-3-烯丙基-1-((S)-2-(叔丁基二苯基甲硅烷基氧基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮,为白色泡沫状物,重量为3.01g(65%产率)。MS(ESI)m/z=696[M+H]+。
根据实施例252步骤A的程序对(3S,5R,6S)-3-烯丙基-1-((S)-2-(叔丁基二苯基甲硅烷基氧基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮(实施例257,步骤A,3.00g,4.31mmol)进行处理,得到(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-羟基乙基)-3-甲基哌啶-2-酮,为白色泡沫状物(1.905g,97%)。
1H NMR(500MHz,氯仿-d)δ0.00-0.15(m,1H),0.18-0.35(m,1H),0.44-0.69(m,2H),0.75-0.87(m,1H),1.28(s,3H),1.87-2.03(m,2H),2.48-2.72(m,2H),3.01-3.22(m,2H),3.41(td,J=10.33,4.52Hz,1H),3.60(dd,J=11.00,4.40Hz,1H),4.86(d,J=10.03Hz,1H),5.06-5.24(m,2H),5.74-5.97(m,1H),6.74(d,J=7.58Hz,1H),6.86-7.10(m,3H),7.10-7.26(m,4H)。MS(ESI)m/z=458[M+H]+
步骤C. (S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-2-环丙基乙醛.(还可见实施例252步骤B)
按照描述的程序将(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-羟基乙基)-3-甲基哌啶-2-酮(实施例257,步骤B,1.01g,2.2mmol)转化为本标题化合物,为白色泡沫状物(866mg,86%)
C.MS(ESI)m/z=456[M+H]+。
步骤D. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((1S,2R)-1-环丙基-2-羟基丙基)-3-甲基哌啶-2-酮和(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((1S,2S)-1-环丙基-2-羟基丙基)-3-甲基哌啶-2-酮
按照实施例149步骤A的程序,用甲基溴化镁处理(S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-2-环丙基乙醛(实施例257,步骤C,866mg,1.897mmol),从而得到非对映异构的醇(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((1S,2R)-1-环丙基-2-羟基丙基)-3-甲基哌啶-2-酮和(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((1S,2S)-1-环丙基-2-羟基丙基)-3-甲基哌啶-2-酮,为白色泡沫状物。MS(ESI)m/z=472[M+H]+。
步骤E. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-氧代丙基)-3-甲基-2-氧代哌啶-3-基)乙酸.
根据实施例71,步骤F中描述的程序对(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-羟基丙基)-3-甲基哌啶-2-酮(实施例257,步骤D,809mg,1.71mmol)进行处理,从而在SFC纯化后得到2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-氧代丙基)-3-甲基-2-氧代哌啶-3-基)乙酸,为白色固体。
1H NMR(500MHz,甲醇-D4)δ-0.70--0.47(m,1H),0.10(dq,J=9.78,5.05Hz,1H),0.31-0.48(m,1H),0.63(tt,J=8.59,5.35Hz,1H),1.34(s,3H),1.47-1.58(m,1H),2.15-2.35(m,6H),2.65(d,J=13.69Hz,1H),2.79(d,J=10.03Hz,1H),2.98(d,J=13.69Hz,1H),3.48-3.57(m,1H),4.65(d,J=10.51Hz,1H),6.94-7.01(m,1H),7.08(s,1H),7.11-7.54(m,6H)。MS(ESI)m/z=488[M+H]+。
步骤F. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((1S,2R)-1-环丙基-2-羟基丙基)-3-甲基-2-氧代哌啶-3-基)乙酸
在0℃下在甲醇中用硼氢化钠还原2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-氧代丙基)-3-甲基-2-氧代哌啶-3-基)乙酸,得到~2:1比例的非对映异构醇的混合物。通过硅胶色谱法用在己烷中的异丙醇梯度洗脱来纯化残余物。浓缩含有主要异构体的级分,然后将其从乙腈/水中冻干从而得到本标题化合物,为蓬松的白色固体
1H NMR(500MHz,甲醇-d4)δppm-0.29(br s,1H),0.20(br s,1H),0.46(br s,1H),0.60(br s,1H),1.19(br s,3H),1.24-1.35(m,1H),1.39(s,3H),2.10-2.29(m,2H),2.63(d,J=13.69Hz,1H),2.82(brs,1H),2.98(d,J=13.94Hz,1H),3.40-3.50(m,1H),3.57(brs,1H),4.82(d,J=11.00Hz,1H),6.61-7.64(m,8H)。MS(ESI)m/z=490[M+H]+。
实施例258
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((1S,2S)-1-环丙基-2-羟基丙基)-3-甲基-2-氧代哌啶-3-基)乙酸
将(Aldrich,St.Louis,MO)(1M在THF中,5.0ml,5.00mmol)用超过5分钟的时间逐滴加入到在-78℃下的2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-氧代丙基)-3-甲基-2-氧代哌啶-3-基)乙酸(实施例257,步骤E,1.035g,2.12mmol)在THF(35ml)中的溶液中。在90min后,让该混合物温度升至0℃,并小心地通过加入饱和氯化铵来淬灭。用乙酸乙酯萃取水相三次。用1M HCl、水、NaCl饱和水溶液洗涤合并的有机层,并经硫酸钠干燥。在真空中浓缩后,通过硅胶色谱法用在己烷中的异丙醇梯度洗脱来纯化残余物。浓缩含有主要异构体的级分,然后将其从乙腈/水中冻干从而得到本标题化合物,为白色粉末。通过类似于实施例152的方法确定立体化学。
1H NMR(500MHz,DMSO-d6)δ-0.69(br s,1H),-0.35(br s,1H),0.17(br s,1H),0.36(br s,1H),1.07(br s,1H),1.27(s,4H),1.98-2.23(m,2H),2.53-2.58(m,1H),2.93(d,J=13.94Hz,1H),3.36-3.49(m,1H),3.74-4.44(m,1H),4.46-5.11(m,2H),6.60-7.59(m,8H)。MS(ESI)m/z=490[M+H]+。
实施例259
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(1-甲基乙基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A: N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-2-环丙基乙基)丙烷-2-磺酰胺
按照如实施例202步骤C中描述的程序,使(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-羟基乙基)-3-甲基哌啶-2-酮(实施例252,步骤A,59.3mg,0.129mmol)与异丙基磺酰胺(48.7mg,0.395mmol)偶联从而形成本标题化合物,其是在硅胶色谱分析后分离的,为灰白色固体。MS(ESI)m/z=563[M+H]+。
步骤B: 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(1-甲基乙基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸.
按照与实施例71步骤F中描述的程序类似的程序,从N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-2-环丙基乙基)丙烷-2-磺酰胺(实施例259,步骤A)获得本标题化合物。通过反相HPLC,用60%至95%的在水中的MeCN(这两种溶剂都含有0.1%TFA)洗脱来纯化产物。合并高纯度级分,汽提挥发物,并将由此产生的溶液冷冻并冻干从而得到本标题化合物,为灰白色固体。
1H NMR(500MHz,CD3OD)δppm-0.98--0.71(m,1H)-0.38--0.16(m,1H)0.12-0.29(m,1H)0.30-0.44(m,1H)1.31-1.39(m,6H)1.41(s,3H)1.52-1.64(m,1H)2.08(dd,J=13.69,3.18Hz,1H)2.26(br.s,1H)2.40(t,J=13.69Hz,1H)2.70(d,J=13.45Hz,1H)3.00(d,J=13.20Hz,1H)3.09(dd,J=13.69,3.42Hz,1H)3.25(dt,J=13.51,6.82Hz,1H)3.33-3.34(m,1H)3.41(ddd,J=13.75,10.82,3.06Hz,1H)3.96(br s,1H)4.94(d,J=11.00Hz,1H)6.98-7.18(m,5H)7.27(br s,3H)。MS(ESI)m/z=581[M+H]+。
实施例260
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-1-环丙基-2-(N-甲基环丙烷磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸.
步骤A: (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-1-环丙基-2-(甲基氨基)乙基)-3-甲基哌啶-2-酮
将(S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-2-环丙基乙醛(实施例252,步骤B,554mg,1.21mmol)溶解在10mL无水甲苯中,并在真空中汽提至干两次从而实现共沸除去微量水分。在高真空下除去残余溶剂后,将该醛溶解在二氯乙烷(12mL)中。将甲胺(2.0M在THF中,6.1mL,12.20mmol)和乙酸(2mL,35.0mmol)加入到该溶液中,将该溶液在室温下搅拌约30分钟。将三乙酰氧基硼氢化钠(1.12g,5.28mmol)以固体形式一次性加入,并将该混合物在室温下搅拌分析显示已发生差向异构化从而产生两个非对映异构体。用饱和碳酸氢钠溶液淬灭反应物。将该胺非对映异构体萃取到二氯甲烷中。用水洗涤有机相,并经硫酸钠干燥。在浓缩后,由此产生的残余物在再溶解于乙酸乙酯中后产生微混浊溶液,因此经硫酸镁对其进行再干燥。浓缩得到非对映异构体混合物,为黄白色泡沫状物(577mg)。这两种差向异构的产物通过SFC色谱法(250x30mm IC柱(Chiral Technologies,Inc.,West Chester,PA,USA)用42g/min IPA和[20mM NH3]及78g/min CO2分离。浓缩时,获得第一洗脱差向异构体(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(甲基氨基)乙基)-3-甲基哌啶-2-酮。浓缩含有第二洗脱组分的级分得到本标题化合物。MS(ESI)m/z=471[M+H]+。
步骤B: N-((R)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-2-环丙基乙基)-N-甲基环丙烷磺酰胺
将(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-1-环丙基-2-(甲基氨基)乙基)-3-甲基哌啶-2-酮(实施例260,步骤A,168mg,0.356mmol)作为在3mL无水甲苯中的溶液转移到烘干的10mL圆底烧瓶中,并将该溶液在旋转蒸发器上汽提至干。将这个操作重复两次从而实现共沸除去微量水分。将环丙烷磺酰氯和吡啶加入到该烧瓶中。通过LC-MS监测反应的完成。最后用超过4天的时间加入5x(0.15ml磺酰氯和0.15mL吡啶)。在开始出现固体时加入二氯甲烷。用乙酸乙酯和柠檬酸溶液(10%)稀释反应混合物。将水相用乙酸乙酯洗涤两次。用NaCl饱和水溶液洗涤合并的有机层并经硫酸钠干燥。在真空中浓缩后,黄色残余油状物通过硅胶色谱法用在己烷中的乙酸乙酯梯度洗脱来进行纯化。级分合并化合物并浓缩从而得到本标题化合物,为白色泡沫状物。MS(ESI)m/z=575[M+H]+
步骤C. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-1-环丙基-2-(N-甲基环丙烷磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸.
按照与实施例71步骤F中描述的程序类似的程序,从N-((R)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-2-环丙基乙基)-N-甲基环丙烷磺酰胺(实施例260,步骤B,153mg,0.265mmol)获得本标题化合物。该化合物通过反相HPLC在SunfireTMC18柱(Waters,Milford,MA)上,用50%至100%的在水中的MeCN(这两种溶剂都含有0.1%TFA)梯度洗脱来进行纯化,然后通过SFC色谱法(250x30mm 柱(Phenomenex,Torrance,CA90501,USA),使用32g/min甲醇[20mM NH3]+48g/min CO2在Thar80 SFC(Thar Technologies,Pittsburg,PA)上进行。出口压力=100bar;温度=23C;波长=220nm。使用0.8mL的95mg/15mL[6.3mg/mL样品的甲醇溶液,即,5.1mg/注射]的注射液。运行时间=6min,循环时间=3.5min)进一步纯化。浓缩汇集的级分从而得到本标题化合物,为白色固体。
1H NMR(500MHz,氯仿-d)δ0.14(d,J=3.91Hz,2H),0.51(t,J=5.26Hz,2H),0.93-1.11(m,2H),1.14-1.23(m,1H),1.25-1.28(m,1H),1.46(br s,3H),1.52-1.76(m,2H),1.87-2.00(m,1H),2.20-2.39(m,2H),2.72(d,J=15.41Hz,4H),2.92-3.07(m,3H),3.13(d,J=15.41Hz,1H),3.98(dd,J=13.82,11.13Hz,1H),4.93(br s,1H),6.90(d,J=5.87Hz,1H),7.00(s,1H),7.05-7.26(m,6H)。MS(ESI)m/z=593[M+H]+。
实施例261
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2S,3S)-2-羟基-4-甲基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸.
(3-氯苯基)-5-(4-氯苯基)-2-甲基-5-氧代戊酸酯
将甲基丙烯酸甲酯(82mL,773mmol)加入到在氮气气氛下的2-(3-氯苯基)-1-(4-氯苯基)乙酮(195.2g,736mmol;实施例1,步骤A)在无水THF(1.5L)中的溶液中。然后制备叔丁醇钾(8.26g,73.6mmol)在无水THF(340mL)中的悬浮液(经超声处理分散该固体),并用插管将其导入到含有2-(3-氯苯基)-1-(4-氯苯基)乙酮的溶液中。将该溶液冷却至~16℃,并让橙色溶液在室温下搅拌2.5d。(在2d后,TLC显示不存在原料)。在真空中浓缩该混合物。用乙酸乙酯(900mL)稀释残余的红棕色油状物,并先后用水(4x190mL)和NaCl饱和水溶液洗涤。经硫酸镁干燥有机层并在减压下浓缩从而得到本标题化合物,为非对映异构体的外消旋混合物。
1H-NMR(500MHz,CDCl3)δ7.88(m,4H),7.39(m,2H),7.27-7.12(系列m,4H),4.62(dd,J=9.0,5.6Hz,0.5H),4.59(dd,J=9.3,5.4Hz,0.5H),3.69(s,1.5H),3.60(s,1.5H),2.46(m,1H),2.33(m,1H),2.08(ddd,J=13.9,9.3,5.4Hz,0.5H),1.97(ddd,J=13.7,9.0,4.4Hz,0.5H),1.23(d,J=6.9Hz,1.5H),1.16(d,J=7.1Hz,1.5H)ppm。
步骤B: (4R,5R)-4-(3-氯苯基)-5-(4-氯苯基)-5-羟基-2-甲基戊酸甲酯和(4S,5S)-4-(3-氯苯基)-5-(4-氯苯基)-5-羟基-2-甲基戊酸甲酯的外消旋混合物
将无水甲醇(600mL)放入在N2气氛下的有棒和温度探头的3L三颈圆底烧瓶中,并将其冷却至约-20℃。将硼氢化钠(26.2g,693mmol)分成几个5g部分加入。经由添加漏斗,将4-(3-氯苯基)-5-(4-氯苯基)-2-甲基-5-氧代戊酸甲酯(253g,693mmol;实施例261,步骤A)在甲醇(600mL)中的溶液逐滴加入到反应物中,将温度维持在-27℃至-30℃之间。将微红色溶液在-30℃下搅拌30分钟,然后让其温度升至-15℃。通过TLC监测反应的完成。通过经由添加漏斗缓慢地加入水(68.6mL,3.8mol)来淬灭反应物。让该混合物温度升至室温。在真空下除去溶剂。将残余的黄色油状物稀释在乙酸乙酯(1.2L)中并用水(400mL)洗涤。用NaCl饱和水溶液(2x300mL)洗涤有机层,形成乳液。等待大部分乳液分离后,经硫酸镁干燥有机层。通过滤纸过滤该溶液并在真空下浓缩从而得到非对映异构体的外消旋混合物。
1H-NMR(500MHz,DMSO-d6)δ7.33(m,2H),7.27-7.17(系列m,5H),7.04(m,1H),5.43(d,J=4.4Hz,0.5H),5.37(d,J=4.6Hz,0.5H),4.77(t,J=5.4Hz,0.5H),4.71(dd,J=6.6,4.9Hz,0.5H),5.33(s,1.5H),3.46(s,1.5H),2.87(dt,J=10.2,4.7Hz,0.5H),2.75(ddd,J=11.2,6.6,4.9Hz,0.5H),2.04(m,1.5H),1.71(m,1H),1.46(m,0.5H),0.97(d,J=6.6Hz,1.5H),0.94(d,J=7.1Hz,1.5H)ppm.TLC(20%EtOAc/己烷)Rf=0.34.
步骤C. (4R,5R)-4-(3-氯苯基)-5-(4-氯苯基)-5-羟基-2-甲基戊酸和(4S,5S)-4-(3-氯苯基)-5-(4-氯苯基)-5-羟基-2-甲基戊酸.
(4R,5R)-4-(3-氯苯基)-5-(4-氯苯基)-5-羟基-2-甲基戊酸甲酯和(4S,5S)-4-(3-氯苯基)-5-(4-氯苯基)-5-羟基-2-甲基戊酸甲酯(245.7g,669mmol;实施例261,步骤B)的外消旋混合物在THF(1.17L)中的溶液通过升温至40℃来制备。将该烧瓶冷却至内部温度为~14℃。将氢氧化锂水合物(42.1g,1.0mol)在水(585mL)中的溶液该THF溶液中。让该混合物在室温下搅拌,并根据LC/MS监测是否存在原料(~2.5h)。在完成后,将该溶液再次冷却至温度为~14℃。缓慢地加入2N HCl(526mL)。分开各层,并用乙酸乙酯(先1x500mL,然后1x250mL)洗涤水层(pH~2)。经硫酸镁干燥合并的有机层并浓缩从而得到264g(4R,5R)-4-(3-氯苯基)-5-(4-氯苯基)-5-羟基-2-甲基戊酸和(4S,5S)-4-(3-氯苯基)-5-(4-氯苯基)-5-羟基-2-甲基戊酸的外消旋混合物。含有一些残余溶剂的粗材料照原样用于随后的转化中。该产物(在溶剂校正后估计为227g)为在2-位置上的非对映异构体的大约1:1的混合物。
1H-NMR(500MHz,CDCl3)δ7.31(m,2H),7.25(m,3H),7.17(m,2H),7.05(m,1H)4.74(m,1H),2.99(ddd,J=11.2,1.7,3.7Hz,0.5H),2.90(ddd,J=11.5,7.3,4.6Hz,1H),2.15(m,1.5H),1.85(m,0.5H),1.67(ddd,J=14.3,11.5,3.4Hz,0.5H),1.52(m,0.5H),1.08(d,J=7.1Hz,1.5H),1.05(d,J=6.9Hz,1.5H)ppm.
或者,可以从外消旋的4-(3-氯苯基)-5-(4-氯苯基)-2-甲基-5-氧代戊酸甲酯制备(4R,5R)-4-(3-氯苯基)-5-(4-氯苯基)-5-羟基-2-甲基戊酸,其为甲基非对映异构体的混合物。
在三颈烧瓶中,装入外消旋的4-(3-氯苯基)-5-(4-氯苯基)-2-甲基-5-氧代戊酸甲酯(500g,1.37mol,1当量)在无水2-丙醇(2.5L)中的溶液和KOtBu(46.1g,0.41mol,0.3当量),并搅拌30min直至形成澄清的黄色溶液。然后将所述溶液用二氯化{(S)-(-)-2,2′-双[二(3,5-二甲苯基)膦基]-1,1′-联萘基}[(2S)-(+)-1,1-双(4-甲氧基苯基)-3-甲基-1,2-丁烷二胺]钌(II)(5g,4.1mmol,0.003当量,Strem Chemicals inc.,Newburyport,MA)在无水甲苯(250mL)中的溶液进行处理,并在室温下搅拌2小时(注意:大部分甲酯转化为异丙酯)。将该溶液转移到两个Parr摇摆反应器(shaker)中,密封并用氢气吹扫3次。使反应物于室温在414千帕氢压力下摇摆。在18hrs后,用饱和NH4Cl淬灭反应物,浓缩并用EtOAc(2LX2)萃取。用盐水洗涤合并的有机物,将其浓缩成棕色油状物,并将其直接用于下一步骤。
将粗中间体(542g,1.37mol)溶解在THF(3L)和MeOH(1L)中,并装入2M LiOH(1L)。使该溶液在室温下旋转过夜,浓缩HF和MeOH,并用1L 2M HCl淬灭。在相分离后,用EtOAc(1LX2)萃取水层。用盐水洗涤合并的有机物,经无水Na2SO4干燥,过滤,并在真空中浓缩。将产物,即作为甲基非对映异构体混合物的(4R,5R)-4-(3-氯苯基)-5-(4-氯苯基)-5-羟基-2-甲基戊酸以粗品形式用于下一步骤。
步骤D. (5R,6R)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基四氢-2H-吡喃-2-酮和(5S,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基四氢-2H-吡喃-2-酮
在氮气气氛下使用吡啶4-甲基苯磺酸盐(PPTS,4.84g,19.28mmol)使羟基酸非对映异构体混合物(227g,643mmol;实施例261,步骤C)在Dean-Stark条件下在甲苯(1.07L)中内酯化。在剧烈回流2h后,将该溶液冷却至室温并将其转移至分液漏斗中。用乙酸乙酯冲洗烧瓶中的残余物。连续地用水(1x250mL)、碳酸氢钠饱和溶液(1x250mL),和NaCl饱和水溶液(1x250mL)洗涤合并的有机相。在经硫酸镁干燥后,在减压下浓缩得到非对映异构的内酯的混合物,为淡棕色固体。
1H-NMR(500MHz,CDCl3)δ7.24-6.95(系列m,6H),6.91(d,J=7.6Hz,0.5H),6.82(m,1.5H),6.73(d,J=7.6Hz,0.5H),5.77(d,J=3.9Hz,0.5H),5.69(d,J=4.6Hz,0.5H),3.67(dt,J=7.6,4.2Hz,0.5H),3.55(td,J=7.8,4.6Hz,0.5H),2.97(m,0.5H),2.81(双五重峰,J=14.4,7.1Hz,0.5H),2.56(dt,16.1,8.0Hz,0.5H),2.32(dt,J=13.7,6.9Hz,0.5H),2.07(ddd,J=13.2,8.6,4.4Hz,0.5H),1.85(ddd,J=14.2,12.7,7.6hz,0.5H),1.41(d,J=7.1Hz,1.5H),1.39(d,J=6.9Hz,1.5H)ppm。
在氮气气氛下在装配有Claisen接头(adapter)、500mL滴液漏斗和内部温度探头的一颈圆底烧瓶中制备来自前面步骤的外消旋内酯(实施例261,步骤D,190.28g,568mmol)在THF(946mL)中的溶液。将该溶液冷却至-35℃的温度。经由添加漏斗加入烯丙基溴(120mL,1.42mol),在添加期间将温度维持在-30℃以下。将LHMDS溶液(1M溶液在THF中,738mL,738mmol)逐滴加入到反应物中,将温度维持在-30℃以下。用超过1h的时间将反应物温度缓慢地升至-5℃。将该溶液再冷却至约-20℃,并经由插管将其加入到在约5C下的氯化铵水溶液中。在分离各层后,用乙酸乙酯萃取水层两次。用NaCl饱和水溶液洗涤合并的有机层并经硫酸钠干燥。在真空下浓缩得到219g淡黄色固体。将该固体在室温下用己烷(2L)浆液化2h。然后通过过滤收集该固体,用己烷(2X100mL)冲洗,并干燥从而得到本标题化合物,为外消旋混合物。
1H-NMR(500MHz,CDCl3)δ7.24(m,1H),7.20-7.15(m,3H),6.91(t,J=1.7Hz,1H),6.77(d,J=7.6Hz,1H),6.59(m,2H),5.84(ddt,J=17.6,10.3,7.6Hz,1H),5.71(d,J=5.4Hz,1H),5.21-5.13(m,2H),3.81(dt,J=12.0,4.2Hz,1H),2.62(ABX JAB=14.0,JAX=7.8Hz,1H),2.52(ABX,JAB=13.9,JAX=7.3Hz,1H),1.98(dd,J=14.0,12.0Hz,1H),1.91(ddd,J=14.0,3.7,1.2Hz,1H),1.42(s,3H)ppm。
步骤F:(3S,5R,6R)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基四氢-2H-吡喃-2-酮和(3R,5S,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基四氢-2H-吡喃-2-酮的分离
(3S,5R,6R)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基四氢-2H-吡喃-2-酮和(3R,5S,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基四氢-2H-吡喃-2-酮的外消旋混合物可以使用如下的手性超临界流体色谱法(SFC)分离:使用250x30mm柱(Phenomenex,Torrance,CA 90501,USA),用20g/min甲醇(20mM NH3)+60g/min CO2在Thar80 SFC上进行。出口压力=100bar;温度=23C;波长=220nm。使用0.3mL的5.0g/80mL(62.5mg/mL在甲醇/二氯甲烷(75:5)中的样品溶液,即,18.75mg/注射)注射液。运行时间=8min,循环时间=3min。
所收集的第一峰被确定为(3R,5S,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基四氢-2H-吡喃-2-酮。所收集的第二峰被确定为(3S,5R,6R)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基四氢-2H-吡喃-2-酮,随后按照针对实施例261,步骤G和H描述的程序将其用(S)-2-氨基-1-丁醇化学衍生化并转化为与实施例91,步骤B中制备的化合物相同的化合物。所分离的对映异构体的NMR与上述外消旋物的光谱一致。
或者,可以从外消旋的4-(3-氯苯基)-5-(4-氯苯基)-2-甲基-5-氧代戊酸甲酯制备(3S,5R,6R)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基四氢-2H-吡喃-2-酮。
在三颈烧瓶中,装入外消旋的4-(3-氯苯基)-5-(4-氯苯基)-2-甲基-5-氧代戊酸甲酯(500g,1.37mol,1当量)在无水2-丙醇(2.5L)中的溶液和KOtBu(46.1g,0.41mol,0.3当量),并搅拌30min直至形成澄清的黄色溶液。然后将所述溶液用二氯化{(S)-(-)-2,2′-双[二(3,5-二甲苯基)膦基]-1,1′-联萘基}[(2S)-(+)-1,1-双(4-甲氧基苯基)-3-甲基-1,2-丁烷二胺]钌(II)(5g,4.1mmol,0.003当量,/Strem Chemicals Inc)在无水甲苯(250mL)中的溶液进行处理,并在室温下搅拌2小时(注意:大部分甲酯转化异丙酯)。将该溶液转移到两个Parr摇摆反应器中,密封并用氢气吹扫3次。使反应物于室温在414千帕氢压力下摇摆。在18hrs后,用饱和NH4Cl淬灭反应物,浓缩并用EtOAc(2L x2)萃取。用盐水洗涤合并的有机物,将其浓缩成棕色油状物并将其直接用于下一步骤。
将粗中间体(542g,1.37mol)溶解在THF(3L)和MeOH(1L)中,并装入2M LiOH(1L)。使该溶液在室温下旋转过夜,浓缩该溶液从而除去大部分THF和MeOH,并用1L 2M HCl淬灭。在相分离后,用EtOAc(1L x2)萃取水层。用盐水洗涤合并的有机物,经无水Na2SO4干燥,过滤,并在真空中浓缩。
步骤G:(S)-2-((2R,3R)-2-(3-氯苯基)-3-(4-氯苯基)-3-羟基丙基)-N-((S)-1-羟基-3-甲基丁烷-2-基)-2-甲基戊-4-烯酰胺
将(S)-2-氨基-3-甲基丁烷-1-醇(550mg,5.33mmol)和(3S,5R,6R)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基四氢-2H-吡喃-2-酮(实施例261,步骤H,第二化合物,500mg,1.332mmol)的混合物加热至100℃并保持24h。在冷却至室温后,将残余物溶解在乙酸乙酯中,并先后用1N HCl(5mL)和NaCl饱和水溶液(5mL)洗涤三次。经MgSO4干燥有机相,过滤,并浓缩滤液从而得到本标题化合物。
1H-NMR(500MHz,DMSO-d6)δ7.21(m,2H),7.10(m,2H),7.06(br s,1H),6.99(m,2H),6.86(br d,J=8.8Hz,1H),6.84(br d,J=7.1Hz,1H),5.53(dddd,J=16.9,10.3,8.1,6.6Hz,1H),5.46(d,J=4.4Hz,1H),4.90(m,2H),4.78(t,J=4.2Hz,1H),4.56(t,J=5.1Hz,1H),3.56(m,1H),3.37(m,2H),2.87(dt,J=7.8,4.2Hz,1H),2.29(dd,J=13.7,6.4Hz,1H),7.8Hz,1H),1.97(dd,J=14.4,3.9Hz,1H),1.88(dd,J=13.9,8.1Hz,1H),1.76(octet,J=6.4Hz,1H),0.97(s,3H),0.81(d,J=6.8Hz,3H),0.75(d,J=6.6Hz,3H)ppm.
步骤H. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基-3-甲基丁烷-2-基)-3-甲基哌啶-2-酮
将(S)-2-((2R,3R)-2-(3-氯苯基)-3-(4-氯苯基)-3-羟基丙基)-N-((S)-1-羟基-3-甲基丁烷-2-基)-2-甲基戊-4-烯酰胺(实施例261,步骤G)作为在无水苯中的溶液转移到预先称重的烘干50mL圆底烧瓶中,并将其汽提至干。再进行两次的苯/水共沸蒸馏,并将残余物在高真空下干燥2h,此后它的重量为550mg。在烧瓶中添加烘干的搅拌棒。将该容器密封并用氮气吹扫,然后加入无水二氯甲烷(23mL),接着加入三乙胺(1.3mL,9.33mmol)。将由此产生的搅拌着的溶液冷却至0℃。通过微量注射器逐滴加入甲烷磺酰氯(0.270mL,3.49mmol)。在1h后,通过加入HCl(1.2M,12mL)来淬灭反应物,并将反应物稀释在乙酸乙酯中。用1.2M HCl(30mL)、饱和碳酸氢钠(2X25mL),和NaCl饱和水溶液洗涤有机层。在经硫酸镁干燥并在真空中浓缩后,获得中间体,为灰白色泡沫状物(0.64g)。向该中间体中加入1,8-双(二甲基氨基)萘(314mg,1.465mmol)和水(0.104mL,5.75mmol),接着加入二噁烷(23mL)。将该混合物在氮气下于110℃加热过夜。在冷却后,将该混合物溶解于乙酸乙酯中,并用饱和氯化铵溶液洗涤。将水相用乙酸乙酯反萃。用NaCl饱和水溶液洗涤合并的有机层,经硫酸钠干燥,过滤,并在真空中浓缩。残余物通过硅胶色谱法用在己烷中的乙酸乙酯洗脱来进行纯化。将主要含有所需产物的色谱分离级分通过色谱法在40g硅胶柱上用0%至50%的在己烷中的乙酸乙酯梯度洗脱来进行再纯化从而得到本标题化合物。
1H NMR(400MHz,氯仿-d)δ0.73(d,J=6.46Hz,3H),0.83(d,J=6.65Hz,3H),1.28(s,3H),1.91-2.00(m,1H),2.00-2.10(m,1H),2.26-2.45(m,1H),2.56-2.74(m,2H),3.16(br.s.,1H),3.26(ddd,J=13.50,10.47,3.42Hz,1H),3.43(br.s.,1H),3.76(dd,J=11.25,3.42Hz,1H),4.49(d,J=10.56Hz,1H),5.18(s,1H),5.21(d,J=6.46Hz,1H),5.87(ddt,J=16.95,9.85,7.53Hz,1H),6.72(明显的d,J=7.63Hz,1H),6.95(t,J=1.66Hz,1H),6.97-7.17(m,4H),7.23(d,J=8.41Hz,2H)。MS(ESI)m/z=460[M+H]+。
步骤I. (S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-3-甲基丁醛
将Dess-Martin过碘烷(938mg,2.212mmol)以固体形式加入到(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基-3-甲基丁烷-2-基)-3-甲基哌啶-2-酮(实施例261,步骤H,365.4mg,0.794mmol)在二氯甲烷(8mL)和水(0.04mL,2.220mmol)中的溶液中。将由此产生的悬浮液在室温下剧烈搅拌1.5h。用硫代硫酸钠溶液(1M水溶液,6mL)淬灭反应物。再加入硫代硫酸钠溶液(1M水溶液,6mL),并搅拌直至白垩悬浮液变成微混浊的两相混合物。分离水相,并用二氯甲烷反萃水相。用硫代硫酸钠溶液、饱和碳酸氢钠水溶液和NaCl饱和水溶液洗涤有机层。在经硫酸钠干燥并浓缩后,残余物通过在硅胶上用0%至30%的在己烷中的乙酸乙酯梯度洗脱来进行纯化。汇集含有所需产物的级分从而得到本标题化合物,为白色泡沫状物。MS(ESI)m/z=458[M+H]+。
)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-羟基-4-甲基戊烷-3-基)-3-甲基哌啶-2-酮.
经由注射器将甲基溴化镁(1.4mL,1.960mmol,1.4M在1:3THF:甲苯中)加入到在0℃在氮气下的预先干燥的(S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-3-甲基丁醛(实施例261,步骤I,286mg,0.624mmol)在THF(6.5mL)中的溶液中。移开冰浴。在2h后,将该溶液再冷却到0℃,并通过小心地加入饱和氯化铵溶液来淬灭。用乙酸乙酯萃取由此产生的混合物。用NaCl饱和水溶液洗涤有机层,经硫酸钠干燥,过滤,并浓缩。通过硅胶色谱法用0%至40%的在己烷中的乙酸乙酯梯度洗脱来纯化残余物。合并含有所需产物的级分并加以再纯化从而得到本标题化合物,为非对映异构的醇的混合物,为白色泡沫状物。MS(ESI)m/z=474[M+H]+。
步骤K. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-2-甲基-4-氧代戊烷-3-基)-2-氧代哌啶-3-基)乙酸.
按照与实施例257步骤E中描述的程序类似的程序将)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-羟基-4-甲基戊烷-3-基)-3-甲基哌啶-2-酮(实施例261,步骤J,244mg,0.51mmol)转化为本标题化合物,其是在用在己烷中的乙酸乙酯洗脱的硅胶色谱分析后获得的,为白色固体。MS(ESI)490[M+H]+。
步骤L. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2S,3S)-2-羟基-4-甲基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸
按照与实施例258中描述的程序类似的程序,从2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-2-甲基-4-氧代戊烷-3-基)-2-氧代哌啶-3-基)乙酸(实施例261,步骤K,79.9mg,0.16mmol)获得本标题化合物。在后处理后,通过色谱法在24g硅胶柱上,用10%至20%的在己烷中的异丙醇梯度洗脱来纯化材料。合并最纯的级分,浓缩,将其再溶解于1:1MeCN/水中,使其通过pall微量过滤器,冷冻,并冻干从而得到本标题化合物,为白色固体。以类似于实施例152的方法确定立体化学。
1H NMR(400MHz,甲醇-d4)δ0.62(d,J=7.04Hz,3H),0.67(d,J=6.65Hz,3H),1.26(d,J=6.46Hz,3H),1.42(s,3H),2.13-2.29(m,3H),2.49(t,J=7.14Hz,1H),2.62(d,J=13.69Hz,1H),3.01(d,J=13.69Hz,1H),3.57(td,J=10.81,6.16Hz,1H),4.23(t,J=6.65Hz,1H),4.70(d,J=10.95Hz,1H),6.65-7.51(m,8H)。MS(ESI)m/z=492[M+H]+。
实施例262
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-环丙基(吡啶-2-基)甲基)-3-甲基-2-氧代哌啶-3-基)乙酸或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-环丙基(吡啶-2-基)甲基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. (1S,2R)-4-羧基-2-(3-氯苯基)-1-(4-氯苯基)丁烷-1-铵氯化物
使(5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)哌啶-2-酮(实施例1,步骤E,29g,91mmol)在5M盐酸(91mL,453mmol)中的悬浮液回流。在2h后,TLC指示原料完全消耗,生成开环产物(用75%的在己烷中的乙酸乙酯洗脱;Rf原料=0.5,Rf产物=0.0)。将反应内容物用甲苯(4x100mL)共蒸馏,然后使其干燥。将固体悬浮在乙醚(100mL)中,过滤,并用乙醚(100mL)洗涤。使白色结晶固体在高真空下干燥从而得到本标题化合物。
1H NMR(500MHz,DMSO-d6)δ7.31-7.39(m,2H),7.24-7.30(m,2H),7.10-7.23(m,3H),6.90-7.01(m,1H),4.65(d,J=10.03Hz,1H),3.27(dt,J=3.67,10.51Hz,1H),2.25-2.36(m,1H),1.95-2.10(m,1H),1.77-1.94(m,2H)。
步骤B. (4R,5S)-4-(3-氯苯基)-5-(4-氯苯基)-5-(环丙基(吡啶-2-基)甲基氨基)戊酸
将环丙基(吡啶-2-基)甲酮(0.393g,2.67mmol)[Meijer,Louis H.P.等人,Tetrahedron,40,5185(1984)]与纯的四异丙氧基钛(0.782mL,2.67mmol)混合,并在室温下搅拌20min。将(1S,2R)-4-羧基-2-(3-氯苯基)-1-(4-氯苯基)丁烷-1-铵氯化物(0.500g,1.334mmol;实施例262,步骤A)以固体形式加入,并搅拌过夜。加入甲醇(13mL),接着小心地加入硼氢化钠(0.151g,4.00mmol)。将由此产生的溶液在室温下搅拌10min。用HCl(1N水溶液)淬灭反应物,用二氯甲烷萃取并用NaCl饱和水溶液洗涤。经硫酸钠干燥合并的有机层并浓缩从而得到粗产物,将该粗产物用于下一步骤而无需进一步纯化。
步骤C. (5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-环丙基(吡啶-2-基)甲基)哌啶-2-酮或(5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-环丙基(吡啶-2-基)甲基)哌啶-2-酮
将来自实施例162步骤B的粗产物在分子筛(15片)的存在下溶解于二氯乙烷(13mL)中,并在回流下加热过夜。通过(J.T.Baker,Phillipsberg,NJ,硅藻土)过滤反应物,用二氯甲烷冲洗,并在减压下浓缩。残余物通过C(洗脱剂:10%至90%的乙腈、水、0.1%TFA,梯度洗脱)纯化从而得到本标题化合物,为第一洗脱非对映异构体。
步骤D. (5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-环丙基(吡啶-2-基)甲基)-3-甲基哌啶-2-酮或(5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-环丙基(吡啶-2-基)甲基)-3-甲基哌啶-2-酮
将LHMDS溶液(1M溶液在THF中,0.585mL,0.585mmol)加入到在-78℃下的来自实施例262步骤C的化合物(0.220g,0.487mmol)和碘甲烷(0.040mL,0.634mmol)在THF(5.0mL)中的溶液中。让反应物温度升至室温,然后淬灭(NH4Cl饱和水溶液),萃取(2×EtOAc),并洗涤(NaCl饱和水溶液)。经硫酸钠干燥合并的有机层,并在减压下浓缩。使粗材料吸附到硅胶塞上并通过色谱法(SiO2,40g,用20%至60%的在己烷中的乙酸乙酯洗脱)纯化从而得到本标题化合物,为非对映异构体混合物。
步骤E. (5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-环丙基(吡啶-2-基)甲基)-3-甲基哌啶-2-酮或(5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-环丙基(吡啶-2-基)甲基)-3-甲基哌啶-2-酮
将LHMDS溶液(1.0M溶液在THF中,0.838mL,0.838mmol)加入到来自实施例262步骤D的非对映异构体混合物(0.130g,0.279mmol)和烯丙基溴(0.095mL,1.117mmol)在THF(2.80mL)中的溶液中。将反应混合物在室温下搅拌5min,然后将其加热至50℃并保持3h。用NH4Cl饱和溶液稀释该溶液,萃取(2×乙酸乙酯),并洗涤(NaCl饱和水溶液)。经硫酸钠干燥合并的有机层并在减压下浓缩。使粗材料吸附到硅胶塞上并通过色谱法(SiO2,40g,用0%至35%的在己烷中的EtOAc梯度洗脱)纯化该粗材料从而得到本标题化合物,为非对映异构体混合物,为白色泡沫状物。
步骤F. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-环丙基(吡啶-2-基)甲基)-3-甲基-2-氧代哌啶-3-基)乙酸或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-环丙基(吡啶-2-基)甲基)-3-甲基-2-氧代哌啶-3-基)乙酸
按照与实施例71步骤F中描述的程序类似的程序对实施例262步骤E的化合物(90mg,0.178mmol)进行处理。通过反相制备型HPLC(洗脱剂:10%至90%的乙腈、水、0.1%TFA,梯度洗脱)分离非对映异构体,得到本标题化合物,为第一洗脱非对映异构体。
1H NMR(400MHz,氯仿-d)δppm 0.09(br s,1H)0.28-0.34(m,1H)0.77-0.95(m,2H)1.37(s,3H)1.51-1.66(m,1H)2.13(dd,J=14.09,3.13Hz,1H)2.28(t,J=13.69Hz,1H)2.79(d,J=15.06Hz,1H)2.98(d,J=15.06Hz,1H)3.29-3.41(m,1H)4.83(d,J=9.98Hz,1H)5.08(d,J=10.37Hz,1H)6.80(d,J=7.63Hz,1H)6.96(m,5H)7.04-7.17(m,2H)7.63(d,J=8.22Hz,1H)7.72(t,J=6.65Hz,1H)8.07(t,J=7.24Hz,1H)9.06(d,J=4.89Hz,1H)。MS(ESI)m/z=523.2(M+1)。
实施例263
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(噻吩-2-磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. 2-((3R,5R,6S)-1-((S)-2-((叔丁基二苯基甲硅烷基)氧基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸
向快速搅拌着的(3S,5R,6S)-3-烯丙基-1-((S)-2-(叔丁基二苯基甲硅烷基氧基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮(1450mg,2.08mmol;实施例251,步骤D)在水(11mL)、乙腈(7.2mL)和CCl4(7.2mL)的混合物中的溶液中加入高碘酸钠(1780mg,8.32mmol),接着加入氯化钌(III)水合物(47mg,0.21mmol)。在剧烈搅拌16h后,再加入水(5.4mL)、乙腈(3.6mL),和CCl4(3.6mL),并再向由此产生的澄清的深色溶液中加入高碘酸钠(890mg,4.16mmol)和氯化钌(III)水合物(24mg,0.10mmol)。在再剧烈搅拌4h后,酸化(10%柠檬酸)反应物并稀释(EtOAc)。通过(J.T.Baker,Phillipsberg,NJ,硅藻土)垫过滤反应混合物并萃取(2×EtOAc)滤液。洗涤(盐水)合并的有机层,干燥(Na2SO4),并在减压下浓缩。通过硅胶色谱法(80g SiO2,30%、40%,和50%的EtOAc/Hex)纯化残余物,得到本标题化合物,为浅黄色泡沫状物。
步骤B. 2-((3R,5R,6S)-1-((S)-2-((叔丁基二苯基甲硅烷基)氧基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸甲酯
在0℃下向2-((3R,5R,6S)-1-((S)-2-(叔丁基二苯基甲硅烷基氧基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸(1400mg,1.96mmol;实施例263,步骤A)在MeOH(3.1mL)和苯(12.5mL)的混合物中的溶液中逐滴加入2.0M在己烷中的(三甲基甲硅烷基)重氮甲烷(1.96mL,3.92mmol)。在0℃下搅拌1h后,在减压下浓缩反应物。通过硅胶色谱法(40g SiO2,10%和20%的EtOAc/Hex)纯化残余物,得到本标题化合物,为浅黄色泡沫状物。
步骤C. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-羟基乙基)-3-甲基-2-氧代哌啶-3-基)乙酸甲酯
在0℃下向2-((3R,5R,6S)-1-((S)-2-(叔丁基二苯基甲硅烷基氧基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸甲酯(578mg,0.793mmol;实施例263,步骤B)在THF(3.2mL)中的溶液中加入在THF中的1M TBAF(2.38mL,2.38mmol),并让反应混合物温度升至室温。在室温下搅拌6h后,淬灭(饱和NH4Cl)反应物,萃取(2×EtOAc)并洗涤(盐水)。干燥(Na2SO4)合并的有机层并在减压下浓缩。通过硅胶色谱法(40g SiO2,10%和50%的EtOAc/Hex)纯化残余物,得到本标题化合物,为无色泡沫状物。
步骤D. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(噻吩-2-磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸甲酯
向2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-羟基乙基)-3-甲基-2-氧代哌啶-3-基)乙酸甲酯(100mg,0.184mmol;实施例263,步骤C)和氰基亚甲基三丁基正膦(177μL,0.734mmol)在甲苯(0.92mL)中的溶液中加入噻吩-2-磺酰胺(90mg,0.55mmol),并将由此产生的溶液在35℃下搅拌过夜。淬灭(饱和NH4Cl)反应物,萃取(2×EtOAc),并洗涤(盐水)。干燥(Na2SO4)合并的有机层并在减压下浓缩。通过硅胶色谱法(24g SiO2,35%的EtOAc/Hex)纯化残余物,得到本标题化合物,为浅黄色泡沫状物。
步骤E. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(噻吩-2-磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
在室温下向2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(噻吩-2-磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸甲酯(30mg,0.048mmol;实施例263,步骤D)在水(0.16mL)、MeOH(0.16mL)和THF(0.16mL)的混合物中的溶液中加入2M LiOH水溶液(48μL,0.095mmol),并将由此产生的溶液在室温下搅拌5h。淬灭(饱和NH4Cl)反应物,萃取(2×EtOAc),并洗涤(盐水)。干燥(Na2SO4)合并的有机层并在减压下浓缩。通过硅胶色谱法(12g SiO2,用50%至100%的在Hex中的EtOAc和30%的iPrOH/DCM梯度洗脱)纯化残余物,得到本标题化合物,为白色粉末。
1H NMR(400MHz,氯仿-d)δppm 7.50-7.66(2H,m),6.95-7.25(8H,m),6.81(1H,d,J=7.4Hz),5.66(1H,br,s),4.87(1H,d,J=10.0Hz),3.05-3.26(3H,m),2.87-3.02(2H,m),2.78-2.84(1H,m),2.18-2.32(1H,m),2.04-2.15(1H,m),1.47(3H,s),1.06-1.18(1H,m),0.41-0.57(2H,m),-0.02-0.10(1H,m),-0.35--0.20(1H,m);MS(ESI)621.0[M+H]+。
实施例264
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-甲基噻吩-2-磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
在室温下向2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(噻吩-2-磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸甲酯(31mg,0.049mmol;实施例263)在DMF(0.25mL)中的溶液中加入氢化钠(在矿物油中的60%分散体;6mg,0.15mmol),并将该溶液搅拌10min。然后加入碘甲烷(28mg,0.20mmol),并将由此产生的溶液在室温下搅拌5h。淬灭(饱和NH4Cl)反应物,萃取(2×EtOAc),并洗涤(盐水)。干燥(Na2SO4)合并的有机层并在减压下浓缩,得到本标题化合物和甲酯的混合物。
在室温下向该粗混合物在水(0.16mL)、MeOH(0.16mL)和THF(0.16mL)中的溶液中加入氢氧化锂(2.4mg,0.098mmol),并将由此产生的溶液在室温下搅拌过夜。淬灭(饱和NH4Cl)反应物,萃取(2×EtOAc)并洗涤(盐水)。干燥(Na2SO4)合并的有机层并在减压下浓缩。通过硅胶色谱法(4g SiO2,50%和90%的EtOAc/Hex)纯化残余物,得到本标题化合物,为白色粉末。
1H NMR(400MHz,CDCl3)δppm 7.50-7.68(2H,m),7.23-7.27(2H,m),7.12-7.22(4H,m),6.88-7.02(3H,m),4.86(1H,d,J=10.0Hz),2.98-3.24(2H,m),2.70-2.96(3H,m),2.80(3H,s),2.35-2.50(2H,m),1.96-2.04(1H,m),1.54(3H,br,s),1.29-1.39(1H,m),0.15-0.50(2H,m),-0.41--0.15(1H,m),-0.95--0.65(1H,m);MS(ESI)635.0[M+H]+。
实施例265
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-(5-氯噻吩-2-磺酰氨基)-1-环丙基乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
按照与实施例263步骤D和E中描述的程序类似的程序,用适量的5-氯噻吩-2-磺酰胺替代步骤D中的噻吩-2-磺酰胺,从2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-羟基乙基)-3-甲基-2-氧代哌啶-3-基)乙酸甲酯(实施例263,步骤C)制备本标题化合物。
1H NMR(400MHz,CDCl3)δppm 7.35(1H,d,J=4.1Hz),6.97-7.25(7H,m),6.94(1H,d,J=4.1Hz),6.78(1H,d,J=7.4Hz),5.82(1H,br,s),4.86(1H,d,J=10.0Hz),2.87-3.20(5H,m),2.78-2.85(1H,m),2.19-2.27(1H,m),2.07-2.16(1H,m),1.46(3H,s),1.01-1.13(1H,m),0.50-0.60(2H,m),0.06-0.17(1H,m),-0.25--0.10(1H,m);MS(ESI)655.0[M+H]+,652.9[M-H]-。
实施例266
2-((3R,5R,6S)-1-((S)-2-(5-氯代-N-甲基噻吩-2-磺酰氨基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸
按照与实施例264中描述的程序类似的程序,从2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-(5-氯噻吩-2-磺酰氨基)-1-环丙基乙基)-3-甲基-2-氧代哌啶-3-基)乙酸(实施例265)的甲酯前体制备本标题化合物。
1H NMR(400MHz,CDCl3)δppm 7.28-7.40(2H,m),6.83-7.18(8H,m),4.75-4.88(1H,m),3.00-3.21(2H,m),2.74-2.86(2H,m),2.81(3H,s),2.25-2.54(2H,m),1.95-2.05(1H,m),1.57-1.84(2H,m),1.53(3H,br,s),0.18-0.55(2H,m),-0.46--0.15(1H,m),-0.95--0.65(1H,m);MS(ESI)m/z=669.0[M+H]+,667.0[M-H]-。
实施例267
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-(二氟甲基)-2-甲基丙烷-2-基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-2-环丙基乙基)-2-甲基丙烷-2-磺酰胺
按照与实施例127步骤F中描述的程序类似并总共反应21h的程序,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-羟基乙基)-3-甲基哌啶-2-酮(300mg,0.654mmol;实施例252,步骤A)和2-甲基丙烷-2-磺酰胺(189mg,1.37mmol)获得本标题化合物。通过硅胶色谱法(40g SiO2,30%和50%的EtOAc/Hex)纯化残余物,得到本标题化合物,为浅黄色泡沫状物。
步骤B. N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-2-环丙基乙基)-N-(二氟甲基)-2-甲基丙烷-2-磺酰胺
向N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-2-环丙基乙基)-2-甲基丙烷-2-磺酰胺(88mg,0.152mmol;实施例267,步骤A)在DMF(1.0mL)中的溶液中加入在矿物油中的60%氢化钠(24mg,0.61mmol),并将由此产生的溶液在室温下搅拌10min。然后在剧烈搅拌反应物的同时向反应物中鼓入氯二氟甲烷10min,并将由此产生的反应物搅拌2h。淬灭(饱和NH4Cl)反应物,萃取(2×EtOAc)并洗涤(盐水)。干燥(Na2SO4)合并的有机层并在减压下浓缩。通过硅胶色谱法(12g SiO2,20%和30%的EtOAc/Hex)纯化残余物,得到本标题化合物,为无色膜状物。
步骤C. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-(二氟甲基)-2-甲基丙烷-2-基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
按照与实施例71步骤F中描述的程序类似的程序,从N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-2-环丙基乙基)-N-(二氟甲基)-2-甲基丙烷-2-磺酰胺(57mg,0.091mmol;实施例267,步骤B)制备本标题化合物。通过反相制备型HPLC(GeminiTMPrep C185μm柱,Phenomenex,Torrance,CA;用50%至75%的在水中的MeCN梯度洗脱,其中这两种溶剂都含有0.1%TFA)纯化残余物,得到本标题化合物,为白色泡沫状物。
1H NMR(400MHz,CDCl3)δppm 7.08-7.27(4H,m),6.93-7.00(2H,m),6.65-6.87(2H,m),5.50(1H,br,s),4.55-4.70(2H,m),3.55-3.68(1H,m),3.09-3.18(2H,m),2.79(1H,d,J=15.1Hz),2.35-2.69(2H,m),1.74-1.94(2H,m),1.53(3H,s),1.47(9H,s.),0.36-0.49(1H,m),0.23-0.35(1H,m),-0.34--0.15(1H,m),-0.87--0.71(1H,m);MS(ESI)m/z=645.0[M+H]+,643.0[M-H]-。
还按照与实施例267中描述的程序类似的程序,用适量的表中所列试剂替代步骤A中的2-甲基丙烷-2-磺酰胺,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-羟基乙基)-3-甲基哌啶-2-酮(实施例252,步骤A)制备了实施例268和269。
实施例268
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-(二氟甲基)乙基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(500MHz,氯仿-d)δppm-0.78(br.s.,1H)-0.22(br.s.,1H)0.31(br.s.,1H)0.42(br.s.,1H)1.38-1.49(m,3H)1.52(s,3H)1.57-2.11(br.s.,2H)2.40-2.52(m.,2H)2.78(d,J=15.41Hz,1H)3.08-3.27(m,4H)3.42–4.02(br.s.,2H)4.57-4.74(m,2H)6.80(d,J=7.34Hz,1H)6.95(s,1H)7.08-7.18(m,2H)7.27(m.,4H);质谱(ESI)m/z=617(M+1)。
实施例269
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-(二氟甲基)环丙烷磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(500MHz,氯仿-d)δppm-0.79(br.s.,1H)-0.23(br.s.,1H)0.31(br.s.,1H)0.42(br.s.,1H)1.12-1.36(m,3H)1.51(s,3H)1.59-1.95(m,5H)2.44(br.s.,2H)2.77(d,J=15.41Hz,1H)3.04-3.26(m,2H)3.53(m,1H)4.48-4.70(m,2H)6.79(d,J=7.34Hz,1H)6.93(s,1H)7.07-7.18(m,2H)7.27(m.,4H);质谱(ESI)m/z=629(M+1)。
实施例270
1-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-(环丙烷磺酰氨基)-1-环丙基乙基)-3-甲基-2-氧代哌啶-3-基)环丙烷羧酸
步骤A. (S)-2-((3R,5R,6S)-1-((S)-2-((叔丁基二苯基甲硅烷基)氧基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)-3-羟基丙酸甲酯
在-15℃下向二异丙基胺(249μL,1.75mmol)在THF(1.2mL)中的溶液中缓慢地加入在己烷中的1.6M n-BuLi(984μL,1.57mmol)。在30分钟后,将2-((3R,5R,6S)-1-((S)-2-(叔丁基二苯基甲硅烷基氧基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸甲酯(255mg,0.35mmol;实施例263,步骤B)在THF(1.2mL)中的溶液逐滴加入到该LDA溶液中,并将由此产生的溶液在-15℃下搅拌30min(该溶液变成亮黄色)。然后,在-15℃下在反应表面上运送N2气流中的甲醛5min(通过用加热枪使多聚甲醛(105mg,3.50mmol)断裂来生成甲醛)。在-15℃下搅拌30min后,让反应物温度升至室温并搅拌4h。淬灭(冰冷的饱和NH4Cl)反应物,萃取(2×EtOAc)并洗涤(盐水×3)。干燥(Na2SO4)合并的有机层并在减压下浓缩。通过硅胶色谱法(24g SiO2,20%和50%的EtOAc/Hex)纯化残余物,得到本标题化合物,为无色膜状物。
步骤B. 2-((3R,5R,6S)-1-((S)-2-((叔丁基二苯基甲硅烷基)氧基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)丙烯酸甲酯
在0℃下向(S)-2-((3R,5R,6S)-1-((S)-2-(叔丁基二苯基甲硅烷基氧基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)-3-羟基丙酸甲酯(132mg,0.173mmol;实施例270,步骤A)和三乙胺(97μL,0.69mmol)在DCM(2.2mL)中的溶液中加入甲烷磺酰氯(27μL,0.35mmol)在DCM(2.2mL)中的溶液。然后让反应物温度升至室温并搅拌3h。淬灭(水)反应物,萃取(2×EtOAc)并洗涤(盐水)。干燥(Na2SO4)合并的有机层,并在减压下浓缩从而得到粗的甲磺酰化化合物,(S)-2-((3R,5R,6S)-1-((S)-2-(叔丁基二苯基甲硅烷基氧基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)-3-(甲基磺酰基氧基)丙酸甲酯。
向上面的粗甲磺酰化化合物在DCM(2.2mL)中的溶液中加入DBU(78μL,0.52mmol),并将由此产生的溶液在室温下搅拌1h。淬灭(冰冷的饱和NH4Cl)反应物,萃取(2×EtOAc)并洗涤(盐水)。干燥(Na2SO4)合并的有机层并在减压下浓缩。通过硅胶色谱法(12g SiO2,10%和20%的EtOAc/Hex)纯化残余物,得到本标题化合物,为无色膜状物。
步骤C. 1-((3R,5R,6S)-1-((S)-2-((叔丁基二苯基甲硅烷基)氧基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)环丙烷羧酸甲酯
向三甲基碘化亚砜(39mg,0.18mmol)在DMSO(0.71mL)中的悬浮液中加入60%氢化钠在矿物油中的悬浮液(7.1mg,0.18mmol)。在搅拌15min后,加入2-((3R,5R,6S)-1-((S)-2-(叔丁基二苯基甲硅烷基氧基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)丙烯酸甲酯(66mg,0.089mmol;实施例270,步骤B)在DMSO(0.71mL)中的溶液,并将该混合物在室温下搅拌3h。淬灭(冰冷的饱和NH4Cl)反应物,萃取(2×EtOAc),并洗涤(盐水×3)。干燥(Na2SO4)合并的有机层并在减压下浓缩。通过硅胶色谱法(4g SiO2,10%和20%的EtOAc/Hex)纯化残余物,得到本标题化合物,为无色膜状物。
步骤D. 1-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-羟基乙基)-3-甲基-2-氧代哌啶-3-基)环丙烷羧酸甲酯
向1-((3R,5R,6S)-1-((S)-2-(叔丁基二苯基甲硅烷基氧基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)环丙烷羧酸甲酯(53mg,0.070mmol;实施例270,步骤C)在THF(0.70mL)中溶液中加入在THF中的1M TBAF(0.21mL,0.21mmol),并将反应物在室温下搅拌过夜。淬灭(饱和NH4Cl)反应物,萃取(2×EtOAc),并洗涤(盐水)。干燥(Na2SO4)合并的有机层并在减压下浓缩。通过硅胶色谱法(4g SiO2,10%、45%和55%的EtOAc/Hex)纯化残余物,得到本标题化合物,为白色泡沫状物。
步骤E. 1-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-(环丙烷磺酰氨基)-1-环丙基乙基)-3-甲基-2-氧代哌啶-3-基)环丙烷羧酸甲酯
按照与实施例202步骤C中描述的程序类似的程序,从1-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-羟基乙基)-3-甲基-2-氧代哌啶-3-基)环丙烷羧酸甲酯(35mg,0.068mmol;实施例270,步骤D)和环丙烷磺酰胺(25mg,0.20mmol)制备本标题化合物。通过硅胶色谱法(4g SiO2,45%和60%的EtOAc/Hex)纯化残余物,得到本标题化合物,为浅黄色。
步骤F. 1-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-(环丙烷磺酰氨基)-1-环丙基乙基)-3-甲基-2-氧代哌啶-3-基)环丙烷羧酸
按照与实施例263步骤E中描述的程序类似的程序,从1-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-(环丙烷磺酰氨基)-1-环丙基乙基)-3-甲基-2-氧代哌啶-3-基)环丙烷羧酸甲酯(27mg,0.043mmol;实施例270,步骤E)制备本标题化合物。通过反相制备型HPLC(GeminiTMPrep C185μm柱,Phenomenex,Torrance,CA;用45%至70%的在水中的MeCN梯度洗脱,其中这两种溶剂都含有0.1%TFA)纯化残余物,得到本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 7.03-7.26(6H,m),6.92-6.96(1H,m),6.79(1H,d,J=7.0Hz),4.79(1H,d,J=10.6Hz),3.37-3.48(1H,m),3.12-3.20(1H,m),2.78(1H,dd,J=14.0,2.2Hz),2.37-2.45(1H,m),2.15-2.25(1H,m),1.80-1.88(1H,m),1.38-1.50(2H,m),1.45(3H,s),1.10-1.31(7H,m),0.93-1.01(2H,m),0.35-0.54(2H,m),-0.09-0.12(1H,m),-0.72--0.23(1H,m);MS(ESI)m/z=605.0[M+H]+,603.1[M-H]-。
实施例271(中间体)
A:N-(2-氟苯基)乙烷磺酰胺
在室温下向乙烷磺酰氯(0.368ml,3.89mmol)在DCM(1ml)和吡啶(1ml)中的溶液中加入2-氟苯胺(0.360ml,3.89mmol),并将反应物在50℃下搅拌5小时。然后将反应物在室温下搅拌过夜。用EtOAc稀释反应物,并用H2O和NaCl饱和溶液洗涤。经Na2SO4干燥有机层并浓缩。通过硅胶快速色谱法(洗脱剂:0%至35%的EtOAc/己烷)纯化残余物,得到本标题化合物,为白色固体。
1H NMR(400MHz,氯仿-d)δppm 1.42(t,J=8Hz,3H),3.15(q,J=8Hz,2H),6.48(s,br,1H),7.17(m,3H),7.64(m,1H)。
以类似方式制备下列物质:
B:N-(苯基)乙烷磺酰胺:1H NMR(400MHz,氯仿-d)δppm 1.38(t,J=8Hz,3H),3.14-3.20(q,J=8Hz,2H),7.15-7.17(m,1H),7.29-7.36(m,4H)。
C:N-(3-氟苯基)乙烷磺酰胺:1H NMR(400MHz,氯仿-d)δppm1.42(t,J=8Hz,3H),3.17-3.23(q,J=8Hz,2H),6.78(s,br,1H),6.89(m,1H),6.99(m,1H),7.04(m,1H),7.77(m,1H)。
D:N-(吡啶-3-基)甲烷磺酰胺:1H NMR(400MHz,甲醇-d4)δppm3.05(s,3H),7.43-7.46(dd,J=4,8Hz,1H),7.78-7.81(dd,J=2,4Hz,1H),8.33(d,J=4Hz,1H),8.45(s,1H)。质谱(ESI)m/z=173.2(M+1)。
E:N-(苯基)环丙烷磺酰胺:1H NMR(400MHz,氯仿-d)δppm0.96-1.00(m,2H),1.18-1.22(m,2H),2.48-2.55(m,1H),7.20-7.22(m,1H),7.28-7.30(m,2H),7.37-7.39(m,2H)。
F:丙烷-1-磺酰胺[CAS no.24243-71-8]
向冰浴上的丙烷-1-磺酰氯(7.3g,51.2mmol)在无水THF(100ml)中的溶液中鼓入无水氨流。持续鼓入1小时,在此期间有许多白色固体沉淀析出。然后将反应物在室温下搅拌2天。用EtOAc稀释反应混合物,用H2O和饱和NaCl洗涤,经Na2SO4干燥,然后浓缩。使用硅胶快速色谱法(0%至35%的EtOAc/己烷洗脱)纯化粗产物,得到本标题化合物,为白色固体(3.0g,47.6%)。
1H NMR(400MHz,氯仿-d)δppm-1.10(t,J=8Hz,3H),1.91(m,2H),3.11(m,2H),4.94(s,2H)。
G:环丁烷磺酰胺[CAS no.445305-91-9]
向在0℃下的搅拌着的环丁烷磺酰氯(5g,32.3mmol;Hande Sciences)在干THF(100mL)中的溶液中鼓入无水氨流30min,导致形成白色沉淀。将该悬浮液温度升至室温并搅拌过夜。过滤该混合物,并用乙酸乙酯充分洗涤滤饼。在减压下浓缩滤液,将其再溶解于约150mLEtOAc中,并用盐水洗涤3次。经硫酸钠干燥有机物,过滤,并在真空中浓缩从而得到白色的部分结晶的残余物,用己烷研磨该残余物并在高真空下干燥从而得到环丁烷磺酰胺,为蓬松的白色固体,1.8g(41%产率)。
1H NMR(400MHz,氯仿-d)δ1.96-2.10(m,2H),2.30-2.43(m,2H),2.43-2.59(m,2H),3.72-4.01(m,1H),4.70(br.s.,2H)。
实施例272
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-(2-氟苯基)乙基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-2-环丙基乙基)-N-(2-氟苯基)乙烷磺酰胺
在室温下向(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-羟基乙基)-3-甲基哌啶-2-酮(实施例252,步骤A,70mg,0.153mmol)和N-(2-氟苯基)乙烷磺酰胺(93mg,0.458mmol)在甲苯(1ml)中的混合物中加入氰基亚甲基三正丁基正膦(0.111ml,0.458mmol),并将该混合物用N2吹扫约20分钟。密封反应物并将其加热至70℃过夜。通过硅胶快速色谱法(洗脱剂:0%至35%的EtOAc/己烷)纯化反应混合物从而得到本标题化合物,为固体。
1H NMR(400MHz,甲醇-d4)ppm-1.25(s,br,1H),-0.64(s,br,1H),0.00(s,br,1H),0.16(s,br,1H),0.73(m,1H),0.92(s,3H),1.19(m,4H),1.48(m,1H),1.66(m,1H),2.00(m,2H),2.24(m,1H),2.52(m,1H),2.97(m,2H),3.71(s,br,1H),4.56(d,J=12Hz,1H),5.01(m,1H),5.05(s,1H),5.73(m,1H),6.83-6.91(m,3H),7.03-7.16(m,7H),7.28(m,1H),7.45(m,1H)。
质谱(ESI)m/z=643.2(M+1)
步骤B:2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-(2-氟苯基)乙基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
向N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-2-环丙基乙基)-N-(2-氟苯基)乙烷磺酰胺(实施例272,步骤A,72mg,0.112mmol)在THF(0.600ml)、水(0.396ml)和BuOH(0.3ml)中的溶液中加入4-甲基吗啉4-氧化物(45.9mg,0.392mmol),接着加入氧化锇(VIII)(0.037ml,2.80μmol)。将反应物在室温下搅拌过夜。加入高碘酸钠(71.8mg,0.336mmol)并将反应物在室温下搅拌2小时。向该反应物中加入1.25M KH2PO4(0.80ml)、在THF中的1M 2-甲基丁-2-烯溶液(2.24ml,4.47mmol)和亚氯酸钠(50.6mg,0.56mmol),并将反应物在室温下搅拌2小时。在反应结束后,加入0.8ml1M NaS2O3水溶液,并将反应物在室温下搅拌10分钟,接着加入0.8ml 1M KHSO4水溶液。
然后用EtOAc稀释反应物,并用H2O和饱和NaCl洗涤。经Na2SO4干燥有机层并浓缩。通过反相制备型HPLC(洗脱剂:40-85%的含有0.1%TFA的在水中的乙腈,在GeminiTMPrepC185um柱上梯度洗脱,Phenomenex,Torrance,CA)纯化产物从而得到本标题化合物,为白色固体。
1H NMR(400MHz,甲醇-d4)ppm-1.28(s,br,1H),-0.63(s,br,1H),0.00(s,br,1H),0.17(s,br,1H),1.07(s,3H),1.20(t,J=4Hz,3H),1.51-1.55(m,1H),1.91-1.95(dd,J=4Hz,16Hz,1H),2.05(s,br,1H),2.11(t,J=12Hz,1H),2.49-2.53(d,J=16Hz,1H),2.79-2.83(d,J=16Hz,1H),2.98(s,br,2H),3.27(m,1H),3.71(s,br,1H),4.62(s,br,2H),6.87(d,J=8Hz,2H),6.92(s,1H),7.03-7.18(m,7H),7.29(m,1H),7.49(s,br,1H)。
质谱(ESI)m/z=661.2(M+1)
以类似于实施例272的方式制备实施例273-289。使用相应的磺酰胺和实施例252步骤A的醇,在步骤A中形成烯丙基磺酰胺并在步骤B中将其转化为相应的羧酸。
实施例273
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-(2-氟苯基)甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A:N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-2-环丙基乙基)-N-(2-氟苯基)甲烷磺酰胺
1H NMR(400MHz,甲醇-d4)δppm-1.20(s,br,1H),-0.63(s,br,1H),0.00(s,br,1H),0.13(s,br,1H),0.88(s,3H),1.48(m,1H),1.64(d,J=12Hz,1H),1.94-1.99(s,2H),2.19(d,J=8Hz,2H),2.72(s,3H),2.99(m,1H),3.54(s,br,1H),4.50(d,J=8Hz,1H),4.59(s,br,1H),4.96-5.01(m,2H),5.65(m,1H),6.70(s,br,2H),6.80(s,br,2H),6.96-7.08(m,6H),7.19(m,1H),7.27(m,1H)。
质谱(ESI)m/z=629.2(M+1)。
步骤B:2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-(2-氟苯基)甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,甲醇-d4)δppm-1.27(s,br,1H),-0.58(s,br,1H),0.00(s,br,1H),0.18(s,br,1H),1.03(s,3H),1.07-1.04(m,1H),1.50(m,1H),1.90-1.94(dd,J=4,12Hz,1H),2.08(t,J=16Hz,1H),2.47(d,J=16Hz,1H),2.78(d,J=16Hz,1H),2.81(s,3H),3.26(m,1H),3.67(s,br,1H),4.57(d,J=12Hz,1H),6.84(d,J=8Hz,2H),6.90(s,1H),7.03(m,4H),7.16(m,2H),7.29(m,1H),7.31(m,1H)。
质谱(ESI)m/z=647.0(M+1)。
实施例274
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-苯基环丙烷磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A:N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-2-环丙基乙基)-N-苯基环丙烷磺酰胺
1H NMR(400MHz,甲醇-d4)δppm-1.24(s,br,1H),-0.56(s,br,1H),0.00(s,br,1H)0.20(s,br,1H),0.69-0.78(m,4H),0.92(s,br,3H),1.55(s,br,1H),1.62-1.66(dd,J=4,12Hz,1H),1.93-2.00(m,2H),2.36-2.45(m,2H),2.51-2.57(m,1H),3.12-3.19(m,1H),3.81(s,br,1H),4.42-4.45(d,br,J=12Hz,1H),4.76(s,br,1H),5.00-5.05(t,J=8Hz,1H),5.09(s,1H),5.70-5.79(m,1H),6.79(m,2H),6.92(s,1H),7.04(m,4H),7.18-7.30(m,2H),7.72(m,2H),7.44(d,J=8Hz)。
质谱(ESI)m/z=637.2(M+1)。
步骤B:2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-苯基环丙烷磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,甲醇-d4)δppm-1.28(s,br,1H),-0.54(s,br,1H),0.00(s,br,1H),0.20(s,br,1H),0.70-0.78(m,5H),1.06(s,3H),1.53(s,br,1H),1.91-2.07(m,3H),2.37(s,br,1H),2.48(d,J=12Hz,1H),2.78(d,J=12Hz,1H),3.24(m,1H),3.80(s,br,1H),4.43(d,J=12Hz,1H),6.82(d,J=8Hz,2H),6.92(s,1H),7.05(m,4H),7.22(t,J=8Hz,2H),7.33(t,J=8Hz,2H),7.44(d,J=8Hz,2H)。
质谱(ESI)m/z=655.2(M+1)。
实施例275
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-苯基乙基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A:N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-2-环丙基乙基)-N-苯基乙烷磺酰胺
1H NMR(400MHz,甲醇-d4)δppm-1.23(s,br,1H),-0.56(s,br,1H),0.00(s,br,1H),0.19(s,br,1H),0.92(s,3H),1.13(t,J=8Hz,3H),1.55(s,br,2H),1.63(dd,J=4,8Hz,1H),1.96(m,2H),2.45(m,1H),2.53(m,1H),2.90(m,2H),3.17(m,1H),3.79(s,br,1H),4.42(d,J=12Hz,1H),4.81(s,br,1H),5.00(m,1H),5.09(s,1H),5.72(m,1H),6.79(m,2H),6.94(s,1H),7.02(m,4H),7.19(m,2H),7.32(t,J=8Hz,2H),7.47(d,J=8Hz,2H)。
质谱(ESI)m/z=625.2(M+1)。
步骤B:2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-苯基乙基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,甲醇-d4)δppm-1.26(s,br,1H),-0.55(s,br,1H),0.19(s,br,1H),1.06(s,3H),1.13(t,J=8Hz,3H),1.51(s,br,1H),1.88(dd,J=4,8Hz,1H),2.00(s,br,1H),2.03(t,J=12Hz,1H),2.48(d,J=12Hz,1H),2.78(d,J=12Hz,1H),2.90(m,2H),3.23(m,1H),3.77(d,J=12Hz,1H),4.46(d,J=8Hz,1H),4.76(s,br,1H),
质谱(ESI)m/z=643.2(M+1)。
实施例276
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(乙基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A:N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-2-环丙基乙基)乙烷磺酰胺
1H NMR(400MHz,甲醇-d4)δppm-1.06(s,br,1H),-0.98(m,1H),-0.02(m,1H),0.14(m,1H),1.08(s,3H),1.14(t,J=4Hz,3H),1.39(m,1H),1.59(dd,J=4,12Hz,1H),2.05(m,1H),2.10(t,J=16Hz,1H),2.42(m,1H),2.50(m,1H),2.89(m,3H),3.12(m,1H),3.74(m,1H),4.68(d,J=12Hz,1H),4.96-5.06(m,2H),5.71(m,1H),6.79(m,2H),6.87(s,1H),6.93(m,3H),7.06(m,2H)。
质谱(ESI)m/z=549.0(M+1)。
步骤B:2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(乙基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,甲醇-d4)δppm-1.06(s,br,1H),-0.47(m,1H),-0.02(m,1H),0.14(m,1H),1.13(t,J=8Hz,3H),1.22(s,3H),1.06(s,br,1H),1.89(dd,J=4,12Hz,1H),2.08(s,1H),2.15(t,J=16Hz,1H),2.46(d,J=12Hz,1H),2.80(d,J=12Hz,1H),3.07(m,3H),3.19(m,1H),3.65(m,1H),4.69(d,J=8Hz,1H),6.81(m,2H),6.92(s,1H),6.87(m,3H),7.05(s,br,2H)。
质谱(ESI)m/z=567.0(M+1)。
实施例277
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-(3-氟苯基)乙基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A:N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-2-环丙基乙基)-N-(3-氟苯基)乙烷磺酰胺
1H NMR(400MHz,甲醇-d4)δppm-1.20(s,br,1H),-0.56(s,br,1H),0.00(s,br,1H),0.19(s,br,1H),0.89(s,3H),1.08(m,3H),1.53(s,br,1H),1.62(dd,J=4,12Hz,1H),1.90(t,J=12Hz,1H),1.95(m,1H),2.38(m,1H),2.52(m,1H),2.86-2.96(m,2H),3.11-3.17(m,1H),3.76(d,J=12Hz,1H),4.77(s,br,1H),5.00(t,J=8Hz,1H),5.06(s,1H),5.72(m,1H),6.77(m,2H),6.89(m,3H),7.00(m,4H),7.28(m,3H)。
质谱(ESI)m/z=643.2(M+1)。
步骤B:2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-(3-氟苯基)乙基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,甲醇-d4)δppm-1.06(s,br,1H),-0.39(s,br,1H),0.16(1H),0.35(s,br,1H),1.21(s,br,3H),1.28(t,J=4Hz,3H),1.67(s,br,1H),2.04-2.18(m,3H),2.63(d,J=12Hz,1H),2.93(d,J=12Hz,1H),3.09(s,br,2H),3.39(m,1H),3.92(m,1H),3.92(s,br,1H),4.56(s,br,1H),6.96(m,2H),7.06(m,3H),7.17(m,4H),7.45(m,3H)。
质谱(ESI)m/z=661.2(M+1)
实施例278
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-(N-(2-氰基苯基)甲基磺酰氨基)-1-环丙基乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A:N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-2-环丙基乙基)-N-(2-氰基苯基)甲烷磺酰胺
1H NMR(400MHz,甲醇-d4)δppm-1.22(s,br,1H),-0.47(s,br,1H),0.00(s,br,1H),0.19(s,br,1H),0.91(s,br,1H),1.45(m,1H),1.67(d,J=12Hz,1H),1.97(m,1H),2.10(s,br,1H),2.42(m,1H),2.52(m,1H),2.87(s,3H),3.15-3.18(m,2H),3.91(s,br,1H),4.47(s,br,1H),4.99(m,1H),5.07(s,1H),5.71(m,1H),6.79(s,br,2H),6.89(s,1H),6.96(s,br,3H),7.05(s,br,2H),7.40(m,1H),7.62(m,2H),7.72(s,br,1H)。
质谱(ESI)m/z=636.2(M+1)。
步骤B:2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-(N-(2-氰基苯基)甲基磺酰氨基)-1-环丙基乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,甲醇-d4)δppm-1.12(s,br,1H),-0.31(s,br,1H),0.15(s,br,1H),0.35(s,br,1H),1.20(s,3H),1.29(m,1H),1.62(s,br,1H),2.06(d,1H),2.24(t,J=12Hz,1H),2.27(s,br,1H),2.60(d,J=12Hz,1H),2.93(d,J=12Hz,1H),3.02(s,3H),3.41(m,1H),4.01(s,br,1H),4.68(s,br,1H),6.98(d,J=8Hz,2H),7.06(s,1H),7.12(m,3H),7.21(s,br,2H),7.57(m,1H),7.79(m,2H),7.88(s,br,1H)。
质谱(ESI)m/z=654.0(M+1)。
实施例279
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(丙基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A:N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-2-环丙基乙基)丙烷-1-磺酰胺
粗产物直接用于步骤B中。
质谱(ESI)m/z=563.2(M+1)。
步骤B:2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(丙基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,甲醇-d4)δppm-0.85(s,br,1H),-0.25(s,br,1H),0.22(s,br,1H),0.35(m,1H),1.08(t,J=4Hz,3H),1.43(s,3H),1.55(s,br,1H),1.84(m,2H),2.10(dd,J=4,8Hz,1H),2.30(s,br,1H),2.36(t,J=12Hz,1H),2.67(d,J=16Hz,1H),2.98(d,J=16Hz,1H),3.05(m,3H),3.41(m,1H),3.88(m,1H),4.92(d,J=8Hz,1H),7.02(m,2H),7.08(s,1H),7.14(m,3H),7.26(s,br,2H)。
质谱(ESI)m/z=581.2(M+1)。
实施例280
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-苯基甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A:N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-2-环丙基乙基)-N-苯基甲烷磺酰胺
质谱(ESI)m/z=611.2(M+1)。
步骤B:2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-苯基甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,甲醇-d4)δppm-1.26(s,br,1H),-0.51(s,br,1H),0.00(s,br,1H),0.20(s,br,1H),1.03(s,3H),1.54(s,br,1H),1.80-2.04(m,3H),2.47(d,J=16Hz,1H),2.73(s,3H),2.78(d,J=16Hz,1H),3.18(m,1H),3.75(s,br,1H),4.42(s,J=12Hz,1H),6.81(m,2H),6.91(s,1H),7.04(m,4H),7.24(m,2H),7.35(m,2H),7.43(m,2H)。
质谱(ESI)m/z=629.0(M+1)。
实施例281
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-(N-(3-氰基苯基)甲基磺酰氨基)-1-环丙基乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A:N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-2-环丙基乙基)-N-(3-氰基苯基)甲烷磺酰胺
1H NMR(400MHz,氯仿-d1)δppm-1.17(s,br,1H),-0.59(s,br,1H),0.00(s,br,1H),0.12(s,br,1H),0.74(s,3H),1.36(m,1H),1.44-1.60(m,2H),1.68(t,J=12Hz,1H),2.36(d,J=8Hz,2H),2.60(s,3H),2.95(m,1H),4.33(s,br,1H),4.70(s,br,1H),4.92(s,1H),4.95(d,J=4Hz,1H),5.58(m,1H),6.62(s,br,2H),6.69(s,br,2H),6.95(m,4H),7.33-7.40(m,2H),7.50(s,1H),7.54(s,1H)。
质谱(ESI)m/z=636.2(M+1)。
步骤B:2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-(N-(3-氰基苯基)甲基磺酰氨基)-1-环丙基乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,甲醇-d4)δppm-1.21(s,br,1H),-0.55(s,br,1H),0.00(s,br,1H),0.18(s,br,1H),0.95(s,3H),1.45(s,br,1H),1.89(d,J=8Hz,2H),1.99(s,br,1H),2.42(d,J=12Hz,1H),2.72(s,3H),2.75(d,J=12Hz,1H),3.19(m,1H),3.73(s,br,1H),4.37(s,br,1H),6.80(s,3H),6.96-7.05(m,5H),7.45-7.49(m,1H),7.52(d,J=8Hz,1H),7.70(s,br,1H),7.77(s,br,1H)。
质谱(ESI)m/z=654.1(M+1)。
实施例282
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-(吡啶-3-基)甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A:N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-2-环丙基乙基)-N-(吡啶-3-基)甲烷磺酰胺
1H NMR(400MHz,甲醇-d4)δppm-1.18(s,br,1H),-0.57(s,br,1H),0.00(s,br,1H),0.17(s,br,1H),0.78(s,3H),1.45(s,br,1H),1.60(m,1H),1.86(m,1H),2.00(s,br,1H),2.38(m,1H),2.47(m,1H),2.74(s,3H),3.14(m,2H),3.76(s,br,1H),4.41(s,br,1H),4.95-5.00(m,2H),5.67(m,1H),6.78-6.82(m,3H),6.97-7.04(m,5H),7.36(m,1H),7.84(s,br,1H),8.31(m,11H),8.60(s,br,1H)。
质谱(ESI)m/z=612.2(M+1)。
步骤B:2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-(吡啶-3-基)甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,甲醇-d4)δppm-1.19(s,br,1H),-0.55(s,br,1H),0.00(s,br,1H),0.16(s,br,1H),0.95(m,4H),1.34(s,br,1H),1.90(m,2H),2.42(d,J=12Hz,1H),2.72(s,J=12Hz,1H),2.75(s,3H),3.20(s,br,1H),3.38(s,br,1H),4.43(s,br,2H),6.83(m,3H),6.98(m,5H),7.52(s,br,1H),8.04(s,br,1H),8.39(s 1H),.68(s,1H)。
质谱(ESI)m/z=630.1(M+1)。
实施例283
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-(噻吩-2-基甲基)甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A:N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-2-环丙基乙基)-N-(噻吩-2-基甲基)甲烷磺酰胺
1H NMR(400MHz,甲醇-d4)δppm(代表信号)5.30-5.35(m,1H),5.40(s,1H),6.06(m,1H)。质谱(ESI)m/z=631.2(M+1)。
步骤B:2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-(噻吩-2-基甲基)甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,甲醇-d4)δppm-1.12(s,br,1H),-0.59(s,br,1H),0.00(s,br,1H),0.14(s,br,1H),1.21(s,3H),1.49(s,br,1H),1.80(d,J=12Hz,1H),1.94(s,br,1H),2.19(t,J=12Hz,1H),2.47(d,J=12Hz,1H),2.58(s,3H),2.73(d,J=12Hz,1H),3.01(s,br,1H),3.14(m,1H),2.47(s,br,1H),4.53-4.47(m,3H),6.76(m,3H),6.85(s,2H),6.95-7.02(m,5H),7.11(d,J=4Hz,1H)。
质谱(ESI)m/z=649.0(M+1)。
实施例284
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-(3-甲氧基苄基)甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A:N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-2-环丙基乙基)-N-(3-甲氧基苄基)甲烷磺酰胺
1H NMR(400MHz,甲醇-d4)δppm-1.07(s,br,1H),-0.43(s,br,1H),0.13(s,br,1H),0.28(s,br,1H),1.25(s,3H),1.68(s,br,2H),1.90(s,br,1H),2.37(s,br,1H),2.62(m,2H),2.83(s,3H),3.19(m,2H),3.78(s,3H),4.21(s,2H),4.50(s,br,2H),5.14-5.22(m,2H),5.87(m,1H),6.82-6.93(m,3H),6.94(m,4H),7.17-7.27(m,5H)。
质谱(ESI)m/z=655.2(M+1)。
步骤B:2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-(3-甲氧基苄基)甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,甲醇-d4)δppm-1.23(s,br,1H),-0.55(s,br,1H),0.00(s,br,1H),0.16(s,br,1H),1.28(s,3H),1.81(m,2H),2.31(m,1H),2.54(d,J=12Hz,1H),2.77(m,4H),3.10(s,br,1H),3.16(m,1H),3.59(s,5H),3.98(s,br,1H),4.45(s,br,2H),6.73-6.78(m,3H),6.85(m,2H),6.94(s,1H),7.06(m,5H)。
质谱(ESI)m/z=673.0(M+1)。
实施例285
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(苯基甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A:N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-2-环丙基乙基)-1-苯基甲烷磺酰胺
1H NMR(400MHz,氯仿-d1)δppm-0.36(s,br,1H),0.00(s,br,1H),0.48(s,br,2H),1.28(s,br,1H),1.32(s,3H),2.00(m,1H),2.16(m,2H),2.72(m,2H),2.89(s,br,2H),3.23(m,1H),3.26(s,1H),4.84(d,J=12Hz,1H),5.11(s,br,1H),5.26(s,1H),5.29(d,J=4Hz,1H),5.93(m,1H),6.89(d,J8Hz,1H),7.05(s,1H),7.10(s,br,1H),7.22(m,2H),7.29(d,J=4Hz,2H),7.48(m,5H)。
质谱(ESI)m/z=611.2(M+1)。
步骤B:2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(苯基甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d1)δppm-0.92(s,br,1H),-0.35(s,br,1H),0.15(s,br,1H),0.29(m,1H),1.42(s,3H),1.48(s,1H),2.05(dd,J=4,12Hz,1H),2.20(s,1H),2.33(t,J=16Hz,1H),2.65(d,J=12Hz,1H),2.84(dd,J=4,12Hz,1H),2.96(d,J=12Hz,1H),3.38(m,1H),3.72(m,1H),4.37(s,2H),4.97(m,1H),7.01(d,J=4Hz,2H),7.06(s,1H),7.13(m,3H),7.24(s,br,2H),7.38-7.46(m,5H)。
质谱(ESI)m/z=629.2(M+1)。
实施例286
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(吡啶-2-基甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A:N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-2-环丙基乙基)-1-(吡啶-2-基)甲烷磺酰胺
1H NMR(400MHz,甲醇-d4)δppm-1.08(s,br,1H),-0.49(s,br,1H),0.02(s,br,1H),0.12(s,br,1H),1.09(s,3H),1.36(s,br,1H),1.63(dd,J=4,12Hz,1H),1.93(s,br,1H),2.08(t,J=12Hz,1H),2.43(m,1H),2.53(m,1H),2.83(m,1H),3.66(m,1H),4.36(s,2H),4.39(s,br,1H),4.64(m,1H),4.98-5.07(m,2H),5.72(m,1H),6.79(m,2H),6.87(s,1H),6.94(m,3H),7.10(s,br,2H),7.24(m,1H),7.42(d,J=8Hz,1H),7.70(m,1H),8.40(m,1H)。
质谱(ESI)m/z=612.2(M+1)。
步骤B:2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(吡啶-2-基甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,甲醇-d4)δppm-1.07(s,br,1H),-0.47(s,br,1H),0.00(s,br,1H),0.16(s,br,1H),1.20(s,3H),1.35(s,br,1H),1.87(dd,J=4,8Hz,1H),2.10(m,2H),2.45(d,J=12Hz,1H),2.75(d,J=12Hz,1H),2.84(m,1H),3.59(m,1H),4.43(s,2H),4.61(m,1H),6.76(m,2H),6.84(s,1H),6.91(m,3H),7.05(s,br,2H),7.45(m,1H),7.57(d,J=8Hz,1H),7.92(t,J=8Hz,1H),8.47(m,1H)。
质谱(ESI)m/z=630.1(M+1)。
实施例287
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(吡啶-3-基甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A:N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-2-环丙基乙基)-1-(吡啶-3-基)甲烷磺酰胺
1H NMR(400MHz,甲醇-d4)δppm-1.06(s,br,1H),-0.48(s,br,1H),0.02(s,br,1H),0.15(s,br,1H),1.08(s,3H),1.37(s,br,1H),1.61(dd,J=4,8Hz,1H),1.99(s,br,1H),2.08(t,J=16Hz,1H),2.43(m,1H),2.50(m,1H),2.78(m,1H),3.14(m,1H),3.69(s,br,1H),4.26(s,2H),4.63(m,1H),4.97-5.05(m,2H),5.71(m,1H),6.78(m,2H),6.86(s,1H),6.93(m,3H),7.10(s,br,2H),7.28(m,1H),7.75(m,1H),8.36(m,1H),8.41(s,1H)。
质谱(ESI)m/z=612.2(M+1)。
步骤B:2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(吡啶-3-基甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,甲醇-d4)δppm-0.59(s,br,1H),0.00(s,br,1H),0.47(s,br,1H),0.61(s,br,1H),1.65(s,3H),1.81(s,br,1H),2.33(m,1H),2.55(m,2H),2.91(d,J=12Hz,1H),3.21(d,J=12Hz,1H),3.32(m,1H),4.13(s,br,1H),4.86(s,2H),5.07(m,1H),7.21(m,2H),7.30(s,1H),7.36(m,3H),7.49(s,2H),8.15(m,1H),8.69(m,1H),9.02(m,1H),9.10(s,1H)。
质谱(ESI)m/z=630.1(M+1)。
实施例288
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-(吡啶-2-基)甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A:N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-2-环丙基乙基)-N-(吡啶-2-基)甲烷磺酰胺
1H NMR(400MHz,甲醇-d4)δppm-0.75(s,br,1H),0.00(s,br,1H),0.45(s,br,1H),0.60(s,br,1H),1.52(s,3H),1.94-2.03(m,3H),2.83-2.95(m,2H),3.08(s,3H),3.12(s,br,1H),3.48(m,1H),3.87(s,br,1H),4.78(s,br,1H),4.94(s,br,1H),5.39-5.50(m,2H),6.11(m,1H),6.83(s,br,1H),6.94(s,br,1H),7.14(m,1H),7.32(m,3H),7.39(s,br,1H),7.50(s,br,2H),7.85(m,1H),7.99(m,1H),8.14(s,br,1H)。
质谱(ESI)m/z=612.2(M+1)。
步骤B:2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-(吡啶-2-基)甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,甲醇-d4)δppm-0.75(s,br,1H),0.00(s,br,1H),0.47(s,br,1H),0.60(s,br,1H),1.68(s,3H),2.02(s,br,2H),2.30(m,1H),2.94(d,J=12Hz,1H),3.11(s,3H),3.19(d,J=12Hz,1H),3.19(s,br,1H),3.62(m,1H),3.99(s,br,1H),4.79(s,br,1H),4.93(s,br,1H),6.92(s,br,2H),7.00(s,br,1H),7.15(s,br,1H),7.35(m,2H),7.51(s,br,3H),7.87(s,br,1H),8.03(d,J=4Hz,1H),8.15(s,br,1H)。
质谱(ESI)m/z=630.1(M+1)。
实施例289
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A:N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-2-环丙基乙基)甲烷磺酰胺
1H NMR(400MHz,甲醇-d4)δppm-0.87(s,br,1H),-0.24(m,1H),0.22(m,1H),0.38(m,1H),0.90(m,1H),1.28(s,3H),1.58(m,2H),1.84(dd,J=4,12Hz,1H),2.13(m,1H),2.27(t,J=16Hz,1H),2.63(dd,J=8,16Hz,1H),2.70(dd,J=8,16Hz,1H),2.97(s,3H),3.13(m,1H),3.90(m,1H),2.42(s,br,1H),5.17-5.27(m,2H),5.92(m,1H),6.98(m,2H),7.06(s,1H),7.14(m,3H),7.27(m,2H)。
质谱(ESI)m/z=535.2(M+1)。
步骤B:2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,甲醇-d4)δppm-1.07(s,br,1H),-0.45(s,br,1H),0.01(s,br,1H),0.13(m,br,1H),1.21(s,3H),1.33(s,br,1H),1.89(dd,J=4,12Hz,1H),2.11(t,J=12Hz,1H),2.15(s,br,1H),2.45(d,J=16Hz,1H),2.75(s,3H),2.76(d,J=16Hz,1H),2.89(m,1H),3.18(m,1H),3.62(m,1H),4.67(d,1H),6.79(m,2H),6.85(s,1H),6.93(m,3H),7.04(s,br,2H)。
质谱(ESI)m/z=553.2(M+1)。
实施例290
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-乙基甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A:N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-2-环丙基乙基)-N-乙基甲烷磺酰胺
在室温下向N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-2-环丙基乙基)甲烷磺酰胺(实施例289,步骤A,86mg,0.161mmol)在DMF(1.5ml)中的溶液中加入氢化钠(16.06mg,0.401mmol),并将反应物在室温下搅拌30分钟。向该反应物中加入碘乙烷(0.058mL,0.723mmol),并将反应物在室温下搅拌2小时。用EtOAc稀释反应物,用水和饱和NaCl洗涤,经Na2SO4干燥,然后浓缩。将粗产物用于下一步反应。
质谱(ESI)m/z=563.2(M+1)。
步骤B:2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-乙基甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
采用与针对实施例272步骤B描述的程序类似的程序制备本标题化合物。
1H NMR(400MHz,甲醇-d4)δppm-0.67(s,br,1H),-0.27(s,br,1H),0.30(s,br,1H),0.40(s,br,1H),1.18(t,J=8Hz,3H),1.41(s,3H),1.71(s,br,1H),2.07(dd,J=4,12Hz,1H),2.24(s,br,1H),2.36(t,J=12Hz,1H),2.68(d,J=16Hz,1H),2.92(s,3H),2.96(d,J=16Hz,1H),3.25(s,br,1H),3.27(m,1H),3.37(m,2H),4.28(s,br,1H),4.81(s,br,1H),6.98(m,2H),7.04(s,1H),7.14(m,3H),7.27(s,br,2H)。
质谱(ESI)m/z=581.2(M+1)。
实施例291
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-异丙基甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A:N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-2-环丙基乙基)-N-异丙基甲烷磺酰胺
采用与针对实施例290步骤A描述的程序类似的程序制备该化合物。
质谱(ESI)m/z=577.2(M+1)。
步骤B:2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-异丙基甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
采用与针对实施例272步骤B描述的程序类似的程序制备该化合物。
1H NMR(400MHz,甲醇-d4)δppm-0.43(s,br,1H),0.00(s,br,1H),0.51(s,br,1H),0.62(s,br,1H),1.36(s,br,3H),1.45(s,br,3H),1.62(s,br,3H),1.97(s,br,1H),2.24(d,br,1H),2.54(d,br,2H),2.90(d,J=12Hz,1H),3.12(s,br,3H),3.16(d,J=12Hz,1H),3.42(s,br,1H),3.59(m,1H),4.17(s,br,1H),4.42(s,br,1H),7.19(m,2H),7.24(s,1H),7.38(m,3H),7.47(s,br,2H)。
质谱(ESI)m/z=595.2(M+1)。
采用与针对实施例272描述的程序类似的程序,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-羟基乙基)-3-乙基哌啶-2-酮(实施例253,步骤C)开始制备实施例292-294。
实施例 | 使用的试剂 | 来源或CAS# |
292 | 丙烷-2-磺酰胺 | [81363-76-0] |
293 | 环丁烷磺酰胺 | 实施例271G |
294 | 环戊烷磺酰胺 | [73945-39-8] |
实施例292
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(1-甲基乙基磺酰氨基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸
步骤A:N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-2-氧代哌啶-1-基)-2-环丙基乙基)丙烷-2-磺酰胺
1H NMR(400MHz,甲醇-d4)δppm-0.32(s,br,1H),0.01(s,br,1H),0.36(d,br,2H),0.71(t,J=8Hz,3H),0.78(m,1H),1.17(m,6H),1.32(m,1H),1.58(dd,J=4,12,Hz,1H),1.70-1.79(m,1H),2.03(t,J=12Hz,1H),2.37(dd,J=4,12Hz,1H),2.47(dd,J=4,12Hz,1H),2.86(s,br,1H),2.93(m,1H),3.02(m,2H),4.59(d,J=12Hz,1H),4.98(s,1H),5.00(d,J=8Hz,1H),5.27(s,1H),5.72(m,1H),6.56(d,J=8Hz,2H),6.77(s,1H),6.89-6.97(m,3H),6.98(s,br,2H)。
质谱(ESI)m/z=577.2(M+1)。
步骤B:2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(1-甲基乙基磺酰氨基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d1)δppm-0.47(s,br,1H),0.00(s,br,1H),0.41(s,br,1H),0.48(s,br,1H),0.97(t,J=8Hz,3H),1.32(m,7H),1.80(m,1H),1.94(m,2H),2.38(t,J=12Hz,3H),2.64(d,J=16Hz,1H),2.70(s,br,1H),2.91(d,J=16Hz,1H),3.01(s,br,1H),3.19(m,1H),3.40(m,1H),3.53(s,br,1H),4.94(s,br,1H),7.00(m,2H),7.06(s,1H),7.17(m,3H),7.25(s,br,2H)。质谱(ESI)m/z=595.2(M+1)。
实施例293
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-(环丁烷磺酰氨基)-1-环丙基乙基)-3-乙基-2-氧代哌啶-3-基)乙酸
步骤A:N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-2-氧代哌啶-1-基)-2-环丙基乙基)环丁烷磺酰胺
质谱(ESI)m/z=589.2(M+1)。
步骤B:2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-(环丁烷磺酰氨基)-1-环丙基乙基)-3-乙基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,甲醇-d4)δppm-0.48(s,br,1H),-0.01(s,br,1H),0.40(s,br,1H),0.48(s,br,1H),0.97(t,J=8Hz,3H),1.33(s,br,1H),1.81(m,1H),1.94-2.05(m,4H),2.34(m,2H),2.37(m,3H),2.64(d,J=12Hz,1H),2.72(s,br,1H),2.91(d,J=12Hz,1H),3.00(s,br,1H),3.39(m,2H),3.90(m,1H),4.92(s,br,1H),6.99(m,2H),7.05(s,br,1H),7.15(m,3H),7.25(s,br,2H)。质谱(ESI)m/z=607.0(M+1)。
实施例294
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-(环戊烷磺酰氨基)-1-环丙基乙基)-3-乙基-2-氧代哌啶-3-基)乙酸
步骤A:N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-2-氧代哌啶-1-基)-2-环丙基乙基)环戊烷磺酰胺
1H NMR(400MHz,甲醇-d4)δppm-0.32(s,br,1H),0.00(s,br,1H),0.36(s,br,1H),0.38(s,br,1H),0.71(t,J=8Hz,3H),0.78(m,1H),1.33(m,1H),1.44(m,2H),1.58(m,3H),1.80(m,6H),2.03(t,J=12Hz,1H),2.36(dd,J=8Hz,16,1H),2.46(dd,J=8,16Hz,1H),2.85(s,br,2H),3.01(m,2H),3.24(m,1H),4.59(d,J=12Hz,1H),4.97(s,1H),5.00(d,J=4Hz,1H),5.32(s,br,1H),5.72(m,1H),6.56(s,1H),6.58(s,1H),6.77(s,1H),6.91(m,3H),6.98(s,br,2H)。质谱(ESI)m/z=603.3(M+1)。
步骤B:2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-(环戊烷磺酰氨基)-1-环丙基乙基)-3-乙基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d1)δppm-0.47(s,br,1H),0.01(s,br,1H),0.41(s,br,1H),0.48(s,br,1H),0.96(t,J=12Hz,3H),1.42(s,br,1H),1.65(m,2H),1.71(m,3H),1.96(m,6H),2.37(t,J=12Hz,1H),2.64(d,J=16Hz,1H),2.71(s,br,1H),2.91(d,J=16Hz,1H),2.97(s,br,1H),3.40(m,1H),3.54(m,2H),4.93(s,br,1H),7.00(s,1H),7.01(s,1H),7.05(s,1H),7.14(m,3H),7.25(s,br,2H)。质谱(ESI)m/z=621.1(M+1)。
实施例295
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-3-甲基-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
步骤A:N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-3-甲基丁基)-N-甲基环丙烷磺酰胺
采用实施例272步骤A中描述的一般程序从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基-3-甲基丁烷-2-基)-3-甲基哌啶-2-酮(实施例261,步骤H,109mg,0.237mmol)和N-甲基环丙烷磺酰胺(WO2005/108358,120mg,0.888mmol)制备本标题化合物,并通过硅胶色谱法用在己烷中的乙酸乙酯洗脱来进行纯化。所获得的产物为米色泡沫状物(113.5mg,83%)。LCMS(ESI):m/z=577.2(M+H)。
步骤B:2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-3-甲基-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
将N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-3-甲基丁基)-N-甲基环丙烷磺酰胺(实施例295,步骤A,112.5mg,0.195mmol)、高碘酸钠(170mg,0.795mmol),和氯化钌(III)水合物(6mg,0.023mmol)在乙腈(1.0mL)、四氯化碳(1.0mL)和水(1.5mL)中的混合物在室温下剧烈搅拌过夜。用柠檬酸水溶液(10重量%)酸化反应混合物,在乙酸乙酯中稀释,并通过(J.T.Baker,Phillipsberg,NJ,硅藻土)垫过滤。将滤液分配在2M HCl水溶液和乙酸乙酯之间。用盐水洗涤合并的有机物,经硫酸钠干燥,过滤,并在真空中浓缩至残余物,该残余物通过制备型HPLC(SunfireTMPrep C18OBD 10μm柱,30X150mm,Waters,Milford,MA)用50%至100%的在水中的乙腈(这两种溶剂都含有0.1%三氟乙酸)梯度洗脱来进行纯化。将含有产物的色谱分离级分中的挥发物汽提除去,将其再溶解于最小体积的乙腈和水中,冷冻,并冻干从而得到产物,为白色固体。
1H NMR(500MHz,甲醇-d4)δppm 0.63(d,J=6.60Hz,3H),0.69(s,3H),0.95-1.22(m,4H),1.40(s,3H),2.07(dd,J=13.7,3.2Hz,1H),2.23(dquin,J=9.5,6.7Hz,1H),2.38(t,J=13.7Hz,1H),2.51-2.60(m,1H),2.60-2.71(m,2H),2.87-2.96(m,4H),3.01(d,J=13.5Hz,1H),3.48(ddd,J=13.8,11.0,3.1Hz,1H),4.13-4.40(m,1H),4.97(d,J=11.0Hz,1H),6.98-7.06(m,2H),7.07-7.16(m,2H),7.29(br s,4H)。LCMS(ESI):m/z=595.2(M+H)。
实施例296
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环丙烷磺酰氨基)-3-甲基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸.
步骤A. N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-3-甲基丁基)环丙烷磺酰胺
使用环丙烷磺酰胺(101mg,0.834mmol)根据实施例272步骤A中描述的程序制备本标题化合物,并通过硅胶色谱法用在己烷中的乙酸乙酯梯度洗脱来进行纯化。获得产物,为固体。LCMS(ESI):m/z=563.2(M+H)。
步骤B. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环丙烷磺酰氨基)-3-甲基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸.
按照实施例295步骤B中描述的一般程序制备本标题化合物。获得产物,为灰白色粉末。
1H NMR(500MHz,甲醇-d4)δppm 0.59(d,J=6.9Hz,3H),0.63(d,J=6.4Hz,3H),0.95-1.10(m,3H),1.10-1.18(m,1H),1.42(s,3H),2.09(dd,J=13.7,3.2Hz,1H),2.14-2.24(m,1H),2.38(t,J=13.7Hz,1H),2.52-2.61(m,1H),2.62-2.80(m,2H),3.01(d,J=13.5Hz,1H),3.21(dd,J=14.1,2.1Hz,1H),3.51(ddd,J=13.6,11.2,3.1Hz,1H),3.83(brs,1H),5.07(d,J=11.25Hz,1H),7.04(d,J=7.34Hz,1H),7.07-7.63(m,7H)。LCMS(ESI):m/z=581.2(M+H)。
实施例297
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(乙基磺酰氨基)-3-甲基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)-3-甲基丁基)乙烷磺酰胺
按照实施例295步骤A中描述的一般程序从乙烷磺酰胺(76mg,0.696mmol;Allichem)制备本标题化合物,并通过硅胶色谱法用在己烷中的乙酸乙酯梯度洗脱来进行纯化。获得产物,产率为89%。LCMS(ESI)m/z=551.2(M+H)。
步骤B. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(乙基磺酰氨基)-3-甲基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸.
采用实施例295步骤B中描述的程序制备本标题化合物,所获得的本标题化合物为白色固体(56%产率)。
1H NMR(500MHz,甲醇-d4)δppm 0.59(d,J=6.9Hz,3H),0.62(d,J=6.6Hz,3H),1.36(t,J=7.5Hz,3H),1.42(s,3H),2.09(d,J=10.5Hz,1H),2.14-2.23(m,1H),2.34-2.47(m,1H),2.64(s,0H),2.70(br.s.,1H),3.02(d,J=13.2Hz,1H),3.06-3.20(m,3H),3.53(ddd,J=13.8,11.1,3.1Hz,1H),3.79(br.s.,1H),5.10(d,J=11.0Hz,1H),7.03-7.08(m,1H),7.09-7.17(m,3H),7.17-7.87(m,4H)。LCMS(ESI):m/z=569.2(M+H)。
实施例298
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环丁烷磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁基)环丁烷磺酰胺
采用实施例272步骤A中描述的一般程序,但使用在40℃下加热的油浴,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)-3-甲基哌啶-2-酮(实施例91,步骤B,250mg,0.560mmol)和环丁烷磺酰胺(实施例271G,256mg,1.894mmol)制备本标题化合物。通过硅胶色谱法用在己烷中的EtOAc梯度洗脱来纯化粗产物。获得产物,为白色粉末(220mg,70%)。LCMS(ESI):m/z=563.2(M+H)。
步骤B. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环丁烷磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸.
按照实施例295步骤B中描述的一般程序,从N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁基)环丁烷磺酰胺(实施例298,步骤A,50mg,0.089mmol)制备本标题化合物。通过制备型HPLC色谱法(SunfireTMPrep C18OBD10μm柱,30X150mm,Waters,Milford,MA)用50%至95%的在水中的乙腈(这两种溶剂都含有0.1%三氟乙酸)梯度洗脱来纯化粗产物从而得到白色粉末。
1H NMR(500MHz,甲醇-d4)δppm 0.44(t,J=7.6Hz,3H),1.42(s,3H),1.50-1.63(m,1H),1.73-1.88(m,1H),1.94-2.14(m,3H),2.20-2.53(m,5H),2.62(s,1H),2.80(t,J=9.2Hz,1H),2.87-3.01(m,2H),3.32-3.39(m,1H),3.80(dd,J=13.9,10.0Hz,1H),3.92(quin,J=8.25Hz,1H),4.93(d,J=11.00Hz,1H),7.03(d,J=7.3Hz,1H),7.08(s,1H),7.11-7.22(m,4H),7.26(d,J=7.6Hz,2H)。LCMS(ESI):m/z=581.2(M+H)。
实施例299
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N-乙基环丁烷磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁基)-N-乙基环丁烷磺酰胺
按照实施例290步骤A的方法,用碘乙烷处理N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁基)环丁烷磺酰胺(实施例298,步骤A)从而得到本标题化合物,为白色泡沫状物。LCMS(ESI)m/z=591.2(M+H)。
步骤B. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N-乙基环丁烷磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸.
按照实施例295步骤B中描述的一般程序从N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁基)-N-乙基环丁烷磺酰胺(实施例299,步骤A)制备本标题化合物,所获得的本标题化合物为蓬松的白色固体。
1H NMR(500MHz,甲醇-d4)δppm 0.50(t,J=7.21Hz,3H),1.05-1.13(m,3H),1.43(s,3H),1.54-1.67(m,1H),1.88(dquin,J=15.2,7.5Hz,1H),1.93-2.12(m,3H),2.22-2.36(m,2H),2.37-2.59(m,3H),2.64(d,J=13.20Hz,1H),2.70-2.99(m,3H),3.17(dq,J=14.6,7.2Hz,1H),3.33-3.43(m,1H),3.96(quin,J=8.4Hz,1H),4.06-4.33(m,1H),4.83(m,1H),7.02(d,J=7.1Hz,1H),7.05(s,1H),7.08-7.21(m,3H),7.27(br.s.,3H)。LCMS(ESI):m/z=609.2(M+H)。
实施例300
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(苯基磺酰基)丁烷-2-基)哌啶-3-基)乙酸
步骤A. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(苯基硫代)丁烷-2-基)哌啶-2-酮
在室温下向(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)-3-甲基哌啶-2-酮(180mg,0.403mmol;实施例91,步骤B)在2mL甲苯中的溶液中加入氰基亚甲基三丁基正膦(324uL,1.21mmol)和苯硫醇(121μL 1.21mmol)。将该混合物加热至110℃并保持2h。冷却该反应物,将其淬灭(NH4Cl饱和水溶液),萃取(2×EtOAc),并用盐水洗涤。经Na2SO4干燥合并的有机层,过滤,并在减压下浓缩滤液。通过硅胶色谱法(4gSiO2,10%、20%、40%的EtOAc/己烷)纯化残余物,得到本标题化合物。
步骤B. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(苯基磺酰基)丁烷-2-基)哌啶-3-基)乙酸
按照与实施例71步骤F中描述的程序类似的程序,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(苯基硫代)丁烷-2-基)哌啶-2-酮(实施例300,步骤A)制备本标题化合物。通过反相制备型HPLC(GeminiTMPrep C185μm柱;Phenomenex,Torrance,CA;含有0.1%TFA的在水中的MeCN,梯度洗脱)纯化粗产物从而得到白色固体。
1H NMR(400MHz,CDCl3)δppm 0.37(t,J=8Hz,3H),1.46(m,1H),1.58(s,3H),1.94(dd,J=12,4Hz,1H),2.08(m,1H),2.50(t,J=16Hz,1H),2.79(d,J=16Hz,1H),2.88(dd,J=16Hz,1H),3.05(d,J=16Hz,1H),3.15(m,1H),3.41(m,1H),4.24(dd,J=16,12Hz,1H),5.04(d,J=8.0Hz,1H),6.88(d,J=8.0Hz,1H),6.99(s,1H),7.14(m,4H),7.27(m,2H),7.61(m,2H),7.71(m,1H),7.93(d,J=8Hz,2H);质谱(ESI)588.1[M+H]+。
实施例301
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(甲基磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
步骤A. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(((三甲基甲硅烷基)甲基)硫代)丁烷-2-基)哌啶-2-酮
按照与实施例300步骤A中描述的程序类似的程序,用适量的(三甲基甲硅烷基)甲烷硫醇代替苯硫醇,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)-3-甲基哌啶-2-酮(实施例91,步骤B)制备本标题化合物。
步骤B. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(甲基硫代)丁烷-2-基)哌啶-2-酮
在室温下将(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(((三甲基甲硅烷基)甲基)硫代)丁烷-2-基)哌啶-2-酮(60mg,0.118mmol,实施例301,步骤A)溶解于四丁基氟化铵在四氢呋喃中的1M溶液(3.5mL,3.5mmol)中。将由此产生的溶液在室温下搅拌16h。在此时间后,在减压下除去挥发物,并通过硅胶色谱法(4g SiO2,10%、20%、40%的EtOAc/己烷)纯化残余物从而得到本标题化合物。
步骤C. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(甲基磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
按照与实施例71步骤F中描述的程序类似的程序,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(甲基硫代)丁烷-2-基)哌啶-2-酮(实施例301,步骤B)制备本标题化合物。
1H NMR(400MHz,CDCl3)δppm 0.42(t,J=8.0Hz,3H),1.45(m,1H),1.48(s,3H),1.90(d,J=12Hz,1H),2.14(m,1H),2.37(t,J=16.0Hz,1H),2.76(d,J=16Hz,1H),2.90(d,J=12Hz,1H),2.97(m,1H),2.99(s,3H),3.13(m,1H),3.37(m,1H),4.24(m,1H),4.90(d,J=8.0Hz,1H),6.84(d,J=8.0Hz,1H),6.95(s,1H),7.12(m,4H),7.27(m,2H);质谱(ESI)526.0[M+H]+。
还按照与实施例300中描述的程序类似的程序,用适量的硫醇代替苯硫醇,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)-3-甲基哌啶-2-酮(实施例91,步骤B)制备了实施例302至311。必需品硫醇商购获得、如下表中所述制备,或按照一般程序从相应的醇制备。
一般硫醇程序
将甲烷磺酰氯(1当量)逐滴加入到相应醇和三乙胺(1当量)在二氯甲烷中的0.5M溶液中。将由此产生的混合物在室温下搅拌2h。然后将反应物分配在水中,用盐水洗涤,经硫酸钠干燥,过滤并浓缩。将该材料溶解于DMF中从而得到0.5M甲磺酸酯溶液。向其中加入氢硫化钠(1.2当量)。将由此产生的混合物在45℃下搅拌过夜。然后将该混合物分配在乙醚/水中,用盐水洗涤,经硫酸钠干燥,过滤并在减压下浓缩滤液。将所获得的粗硫醇用于下一步骤而无需进一步纯化。
实施例302
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(丙基磺酰基)丁烷-2-基)哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 7.23-7.27(2H,m),7.01-7.21(4H,m),6.93-7.00(1H,m),6.84(1H,dt,J=7.1,1.6Hz),4.93(1H,d,J=10.8Hz),4.05-4.20(1H,m),3.33(1H,t,J=10.1Hz),3.12(1H,ddd,J=13.7,10.9,2.6Hz),2.95-3.04(3H,m),2.71-2.85(2H,m),2.38(1H,t,J=13.8Hz),2.14(1H,ddd,J=14.3,9.9,7.3Hz),1.86-1.98(3H,m),1.49(3H,s),1.39-1.48(1H,m),1.13(3H,t,J=7.5Hz),0.41(3H,t,J=7.5Hz);质谱(ESI)554.2[M+H]+。
实施例303
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(异丁基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 7.27-7.24(2H,m),7.02-7.20(4H,m),6.93-7.00(1H,m),6.84(1H,dt,J=7.2,1.5Hz),4.93(1H,d,J=10.6Hz),4.15(1H,t,J=12.2Hz),3.33(1H,t,J=9.5Hz),3.13(1H,ddd,J=13.6,10.9,2.6Hz),2.84-3.03(3H,m),2.66-2.83(2H,m),2.33-2.47(2H,m),2.12(1H,ddd,J=14.3,9.9,7.3Hz),1.90(1H,dd,J=13.7,2.7Hz),1.48(3H,s),1.40-1.47(1H,m),1.17(3H,d,J=6.8Hz),1.15(3H,d,J=6.8Hz)0.41(3H,t,J=7.5Hz);质谱(ESI)568.2[M+H]+。
实施例304
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-((环丙基甲基)磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 7.23-7.27(2H,m),7.00-7.22(4H,m),6.94-6.98(1H,m),6.85(1H,dt,J=7.1,1.5Hz),4.95(1H,d,J=10.8Hz),4.17(1H,t,J=12.1Hz),3.35(1H,t,J=9.7Hz),3.13(1H,ddd,J=13.6,10.9,2.7Hz),2.83-3.07(4H,m),2.77(1H,d,J=14.9Hz),2.39(1H,t,J=13.8Hz),2.07-2.22(1H,m),1.91(1H,dd,J=13.9,2.7Hz),1.48(3H,s),1.40-1.47(1H,m),1.12-1.25(1H,m),0.75-0.85(2H,m),0.37-0.48(5H,m);质谱(ESI)566.2[M+H]+。
实施例305
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-((环丁基甲基)磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 7.22-7.27(2H,m),6.99-7.20(4H,m),6.93-6.98(1H,m),6.84(1H,dt,J=7.2,1.4Hz),4.91(1H,d,J=10.8Hz),4.09(1H,t,J=12.2Hz),3.31(1H,t,J=10.1Hz),3.05-3.18(3H,m),2.84-3.02(2H,m),2.67-2.82(2H,m),2.36(1H,t,J=13.8Hz),2.20-2.31(2H,m),2.01-2.18(2H,m),1.82-1.97(4H,m),1.47(3H,s),1.38-1.46(1H,m),0.40(3H,t,J=7.5Hz);质谱(ESI)580.2[M+H]+。
实施例306
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环戊基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 0.40(t,J=8.0Hz,3H),1.46(m,1H),1.49(s,3H),1.70(m,2H),1.80-1.95(m,3H),2.09(m,5H),2.40(t,J=12Hz,1H),2.76(d,J=16.0Hz,2H),3.00(d,J=16Hz,1H),3.12(m,1H),3.36(m,2H),4.10(t,J=12Hz,1H),4.97(d,J=8.0Hz,1H),6.85(d,J=8.0Hz,1H),6.96(s,1H),7.12(m,4H),7.25(m,2H);质谱(ESI)580.1[M+H]+。
实施例307
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(氧杂环丁烷-3-基磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,CD3OD)δppm 0.39(t,J=7.63Hz,3H)1.34-1.43(m,3H)1.46-1.63(m,1H)2.02-2.10(m,2H)2.29(t,J=13.69Hz,1H)2.61(d,J=13.69Hz,1H)2.95(d,J=13.69Hz,1H)2.98-3.07(m,1H)3.41(ddd,J=13.60,10.96,2.84Hz,1H)3.94-4.20(m,1H)4.55-4.76(m,1H)4.87-4.93(m,4H)4.94-5.01(m,2H)6.97(dt,J=6.65,1.76Hz,1H)7.00-7.07(m,1H)7.07-7.22(m,3H)7.28(brs,3H);质谱(ESI)m/z=568(M+1)。
实施例308
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(((3-甲基氧杂环丁烷-3-基)甲基)磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
1H NMR(500MHz,CD3OD)δppm-1.06(br s,1H)-0.21(br s,1H)0.23(br s,1H)0.37(br s,1H)1.22-1.30(m,3H)1.38-1.45(m,3H)1.70-1.77(m,3H)1.99-2.09(m,1H)2.31(t,J=13.69Hz,1H)2.65-2.73(m,1H)2.95-3.03(m,1H)3.39-3.49(m,1H)3.59-3.66(m,1H)3.66-3.73(m,1H)4.07-4.16(m,2H)4.40-4.45(m,2H)4.80(d,J=6.11Hz,2H)4.91(d,J=10.76Hz,2H)6.94-7.00(m,1H)7.06(s,1H)7.08-7.22(m,3H)7.32(br s,3H);质谱(ESI)m/z=608(M+1)。
实施例309
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-((四氢-2H-吡喃-4-基)磺酰基)丁烷-2-基)哌啶-3-基)乙酸
1H NMR(400MHz,CD3OD)δppm 0.41(t,J=7.53Hz,3H)1.26(t,J=7.14Hz,2H)1.39(s,3H)1.87(dd,J=12.52,4.50Hz,2H)2.04-2.16(m,4H)2.28(t,J=13.69Hz,1H)2.61(d,J=13.69Hz,1H)2.96(d,J=13.69Hz,1H)3.34-3.58(m,4H)3.98-4.26(m,4H)4.98(d,J=10.96Hz,1H)6.97(dt,J=6.55,1.81Hz,1H)7.04(s,1H)7.09-7.22(m,3H)7.30(br s,3H);质谱(ESI)m/z=596(M+1)。
实施例310
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-((2-羟基-2-甲基丙基)磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,CD3OD)δppm 0.38(t,J=7.43Hz,3H)1.17-1.27(m,2H)1.38(s,3H)1.44(s,6H)1.46-1.56(m,1H)2.01-2.12(m,2H)2.26(t,J=13.69Hz,1H)2.50-2.66(m,1H)2.94(d,J=13.50Hz,1H)3.33-3.46(m,3H)4.19(dd,J=13.99,11.05Hz,1H)4.97(d,J=10.76Hz,1H)6.85-6.99(m,1H)7.03(s,1H)7.08-7.18(m,3H)7.26(br s,3H);质谱(ESI)m/z=584(M+1)。
实施例311
2-((3R,5R,6S)-1-((S)-1-((R)-仲丁基磺酰基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸或2-((3R,5R,6S)-1-((S)-1-((S)-仲丁基磺酰基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸
通过反相制备型HPLC(GeminiTMPrep C185mm柱;Phenomenex,Torrance,CA)(用50%至85%的在水中的MeCN梯度洗脱27min,其中这两种溶剂都含有0.1%TFA)纯化该粗产物,从而得到本标题化合物,为较快地洗脱的异构体(tR=9.43min)。
1H NMR(400MHz,氯仿-d)δppm 7.24(d,J=7.43Hz,2H),7.04-7.15(m,3H),6.96(s,1H),6.85(td,J=1.83,6.70Hz,1H),4.96(d,J=10.56Hz,1H),4.15(ddd,J=3.13,10.81,13.45Hz,1H),3.29(t,J=10.17Hz,1H),3.14(ddd,J=2.93,10.86,13.60Hz,1H),2.77-2.93(m,2H),2.62-2.74(m,2H),2.38(t,J=13.79Hz,1H),2.02-2.20(m,2H),1.85(dd,J=2.84,13.79Hz,1H),1.54-1.66(m,1H),1.37-1.53(m,7H),1.08(dt,J=3.33,7.43Hz,3H),0.41(t,J=7.53Hz,3H)。质谱(ESI)m/z=668.2[M]+。
实施例312
2-((3R,5R,6S)-1-((S)-1-((R)-仲丁基磺酰基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸或2-((3R,5R,6S)-1-((S)-1-((S)-仲丁基磺酰基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸
通过反相制备型HPLC(GeminiTMPrep C18 5mm柱;Phenomenex,Torrance,CA)(用50%至85%的在水中的MeCN梯度洗脱,其中这两种溶剂都含有0.1%TFA)纯化该粗产物,从而得到本标题化合物,为较慢地洗脱的异构体(tR=10.2min)。
1H NMR(400MHz,氯仿-d)δppm 9.97(t,J=2.74Hz,1H),7.24(d,J=7.43Hz,2H),7.04-7.15(m,3H),6.96(s,1H),6.85(td,J=1.83,6.70Hz,1H),4.96(d,J=10.56Hz,1H),4.15(ddd,J=3.13,10.81,13.45Hz,1H),3.29(t,J=10.17Hz,1H),3.14(ddd,J=2.93,10.86,13.60Hz,1H),2.77-2.93(m,2H),2.62-2.74(m,2H),2.38(t,J=13.79Hz,1H),2.02-2.20(m,2H),1.85(dd,J=2.84,13.79Hz,1H),1.54-1.66(m,1H),1.37-1.53(m,7H),1.08(dt,J=3.33,7.43Hz,3H),0.41(t,J=7.53Hz,3H);质谱(ESI)m/z=668.2[M]+。
按照与实施例300中描述的程序类似的程序,用适量的硫醇代替苯硫醇,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-羟基乙基)-3-甲基哌啶-2-酮(实施例252,步骤A)制备实施例313至323。
实施例313
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-(环戊基磺酰基)-1-环丙基乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm-1.08(br.s,1H)-0.30(br.s,1H)0.21-0.29(m,1H)0.33-0.42(m,1H)1.51(s,3H)1.65-1.77(m,2H)1.80-1.92(m,4H)2.10(m,4H)2.48(t,J=13.79Hz,1H)2.75(m,2H)2.89(dd,J=13.60,2.25Hz,1H)3.09-3.18(m,2H)3.38(quin,J=8.02Hz,1H)4.33(m 1H)4.92(d,J=10.56Hz,1H)6.84-6.90(m,1H)6.95(s,1H)7.07-7.17(m,2H)7.37(m.,4H);质谱(ESI)m/z=592(M+1)。
实施例314
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(((3-甲基氧杂环丁烷-3-基)甲基)磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(500MHz,CD3OD)δppm-1.06(br s,1H)-0.21(br s,1H)0.23(br s,1H)0.37(br s,1H)1.22-1.30(m,3H)1.38-1.45(m,3H)1.70-1.77(m,3H)1.99-2.09(m,1H)2.31(t,J=13.69Hz,1H)2.65-2.73(m,1H)2.95-3.03(m,1H)3.39-3.49(m,1H)3.59-3.66(m,1H)3.66-3.73(m,1H)4.07-4.16(m,2H)4.40-4.45(m,2H)4.80(d,J=6.11Hz,2H)4.91(d,J=10.76Hz,2H)6.94-7.00(m,1H)7.06(s,1H)7.08-7.22(m,3H)7.32(br s,3H);质谱(ESI)m/z=608(M+1)。
实施例315
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(苯基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(500MHz,氯仿-d)δppm-1.12--1.02(m,1H)-0.33(m,1H)0.19-0.27(m,1H)0.29-0.35(m,1H)1.60(s,3H)1.77-1.89(m,1H)1.92(dd,J=13.69,2.93Hz,1H)2.57(t,J=13.94Hz,1H)2.81(d,J=15.16Hz,2H)3.00(dd,J=13.94,2.45Hz,1H)3.08-3.25(m,2H)4.47(t,J=12.35Hz,1H)5.01(d,J=10.51Hz,1H)6.90(dt,J=7.03,1.62Hz,1H)6.96-7.02(m,1H)7.07-7.19(m,2H)7.20-7.30(m,4H)7.56-7.67(m,2H)7.67-7.77(m,1H)7.87-7.98(m,2H);质谱(ESI)m/z=600(M+1)。
实施例316
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(邻甲苯磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 8.00(1H,dd,J=7.9,1.1Hz),7.51-7.64(1H,m),7.34-7.48(3H,m),7.22-7.34(2H,m),7.06-7.18(3H,m),6.98-7.04(1H,m),6.86-6.96(1H,m),5.02(1H,d,J=10.8Hz),4.60(1H,t,J=12.4Hz),3.20(1H,ddd,J=13.7,10.8,2.7Hz),3.09(1H,d,J=14.9Hz),2.99(1H,dd,J=14.0,2.2Hz),2.77-2.87(2H,m),2.71(3H,s),2.53(1H,t,J=13.8Hz),1.94(1H,dd,J=13.8,2.8Hz),1.78-1.86(1H,m),1.56(3H,s),0.17-0.40(2H,m),-0.40--0.30(1H,m),-1.12--1.00(1H,m);质谱(ESI)614.2[M+H]+。
实施例317
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-((2-氯苯基)磺酰基)-1-环丙基乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(500MHz,氯仿-d)δppm-1.08(br s,1H)-0.27(m,1H)0.20-0.29(m,1H)0.31-0.40(m,1H)1.58(s,3H)1.82-1.96(m,2H)2.53(t,J=13.82Hz,1H)2.77-2.90(m,2H)3.11-3.22(m,2H)3.37(dd,J=13.94,2.45Hz,1H)4.76(t,J=12.23Hz,1H)4.97(d,J=10.51Hz,1H)6.89(d,J=7.09Hz,1H)7.00(s,1H)7.09-7.19(m,2H)7.27-7.35(m,4H)7.49-7.57(m,1H)7.57-7.68(m,2H)8.15(dd,J=7.83,1.47Hz,1H);质谱(ESI)m/z=636(M+1)。
实施例318
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-((4-氯苯基)磺酰基)-1-环丙基乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(500MHz,氯仿-d)δppm-0.38--0.22(m,1H)0.26(brs,1H)0.33(dd,J=8.93,4.52Hz,2H)1.59(s,3H)1.83(br s,1H)1.96(dd,J=13.82,2.81Hz,1H)2.55(t,J=13.94Hz,1H)2.84(d,J=15.16Hz,2H)2.98(dd,J=13.94,2.45Hz,1H)3.11(d,J=14.92Hz,1H)3.22(ddd,J=13.69,10.76,2.93Hz,1H)4.99(d,J=10.51Hz,1H)6.88-6.96(m,1H)6.98-7.03(m,1H)7.09-7.21(m,2H)7.29(m,4H)7.56-7.66(m,2H)7.83-7.94(m,2H);质谱(ESI)m/z=636(M+1)。
实施例319
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-((4-氟苯基)磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(500MHz,氯仿-d)δppm-1.05(br s,1H)-0.33(br s,1H)0.17-0.38(m,2H)1.59(s,3H)1.76-1.88(m,1H)1.93(dd,J=13.82,2.81Hz,1H)2.55(t,J=13.82Hz,1H)2.82(m,2H)2.98(dd,J=13.94,2.45Hz,1H)3.06-3.28(m,2H)4.48(t,J=12.10Hz,1H)4.99(d,J=10.51Hz,1H)6.89(dt,J=7.09,1.59Hz,1H)6.95-7.04(m,1H)7.06-7.21(m,2H)7.21-7.40(m,6H)7.86-8.01(m,2H);质谱(ESI)m/z=618(M+1)。
实施例320
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(吡啶-4-基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(500MHz,氯仿-d)δppm-1.01(br s,1H)-0.30(br s,1H)0.28(br s,1H)0.30-0.46(m,1H)1.58(s,3H)1.83(br s,1H)1.96(dd,J=13.94,2.93Hz,1H)2.52(t,J=13.94Hz,1H)2.83(m,2H)3.00(dd,J=13.94,2.45Hz,1H)3.11(d,J=15.16Hz,1H)3.21(ddd,J=13.69,10.64,2.81Hz,1H)4.55(br s,1H)4.94(d,J=10.51Hz,1H)6.88(d,J=7.09Hz,1H)6.99(s,1H)7.08-7.20(m,2H)7.20-7.39(m,4H)7.77-7.83(m,2H)8.92-8.99(m,2H);质谱(ESI)m/z=601(M+1)。
实施例321
2-((3R,5R,6S)-1-((S)-2-((2-氯代-4-氟苯基)磺酰基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm-1.05(br s,1H),-0.29(br s,1H),0.25(br s,1H),0.29-0.44(m,1H),1.56(s,3H),1.84(br s,1H),1.89-2.03(m,1H),2.50(t,J=13.89Hz,1H),2.82(d,J=14.87Hz,2H),3.08(d,J=14.67Hz,1H),3.15-3.26(m,1H),3.31(d,J=13.69Hz,1H),4.75(brs,1H),4.96(d,J=10.56Hz,1H),6.89(d,J=6.85Hz,1H),7.00(s,1H),7.08-7.18(m,3H),7.18-7.25(m,2H),7.26-7.31(m,1H),7.33(dd,J=7.92,2.25Hz,2H),8.17(dd,J=8.80,5.87Hz,1H);质谱(ESI)m/z=652.0和653.9(M+1)。
实施例322
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-((环丙基甲基)磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm-1.06(m,1H),-0.27(m,1H),0.39(m,1H),0.43(m,3H),0.80(m,2H),1.18(m,1H),1.52(s,3H),1.85(d,J=12Hz,1H),1.95(m,1H),2.44(t,J=12Hz,1H),2.76(d,J=16Hz,2H),2.90(m,1H),3.02(m,2H),3.14(m,2H),4.39(m,1H),4.92(d,J=12Hz,1H),6.86(d,J=8.0Hz,1H),6.96(s,1H),7.13(m,3H),7.27(m,3H);质谱(ESI)m/z=578.0[M+H]+。
实施例323
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-((2,2,2-三氟乙基)磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(500MHz,氯仿-d)δppm 7.08-7.17(2H,m),6.95(1H,s),6.83(1H,d,J=7.3Hz),4.79(1H,d,J=10.5Hz),3.80-3.93(2H,m),3.11-3.23(2H,m),3.04(1H,d,J=14.7Hz),2.82(2H,d,J=14.7Hz),2.37(1H,t,J=13.7Hz),1.94(1H,d,J=13.0Hz),1.49(3H,s),0.43(1H,br.s.),0.31(1H,br.s.),-0.24(1H,br.s.),-1.03(1H,br.s.);质谱(ESI)m/z=606(M+1)。
实施例324
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-((三氟甲基)磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-((三氟甲基)硫代)乙基)-3-甲基哌啶-2-酮
将((三氟甲基)硫代)铜(41.3mg,0.251mmol,TCI America,Portland,OR)、2-(三丁基正膦亚基)乙腈(194mg,0.803mmol),和(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-羟基乙基)-3-甲基哌啶-2-酮(115mg,0.251mmol,实施例252,步骤A)的混合物在110℃下搅拌3h。加入几滴在二噁烷中的4N HCl,并将该混合物搅拌30min。加入甲苯(0.15ml)并继续在110℃下搅拌20h。HPLC纯化(GeminiTMPrep C185μm柱;Phenomenex,Torrance,CA;用10%至95%的含有0.1%TFA的在水中的MeCN梯度洗脱)得到本标题化合物。质谱(ESI)m/z=542(M+1)。
步骤B. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-((三氟甲基)磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
按照与实施例71步骤F中描述的程序类似的程序,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-((三氟甲基)硫代)乙基)-3-甲基哌啶-2-酮(实施例324,步骤A)制备本标题化合物。通过反相制备型HPLC(GeminiTMPrep C185μm柱;Phenomenex,Torrance,CA;用10%至95%的在水中的MeCN梯度洗脱,其中这两种溶剂都含有0.1%TFA)纯化该粗产物。
1H NMR(500MHz,CDCl3)δppm 7.10-7.17(3H,m),6.93(1H,s),6.82-6.86(1H,m),4.70(1H,d,J=10.5Hz),3.17-3.26(2H,m),3.02(1H,d,J=14.7Hz),2.85(1H,d,J=14.9Hz),2.77(1H,br.s.),2.35(1H,t,J=13.9Hz),1.99(2H,dd,J=13.9,2.9Hz),1.51(3H,s),1.26(1H,s),0.41-0.50(1H,m),0.31(1H,br.s.),-0.23(1H,br.s.),-1.01(1H,br.s.);质谱(ESI)m/z=592(M+1)。
按照与实施例300中描述的程序类似的程序,用适量的硫醇代替苯硫醇,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-羟基乙基)-3-乙基哌啶-2-酮(实施例253,步骤C)制备实施例325至335。
实施例325
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(苯基磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸
1H NMR(500MHz,氯仿-d)δppm-1.01(br.m.,1H)-0.32(br.m.,1H)0.19-0.37(m,2H)1.06(t,J=7.46Hz,3H)1.87(m,2H)2.02-2.17(m,2H)2.54(t,J=13.82Hz,1H)2.83(m,2H)3.03(d,J=12.96Hz,1H)3.07-3.23(m,2H)4.38(br s,1H)5.03(d,J=10.51Hz,1H)6.91(d,J=7.09Hz,1H)6.98-7.04(m,1H)7.08-7.20(m,3H)7.48(m,3H)7.56-7.67(m,2H)7.67-7.78(m,1H)7.84-7.99(m,2H);质谱(ESI)m/z=614(M+1)。
实施例326
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-((2-氯苯基)磺酰基)-1-环丙基乙基)-3-乙基-2-氧代哌啶-3-基)乙酸
1H NMR(500MHz,氯仿-d)δppm-1.01(br.m.,1H)-0.26(br.m.,1H)0.28(br.m.,1H)0.31-0.44(m,1H)1.02(t,J=7.46Hz,3H)1.88(m,2H)2.02-2.16(m,2H)2.48(t,J=13.82Hz,1H)2.83(d,J=15.65Hz,1H)2.90(br s,1H)3.07-3.23(m,2H)3.42(dd,J=14.06,2.08Hz,1H)4.64(br s,1H)4.98(d,J=10.51Hz,1H)6.89(d,J=7.09Hz,1H)6.97-7.04(m,1H)7.09-7.22(m,3H)7.33-7.48(m,3H)7.48-7.56(m,1H)7.56-7.67(m,2H)8.14(dd,J=7.95,1.59Hz,1H);质谱(ESI)m/z=648(M+1)。
实施例327
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-((2-氟苯基)磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm-1.00(br s,1H),-0.26(br s,1H),0.19-0.45(m,2H),1.02(t,J=7.43Hz,3H),1.87(dd,J=13.69,2.93Hz,2H),1.97-2.20(m,2H),2.49(t,J=13.79Hz,1H),2.83(d,J=15.26Hz,2H),3.08(d,J=15.26Hz,1H),3.19(ddd,J=13.55,10.71,2.74Hz,1H),3.30(d,J=13.89Hz,1H),4.57(br s,1H),4.95(d,J=10.76Hz,1H),6.89(d,J=6.85Hz,1H),7.02(s,1H),7.08-7.23(m,3H),7.23-7.35(m,3H),7.35-7.52(m,2H),7.67-7.81(m,1H),7.91-8.05(m,1H);质谱(ESI)m/z=632.0(M+1)。
实施例328
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-((3-氟苯基)磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm-0.97(br s,1H),-0.31(br s,1H),0.18-0.48(m,2H),1.05(t,J=7.43Hz,3H),1.88(dd,J=13.79,2.84Hz,2H),1.96-2.21(m,2H),2.51(t,J=13.79Hz,1H),2.84(d,J=15.06Hz,2H),2.95-3.13(m,2H),3.13-3.31(m,1H),4.41(brs,1H),5.00(d,J=10.56Hz,1H),5.72(br s,2H),6.91(d,J=6.85Hz,1H),7.01-7.04(m,2H),7.09-7.18(m,3H),7.36-7.45(m,2H),7.57-7.66(m,3H),7.70(d,J=7.83Hz,1H);质谱(ESI)m/z=632.0(M+1)。
实施例329
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-((4-氟苯基)磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm-0.97(br s,1H),-0.31(br s,1H),0.32(d,J=4.89Hz,2H),1.05(t,J=7.53Hz,3H),1.26(s,1H),1.88(dd,J=13.69,2.93Hz,2H),1.97-2.21(m,2H),2.52(t,J=13.79Hz,1H),2.83(d,J=15.26Hz,1H),2.92-3.13(m,2H),3.13-3.30(m,1H),4.38(br s,2H),5.01(d,J=10.56Hz,1H),6.91(d,J=6.65Hz,2H),7.01(s,2H),7.07-7.22(m,3H),7.28-7.37(m,3H),7.83-8.03(m,2H);质谱(ESI)m/e=632.0(M+1)。
实施例330
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(丙基磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,甲醇-d4)δppm-0.71(s,br,1H),0.00(br s,1H),0.51(br s,1H),0.60(br s,1H),1.19(t,J=8Hz,3H),1.32(t,J=8Hz,3H),1.93-2.14(m,5H),2.24(m,1H),2.61(t,J=12Hz,1H),2.87(d,J=12Hz,1H),2.97(br s,1H),3.13(d,J=12Hz,1H),3.32(m,3H),3.69(m,1H),4.45(s,br,1H),5.16(d,J=12Hz,1H),7.20-7.21(d,J=4Hz,2H),7.28(s,1H),7.36(m,3H),7.51(br s,2H);质谱(ESI)m/z=580.2(M+1)。
实施例331
2-((3R,5R,6S)-1-((S)-2-(丁基磺酰基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,甲醇-d4)δppm-0.73(s,br,1H),0.00(br s,1H),0.51(br s,1H),0.60(br s,1H),1.17-1.23(m,6H),1.70-1.76(m,2H),2.01(m,4H),2.13(d,J=8Hz,1H),2.24(m,1H),2.61(t,J=12Hz,1H),2.87(d,J=16Hz,1H),2.98(br s,1H),4.14(d,J=16Hz,1H),3.31-3.42(m,3H),3.69(m,1H),4.48(br s,1H),5.17(d,J=16Hz,1H),7.20(m,2H),7.28(s,1H),7.36(m,3H),7.50(br s,2H);质谱(ESI)m/z=594.2(M+1)。
实施例332
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(异戊基磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,甲醇-d4)δppm-0.73(br s,1H),0.00(br s,1H),0.50(br s,1H),0.60(br s,1H),1.17-1.20(m,9H),1.92(m,5H),2.10(dd,J=4,12Hz,1H),2.24(m,1H),2.61(t,J=12Hz,1H),2.87(d,J=12Hz,1H),2.97(br s,1H),3.13(d,J=12Hz,1H),3.37(m,3H),3.69(m,1H),4.46(br s,1H),5.16(d,J=12Hz,1H),7.20(m,2H),7.27(s,1H),7.36(m,3H),7.50(br s,2H);质谱(ESI)m/z=608.2(M+1)。
实施例333
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-(环戊基磺酰基)-1-环丙基乙基)-3-乙基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,甲醇-d4)δppm-0.94(br s,1H),-0.23(br s,1H),0.30(br s,1H),0.39(br s,1H),0.99(t,J=4Hz,3H),1.73-1.83(m,6H),1.87(m,1H),2.05(m,5H),2.42(t,J=12Hz,1H),2.68(d,J=12Hz,1H),2.78(br s,1H),2.94(d,J=12Hz,1H),3.48(br s,1H),3.50(m,1H),3.61(m,1H),4.27(br s,1H),4.98(d,J=12Hz,1H),7.02(d,J=8Hz,2H),7.08(s,1H),7.17(m,3H),7.31(br s,2H);质谱(ESI)m/z=606.2(M+1)。
实施例334
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-(环己基磺酰基)-1-环丙基乙基)-3-乙基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,甲醇-d4)δppm-0.97(s,br,1H),-0.25(br s,1H),0.29(s,1H),0.39(s,1H),0.99(t,J=8Hz,3H),1.24-1.52(m,6H),1.75-1.78(m,2H),1.91-1.96(m,3H),2.05(m,1H),2.18(s,br,2H),2.39-2.46(t,J=12Hz,1H),2.68-2.71(d,J=12Hz,1H),2.78(br s,1H),2.94-2.98(d,J=12Hz,1H),3.08(m,2H),3.48-3.53(m,1H),4.27(s,br,1H),4.99(d,J=12Hz,1H),7.01(d,J=8Hz,2H),7.08(s,1H),7.16-7.21(m,3H),7.31(s,br,2H);质谱(ESI)m/z=620.2(M+1)
实施例335
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(甲基磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,甲醇-d4)δppm-0.71(s,br,1H),0.00m(s,br,1H),0.47(s,br,1H),0.55(s,br,1H),1.14(t,J=8Hz,3H),1.92-1.94(m,2H),2.08(dd,J=4,12Hz,1H),2.18(m,1H),2.55(t,J=12Hz,1H),2.86(d,J=16Hz,1H),3.03(s,br,1H),3.12(d,J=16Hz,1H),3.43(s,br,1H),3.48(s,3H),3.63(m,1H),4.41(s,br,1H),5.09(d,J=12Hz,1H),7.14(m,2H),7.30(s,1H),7.32(m,3H),7.46(s,br,2H);质谱(ESI)m/z=552.2(M+1)。
按照与实施例300中描述的程序类似的程序,用指定的试剂代替苯硫醇,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基-3-甲基丁烷-2-基)-3-甲基哌啶-2-酮(实施例261,步骤H)制备实施例336至339。
实施例336
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-3-甲基-1-((2,2,2-三氟乙基)磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
1H NMR(500MHz,甲醇-d4)δppm 0.52(s,3H),0.67(s,3H),1.35(br s,3H),2.07(dd,J=13.7,2.9Hz,1H),2.19(dq,J=14.4,7Hz,1H),2.27(t,J=13.7Hz,1H),2.61(d,J=13.5Hz,1H),2.99(d,J=13.5Hz,1H),3.26-3.30(m,1H),3.41(dd,J=13.8,1.6Hz,1H),3.58(ddd,J=13.7,11,2.9Hz,1H),4.24(dd,J=13.9,10.5Hz,1H),4.36-4.60(m,2H),4.99-5.07(m,1H),6.95-7.01(m,1H),7.01-7.05(m,1H),7.08-7.16(m,3H),7.17-8.26(m,3H);质谱(ESI)m/z=608(M+H)
实施例337
2-((3R,5R,6S)-1-((S)-1-(叔丁基磺酰基)-3-甲基丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(500MHz,甲醇-d4)δppm 0.51(d,J=6.9Hz,3H),0.65(d,J=6.6Hz,3H),1.37(s,3H),1.45(s,9H),2.01-2.10(m,1H),2.11-2.25(m,1H),2.30(t,J=13.7Hz,1H),2.61(d,J=13.5Hz,1H),2.99(d,J=13.7Hz,1H),3.10(dd,J=13.7,1.71Hz,1H),3.25-3.29(m,1H),3.57(ddd,J=13.6,11.1,2.9Hz,1H),3.96(dd,J=13.8,10.4Hz,1H),5.15(d,J=11.3Hz,1H),6.98-7.03(m,1H),7.04-7.17(m,3H),7.18-8.01(m,3H);质谱(ESI)m/z=582.2(M+H)。
实施例338
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-3-甲基-1-(甲基磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
1H NMR(500MHz,甲醇-d4)δppm 0.50(d,J=6.9Hz,3H),0.67(d,J=6.6Hz,3H),1.37(s,3H),2.05(dd,J=13.8,3.1Hz,1H),2.18(dq,J=14.2,6.9Hz,1H),2.29(t,J=13.6Hz,1H),2.62(d,J=13.5Hz,1H),2.99(d,J=13.5Hz,1H),3.09(br s,3H),3.20-3.29(m,1H),3.32-3.35(m,1H),3.56(ddd,J=13.8,10.9,2.9Hz,1H),4.07(dd,J=13.9,10.5Hz,1H),5.09(d,J=11Hz,1H),6.98(dt,J=7.2,1.4Hz,1H),7.03-7.08(m,1H),7.08-7.16(m,2H),7.29(br s,4H);质谱(ESI)m/z=540.2(M+H)。
实施例339
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(乙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. (3S,5S,6R,8S)-8-烯丙基-6-(3-氯苯基)-5-(4-氯苯基)-3-乙基-8-甲基-2,3,5,6,7,8-六氢噁唑并[3,2-a]吡啶-4-鎓三氟甲烷磺酸盐
按照实施例361步骤A的方法使用(S)-2-氨基丁醇替代L-缬氨醇获得本标题化合物,为第一洗脱非对映异构体。
1H NMR(500MHz,DMSO-d6)δppm 7.95(1H,br.s),7.34-7.60(2H,m),7.18-7.34(4H,m),7.13(1H,dt,J=7.5,1.3Hz),5.88(1H,m),5.37(1H,dd,J=16.8,1.6Hz),5.28(1H,dd,J=10.0,2.0Hz),5.16(1H,d,J=10.8Hz),5.06(1H,t,J=9.8Hz),4.78(1H,dd,J=9.5,7.1Hz),4.45(1H,m,J=2.7Hz),3.88-3.98(1H,m),2.66-2.85(2H,m),2.33(1H,t,J=13.4Hz),1.99(1H,dd,J=13.7,3.4Hz),1.32(3H,s),0.94(1H,m),0.59(3H,t,J=7.2Hz),0.41-0.53(1H,m);质谱(ESI)m/z=428.2(M+)。
步骤B. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(乙基硫代)丁烷-2-基)-3-甲基哌啶-2-酮
向(3S,5S,6R,8S)-8-烯丙基-6-(3-氯苯基)-5-(4-氯苯基)-3-乙基-8-甲基-2,3,5,6,7,8-六氢噁唑并[3,2-a]吡啶-4-鎓三氟甲烷磺酸盐(86mg,0.15mmol;实施例339,步骤A)在DMF(0.74ml)中的溶液中加入乙烷硫醇钠(38mg,0.45mmol)。在25℃下搅拌1.5h后,淬灭(NH4Cl饱和水溶液)反应物,萃取(2×EtOAc),并洗涤(2×盐水)。经Na2SO4干燥合并的有机层,过滤,并在减压下浓缩滤液。通过硅胶色谱法(12g SiO2,10%和20%的EtOAc/hex)纯化残余物,得到本标题化合物,为无色液体。
步骤C. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(乙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
向快速搅拌着的(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(乙基硫代)丁烷-2-基)-3-甲基哌啶-2-酮(60mg,0.12mmol;实施例339,步骤B)在水(0.66mL)、乙腈(0.44mL)和CCl4(0.44mL)的混合物中的溶液中加入高碘酸钠(157mg,0.734mmol),接着加入氯化钌(III)水合物(2.8mg,0.012mmol)。在剧烈搅拌5h后,酸化(10%柠檬酸)反应物并稀释(EtOAc)。通过(J.T.Baker,Phillipsberg,NJ,硅藻土)垫过滤反应混合物,并萃取(2×EtOAc)滤液。用盐水洗涤合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过反相制备型HPLC(GeminiTMPrep C185μm柱,Phenomenex,Torrance,CA;用40%至60%的在水中的MeCN梯度洗脱,其中这两种溶剂都含有0.1%TFA)纯化残余物,得到本标题化合物,为白色泡沫状物。
1H NMR(400MHz,氯仿-d)δppm 7.24-7.26(2H,m),7.01-7.20(4H,m),6.93-6.98(1H,m),6.85(1H,d,J=7.0Hz),4.94(1H,d,J=10.6Hz),4.15(1H,t,J=12.1Hz),3.24-3.37(1H,m),2.92-3.18(4H,m),2.71-2.82(2H,m),2.38(1H,t,J=13.8Hz),2.06-2.21(1H,m),1.92(1H,dd,J=13.7,2.7Hz),1.48(3H,s),1.42-1.46(1H,m)1.44(3H,t,J=7.5Hz),0.41(3H,t,J=7.5Hz);质谱(ESI)m/z=540.1[M+H。
实施例340
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环丙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环丙基磺酰基)丁烷-2-基)-3-甲基哌啶-2-酮
在25℃下向(3S,5S,6R,8S)-8-烯丙基-6-(3-氯苯基)-5-(4-氯苯基)-3-乙基-8-甲基-2,3,5,6,7,8-六氢噁唑并[3,2-a]吡啶-4-鎓三氟甲烷磺酸盐(75mg,0.130mmol;实施例339,步骤A)在乙腈(1.3mL)中的溶液中加入环丙烷亚磺酸钠盐(50mg,0.39mmol)。在90℃下搅拌1天后,用NH4Cl饱和水溶液淬灭反应物,对反应物进行萃取(2×EtOAc),并且用盐水洗涤(2×)合并的有机层,经Na2SO4干燥,过滤,并在减压下浓缩滤液。通过硅胶色谱法(12gSiO2,35%和45%的EtOAc/hex)纯化残余物,得到本标题化合物,为无色液体。
步骤B. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环丙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
按照与实施例339步骤C中描述的程序类似的程序,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环丙基磺酰基)丁烷-2-基)-3-甲基哌啶-2-酮(实施例340,步骤A)制备本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 7.22-7.26(2H,m),6.99-7.19(4H,m),6.91-6.97(1H,m),6.76-6.89(1H,m),4.91(1H,d,J=10.8Hz),4.21(1H,dd,J=13.5,11.3Hz),3.31(1H,t,J=10.3Hz),3.12(1H,ddd,J=13.6,10.9,2.6Hz),2.88-3.02(2H,m),2.76(1H,d,J=14.9Hz),2.31-2.49(2H,m),2.06-2.24(1H,m),1.90(1H,dd,J=13.7,2.7Hz),1.40-1.56(1H,m),1.47(3H,s),1.23-1.36(2H,m),1.01-1.16(2H,m),0.42(3H,t,J=7.5Hz);质谱(ESI)552.2[M+H]+。
按照与实施例339或实施例340中描述的程序类似的程序,在步骤B中使用等效量的合适的试剂,从(3S,5S,6R,8S)-8-烯丙基-6-(3-氯苯基)-5-(4-氯苯基)-3-乙基-8-甲基-2,3,5,6,7,8-六氢噁唑并[3,2-a]吡啶-4-鎓三氟甲烷磺酸盐(实施例339,步骤A)制备实施例340和341。
实施例341
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(异丙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 7.22-7.26(2H,br s),7.02-7.21(4H,m),6.92-6.94(1H,s),6.85(1H,d,J=7.0Hz),4.97(1H,d,J=10.8Hz),4.10(1H,t,J=11.7Hz),3.27-3.42(1H,m),2.98-3.16(3H,m),2.70-2.78(2H,m),2.40(1H,t,J=13.9Hz),2.08-2.26(1H,m),1.86-1.93(1H,s),1.49(3H,s),1.43(3H,d,J=6.8Hz),1.43(3H,d,J=6.8Hz),1.40-1.50(1H,m)0.41(3H,t,J=7.5Hz);质谱(ESI)m/z=554.2[M+H]+。
实施例342
2-((3R,5R,6S)-1-((S)-1-(叔丁基磺酰基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(500MHz,氯仿-d)δppm 7.21-7.26(2H,m),7.01-7.20(4H,m),6.92-6.94(1H,m),6.85(1H,d,J=7.1Hz),4.99(1H,d,J=10.8Hz),4.04(1H,dd,J=13.2,11.2Hz),3.33(1H,t,J=10.4Hz),3.03-3.15(2H,m),2.80(1H,dd,J=13.2,2.0Hz),2.72(1H,d,J=15.4Hz),2.43(1H,t,J=13.8Hz),2.08-2.23(1H,m),1.86(1H,dd,J=13.7,2.4Hz),1.50(3H,s),1.46-1.49(1H,m),1.44(9H,s),0.41(3H,t,J=7.6Hz);质谱(ESI)568.2[M+H]+。
实施例343
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环丁基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(500MHz,氯仿-d)δppm 7.21-7.27(2H,m),7.00-7.21(4H,m),6.93-6.97(1H,s),6.86(1H,d,J=7.1Hz),4.97(1H,d,J=10.8Hz),3.98(1H,t,J=12.2Hz),3.76(1H,quin,J=8.3Hz),3.31(1H,t,J=9.9Hz),3.12(1H,ddd,J=13.6,10.9,2.7Hz),2.99(1H,d,J=14.9Hz),2.75(1H,d,J=14.9Hz),2.50-2.69(3H,m),2.27-2.46(3H,m),2.04-2.19(3H,m),1.91(1H,dd,J=13.7,2.7Hz),1.48-1.52(3H,m),1.41-1.47(1H,m),0.40(3H,t,J=7.6Hz);质谱(ESI)566.2[M+H]+。
环丁烷亚磺酸,钠盐的合成
该试剂按照与WO2007/14011和WO2010/39982中描述的程序类似的程序制备。在25℃下将溴环丁烷(1.00g,7.41mmol)在乙醚(7.4mL)中的溶液分成数个小部分加入到镁(306mg,12.6mmol)在乙醚(7.4mL)中的悬浮液中。在初始放热已停止后,将该混合物进一步加热至回流1h。然后将该悬浮液分成几个小部分加入到冰冷的硫酰二氯(3.00g,22.2mmol)在DCM(12mL)中的溶液中。将该悬浮液温度升至室温,并在减压下除去挥发物。在真空下干燥残余物,然后用己烷(80mL)萃取。过滤该己烷悬浮液,并用己烷洗涤滤饼。干燥(Na2SO4)合并的滤液,并在减压下浓缩从而得到粗的环丁烷磺酰氯。将粗的环丁烷磺酰氯(1.15g,7.44mmol)加入到亚硫酸钠(2.16g,17.1mmol)在水(9.7ml)和碳酸钠(1.42g,13.4mmol)中的悬浮液中。将由此产生的溶液加热至回流1h。冷却该反应物并冻干以除去水。向残余物中加入乙醇(50mL),并将由此产生的混合物在回流下加热2h。过滤该混合物。在减压下浓缩滤液从而得到粗的本标题化合物,将其直接用于下一步骤。
实施例344
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-1-((S)-1-(乙基磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
步骤A. (3S,5S,6R,8S)-8-烯丙基-6-(3-氯苯基)-5-(4-氯苯基)-3,8-二乙基-2,3,5,6,7,8-六氢噁唑并[3,2-a]吡啶-4-鎓甲烷磺酸盐
在0℃下向(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-1-((S)-1-羟基丁烷-2-基)哌啶-2-酮(300mg,0.652mmol)(实施例202,步骤B)在DCM(6mL)中的溶液中依次加入三乙胺(270μl,1.955mmol)和甲烷磺酸酐(170mg,0.977mmol)。让反应物温度升至室温。在室温下搅拌2h后,用10%柠檬酸水溶液淬灭反应物,用DCM萃取,用水洗涤合并的萃取物,经Na2SO4干燥,过滤,并浓缩滤液从而得到本标题化合物。
步骤B. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-1-((S)-1-(乙基硫代)丁烷-2-基)哌啶-2-酮
按照与实施例339步骤B中描述的程序类似的程序,从(3S,5S,6R,8S)-8-烯丙基-6-(3-氯苯基)-5-(4-氯苯基)-3,8-二乙基-2,3,5,6,7,8-六氢噁唑并[3,2-a]吡啶-4-鎓甲烷磺酸盐(实施例344,步骤A)制备本标题化合物。
步骤C. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-1-((S)-1-(乙基磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
按照与实施例339步骤C中描述的程序类似的程序,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-1-((S)-1-(乙基硫代)丁烷-2-基)哌啶-2-酮(实施例344,步骤B)制备本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 0.41(t,J=8.0Hz,3H),0.97(t,J=8.0Hz,3H),1.44(s,3H),1.50(m,1H),1.86(dd,J=12,4Hz,1H),1.97(m,2H),2.15(m,1H),2.36(t,J=12Hz,1H),2.79(m,1H),2.81(d,J=16Hz,1H),2.92(d,J=16.0Hz,1H),3.04(m,2H),3.16(m,1H),3.19(m,1H),4.11(m,1H),4.97(d,J=12Hz,1H),6.86(d,J=8.0Hz,1H),6.97(s,1H),7.13(m,3H),7.38(m,3H);质谱(ESI)m/z=554.0[M+H]+。
按照与实施例339或实施例340中描述的程序类似的程序,在步骤B中使用等效量的合适的试剂,从(3S,5S,6R,8S)-8-烯丙基-6-(3-氯苯基)-5-(4-氯苯基)-3,8-二乙基-2,3,5,6,7,8-六氢噁唑并[3,2-a]吡啶-4-鎓甲烷磺酸盐(实施例344,步骤A)制备实施例345至347。
实施例345
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-1-((S)-1-(异丙基磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 0.40(t,J=8.0Hz,3H),0.97(t,J=8.0Hz,3H),1.43(d,J=4Hz,6H),1.50(m,1H),1.86(dd,J=12,4Hz,1H),1.98(m,2H),2.19(m,1H),2.37(t,J=12Hz,1H),2.73(d,J=12Hz,1H),2.79(d,J=12.0Hz,1H),2.97(d,J=12Hz,1H),3.10(m,2H),3.37(m,1H),4.09(m,1H),4.99(d,J=12Hz,1H),6.86(d,J=8.0Hz,1H),6.98(s,1H),7.12(m,4H),7.27(m,2H);质谱(ESI)m/z=568.0[M+H]+。
实施例346
2-((3R,5R,6S)-1-((S)-1-(叔丁基磺酰基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 0.39(t,J=8.0Hz,3H),0.97(t,J=8.0Hz,3H),1.43(s,9H),1.50(m,1H),1.85(dd,J=12,4Hz,1H),1.97(m,2H),2.15(m,1H),2.38(t,J=12Hz,1H),2.80(d,J=16Hz,1H),2.96(d,J=16.0Hz,1H),3.14(m,2H),3.35(m,1H),4.01(m,1H),5.02(d,J=8Hz,1H),6.87(d,J=8.0Hz,1H),6.98(s,1H),7.13(m,4H),7.38(m,2H);质谱(ESI)m/z=582.1[M+H]+。
实施例347
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环丁基磺酰基)丁烷-2-基)-3-乙基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 0.39(t,J=8.0Hz,3H),0.98(t,J=8.0Hz,3H),1.50(m,1H),1.84-2.45(m,6H),2.38(m,3H),2.62(m,3H),2.80(d,J=16Hz,1H),2.94(d,J=16.0Hz,1H),3.15(d,J=12Hz,1H),3.34(m,1H),3.76(m,1H),3.94(m,1H),5.00(d,J=12Hz,1H),6.87(d,J=8.0Hz,1H),6.98(s,1H),7.13(m,3H),7.28(m,3H);质谱(ESI)580.0[M+H]+。
实施例348
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环丙基磺酰基)丁烷-2-基)-3-乙基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 0.42(t,J=8.0Hz,3H),0.97(t,J=8.0Hz,3H),1.10(m,2H),1.26(m,2H),1.52(m,1H),1.83(dd,J=16,4Hz,1H),1.96(m,2H),2.14(m,1H),2.34(d,J=16.0Hz,1H),2.42(m,1H),2.79(d,J=12Hz,1H),2.95(m,1H),2.98(d,J=16Hz,1H),3.12(m,1H),3.34(m,1H),4.15(m,1H),5.00(d,J=12Hz,1H),6.84(d,J=8.0Hz,1H),6.96(s,1H),7.12(m,4H),7.27(m,2H);质谱(ESI)m/z=566.0[M+H]+。
实施例349
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(乙基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. (3S,5S,6R,8S)-8-烯丙基-6-(3-氯苯基)-5-(4-氯苯基)-3-环丙基-8-甲基-2,3,5,6,7,8-六氢噁唑并[3,2-a]吡啶-4-鎓甲烷磺酸盐
按照与实施例344步骤A中描述的程序类似的程序,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-羟基乙基)-3-甲基哌啶-2-酮(实施例252,步骤A)制备本标题化合物。
步骤B. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(乙基硫代)乙基)-3-甲基哌啶-2-酮
如实施例339中所述,从(3S,5S,6R,8S)-8-烯丙基-6-(3-氯苯基)-5-(4-氯苯基)-3-环丙基-8-甲基-2,3,5,6,7,8-六氢噁唑并[3,2-a]吡啶-4-鎓甲烷磺酸盐(实施例349,步骤A)和乙烷硫醇钠制备本标题化合物。
步骤C. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(乙基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
按照与实施例339步骤C中描述的程序类似的程序,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(乙基硫代)乙基)-3-甲基哌啶-2-酮(实施例349,步骤B)制备本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 7.20-7.26(3H,m),7.07-7.17(3H,m),6.95-6.98(1H,m),6.82-6.88(1H,m),4.90(1H,d,J=10.6Hz),4.25-4.46(1H,m),3.11-3.24(1H,m),2.99-3.09(3H,m),2.92(1H,d,J=12.1Hz),2.80(1H,d,J=14.7Hz),2.64-2.77(1H,m),2.42(1H,t,J=13.8Hz),1.91(1H,dd,J=13.9,2.5Hz),1.83(1H,br.s.),1.49(3H,s),1.44(3H,t,J=7.5Hz),0.32-0.42(1H,m),0.18-0.27(1H,m),,-0.35--0.24(1H,m),-1.15--0.95(1H,m);质谱(ESI)552.2[M+H]+。
按照与实施例339或实施例340中描述的程序类似的程序,在步骤B中使用等效量的合适的试剂,从(3S,5S,6R,8S)-8-烯丙基-6-(3-氯苯基)-5-(4-氯苯基)-3-环丙基-8-甲基-2,3,5,6,7,8-六氢噁唑并[3,2-a]吡啶-4-鎓甲烷磺酸盐(实施例349,步骤A)制备实施例350至356。
实施例350
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(异丙基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 7.23-7.26(3H,m),7.04-7.20(3H,m),6.93-6.97(1H,m),6.84-6.88(1H,m),4.93(1H,d,J=10.8Hz),4.34(1H,br.s.),3.05-3.18(3H,m),2.86(1H,d,J=13.3Hz),2.77(2H,d,J=15.3Hz),2.46(1H,t,J=13.8Hz),1.86(2H,dd,J=13.5,2.5Hz),1.51(3H,s),1.44(6H,d,J=6.8Hz),0.31-0.44(1H,m),0.18-2.80(1H,m),-0.35--0.23(1H,m),-1.15--1.02(1H,br.s.);质谱(ESI)566.2[M+H]+。
实施例351
2-((3R,5R,6S)-1-((S)-2-(叔丁基磺酰基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 7.20-7.26(3H,m),7.03-7.17(3H,m),6.93-6.97(1H,m),6.82-6.92(1H,m),4.95(1H,d,J=10.6Hz),4.30(1H,t,J=12.0Hz),3.14(1H,ddd,J=13.6,10.8,2.6Hz),3.07(1H,d,J=15.1Hz),2.92(1H,d,J=11.9Hz),2.79(1H,d,J=15.1Hz),2.72(1H,t,J=9.6Hz),2.45(1H,t,J=13.8Hz),1.88(2H,dd,J=13.6,2.4Hz),1.50(3H,s),1.44(9H,s),0.30-0.44(1H,m),0.17-0.30(1H,m),-0.37--0.26(1H,m),-1.15--1.05(1H,m);质谱(ESI)580.2[M+H]+。
实施例352
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-(环丁基磺酰基)-1-环丙基乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 7.20-7.27(3H,m),7.07-7.15(3H,m),6.94-6.98(1H,m),6.84-6.93(1H,m),4.93(1H,d,J=10.6Hz),4.23(1H,t,J=11.3Hz),3.77(1H,quin,J=8.3Hz),3.12-3.22(1H,m),3.08(1H,d,J=15.1Hz),2.70-2.83(3H,m),2.53-2.69(2H,m),2.47(1H,t,J=13.8Hz),2.27-2.40(2H,m),2.04-2.19(2H,m),1.73-1.97(2H,m),1.51(3H,s),0.30-0.41(1H,m),0.20-0.30(1H,m),-0.35--0.25(1H,m),-1.12--0.95(1H,m);质谱(ESI)578.1[M+H]+。
实施例353
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(环丙基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 7.18-7.26(3H,m),7.06-7.15(3H,m),6.92-6.97(1H,m),6.82-6.88(1H,m),4.87(1H,d,J=10.6Hz),4.44(1H,br.s.),3.11-3.23(1H,m),3.01-3.10(2H,m),2.78(1H,d,J=15.1Hz),2.73(1H,br.s.),2.35-2.47(2H,m),1.88(1H,dd,J=13.8,2.6Hz),1.76-1.85(1H,m),1.49(3H,s),1.24-1.35(2H,m),1.03-1.16(2H,m),0.32-0.44(1H,m),0.20-0.30(1H,m),-0.33--0.21(1H,m),-1.02--0.98(1H,br.s.);质谱(ESI)564.1[M+H]+。
实施例354
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(甲基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm-1.03(br s,1H)-0.26(br s,1H)0.27(br s,1H)0.33-0.49(m,1H)1.51(s,3H)1.71-1.97(m,2H)2.43(t,J=13.79Hz,1H)2.78(m,2H)3.00(s,3H)3.01-3.24(m,3H)4.44(br s,1H)4.87(d,J=10.56Hz,1H)6.81-6.92(m,1H)6.96(s,1H)7.07-7.20(m,2H)7.27(m,4H);质谱(ESI)m/z=540(M+1)。
实施例355
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(叔戊基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm-1.11(br s,1H),-0.31(br s,1H),0.23(br s,1H),0.36(br s,1H),1.04(t,J=7.53Hz,3H),1.28-1.44(m,6H),1.50(s,3H),1.73-1.95(m,4H),2.48(t,J=13.89Hz,1H),2.76(d,J=15.26Hz,2H),2.91(d,J=13.11Hz,1H),3.04-3.23(m,2H),4.28(t,J=11.15Hz,1H),4.90-5.07(m,1H),6.84-6.93(m,1H),6.94-7.03(m,1H),7.05-7.37(br s,6H);质谱(ESI)m/z=594.0(M+1)。
实施例356
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-((2,4-二氟苯基)磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm-1.06(br s,1H),-0.29(br s,1H),0.15-0.28(m,1H),0.28-0.44(m,1H),1.37(s,1H),1.54(s,3H),1.77-1.95(m,2H),2.48(t,J=13.79Hz,1H),2.67-2.85(m,1H),3.07(d,J=14.87Hz,1H),3.13-3.32(m,2H),4.65(br s,1H),4.92(d,J=10.56Hz,1H),6.81-6.94(m,2H),6.94-7.21(m,8H),7.99(td,J=8.31,6.06Hz,1H);MS(ESI)m/e=636.0(M+1)。
实施例357
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(乙基磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸
步骤A. (3S,5S,6R,8S)-8-烯丙基-6-(3-氯苯基)-5-(4-氯苯基)-3-环丙基-8-乙基-2,3,5,6,7,8-六氢噁唑并[3,2-a]吡啶-4-鎓甲烷磺酸盐
按照与实施例344步骤A中描述的程序类似的程序,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-羟基乙基)-3-乙基哌啶-2-酮(实施例253,步骤C)制备本标题化合物。
步骤B. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(乙基硫代)乙基)-3-乙基哌啶-2-酮
按照实施例339中描述的方法,从(3S,5S,6R,8S)-8-烯丙基-6-(3-氯苯基)-5-(4-氯苯基)-3-环丙基-8-乙基-2,3,5,6,7,8-六氢噁唑并[3,2-a]吡啶-4-鎓甲烷磺酸盐(实施例357,步骤A)和乙烷硫醇钠制备本标题化合物。
步骤C. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(乙基磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸
按照与实施例339步骤C中描述的程序类似的程序,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(乙基硫代)乙基)-3-乙基哌啶-2-酮(实施例357,步骤B)制备本标题化合物。
1H NMR(500MHz,氯仿-d)δppm-0.99(br s,1H)-0.25(br s,1H)0.30(br s,1H)0.40(br s,1H)0.98(t,J=7.46Hz,3H)1.44(t,J=7.58Hz,3H)1.83(m,2H)1.92-2.09(m,2H)2.41(t,J=13.69Hz,1H)2.71-2.88(m,2H)2.94(d,J=13.45Hz,1H)3.00-3.20(m,4H)4.30(br.s,,1H)4.92(d,J=10.76Hz,1H)6.81-6.87(m,1H)6.97(m,1H)7.08-7.26(m,3H);7.30-7.50(m,4H);质谱(ESI)m/z=566(M+1)。
按照与实施例339或实施例340中描述的程序类似的程序,在步骤B中使用等效量的合适的试剂,从(3S,5S,6R,8S)-8-烯丙基-6-(3-氯苯基)-5-(4-氯苯基)-3-环丙基-8-乙基-2,3,5,6,7,8-六氢噁唑并[3,2-a]吡啶-4-鎓甲烷磺酸盐(实施例357,步骤A)制备实施例358至360。
实施例358
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(异丙基磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm-1.01(br s,1H),-0.27(br s,1H),0.29(br s,1H),0.39(br s,1H),0.98(t,J=7.53Hz,3H),1.33-1.52(m,6H),1.71-1.94(m,2H),2.01(q,J=7.43Hz,2H),2.42(t,J=13.79Hz,1H),2.70-2.95(m,3H),2.99-3.24(m,3H),4.28(br s,1H),4.95(d,J=10.56Hz,1H),6.83-6.94(m,2H),6.94-7.05(m,2H),7.05-7.21(m,4H);MS(ESI)m/z=580.0和581.9(M+1)。
实施例359
2-((3R,5R,6S)-1-((S)-2-(叔丁基磺酰基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-2-氧代哌啶-3-基)乙酸
1H NMR(500MHz,氯仿-d)δppm-1.05(br s,1H)-0.29(br s,1H)0.27(br s,1H)0.34-0.42(m,1H)0.98(t,J=7.46Hz,3H)1.44(s,9H)1.81(dd,J=13.69,2.93Hz,1H)1.87-2.11(m,3H)2.43(t,J=13.82Hz,1H)2.79(d,J=15.89Hz,2H)2.95(d,J=13.20Hz,1H)3.04-3.19(m,2H)4.21(m,1H)4.97(d,J=10.76Hz,1H)6.75-6.92(m,2H)6.92-7.01(m,1H)7.06-7.17(m,3H)7.43(m,2H);质谱(ESI)m/z=594(M+1)。
实施例360
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(环丙基磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸
1H NMR(500MHz,氯仿-d)δppm-0.99(br s,1H)-0.25(br s,1H)0.29(br s,1H)0.36-0.45(m,1H)0.97(t,J=7.46Hz,3H)1.07-1.16(m,2H)1.21-1.34(m,2H)1.82(dd,J=13.69,2.93Hz,1H)1.86-1.92(m,1H)1.92-2.14(m,2H)2.36-2.46(m,2H)2.80(d,J=15.65Hz,1H)3.03-3.16(m,3H)4.34(m,1H)4.90(d,J=10.51Hz,1H)6.80-6.89(m,1H)6.92-6.99(m,1H)7.06-7.17(m,3H)7.35-7.45(m,3H);质谱(ESI)m/z=578(M+1)。
实施例361
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(乙基磺酰基)-3-甲基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. (3S,5S,6R,8S)-8-烯丙基-6-(3-氯苯基)-5-(4-氯苯基)-3-异丙基-8-甲基-2,3,5,6,7,8-六氢噁唑并[3,2-a]吡啶-4-鎓三氟甲烷磺酸盐
使用在135℃的油浴装置将L-缬氨醇(Sigma Aldrich,St.Louis,MO)(3.64g)、外消旋的(3S/R,5R/S,6R/S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基四氢-2H-吡喃-2-酮(3.17g;实施例261,步骤E)和叔丁醇锂(0.025g)加热成熔化物并保持17hr。在冷却后,将玻璃状固体溶解在二氯甲烷中。先用氯化铵饱和溶液,接着用1N氢氧化钠溶液,然后用盐水洗涤有机层。经硫酸镁干燥有机层并浓缩从而得到3.88g非对映异构体混合物。将上面获得的约1:1混合物的2.61g部分(占总体的67%)溶解在甲苯中,并三次将其蒸发至干以除去残余水分。加入二氯甲烷(55ml)和2,6-二甲基吡啶(3.3ml,28.5mmol),并将由此产生的搅拌着的溶液在干冰/乙腈浴中冷却至-50℃。用超过10分钟的时间加入三氟甲烷磺酸酐(2.4ml,14.27mmol),使得内部温度从不超过-45℃。在40min后,通过加入2M HCl来淬灭反应物。将该混合物温度升至室温,将其稀释在二氯甲烷中,用2N HCl、水,并最后用盐水洗涤。经硫酸镁干燥有机物,过滤,并浓缩至黄色泡沫状物,其重量为约2.6g。通过中压液相色谱法使用120g柱,用20%至100%的在己烷中的丙酮梯度洗脱来对该材料的一部分(1.92g,74%)进行纯化。对含有较快洗脱(极性较小)的非对映异构体的级分进行浓缩从而得到本标题化合物,为白色泡沫状物。
1H NMR(400MHz,CDCl3)δppm 0.62(d,J=2.4Hz,3H),0.64-0.74(m,4H),1.51(s,3H),2.04(dd,J=14.1,3.5Hz,1H),2.54-2.79(m,3H),3.58(ddd,J=13.7,10.8,3.5Hz,1H),4.59(dd,J=10.2,4.7Hz,1H),4.67(dd,J=9.2,4.9Hz,1H),5.23-5.45(m,3H),5.71(d,J=11Hz,1H),5.83(ddt,J=17,9.9,7.4Hz,1H),7.06(t,J=1.8Hz,1H),7.11-7.16(m,1H),7.19(t,J=7.7Hz,1H),7.23-7.32(m,3H),7.39(br s,2H);质谱(ESI)m/z=442.2(M+)。
步骤B. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(乙基磺酰基)-3-甲基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
按照与实施例339中描述的程序类似的程序,在步骤B中使用等效量的乙烷硫醇,从(3S,5S,6R,8S)-8-烯丙基-6-(3-氯苯基)-5-(4-氯苯基)-3-异丙基-8-甲基-2,3,5,6,7,8-六氢噁唑并[3,2-a]吡啶-4-鎓三氟甲烷磺酸盐(实施例361,步骤A)制备本标题化合物。
1H NMR(500MHz,甲醇-d4)δppm 0.51(d,J=7.1Hz,3H),0.66(d,J=6.6Hz,3H),1.37(s,3H),1.41(t,J=7.5Hz,3H),2.05(dd,J=13.7,2.9Hz,1H),2.18(dq,J=14.2,6.9Hz,1H),2.31(t,J=13.7Hz,1H),2.62(d,J=13.7Hz,1H),3.00(d,J=13.7Hz,1H),3.14-3.24(m,3H),3.25-3.30(m,1H),3.57(ddd,J=13.8,10.9,2.9Hz,1H),4.02(dd,J=13.9,10.5Hz,1H),5.12(d,J=11Hz,1H),7.00(dt,J=7.3,1.5Hz,1H),7.04-8.17(m,7H);质谱(ESI)m/z=554.2(M+1)。
实施例362
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(异丙基磺酰基)-3-甲基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
按照与实施例339中描述的程序类似的程序,在步骤B中使用等效量的丙烷-2-硫醇,从(3S,5S,6R,8S)-8-烯丙基-6-(3-氯苯基)-5-(4-氯苯基)-3-异丙基-8-甲基-2,3,5,6,7,8-六氢噁唑并[3,2-a]吡啶-4-鎓三氟甲烷磺酸盐(实施例361,步骤A)制备本标题化合物。
1H NMR(500MHz,甲醇-d4)δppm 0.50(d,J=6.9Hz,3H),0.65(d,J=6.6Hz,3H),1.37(s,3H),1.41(d,J=6.9Hz,6H),2.05(dd,J=13.6,2.8Hz,1H),2.18(dq,J=14,6.9Hz,1H),2.31(t,J=13.7Hz,1H),2.61(d,J=13.5Hz,1H),2.99(d,J=13.7Hz,1H),3.11(d,J=13.7Hz,1H),3.25-3.29(m,1H),3.32-3.37(m,1H),3.49-3.65(m,1H),4.01(dd,J=13.7,10.5Hz,1H),5.13(d,J=11Hz,1H),6.93-7.03(m,1H),7.03-8.23(m,7H);质谱(ESI)m/z=568.0(M+1)。
实施例363
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-3,3-二甲基-1-(甲基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. (S)-2-((2R,3R)-2-(3-氯苯基)-3-(4-氯苯基)-3-羟基丙基)-N-((S)-1-羟基-3,3-二甲基丁烷-2-基)-2-甲基戊-4-烯酰胺
将(S)-叔亮氨醇(0.937g,7.99mmol)和(3S,5R,6R)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基四氢-2H-吡喃-2-酮(1g,2.66mmol;实施例261,步骤F)合并在反应烧瓶中,并将其加热至100℃。在2d后,将反应混合物冷却至室温并将其溶解在乙酸乙酯中。用3x10mL 1N HCl和1x10mL盐水洗涤有机相,经MgSO4干燥,过滤并浓缩从而得到本标题化合物。
1H-NMR(500MHz,CDCl3)δ7.21-7.10(系列m,5H),7.07(t,J=1.7Hz,1H),6.97(m,2H),6.87(br d,J=7.6Hz,1H),5.91(br d,J=8.3Hz,1H),5.65(ddt,J=17.4,10.3,7.3Hz,1H),5.05(dd,J=10.5,2.0Hz,1H),4.77(d,J=4.9Hz,1H),3.77(m,2H),3.42(m,1H),3.02(dt,J=7.6,5.4Hz,1H),2.42(dd,J=13.9,7.1Hz,1H),2.23(dd,J=14.7,5.6Hz,1H),2.05(dd J=13.7,7.6Hz,1H),1.87(dd,J=14.4,7.6Hz,1H),1.17(s,3H),0.92(s,9H);质谱(ESI)m/z=492.2(M+1)。
步骤B. (3S,5S,6R,8S)-8-烯丙基-3-(叔丁基)-6-(3-氯苯基)-5-(4-氯苯基)-8-甲基-2,3,5,6,7,8-六氢噁唑并[3,2-a]吡啶-4-鎓三氟甲磺酸盐
向在-50℃下的(S)-2-((2R,3R)-2-(3-氯苯基)-3-(4-氯苯基)-3-羟基丙基)-N-((S)-1-羟基-3,3-二甲基丁烷-2-基)-2-甲基戊-4-烯酰胺(实施例363,步骤A,950mg,1.929mmol)在DCM(19mL)中的溶液中加入2,6-二甲基吡啶(896μl,7.72mmol),接着加入三氟甲烷磺酸酐溶液(1M DCM,4.34mL,4.34mmol)。根据LC/MS监测反应的进展。再装入450uL(2当量)2,6-二甲基吡啶,接着装入1.12当量三氟甲磺酸酐(2.16mmol,2.16mL在二氯甲烷中的1M溶液)。让反应物温度升至0℃,然后将其倒入CuSO4饱和水溶液中。向该混合物中加入100mL乙酸乙酯。分离各层,并用CuSO4饱和水溶液洗涤有机相。浓缩合并的有机层,并通过硅胶柱色谱法(洗脱剂:20%至50%的在己烷中的丙酮)纯化从而得到本标题化合物。
1H-NMR(500MHz,DMSO-d6)δppm 7.80-7.42(系列m,3H),7.38-7.28(系列m,4H),7.14(d,J=7.6Hz,1H),5.85(ddt,J=17.2,10.0,7.3Hz,1H),5.61(d,J=7.1Hz,1H),5.37(dd,J=16.9,1.7Hz,1H),5.22(dd,J=10.0,7.0Hz,1H),5.17(t,J=9.7Hz,1H),4.61(dd,J=9.3,6.9Hz,1H),3,92(ddd,J=9.8,7.6,4.2Hz,1H),2.71(m,2H),2.23(dd,J=14.2,9.5Hz,1H),2.10(dd,J=14.2,4.4Hz,1H),1.08(s,3H),0.62(s,9H);质谱(ESI)m/z=474.2(M+)。
步骤C. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-3,3-二甲基-1-(甲基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
按照与实施例340中描述的程序类似的程序,在步骤B中使用等效量的甲烷亚磺酸钠,从(3S,5S,6R,8S)-8-烯丙基-3-(叔丁基)-6-(3-氯苯基)-5-(4-氯苯基)-8-甲基-2,3,5,6,7,8-六氢噁唑并[3,2-a]吡啶-4-鎓三氟甲磺酸盐(实施例363,步骤B)制备本标题化合物。
实施例364
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(乙基磺酰基)-3,3-二甲基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
按照与实施例340中描述的程序类似的程序,在步骤B中使用等效量的乙烷亚磺酸钠,从(3S,5S,6R,8S)-8-烯丙基-3-(叔丁基)-6-(3-氯苯基)-5-(4-氯苯基)-8-甲基-2,3,5,6,7,8-六氢噁唑并[3,2-a]吡啶-4-鎓三氟甲磺酸盐(实施例363,步骤B)制备本标题化合物。
1H NMR(500MHz,氯仿-d)δppm 7.13-7.60(m,4H),7.04-7.12(m,2H),6.94-7.00(m,2H),5.90(ddt,J=17.2,9.8,7.5Hz,1H),5.17-5.29(m,2H),5.12(d,J=11.0Hz,1H),4.27(dd,J=13.2,11.2Hz,1H),3.56(dd,J=11.0,2.2Hz,1H),3.45(ddd,J=13.8,10.9,3.2Hz,1H),3.03-3.14(m,2H),2.78(dd,J=13.2,2.2Hz,1H),2.67(ABX,JAB=13.7Hz,JAX=8.1Hz,1H),2.61(ABX JAB=13.7Hz,JBX=6.8Hz,1H)(m,2H),2.27(t,J=13.7Hz,1H),1.81(dd,J=13.6,3.3Hz,1H),1.47(t,J=7.5Hz,3H),1.25(s,3H),0.71(s,9H);质谱(ESI)m/z=550.2(M+1)。
实施例365
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(异丙基磺酰基)-3,3-二甲基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基-3,3-二甲基丁烷-2-基)-3-甲基哌啶-2-酮
向(3S,5S,6R,8S)-8-烯丙基-3-(叔丁基)-6-(3-氯苯基)-5-(4-氯苯基)-8-甲基-2,3,5,6,7,8-六氢噁唑并[3,2-a]吡啶-4-鎓三氟甲烷磺酸盐(290mg,0.478mmol;实施例363,步骤B)在1,2-二氯乙烷(4.78mL)中的溶液中加入5mLNaHCO3饱和水溶液。将反应混合物加热至50℃并保持3天。将反应混合物倒入分液漏斗中,并用二氯甲烷萃取水层。用NaHCO3饱和水溶液洗涤合并的有机层,经MgSO4干燥,过滤,并浓缩滤液。通过柱色谱法使用25-35%的在己烷中的乙酸乙酯在4g硅胶柱上纯化,得到本标题化合物。
1H-NMR(500MHz,DMSO-d6)δppm 7.50-7.05(系列m,7H),6.97(d,J=7.3Hz,1H),5.87(dddd,J=16.9,10.0,8.3,6.6Hz,1H),5.26(brd,J=16.6Hz,1H),5.14(dd,J=10.0,2.2Hz,1H),4.76(d,J=11.0Hz,1H),3.97(td,J=10.3,6.8Hz,1H),2.51(m,2H),2.76(dd,J=9.5,4.4Hz),2.65(dd,J=13.7,8.3Hz,1H),2.50(m,被溶剂掩蔽),2.07(t,J=13.5Hz,1H),1.75(dd,J=13.2,3.0Hz,1H),1.12(s,3H),0.63(s,9H);质谱(ESI)m/z=474.2(M+1)。
步骤B. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(异丙基磺酰基)-3,3-二甲基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
按照与实施例300中描述的程序类似的程序,用适量的丙烷-2-硫醇代替苯硫醇,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基-3,3-二甲基丁烷-2-基)-3-甲基哌啶-2-酮(实施例365,步骤A)制备本标题化合物。
1H-NMR(500MHz,DMSO-d6)δppm 12.36(s,1H),7.81(br s,1H),7.48(br s,1H),7.25(br s,1H),7.22(t,J=7.8Hz,1H),7.15(ddd,J=7.8.2.0,0.7Hz,1H),7.04(t,J=1.7Hz,1H),7.00(br d,J=7.8Hz,1H),5.05(d,J=11.2Hz,1H),3.90(dd,J=13.7,11.0,2.6Hz,1H),3.70(ddd,J=13.7,11.0,2.6Hz,1H),3.45(m,2H),3.12(dd,J=13.4,2.0,1H),2.97(d,J=13.9Hz,1H),2.52(m,被溶剂掩蔽),2.14(t,J=13.2Hz,1H),2.03(dd,J=13.4Hz,1H),1.32(d,J=6.8Hz,3H),1.31(d,J=6.6Hz,3H),1.23(s,3H),0.62(s,9H);质谱(ESI)m/z=582.2(M+1)。
实施例366
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(戊烷-3-基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-巯基乙基)-3-甲基哌啶-2-酮
向(3S,5S,6R,8S)-8-烯丙基-6-(3-氯苯基)-5-(4-氯苯基)-3-环丙基-8-甲基-2,3,5,6,7,8-六氢噁唑并[3,2-a]吡啶-4-鎓甲烷磺酸盐(370mg;实施例349,步骤A)在DMF(1.6mL)中的溶液中加入氢硫化钠(105mg,1.88mmol)。在室温下搅拌过夜后,淬灭(NH4Cl饱和水溶液)反应物,对其进行萃取(2×EtOAc),并用盐水洗涤(3×)合并的有机物。干燥(Na2SO4)合并的有机层并在减压下浓缩。通过硅胶色谱法(24gSiO2,用10%至40%的在hex中的EtOAc梯度洗脱)纯化残余物,得到本标题化合物。
步骤B. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(戊烷-3-基硫代)乙基)-3-甲基哌啶-2-酮
在25℃下向(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-巯基乙基)-3-甲基哌啶-2-酮(49mg,0.10mmol;实施例366,步骤A)和3-溴戊烷(51μl,0.41mmol)在DMF(0.52mL)中的溶液中加入在矿物油中的60%氢化钠(17mg,0.41mmol)。将反应物在25℃下搅拌1h,然后将其加热至60℃。在60℃下搅拌过夜后,淬灭(10%柠檬酸水溶液)反应物,萃取(2×EtOAc),并洗涤(3×盐水)。干燥(Na2SO4)合并的有机层并在减压下浓缩。通过硅胶色谱法(4g SiO2,9%和18%的EtOAc/hex)纯化残余物,得到本标题化合物。
步骤C. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(戊烷-3-基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
按照与实施例71步骤F中描述的程序类似的程序,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(戊烷-3-基硫代)乙基)-3-甲基哌啶-2-酮(实施例366,步骤B)制备本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 7.20-7.34(3H,m),7.06-7.16(3H,m),6.93-6.98(1H,s),6.83-6.90(1H,m),4.93(1H,d,J=10.6Hz),4.35(1H,br,s),3.05-3.20(2H,m),2.65-2.92(4H,m),2.46(1H,t,J=13.8Hz),1.92-2.11(2H,m),1.75-1.91(4H,m),1.50(3H,s),1.06-1.19(6H,m),0.32-0.42(1H,m),0.18-0.28(1H,m),-0.35--0.25(1H,m),-1.12--1.02(1H,m);质谱(ESI)m/z=594.2[M+H]+。
实施例367
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-((S)-异丙基亚磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-((R)-异丙基亚磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;极性较大的异构体
步骤A. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(异丙基硫代)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸甲酯
按照与实施例300步骤A中描述的程序类似的程序,使用适量的丙烷硫醇并总共反应3h,从2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸甲酯(实施例186,步骤A,187mg,0.391mmol)和丙烷-2-硫醇(119mg,1.56mmol)获得上面的化合物。通过硅胶色谱法(12g,SiO2,5%至20%的EtOAc/Hex)纯化残余物,得到本标题化合物,为浅黄色油状物。
1H NMR(400MHz,氯仿-d)δppm 7.22(d,J=8.4Hz,2H),7.05-7.18(m,2H),7.02(t,J=1.7Hz,2H),6.79(td,J=1.4,7.4Hz,1H),4.66(d,J=10.6Hz,1H),3.70(s,3H),3.41(dd,J=11,12.7Hz,1H),3.16(ddd,J=3.1,10.6,13.6Hz,1H),2.82-2.94(m,2H),2.67-2.79(m,2H),2.57(dd,J=4.1,12.9Hz,1H),2.16-2.27(m,1H),1.97-2.12(m,2H),1.57(ddd,J=3.8,7.8,14.Hz,1H),1.41(d,J=6.9Hz,3H),1.29-1.34(m,5H),0.49(d,J=15.3Hz,3H);质谱(ESI)m/z=558.1[M-H]-,560.1[M+H]+。
步骤B. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-((S)-异丙基亚磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸甲酯和2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-((R)-异丙基亚磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸甲酯
将3-氯过氧苯甲酸(45.4mg,0.203mmol)加入到在0℃下的2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(异丙基硫代)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸甲酯(136mg,0.253mmol;实施例367,步骤A)在DCM(3mL)中的溶液中。在0℃下1h后,根据LCMS(MS(ESI)552.2[M+H]+,554.0[M-H]-)监测反应,显示为60%转化。在此时再加入0.2当量3-氯过氧苯甲酸。在2小时后再次监测反应,显示为85%转化,在此时用NaHCO3饱和水溶液淬灭反应。用EtOAc萃取该溶液,并且用盐水洗涤合并的有机层,经MgSO4干燥,过滤并浓缩滤液。通过硅胶色谱法(12g,SiO2,10-60%的EtOAc/己烷,50min)纯化残余物从而得到本标题化合物,为非对映异构体的2:1混合物,为浅黄色油状物。
1H NMR(400MHz,氯仿-d)δppm 7.20-7.29(m,4H),7.20-7.26(m,2H),7.19-7.20(m,1H),7.04-7.20(m,6H),6.95-7.02(m,2H),6.82-6.95(m,2H),4.75-4.90(m,1H),3.62-3.74(m,5H),3.37-3.48(m,1H),3.07-3.32(m,3H),2.59-2.95(m,6H),1.93-2.33(m,5H),1.47-1.74(m,3H),1.22-1.42(m,17H),0.79-0.95(m,2H),0.37-0.56(m,4H);质谱(ESI)m/z=552.2[M-H]-,554.0[M+H]+。
步骤C. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-((S)-异丙基亚磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-((R)-异丙基亚磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;极性较大的异构体
向2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-((S)-异丙基亚磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸甲酯和2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-((R)-异丙基亚磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸甲酯(100mg,0.181mmol,为异构体的2:1混合物;实施例267,步骤B)在MeOH/THF/H2O(1mL/2mL/1mL)中的溶液中加入氢氧化锂(43.3mg,1.810mmol)。让反应混合物搅拌18h。在这段时间后,用1N HCl酸化反应混合物,并用EtOAc(3x10mL)萃取。将有机物汇集在一起,用盐水洗涤,干燥(MgSO4),过滤,并在真空中浓缩。通过反相制备型HPLC(GeminiTMPrep C185mm柱;Phenomenex,Torrance,CA;用25%至55%的在水中的MeCN梯度洗脱30min,其中这两种溶剂都含有0.1%TFA)纯化粗材料从而得到本标题化合物中的一种,为极性较大的异构体(tR=21.45min)。
1H NMR(400MHz,氯仿-d)δppm7.22(d,J=8.0Hz,2H),7.00-7.17(m,4H),6.80-6.98(m,2H),4.80(d,J=10.8Hz,1H),3.53-3.73(m,1H),3.11-3.30(m,2H),2.68-3.00(m,4H),1.97-2.29(m,3H),1.40-1.54(m,4H),1.36(d,J=6.9Hz,3H),1.28(d,J=6.9Hz,3H),0.41(t,J=7.5Hz,3H);质谱(ESI)538.2[M-H]-,540.2[M+H]+。
从实施例367进一步洗脱得到极性较小的异构体:
实施例368
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-((S)-异丙基亚磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-((R)-异丙基亚磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
极性较小的异构体(tR=21.45min)。
1H NMR(400MHz,氯仿-d)δppm 7.23-7.27(m,2H),7.10(td,J=7.9,15.7Hz,4H),6.96(s,1H),6.81(d,J=7.4Hz,1H),4.75(s,1H),3.07-3.54(m,3H),2.70-3.01(m,3H),2.58(d,J=10.4Hz,1H),2.27-2.40(m,1H),2.01-2.17(m,1H),1.95(dd,J=2.6,13.8Hz,1H),1.55-1.69(m,1H),1.46(s,3H),1.23-1.35(m,6H),0.52(d,J=14.3Hz,3H);质谱(ESI)m/z=538.2[M-H]-,540.2[M+H]+。
实施例369
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((2S,3S)-2-(甲基磺酰基)戊烷-3-基)-2-氧代哌啶-3-基)乙酸或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((2R,3S)-2-(甲基磺酰基)戊烷-3-基)-2-氧代哌啶-3-基)乙酸
步骤A. (3S,5S,6R,8S)-8-烯丙基-6-(3-氯苯基)-5-(4-氯苯基)-3-乙基-2,8-二甲基-2,3,5,6,7,8-六氢噁唑并[3,2-a]吡啶-4-鎓4-甲基苯磺酸盐
向(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S)-2-羟基戊烷-3-基)-3-甲基哌啶-2-酮(2.25g,4.89mmol;实施例151,步骤C)在甲苯(65mL)中的溶液中加入对甲苯磺酸一水合物(930mg,4.89mmol)。在使用Dean-Stark蒸馏器加热至回流2.5h后,在减压下浓缩反应物从而得到本标题化合物,为浅黄色粉末。
步骤B. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((2S,3S)-2-(甲基磺酰基)戊烷-3-基)哌啶-2-酮和(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((2R,3S)-2-(甲基磺酰基)戊烷-3-基)哌啶-2-酮
该反应在高压反应容器中进行。在25℃下向(3S,5S,6R,8S)-8-烯丙基-6-(3-氯苯基)-5-(4-氯苯基)-3-乙基-2,8-二甲基-2,3,5,6,7,8-六氢噁唑并[3,2-a]吡啶-4-鎓4-甲基苯磺酸盐(0.200g,0.325mmol;实施例370,步骤A)在乙腈(2ml)中的溶液中加入甲烷亚磺酸钠(0.166g,1.627mmol)。然后将反应物加热至110℃并保持24h。用NH4Cl饱和水溶液淬灭反应物,萃取(2×EtOAc)并洗涤(2×盐水)。干燥(Na2SO4)合并的有机层并在减压下浓缩。通过硅胶色谱法(40g SiO2,用20%至40%的在己烷中的EtOAc梯度洗脱)纯化,得到本标题化合物,为两个立体异构体的混合物。
步骤C. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((2S,3S)-2-(甲基磺酰基)戊烷-3-基)-2-氧代哌啶-3-基)乙酸或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((2R,3S)-2-(甲基磺酰基)戊烷-3-基)-2-氧代哌啶-3-基)乙酸
按照与实施例71步骤F中描述的程序类似的程序,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((2S,3S)-2-(甲基磺酰基)戊烷-3-基)哌啶-2-酮和(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((2R,3S)-2-(甲基磺酰基)戊烷-3-基)哌啶-2-酮的混合物(实施例370,步骤B)获得本标题化合物。通过反相制备型HPLC(GeminiTMPrep C185μm柱;Phenomenex,Torrance,CA;洗脱剂:40%至60%的乙腈、水、0.1%TFA,梯度洗脱)纯化粗产物从而得到本标题化合物,为第一洗脱异构体,为单一立体异构体。
1H NMR(400MHz,氯仿-d)δppm 0.46(t,J=7.5Hz,3H)1.55(s,3H)1.60(d,J=7.2Hz,3H)1.78-1.81(m,1H)1.84-1.93(m,1H)2.29-2.43(m,2H)2.72(d,J=15.5Hz,1H)2.93(s,3H)2.97-3.09(m,2H)3.14(m,1H)3.53(m,1H)5.00(d,J=10.6Hz,1H)6.82(m,1H)6.92-6.97(m,1H)7.07-7.18(m,2H),7.27(m,4H);质谱(ESI)m/z=540(M+1)。
实施例370
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2S,3S)-2-(乙基磺酰基)戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2R,3S)-2-(乙基磺酰基)戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;第一洗脱异构体
按照与实施例369中描述的程序类似的程序,用乙烷亚磺酸钠代替步骤B中的甲烷亚磺酸钠,从(3S,5S,6R,8S)-8-烯丙基-6-(3-氯苯基)-5-(4-氯苯基)-3-乙基-2,8-二甲基-2,3,5,6,7,8-六氢噁唑并[3,2-a]吡啶-4-鎓4-甲基苯磺酸盐(实施例369,步骤A)制备本标题化合物。通过反相制备型HPLC(GeminiTMPrep C185mm柱;Phenomenex,Torrance,CA;洗脱剂:40%至60%的乙腈、水、0.1%TFA,梯度洗脱)纯化粗产物从而得到本标题化合物,为第一洗脱异构体,为单一立体异构体。
1H NMR(400MHz,氯仿-d)δppm 0.45(t,J=7.53Hz,3H)1.41(t,J=7.53Hz,3H)1.48-1.62(m,6H)1.69-1.92(m,2H)2.29-2.43(m,2H)2.70(d,J=15.45Hz,1H)2.92-3.19(m,5H)3.49-3.56(m,1H)5.02(d,J=10.56Hz,1H)6.84(dt,J=6.99,1.88Hz,1H)6.95(t,J=1.96Hz,1H)7.08-7.19(m,3H)7.25(br s,3H);质谱(ESI)m/z=554(M+1)。
进一步洗脱得到:
实施例371
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2R,3S)-2-(乙基磺酰基)戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2S,3S)-2-(乙基磺酰基)戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;第二洗脱异构体
本标题化合物是在实施例370获得的,为第二洗脱异构体。
1H NMR(400MHz,氯仿-d)δppm 0.20(t,J=7.63Hz,3H)1.12-1.30(m,3H)1.30-1.45(m,6H)1.45-1.60(m,1H)1.71-1.80(m,1H)1.85-1.98(m,1H)2.40(t,J=13.79Hz,1H)2.63(d,J=15.26Hz,1H)2.86-3.09(m,5H)4.05-4.19(m,1H)4.93(d,J=10.76Hz,1H)6.78(dt,J=6.90,1.93Hz,1H)6.89(t,J=1.96Hz,1H)6.95-7.11(m,4H)7.11-7.25(m,2H);质谱(ESI)m/z=554(M+1)。
实施例372
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-(氧杂环丁烷-3-基)氨磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
步骤A. 2-((3R,5R,6S)-1-((S)-1-(苄基硫代)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸甲酯
向2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸甲酯(214.4mg,0.448mmol;实施例186,步骤A)在甲苯(2.0mL)中的溶液中加入苄基硫醇(0.106mL,0.90mmol),接着加入氰基亚甲基三丁基正膦(0.235mL,0.896mmol;TCI)。将该溶液在100℃下加热3.75小时,然后在真空中浓缩。通过硅胶色谱法(12g SiO2,0%至50%的在己烷中的EtOAc)纯化残余物,得到本标题化合物,为无色油状物。
步骤B. (S)-2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-(2-甲氧基-2-氧代乙基)-3-甲基-2-氧代哌啶-1-基)丁烷-1-磺酸
向2-((3R,5R,6S)-1-((S)-1-(苄基硫代)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸甲酯(1.31g,2.24mmol;实施例372,步骤A)在乙酸(9.5ml)和水(1.0ml)中的溶液中加入过氧化氢(31.3%的水溶液,0.23ml,2.35mmol)。将由此产生的溶液在室温下搅拌3小时,然后向该反应物中鼓入氯气1分钟。在室温下搅拌1小时后,在真空中浓缩反应物,然后加入几毫升无水苯,并在减压下在旋转蒸发器上除去该溶剂。将这个程序重复数次从而得到本标题化合物,为黄色固体。将该粗材料直接用于下一步骤而无需纯化。
步骤C. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-(氧杂环丁烷-3-基)氨磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸甲酯
向(S)-2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-(2-甲氧基-2-氧代乙基)-3-甲基-2-氧代哌啶-1-基)丁烷-1-磺酸(189.8mg,0.35mmol;实施例372,步骤B)在二氯甲烷(5.0mL)中的溶液中加入乙二酰氯(0.061mL,0.70mmol),接着加入DMF(2滴)。将反应物在室温下搅拌3.5小时,然后在真空中浓缩。将磺酰氯中间体溶解在二氯甲烷(5.0mL)中,然后用3-氧杂环丁烷胺(50.0mg,0.684mmol;Pharmablock R&D Co.Ltd.,Nanjing,China)和N,N-二异丙基乙胺(0.122mL,0.699mmol)处理。在室温下搅拌16小时后,用甲醇(2.0mL)淬灭反应物,然后在真空中浓缩。通过硅胶色谱法(4g SiO2,0%-50%的在己烷中的EtOAc)纯化残余物,得到本标题化合物,为无色油状物。
步骤D. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-(氧杂环丁烷-3-基)氨磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
向2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-(氧杂环丁烷-3-基)氨磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸甲酯(41.1mg,0.069mmol;实施例372,步骤C)在THF(2.0ml)和MeOH(1.0ml)中的溶液中加入1N氢氧化锂(3.0ml,3.0mmol)。将悬浮液在室温下搅拌15小时,然后使用1N HCl将其酸化至pH为4,然后在真空中浓缩。通过硅胶色谱法(4g SiO2,用5%至25%的在己烷中的1:6.5MeOH/丙酮混合物梯度洗脱)纯化残余物,得到本标题化合物。通过反相制备型HPLC(Eclipse Plus C18,30x250mm,5μm柱;Agilent,Santa Clara,CA)(洗脱剂:含有0.1%TFA的乙腈/水,用30%至60%的梯度洗脱超过25min)进一步纯化该材料从而得到本标题化合物,为白色固体。
1H NMR(500MHz,甲醇-d4)δppm 0.39(t,J=7.5Hz,3H)1.38(s,3H)1.45-1.56(m,1H)1.91-2.01(m,1H)2.02-2.08(m,1H)2.26(t,J=13.7Hz,1H)2.59(d,J=13.7Hz,1H)2.88-2.99(m,2H)3.07-3.19(m,1H)3.34-3.41(m,2H)3.91-4.01(m,1H)4.55-4.66(m,3H)6.91-6.97(m,1H)7.02(s,1H)7.10-7.19(m,3H)7.28(br s,3H);质谱(ESI)m/z=583.2[M+H]+。
按照与实施例372中描述的程序类似的程序,用合适的试剂代替步骤B中的3-氧杂环丁烷胺,从(S)-2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-(2-甲氧基-2-氧代乙基)-3-甲基-2-氧代哌啶-1-基)丁烷-1-磺酸(实施例372,步骤B)制备实施例373和374。
实施例373
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-((3-甲基氧杂环丁烷-3-基)甲基)氨磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
1H NMR(500MHz,甲醇-d4)δppm 0.42(t,J=7.58Hz,3H)1.25(s,2H)1.34(s,3H)1.39(s,3H)1.53(ddd,J=14.24,7.76,3.18Hz,1H)1.97-2.08(m,2H)2.16(s,1H)2.18(s,1H)2.29(t,J=13.69Hz,1H)2.57-2.64(m,1H)2.95(d,J=13.45Hz,1H)3.00-3.06(m,1H)3.19(br s,1H)3.35-3.42(m,1H)4.04(t,J=12.35Hz,1H)4.37(d,J=6.11Hz,1H)4.54(d,J=6.11Hz,1H)4.91(d,J=10.76Hz,1H)6.96(d,J=7.34Hz,1H)7.03(s,1H)7.11-7.20(m,3H)7.28(br s,3H);质谱(ESI)611.2[M+H]+。
实施例374
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-(氧杂环丁烷-3-基甲基)氨磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
1H NMR(500MHz,甲醇-d4)δppm 0.41(t,J=7.58Hz,3H)1.38(s,3H)1.46-1.59(m,1H)2.01-2.08(m,2H)2.28(t,J=13.69Hz,1H)2.60(d,J=13.69Hz,1H)2.94(d,J=13.69Hz,1H)3.03(d,J=12.47Hz,1H)3.10-3.25(m,3H)3.34-3.42(m,2H)3.95-4.07(m,1H)4.42-4.51(m,2H)4.76-4.82(m,2H)4.88-4.91(m,1H)6.95(dt,J=7.03,1.62Hz,1H)7.00-7.04(m,1H)7.09-7.18(m,3H)7.28(br s,3H);质谱(ESI)597.1[M+H]+。
实施例375
2-((3R,5R,6S)-1-((S)-2-(N-(叔丁基)氨磺酰基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. (3S,5R,6S)-3-烯丙基-1-((S)-2-(苄基硫代)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮
将(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-羟基乙基)-3-甲基哌啶-2-酮(1.35g,2.94mmol;实施例252,步骤A)、苄基硫醇(0.691ml,5.89mmol)和2-(三丁基正膦亚基)在乙腈(1.579ml,5.89mmol)中的混合物加热至100℃并保持2h。将反应混合物冷却至室温,并用80mL EtOAc萃取。用NH4Cl饱和水溶液和盐水洗涤合并的有机物,经Na2SO4干燥,过滤,并浓缩滤液。通过硅胶色谱法用0%至50%的EtOAc/己烷洗脱来纯化粗产物从而得到本标题化合物。
质谱(ESI)m/z=564.1(M+1)。
步骤B. 2-((3R,5R,6S)-1-((S)-2-(N-(叔丁基)氨磺酰基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸
向在0℃下的(3S,5R,6S)-3-烯丙基-1-((S)-2-(苄基硫代)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮(0.075g,0.133mmol;实施例375,步骤A)在5mL MeCN/HOAc/H2O(40:1.5:1)混合物中的溶液中分批加入1,3-二氯-5,5-二甲基咪唑烷-2,4-二酮(0.052g,0.266mmol)(Alfa Aesar,Ward Hill,MA)。将反应混合物在0℃-5℃下搅拌2h。将该溶液加入到在0℃下的叔丁胺(97mg,140μL,5.0当量)和DIEA(5.0当量)在2mLDCM中的混合物中。将由此产生的混合物在室温下搅拌3h。在减压下除去该溶剂,并通过硅胶色谱法用30%至80%的EtOAc/己烷洗脱来纯化残余物从而得到相应的磺酰胺。按照与实施例71,步骤F中描述的程序类似的程序将该磺酰胺转化为本标题化合物。通过反相HPLC(用40%至90%的含有0.1%TFA的在水中的乙腈梯度洗脱)纯化粗产物从而得到本标题化合物。
1H NMR(400MHz,氯仿-d)δppm-1.09(br s,1H),-0.26(br s,1H),0.19-0.50(m,2H),1.42(s,9H),1.54(s,3H),1.88(d,J=13.30Hz,2H),2.48(d,J=12.32Hz,1H),2.76(d,J=15.26Hz,1H),2.97-3.26(m,3H),4.14-4.52(m,2H),4.82(d,J=10.76Hz,1H),6.86(d,J=5.87Hz,1H),6.97(s,1H),7.06-7.22(m,3H),7.29(br s,3H)。质谱(ESI)m/z=595.2(M+1)。
按照与实施例375中描述的程序类似的程序,用合适的试剂代替步骤B中的叔丁胺,从(3S,5R,6S)-3-烯丙基-1-((S)-2-(苄基硫代)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮(实施例375,步骤A)制备实施例376至382。
实施例376
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-甲基氨磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm-1.13--0.88(m,1H),-0.23(br s,1H),0.23-0.50(m,2H),1.51(s,3H),1.70–1.89(m,1H),2.10-2.16(m,1H),2.21-2.32(m,1H),2.40-2.51(m,1H),2.78(d,J=15.26Hz,1H),2.84(d,J=3.52Hz,3H),2.93-3.06(m,1H),3.07-3.23(m,2H),3.52-3.67(m,1H),4.82(d,J=10.37Hz,1H),6.83(d,J=7.24Hz,1H),6.96(s,1H),7.12-7.15(m,3H),7.19-7.27(m,3H)。质谱(ESI)m/z=553.0.(M+1)。
实施例377
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N,N-二甲基氨磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm-1.07(br s,1H),-0.28(br s,1H),0.18-0.44(m,2H),1.53(s,3H),1.87(dd,J=13.79,2.84Hz,2H),2.50(t,J=13.79Hz,1H),2.60(br s,1H),2.73-2.84(m,2H),2.90(s,6H),3.07-3.19(m,2H),4.19(t,J=12.42Hz,1H),4.83(d,J=10.56Hz,1H),6.83-6.89(m,1H),6.95(s,1H),7.07-7.16(m,3H),7.27(br s,3H)。质谱(ESI)m/z=567.0(M+1)。
实施例378
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-异丙基氨磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm-1.08(br s,1H),-0.27(br s,1H),0.19-0.49(m,2H),1.22-1.33(m,6H),1.50(s,3H),1.67-1.99(m,2H),2.44(br s,1H),2.58(br s,1H),2.77(d,J=14.87Hz,1H),2.98(d,J=10.76Hz,1H),3.02-3.25(m,2H),3.64(d,J=6.26Hz,1H),4.10-4.46(m,1H),4.81(d,J=10.56Hz,1H),6.84(d,J=6.46Hz,1H),6.95(s,1H),7.06-7.16(m,3H),7.27(br s,3H)。质谱(ESI)m/z=581.2(M+1)。
实施例379
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(吗啉代磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm-1.06(br s,1H),-0.29(br s,1H),0.19-0.44(m,2H),1.50(s,3H),1.79-1.94(m,2H),2.47(t,J=13.89Hz,1H),2.60(br s,1H),2.79(d,J=15.06Hz,2H),3.08(d,J=15.06Hz,1H),3.11-3.20(m,1H),3.24-3.30(m,4H),3.77-3.83(m,4H),4.22(t,J=12.52Hz,1H),4.82(d,J=10.76Hz,1H),6.86(d,J=7.04Hz,1H),6.95(s,1H),7.06-7.16(m,3H),7.21-7.33(m,3H)。质谱(ESI)m/z=609.2(M+1)。
实施例380
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(哌啶-1-基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm-1.09(br s,1H),-0.30(br s,1H),0.20-0.43(m,2H),1.53(s,3H),1.56-1.62(m,2H),1.63-1.96(m,5H),2.00-2.13(m,1H),2.52(t,J=13.79Hz,1H),2.60(br s,1H),2.71-2.81(m,2H),3.07-3.20(m,2H),3.24(t,J=5.28Hz,4H),4.13(d,J=13.11Hz,1H),4.85(d,J=10.76Hz,1H),6.86(d,J=7.04Hz,1H),6.94(s,1H),7.07-7.18(m,3H),7.23-7.38(m,3H)。质谱(ESI)m/z=607.2(M+1)。
实施例381
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(吡咯烷-1-基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm-1.08(br s,1H),-0.28(br s,1H),0.17-0.42(m,2H),1.52(s,3H),1.81(br s,1H),1.88(dd,J=13.79,2.84Hz,1H),1.94-2.01(m,4H),2.50(t,J=13.79Hz,1H),2.62(br s,1H),2.78(d,J=15.06Hz,1H),2.86(d,J=12.13Hz,1H),3.05-3.20(m,2H),3.28-3.45(m,4H),4.24(br s,1H),4.84(d,J=10.56Hz,1H),6.89(d,J=6.65Hz,1H),6.98(s,1H),7.07-7.19(m,3H),7.21-7.37(m,3H)。质谱(ESI)m/z=593.0(M+1)。
实施例382
2-((3R,5R,6S)-1-((S)-2-(氮杂环丁烷-1-基磺酰基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm-1.07(br s,1H),-0.28(br s,1H),0.18-0.44(m,2H),1.51(s,3H),1.80(br s,1H),1.90(dd,J=13.79,2.84Hz,1H),2.31(quin,J=7.68Hz,2H),2.45(t,J=13.79Hz,1H),2.60(br s,1H),2.74-2.82(m,1H),2.94(d,J=13.69Hz,1H),3.07(d,J=14.87Hz,1H),3.16(ddd,J=13.74,10.71,2.74Hz,1H),3.94-4.06(m,4H),4.27(br s,1H),4.82(d,J=10.56Hz,1H),6.81-6.88(m,1H),6.97(m,1H),7.07-7.17(m,3H),7.24-7.28(m,3H)。质谱(ESI)m/z=579.0(M+1)。
实施例383
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-((N,N-二甲基氨磺酰基)氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. (3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-[(1S)-1-环丙基-2-[(二甲基氨磺酰基)氨基]乙基]-3-甲基-3-(丙-2-烯-1-基)哌啶-2-酮
按照与实施例202步骤C中描述的程序类似的程序,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-羟基乙基)-3-甲基哌啶-2-酮(实施例252,步骤A)和N,N-二甲基磺酰胺(TCIAmerica,Portland,OR)制备本标题化合物。
质谱(ESI)m/z=561.5(M+1)。
步骤B. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-((N,N-二甲基氨磺酰基)氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
按照与实施例226步骤D中描述的程序类似的程序,从(3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-[(1S)-1-环丙基-2-[(二甲基氨磺酰基)氨基]乙基]-3-甲基-3-(丙-2-烯-1-基)哌啶-2-酮(实施例383,步骤A)制备本标题化合物。
1H NMR(400MHz,氯仿-d)δppm-0.34(br s,1H),0.02-0.19(m,1H),0.42-0.60(m,2H),1.14(br s,1H),1.40-1.52(m,4H),2.00-2.14(m,1H),2.18-2.38(m,1H),2.79(s,6H),2.80-2.83(m,1H),2.90-3.00(m,1H),3.00-3.12(m,1H),3.12-3.29(m,2H),3.79(br s,1H),4.89(d,J=10.2Hz,1H),6.82(d,J=7.4Hz,1H),6.94-7.02(m,1H),7.03-7.21(m,4H),7.24–7.28(m,2H);质谱(ESI)m/z=582.0(M+1)。
实施例384
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-((N,N-二甲基氨磺酰基)(甲基)氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. (3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-[(1S)-1-环丙基-2-[(二甲基氨磺酰基)(甲基)氨基]乙基]-3-甲基-3-(丙-2-烯-1-基)哌啶-2-酮
按照与实施例264中描述的程序类似的程序,从(3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-[(1S)-1-环丙基-2-[(二甲基氨磺酰基)氨基]乙基]-3-甲基-3-(丙-2-烯-1-基)哌啶-2-酮(实施例383,步骤A)制备本标题化合物。
步骤B. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-((N,N-二甲基氨磺酰基)(甲基)氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
按照与实施例226步骤D中描述的程序类似的程序,从(3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-[(1S)-1-环丙基-2-[(二甲基氨磺酰基)(甲基)氨基]乙基]-3-甲基-3-(丙-2-烯-1-基)哌啶-2-酮(实施例384,步骤A)制备本标题化合物。
1H NMR(400MHz,氯仿-d)δppm-0.76(br s,1H),-0.34(br s,1H),0.32(br s,1H),0.42(br s,1H),1.43-1.61(m,3H),1.62-1.84(m,1H),1.94(d,J=13.3Hz,2H),2.21(d,J=12.9Hz,1H),2.44(br s,1H),2.73-2.90(m,9H),3.03-3.21(m,3H),4.65(br s,6H),4.81(d,J=10.2Hz,2H),6.83-6.96(m,2H),7.00(s,2H),7.08-7.18(m,3H),7.25(br s,1H);质谱(ESI)m/z=596.0(M+1)。
按照与实施例202步骤C和D中描述的程序类似的程序,用合适的试剂替代步骤B中的N-甲基环丙烷磺酰胺,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-羟基乙基)-3-甲基哌啶-2-酮(实施例252,步骤A)制备实施例385至389。
实施例385
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(3-甲基-2,5-二氧代咪唑烷-1-基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 0.24(br s,1H),0.58(br s,2H),1.12-1.36(m,1H),1.36-1.55(m,3H),1.99-2.11(m,1H),2.11-2.26(m,1H),2.71(d,J=15.1Hz,1H),3.01-3.08(m,4H),3.08-3.23(m,2H),3.53(br s,1H),3.78-4.01(m,3H),4.63(br s,1H),5.58(br s,1H),6.68(d,J=7.6Hz,1H),6.92-7.02(m,1H),7.06-7.22(m,3H),(7.24-7.32(m,3H);质谱(ESI)m/z=572.0(M+1)。
实施例386
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(3,4,4-三甲基-2,5-二氧代咪唑烷-1-基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 0.23(br s,1H),0.56(br s,2H),1.32-1.55(m,10H),2.02(dd,J=13.9,2.7Hz,1H),2.15-2.32(m,1H),2.72(d,J=15.1Hz,1H),2.84-2.96(m,4H),3.04-3.25(m,3H),3.55(br s,1H),3.87–4.10(br s,1H),4.87(br s,1H),6.66(d,J=7.0Hz,1H),6.99(s,1H),7.08(t,J=7.8Hz,2H),7.17(d,J=8.6Hz,2H),7.287.32(m,2H);质谱(ESI)m/z=600.0(M+1)。
实施例387
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(4,4-二甲基-2,5-二氧代咪唑烷-1-基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 0.18(br s,1H),0.56(br s,2H),1.37-1.52(m,11H),2.05(dd,J=13.89,2.93Hz,1H),2.20(t,J=13.40Hz,1H),2.74(d,J=14.9Hz,1H),3.05(d,J=14.9Hz,1H),3.18(ddd,J=12.819.9,3.1Hz,1H),3.53(br s,1H),3.99(br s,1H),4.67(br s,1H),5.31(s,1H),5.44-5.73(m,5H),6.27(br s,1H),6.68(d,J=7.4Hz,1H),6.99(s,1H),7.05-7.13(m,2H),7.13-7.21(m,2H),7.22(br s,1H);质谱(ESI)m/z=586.0(M+1)。
实施例388
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(3-异丙基-2,2-二氧化-4-氧代-3,4-二氢-1H-苯并[c][1,2,6]噻二嗪-1-基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm-0.11(br s,1H),0.45(br s,2H),1.22-1.34(m,1H),1.43-1.66(m,9H),1.95-2.14(m,1H),2.21(t,J=13.60Hz,1H),2.83(d,J=14.7Hz,1H),3.07(d,J=14.5Hz,1H),3.14-3.28(m,1H),3.51(s,3H),3.69(br s,1H),4.79(br s,1H),4.95-5.12(m,1H),6.78(d,J=7.43Hz,1H),6.93(br s,1H),7.01(br s,1H),7.04-7.20(m,3H),7.28-7.31(m,3H),7.39(t,J=7.4Hz,1H),7.59-7.70(m,1H),8.19(d,J=8.0Hz,1H);质谱(ESI)m/z=698.0(M+1)。
实施例389
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-1-基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm-0.29--0.06(m,1H),0.41(br s,2H),1.32-1.43(m,3H),1.43-1.60(m,2H),1.64-1.94(m,3H),2.75(d,J=14.1Hz,1H),2.97(d,J=14.1Hz,1H),3.11(br s,1H),3.51-3.72(m,1H),3.74(m,1H),4.34(s,1H),6.45(br s,1H),6.63(brs,1H),6.75(brs,1H),7.01(d,J=6.5Hz,2H),7.11(d,J=7.6Hz,2H),7.15-7.27(m,4H),9.55(br s,1H);质谱(ESI)m/z=592.0(M+1)。
实施例390
2-((3R,5R,6S)-5-(3-氯代-4-氟苯基)-6-(4-氯苯基)-1-异丙基-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. (5R,6S)-5-(3-氯代-4-氟苯基)-6-(4-氯苯基)哌啶-2-酮
使用2-(3-氯代-4-氟苯基)乙酸根据实施例1,步骤A-E中描述的程序制备本标题化合物。通过手性HPLC(流速:400mL/min,在Varian SD-2prep HPLC系统(Wakefield,RI)和得自Grace(Hesperia,CA)的MODCOL弹簧负载柱上,该柱内径为10cm,用2.0kg OD CSP(Chiral Technologies,Inc.,West Chester,PA,USA)装填该柱的约35cm长度,使用25%的异丙醇/甲醇作为洗脱剂)分离各个对映异构体从而得到本标题化合物,为灰白色固体。[α]D=+152°(T=23℃,c=1.0,CHCl3)。
步骤B. (4R,5S)-5-氨基-4-(3-氯代-4-氟苯基)-5-(4-氯苯基)戊酸盐酸盐
将(5R,6S)-5-(3-氯代-4-氟苯基)-6-(4-氯苯基)哌啶-2-酮(5.00g,14.78mmol;实施例390,步骤A)在5M HCl(15mL)中的悬浮液加热至回流7小时。将反应混合物冷却至室温并用甲苯稀释。在真空中除去该溶剂,并通过用甲苯共沸蒸馏四次来除去任何剩余的水从而得到白色固体(5.81g)。
步骤C. (5R,6S)-5-(3-氯代-4-氟苯基)-6-(4-氯苯基)-1-异丙基哌啶-2-酮
将三乙酰氧基硼氢化钠(1.796g,8.48mmol)加入到在室温下的(4R,5S)-5-氨基-4-(3-氯代-4-氟苯基)-5-(4-氯苯基)戊酸盐酸盐(2.56g,6.52mmol;实施例390,步骤B)和丙酮(0.491mL,6.68mmol)在无水DMF(6.52mL)中的溶液中。将反应混合物在室温下搅拌16小时。加入二氯乙烷(25mL),接着加入分子筛。将反应混合物加热至70℃并保持22小时,过滤并在真空中浓缩。通过硅胶快速色谱法使用220g柱,用30%至100%的EtOAc/己烷洗脱来进行纯化,得到所需的产物,为白色固体。
步骤D. (3S,5R,6S)-3-烯丙基-5-(3-氯代-4-氟苯基)-6-(4-氯苯基)-1-异丙基-3-甲基哌啶-2-酮
通过向(5R,6S)-5-(3-氯代-4-氟苯基)-6-(4-氯苯基)-1-异丙基哌啶-2-酮(0.50g,1.32mmol;实施例390,步骤C)在无水THF(3mL)中的溶液中鼓入氩气15分钟来将该溶液脱气。将LHMDS(1M THF溶液,已通过向该溶液中鼓入氩气15分钟来对将该溶液脱气)(1.64mL,1.64mmol)逐滴加入到在-15℃下的内酰胺溶液中,同时保持温度低于-8℃。在-15℃下15分钟后,加入碘甲烷(0.085mL,1.354mmol)。35分钟后,向反应混合物中加入新制备的在THF(1mL)中的LDA(3.29mmol)。在30分钟后,将反应混合物冷却至-78℃,并缓慢地加入烯丙基溴(0.398mL,4.60mmol),同时将温度保持在或低于-68℃。让反应混合物随着冷浴的升温而升温。在16小时后,反应混合物温度为18℃。用MeOH(0.5mL)淬灭反应物,用10mL50%的盐水/水、盐水洗涤,干燥(Na2SO4),将其轻轻倒出并在真空中浓缩从而得到黄色油状物。通过硅胶快速色谱法(洗脱剂:5-15%的EtOAc/己烷,梯度洗脱)纯化,得到本标题化合物。
步骤E. 2-((3R,5R,6S)-5-(3-氯代-4-氟苯基)-6-(4-氯苯基)-1-异丙基-3-甲基-2-氧代哌啶-3-基)乙酸
将高锰酸钾(0.341g,2.155mmol)在水(2mL)中的溶液加入到在0℃下的(3S,5R,6S)-3-烯丙基-5-(3-氯代-4-氟苯基)-6-(4-氯苯基)-1-异丙基-3-甲基哌啶-2-酮(0.312g,0.718mmol;实施例390,步骤D)和四丁基氯化铵水合物(0.021g,0.072mmol)在DCM(2mL)中的溶液中。在5分钟后,将反应混合物从冰浴上移开并将其在室温下搅拌。在室温下2小时后,用亚硫酸氢钠水溶液稀释反应混合物。过滤该溶液,然后用DCM萃取三次。将合并的有机物汇集在一起,用50mL10%亚硫酸氢钠、盐水洗涤,干燥(MgSO4),过滤,并在真空中浓缩从而得到黄色油状物。通过硅胶快速色谱法使用24g柱,用0%至50%的IPA/己烷洗脱来进行纯化,得到含有所需产物和杂质的级分。在静置过夜后,所需的产物结晶为无色棱形晶体,通过真空过滤收集该晶体从而得到本标题化合物。
1H NMR(500MHz,氯仿-d)δppm 1.25(d,J=6.8Hz,3H),1.26(d,J=6.8Hz,3H),1.40(s,3H),2.00(dd,J=3.4和13.9Hz,1H),2.09(dd,J=11.9和13.7Hz,1H),2.67(d,J=15.4Hz,1H),3.02(dt,J=3.2和9.3Hz,1H),3.03(d,J=15.4Hz,1H),3.41(m,1H),4.41(d,J=9.0Hz,1H),6.70-6.73(m,1H),6.95-6.99(m,3H),7.06(dd,J=2.5和6.9Hz,1H),7.28(d,J=9.5Hz,2H);质谱(ESI)m/z=452.2[M+H]+。
实施例391
2-((3R,5R,6S)-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-异丙基-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. (5R,6S)-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)哌啶-2-酮
使用2-(3-氯代-5-氟苯基)乙酸根据实施例1步骤A-E中描述的程序制备本标题化合物。通过手性HPLC(150×50mm AD-H柱(Chiral Technologies,Inc.,WestChester,PA,USA),使用50g/min甲醇+(20mM NH3)+130g/min CO2,在Thar 350SFC(TharTechnologies,Inc.,Pittsburg,PA)上)分离各个对映异构体。[α]D=+114°(T=23℃,c=4.0,CHCl3)。
步骤B. (4R,5S)-5-氨基-4-(3-氯代-5-氟苯基)-5-(4-氯苯基)戊酸盐酸盐
使用实施例390步骤B中描述的程序,从(5R,6S)-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)哌啶-2-酮(实施例391,步骤A)制备本标题化合物。
步骤C. (5R,6S)-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-异丙基哌啶-2-酮
使用实施例390步骤C中描述的程序,从(4R,5S)-5-氨基-4-(3-氯代-5-氟苯基)-5-(4-氯苯基)戊酸盐酸盐(实施例391,步骤B)制备本标题化合物。
步骤D. (3S,5R,6S)-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-异丙基-3-甲基哌啶-2-酮和(3R,5R,6S)-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-异丙基-3-甲基哌啶-2-酮
将(5R,6S)-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-异丙基哌啶-2-酮溶液(0.400g,1.052mmol;实施例391,步骤C)溶解在苯中,并在真空下除去该溶剂三次。将由此产生的油状物溶解在无水2-甲基THF(2mL)中,并通过向该溶液中鼓入氩气15分钟来对进行脱气,同时将其冷却至-15℃。加入LHMDS(1.0M在THF中)(1.315ml,1.315mmol),该溶液变成黄色。在10分钟后,逐滴加入碘甲烷(0.069ml,1.104mmol),同时保持温度低于-10℃。40分钟后,用NH4Cl饱和水溶液淬灭反应混合物,并升温至室温。分离各层并用EtOAc萃取水层两次。将有机物汇集在一起,用盐水洗涤,干燥(Na2SO4),将其轻轻倒出并在真空中浓缩从而得到橙色油状物。通过硅胶快速色谱法使用24g柱,用10%至30%的EtOAc/己烷洗脱来进行纯化,得到(3S,5R,6S)-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-异丙基-3-甲基哌啶-2-酮和(3R,5R,6S)-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-异丙基-3-甲基哌啶-2-酮的96:4混合物,为无色浆液。
步骤E. (3S,5R,6S)-3-烯丙基-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-异丙基-3-甲基哌啶-2-酮和(3R,5R,6S)-3-烯丙基-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-异丙基-3-甲基哌啶-2-酮
通过向(3S,5R,6S)-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-异丙基-3-甲基哌啶-2-酮和(3R,5R,6S)-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-异丙基-3-甲基哌啶-2-酮(0.320g,0.812mmol;实施例391,步骤D)在无水2-甲基THF(1.5mL)中的溶液中鼓入氩气15分钟来将该溶液脱气,然后将该溶液冷却至-15℃。缓慢地加入新制备的在2-甲基-THF(1.5mL)中的LDA(1.22mmol),同时保持温度在或低于-14℃。在-15℃下30分钟后,将反应混合物冷却至-74℃,并缓慢地加入烯丙基溴(0.176ml,2.029mmol),同时保持温度低于-70℃。在2小时后,再加入烯丙基溴(0.176ml,2.029mmol),并将反应混合物温度升至室温。用NH4Cl饱和水溶液淬灭反应物并分离各层。用EtOAc萃取水层两次,将有机物汇集在一起,用盐水洗涤,干燥(Na2SO4),将其轻轻倒出并在真空下浓缩从而得到浅黄色油状物。通过硅胶快速色谱法使用24g柱,用0%至50%的丙酮/己烷洗脱来进行纯化,得到无色油状物,为(3S,5R,6S)-3-烯丙基-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-异丙基-3-甲基哌啶-2-酮和(3R,5R,6S)-3-烯丙基-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-异丙基-3-甲基哌啶-2-酮的3.3:1混合物。
步骤F. 2-((3R,5R,6S)-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-异丙基-3-甲基-2-氧代哌啶-3-基)乙酸
将氯化钌(III)水合物(2.19mg,9.72μmol)加入到在室温下的(3S,5R,6S)-3-烯丙基-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-异丙基-3-甲基哌啶-2-酮和(3R,5R,6S)-3-烯丙基-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-异丙基-3-甲基哌啶-2-酮(0.192g,0.442mmol;实施例391,步骤E)和NaIO4(97mg)在EtOAc(1mL)、ACN(1mL)和水(2mL)中的溶液中。在3分钟后,加入NaIO4(97mg)。分别在3分钟和6分钟后加入剩余的两份NaIO4(每份97mg)。在30分钟后,过滤反应混合物并分离各层。用EtOAc萃取水层两次,将有机物汇集在一起,用10%NaHSO3水溶液、盐水洗涤,干燥(Na2SO4),将其轻轻倒出并在真空中浓缩从而得到棕褐色油状物。通过硅胶快速色谱法使用24g柱,用5%至30%的(15%MeOH/丙酮)/己烷洗脱来进行纯化,得到2-((3R,5R,6S)-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-异丙基-3-甲基-2-氧代哌啶-3-基)乙酸和2-((3S,5R,6S)-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-异丙基-3-甲基-2-氧代哌啶-3-基)乙酸的3.3:1混合物(170mg,85%)。通过手性HPLC(2×(250mm×30mm)AD-H柱(Chiral Technologies,Inc.,West Chester,PA,USA),使用20g/min甲醇+(20mM NH3)+80g/min CO2,在Thar 350SFC(Thar Technologies,Inc.,Pittsburg,PA)上)分离各个异构体从而得到本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 1.26(d,J=6.9Hz,3H),1.27(d,J=6.7Hz,3H),1.38(s,3H),1.99-2.11(m,2H),2.65(d,J=15.7Hz,1H),3.02(d,J=15.7Hz,1H),3.30(dt,J=2.2和8.8Hz,1H),3.46(m,1H),4.48(d,J=8.8Hz,1H),6.57(dt,J=1.8和9.2Hz,1H),6.79(s,1H),6.97(dt,J=2.2和8.4Hz,1H),6.99(d,J=8.4Hz,2H),7.30(d,J=8.6Hz,2H);质谱(ESI)m/z=452.2[M+H]+。
实施例392
2-((3S,5R,6S)-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-异丙基-3-甲基-2-氧代哌啶-3-基)乙酸
在实施例391,步骤F中从HPLC柱进一步洗脱,得到本标题化合物(14.8mg)。1H NMR(400MHz,氯仿-d)δppm 1.22(d,J=6.9Hz,3H),1.27(d,J=7.0Hz,3H),1.58(s,3H),1.72(dd,J=3.1和13.3Hz,1H),2.32(t,J=13.5Hz,1H),2.65-2.75(m,2H),3.13(dt,J=2.9和10.6Hz,1H),3.26(m,1H),4.33(d,J=10.4Hz,1H),6.53(d,J=9.0Hz,1H),6.74(s,1H),6.91-6.97(m,3H),7.27(d,J=8.6Hz,2H);质谱(ESI)m/z=452.2[M+H]+。
实施例393
2-((3R,5R,6S)-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-((S)-1-(乙基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. (3S,5R,6S)-3-烯丙基-1-((S)-1-((叔丁基二苯基甲硅烷基)氧基)丁烷-2-基)-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮
在实施例1步骤A中用2-(3-氯代-5-氟苯基)乙酸代替2-(3-氯苯基)乙酸,如实施例185步骤E中所述制备本标题化合物。
步骤B. (3S,5R,6S)-3-烯丙基-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)-3-甲基哌啶-2-酮
向在室温下的(3S,5R,6S)-3-烯丙基-1-((S)-1-((叔丁基二苯基甲硅烷基)氧基)丁烷-2-基)-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮(2.15g,3.06mmol;实施例393,步骤A)在THF(30.6ml)中的溶液中加入TBAF(1.0M在THF中)(6.12ml,6.12mmol)。将淡黄色混合物在室温下搅拌过夜。用水和EtOAc稀释该混合物。用盐水洗涤有机层,经Na2SO4干燥,过滤,并浓缩滤液。通过硅胶快速色谱法(40g柱;洗脱剂:0%至50%的在己烷中的EtOAc)纯化残余物从而得到本标题化合物。
步骤C. N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁基)乙烷磺酰胺
按照如实施例202步骤C中描述的程序使(3S,5R,6S)-3-烯丙基-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)-3-甲基哌啶-2-酮(100mg,0.215mmol;实施例393,步骤B)与乙烷磺酰胺(70.5mg,0.646mmol)偶联,从而形成本标题化合物,其是在硅胶色谱分析(4g柱;洗脱剂为0%至50%的EtOAC/己烷)后分离的,为灰白色固体。
步骤D. 2-((3R,5R,6S)-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-((S)-1-(乙基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
向在室温下的N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁基)乙烷磺酰胺(实施例393,步骤C,120mg,0.216mmol)在EtOAc:MeCN:水(1.450mL)(2/2/3)中的溶液中缓慢地加入高碘酸钠(185mg,0.864mmol)。然后加入氯化钌水合物(1.071mg,4.75μmol)。将该混合物在室温下剧烈搅拌2h。然后将该混合物过滤并用EtOAc洗涤固体。用EtOAc萃取滤液2次。经Na2SO4干燥合并的有机层,过滤,并在减压下浓缩滤液。通过反相制备型HPLC(柱:GeminiTMPrep C185um柱;Phenomenex,Torrance,CA;洗脱剂:0%至100%MeCN+0.1%TFA于水+0.1%TFA中,超过20分钟)纯化残余物从而得到本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 0.53(t,J=7.6Hz,3H)1.40(t,J=7.3Hz,3H)1.46-1.56(m,4H)1.80-1.94(m,1H)1.96-2.00(m,2H)2.36(t,J=13.9Hz,1H)2.77(d,J=14.9Hz,1H)2.97(d,J=14.9Hz,1H)3.02-3.21(m,5H)4.61(br s,1H)4.81(d,J=10.6Hz,1H)6.62-6.69(m,1H)6.79(t,J=1.8Hz,1H)6.90(dt,J=8.3,2.1Hz,1H)7.07(br s,2H)7.24-7.30(m,2H);质谱(ESI)m/z=573(M+1)。
实施例394
2-((3R,5R,6S)-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基乙基磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
向在室温下的2-((3R,5R,6S)-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-((S)-1-(乙基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸(实施例393,步骤D,26.6mg,0.046mmol)在DMF(464μl)中的溶液中加入60%氢化钠在矿物油中的分散体(5.57mg,0.139mmol)。将灰色浆液在室温下搅拌30min,然后加入碘甲烷(5.80μl,0.093mmol)。将该混合物在室温下搅拌1h。用1M HCl淬灭该混合物并用EtOAc稀释。用EtOAc萃取水层2次。经Na2SO4干燥有机层,过滤,并浓缩滤液。通过反相制备型HPLC(柱:GeminiTMPrep C1810um柱;Phenomenex,Torrance,CA;洗脱剂:0%至100%MeCN+0.1%TFA于水+0.1%TFA中,超过20分钟)纯化残余物从而得到本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 0.50(t,J=7.5Hz,3H)1.38(t,J=7.4Hz,3H)1.52(s,3H)1.57-1.63(m,1H)1.85-2.00(m,2H)2.46(t,J=13.9Hz,1H)2.66-2.89(m,6H)2.94-3.16(m,4H)4.31(dd,J=13.7,10.8Hz,1H)4.81(d,J=10.8Hz,1H)6.59(br s,1H)6.69(dt,J=9.1,2.1Hz,1H)6.80(t,J=1.8Hz,1H)6.91(dt,J=8.3,2.0Hz,1H)7.01(br s,1H)7.29(br s,2H);质谱(ESI)m/z=587(M+1)。
实施例395
2-((3R,5R,6S)-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(甲基磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
步骤A. (3S,5S,6R,8S)-8-烯丙基-6-(3-氯代-5-氟苯基)-5-(4-氯苯基)-3-乙基-8-甲基-2,3,5,6,7,8-六氢噁唑并[3,2-a]吡啶-4-鎓甲烷磺酸盐
按照与实施例344步骤A中描述的程序类似的程序,从(3S,5R,6S)-3-烯丙基-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)-3-甲基哌啶-2-酮(实施例393,步骤B)制备本标题化合物。
步骤B. (3S,5R,6S)-3-烯丙基-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(甲基磺酰基)丁烷-2-基)哌啶-2-酮
向(3S,5S,6R,8S)-8-烯丙基-6-(3-氯代-5-氟苯基)-5-(4-氯苯基)-3-乙基-8-甲基-2,3,5,6,7,8-六氢噁唑并[3,2-a]吡啶-4-鎓甲烷磺酸盐(实施例395,步骤A,100mg,0.184mmol)在MeCN(1.8mL)中的溶液中加入甲烷亚磺酸,钠盐(56.5mg,0.553mmol)。将该混合物加热至114℃。在加热24小时后,将该混合物冷却至室温并搅拌2天。将该混合物分配在EtOAc和NH4Cl水溶液之间。用盐水洗涤有机层,经Na2SO4干燥,过滤,并浓缩滤液。通过硅胶快速色谱法(洗脱剂:20%至60%的EtOAc/己烷,梯度洗脱)纯化残余物从而得到本标题化合物。
步骤C. 2-((3R,5R,6S)-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(甲基磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
向(3S,5R,6S)-3-烯丙基-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(甲基磺酰基)丁烷-2-基)哌啶-2-酮(实施例395,步骤B,58mg,0.110mmol)在乙腈(1.0mL)、EtOAc(1.0mL)和水(1.5mL)中的溶液中加入氯化钌(III)水合物(0.55mg,2.42μmol)和高碘酸钠(144mg,0.672mmol)。在2小时后,将该混合物分配在水和EtOAc之间。用盐水洗涤有机层,经Na2SO4干燥,过滤,并浓缩滤液。通过制备型硅胶薄层色谱法(洗脱剂:10%MeOH/DCM)纯化残余物从而得到本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 0.43(t,J=7.5Hz,3H)1.48(s,3H)1.64(br s,1H)1.91(dd,J=13.7,2.4Hz,1H)2.06-2.22(m,1H)2.33(t,J=13.8Hz,1H)2.76(d,J=15.1Hz,1H)2.90(d,J=12.1Hz,1H)2.94-3.03(m,4H)3.13(t,J=11Hz,1H)3.33(t,J=9.7Hz,1H)4.22(t,J=12.3Hz,1H)4.88(d,J=10.8Hz,1H)6.61(d,J=9.2Hz,1H)6.75(s,1H)6.89(dt,J=8.3,1.9Hz,1H)7.12(br s,2H)7.21-7.35(m,2H)。质谱(ESI)m/z=544.0(M+1)。
按照与实施例339或实施例395中描述的程序类似的程序,在步骤B中使用等效量的合适的试剂,从(3S,5S,6R,8S)-8-烯丙基-6-(3-氯代-5-氟苯基)-5-(4-氯苯基)-3-乙基-8-甲基-2,3,5,6,7,8-六氢噁唑并[3,2-a]吡啶-4-鎓甲烷磺酸盐(实施例395,步骤A)制备实施例396至398。按照与实施例300中描述的程序类似的程序,在步骤A中使用等效量的合适的硫醇,从(3S,5R,6S)-3-烯丙基-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)-3-甲基哌啶-2-酮(实施例393,步骤B)制备实施例399。
实施例396
2-((3R,5R,6S)-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-((S)-1-(乙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 0.42(t,J=7.5Hz,3H)1.45(t,J=7.5Hz,3H)1.49(s,3H)1.65(br s,1H)1.90(dd,J=13.7,2.4Hz,1H)2.06-2.21(m,1H)2.35(t,J=13.8Hz,1H)2.73-2.82(m,2H)2.98(d,J=15.1Hz,1H)3.01-3.08(m,2H)3.13(t,J=11.0Hz,1H)3.34(t,J=10.2Hz,1H)4.13(t,J=12.1Hz,1H)4.92(d,J=10.8Hz,1H)6.62(d,J=9.2Hz,1H)6.75(s,1H)6.89(dt,J=8.4,2.0Hz,1H)7.12(br s,2H)7.21-7.34(m,2H)。质谱(ESI)m/z=558.0(M+1)。
实施例397
2-((3R,5R,6S)-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-((S)-1-(环丙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
1H NMR(400MHz,氯仿-d)δppm 0.43(t,J=7.6Hz,3H)1.05-1.15(m,2H)1.25-1.33(m,2H)1.38-1.54(m,4H)1.90(dd,J=13.8,2.8Hz,1H)2.07-2.21(m,1H)2.34(t,J=13.8Hz,1H)2.42(tt,J=8.0,4.8Hz,1H)2.76(d,J=15.1Hz,1H)2.88-3.01(m,2H)3.13(ddd,J=13.4,10.8,2.5Hz,1H)3.31(t,J=10.4Hz,1H)4.20(dd,J=13.5,11.2Hz,1H)4.90(d,J=10.8Hz,1H)6.61(dt,J=9.0,2.0Hz,1H)6.74(s,1H)6.88(dt,J=8.4,2.1Hz,1H)7.11(br s,2H)7.21-7.34(m,2H)。质谱(ESI)m/z=570.0(M+1)。
实施例398
2-((3R,5R,6S)-1-((S)-1-(叔丁基磺酰基)丁烷-2-基)-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸
通过SFC 20mL/min;30x250mm IC柱(Chiral Technologies,Inc.,West Chester,PA,USA)使用甲醇(20mM NH3)/CO2作为洗脱剂在Thor SFC(ThorTechnologies,Inc.Pittsburg,PA)上纯化粗产物从而得到本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 0.41(t,J=7.5Hz,3H)1.38-1.68(m,13H)1.88(dd,J=13.7,2.5Hz,1H)2.06-2.26(m,1H)2.38(t,J=13.8Hz,1H)2.73(d,J=15.5Hz,1H)2.80(d,J=13.5Hz,1H)3.01(d,J=15.3Hz,1H)3.11(t,J=11.8Hz,1H)3.33(t,J=10.4Hz,1H)4.03(dd,J=13.0,11.3Hz,1H)4.97(d,J=10.8Hz,1H)6.63(d,J=9.2Hz,1H)6.75(s,1H)6.89(d,J=8.4Hz,1H)7.14(br s,2H)7.25-7.36(m,2H)。质谱(ESI)m/z=586.0(M+1)。
实施例399
2-((3R,5R,6S)-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-((S)-1-(异丙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
粗产物先通过制备型硅胶薄层色谱法(洗脱剂:10%MeOH/DCM)纯化,接着通过反相制备型HPLC(柱:GeminiTMPrep C1810um柱;Phenomenex,Torrance,CA;洗脱剂:0%至100%MeCN+0.1%TFA于水+0.1%TFA中,超过20分钟)纯化从而得到本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 0.41(t,J=7.5Hz,3H)1.34-1.55(m,10H)1.88(dd,J=13.8,2.6Hz,1H)2.07-2.24(m,1H)2.38(t,J=13.8Hz,1H)2.68-2.81(m,2H)3.01(d,J=15.5Hz,1H)3.06-3.18(m,2H)3.35(t,J=10.2Hz,1H)4.08(dd,J=13.1,11.5Hz,1H)4.95(d,J=10.8Hz,1H)6.63(d,J=9.0Hz,1H)6.75(s,1H)6.89(dt,J=8.2,2.0Hz,1H)7.14(brs,2H)7.24-7.37(m,2H)。质谱(ESI)m/z=572.0(M+1)。
实施例400
2-((3R,5R,6S)-6-(4-氯苯基)-5-(5-氯吡啶-3-基)-1-((S)-1-(环丙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. 1-(4-氯苯基)-2-(5-氯吡啶-3-基)乙酮
将1-(4-氯苯基)乙酮(17.22ml,133mmol)加入到冰冷的在氩气气氛下的3-溴代-5-氯吡啶(24.3g,126mmol)和2-甲基丙烷-2-醇钠(30.3g,316mmol)在THF(158ml)中的溶液中。然后加入(9,9-二甲基-9H-氧杂蒽-4,5-二基)双(二苯基膦)(0.731g,1.263mmol)和二乙酰氧基钯(0.283g,1.263mmol),将该溶液加热至70℃并保持1.5小时。将该溶液冷却至室温,并先后用冰的2N HCl(95mL)和EtOAc(300ml)稀释。分配各层并用EtOAc(2x100ml)洗涤水层。用盐水洗涤有机物,经Na2SO4干燥,过滤,并浓缩。使所获得的残余物富集在硅胶柱上。合并含有产物的级分并浓缩。向所获得的残余物中加入130ml Et2O,并将悬浮液在水浴中加热至回流。然后在冰浴中冷却该悬浮液。通过过滤收集固体从而得到本标题化合物。
1H NMR(500MHz,DMSO-d6)δppm 8.53(1H,d,J=2.4Hz),8.43(1H,d,J=1.7Hz),8.05-8.11(2H,m),7.85(1H,t,J=2.1Hz),7.63-7.68(2H,m),4.55(2H,s)。
步骤B. 5-(4-氯苯基)-4-(5-氯吡啶-3-基)-2-甲基-5-氧代-1-戊酸甲酯
按照与实施例261步骤A中描述的程序类似的程序,从1-(4-氯苯基)-2-(5-氯吡啶-3-基)乙酮(实施例400,步骤A,25.3g,95mmol)获得本标题化合物。外消旋产物为非对映异构体的1:1混合物。
1H NMR(500MHz,DMSO-d6)δppm 8.57(1H,d,J=2.0Hz),8.54(1H,d,J=1.7Hz),8.50(2H,dd,J=4.4,2.4Hz),8.05-8.09(4H,m),7.90(2H,t,J=2.1Hz),7.57-7.64(4H,m),4.93-5.04(2H,m),3.54(3H,s),3.45(3H,s),2.34-2.42(1H,m),2.24-2.33(2H,m),2.19(1H,dt,J=13.7,6.8Hz),2.05-2.13(1H,m),1.88-1.96(1H,m),1.13(3H,d,J=7.1Hz),1.08(3H,d,J=7.1Hz);质谱(ESI)m/z=366.1[M+H]+。
步骤C. (4R,5R)-5-(4-氯苯基)-4-(5-氯吡啶-3-基)-5-羟基-2-甲基戊酸甲酯和(4S,5S)-5-(4-氯苯基)-4-(5-氯吡啶-3-基)-5-羟基-2-甲基戊酸甲酯的外消旋混合物
按照与实施例261步骤B中描述的程序类似的程序,将5-(4-氯苯基)-4-(5-氯吡啶-3-基)-2-甲基-5-氧代-1-戊酸甲酯(实施例400,步骤B,31g,85mmol)转化为本标题化合物。产物为在2位置上的非对映异构体的1:1混合物。
1H NMR(500MHz,氯仿-d)δppm 8.43(2H,s),8.13(2H,d,J=11.7Hz),7.59(2H,dt,J=6.8,2.0Hz),7.24-7.30(4H,m),7.03-7.10(4H,m),4.88(1H,d,J=5.6Hz),4.84(1H,d,J=5.6Hz),3.64(3H,s),3.56(3H,s),2.91(2H,tt,J=10.7,5.3Hz),2.22-2.29(1H,m),2.13-2.22(4H,m),2.00-2.10(1H,m),1.72-1.87(2H,m),1.11(3H,d,J=7.1Hz),1.09(3H,d,J=6.8Hz);质谱(ESI)m/z=368.0[M+H]+。
步骤D. (4R,5R)-5-(4-氯苯基)-4-(5-氯吡啶-3-基)-5-羟基-2-甲基戊酸和(4S,5S)-5-(4-氯苯基)-4-(5-氯吡啶-3-基)-5-羟基-2-甲基戊酸
按照实施例261步骤C中描述的程序,将(4R,5R)-5-(4-氯苯基)-4-(5-氯吡啶-3-基)-5-羟基-2-甲基戊酸甲酯和(4S,5S)-5-(4-氯苯基)-4-(5-氯吡啶-3-基)-5-羟基-2-甲基戊酸甲酯的外消旋混合物(实施例400,步骤C,16.5g,43.4mmol)转化为本标题化合物。质谱(ESI)m/z=354.1[M+H]+。
步骤E. (5R,6R)-6-(4-氯苯基)-5-(5-氯吡啶-3-基)-3-甲基四氢-2H-吡喃-2-酮和(5S,6S)-6-(4-氯苯基)-5-(5-氯吡啶-3-基)-3-甲基四氢-2H-吡喃-2-酮
按照实施例261步骤D中描述的程序,将(4R,5R)-5-(4-氯苯基)-4-(5-氯吡啶-3-基)-5-羟基-2-甲基戊酸和(4S,5S)-5-(4-氯苯基)-4-(5-氯吡啶-3-基)-5-羟基-2-甲基戊酸的非对映异构体混合物(实施例400,步骤D,15.39g,43.4mmol)转化为本标题化合物。产物为在2位置上的非对映异构体的3:2混合物。
1H NMR(500MHz,氯仿-d)δppm 8.42(0.6H,d,J=2.4Hz),8.37(1H,d,J=2.2Hz),8.22(0.6H,d,J=2.0Hz),7.91(1H,d,J=2.0Hz),7.35(0.6H,t,J=2.1Hz),7.23-7.27(1.3H,m),7.16-7.23(3H,m),7.08(1.3H,d,J=8.6Hz),6.90(2H,d,J=8.6Hz),5.80(0.6H,d,J=3.9Hz),5.74(1H,d,J=4.4Hz),3.67-3.73(0.6H,m),3.60(1H,ddd,J=9.3,6.4,4.6Hz),2.96-3.10(1H,m),2.74-2.84(0.6H,m),2.69(1H,ddd,J=14.4,9.0,8.1Hz),2.30-2.39(0.6H,m),2.18(0.6H,ddd,J=13.8,9.2,4.4Hz),1.76-1.86(1H,m),1.44(1.8H,d,J=7.1Hz),1.42(3H,d,J=6.6Hz)。
步骤F. (3S,5R,6R)-3-烯丙基-6-(4-氯苯基)-5-(5-氯吡啶-3-基)-3-甲基四氢-2H-吡喃-2-酮和(3R,5S,6S)-3-烯丙基-6-(4-氯苯基)-5-(5-氯吡啶-3-基)-3-甲基四氢-2H-吡喃-2-酮
按照实施例261步骤E中描述的程序,将(5R,6R)-6-(4-氯苯基)-5-(5-氯吡啶-3-基)-3-甲基四氢-2H-吡喃-2-酮和(5S,6S)-6-(4-氯苯基)-5-(5-氯吡啶-3-基)-3-甲基四氢-2H-吡喃-2-酮的非对映异构体混合物(实施例400,步骤E,12.2g,36.28mmol)转化为本标题化合物。
1H NMR(500MHz,氯仿-d)δppm 8.44(1H,d,J=2.2Hz),8.11(1H,d,J=2.0Hz),7.18-7.24(2H,m),7.07(1H,t,J=2.1Hz),6.62-6.67(2H,m),5.82(1H,ddt,J=17.1,9.9,7.4Hz),5.71(1H,d,J=5.1Hz),5.13-5.23(2H,m),3.85(1H,dt,J=11.7,4.7Hz),2.48-2.66(2H,m),1.93-2.07(2H,m),1.42(3H,s)。
步骤G. (S)-2-((2R,3R)-3-(4-氯苯基)-2-(5-氯吡啶-3-基)-3-羟基丙基)-N-((S)-1-羟基丁烷-2-基)-2-甲基戊-4-烯酰胺和(R)-2-((2S,3S)-3-(4-氯苯基)-2-(5-氯吡啶-3-基)-3-羟基丙基)-N-((S)-1-羟基丁烷-2-基)-2-甲基戊-4-烯酰胺
按照实施例261步骤G中描述的程序,将(3S,5R,6R)-3-烯丙基-6-(4-氯苯基)-5-(5-氯吡啶-3-基)-3-甲基四氢-2H-吡喃-2-酮和(3R,5S,6S)-3-烯丙基-6-(4-氯苯基)-5-(5-氯吡啶-3-基)-3-甲基四氢-2H-吡喃-2-酮的外消旋混合物(实施例400,步骤F,12.4g,33.0mmol)转化为本标题化合物。
质谱(ESI)m/z=465.2[M+H]+。
步骤H. (3S,5R,6S)-3-烯丙基-6-(4-氯苯基)-5-(5-氯吡啶-3-基)-1-((S)-1-羟基丁烷-2-基)-3-甲基哌啶-2-酮
将(S)-2-((2R,3R)-3-(4-氯苯基)-2-(5-氯吡啶-3-基)-3-羟基丙基)-N-((S)-1-羟基丁烷-2-基)-2-甲基戊-4-烯酰胺和(R)-2-((2S,3S)-3-(4-氯苯基)-2-(5-氯吡啶-3-基)-3-羟基丙基)-N-((S)-1-羟基丁烷-2-基)-2-甲基戊-4-烯酰胺的非对映异构体混合物(实施例400,步骤G,6.34g)合并在DCM(68ml)和三乙胺(13.3ml,95mmol)中。在冰浴中冷却后,加入三甲胺盐酸盐(1.953g,20.43mmol)。缓慢地加入固体形式的4-甲基苯磺酸酐(17.78g,54.5mmol),保持温度低于10℃。让呈棕色的溶液的温度缓慢地升至室温,然后将其搅拌过夜。第二天,再加入三甲胺盐酸盐(0.271mg,2.91mmol),将该溶液再搅拌一天。用冰水淬灭反应物。分配各层并用DCM洗涤水层。经MgSO4干燥合并的有机物,过滤,并浓缩从而得到棕色油状物。将该油状物溶解在MeCN(100ml)中,然后将其加热至60℃并保持4小时。浓缩该溶液,并将残余物溶解在100ml DCM中。向其中加入100ml饱和NaHCO3,并将两相溶液在室温下搅拌5天。分配该溶液并用DCM洗涤水层。经MgSO4干燥有机物,过滤并浓缩。通过硅胶色谱法纯化产物从而得到(3S,5R,6S)-3-烯丙基-6-(4-氯苯基)-5-(5-氯吡啶-3-基)-1-((S)-1-羟基丁烷-2-基)-3-甲基哌啶-2-酮,为第二洗脱非对映异构体。
1H NMR(500MHz,氯仿-d)δppm 8.40(1H,d,J=2.0Hz),7.91(1H,d,J=1.5Hz),7.35(1H,t,J=1.8Hz),7.26(1H,br s),7.00(2H,br d,J=6.8Hz),5.78-5.94(1H,m),5.15-5.24(2H,m),4.45(1H,d,J=10.3Hz),3.59-3.73(2H,m),3.13-3.27(3H,m),2.62(2H,d,J=7.6Hz),2.02-2.11(1H,m),1.85-2.00(2H,m),1.40-1.52(1H,m),1.30(3H,s),0.66(3H,t,J=7.5Hz)。质谱(ESI)m/z=447.2[M+H]+。
步骤I. (3S,5S,6R,8S)-8-烯丙基-5-(4-氯苯基)-6-(5-氯吡啶-3-基)-3-乙基-8-甲基-2,3,5,6,7,8-六氢噁唑并[3,2-a]吡啶-4-鎓甲烷磺酸盐
按照与实施例344步骤A中描述的程序类似的程序,从(3S,5R,6S)-3-烯丙基-6-(4-氯苯基)-5-(5-氯吡啶-3-基)-1-((S)-1-羟基丁烷-2-基)-3-甲基哌啶-2-酮(实施例400,步骤H)制备本标题化合物。
质谱(ESI)m/z=429.2[M]+。
步骤J. (3S,5R,6S)-3-烯丙基-6-(4-氯苯基)-5-(5-氯吡啶-3-基)-1-((S)-1-(环丙基磺酰基)丁烷-2-基)-3-甲基哌啶-2-酮
按照与实施例340中描述的程序类似的程序,使用环丙烷亚磺酸,钠盐(OakwoodProducts,West Columbia,SC),将(3S,5S,6R,8S)-8-烯丙基-5-(4-氯苯基)-6-(5-氯吡啶-3-基)-3-乙基-8-甲基-2,3,5,6,7,8-六氢噁唑并[3,2-a]吡啶-4-鎓甲烷磺酸盐(实施例400,步骤I,0.188g,0.358mmol)转化为本标题化合物。
MS(ESI)m/z=535.1[M+H]+。
步骤K. 2-((3R,5R,6S)-6-(4-氯苯基)-5-(5-氯吡啶-3-基)-1-((S)-1-(环丙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
向(3S,5R,6S)-3-烯丙基-6-(4-氯苯基)-5-(5-氯吡啶-3-基)-1-((S)-1-(环丙基磺酰基)丁烷-2-基)-3-甲基哌啶-2-酮(实施例400,步骤J,0.06g,0.112mmol)在DCM(2.241ml)中的溶液中加入乙酸(0.160ml,2.80mmol)和四丁基氯化铵水合物(3.32mg,0.011mmol)。在冰浴中冷却该溶液。制备高锰酸钾(0.053g,0.336mmol)在1ml水中的溶液,并将其逐滴加入到上面的溶液中(用1ml水冲洗)。将紫色溶液在该冰浴中搅拌30分钟,然后让其温度升至室温并放置过夜。第二天加入亚硫酸氢钠溶液(10%水溶液)。用30%的在水中的H2SO4将水层的pH调节至2。分配各层,然后先后用DCM和10%iPrOH/DCM洗涤水层。在真空下浓缩合并的有机物。通过硅胶色谱法纯化产物从而得到本标题化合物,为白色固体。
1H NMR(500MHz,氯仿-d)δppm 8.38(1H,d,J=2.2Hz),8.00(1H,d,J=1.7Hz),7.67(1H,t,J=2.0Hz),7.26(2H,br s,overlaps with solvent),7.17(2H,br s),4.99(1H,d,J=11.0Hz),4.28(1H,dd,J=13.4,11.2Hz),3.51(1H,ddd,J=13.6,11.1,2.4Hz),3.30(1H,t,J=10.0Hz),2.89-2.97(2H,m),2.78(1H,d,J=13.7Hz),2.38-2.46(1H,m),2.19-2.26(1H,m),2.03-2.14(1H,m),1.85-1.93(1H,m),1.46-1.53(1H,m),1.44(3H,s),1.27(2H,m,J=5.6Hz),1.07-1.11(2H,m),0.43(3H,t,J=7.6Hz)质谱(ESI)m/z=553.0[M+H]+。
实施例401
2-((3R,5R,6S)-1-((S)-1-(叔丁基磺酰基)丁烷-2-基)-6-(4-氯苯基)-5-(5-氯吡啶-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. 2-(3S,5R,6S)-3-烯丙基-1-((S)-1-(叔丁基硫代)丁烷-2-基)-6-(4-氯苯基)-5-(5-氯吡啶-3-基)-3-甲基哌啶-2-酮
按照实施例339步骤B中描述的程序,使用等效的2-甲基丙烷硫醇,将(3S,5R,6S)-3-烯丙基-6-(4-氯苯基)-5-(5-氯吡啶-3-基)-1-((S)-1-羟基丁烷-2-基)-3-甲基哌啶-2-酮(实施例400,步骤H,0.2g,0.447mmol)转化为本标题化合物,为透明的膜状物(0.145g,62%)。
1H NMR(500MHz,氯仿-d)δppm 8.40(1H,d,J=2.2Hz),7.98(1H,d,J=1.7Hz),7.41(1H,t,J=2.1Hz),7.24(2H,br d,J=8.3Hz),6.99(2H,br d,J=6.6Hz),5.87(1H,m),5.13-5.23(2H,m),4.65(1H,d,J=10.8Hz),3.51(1H,t,J=11.4Hz),3.19(1H,ddd,J=13.7,10.8,2.9Hz),2.63-2.74(1H,m),2.53-2.62(3H,m),2.16(1H,t,J=13.6Hz),2.08(1H,m,J=14.2,8.8,7.3Hz),1.88(1H,dd,J=13.4,3.2Hz),1.51-1.60(1H,m),1.36(9H,brs),1.31(3H,br s),0.49(3H,t,J=7.6Hz)。质谱(ESI)m/z=519.2[M+H]+。
步骤B. 2-((3R,5R,6S)-1-((S)-1-(叔丁基磺酰基)丁烷-2-基)-6-(4-氯苯基)-5-(5-氯吡啶-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸
将(3S,5R,6S)-3-烯丙基-1-((S)-1-(叔丁基硫代)丁烷-2-基)-6-(4-氯苯基)-5-(5-氯吡啶-3-基)-3-甲基哌啶-2-酮(实施例401,步骤A,0.147g,0.283mmol)与乙酸(0.972mL,16.98mmol)和四丁基氯化铵水合物(8.37mg,0.028mmol)在4ml DCM中的溶液在冰浴中冷却。加入高锰酸钾(0.268g,1.698mmol)在3mL水中的溶液。在用冰浴冷却的同时搅拌该紫色溶液,并将其温度用超过2小时的时间升至室温。加入NaS2O3水溶液以及另外的DCM。在通过滤纸过滤该溶液后,分配滤液,然后用DCM洗涤水层。经Na2SO4干燥合并的有机物并浓缩。产物先通过硅胶色谱法纯化,接着通过制备型HPLC(Agilent柱,EXTEND C18PrepHT,5μM,30x250mm)用20%MeCN/H2O/0.1%TFA至80%MeCN/H2O/0.1%TFA梯度洗脱超过25分钟来进行纯化。合并含有产物的级分,将其冷冻在丙酮/干冰浴中,并在冻干机上除去该溶剂从而得到本标题化合物,为灰白色固体。
1H NMR(500MHz,DMSO-d6)δppm 12.38(1H,br s),8.42(1H,d,J=2.2Hz),8.02(1H,d,J=1.7Hz),7.57(1H,t,J=2.0Hz),7.11-7.47(4H,m),4.83(1H,d,J=11.0Hz),3.84(1H,dd,J=13.0,10.5Hz),3.47-3.57(1H,m),3.13(1H,br s),3.05(1H,d,J=12.5Hz),2.91(1H,d,J=13.9Hz),2.13-2.23(1H,m),2.03-2.13(2H,m),1.81-1.97(1H,m),1.43-1.53(1H,m),1.33(9H,s),1.26(3H,s),0.33(3H,t,J=7.6Hz)。质谱(ESI)m/z=569.2[M+H]+。
实施例402
2-((3R,5R,6S)-6-(4-氯苯基)-5-(5-氯吡啶-3-基)-1-((S)-1-(环丙烷磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. N-((S)-2-((3S,5R,6S)-3-烯丙基-6-(4-氯苯基)-5-(5-氯吡啶-3-基)-3-甲基-2-氧代哌啶-1-基)丁基)环丙烷磺酰胺
按照与实施例272步骤A中描述的程序类似的程序,使用环丙烷磺酰胺,将(3S,5R,6S)-3-烯丙基-6-(4-氯苯基)-5-(5-氯吡啶-3-基)-1-((S)-1-羟基丁烷-2-基)-3-甲基哌啶-2-酮(实施例400,步骤H,0.076g,0.170mmol)转化为本标题化合物。
MS(ESI)m/z=550.2[M+H]+。
步骤B. 2-((3R,5R,6S)-6-(4-氯苯基)-5-(5-氯吡啶-3-基)-1-((S)-1-(环丙烷磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
按照与实施例400步骤K中描述的程序类似的程序将N-((S)-2-((3S,5R,6S)-3-烯丙基-6-(4-氯苯基)-5-(5-氯吡啶-3-基)-3-甲基-2-氧代哌啶-1-基)丁基)环丙烷磺酰胺(实施例402,步骤A,0.073g,0.133mmol)转化为本标题化合物。
1H NMR(500MHz,氯仿-d)δppm 8.46(1H,d,J=1.7Hz),8.17(1H,br s),7.75(1H,s),7.25(2H,br s,overlaps with solvent),7.02-7.18(2H,m),5.08(1H,br s),4.92(1H,d,J=11.0Hz),3.78(1H,br s),3.46-3.56(1H,m),3.14(1H,dt,J=14.2,4.5Hz),3.02(1H,br s),2.77-2.95(2H,m),2.43-2.50(1H,m),2.36(1H,t,J=13.8Hz),2.00(1H,dd,J=13.7,2.7Hz),1.79-1.89(1H,m),1.50-1.59(1H,m),1.48(3H,s),1.15-1.20(2H,m),0.98-1.05(2H,m),0.51(3H,t,J=7.6Hz)。质谱(ESI)m/z=568.2[M+H]+。
实施例403
2-((3R,5R,6S)-6-(4-氯苯基)-5-(5-氯吡啶-3-基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
步骤A:N-((S)-2-((3S,5R,6S)-3-烯丙基-6-(4-氯苯基)-5-(5-氯吡啶-3-基)-3-甲基-2-氧代哌啶-1-基)丁基)-N-甲基环丙烷磺酰胺
按照与实施例272步骤A中描述的程序类似的程序,使用N-甲基环丙烷磺酰胺,将(3S,5R,6S)-3-烯丙基-6-(4-氯苯基)-5-(5-氯吡啶-3-基)-1-((S)-1-羟基丁烷-2-基)-3-甲基哌啶-2-酮(实施例400,步骤H,0.1g,0.224mmol)转化为本标题化合物。
MS(ESI)m/z=564.2[M+H]+。
步骤B. 2-((3R,5R,6S)-6-(4-氯苯基)-5-(5-氯吡啶-3-基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸
按照与实施例400步骤K中描述的程序类似的程序,将N-((S)-2-((3S,5R,6S)-3-烯丙基-6-(4-氯苯基)-5-(5-氯吡啶-3-基)-3-甲基-2-氧代哌啶-1-基)丁基)-N-甲基环丙烷磺酰胺(实施例403,步骤A,0.090g,0.159mmol)转化为本标题化合物。
1H NMR(500MHz,丙酮-d6)δppm 8.38(1H,d,J=1.7Hz),8.11(1H,s),7.68(1H,t,J=2.0Hz),7.21-7.43(4H,m),4.92(1H,d,J=10.8Hz),4.02-4.21(1H,m),3.57(1H,ddd,J=13.8,10.9,2.9Hz),2.99(1H,d,J=14.2Hz),2.91-2.96(5H,m),2.76(1H,d,J=14.2Hz),2.53-2.62(1H,m),2.39(1H,t,J=13.7Hz),2.19(1H,dd,J=13.4,2.9Hz),1.75-1.86(1H,m),1.66-1.74(1H,m),1.42(3H,s),0.96-1.12(4H,m),0.52(3H,t,J=7.6Hz)。质谱(ESI)m/z=582.0[M+H]+。
实施例404
2-((3R,5R,6S)-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-1-((S)-1-(乙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-1-((S)-1-(乙基硫代)丁烷-2-基)-3-甲基哌啶-2-酮
在旋转蒸发器上将(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-1-((S)-1-羟基丁烷-2-基)-3-甲基哌啶-2-酮(实施例121,步骤L,100mg,0.224mmol)在苯中共沸三次。将残余物溶解在甲苯中,并转移到反应容器中。用氩气吹扫该容器。加入乙烷硫醇(33.1μl,0.447mmol),接着加入氰基亚甲基三丁基正膦(216μl,0.894mmol)。将该容器密封,将该溶液加热至100℃并保持4h。用DCM(10ml)稀释反应混合物,并加入Si-马来酰亚胺(Silicycle,2.1g;0.66mmol/g;40-63微米)以清除多余的硫醇。在搅拌约1h后,将该混合物过滤并用DCM冲洗硅胶。在旋转蒸发器上浓缩滤液。将残余物溶解在DCM中,并将其直接上样到干燥的12g金封端的柱(Teledyne Isco,Lincoln,NE)上。用0%至5%的MeOH:DCM梯度洗脱该柱。合并含有所需产物的级分并浓缩从而得到本标题化合物,为无色膜状物。
步骤B. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-1-((S)-1-(乙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
按照与实施例395步骤C中描述的程序类似的程序,将(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-1-((S)-1-(乙基硫代)丁烷-2-基)-3-甲基哌啶-2-酮(实施例404,步骤A)转化为本标题化合物。
1H NMR(400MHz,CDCl3)δppm 8.65(d,J=2.3Hz,1H),7.48(dd,J=2.4,8.1Hz,1H),7.16-7.07(m,2H),6.98(s,1H),6.92-6.86(m,2H),5.00(d,J=10.2Hz,1H),4.25-4.16(m,1H),3.57-3.46(m,1H),3.26(br s,1H),3.15(d,J=15.3Hz,1H),3.10-3.01(m,2H),2.91(d,J=15.5Hz,1H),2.80(d,J=11.7Hz,1H),2.36(t,J=13.9Hz,1H),2.04-1.90(m,2H),1.50-1.40(m,7H),0.38(t,J=7.0Hz,3H);质谱(ESI)m/z=541.2[M+H]+。
实施例405
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-((S)-吗啉-2-基)丙基)-2-氧代哌啶-3-基)乙酸,TFA盐或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-((R)-吗啉-2-基)丙基)-2-氧代哌啶-3-基)乙酸,TFA盐
步骤A. (S)-2-((S)-1-羟基丙基)吗啉-4-羧酸叔丁酯和(R)-2-((S)-1-羟基丙基)吗啉-4-羧酸叔丁酯和(S)-2-((R)-1-羟基丙基)吗啉-4-羧酸叔丁酯和(R)-2-((R)-1-羟基丙基)吗啉-4-羧酸叔丁酯
向在室温下的(外消旋)-2-甲酰基吗啉-4-羧酸叔丁酯(0.996g,4.63mmol)(TygerScientific Inc.,Ewing,NJ,USA)在THF(25mL)中的溶液中逐滴加入乙基溴化镁在乙醚中的3.0M溶液(1.851mL,5.55mmol)。在4h后,用NH4Cl饱和水溶液淬灭该混合物。用EtOAc萃取该混合物。用盐水洗涤有机层,经Na2SO4干燥,过滤,并浓缩滤液从而得到本标题化合物的混合物。
步骤B. (S)-2-((S)-1-(((4-溴苯基)磺酰基)氧基)丙基)吗啉-4-羧酸叔丁酯和(R)-2-((S)-1-(((4-溴苯基)磺酰基)氧基)丙基)吗啉-4-羧酸叔丁酯和(S)-2-((R)-1-(((4-溴苯基)磺酰基)氧基)丙基)吗啉-4-羧酸叔丁酯和(R)-2-((R)-1-(((4-溴苯基)磺酰基)氧基)丙基)吗啉-4-羧酸叔丁酯
向来自实施例405步骤A的非对映异构体混合物(509mg,2.075mmol)在DCM(6.9mL)中的溶液中加入DMAP(558mg,4.56mmol)和4-溴苯磺酰氯(795mg,3.11mmol)。在搅拌18h后,将该混合物分配在EtOAc和水之间。用盐水洗涤有机层,经Na2SO4干燥,过滤,并浓缩滤液。通过硅胶快速色谱法(40g柱,洗脱剂:5%至30%的EtOAc/己烷)纯化残余物从而得到本标题化合物的混合物。
步骤C. (S)-2-((S)-1-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丙基)吗啉-4-羧酸叔丁酯和(R)-2-((S)-1-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丙基)吗啉-4-羧酸叔丁酯和(S)-2-((R)-1-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丙基)吗啉-4-羧酸叔丁酯和(R)-2-((R)-1-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丙基)吗啉-4-羧酸叔丁酯
将非对映异构的对溴苯磺酸酯(实施例404,步骤B,124mg,0.267mmol)溶解在甲苯中,并在真空中浓缩两次。加入二噁烷(1mL),接着加入叔丁醇钠(25.7mg,0.267mmol)。将该混合物在85℃下加热2天。将该混合物分配在EtOAc和稀NH4Cl水溶液之间。用盐水洗涤有机层,经Na2SO4干燥,过滤,并浓缩滤液。通过硅胶快速色谱法(4g柱,洗脱剂:5%至35%的EtOAc/己烷)纯化残余物从而得到标题化合物的混合物。
步骤D. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-((S)-吗啉-2-基)丙基)-2-氧代哌啶-3-基)乙酸,TFA盐或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-((R)-吗啉-2-基)丙基)-2-氧代哌啶-3-基)乙酸,TFA盐
将实施例404步骤C中获得的非对映异构体混合物(100mg,0.166mmol)溶解在THF(1mL)中。加入水(约0.5mL)直至该溶液变得混浊。加入t-BuOH直至该溶液变得澄清。加入NMO(29.2mg,0.249mmol),接着加入4%四氧化锇水溶液(5.28μl,0.831μmol)。在搅拌18h后,再加入3滴4%OsO4水溶液。在搅拌4h后,加入0.20mL琼斯试剂。在2天后,将该混合物分配在NaHCO3水溶液和DCM之间。用DCM和EtOAc萃取水层。用盐水洗涤合并的有机层,经Na2SO4干燥,过滤,并浓缩滤液。将该混合物在DCM(3mL)和TFA(1mL,12.98mmol)中搅拌25分钟并浓缩。通过反相制备型HPLC(柱:Gemini-NX C185um柱;Phenomonex,Torrance,CA;洗脱剂:30%至50%MeCN+0.1%TFA于水+0.1%TFA中,超过20分钟)纯化残余物从而得到本标题化合物的四个可能的非对映异构体中的三个。这些非对映异构体中第一个洗脱的是实施例405:
1H NMR(400MHz,氯仿-d)δppm 0.33(t,J=7.5Hz,3H)1.30-1.42(m,1H)1.47(s,3H)1.68-1.82(m,1H)1.82-1.91(m,1H)2.19–2.26(m,2H)2.56-2.64(m,3H)2.68-2.87(m,1H)3.03(d,J=12.3Hz,1H)3.07-3.33(m,2H)3.54-3.76(m,1H)3.76-3.99(m,1H)4.25-4.36(m,1H)4.51(d,J=10.6Hz,1H)4.57-4.71(m,1H)6.70(d,J=7.8Hz,1H)7.00(t,J=1.9Hz,1H)7.14(t J=7.6Hz,1H)7.21(d,J=8.0Hz,1H)7.28–7.32(m,4H)8.13(br s,1H)11.54(brs,1H)。质谱(ESI)m/z=519.1(M+1)。
实施例406
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((R)-1-((S)-吗啉-2-基)丙基)-2-氧代哌啶-3-基)乙酸,TFA盐或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((R)-1-((R)-吗啉-2-基)丙基)-2-氧代哌啶-3-基)乙酸,TFA盐
在实施例405步骤D中进一步洗脱HPLC柱,得到本标题化合物中的一种,为第二洗脱异构体。
1H NMR(400MHz,氯仿-d)δppm 0.93-1.11(m,3H)1.39-1.58(m,3H)1.62-1.78(m,1H)1.79-1.92(m,1H)1.93-2.02(m,1H)2.16-2.29(m,1H)2.55-2.70(m,2H)2.73-3.00(m,2H)3.03-3.24(m,2H)3.26-3.44(m,2H)3.45–3.54(m,1H)3.60–3.67(m,1H)3.75-3.97(m,1H)4.30-4.47(m,2H)6.73(d,J=7.4Hz,1H)6.98(brs,1H)7.11(t,J=8.0Hz,1H)7.17(d,J=8.0Hz,1H)7.23–7.33(m,4H)8.99(br s,1H)9.96(br s,1H)。质谱(ESI)m/z=519.1(M+1)。
实施例407
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((R)-1-((R)-吗啉-2-基)丙基)-2-氧代哌啶-3-基)乙酸,TFA盐或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((R)-1-((S)-吗啉-2-基)丙基)-2-氧代哌啶-3-基)乙酸,TFA盐
在实施例405中从HPLC柱进一步洗脱,得到本标题化合物的另一种(相对于实施例406而言),为第三洗脱异构体。
1H NMR(400MHz,氯仿-d)δppm 1.10(t,J=7.5Hz,3H)1.47(s,3H)1.83–1.93(m,1H)1.98-2.09(m,2H)2.15-2.32(m,2H)2.59-2.64(m,1H)2.66-2.72(m,2H)2.73-2.85(m,2H)3.23(d,J=13.3Hz,1H)3.43(t,J=12.2Hz,1H)3.66(t,J=11.7Hz,1H)3.77-3.92(m,2H)4.34(t,J=8.1Hz 1H)4.41(d,J=10.6Hz,1H)6.73(d,J=7.6Hz 1H)6.96(br s,1H)7.08(t,J=8.0Hz,1H)7.13(d,J=8.0Hz,1H)7.25-7.42(m,4H)9.16(br s,1H)9.43(br s,1H)。质谱(ESI)m/z=519.1(M+1)。
实施例408
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-3-(2-吗啉代乙基)-2-氧代哌啶-3-基)乙酸
步骤A. (3R,5R,6S)-3-烯丙基-1-((S)-1-((叔丁基二苯基甲硅烷基)氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-(2-((4-甲氧基苄基)氧基)乙基)哌啶-2-酮和(3S,5R,6S)-3-烯丙基-1-((S)-1-((叔丁基二苯基甲硅烷基)氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-(2-((4-甲氧基苄基)氧基)乙基)哌啶-2-酮
按照与实施例69步骤A中描述的程序类似的程序,从(3R,5R,6S)-1-((S)-1-((叔丁基二苯基甲硅烷基)氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)哌啶-2-酮(实施例127,步骤A)和1-((2-碘乙氧基)甲基)-4-甲氧基苯[J.Am.Chem.Soc.,124,8206–8219,(2002)]获得本标题化合物。通过硅胶快速色谱法(洗脱剂:0%至20%的EtOAc/己烷,梯度洗脱超过30min)纯化残余物,得到所需的产物,为C3差向异构体的混合物。
质谱(ESI)m/z=834.4(M+1)和856.4(M+Na)。
步骤B. (3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)-3-(2-((4-甲氧基苄基)氧基)乙基)哌啶-2-酮
向在室温下的(3R,5R,6S)-3-烯丙基-1-((S)-1-((叔丁基二苯基甲硅烷基)氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-(2-((4-甲氧基苄基)氧基)乙基)哌啶-2-酮和(3S,5R,6S)-3-烯丙基-1-((S)-1-((叔丁基二苯基甲硅烷基)氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-(2-((4-甲氧基苄基)氧基)乙基)哌啶-2-酮的混合物(19.23g,23.03mmol;实施例408,步骤A)在THF(92ml)中的溶液中缓慢地加入TBAF溶液(1.0M在THF中,34.5ml,34.5mmol)。通过LCMS监测反应,当判断反应完成时在减压下浓缩(不加热)反应物,然后将其稀释在400mLEtOAc中。加入HCl(1N,150ml)。分离各层并用EtOAc萃取水层。用水洗涤合并的有机物数次,经MgSO4干燥,过滤,并浓缩滤液。通过硅胶色谱法(洗脱剂:10%至20%的EtOAc/己烷,梯度洗脱超过30min)纯化,得到与其C3差向异构体在一起的本标题化合物,为透明的无色膜状物。通过手性HPLC(流速:120ml/min,每次注射1g,在OD-H 5cm I.D.×50cm,20μm柱(Daicel Chemical Industries LTD)上,使用6%的异丙醇/己烷作为洗脱剂)分离各个立体异构体从而得到本标题化合物,为第一洗脱异构体(tR=11-23min),为澄清的粘稠油状物。
1H NMR(500MHz,氯仿-d)δppm 0.61(t,J=7.5Hz,3H)1.33(ddd,J=13.9,7.8,5.8Hz,1H)1.79(dd,J=13.7,2.9Hz,1H)1.94(dt,J=14.8,7.5Hz,1H)2.02(s,1H)2.11-2.21(m,3H)2.26(t,J=13.6Hz,1H)2.77(dd,J=13.3,6Hz,1H)3.12(br s,1H)3.22(ddd,J=13.5,10.6,2.8Hz,1H)3.58(d,J=3.7Hz,2H)3.70(t,J=6.4Hz,2H)3.81(s,3H)4.35(d,J=10.5Hz,1H)4.37-4.50(m,2H)5.12-5.22(m,2H)5.75-5.86(m,1H)6.64(d,J=7.8Hz,1H)6.85(m,2H)6.92(s,2H)7.06(t,J=7.8Hz,1H)7.10-7.19(m,3H)7.21(m,J=8.6Hz,2H)。质谱(ESI)m/z=596.2(M+H)和618.2(M+Na)。
步骤C. N-((S)-2-((3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-(2-(4-甲氧基苄基氧基)乙基)-2-氧代哌啶-1-基)丁基)-N-甲基环丙烷磺酰胺
按照与实施例201步骤A中描述的程序类似的程序,从(3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)-3-(2-(4-甲氧基苄基氧基)乙基)哌啶-2-酮(实施例408,步骤B)和N-甲基环丙烷磺酰胺制备本标题化合物。
1H NMR(500MHz,氯仿-d)δppm 0.55(br s,3H)0.87-0.99(m,2H)1.19(td,J=5.4,1.6Hz,1H)1.48-1.65(m,4H)1.75(dd,J=13.7,3.2Hz,1H)1.85(dquin,J=14.7,7.5Hz,1H)2.02(s,1H)2.06-2.11(m,1H)2.16-2.30(m,3H)2.52(br s,2H)2.87(s,1H)2.89(s,3H)3.20(ddd,J=13.6,10.7,3.1Hz,1H)3.71(t,J=7Hz,2H)3.81(s,3H)4.41-4.50(m,2H)4.66(brs,1H)5.04-5.12(m,2H)5.76-5.88(m,1H)6.83(d,J=6.9Hz,1H)6.85-6.90(m,2H)6.91(s,1H)7.08-7.20(m,4H)7.25(s,1H)。质谱(ESI)m/z=713.2(M+1)和735.2(M+Na)。
步骤D. N-((S)-2-((3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-(2-羟基乙基)-2-氧代哌啶-1-基)丁基)-N-甲基环丙烷磺酰胺
向3.09g(4.33mmol)N-((S)-2-((3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-(2-(4-甲氧基苄基氧基)乙基)-2-氧代哌啶-1-基)丁基)-N-甲基环丙烷磺酰胺(实施例408,步骤C)在DCM(82mL)和水(4.56mL)[18:1]的混合物中的溶液中加入2,6-二-叔丁基吡啶(2.93mL,12.99mmol),接着加入DDQ(3.93g,17.32mmol)。将反应混合物在室温下剧烈搅拌15min。用150mL饱和NaHCO3/盐水溶液稀释反应混合物,并将其萃取到600mL乙酸乙酯中,然后用200mL EtOAc x2萃取(通过过滤除去沉淀)。经MgSO4干燥合并的有机层,过滤,并蒸发滤液。通过硅胶色谱法(洗脱剂:50-100%%EtOAc/己烷,梯度洗脱)纯化,得到所需的产物,为泡沫状物。
1H NMR(500MHz,氯仿-d)δppm 0.54(br s,3H)0.92-1.06(m,2H)1.20(dd,J=4.8,2.1Hz,2H)1.27(t,J=7.2Hz,1H)1.53-1.66(m,1H)1.66-1.76(m,2H)1.95(dt,J=14.9,7.6Hz,1H)2.23-2.39(m,3H)2.59(br s,1H)2.87(s,1H)2.90(s,3H)3.17(ddd,J=13.8,10.6,3.1Hz,1H)3.77(dt,J=12.0,4.6Hz,1H)4.10-4.20(m,1H)4.71(br s,1H)5.07-5.21(m,2H)5.65-5.80(m,1H)6.90(br s,1H)6.96(s,1H)7.11-7.16(m,2H)7.22(br s,1H)7.26(br s,2H)。质谱(ESI)m/z=593.2(M+1)和615.2(M+Na)。
步骤E. N-((S)-2-((3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-3-(2-((三异丙基甲硅烷基)氧基)乙基)哌啶-1-基)丁基)-N-甲基环丙烷磺酰胺
通过注射器向在0℃下的2.52g(4.25mmol)N-((S)-2-((3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-(2-羟基乙基)-2-氧代哌啶-1-基)丁基)-N-甲基环丙烷磺酰胺(实施例408,步骤D)、DMAP(0.026g,0.212mmol),和咪唑(0.723g,10.61mmol)在DCM(16.98mL)中的溶液中缓慢地加入TIPS-Cl(1.17mL,5.52mmol)。在室温下搅拌反应物,并添加试剂直至根据LCMS和TLC判断反应已完成。通过加入6mL MeOH来淬灭反应混合物,然后用DCM(70ml x2)萃取。用水(30mL)、NH4Cl饱和水溶液(20mL)洗涤合并的有机物,经Na2SO4干燥,过滤,并浓缩滤液。通过硅胶色谱法(洗脱剂:0%至40%的EtOAc/DCM,梯度洗脱)纯化,得到本标题化合物,为澄清的无色油状物。
质谱(ESI)m/z=749.4(M+1)。
步骤F. N-((S)-2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-3-(2-氧代乙基)-3-(2-(三异丙基甲硅烷基氧基)乙基)哌啶-1-基)丁基)-N-甲基环丙烷磺酰胺
按照与实施例91步骤E中描述的程序类似的程序,对N-((S)-2-((3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-3-(2-(三异丙基甲硅烷基氧基)乙基)哌啶-1-基)丁基)-N-甲基环丙烷磺酰胺(实施例408,步骤E)进行处理。通过硅胶色谱法(12g SiO2,洗脱剂:0%至30%的EtOAc/己烷,梯度洗脱)纯化,得到本标题化合物,为无色油状物。
质谱(ESI)m/z=751.2(M+1)
步骤G. N-((S)-2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-(2-吗啉代乙基)-2-氧代-3-(2-(三异丙基甲硅烷基氧基)乙基)哌啶-1-基)丁基)-N-甲基环丙烷磺酰胺
根据与实施例91步骤F中描述的程序类似的程序合并N-((S)-2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-3-(2-氧代乙基)-3-(2-((三异丙基甲硅烷基)氧基)乙基)哌啶-1-基)丁基)-N-甲基环丙烷磺酰胺(实施例408,步骤F)和吗啉。通过硅胶色谱法(洗脱剂:50%至100%的EtOAc/DCM,梯度洗脱超过15min)纯化,得到本标题化合物,为透明的无色玻璃状物。
质谱(ESI)m/z=822.4(M+1)
步骤H. N-((S)-2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-(2-羟基乙基)-3-(2-吗啉代乙基)-2-氧代哌啶-1-基)丁基)-N-甲基环丙烷磺酰胺
根据与实施例69步骤D中描述的程序类似的程序,对N-((S)-2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-(2-吗啉代乙基)-2-氧代-3-(2-(三异丙基甲硅烷基氧基)乙基)哌啶-1-基)丁基)-N-甲基环丙烷磺酰胺(实施例408,步骤G)进行处理,从而得到本标题化合物。
1H NMR(500MHz,氯仿-d)δppm 0.53(t,J=7.6Hz,3H)1.02-1.06(m,1H)1.06-1.14(m,1H)1.14-1.22(m,1H)1.22-1.31(m,1H)1.49(d,J=7.1Hz,1H)1.64(ddd,J=14.2,7.8,3.7Hz,3H)1.77-1.98(m,4H)1.98-2.02(m,1H)2.02-2.06(m,3H)2.25-2.43(m,4H)2.44-2.50(m,1H)2.61(dd,J=13.8,1.8Hz,1H)2.79-2.89(m,3H)2.89-3.06(m,2H)3.12-3.26(m,1H)3.39-3.50(m,2H)3.50-3.56(m,1H)3.61(d,J=12.7Hz,1H)3.75-3.90(m,1H)3.92-4.09(m,3H)4.14-4.38(m,2H)4.48(br s,1H)4.68(d,J=10.5Hz,1H)6.82-6.93(m,1H)6.98(s,2H)7.08-7.21(m,2H)12.31(br s,1H)。
质谱(ESI)m/z=666.2(M+1)
步骤I. 2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-3-(2-吗啉代乙基)-2-氧代哌啶-3-基)乙酸
根据与实施例69步骤E中描述的程序类似的程序,对N-((S)-2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-(2-羟基乙基)-3-(2-吗啉代乙基)-2-氧代哌啶-1-基)丁基)-N-甲基环丙烷磺酰胺(实施例408,步骤H)进行处理。该反应(使用4当量琼斯试剂)在0℃下在少于2分钟的时间内完成,在此之后用MeOH(10当量)淬灭反应物并将其稀释在EtOAc中。将该溶液从不溶性材料上方轻轻倒出,用NaHCO3水溶液洗涤,经MgSO4干燥,过滤,并在减压下浓缩。通过反相制备型HPLC(Sunfire Prep C18OBD 10μm柱(Waters,Milford,MA),用40%的在水中的MeCN至75%的在水中的MeCN梯度洗脱超过30min,其中这两种溶剂都含有0.1%TFA)纯化,得到本标题化合物,为TFA盐。
1H NMR(500MHz,氯仿-d)δppm 0.49(t,J=7.5Hz,3H)0.96-1.16(m,3H)1.17-1.28(m,1H)1.56-1.67(m,1H)1.85(dt,J=15.2,7.7Hz,1H)2.00(dd,J=13.6,3.1Hz,1H)2.06-2.16(m,1H)2.22-2.41(m,3H)2.57-2.66(m,1H)2.71(br s,1H)2.85(s,3H)2.87-2.96(m,3H)2.99(br s,1H)3.03(br s,1H)3.16-3.27(m,1H)3.34(br s,1H)3.52-3.66(m,2H)3.70(d,J=12Hz,1H)3.79-3.96(m,2H)4.03(d,J=11Hz,2H)4.38(br s,1H)4.68(d,J=10.5Hz,1H)6.84-6.94(m,2H)6.98(s,2H)7.10-7.17(m,2H)7.22-7.27(m,1H)8.42(br s,3H)11.01(br s,1H)。质谱(ESI)m/z=680.2(M+1)。
按照与实施例408中描述的程序类似的程序,用合适的胺代替步骤G中的吗啉,从N-((S)-2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-3-(2-氧代乙基)-3-(2-(三异丙基甲硅烷基氧基)乙基)哌啶-1-基)丁基)-N-甲基环丙烷磺酰胺(实施例408,步骤F)制备实施例409–411。
实施例409
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-(2-(1,1-二氧化硫代吗啉代)乙基)-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸,TFA盐
1H NMR(500MHz,CD3OD)δppm 0.51(t,J=7.5Hz,3H)1.00-1.07(m,1H)1.07-1.19(m,2H)1.21-1.30(m,2H)1.54-1.68(m,1H)1.79-1.91(m,1H)1.95(dd,J=13.7,2.7Hz,1H)2.26(t,J=13.5Hz,2H)2.29-2.39(m,2H)2.61(d,J=13Hz,1H)2.73(br s,1H)2.79(d,J=13.7Hz,1H)2.84(s,3H)2.88-2.96(m,1H)3.20(ddd,J=13.4,10.7,3.1Hz,1H)3.52(br s,3H)3.57(d,J=8.3Hz,3H)3.86(br s,4H)4.43(t,J=12.1Hz,1H)4.70(d,J=10.8Hz,1H)6.87(d,J=7.1Hz,1H)6.99(s,3H)7.12-7.21(m,2H)7.27(br s,1H)。质谱(ESI)m/z=728.2(M+1)。
实施例410
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代-3-(2-(吡咯烷-1-基)乙基)哌啶-3-基)乙酸,HCl盐
1H NMR(500MHz,CD3OD)δppm 0.52(t,J=7.6Hz,3H)0.98-1.21(m,4H)1.69(ddd,J=14.2,7.6,4.9Hz,1H)1.77-1.92(m,1H)1.92-2.10(m,3H)2.10-2.24(m,3H)2.27-2.42(m,2H)2.54-2.62(m,1H)2.76(dd,J=14.2,2Hz,1H)2.79-2.87(m,1H)2.88(s,3H)2.91-3.03(m,1H)3.12(dtd,J=11.3,8.0,3.2Hz,2H)3.33-3.46(m,2H)3.63(ddd,J=12.9,8.9,7.1Hz,1H)3.66-3.77(m,2H)4.39(t,J=10.9Hz,1H)4.81(d,J=11Hz,1H)6.94-7.02(m,1H)7.08(s,1H)7.12-7.24(m,3H)7.32(d,J=7.8Hz,2H)。质谱(ESI)m/z=728.2(M+1)。
实施例411
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-(2-(二甲基氨基)乙基)-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸,HCl盐
1H NMR(500MHz,CD3OD)δppm 0.52(t,J=7.6Hz,3H)0.98-1.21(m,4H)1.69(ddd,J=14.3,7.7,4.2Hz,1H)1.76-1.93(m,1H)1.98(dd,J=13.7,3.2Hz,1H)2.12(ddd,J=14.5,7.6,5Hz,1H)2.29-2.44(m,2H)2.55-2.66(m,1H)2.76(dd,J=14.2,2Hz,1H)2.80-2.88(m,1H)2.88-3.06(m,11H)3.24-3.37(m,2H)3.42(ddd,J=13.6,10.8,3.1Hz,1H)3.61(dt,J=13.3,7.8Hz,1H)4.42(t,J=11.3Hz,1H)4.81(d,J=11Hz,1H)6.93-7.04(m,1H)7.09(s,1H)7.12-7.26(m,3H)7.32(d,J=7.6Hz,2H)。质谱(ESI)m/z=638.2(M+1)。
实施例412
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-3-(2-吗啉代乙基)-2-氧代哌啶-3-基)乙酰胺,HCl盐
将HATU(119mg,0.313mmol)加入到83mg(0.522mmol)2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-3-(2-吗啉代乙基)-2-氧代哌啶-3-基)乙酸的TFA盐(实施例408,步骤I)和TEA(72.8μL,0.522mmol)在DMF(2.09mL)中的溶液中。将该混合物在室温下搅拌3min,然后加入NH3溶液(7M在MeOH中,0.45mL,3.13mmol)。原料在几分钟内消耗完。在减压下浓缩该混合物并通过反相制备型HPLC(Sunfire Prep C18OBD 10μm柱(Waters,Milford,MA),用40%的在水中的MeCN至75%的在水中的MeCN梯度洗脱超过30min,其中这两种溶剂都含有0.1%TFA)纯化。在冻干前加入几滴HCl,使得本标题化合物以HCl盐形式产生。
1H NMR(500MHz,氯仿-d)δppm 0.55(t,J=7.6Hz,3H)0.98-1.09(m,2H)1.09-1.24(m,2H)1.61-1.78(m,1H)1.83-1.99(m,1H)2.08-2.17(m,1H)2.33(t,J=13.7Hz,1H)2.46(ddd,J=15,8.1,7.2Hz,1H)2.56-2.64(m,1H)2.73-2.83(m,2H)2.83-2.93(m,4H)2.99(d,J=14.4Hz,1H)3.11(td,J=12.1,3.4Hz,1H)3.16-3.27(m,1H)3.36-3.51(m,2H)3.51-3.67(m,2H)3.67-3.73(m,1H)3.74-3.88(m,2H)4.13(t,J=9.8Hz,2H)4.39(t,J=12.4Hz,1H)4.81(d,J=11Hz,1H)6.89-7.05(m,1H)7.08(s,1H)7.11-7.27(m,3H)7.34(d,J=7.1Hz,2H)。质谱(ESI)m/z=679.2(M+1)。
实施例413
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-3-(2-吗啉代乙基)-2-氧代哌啶-3-基)乙酰胺,HCl盐
根据与实施例412中描述的程序类似的程序,对2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-(2-(1,1-二氧化硫代吗啉代)乙基)-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸(实施例409)进行处理,从而得到本标题化合物。
1H NMR(500MHz,CD3OD)δppm 0.53(t,J=7.6Hz,3H)0.98-1.07(m,2H)1.07-1.16(m,1H)1.20(td,J=8.6,4.4Hz,1H)1.70(ddd,J=14.2,7.8,3.9Hz,1H)1.91(dt,J=15,7.6Hz,1H)2.01(dd,J=13.5,2.9Hz,1H)2.12(dt,J=14.8,5.3Hz,1H)2.32(t,J=13.7Hz,1H)2.39-2.51(m,1H)2.59(dt,J=12.6,6.4Hz,1H)2.75-2.87(m,3H)2.89(s,3H)2.98(d,J=14.7Hz,1H)3.37-3.49(m,1H)3.50-3.65(m,5H)3.65-3.75(m,1H)3.95(br s,4H)4.38(t,J=12Hz,1H)4.79(d,J=10.8Hz,1H)7.01(dd,J=6.5,2.1Hz,1H)7.07(s,1H)7.10-7.26(m,3H)7.32(d,J=7.1Hz,2H)。质谱(ESI)m/z=727.2(M+1)。
实施例414
(1R,3S,6S,7R)-7-(3-氯苯基)-6-(4-氯苯基)-5-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-4-氧代-5-氮杂螺[2.5]辛烷-1-羧酸和(3S,6S,7R)-7-(3-氯苯基)-6-(4-氯苯基)-5-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-4-氧代-5-氮杂螺[2.5]辛烷-1-羧酸
步骤A. (3R,5R,6S)-3-烯丙基-1-((S)-1-(叔丁基二苯基甲硅烷基氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-((2-(三甲基甲硅烷基)乙氧基)甲基)哌啶-2-酮
将双(三甲基甲硅烷基)氨基锂(在甲苯中的1M溶液,4.76mL,4.76mmol)加入到在-78℃下的(5R,6S)-1-((S)-1-(叔丁基二苯基甲硅烷基氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)哌啶-2-酮(实施例185,步骤C,2.0g,3.17mmol)和3-溴丙烯(0.274mL,3.17mmol)在THF中的溶液中。将反应物温度升至0℃并搅拌2小时。在再冷却至-78℃后,加入LDA溶液(7.93mmol在THF中),接着加入2-(氯甲氧基)乙基三甲基甲硅烷(0.842mL,4.76mmol)。将反应物温度升至50℃并搅拌1.5小时。用EtOAc稀释反应混合物并用HCl(1N)洗涤。用饱和NaCl洗涤有机萃取物并经Na2SO4干燥。将该溶液过滤并在真空中浓缩。通过硅胶色谱法用0%至20%的在己烷中的EtOAc梯度洗脱来纯化粗材料,从而得到(3S,5R,6S)-3-烯丙基-1-((S)-1-(叔丁基二苯基甲硅烷基氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-((2-(三甲基甲硅烷基)乙氧基)甲基)哌啶-2-酮(其为第一洗脱非对映异构体)和本标题化合物(其为第二洗脱非对映异构体,为油状物)。
1H NMR(400MHz,氯仿-d)δppm-0.07-0.05(m,9H)0.37(t,J=7.6Hz,3H)0.91-1.05(m,3H)1.28-1.46(m,2H)1.79(dd,J=13.6,2.8Hz,1H)1.86(ddd,J=14.1,9.3,7.2Hz,1H)2.35(dd,J=13.8,7.9Hz,1H)2.49-2.65(m,2H)2.68-2.83(m,1H)3.02-3.17(m,2H)3.39-3.53(m,2H)3.59(td,J=10,7.0Hz,2H)3.84(d,J=7.8Hz,1H)4.08(t,J=10Hz,1H)4.42(d,J=10.6Hz,1H)5.03-5.19(m,2H)5.76-5.95(m,1H)6.66(d,J=7.6Hz,1H)6.92(t,J=1.8Hz,2H)6.97-7.10(m,3H)7.15(d,J=7.4Hz,2H)。
步骤B. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)-3-((2-(三甲基甲硅烷基)乙氧基)甲基)哌啶-2-酮
将1M TBAF的THF溶液(2.15mL,2.15mmol)加入到(3S,5R,6S)-3-烯丙基-1-((S)-1-(叔丁基二苯基甲硅烷基氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-((2-(三甲基甲硅烷基)乙氧基)甲基)哌啶-2-酮(实施例414,步骤A;860mg,1.074mmol)的THF溶液中。将反应物加热至回流3小时。在冷却后,用EtOAc稀释该反应物并用HCl(1N在水中)洗涤。用饱和NaCl洗涤有机萃取物并经Na2SO4干燥。将该溶液过滤并浓缩从而得到为玻璃状物的粗材料,通过硅胶色谱法用20%的在己烷中的EtOAc洗脱来对该粗材料进行纯化从而得到本标题化合物,为固体。
步骤C. N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-3-((2-(三甲基甲硅烷基)乙氧基)甲基)哌啶-1-基)丁基)环丙烷磺酰胺
按照与实施例201步骤A中描述的程序类似的程序,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)-3-((2-(三甲基甲硅烷基)乙氧基)甲基)哌啶-2-酮(实施例414,步骤B)和N-甲基环丙烷磺酰胺制备本标题化合物。采用色谱法通过预装填的硅胶柱(Teledyne Isco,Lincoln,NE)(12g),用0%至80%的在己烷中的EtOAc梯度洗脱来纯化该产物,从而得到本标题化合物,为油状物。
质谱(ESI)m/z=665.2(M+1)。
步骤D. N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-3-((2-(三甲基甲硅烷基)乙氧基)甲基)哌啶-1-基)丁基)-N-甲基环丙烷磺酰胺
将N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-3-((2-(三甲基甲硅烷基)乙氧基)甲基)哌啶-1-基)丁基)环丙烷磺酰胺(实施例414,步骤C,1.5g,2.253mmol)在THF中的溶液用氢化钠(在矿物油中的60%分散体,6.76mmol)和碘甲烷(0.280ml,4.51mmol)在室温下处理3小时。用HCl(1N)淬灭反应混合物并用DCM稀释。用饱和NaCl洗涤有机萃取物并经Na2SO4干燥。将该溶液过滤并在真空中浓缩从而得到粗材料,为油状物。采用色谱法通过预装填的硅胶柱(Teledyne Isco,Lincoln,NE)(4g),用0%至80%的在己烷中的EtOAc梯度洗脱来纯化该产物,从而得到本标题化合物,为油状物。
1H NMR(400MHz,氯仿-d)δppm-0.06-0.03(m,9H)0.54(t,J=6.9Hz,3H)0.80-1.03(m,5H)1.13(d,J=8.8Hz,1H)1.14-1.23(m,2H)1.56-1.65(m,2H)1.75-1.93(m,2H)2.28(t,J=4.5Hz,1H)2.51(t,J=13.8Hz,1H)2.60(d,J=7.4Hz,2H)3.01(s,3H)3.20(ddd,J=13.9,10.8,3.1Hz,1H)3.31-3.40(m,1H)3.40-3.49(m,1H)3.49-3.60(m,1H)3.79(d,J=8.6Hz,1H)4.71(d,J=10.8Hz,1H)5.11-5.24(m,2H)5.83-6.00(m,1H)6.84-6.91(m,1H)6.94(s,1H)7.01(d,J=7.8Hz,2H)7.07-7.16(m,2H)7.21(d,J=8.2Hz,2H)。
步骤E. ((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)甲基甲烷磺酸酯
将N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-3-((2-(三甲基甲硅烷基)乙氧基)甲基)哌啶-1-基)丁基)-N-甲基环丙烷磺酰胺(实施例414,步骤D,1.85g,2.72mmol)在DCM中的溶液用三氟化硼(纯化的再蒸馏的乙醚络合物,0.672ml,5.44mmol)处理2小时。用DCM稀释反应混合物并用饱和NaCl洗涤。经Na2SO4干燥有机萃取物,过滤,并在真空中浓缩从而得到粗材料,为油状物。通过色谱法在预装填的硅胶柱(Teledyne Isco,Lincoln,NE)(12g)上,用0%至80%的在己烷中的EtOAc梯度洗脱来纯化该产物,从而得到中间体N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-(羟基甲基)-2-氧代哌啶-1-基)丁基)-N-甲基环丙烷磺酰胺(1.55g,2.67mmol,98%产率),为油状物,将其直接用于下一反应。
将甲烷磺酰氯(0.200ml,2.59mmol)加入到N-((S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-(羟基甲基)-2-氧代哌啶-1-基)丁基)-N-甲基环丙烷磺酰胺(1.0g,1.725mmol)和三乙胺(0.480ml,3.45mmol)在DCM中的溶液中。将反应物搅拌2小时。用DCM稀释反应混合物,用HCl(1N)和饱和NaCl洗涤,并经Na2SO4干燥。将该溶液过滤并在真空中浓缩从而得到粗材料,为油状物。采用色谱法通过预装填的硅胶柱(Teledyne Isco,Lincoln,NE)(12g),用0%至80%的在己烷中的EtOAc梯度洗脱来纯化该产物,从而得到本标题化合物,为油状物。质谱(ESI)m/z=657.2(M+1)。
步骤F. ((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代-3-(2-氧代乙基)哌啶-3-基)甲基甲烷磺酸酯
向在-78℃下的((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)甲基甲烷磺酸酯(实施例414,步骤E,1.12g,1.703mmol)在10%MeOH-DCM中的溶液中鼓入臭氧直至形成蓝色。用氮气吹扫反应物,接着加入二甲基硫醚(1.251ml,17.03mmol)。将反应物温度升至室温。通过色谱法在预装填的硅胶柱(Teledyne Isco,Lincoln,NE)(12g)上,用0%至80%的在己烷中的EtOAc梯度洗脱来纯化粗材料,从而得到本标题化合物,为油状物。
1H NMR(400MHz,氯仿-d)δppm 0.35-0.59(m,3H)0.95(dt,J=5.0,2.5Hz,2H)1.05-1.17(m,2H)1.43-1.69(m,1H)1.69-1.90(m,2H)2.04-2.18(m,1H)2.17-2.32(m,2H)2.32-2.53(m,1H)2.58-2.94(m,5H)2.94-3.11(m,4H)3.49(s,1H)3.53-3.72(m,2H)4.34-4.82(m,3H)5.02-5.52(m,1H)7.01-7.15(m,2H)7.15-7.23(m,2H),9.89(s,1H)。
步骤G:2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-3-(((甲基磺酰基)氧基)甲基)-2-氧代哌啶-3-基)乙酸甲酯
将((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代-3-(2-氧代乙基)哌啶-3-基)甲基甲烷磺酸酯(实施例414,步骤F,1.0g,1.516mmol)的MeOH溶液用Oxone(0.932g,1.516mmol)处理整个周末的时间(over aweekend)。用DCM和水稀释反应混合物。用饱和NaCl洗涤有机萃取物并经Na2SO4干燥。将该溶液过滤并在真空中浓缩从而得到粗材料,为白色固体。采用色谱法通过预装填的硅胶柱(Teledyne Isco,Lincoln,NE)(12g),用0%至80%的在己烷中的EtOAc梯度洗脱来纯化该产物,从而得到本标题化合物,为油状物。
1H NMR(400MHz,氯仿-d)δppm 0.46-0.63(m,5H)1.01(dd,J=7.7,2.3Hz,4H)1.15-1.26(m,4H)1.79-1.98(m,2H)2.05(dd,J=13.9,3.1Hz,1H)2.19(dd,J=13.5,5.1Hz,1H)2.28-2.40(m,2H)2.47-2.61(m,1H)2.76-2.91(m,5H)2.91-3.02(m,6H)3.03-3.12(m,5H)3.12-3.26(m,2H)3.42(d,J=0.8Hz,2H)3.75(s,3H)4.05-4.28(m,1H)4.50-4.62(m,2H)4.64-4.75(m,2H)4.81(d,J=10.6Hz,1H)6.87-7.01(m,3H)7.01-7.12(m,2H)7.13-7.21(m,3H)7.27(d,J=7.6Hz,2H)。
步骤H. (1S,3S,6S,7R)-7-(3-氯苯基)-6-(4-氯苯基)-5-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-4-氧代-5-氮杂螺[2.5]辛烷-1-羧酸甲酯和(1R,3S,6S,7R)-7-(3-氯苯基)-6-(4-氯苯基)-5-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-4-氧代-5-氮杂螺[2.5]辛烷-1-羧酸甲酯
用超过10min的时间将双(三甲基甲硅烷基)氨基锂溶液(在甲苯中的1.0M,290μl,0.290mmol)加入到在0℃下的2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-3-(((甲基磺酰基)氧基)甲基)-2-氧代哌啶-3-基)乙酸甲酯(实施例414,步骤G,200mg,0.290mmol)在THF中的溶液中。用1N HCl淬灭反应混合物并用DCM萃取。用Na2CO3饱和水溶液洗涤有机萃取物,并经Na2SO4干燥。将该溶液过滤并在真空中浓缩从而得到粗材料,为白色玻璃状物。通过色谱法在Redi-Sep预装填的硅胶柱(4g)上,用0%至80%的在己烷中的EtOAc梯度洗脱来纯化该产物,从而得到本标题化合物,为非对映异构体混合物。
1H NMR(400MHz,氯仿-d)δppm 0.40(t,J=7.5Hz,3H)0.69-0.86(m,3H)0.86-0.95(m,2H)1.01-1.14(m,3H)1.14-1.23(m,2H)1.25(dd,J=6.5,4.3Hz,2H)1.43(br.s.,3H)1.77(dt,J=14.7,7.4Hz,1H)1.89-2.02(m,2H)2.14-2.26(m,2H)2.51(t,J=11.7Hz,1H)2.70-2.82(m,2H)2.84(s,3H)3.57-3.73(m,3H)4.67(d,J=9.6Hz,1H)6.74-6.88(m,2H)6.98(d,J=8.0Hz,2H)7.06(d,J=5.1Hz,2H)7.17(s,2H)。质谱(ESI)m/z=593.2(M+H+)。
步骤I:(1R,3S,6S,7R)-7-(3-氯苯基)-6-(4-氯苯基)-5-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-4-氧代-5-氮杂螺[2.5]辛烷-1-羧酸和(1S,3S,6S,7R)-7-(3-氯苯基)-6-(4-氯苯基)-5-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-4-氧代-5-氮杂螺[2.5]辛烷-1-羧酸
将来自实施例414步骤H的非对映异构酯的混合物用NaOH(3N在MeOH中)在室温下处理过夜。用1N HCl(1N)酸化反应混合物并将其萃取到DCM中。用饱和NaCl洗涤有机萃取物并经Na2SO4干燥。通过硅胶色谱法,用40%的在己烷中的EtOAc梯度洗脱来纯化该产物,从而得到本标题化合物,为非对映异构体混合物,为白色玻璃状物。
1H NMR(400MHz,氯仿-d)δppm 0.39(t,J=7.5Hz,3H)0.81(s,1H)0.89-1.02(m,2H)1.16-1.21(m,2H)1.21-1.30(m,1H)1.37(dd,J=9.2,5.7Hz,1H)1.47(ddd,J=14.5,7.6,4.1Hz,1H)1.84(ddd,J=14.5,8.7,7.3Hz,1H)1.95-2.05(m,1H)2.18(dd,J=7.0,5.7Hz,1H)2.22-2.32(m,1H)2.66-2.85(m,3H)2.87(s,3H)3.11(ddd,J=13.1,10.4,2.9Hz,1H)3.42(s,1H)4.05(d,J=7.0Hz,1H)4.71(d,J=10.4Hz,1H)6.74(dt,J=6.9,1.6Hz,1H)6.82-6.95(m,3H)6.98-7.11(m,2H)7.18(d,J=8.4Hz,2H);质谱(ESI)m/z=579.1(M+H+)。
实施例415
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2S,3S)-1,2-二羟基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2R,3S)-1,2-二羟基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-氧代丁烷-2-基)哌啶-3-基)乙酸甲酯
向搅拌着的2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸甲酯(实施例186,步骤A,360mg,0.752mmol)在DCM(3.76mL)中的溶液中加入Dess-Martin过碘烷(383mg,0.903mmol),并将反应物在室温下搅拌20分钟。在此时间后,用Na2S2O3(30mL,饱和水溶液)和DCM(40mL)处理该反应物并将其在室温下搅拌10分钟。分离有机层,用Na2S2O3(20mL,饱和水溶液)和NaHCO3(20mL,饱和水溶液)洗涤,经MgSO4干燥,过滤并浓缩从而得到本标题化合物。MS(ESI)m/z=476.0(M+1)。
步骤B. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-戊-1-烯-3-基)哌啶-3-基)乙酸甲酯
用超过5分钟的时间将Tebbe试剂(双(环戊二烯基)-μ-氯(二甲基铝)-μ-亚甲基钛,在甲苯中的0.5M溶液,1.7mL,0.85mmol)逐滴加入到在0℃下的搅拌着的2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-氧代丁烷-2-基)哌啶-3-基)乙酸甲酯(实施例415,步骤A,360mg,0.756mmol)在甲苯(4.7mL)中的溶液中。将反应物在0℃下搅拌20分钟并将其在室温下30分钟。将反应物再冷却至0℃,并加入另外一部分Tebbe试剂(在甲苯中的0.5M溶液,1mL,0.5mmol)。让反应物温度升至室温并保持20分钟。将反应物再冷却至0℃并用NaHCO3饱和水溶液(40mL)和EtOAc(100mL)处理。用EtOAc(2x60mL)萃取分离的水层,并且用盐水洗涤(80ml)合并的有机萃取物,经MgSO4干燥,过滤并在减压下浓缩滤液。硅胶柱色谱分离(24g,SiO2,洗脱剂:1:0至3:1的己烷:EtOAc,梯度洗脱)得到本标题化合物。
MS(ESI)m/z=474.0(M+1)。
步骤C. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S)-1,2-二羟基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸甲酯
向搅拌着的2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-戊-1-烯-3-基)哌啶-3-基)乙酸甲酯(实施例415,步骤B,85mg,0.18mmol)在THF(1mL)、叔丁醇(1mL)和水(1.5mL)中的溶液中加入4-甲基吗啉4-氧化物(63.0mg,0.54mmol)和OsO4(1.1mg,4.5μmol)。将反应物在室温下搅拌过夜。用EtOAc(40mL)和Na2S2O3(20mL,饱和水溶液)稀释反应物。用EtOAc(20mL)萃取分离的水层,并且用盐水(20mL)洗涤合并的有机萃取物,经MgSO4干燥,过滤并在真空中蒸发从而得到本标题化合物,为非对映异构体的5:1混合物。
质谱(ESI)m/e=508.0(M+1)。
步骤D. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2S,3S)-1,2-二羟基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2R,3S)-1,2-二羟基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸
将LiOH在水中的溶液(1M,502μl,0.502mmol)加入到搅拌着的2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S)-1,2-二羟基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸甲酯(实施例415,步骤C;85mg,0.167mmol)在EtOH(1.67mL)中的溶液中。将反应物在室温下搅拌4小时。在此时间后,用NH4Cl饱和水溶液(20mL)淬灭反应物并用EtOAc(40mL)处理。用EtOAc(2x 20mL)萃取分离的水层,并且经MgSO4干燥合并的有机萃取物,过滤,并在减压下浓缩滤液。通过反相制备型HPLC(GeminiTMPrep C1810μm柱;Phenomenex,Torrance,CA,使用25%至75%的含有0.1%TFA的在水中的乙腈作为洗脱剂)纯化产物从而得到本标题化合物中的一种,其为次要非对映异构体,为第一洗脱组分。
1H NMR(400MHz,甲醇-d4)δppm 7.26(4H,br s),7.11-7.17(2H,m),7.07(1H,s),6.93-6.98(1H,m),4.75(1H,d,J=10.8Hz),3.78(1H,br s),3.56-3.66(2H,m),3.43(1H,td,J=11.3,4.8Hz),2.92-3.01(2H,m),2.60(1H,d,J=13.7Hz),2.14-2.22(2H,m),1.94-2.05(1H,m),1.72(1H,ddd,J=14.6,7.6,5.2Hz),1.38(3H,s),0.51(3H,t,J=7.5Hz);质谱(ESI)m/z=494.0(M+1)。
实施例416
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2R,3S)-1,2-二羟基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2S,3S)-1,2-二羟基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸
在实施例415步骤D中描述的纯化中,分离出本标题化合物中的另一种,其为主要非对映异构体,为第二洗脱组分。
1H NMR(500MHz,甲醇-d4)δppm 7.18-7.25(3H,br s),7.05-7.17(4H,m),6.88-6.98(1H,m),4.83(1H,d,J=10.8Hz),3.96(1H,br s),3.59(1H,dd,J=11.2,5.4Hz),3.51(1H,dd,J=11.2,5.1Hz),3.39-3.46(1H,m),2.81-2.99(2H,m),2.61(1H,d,J=13.7Hz),2.12-2.27(2H,m),1.84-1.96(1H,m),1.60(1H,ddd,J=14.2,7.8,4.6Hz),1.41(3H,m),0.43(3H,t,J=7.3Hz);质谱(ESI)m/z=494.0(M+1)。
实施例417
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((1S,2S)-1-环丙基-1-羟基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((1R,2S)-1-环丙基-1-羟基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. (3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((2S)-1-环丙基-1-羟基丁烷-2-基)-3-甲基哌啶-2-酮
经由注射器用超过1min的时间将环丙基溴化镁(0.5M溶液在THF中,2.0mL,1.013mmol)逐滴加入到在室温下的搅拌着的(S)-2-((3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁醛(实施例91,步骤C,150mg,0.338mmol)在THF(1.7mL)中的溶液中。将反应混合物在室温下搅拌20分钟,然后用NH4Cl(30mL,饱和水溶液)淬灭并用EtOAc(50mL)稀释。经MgSO4干燥有机层,过滤并在真空中蒸发。通过柱色谱法(24g SiO2,1:0至4:1的己烷:EtOAc)纯化,得到本标题化合物,为非对映异构体混合物。
MS(ESI)m/z=486.2(M+1)。
步骤B. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-1-氧代丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
向搅拌着的(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((2S)-1-环丙基-1-羟基丁烷-2-基)-3-甲基哌啶-2-酮(实施例417,步骤A;60mg,0.123mmol)在EtOAc(1mL)、乙腈(1mL)和水(1.5mL)中的溶液中加入氯化钌水合物(2.8mg,0.012mmol)和偏高碘酸钠(6.83μl,0.123mmol)(用超过5分钟的时间分批加入)。将反应物在室温下搅拌20分钟,然后将其分配在EtOAc(60mL)和水(20mL)之间。用EtOAc(2x20mL)萃取分离的水层,并且经MgSO4干燥合并的有机萃取物,过滤并在真空中蒸发。通过柱色谱法(12g,SiO2,1:0至9:1的己烷/IPA)纯化,得到本标题化合物。
MS(ESI)m/z=502.1(M+1)。
步骤C. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((1S,2S)-1-环丙基-1-羟基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((1R,2S)-1-环丙基-1-羟基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
向在-78℃下的搅拌着的2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-1-氧代丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸(实施例417,步骤B,33mg,0.066mmol)在THF(657μl)中的溶液中逐滴加入L-selectride溶液(144μl,0.144mmol)。将反应混合物在-78℃下搅拌20分钟,然后让其温度升至室温并保持30分钟。在此时间后,用过硫酸氢钾(oxone)(121mg,0.197mmol)在水(3mL)中的溶液淬灭反应物。用EtOAc(30mL)稀释反应物,并且用EtOAc(2x10mL)萃取分离的水层,经MgSO4干燥,过滤并在真空中蒸发。柱色谱分离(4g,SiO2,1:0至4:1的己烷:IPA)得到本标题化合物,为单一立体异构体。
1H NMR(400MHz,CDCl3)δppm 6.95-7.27(7H,m),6.72(1H,dt,J=7.6,1.6Hz),4.58-4.70(1H,m),3.07-3.34(1H,m),2.80-2.93(2H,m),2.09-2.25(4H,m),1.47(3H,s),0.28-1.47(10H,m);质谱(ESI)m/z=504.0(M+1)。
实施例418
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-异丙基-6-甲基-2-氧代哌啶-3-基)乙酸
步骤A. (S)-2-(3-氯苯基)-1-(4-氯苯基)戊-4-烯-1-酮和(R)-2-(3-氯苯基)-1-(4-氯苯基)戊-4-烯-1-酮
向KOH(57.1g,1.02mol)在水(113mL)中的溶液中加入N-苄基-N,N-二乙基乙铵氯化物(1.289g,5.66mmol)。加入2-(3-氯苯基)-1-(4-氯苯基)乙酮(实施例1,步骤A)(30g,113mmol)在甲苯(113mL)中的溶液,接着加入3-溴丙-1-烯(10.77mL,124mmol)。将由此产生的两相在室温下剧烈搅拌21小时,然后分离该两相。先后用柠檬酸水溶液和盐水洗涤有机层,然后经无水MgSO4干燥,并浓缩从而得到本标题化合物,为浅黄色油状物。
1H NMR(400MHz,氯仿-d)δppm 2.49-2.67(m,1H)2.86-3.04(m,1H)4.57(t,J=7.3Hz,1H)4.95-5.15(m,2H)5.75(ddt,J=17.1,10.2,6.9Hz,1H)7.14-7.35(m,4H)7.36-7.47(m,2H)7.83-7.98(m,2H)。
步骤B. (R)-N-((R)-2-(3-氯苯基)-1-(4-氯苯基)戊-4-烯-1-亚基)-2-甲基丙烷-2-亚磺酰胺
将2-(3-氯苯基)-1-(4-氯苯基)戊-4-烯-1-酮(实施例418,步骤A,48g,157mmol)、工业级乙醇钛(IV)(65.9mL,315mmol)和(R)-(+)-2-甲基-2-丙烷亚磺酰胺(Combi-Blocks,San Diego,California,33.1g,267mmol)溶解在400mL THF中。在搅拌的条件下将该混合物在回流下加热18小时。冷却反应物并将其倒入盐水中。将由此产生的白色固体通过过滤除去,用乙酸乙酯冲洗。将乙酸乙酯加入到该两相滤液中,并分离各层。用盐水洗涤有机层,然后经无水硫酸镁干燥,并浓缩。通过三次色谱分离(330g 预装填的硅胶柱(Teledyne Isco,Lincoln,NE),用95:5至85:5的己烷:乙酸乙酯洗脱)纯化粗产物从而得到在硅胶TLC上在己烷/乙酸乙酯中第二个洗脱的本标题化合物、在硅胶TLC上在己烷/乙酸乙酯中第三个洗脱的非对映异构体(R)-N-((S)-2-(3-氯苯基)-1-(4-氯苯基)戊-4-烯-1-亚基)-2-甲基丙烷-2-亚磺酰胺,和在硅胶TLC上在己烷/乙酸乙酯中第一个洗脱的一些起始酮。
1H NMR(400MHz,氯仿-d)δppm 1.28(s,9H)2.58-2.75(m,1H)2.85-3.02(m,1H)3.80-4.12(m,1H)5.01-5.16(m,2H)5.76(ddt,J=17.0,10.2,6.8Hz,1H)6.94-7.11(m,2H)7.11-7.20(m,1H)7.20-7.38(m,5H)。
步骤C. (R)-N-((2S,3R)-3-(3-氯苯基)-2-(4-氯苯基)己-5-烯-2-基)-2-甲基丙烷-2-亚磺酰胺
将(R)-N-((R)-2-(3-氯苯基)-1-(4-氯苯基)戊-4-烯亚基)-2-甲基丙烷-2-亚磺酰胺(实施例418,步骤B,9.97g,24.41mmol)在THF(98ml)中的溶液冷却至-78℃。用超过6min的时间加入甲基锂(1.6M在乙醚中,16.78ml,26.9mmol)。将反应物从冷浴上移开,并用500mL乙醚稀释,并用150mL饱和氯化铵水溶液淬灭。分离有机层,用盐水洗涤,然后经无水硫酸镁干燥并浓缩从而得到无色油状物。使该粗材料吸附到硅胶塞上并采用色谱法通过(3x80g)预装填的硅胶柱(Teledyne Isco,Lincoln,NE),用30%的在己烷中的乙酸乙酯洗脱来进行纯化。合并含有所需产物的级分(其作为硅胶TLC上的最低点在己烷/乙酸乙酯中洗脱),并在减压下浓缩从而得到本标题化合物,为玻璃状物。
1H NMR(400MHz,DMSO-d6)δppm 1.06(s,9H)1.80(s,3H)2.23(td,J=13.3,7.5Hz,1H)2.62-2.76(m,1H)3.30(d,J=3.3Hz,1H)4.81(d,J=10.4Hz,1H)4.85-4.97(m,1H)5.10(s,1H)5.31-5.52(m,1H)6.79(d,J=7.2Hz,1H)6.97(s,1H)7.05-7.23(m,4H)7.28(d,J=8.8Hz,2H)。
步骤D. (2S,3R)-3-(3-氯苯基)-2-(4-氯苯基)己-5-烯-2-胺
将(R)-N-((2S,3R)-3-(3-氯苯基)-2-(4-氯苯基)己-5-烯-2-基)-2-甲基丙烷-2-亚磺酰胺(实施例418,步骤C,5.96g,14.04mmol)在THF(56.2ml)中的溶液用在水中的盐酸(36-38%wt,6.40ml,211mmol)处理3小时。用300m乙醚稀释反应物,并用NaHCO3饱和水溶液使酸性水层变为碱性。用NaHCO3饱和水溶液洗涤有机层,经MgSO4干燥并浓缩从而得到本标题化合物,为无色玻璃状物。
1H NMR(400MHz,氯仿-d)δppm 1.29(s,3H)1.46(br s,2H)2.09-2.25(m,1H)2.41(ddd,J=13.6,12.7,6.9Hz,1H)2.99(dd,J=11.9,3.3Hz,1H)4.71-4.88(m,2H)5.39(ddt,J=17.0,10.2,6.8Hz,1H)6.99-7.13(m,1H)7.17-7.31(m,3H)7.31-7.38(m,2H)7.38-7.48(m,2H)。
步骤E. (2S,3R)-3-(3-氯苯基)-2-(4-氯苯基)-N-异丙基己-5-烯-2-胺
将(2S,3R)-3-(3-氯苯基)-2-(4-氯苯基)己-5-烯-2-胺(实施例418,步骤D)(270mg,0.843mmol)、乙酸(0.243mL,4.22mmol)、丙酮(3.10mL,42.2mmol)和氰基硼氢化钠(0.442mL,8.43mmol)在甲醇(4mL)中的混合物加热至65℃过夜。在16小时后,再加入10当量的氰基硼氢化钠,并再继续加热5小时,然后将其平衡到室温并在减压下浓缩。将浓缩物分配在氢氧化钠水溶液和乙酸乙酯之间。再次用乙酸乙酯萃取水层。用盐水洗涤合并的有机层,经MgSO4干燥并浓缩从而得到黄色油状物。使粗产物吸附到硅胶上并通过色谱法(24g预装填的硅胶柱(Teledyne Isco,Lincoln,NE))用30%至100%的在己烷中的乙酸乙酯梯度洗脱来进行纯化。合并含有产物的级分并浓缩从而得到本标题化合物,为无色玻璃状物。
1H NMR(400MHz,氯仿-d)δppm 0.95(d,J=6.1Hz,3H)1.09(d,J=6.1Hz,3H)1.38(br s,1H)1.51(s,3H)2.32-2.50(m,1H)2.59-2.81(m,3H)4.78-4.86(m,1H)4.86-4.98(m,1H)5.46(ddt,J=17,10.2,6.7Hz,1H)6.78(d,J=7.6Hz,1H)6.96(t,J=1.8Hz,1H)7.03-7.11(m,1H)7.11-7.21(m,3H)7.21-7.29(m,2H)。
步骤F. (4R,5S)-4-(3-氯苯基)-5-(4-氯苯基)-5-(异丙基氨基)己烷-1-醇
向用冰-水浴冷却的(2S,3R)-3-(3-氯苯基)-2-(4-氯苯基)-N-异丙基己-5-烯-2-胺(实施例418,步骤E,160mg,0.442mmol)在THF(4mL)中的溶液中加入硼烷-四氢呋喃络合物(1.0M在THF中,2.21mL,2.21mmol)。在90分钟后,再加入5当量的硼烷-THF并移开该冷浴。在30分钟后,在冰-水浴中冷却反应物,并且通过加入0.5mL水,接着加入4N氢氧化钠水溶液(1.1mL,4.42mmol)和过氧化氢水溶液(30%(w/w),0.45mL,4.42mmol)来淬灭反应物。将两相混合物在0-5℃下快速搅拌15分钟,然后将其分在水和乙酸乙酯之间。再次用乙酸乙酯萃取水层。用盐水洗涤合并的有机层,然后经无水硫酸镁干燥并浓缩从而得到无色油状物。通过硅胶色谱法(24g 预装填的硅胶柱(Teledyne Isco,Lincoln,NE))用50%至100%的在己烷中的乙酸乙酯梯度洗脱来分离该产物从而得到本标题化合物,为无色油状物。
1H NMR(400MHz,氯仿-d)δppm 0.91(d,J=6.3Hz,3H)1.06(d,J=6.3Hz,3H)1.13-1.37(m,2H)1.48(s,3H)1.56-1.86(m,3H)1.89-2.04(m,1H)2.50-2.75(m,2H)3.52(t,J=6.4Hz,2H)6.76(d,J=7.6Hz,1H)6.89-6.98(m,1H)7.01-7.08(m,1H)7.08-7.17(m,3H)7.17-7.26(m,2H)。
步骤G. (4R,5S)-4-(3-氯苯基)-5-(4-氯苯基)-5-(异丙基氨基)己酸
用超过3分钟的时间向在室温下的(4R,5S)-4-(3-氯苯基)-5-(4-氯苯基)-5-(异丙基氨基)己烷-1-醇(实施例418,步骤F,185mg,0.486mmol)在湿乙腈(0.75%水v/v)(3mL)中的溶液中加入高碘酸溶液(0.44M在乙腈(0.75%水v/v)中,2.76mL,1.216mmol)和三氧化铬(2.43mg,0.024mmol)。将反应物搅拌15分钟。向反应物中加入0.6g磷酸氢二钠在10mL水中的溶液。用甲苯萃取该含水混合物。先用水/盐水洗涤有机层,然后用0.2g亚硫酸氢钠在5mL水中的溶液洗涤有机层。经无水硫酸镁干燥有机层并浓缩从而得到桃红色泡沫状固体。通过硅胶色谱法(24g 预装填的硅胶柱(Teledyne Isco,Lincoln,NE))用50-100%的在己烷中的乙酸乙酯梯度洗脱来纯化该产物从而得到本标题化合物,为无色泡沫状物。
1H NMR(400MHz,氯仿-d)δppm 1.16(d,J=6.7Hz,4H)1.32(d,J=6.7Hz,4H)1.43(s,3H)1.76-1.88(m,1H)2.22-2.38(m,1H)2.55-2.67(m,2H)2.79(quin,J=6.65Hz,1H)3.11(dd,J=13.1,2.4Hz,1H)6.21(d,J=7.8Hz,1H)6.49(s,1H)6.91(dd,J=7.9,7.9Hz,1H)6.96-7.17(m,3H)7.23(d,J=8.2Hz,2H)。
步骤H. (5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-异丙基-6-甲基哌啶-2-酮
将乙二酰氯(~0.38M在苯中,0.617mL,0.234mmol)加入到室温的(4R,5S)-4-(3-氯苯基)-5-(4-氯苯基)-5-(异丙基氨基)己酸(实施例418,步骤G,84mg,0.213mmol)在苯(3mL)中的溶液中,接着加入1滴DMF。将反应溶液在室温下搅拌25分钟,然后将其加热至80℃。在3.5小时后,将反应物从热源上移开,并加入饱和碳酸氢钠水溶液。用乙酸乙酯稀释有机相。再次用乙酸乙酯萃取水层。用盐水洗涤合并的有机层,然后经无水硫酸镁干燥并浓缩从而得到红橙色油状物。通过硅胶色谱法(12g RediSep Rfcartridge)用20-40%的在己烷中的乙酸乙酯梯度洗脱来分离该产物从而得到本标题化合物,为浅黄色膜状物。[α]D=+89.33°(T=24.0℃;c=1,CHCl3)
1H NMR(400MHz,氯仿-d)δppm 1.25(d,J=6.7Hz,3H)1.41(d,J=6.7Hz,3H)1.52(s,3H)1.84-1.98(m,1H)2.30-2.50(m,1H)2.64-2.75(m,2H)2.88(quin,J=6.7Hz,1H)3.20(dd,J=13.2,2.5Hz,1H)6.31(d,J=7.6Hz,1H)6.58(dd,J=1.8,1.8Hz,1H)7.00(dd,J=7.9,7.9Hz,1H)7.05-7.27(m,3H)7.27-7.42(m,2H);质谱(ESI)m/z=376.1[M+H]+.
步骤I. (3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-异丙基-6-甲基哌啶-2-酮和(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-异丙基-6-甲基哌啶-2-酮
用超过1分钟的时间将仲丁基锂(0.8N在环己烷中,0.274mL,0.219mmol)加入到用丙酮-干冰浴冷却的经脱气(通过在室温下向其中鼓入氩气10分钟脱气)的(5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-异丙基-6-甲基哌啶-2-酮(实施例418,步骤H,75mg,0.199mmol)在THF(6mL)中的溶液中。将该冷浴移开,并用超过15分钟的时间将反应物平衡到室温。将反应物在室温下搅拌30分钟。在室温下用超过1分钟的时间加入烯丙基溴(1M在THF中,0.219mL,0.219mmol)。在2小时后,通过加入饱和氯化铵水溶液来淬灭反应物。用乙酸乙酯稀释有机层并分离有机层。再次用乙酸乙酯萃取水层。然后经无水硫酸镁干燥合并的有机层并浓缩从而得到微橙色玻璃状物。通过硅胶色谱法(12g 预装填的硅胶柱(Teledyne Isco,Lincoln,NE))用20%至80%的在己烷中的乙酸乙酯梯度洗脱来分离该非对映异构的产物从而得到25mg(3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-异丙基-6-甲基哌啶-2-酮(其为在硅胶TLC板上第一个洗脱的产物(Rf=0.52,在3:1的己烷:乙酸乙酯洗脱剂中))和25mg(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-异丙基-6-甲基哌啶-2-酮(其为在硅胶TLC板上第二个洗脱的产物(Rf=0.28,在3:1的己烷:乙酸乙酯洗脱剂中))。
非对映异构体1:(3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-异丙基-6-甲基哌啶-2-酮
1H NMR(400MHz,氯仿-d)δppm 1.17(d,J=6.7Hz,3H)1.31(d,J=6.7Hz,3H)1.41(s,3H)1.84(ddd,J=13.3,5.8,2.5Hz,1H)2.03-2.21(m,1H)2.41-2.54(m,1H)2.54-2.69(m,2H)2.78(quin,J=6.7Hz,1H)3.18(dd,J=13.4,2.3Hz,1H)4.92-5.18(m,2H)5.56-5.84(m,1H)6.20(d,J=7.8Hz,1H)6.50(s,1H)6.90(dd,J=7.8,7.8Hz,1H)7.00-7.08(m,1H)7.08-7.37(m,4H);MS(ESI)416.2[M+H]+
非对映异构体2:(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-异丙基-6-甲基哌啶-2-酮
1H NMR(400MHz,氯仿-d)δppm 1.16(d,J=6.7Hz,3H)1.35(d,J=6.7Hz,3H)1.43(s,3H)1.75-1.80(m,1H)2.25-2.48(m,2H)2.56-2.68(m,1H)2.69-2.89(m,2H)3.23(dd,J=13.6,2.6Hz,1H)4.91-5.06(m,2H)5.76(dddd,J=17.6,9.5,8.3,5.9Hz,1H)6.25(d,J=7.8Hz,1H)6.51(dd,J=1.8,1.8Hz,1H)6.87-6.97(m,1H)6.97-7.12(m,3H)7.19-7.32(m,2H);MS(ESI)416.2[M+H]+
步骤J. 2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-异丙基-6-甲基-2-氧代哌啶-3-基)乙酸
按照与实施例1步骤H中描述的程序类似的程序,从(3R,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-异丙基-6-甲基哌啶-2-酮(实施例418,步骤I,非对映异构体1)制备本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 1.16(d,J=6.7Hz,3H)1.33(d,J=6.7Hz,3H)1.46(s,3H)1.87-2.01(m,1H)2.27(q,J=13Hz,1H)2.62(dd,J=15.8,3.2Hz,1H)2.76-3.06(m,3H)3.24(dd,J=13.3,2.2Hz,1H)6.19(d,J=7.8Hz,1H)6.40-6.52(m,1H)6.92(dd,J=7.9,7.9Hz,1H)7.07(ddd,J=8.0,2,0.98Hz,1H)7.10-7.40(m,4H);MS(ESI)432.0[M–H]-。
实施例419
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-异丙基-6-甲基-2-氧代哌啶-3-基)乙酸
按照与实施例1,步骤H中描述的程序类似的程序,从(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-异丙基-6-甲基哌啶-2-酮(实施例418,步骤I,非对映异构体2)制备本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 1.18(d,J=6.7Hz,3H)1.34(d,J=6.7Hz,3H)1.47(s,3H)1.75(d,J=13.9Hz,1H)2.46-2.65(m,2H)2.92(quin,J=6.7Hz,1H)2.99-3.22(m,3H)6.26(d,J=7.8Hz,1H)6.51(s,1H)6.94(dd,J=7.9,7.9Hz,1H)6.98-7.12(m,3H)7.28(d,J=8.6Hz,2H);质谱(ESI)m/z=432.0[M-H]-。
实施例420
(3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-((6-甲氧基吡啶-2-基)甲基)哌啶-2-酮.
步骤A:(5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)哌啶-2-酮.
根据实施例174,步骤A的程序,利用丙烷磺内酰胺(propanesulfatam)(J.Org.Chem.,1963,283537,4.63g,38.2mmol)和(5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)哌啶-2-酮(实施例185,步骤B,6.0g,15.29mmol)制备该化合物。使本标题化合物从乙酸乙酯和己烷中结晶。
1H NMR(500MHz,氯仿-d)δppm 7.24(d,J=8.1Hz,2H),7.10-7.20(m,2H),6.99-7.09(m,3H),6.86(d,J=7.1Hz,1H),4.74(d,J=9.3Hz,1H),3.36-3.46(m,1H),2.96-3.33(m,5H),2.93(ddd,J=3.2,9.3,12Hz,1H),2.63-2.71(m,2H),2.32-2.50(m,2H),2.12-2.26(m,1H),1.97-2.04(m,1H),1.91(quind,J=7.5,14.8Hz,1H),1.44-1.61(m,1H),0.53(t,J=7.5Hz,3H)。质谱(ESI)m/z=495.1(M+1)。
步骤B. 2-(碘甲基)-6-甲氧基吡啶.
向0℃的碘(1.094g,4.31mmol)和咪唑(0.294g,4.31mmol)在二氯甲烷(10.27ml)中的溶液中分批加入三苯基膦(1.131g,4.31mmol)。在搅拌20min后,向该溶液中加入(6-甲氧基吡啶-2-基)甲醇(Adesis,New Castle,DE,0.5g,3.59mmol)。让反应物在0℃下搅拌1h,用水(50mL)淬灭并用Et2O萃取。经MgSO4干燥合并的有机物,并在真空中浓缩。硅胶色谱分离(用1%至5%的在戊烷中的Et2O梯度洗脱)得到2-(碘甲基)-6-甲氧基吡啶。1H NMR(500MHz,氯仿-d)δppm 7.49(dd,J=7.3,8.3Hz,1H),6.96(d,J=7.1Hz,1H),6.61(d,J=8.1Hz,1H),4.44(s,2H),3.94(s,3H)。质谱(ESI)m/z=249.9(M+1)。
步骤C. (3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-((6-甲氧基吡啶-2-基)甲基)哌啶-2-酮.
向在-78℃下的(5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)哌啶-2-酮(实施例420,步骤A,0.7g,1.413mmol)在THF(5.65ml)中的溶液中逐滴加入仲丁基锂(1.4M在环己烷中,1.06ml,1.483mmol)。让反应物温度升至-10℃。在约5分钟后,使反应物返回到-78℃浴中。向冷却的该反应混合物中逐滴加入2-(碘甲基)-6-甲氧基吡啶(实施例420,步骤B,0.387g,1.554mmol)在THF(1mL)中的溶液。让反应物温度升至室温并搅拌1h。将反应内容物倒入饱和碳酸氢钠中,并用二氯甲烷(3x50mL)萃取水层。经硫酸钠干燥合并的有机物并在真空中浓缩。硅胶色谱分离(用5%至50%的在二氯甲烷中乙醚分步梯度洗脱),得到本标题化合物,为极性较大的非对映异构体.
1H NMR(500MHz,氯仿-d)δppm 7.50(t,J=7.8Hz,1H),7.25(d,J=8.6Hz,2H),7.09-7.18(m,3H),7.03(d,J=8.3Hz,2H),6.92-6.99(m,1H),6.82(d,J=7.3Hz,1H),6.58(d,J=8.1Hz,1H),4.87(d,J=7.6Hz,1H),3.80(s,3H),3.36-3.46(m,2H),2.99-3.32(m,7H),2.26-2.50(m,2H),2.03-2.15(m,1H),1.90-2.03(m,2H),1.43-1.73(m,2H),0.56(t,J=7.6Hz,3H)。质谱(ESI)m/z=616.1(M+1)。
实施例421
(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-((6-甲氧基吡啶-2-基)甲基)哌啶-2-酮
从实施例420步骤C中描述的纯化中,分离出(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-((6-甲氧基吡啶-2-基)甲基)哌啶-2-酮,为极性较小的非对映异构体。
1H NMR(500MHz,氯仿-d)δppm 7.46(t,J=7.8Hz,1H),7.22(d,J=8.31Hz,2H),7.10-7.17(m,1H),7.05-7.10(m,1H),6.98-7.03(m,3H),6.79(d,J=7.1Hz,1H),6.75(d,J=7.3Hz,1H),6.54(d,J=8.3Hz,1H),4.68(d,J=10.3Hz,1H),3.91(s,3H),3.72(dd,J=3.8,14.1Hz,1H),3.30(t,J=6.7Hz,2H),3.09-3.26(m,4H),3.00-3.08(m,J=14.4Hz,1H),2.95(ddd,J=3.2,10.2,13.0Hz,2H),2.68(dd,J=10.0,14.2Hz,1H),2.30-2.53(m,2H),2.10(q,J=12.9Hz,1H),1.85-2.01(m,2H),1.57-1.63(m,J=2.2,7.1Hz,1H),0.53(t,J=7.6Hz,3H)。质谱(ESI)m/z=616.1(M+1)。
实施例422
(3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-((6-羟基吡啶-2-基)甲基)哌啶-2-酮
向在氯仿(1.622ml)中的实施例420步骤C的产物(0.05g,0.081mmol)中加入碘代三甲基甲硅烷(0.046ml,0.324mmol)。将反应物温度升至50℃。在4小时后,用饱和碳酸氢盐(10mL)淬灭反应物,并用二氯甲烷(2x15mL)和在CH2Cl2中的5%MeOH(1x15mL)萃取。经硫酸钠干燥合并的有机物并在真空中浓缩。硅胶色谱分离(在二氯甲烷中的0.5%至7.5%MeOH),得到本标题化合物。
1H NMR(500MHz,氯仿-d)δ7.36(dd,J=6.7,9.2Hz,2H),7.28(br s,1H),7.26(s,1H),7.12-7.20(m,J=7.1Hz,3H),7.05(d,J=7.1Hz,1H),7.00(d,J=8.3Hz,2H),6.46(d,J=9.1Hz,1H),6.03(d,J=6.6Hz,1H),5.01(d,J=4.9Hz,1H),3.64-4.03(m,1H),3.40-3.57(m,1H),2.85-3.34(m,8H),2.74(quin,J=6.4Hz,1H),2.25-2.50(m,2H),1.91-2.17(m,J=6.8Hz,3H),1.39-1.55(m,1H),0.61(t,J=7.5Hz,3H)。质谱(ESI)m/z=602.2(M+1)。
实施例423
(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-((6-羟基吡啶-2-基)甲基)哌啶-2-酮
按照实施例422的程序使用实施例421的产物,获得(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-((6-羟基吡啶-2-基)甲基)哌啶-2-酮。
1H NMR(500MHz,氯仿-d)δppm 7.22(dd,J=6.6,9.3Hz,1H),7.16(d,J=8.3Hz,2H),7.07-7.11(m,1H),7.00-7.06(m,1H),6.95(s,1H),6.90(d,J=8.07Hz,2H),6.70(d,J=7.6Hz,1H),6.36(d,J=9.1Hz,1H),5.87(d,J=6.6Hz,1H),4.65(d,J=10.5Hz,1H),3.29(td,J=6.7,9.60Hz,1H),3.18(td,J=6.7,9.6Hz,1H),3.11(t,J=7.5Hz,2H),2.87-3.04(m,3H),2.76-2.86(m,1H),2.71(dd,J=2.7,14.4Hz,1H),2.32(quin,J=7.0Hz,2H),2.17(q,J=13Hz,1H),1.84-1.99(m,2H),1.37-1.58(m,2H),0.43(t,J=7.6Hz,3H)。
实施例424
(3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-((6-甲氧基吡啶-2-基)甲基)-3-甲基哌啶-2-酮
将仲丁基锂(1.4M在环己烷中,0.59ml,0.824mmol)加入到在-78℃下的(3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-((6-甲氧基吡啶-2-基)甲基)哌啶-2-酮(实施例420,步骤C,0.484g,0.785mmol)在THF(3.92ml)中的溶液中。在15分钟后,加入碘甲烷(0.098ml,1.57mmol),并让反应物温度升至室温。将反应内容物倒入饱和碳酸氢钠(20mL)中,并用二氯甲烷(3x30mL)萃取。经硫酸钠干燥合并的有机物并在真空中浓缩。硅胶色谱分离(用30%至90%的在己烷中的EtOAc进行10%分步梯度洗脱),得到本标题化合物,为第一洗脱非对映异构体。
1H NMR(500MHz,氯仿-d)δ7.48(t,J=7.6Hz,1H),7.21(d,J=8.1Hz,2H),6.92-7.15(m,5H),6.88(d,J=7.1Hz,1H),6.74(d,J=7.6Hz,1H),6.57(d,J=8.3Hz,1H),4.64(d,J=10.5Hz,1H),3.04-3.25(m,7H),2.98(d,J=14.7Hz,2H),2.69(t,J=13.8Hz,1H),2.21-2.44(m,2H),1.89(td,J=7.4,14.6Hz,1H),1.75(dd,J=2.8,13.6Hz,1H),0.50(t,J=7.6Hz,3H)。质谱(ESI)m/z=630.2(M+1)。
实施例425
(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-((6-甲氧基吡啶-2-基)甲基)-3-甲基哌啶-2-酮
本标题化合物是从实施例424中描述的纯化获得的第二洗脱非对映异构体。
1H NMR(500MHz,氯仿-d)δppm 7.53(t,J=7.7Hz,1H),7.19(d,J=8.1Hz,2H),7.03-7.13(m,2H),6.87-7.03(m,3H),6.84(d,J=7.3Hz,1H),6.76(d,J=7.3Hz,1H),6.62(d,J=8.3Hz,1H),4.72(d,J=10.8Hz,1H),3.86-4.00(m,1H),3.69(s,3H),3.43(d,J=12.7Hz,1H),3.26-3.39(m,2H),3.14-3.26(m,3H),2.96-3.05(m,2H),2.91(br.s.,1H),2.31-2.51(m,2H),2.14-2.23(m,1H),2.02-2.12(m,1H),1.95(quind,J=7.6,14.8Hz,1H),1.39-1.64(m,2H),1.29(s,3H),0.51(t,J=7.6Hz,3H)。质谱(ESI)m/z=630.2(M+1)。
实施例426
(3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-((6-羟基吡啶-2-基)甲基)-3-甲基哌啶-2-酮
按照实施例422的程序使用实施例424的产物,获得(3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-((6-羟基吡啶-2-基)甲基)-3-甲基哌啶-2-酮。
1H NMR(500MHz,氯仿-d)δppm 7.33(dd,J=6.7,9.2Hz,1H),7.23(d,J=8.1Hz,2H),7.08-7.19(m,2H),6.87-7.05(m,4H),6.81(d,J=7.6Hz,1H),6.49(d,J=9.1Hz,1H),5.95(d,J=6.6Hz,1H),4.74(d,J=10.3Hz,1H),3.75-4.14(m,1H),3.30-3.42(m,1H),3.10-3.28(m,4H),2.68-3.09(m,J=4.2Hz,4H),2.26-2.50(m,3H),1.89-2.06(m,1H),1.53-1.70(m,J=3.2,13.2Hz,2H),1.49(s,3H),0.52(t,J=7.5Hz,3H)。质谱(ESI)m/z=616.1(M+1)。
实施例427
(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-((6-羟基吡啶-2-基)甲基)-3-甲基哌啶-2-酮
按照实施例422的程序使用实施例425的产物,获得(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-((6-羟基吡啶-2-基)甲基)-3-甲基哌啶-2-酮。
1H NMR(500MHz,氯仿-d)δppm 7.36-7.44(m,1H),7.10-7.23(m,2H),6.77-7.07(m,5H),6.66(d,J=7.8Hz,1H),6.48(d,J=9.1Hz,1H),6.11(d,J=6.6Hz,1H),4.74(d,J=10.5Hz,1H),3.93(dd,J=9.8,13.9Hz,1H),3.29(t,J=6.6Hz,2H),3.20(dt,J=0.9,7.5Hz,2H),3.15(d,J=13.9Hz,1H),2.75-2.99(m,4H),2.32-2.48(m,1H),2.24(t,J=13.8Hz,1H),1.98-2.10(m,1H),1.88-1.96(m,J=2.9Hz,1H),1.44-1.59(m,1H),1.39(s,3H),0.48(t,J=7.6Hz,3H)。质谱(ESI)m/z=616.1(M+1)。
实施例428
(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(乙基磺酰基)乙基)-3-(3-羟基-2-氧代丙基)-3-甲基哌啶-2-酮.
将乙二酰氯(0.063ml,0.715mmol)加入到2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(乙基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸(实施例349,0.316g,0.572mmol)在二氯甲烷(1.9ml)中的溶液中。将反应物在室温下搅拌3h。在真空中除去该溶剂。向固体中加入三(三甲基甲硅烷基氧基)乙烯(0.42ml,1.26mmol),并在90℃下搅拌反应物。在2h后,冷却反应物,向反应物中加入THF(1mL)和HCl(1.4M,0.982ml,1.375mmol),并将反应物回流30min。在冷却后,将反应物倒入水(20mL)中,并用二氯甲烷(3x20mL)萃取。经硫酸钠干燥合并的有机物并在真空中浓缩。硅胶色谱分离(用1%至5%的在二氯甲烷中的2M氨的MeOH溶液分步梯度洗脱),得到本标题化合物。
1H NMR(500MHz,氯仿-d)δ7.11-7.30(m,3H),6.96-7.10(m,3H),6.89(s,1H),6.70-6.85(m,1H),4.82(d,J=10.8Hz,1H),4.13-4.45(m,J=1.7Hz,3H),3.15(ddd,J=2.9,10.6,13.6Hz,1H),2.74-3.10(m,6H),2.60(br s,1H),2.28(t,J=13.8Hz,1H),1.96(dd,J=3.1,13.8Hz,1H),1.77(br s,1H),1.27-1.42(m,6H),0.10-0.41(m,2H),-0.33(brs,1H),-1.01(br s,1H)。质谱(ESI)m/z=566.2(M+1)。
实施例429
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(二乙基氨基)-3-甲基-2-氧代哌啶-3-基)乙酸
步骤A. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸甲酯
将高碘酸钠(21.03g,98mmol)缓慢地加入到含有在乙腈(35.1mL)、乙酸乙酯(35.1mL)和水(52.7mL)中的氯化钌(III)水合物(0.277g,1.229mmol)和(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基哌啶-2-酮(4.6g,12.29mmol;实施例71,步骤D)的溶液中,同时将温度维持在20℃以下。然后将由此产生的混合物在室温下搅拌2h。接着,将反应物过滤并浓缩,并且通过将由此产生的残余物溶解在乙酸乙酯中来对残余物进行进一步加工。用水和盐水洗涤有机物,经MgSO4干燥,过滤并浓缩。接着,将残余物溶解在少量乙醚和甲醇(1:1)的混合物中,并向其中加入2M(三甲基甲硅烷基)重氮甲烷的乙醚溶液(12.29ml,24.58mmol)。然后让该溶液在室温下搅拌过夜。浓缩该溶液,并在硅胶上纯化(洗脱剂:0%至100%的己烷/乙酸乙酯,梯度洗脱)由此产生的残余物从而得到本标题化合物。质谱(ESI)m/z=406(M+1)。
步骤B. 2-((3R,5R,6S)-1-氨基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸甲酯
将60%氢化钠在矿物油中的悬浮液(0.953g,23.82mmol)加入到2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸甲酯(实施例429,步骤A,4.84g,11.9mmol)在DMF(25mL)中的溶液中。将由此产生的混合物在23℃下搅拌15min。在室温下加入O-(2,4-二硝基苯基)羟胺(4.74g,23.82mmol)。将该溶液在室温下搅拌1h,然后用MeOH(1mL)淬灭。在减压下除去多余的溶剂,并通过硅胶色谱法(洗脱剂:0%至5%的在DCM中的MeOH;分级梯度)纯化残余物从而得到本标题化合物。
质谱(ESI)m/z=421(M+1),443(M+23)。
步骤C. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(二乙基氨基)-3-甲基-2-氧代哌啶-3-基)乙酸甲酯
将碘乙烷(67.1μL,0.831mmol)加入到2-((3R,5R,6S)-1-氨基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸甲酯(实施例429,步骤B,35mg,0.083mmol)和DIEA(145μL,0.831mmol)在DMF中的溶液中。将由此产生的混合物在80℃下搅拌12h。将该混合物浓缩并通过反相HPLC(SunfireTMPrep C18OBD 10μm柱;Waters,Milford,MA;用40-90%的含有0.1%TFA的水/乙腈梯度洗脱)进行纯化。将所需的级分汇集在一起,并浓缩从而得到本标题化合物。
质谱(ESI)m/z=477(M+1)。
步骤D. 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(二乙基氨基)-3-甲基-2-氧代哌啶-3-基)乙酸
将2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(二乙基氨基)-3-甲基-2-氧代哌啶-3-基)乙酸甲酯(实施例429,步骤C)在水/甲醇(1:1)中的溶液用氢氧化锂(1N,5当量)在室温下处理15h。将该混合物浓缩并通过反相HPLC(SunfireTMPrep C18OBD 10μm柱;Waters,Milford,MA;用40-90%的含有0.1%TFA的水/乙腈梯度洗脱)进行纯化。然后将所需的级分汇集在一起,并浓缩从而得到本标题化合物。
1H NMR(500MHz,甲醇-d4)δppm 0.222(t,J=7Hz,3H)1.179(t,J=7Hz,3H)1.389(s,3H)2.143(dd,J=14,3.5Hz,1H)2.200(t,J=13.5Hz,1H)2.570(d,J=13.5Hz,1H)2.713(m,1H)2.967(d,J=13.5Hz,1H)3.116(m,1H)3.251(m,1H)3.519(ddd,J=13,11,3.5Hz,1H)4.598(d,J=11Hz,1H)6.972(d,J=7Hz,1H)7.070(m,1H)7.099-7.16(m,2H)7.229(m,4H);质谱(ESI)m/z=463(M+1),485(M+23)。
实施例430
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(二甲基氨基)-3-甲基-2-氧代哌啶-3-基)乙酸
按照与实施例429中描述的程序类似的程序,使用碘甲烷替代步骤C中的碘乙烷来对2-((3R,5R,6S)-1-氨基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸甲酯(实施例429步骤C)进行处理。
1H NMR(500MHz,甲醇-d4)δppm 1.356(s,3H)2.088(dd,J=14,3.5Hz,1H)2.166(t,J=13.5Hz,1H)2.599(br s,6H)2.601(d,J=13.5,1H)(m,7H)2.933(d,J=13.5Hz,1H)3.429(ddd,J=13,10.5,3.5Hz,1H)4.672(d,J=10.5Hz,1H)6.965(m,1H)7.10-7.16(m,5H)7.206(d,J=8.5Hz,2H);质谱(ESI)m/z=435(M+1)。
实施例431
(2S,3S,5S,6R,7aR,10aS)-6-(3-氯苯基)-5-(4-氯苯基)-3-乙基-2,7a-二甲基六氢呋喃并[2,3-b]噁唑并[3,2-a]吡啶-9(5H)-酮
步骤A:(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((2S,3S)-2-羟基戊烷-3-基)-3-甲基哌啶-2-酮
将L-SelectrideTM(1M在THF中,5.24ml,5.24mmol)加入到-10℃下的(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-2-氧代戊烷-3-基)哌啶-2-酮(实施例149,步骤A,2g,4.36mmol)在THF(29.1ml)中的溶液中,并小心地将温度维持在-7℃以下。将反应物搅拌40min,然后将其淬灭到OxoneTM(10.73g,17.45mmol)在60mL水中的水溶液中。注意到在添加期间温度上升到40℃。使用水/冰浴将反应物冷却至室温并将其在室温下搅拌1h,然后用乙酸乙酯稀释。分离各层并用乙酸乙酯萃取水层。用盐水洗涤合并的有机物,经MgSO4干燥,过滤并浓缩。将粗材料在高真空下干燥过夜。通过柱色谱法使用10-20%的在己烷中的丙酮纯化,得到本标题化合物。
1H NMR(400MHz,氯仿-d)δppm 7.21-7.27(m,2H),7.16(ddd,J=8,2,1.2Hz,1H),7.10(t,J=7.7Hz,1H),6.95-7.07(m,2H),6.93(t,J=1.8Hz,1H),6.70(dt,J=7.5,1.2Hz,1H),5.80-5.92(m,1H),5.13-5.25(m,2H),4.66(br s,1H),4.37(d,J=10.6Hz,1H),3.52-4.11(m,1H),3.20(ddd,J=13.4,10.5,3.2Hz,1H),2.61(d,J=7.4Hz,3H),2.11-2.30(m,1H),2.06(t,J=13.7Hz,1H),1.95(dd,J=13.7,3.3Hz,1H),1.32-1.42(m,1H),1.22(d,J=6.3Hz,3H),0.59(br s,3H)。LC/MS(M+H)m/z=460.2。
步骤B:(2S,3S,5S,6R,8S)-8-烯丙基-6-(3-氯苯基)-5-(4-氯苯基)-3-乙基-2,8-二甲基-2,3,5,6,7,8-六氢噁唑并[3,2-a]吡啶-4-鎓4-甲基苯磺酸盐
将与对甲苯磺酸吡啶鎓(PPTS,327mg,1.30mmol)在一起的(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-1-((2S,3S)-2-羟基戊烷-3-基)-3-甲基哌啶-2-酮(实施例431,步骤A,600mg,1.303mmol)在甲苯(43mL)中的溶液在Dean-Stark条件下处理1h。当NMR监测指示完成了约95%至97%时,用另外的3%(10mg)PPTS处理反应物并使其返回至回流状态并保持回流30min。在高真空下浓缩反应混合物,将其直接用于随后的反应中。
1H NMR(500MHz,DMSO-d6)δppm 8.15-7.10(系列m,12H),5.89(ddt,J=17.4,10.3,7.3,Hz,1H),5.38(d,J=11.0Hz,1H),5.36(dd,J=16.9,1.7Hz,1H),5.27(dd,J=10.1,2.1Hz,1H),5.17(quin,J=6.3Hz,1H),4.12(td,J=6.5,2.6Hz,1H),3.97(ddd,J=13.7,11.0,3.4Hz,1H),2.81(ABX,JAB=13.7Hz,JAX=7.1Hz,1H),2.72(ABX,JAB=13.7Hz,JBX=7.8Hz,1H),2.43(t,J=13.2Hz,1H),2.29(s,3H),1.99(dd,J=13.3,3.3Hz,1H),1.57(d,J=6.1Hz,3H),1.32(s,3H),0.95(dqd,J=14.7,7.3,3.4Hz,1H),0.58(t,J=7.2Hz,3H),0.45(dquin,J=14.7,7.2,Hz,1H)。LC/MS m/z=442.2(M+)。
步骤C:(2S,3S,5S,6R,7aR,10aS)-6-(3-氯苯基)-5-(4-氯苯基)-3-乙基-2,7a-二甲基六氢呋喃并[2,3-b]噁唑并[3,2-a]吡啶-9(5H)-酮
对在0℃下的与乙酸(2.89mL,50.4mmol)和四正丁基氯化铵(35.0mg,0.126mmol)在一起的(2S,3S,5S,6R,8S)-8-烯丙基-6-(3-氯苯基)-5-(4-氯苯基)-3-乙基-2,8-二甲基-2,3,5,6,7,8-六氢噁唑并[3,2-a]吡啶-4-鎓4-甲基苯磺酸盐(实施例431,步骤B,775mg,1.261mmol)在二氯甲烷(12mL)中的溶液进行处理,这通过加入作为在水(12mL)中的溶液的KMnO4(797mg,5.04mmol),接着加入水(12mL)冲洗来进行。
在0℃下20min后,通过加入15mL饱和Na2S2O3来淬灭反应物。用150mL乙酸乙酯稀释反应物并分离各层。用水和盐水洗涤有机相,经MgSO4干燥,通过(J.T.Baker,Phillipsberg,NJ,硅藻土)过滤,并浓缩。将该样品放置在高真空下过夜从而得到夹带有乙酸(约4当量)的产物。使用60-80%在己烷中的乙酸乙酯纯化等分试样从而得到本标题化合物。
1H NMR(400MHz,DMSO-d6)δppm 7.18-7.26(m,5H),7.07-7.16(m,2H),7.05(dt,J=7.0,1.7Hz,1H),3.92(quin,J=6.1Hz,1H),3.84(d,J=10.8Hz,1H),3.48(d,J=17.4Hz,1H),3.34-3.42(m,1H),2.52-2.56(m,1H),2.34(d,J=17.6Hz,1H),1.92(ABX,JAB=13.9Hz,JAX=13.2Hz,1H),1.82(ABX,JAB=13.9Hz,JBX=2.9Hz,1H),1.43(d,J=6.3Hz,3H),1.22(s,5H),0.41(t,J=7.5Hz,3H)。LC/MS(M+H)m/z=460.2。
本发明化合物在下列测定中显示出对HDM2和p53之间的相互作用的抑制。
均相时间分辨荧光测定(HTRF1测定)
体外HTRF测定的标准测定条件由以下组成:总反应体积为50ul的在黑色384-孔Costar聚丙烯板中在1X PBS缓冲液pH为7.4中的1mMDTT、0.1%BSA、2.5nM GST-hMDM2(aa1-188)、5nM生物素化-p53(aa 1-83)、1.8nM SA-XLent(Cisbio;Bedford,MA)、0.6nM抗-GST穴状化合物(cryptate)单克隆抗体(Cisbio;Bedford,MA)和200mM KF。人MDM2的氨基酸残基1-188在大肠杆菌中被表达为氨基末端的谷胱甘肽-S-转移酶(GST)融合蛋白(GST-hMDM2)。人p53的残基1-83在大肠杆菌中被表达为氨基末端的AviTagTM-TrxA-6xHis融合蛋白(生物素化p53)。每种蛋白质均通过亲和色谱法从细胞匀浆中分离出来。
具体地,将10uL GST-hMDM2与10ul在10%DMSO中的稀释的化合物(各种浓度,连续稀释)一起在室温下温育20分钟。将20uL生物素化-p53加入到GST-hMDM2+化合物混合物中,然后在室温下温育60min。将10uL由SA-XLent、抗-GST穴状化合物抗体和KF组成的检测缓冲液加入到GST-hMDM2、生物素化-p53和化合物反应物中,并放置在室温下以达到平衡并保持平衡>4hr。该反应物中的DMSO的最终浓度为2%。在微板多标记读取器上测量时间分辨荧光读数。相对于nutlin-3计算抑制百分比。
当HDM2抑制剂的效价增大时,执行改进的HTRF测定(HTRF2测定)。除了下面的试剂浓度变化之外,所有测定条件都与上述条件相同:0.2nM GST-hMDM2(1-188)、0.5nM生物素化-p53(1-83)、0.18nM SA-XLent,和100mMKF。
结果在下表中给出。
表1
实施例 | HTRF1 IC<sub>50</sub>(μM) | HTRF2 IC<sub>50</sub>(μM) |
实施例 | HTRF1 IC<sub>50</sub>(μM) | HTRF2 IC<sub>50</sub>(μM) |
1 | 0.04 | 0.004 |
2 | 0.20 | |
3 | 0.06 | 0.01 |
4 | 0.19 | |
5 | 0.27 | |
6 | 0.04 | |
7 | 0.05 | |
8 | 0.04 | |
9 | 0.03 | |
10 | 0.07 | |
11 | 0.09 | |
12 | 0.04 | |
13 | 0.11 | |
14 | 0.29 | |
15 | 0.24 | |
16 | 0.07 | |
17 | 0.24 | |
18 | 0.11 | |
19 | 0.01 | |
20 | 0.07 | |
21 | 0.07 |
实施例 | HTRF1 IC<sub>50</sub>(μM) | HTRF2 IC<sub>50</sub>(μM) |
22 | 0.49 | |
23 | 0.17 | |
24 | 0.57 | |
25 | 0.14 | |
26 | 0.13 | |
27 | 0.10 | |
28 | 0.18 | |
29 | 0.03 | |
30 | 0.03 | 0.004 |
31 | 0.05 | |
32 | 0.09 | |
33 | 0.41 | |
34 | 0.71 | |
35 | 0.15 | 0.03 |
36 | 4.3 | |
37 | 0.06 | |
38 | 0.19 | |
39 | 0.30 | |
40 | 0.17 | |
41 | 0.32 | |
42 | 0.41 |
实施例 | HTRF1 IC<sub>50</sub>(μM) | HTRF2 IC<sub>50</sub>(μM) |
43 | 1.97 | |
44 | 0.45 | |
45 | 0.55 | |
46 | 0.27 | |
47 | 3.63 | |
48 | 1.37 | |
49 | 2.38 | |
50 | 0.83 | |
51 | 3.06 | |
52 | 1.70 | |
53 | 0.13 | |
54 | 2.09 | |
55 | 0.09 | |
56 | 1.89 | |
57 | 1.60 | |
58 | 0.70 | |
59 | 0.87 | |
60 | 0.16 | |
61 | 0.31 | |
62 | 0.09 | |
63 | 0.43 |
实施例 | HTRF1 IC<sub>50</sub>(μM) | HTRF2 IC<sub>50</sub>(μM) |
64 | 0.22 | |
65 | 0.02 | 0.003 |
66 | 0.31 | |
67 | 0.02 | 0.002 |
68 | 0.03 | 0.002 |
69 | 0.06 | |
70 | 0.13 | |
71 | 0.02 | 0.003 |
72 | 0.06 | |
73 | 0.03 | 0.006 |
74 | 0.07 | |
75 | 0.03 | 0.005 |
76 | 0.22 | |
77 | 0.26 | |
78 | 0.53 | |
79 | 0.58 | |
80 | 0.08 | |
81 | 0.49 | |
82 | 0.02 | |
83 | 0.03 | |
84 | 1.76 |
实施例 | HTRF1 IC<sub>50</sub>(μM) | HTRF2 IC<sub>50</sub>(μM) |
85 | 1.98 | |
86 | 0.01 | |
87 | 0.02 | |
88 | 0.84 | |
89 | 0.08 | |
90 | 0.04 | |
91 | 0.01 | 0.004 |
92 | 0.04 | |
93 | 0.01 | 0.003 |
94 | 0.01 | |
95 | 0.03 | 0.009 |
96 | 0.02 | 0.008 |
97 | 0.01 | 0.002 |
98 | 0.01 | 0.004 |
99 | 0.01 | 0.002 |
100 | 0.02 | |
101 | 0.02 | 0.006 |
102 | 0.05 | |
103 | 0.28 | |
104 | 0.04 | |
105 | 1.09 |
实施例 | HTRF1 IC<sub>50</sub>(μM) | HTRF2 IC<sub>50</sub>(μM) |
106 | 0.19 | |
107 | 0.21 | |
108 | 0.11 | |
109 | 0.30 | |
110 | 0.34 | |
111 | 0.61 | |
112 | 0.23 | |
113 | 0.03 | |
114 | 0.03 | |
115 | <0.01 | 0.001 |
116 | 0.39 | |
117 | 0.71 | |
118 | 0.65 | |
119 | 0.12 | |
120 | 0.56 | |
121 | 0.05 | |
122 | 0.05 | 0.011 |
123 | 0.92 | |
124 | 0.02 | |
125 | 0.02 | 0.005 |
表2
实施例 | HTRF1 IC<sub>50</sub>(μM) | HTRF2 IC<sub>50</sub>(μM) |
126 | ` | 0.012 |
127 | 0.02 | |
128 | 0.01 | 0.001 |
129 | 0.01 | 0.001 |
130 | 0.01 | 0.003 |
131 | 0.07 | |
132 | 0.12 | 0.070 |
133 | 0.01 | 0.002 |
134 | 0.01 | 0.002 |
135 | 0.01 | |
136 | 0.01 | 0.001 |
137 | 0.01 | 0.002 |
138 | 0.01 | 0.002 |
139 | <0.01 | 0.001 |
140 | 0.01 | 0.004 |
141 | <0.01 | 0.001 |
142 | 0.01 | 0.001 |
143 | 0.03 | 0.019 |
144 | 0.04 | 0.014 |
实施例 | HTRF1 IC<sub>50</sub>(μM) | HTRF2 IC<sub>50</sub>(μM) |
145 | 0.01 | 0.004 |
146 | 0.01 | 0.004 |
147 | 0.01 | 0.002 |
148 | <0.01 | 0.001 |
149 | 0.04 | 0.006 |
150 | 0.01 | 0.002 |
151 | 0.02 | 0.006 |
152 | 0.01 | 0.001 |
153 | 0.002 | |
154 | 0.01 | 0.002 |
155 | 0.011 | |
156 | ||
157 | 0.01 | 0.002 |
158 | 0.01 | |
159 | 0.01 | 0.002 |
160 | 0.01 | |
161 | 0.10 | |
162 | 0.006 | |
163 | 0.053 | |
164 | 0.049 | |
165 | 0.026 |
实施例 | HTRF1 IC<sub>50</sub>(μM) | HTRF2 IC<sub>50</sub>(μM) |
166 | 0.044 | |
167 | 0.064 | |
168 | 0.058 | |
169 | 0.002 | |
170 | 0.106 | |
171 | 0.028 | |
172 | 0.001 | |
173 | 0.015 | |
174 | 0.002 | |
175 | 0.001 | |
176 | 0.003 | |
177 | 0.053 | |
178 | 0.02 | 0.006 |
179 | 0.04 | |
180 | 0.03 | 0.008 |
181 | 0.002 | |
182 | 0.004 | |
183 | 0.003 | |
184 | 0.013 | |
185 | 0.02 | 0.002 |
186 | 0.007 |
实施例 | HTRF1 IC<sub>50</sub>(μM) | HTRF2 IC<sub>50</sub>(μM) |
187 | 0.003 | |
188 | 0.001 | |
189 | 0.003 | |
190 | 0.005 | |
191 | 0.001 | |
192 | 0.001 | |
193 | 0.001 | |
194 | 0.005 | |
195 | 0.002 | |
196 | <0.001 | |
197 | <0.001 | |
198 | <0.001 | |
199 | 0.001 | |
200 | 0.001 | |
201 | 0.044 | |
202 | 0.002 | |
203 | 0.001 | |
204 | 0.002 | |
205 | 0.01 | 0.001 |
206 | 0.01 | 0.003 |
207 | 0.04 | 0.009 |
实施例 | HTRF1 IC<sub>50</sub>(μM) | HTRF2 IC<sub>50</sub>(μM) |
208 | 0.02 | 0.007 |
209 | 0.07 | 0.009 |
210 | 0.01 | 0.002 |
211 | 0.02 | 0.004 |
212 | 0.03 | 0.005 |
213 | 0.03 | |
214 | 0.02 | 0.003 |
215 | 0.04 | 0.006 |
216 | 0.03 | 0.003 |
217 | 0.03 | 0.005 |
218 | 0.08 | 0.019 |
219 | 0.03 | 0.012 |
220 | 0.03 | |
221 | 0.02 | 0.003 |
222 | 0.01 | 0.001 |
223 | 0.02 | 0.004 |
224 | 0.001 | |
225 | 0.002 | |
226 | 0.09 | |
227 | 0.07 | |
228 | 0.04 |
实施例 | HTRF1 IC<sub>50</sub>(μM) | HTRF2 IC<sub>50</sub>(μM) |
229 | 0.001 | |
230 | 0.03 | 0.010 |
231 | 0.08 | |
232 | 0.08 | |
233 | 0.08 | |
234 | 0.05 | 0.011 |
235 | 0.06 | |
236 | 0.01 | |
237 | 0.04 | 0.009 |
238 | 0.001 | |
239 | ||
240 | 0.05 | |
241 | 0.02 | 0.003 |
242 | 0.03 | |
243 | 0.03 | |
244 | 0.04 | |
245 | 0.03 | 0.009 |
246 | 0.02 | 0.003 |
247-A | 0.100 | |
247-B | 0.371 | |
248 | 0.100 |
实施例 | HTRF1 IC<sub>50</sub>(μM) | HTRF2 IC<sub>50</sub>(μM) |
249 | 0.03 | 0.006 |
250 | 0.01 | 0.001 |
251 | 0.01 | 0.001 |
252 | 0.06 | |
253 | 0.001 | |
254 | <0.001 | |
255 | <0.001 | |
256 | <0.01 | <0.001 |
257 | 0.001 | |
258 | 0.08 | 0.002 |
259 | 0.002 | |
260 | 0.007 | |
261 | 0.001 | |
262 | 0.02 | 0.003 |
表3
实施例 | HTRF1 IC<sub>50</sub>(μM) | HTRF2 IC<sub>50</sub>(μM) |
263 | 0.0002 | |
264 | 0.0003 | |
265 | 0.0005 | |
266 | 0.0005 |
实施例 | HTRF1 IC<sub>50</sub>(μM) | HTRF2 IC<sub>50</sub>(μM) |
267 | 0.0003 | |
268 | 0.0001 | |
269 | 0.0001 | |
270 | 0.0055 | |
272 | 0.0001 | |
273 | 0.0002 | |
274 | 0.0002 | |
275 | 0.0003 | |
276 | 0.0005 | |
277 | 0.0002 | |
278 | 0.0002 | |
279 | 0.0005 | |
280 | 0.0006 | |
281 | 0.0003 | |
282 | 0.0002 | |
283 | 0.0007 | |
284 | 0.0015 | |
285 | 0.0008 | |
286 | 0.0006 | |
287 | 0.0003 | |
288 | 0.0135 |
实施例 | HTRF1 IC<sub>50</sub>(μM) | HTRF2 IC<sub>50</sub>(μM) |
289 | 0.0003 | |
290 | ||
291 | ||
292 | 0.0009 | |
293 | 0.0008 | |
294 | 0.0007 | |
295 | 0.0018 | |
296 | 0.0044 | |
297 | 0.0161 | |
298 | 0.0013 | |
299 | 0.0100 | |
300 | ||
301 | 0.0003 | |
302 | 0.0004 | |
303 | 0.0005 | |
304 | 0.0003 | |
305 | 0.0005 | |
306 | 0.0003 | |
307 | 0.0003 | |
308 | 0.0001 | |
309 | 0.0002 |
实施例 | HTRF1 IC<sub>50</sub>(μM) | HTRF2 IC<sub>50</sub>(μM) |
310 | 0.0002 | |
311 | 0.0001 | |
312 | 0.0112 | |
313 | 0.0002 | |
314 | 0.0001 | |
315 | 0.0014 | |
316 | 0.0029 | |
317 | 0.0012 | |
318 | 0.0029 | |
319 | 0.0024 | |
320 | 0.0005 | |
321 | 0.0013 | |
322 | 0.0001 | |
323 | 0.0002 | |
324 | 0.0003 | |
325 | 0.0016 | |
326 | 0.0004 | |
327 | 0.0004 | |
328 | 0.0014 | |
329 | 0.0016 | |
330 | 0.0002 |
实施例 | HTRF1 IC<sub>50</sub>(μM) | HTRF2 IC<sub>50</sub>(μM) |
331 | 0.0002 | |
332 | 0.0003 | |
333 | 0.0002 | |
334 | 0.0001 | |
335 | 0.0003 | |
336 | 0.0018 | |
337 | 0.0006 | |
338 | 0.0003 | |
339 | 0.0003 | |
340 | 0.0002 | |
341 | 0.0002 | |
342 | 0.0001 | |
343 | 0.0002 | |
344 | 0.0004 | |
345 | 0.0002 | |
346 | 0.0001 | |
347 | 0.0003 | |
348 | 0.0003 | |
349 | 0.0001 | |
350 | 0.0001 | |
351 | 0.0001 |
实施例 | HTRF1 IC<sub>50</sub>(μM) | HTRF2 IC<sub>50</sub>(μM) |
352 | 0.0002 | |
353 | 0.0001 | |
354 | 0.0001 | |
355 | 0.0006 | |
356 | 0.0009 | |
357 | 0.0002 | |
358 | 0.0001 | |
359 | 0.0002 | |
360 | 0.0003 | |
361 | 0.0005 | |
362 | 0.0010 | |
363 | 0.0002 | |
364 | 0.0003 | |
365 | 0.0008 | |
366 | 0.0001 | |
367 | 0.0026 | |
368 | 0.0019 | |
369 | 0.0006 | |
370 | 0.0004 | |
371 | 0.0001 | |
372 | 0.0002 |
实施例 | HTRF1 IC<sub>50</sub>(μM) | HTRF2 IC<sub>50</sub>(μM) |
373 | 0.0002 | |
374 | 0.0002 | |
375 | 0.0001 | |
376 | 0.0010 | |
377 | 0.0002 | |
378 | 0.0001 | |
379 | 0.0001 | |
380 | 0.0006 | |
381 | 0.0001 | |
382 | 0.0002 | |
383 | 0.0005 | |
384 | 0.0005 | |
385 | ||
386 | 0.0018 | |
387 | 0.0070 | |
388 | ||
389 | 0.0014 | |
390 | ||
391 | 0.0050 | |
392 | 0.1230 | |
393 | 0.0007 |
实施例 | HTRF1 IC<sub>50</sub>(μM) | HTRF2 IC<sub>50</sub>(μM) |
394 | 0.0004 | |
395 | 0.0005 | |
396 | 0.0002 | |
397 | 0.0002 | |
398 | 0.0001 | |
399 | 0.0001 | |
400 | 0.0038 | |
401 | 0.0015 | |
402 | 0.0046 | |
403 | 0.0040 | |
404 | 0.0009 | |
405 | ||
406 | ||
407 | ||
408 | 0.0035 | |
409 | ||
410 | 0.0026 | |
411 | ||
412 | ||
413 | 0.0010 | |
414 | 0.0238 |
实施例 | HTRF1 IC<sub>50</sub>(μM) | HTRF2 IC<sub>50</sub>(μM) |
415 | 0.0010 | |
416 | 0.0027 | |
417 | 0.0013 | |
418 | 0.0183 | |
419 | 0.0034 | |
420 | 0.1230 | |
421 | 0.1940 | |
422 | 0.1040 | |
423 | 0.0231 | |
424 | 0.1300 | |
425 | 0.2750 | |
426 | 0.0526 | |
427 | 0.1190 | |
428 | 0.0041 | |
429 | 0.01 | 0.0024 |
430 | 0.02 | |
431 | 0.0018 |
本发明化合物显示出对细胞周期蛋白依赖性激酶抑制剂p21WAF1/CIP1的激活。
hMDM2和p53之间的相互作用的抑制导致经由p53的稳定化和积累的p53通路的激活。p53激活许多基因的转录,其中一个基因是p21WAF1/CIP1。为了评估hMDM2抑制剂的效价,利用定量逆转录聚合酶链反应(qRT-PCR或)测量相对于二甲亚砜(DMSO)-处理的对照细胞而言化合物相关的细胞中的p21转录本水平。
在第1天,将SJSA-1细胞以3x104个细胞/孔的密度接种在96-孔细胞培养板中的100ul生长培养基(RPMI 1640;10mM HEPES;1mM丙酮酸钠;1X青霉素-链霉素-谷氨酰胺(PSQ);和10%胎牛血清(所有试剂都得自Invitrogen;Carlsbad,CA))中。将该细胞在37℃和5%CO2下培养过夜。
在第2天,将hMDM2抑制剂连续稀释在DMSO(Sigma-Aldrich;St.Louis,MO)中。将5ul的每种化合物稀释液加入到245ul含有10%FBS的经过滤的测定培养基(RPMI 1640,10mM HEPES,1mM丙酮酸钠,和1X PSQ)中。或者,还在存在10%人血清或10%小鼠血清的情况下,或者在不存在任何血清的情况下进行该测定。将生长培养基从接种的SJSA-1细胞上除去并用100ul/孔的测定培养基代替。然后将100ul含有稀释的抑制剂的培养基加入到每个孔中至最终体积为200ul。该化合物的剂量滴定产生范围为0.049uM–50uM的最终浓度,外加DMSO对照。将该细胞在抑制剂存在下在37℃和5%CO2下温育7小时。在温育结束时,将培养基从细胞上除去,并将该板储存在-80℃。
在第3天,使用Qiagen BioRobot Universal workstation从抑制剂-和DMSO-处理的SJSA-1细胞中纯化出总RNA,所述纯化按照来自制造商(Qiagen;Valencia,CA)的RNeasy96BioRobot 8000试剂盒方案进行,但有以下不同:该方案以RLT裂解缓冲液的添加开始,省去DNase处理,省去顶部洗脱流体(Top Elute fluid)的添加,并将最终洗脱体积改为120ul。在BioRobot Universal完成RNA提取程序后,对含有来自每个孔的总RNA的收集板短暂地离心从而在该管底部收集洗脱物。
为了测量存在的p21转录本的水平,使用qRT-PCR。p21和管家基因、甘油醛3-磷酸脱氢酶(GAPDH)的水平都从来自每个抑制剂-或DMSO-处理的孔的总RNA以技术重复测定。每个qRT-PCR测定孔均含有来自 One-Step RT-PCR Master Mix Reagents Kit(Invitrogen)的下列组分:10ul 2X Universal PCR Master Mix、0.5ul 40XMultiscribeTMReverse Transcriptase/RNase Inhibitor Mix、1ul p21 20X Gene Expression Assay(Invitrogen)或1ul GAPDH20X Gene ExpressionAssay(Invitrogen),加上5ul总RNA和3.5ul DEPC-H2O(EMD Chemicals;Gibbstown,NJ)。在Applied Biosystems Prism 7900HT仪器上采用相对定量(ΔΔCt)方法使用下列循环条件测定qRT-PCR反应:48℃30分钟,接着是95℃10分钟,然后为40个由95℃15秒和60℃1分钟组成的循环。利用Applied Biosystems SDS2.2软件用GAPDH作为内源对照以及用DMSO-处理的样品作为校准器来分析数据。SDS2.2软件为每个所处理样品计算出相对于DMSO对照的p21水平的相对定量(RQ)或增大倍数。由参考化合物的拟合曲线的最大值定义最大(100%)的p21诱导倍数。将所测试的每种抑制剂剂量下的p21诱导倍数转化为代表最大值百分比的值。利用XLFit软件(ID Business Solutions,Alameda,CA)制作剂量反应曲线以计算所测试的每种抑制剂的IC50转变值(transit value)。
Claims (32)
1.一种化合物,其具有式IE结构
或其药学上可接受的盐,其中
R1是:
-COOH;
-C(O)OC1-6烷基;
-C(O)NHOH;
-C(O)NH-NH2;
-C(O)NHS(O)2-C1-6烷基;
-C(O)NHS(O)2卤代C1-6烷基;
-C(O)NH2;
-C(O)NH-C1-6烷基,其中C1-6烷基被一个-CO(O)C1-6烷基取代;
-C(O)NH-C1-6烷基,其中C1-6烷基被一个-COOH取代;
-C(O)NH-C1-6烷基,其中C1-6烷基被一个吗啉基取代;
-C(O)NH-C1-6烷基,其中C1-6烷基被一个或多个-OH取代;
-C(O)NH-C1-6烷基,其中C1-6烷基被一个-N(C1-6烷基)2取代;
-C(O)NH-OC1-6烷基;
-C(O)NH-氰基;
-S(O)2C1-6烷基;
羟基C1-6烷基;
-环丙基-COOH;
噁二唑基,其任选被C1-6烷基取代;
异噁唑,其被C1-6烷基或-OH取代;
吡唑基,其被-OH取代;
吡啶基,其被C1-6烷氧基或-OH取代;
R2是:
–N(C1-6-烷基)2;
–C(H)R5R6;
C3-6环烷基,其任选被C1-6-烷基或-OH取代;
哌啶基,其被C1-6卤代烷基取代;
四氢吡喃基;
吡嗪基;
吡唑基,其被C1-6烷基取代;或
嘧啶基,其任选被卤素取代;
Re是:
H;
(C1-C3)烷基;或
-OC1-6-烷基;
R5是:
-C(O)OC1-6烷基;
-(亚烷基)1-6-OC1-6烷基,其中C1-6烷基任选被C3-8环烷基、C1-6烷氧基、CN、-C(O)NH2或-OH取代;
-(亚烷基)1-6-NH-C1-6烷基;
-(亚烷基)1-6-NH-C1-6卤代烷基;
C1-6-烷基,其任选被以下基团取代:-OH、C1-6卤代烷基、吗啉基、吡咯烷基、-N(H)C(=O)C1-6烷基、-N(H)SO2C1-6烷基、氰基、-SO2C1-6烷基、吡啶基、-N(H)SO2-吡啶基、-NH-C1-6卤代烷基、C1-6烷基取代的吗啉基、-SO2-C3-8环烷基取代的哌嗪基、-SO2-C1-6烷基、-C(O)C1-6烷基、–C(O)C3-8环烷基、-N(C1-6-烷基)-SO2-C3-8环烷基、-N(C1-6-烷基)-SO2-C1-6-烷基、C3-8环烷基、-N(C3-8环烷基)-SO2-C1-6-烷基、-N(C1-6卤代烷基)-SO2-C1-6-烷基、C1-6烷氧基、-N(H)SO2-C3-8环烷基、-N(C1-6卤代烷基)C(=O)C1-6烷基、-N(H)SO2-C1-6卤代烷基、-N(H)SO2-苯基其中苯基任选被卤素、C1-6-烷基、C1-6烷氧基或氰基取代、-SO2-C1-6烷基其中C1-6烷基任选被C3-8环烷基取代、任选被卤素、C1-6烷基、C1-6卤代烷基或C3-8环烷基取代的吡啶基、吡嗪基、嘧啶基、噻唑基、-N(H)SO2-2-噻吩基其中2-噻吩基任选被卤素取代、-N(C1-6-烷基)SO2-2-噻吩基、-N(C1-6卤代烷基)-SO2-C3-8环烷基、-N(苯基)-SO2-C1-6-烷基其中苯基任选被卤素或氰基取代、-N(苯基)-SO2-C3-8环烷基、-N(吡啶基)-SO2-C1-6-烷基、-SO2-苯基、被C3-8环烷基或OH取代的-SO2C1-6烷基、-SO2-四氢吡喃基、被C1-6-烷基或卤素取代的-SO2-苯基、-SO2-吡啶基、-SO2-C1-6卤代烷基、-SO2-C3-8环烷基、-SO2NH(C1-6-烷基)-、-SO2-吗啉基、-SO2-吡咯烷基、-N(H)SO2N(C1-6-烷基)2或-N(C1-6-烷基)SO2N(C1-6-烷基)2;
C3-8环烷基;
-(亚烷基)1-6-NH-异噻唑基;
-C(O)NHC1-6烷基;
噁二唑,其被C1-6烷基或C3-8环烷基取代;
-C(O)C1-6烷基;或
吗啉基;
R6是:
C1-6烷基;
C3-8环烷基;或
H。
2.根据权利要求1所述的化合物,或其药学上可接受的盐,其中Re为H或甲基或乙基。
6.一种选自以下的化合物,或其药学上可接受的盐:
2-((3R,5R,6S)-1-((S)-1-叔丁氧基-1-氧代丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-3-基)乙酸;
2-((3S,5R,6S)-1-((S)-1-叔丁氧基-1-氧代丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-乙氧基-1-氧代丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-乙氧基-4-甲基-1-氧代戊烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-乙氧基-1-氧代戊烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3S,5S,6R)-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-1-乙氧基-1-氧代戊烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-2-叔丁氧基-1-环丙基-2-氧代乙基)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-羟基乙基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环丙基甲氧基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-甲氧基丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(2-甲氧基乙氧基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-((1-氰基环丙基)甲氧基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环丙基甲氧基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-甲氧基丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(2-甲氧基乙氧基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-1-((1-氨基甲酰基环丙基)甲氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-3-基)乙酸(异构体1);
2-((3S,5R,6S)-1-((S)-1-((1-氨基甲酰基环丙基)甲氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-3-基)乙酸(异构体2);
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(2-羟基-2-甲基丙氧基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-((3S)-1,1,1-三氟代-2-羟基戊烷-3-基)哌啶-3-基)乙酸(异构体1);
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-((3S)-1,1,1-三氟代-2-羟基戊烷-3-基)哌啶-3-基)乙酸(异构体2);
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-吗啉代丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(乙基氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-((S)-1-(2,2,2-三氟乙基氨基)丁烷-2-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-((S)-1-(吡咯烷-1-基)丁烷-2-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-((S)-1-(2-氧代吡咯烷-1-基)丁烷-2-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二氧化硫代吗啉代)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-((S)-1-(噻唑-2-基氨基)丁烷-2-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-1-乙酰氨基丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(甲基磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-氰基戊烷-3-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(甲基磺酰基)戊烷-3-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-((S)-1-(吡啶-2-基)戊烷-3-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(乙基氨基)-1-氧代丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-1-(乙基氨基)-1-氧代丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(5-甲基-1,3,4-噁二唑-2-基)丙基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-1-(5-甲基-1,3,4-噁二唑-2-基)丙基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丁基甲基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(2-乙基丁基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环戊基甲基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2,2-二甲基环戊基)甲基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环己基甲基)-2-氧代哌啶-3-基)乙酸;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酸;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-丙基哌啶-3-基)乙酸;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丁基甲基)-2-氧代哌啶-3-基)乙酸;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-异丁基-2-氧代哌啶-3-基)乙酸;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环戊基甲基)-2-氧代哌啶-3-基)乙酸;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-(戊烷-3-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酸甲酯;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酰胺;
2-(2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酰氨基)乙酸乙酯;
2-(2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙)乙酰氨基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酰肼;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)-N-羟基乙酰胺;
(S)-2-((2S,3R,5R)-3-(3-氯苯基)-2-(4-氯苯基)-5-(2-(甲基磺酰氨基)-2-氧代乙基)-6-氧代哌啶-1-基)丁酸乙酯;
(S)-2-((2S,3R,5R)-3-(3-氯苯基)-2-(4-氯苯基)-5-(2-((3-吗啉代丙基)氨基)-2-氧代乙基)-6-氧代哌啶-1-基)丁酸乙酯;
(3R,5R,6S)-3-((1H-四唑-5-基)甲基)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)哌啶-2-酮;
(3R,5R,6S)-3-((1,3,4-噁二唑-2-基)甲基)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)哌啶-2-酮;
(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-3-((5-甲基-1,3,4-噁二唑-2-基)甲基)哌啶-2-酮;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)-N-(甲基磺酰基)乙酰胺;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酰胺;
(3S,5R,6S)-3-((1H-四唑-5-基)甲基)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)哌啶-2-酮;
(3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-3-((5-甲基异噁唑-3-基)甲基)哌啶-2-酮;
2-((2'S,3'R,5'R)-6-氯代-3'-(3-氯苯基)-1'-(环丙基甲基)-2,6'-二氧代螺[二氢吲哚-3,2'-哌啶-5'-基)乙酸;
2-((2'R,3'S,5'S)-6-氯代-3'-(3-氯苯基)-1'-(环丙基甲基)-2,6'-二氧代螺[二氢吲哚-3,2'-哌啶-5'-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(5-氯噻吩-2-基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酸;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(5-氯噻吩-2-基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-乙氧基-1-氧代丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-1-叔丁氧基-1-氧代丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((R)-1-叔丁氧基-1-氧代丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环丙基甲氧基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代-3-(2-(吡咯烷-1-基)乙基)哌啶-3-基)乙酸;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-3-(2-吗啉代乙基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-异丙基-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-环丁基-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-环戊基-3-甲基-2-氧代哌啶-3-基)乙酸;
(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-3-((5-氧代-4,5-二氢-1H-1,2,4-三唑-3-基)甲基)-1-(戊烷-3-基)哌啶-2-酮;
5-(((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)甲基)-1,3,4-噁二唑-2(3H)-酮;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)-N-(三氟甲基磺酰基)乙酰胺;
(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-((3-羟基-1H-吡唑-5-基)甲基)-3-甲基-1-(戊烷-3-基)哌啶-2-酮;
(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-((3-羟基异噁唑-5-基)甲基)-3-甲基-1-(戊烷-3-基)哌啶-2-酮;
5-(((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)甲基)噁唑烷-2,4-二酮;
3-(((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)甲基)-1,2,4-噁二唑-5(4H)-酮;
3-(((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-异丙基-3-甲基-2-氧代哌啶-3-基)甲基)-1,2,4-噁二唑-5(4H)-酮;
3-(((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)甲基)-1,2,4-噻二唑-5(4H)-酮;
3-(((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-异丙基-3-甲基-2-氧代哌啶-3-基)甲基)-1,2,4-噻二唑-5(4H)-酮;
(3R,5R,6S)-3-((1H-四唑-5-基)甲基)-5-(3-氯苯基)-6-(4-氯苯基)-1-异丙基-3-甲基哌啶-2-酮;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-2-氧代-1-(戊烷-3-基)哌啶-3-基)乙酸;
(3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-3-(甲基磺酰基甲基)-1-(戊烷-3-基)哌啶-2-酮;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(3-环丙基-1,2,4-噁二唑-5-基)丙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-1-(3-环丙基-1,2,4-噁二唑-5-基)丙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-吗啉代丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(2,2,2-三氟乙基氨基)丁烷-2-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(2,2-二甲基吗啉代)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2S)-1-(2,6-二甲基吗啉代)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(4-(环丙基磺酰基)哌嗪-1-基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(4-(甲基磺酰基)哌嗪-1-基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-1-(4-乙酰基哌嗪-1-基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(4-(环丙烷羰基)哌嗪-1-基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
3-(((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-吗啉代丁烷-2-基)-2-氧代哌啶-3-基)甲基)-1,2,4-噁二唑-5(4H)-酮;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(5,5-二甲基-2-氧代噁唑烷-3-基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-1-(叔丁基氨基)-1-氧代丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((1S,2R,3S)-2,3-二羟基环戊基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((1R,2R,3S)-2,3-二羟基环戊基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,3'S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1'-(2,2,2-三氟乙基)-1,3'-联哌啶-3-基)乙酸;
2-((3R,3'R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1'-(2,2,2-三氟乙基)-1,3'-联哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((1S,3S)-3-羟基环戊基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((1S,3R)-3-羟基环戊基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-四氢-2H-吡喃-3-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((R)-四氢-2H-吡喃-3-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(吡嗪-2-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-甲基-1H-吡唑-4-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(嘧啶-4-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(2-氯嘧啶-4-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(嘧啶-2-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(3-甲基吡啶-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(4-甲基吡啶-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(二环丙基甲基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(二环丙基甲基)-3-甲基-2-氧代哌啶-3-基)乙酸;
((3S,4R,6R)-4-(3-氯苯基)-3-(4-氯苯基)-1,1-二氧化-2-(2-丙基)-1,2-噻嗪烷-6-基)乙酸;
((3S,4R,6S)-4-(3-氯苯基)-3-(4-氯苯基)-1,1-二氧化-2-(2-丙基)-1,2-噻嗪烷-6-基)乙酸;
((3S,4R,6R)-4-(3-氯苯基)-3-(4-氯苯基)-6-甲基-1,1-二氧化-2-(2-丙基)-1,2-噻嗪烷-6-基)乙酸;
((3S,4R,6S)-4-(3-氯苯基)-3-(4-氯苯基)-6-甲基-1,1-二氧化-2-(2-丙基)-1,2-噻嗪烷-6-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-3-甲基-1-((S)-1-吗啉代丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)乙酸;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-1-叔丁氧基-1-氧代丁烷-2-基)-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;或
2-((3R,5S,6S)-1-((S)-1-叔丁氧基-1-氧代丁烷-2-基)-6-(4-氯苯基)-5-(4-氯吡啶-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸。
7.一种选自以下的化合物,或其药学上可接受的盐:
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)丙酸;
(S)-2-((3R,5R,6S)-3-((1H-四唑-5-基)甲基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁酸叔丁酯;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(甲基磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-5-氧代己烷-3-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-5-羟基-5-甲基己烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((3S,5S)-6,6,6-三氟代-5-羟基-5-甲基己烷-3-基)哌啶-3-基)乙酸(异构体1);
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((3S,5R)-6,6,6-三氟代-5-羟基-5-甲基己烷-3-基)哌啶-3-基)乙酸(异构体2);
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基甲基磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S)-5-环丙基-6,6,6-三氟代-5-羟基己烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-6-羟基-6-甲基庚烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-6,6,6-三氟代-5,5-二羟基己烷-3-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((3S)-7,7,7-三氟代-6-羟基-6-甲基庚烷-3-基)哌啶-3-基)乙酸(异构体1);
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((3S)-7,7,7-三氟代-6-羟基-6-甲基庚烷-3-基)哌啶-3-基)乙酸(异构体2);
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-7-羟基-7-甲基辛烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N-环丙基甲基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((3S)-6,6,6-三氟代-5-羟基己烷-3-基)哌啶-3-基)乙酸(异构体1);
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((3S)-6,6,6-三氟代-5-羟基己烷-3-基)哌啶-3-基)乙酸(异构体2);
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S)-5-羟基己烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸(异构体1);
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S)-5-羟基己烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸(异构体2);
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(N-(2,2,2-三氟乙基)甲基磺酰氨基)丁烷-2-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S,4R)-5-羟基-4,5-二甲基己烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S,4S)-5-羟基-4,5-二甲基己烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-5-氰基-5-甲基己烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-2-氧代戊烷-3-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2S,3S)-2-羟基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2S,3S)-2-甲氧基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2R,3S)-2-羟基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2S,3R)-2-羟基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2R,3R)-2-羟基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-羟基-2-甲基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S,4S)-4-羟基己烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((3S,4R)-4-羟基己烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-甲氧基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(3S)-1,1,1-三氟代-2-羟基-2-甲基戊烷-3-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酰胺;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-(甲基磺酰基)乙酰胺;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-(3-羟基丙基)乙酰胺;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-(2-羟基乙基)乙酰胺;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-羟基乙酰胺;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-甲氧基乙酰胺;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-((R)-2,3-二羟基丙基)乙酰胺;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-((S)-2,3-二羟基丙基)乙酰胺;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-氰基乙酰胺;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-(2-(二甲基氨基)乙基)乙酰胺;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-(3,4-二羟基丁基)乙酰胺;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环丙烷磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
(S)-2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)丙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(3S)-2-(环丙烷磺酰氨基)戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸(异构体1);
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(3S)-2-(环丙烷磺酰氨基)戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸(异构体2);
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((2R,3S)-2-(1-甲基乙基磺酰氨基)戊烷-3-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)-1-氧代丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(新戊基氨基)-1-氧代丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(4,4-二甲基-4,5-二氢噁唑-2-基)丙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(N-(2,2,2-三氟乙基)乙酰氨基)丁烷-2-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二甲基乙基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N,2-二甲基丙烷-2-基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(1-甲基乙基磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N-乙基丙烷-2-基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(三氟甲基磺酰氨基)丁烷-2-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(4-氯苯基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(4-甲基苯基磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(2-氯苯基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(2-甲基苯基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(4-甲氧基苯基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(苯基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1-甲基环丙烷磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二氧化苯并[d]异噻唑-2(3H)-基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(3,3-二甲基-1,1-二氧化苯并[d]异噻唑-2(3H)-基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(吡啶-3-磺酰氨基)丁烷-2-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(4-氰基苯基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(3-氰基苯基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(吡啶-2-磺酰氨基)丁烷-2-基)哌啶-3-基)乙酸.
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N,1-二甲基环丙烷磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
3-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)丙酸;
3-((3R,5S,6R)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)丙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲氧基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-6-甲基-4-氧代庚烷-3-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(乙基磺酰基)戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(异丙基磺酰基)戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环丙基甲基磺酰基)戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(2-氧代吡咯烷-1-基)丁烷-2-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-1-((1R,4R)-2-氧杂-5-氮杂二环[2.2.1]庚烷-5-基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-((S)-3-甲基吗啉代)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-((R)-3-甲基吗啉代)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(硫代吗啉代-1,1-二氧化物)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(3,3-二氟氮杂环丁烷-1-基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((2S)-1-(8-氧杂-3-氮杂二环[3.2.1]辛烷-3-基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(3,3-二甲基吗啉代)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(3-羟基-3-(三氟甲基)氮杂环丁烷-1-基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(甲基(氧杂环丁烷-3-基)氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(2-氧代噁唑烷-3-基)丁烷-2-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(2-氧代吡啶-1(2H)-基)丁烷-2-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(2-氧代-5-(三氟甲基)吡啶-1(2H)-基)丁烷-2-基)哌啶-3-基)乙酸;
(3S,5R,6S)-3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(吡啶-3-基氧基)丁烷-2-基)哌啶-2-酮;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((1S)-1-(四氢呋喃-2-基)丙基)哌啶-3-基)乙酸(异构体1);
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((1S)-1-(四氢呋喃-2-基)丙基)哌啶-3-基)乙酸(异构体2);
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((1S)-1-5-氧代四氢呋喃-2-基)丙基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((1S)-1-(四氢-2H-吡喃-2-基)丙基)哌啶-3-基)乙酸(异构体1);
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((1S)-1-(四氢-2H-吡喃-2-基)丙基)哌啶-3-基)乙酸(异构体2);
2-((3R,5R,6S)-1-((R)-1-(苯并[d]噻唑-2-基)丙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-1-(苯并[d]噻唑-2-基)丙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(3-甲基异噁唑-5-基)丙基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((R)-1-(3-甲基异噁唑-5-基)丙基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(6-氯吡啶-2-基)丙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-1-(6-氯吡啶-2-基)丙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(吡啶-2-基)丙基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((R)-1-(吡啶-2-基)丙基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(吡啶-2-基)丁基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((R)-1-(吡啶-2-基)丁基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-环丙基-1-(吡啶-2-基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-2-环丙基-1-(吡啶-2-基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(吡啶-3-基)丙基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((R)-1-(吡啶-3-基)丙基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(吡嗪-2-基)丙基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((R)-1-(吡嗪-2-基)丙基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(嘧啶-2-基)丙基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((R)-1-(嘧啶-2-基)丙基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(6-甲基吡啶-2-基)丙基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((R)-1-(6-甲基吡啶-2-基)丙基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(吡啶-4-基)丙基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((R)-1-(吡啶-4-基)丙基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(6-(三氟甲基)吡啶-2-基)丙基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((R)-1-(6-(三氟甲基)吡啶-2-基)丙基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-1-(6-溴吡啶-2-基)丙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((R)-1-(6-溴吡啶-2-基)丙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(噻唑-2-基)丙基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((R)-1-(噻唑-2-基)丙基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(6-(2-羟基丙烷-2-基)吡啶-2-基)丙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-1-(6-(2-羟基丙烷-2-基)吡啶-2-基)丙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(6-环丙基吡啶-2-基)丙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-1-(6-环丙基吡啶-2-基)丙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-3,3,3-三氟代-1-(吡啶-2-基)丙基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((R)-3,3,3-三氟代-1-(吡啶-2-基)丙基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-2-甲基-1-(吡啶-2-基)丙基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((R)-2-甲基-1-(吡啶-2-基)丙基)-2-氧代哌啶-3-基)乙酸;
(3R,5R,6S)-3-((1H-四唑-5-基)甲基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(戊烷-3-基)哌啶-2-酮;
(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-((R)-2,3-二羟基丙基)-1-((2S,3S)-2-羟基戊烷-3-基)-3-甲基哌啶-2-酮;
(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-((S)-2,3-二羟基丙基)-1-((2S,3S)-2-羟基戊烷-3-基)-3-甲基哌啶-2-酮;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-羟基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)环丙烷羧酸;
2-((3R,5R,6S)-1-((S)-2-(叔丁氧基)-1-环丙基-2-氧代乙基)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-乙氧基-2-氧代乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-羟基乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((1S,2S)-1-环丙基-2-羟基丁基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((1S,2R)-1-环丙基-2-羟基丁基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-甲基环丙烷磺酰氨基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-(环丙烷磺酰氨基)-1-环丙基乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(乙基磺酰氨基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-甲基环丙烷磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((1S,2R)-1-环丙基-2-羟基丙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((1S,2S)-1-环丙基-2-羟基丙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(1-甲基乙基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-1-环丙基-2-(N-甲基环丙烷磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2S,3S)-2-羟基-4-甲基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-环丙基(吡啶-2-基)甲基)-3-甲基-2-氧代哌啶-3-基)乙酸;或
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((R)-环丙基(吡啶-2-基)甲基)-3-甲基-2-氧代哌啶-3-基)乙酸。
8.一种选自以下的化合物,或其药学上可接受的盐:
2-(1-(1-叔丁氧基-1-氧代丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-乙氧基-1-氧代丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-乙氧基-4-甲基-1-氧代戊烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-乙氧基-1-氧代戊烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(1-(2-叔丁氧基-1-环丙基-2-氧代乙基)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-羟基丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-羟基乙基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(环丙基甲氧基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-甲氧基丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(2-甲氧基乙氧基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-((1-氰基环丙基)甲氧基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(环丙基甲氧基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-甲氧基丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(2-甲氧基乙氧基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(1-(1-((1-氨基甲酰基环丙基)甲氧基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(2-羟基-2-甲基丙氧基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-(1,1,1-三氟代-2-羟基戊烷-3-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-吗啉代丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(乙基氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-(1-(2,2,2-三氟乙基氨基)丁烷-2-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-(1-(吡咯烷-1-基)丁烷-2-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-(1-(2-氧代吡咯烷-1-基)丁烷-2-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(1,1-二氧化硫代吗啉代)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-(1-(噻唑-2-基氨基)丁烷-2-基)哌啶-3-基)乙酸;
2-(1-(1-乙酰氨基丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(甲基磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-氰基戊烷-3-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(甲基磺酰基)戊烷-3-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-(1-(吡啶-2-基)戊烷-3-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(乙基氨基)-1-氧代丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(5-甲基-1,3,4-噁二唑-2-基)丙基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(环丁基甲基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-乙基丁基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(环戊基甲基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-((2,2-二甲基环戊基)甲基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(环己基甲基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-丙基哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(环丁基甲基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-异丁基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(环戊基甲基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-2-氧代-1-(戊烷-3-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酸甲酯;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酰胺;
2-(2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酰氨基)乙酸乙酯;
2-(2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酰氨基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酰肼;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)-N-羟基乙酰胺;
2-(3-(3-氯苯基)-2-(4-氯苯基)-5-(2-(甲基磺酰氨基)-2-氧代乙基)-6-氧代哌啶-1-基)丁酸乙酯;
2-(3-(3-氯苯基)-2-(4-氯苯基)-5-(2-((3-吗啉代丙基)氨基)-2-氧代乙基)-6-氧代哌啶-1-基)丁酸乙酯;
3-((1H-四唑-5-基)甲基)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)哌啶-2-酮;
3-((1,3,4-噁二唑-2-基)甲基)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)哌啶-2-酮;
5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-3-((5-甲基-1,3,4-噁二唑-2-基)甲基)哌啶-2-酮;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)-N-(甲基磺酰基)乙酰胺;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酰胺。
3-((1H-四唑-5-基)甲基)-5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)哌啶-2-酮;
5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-3-((5-甲基异噁唑-3-基)甲基)哌啶-2-酮;
2-(6-氯代-3'-(3-氯苯基)-1'-(环丙基甲基)-2,6'-二氧代螺[二氢吲哚-3,2'-哌啶-5'-基)乙酸;
2-(5-(3-氯苯基)-6-(5-氯噻吩-2-基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(5-氯噻吩-2-基)-1-(环丙基甲基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-乙氧基-1-氧代丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(1-(1-叔丁氧基-1-氧代丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(环丙基甲氧基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-2-氧代-3-(2-(吡咯烷-1-基)乙基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-3-(2-吗啉代乙基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基甲基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-异丙基-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-环丁基-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-环戊基-3-甲基-2-氧代哌啶-3-基)乙酸;
5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-3-((5-氧代-4,5-二氢-1H-1,2,4-三唑-3-基)甲基)-1-(戊烷-3-基)哌啶-2-酮;
5-((5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)甲基)-1,3,4-噁二唑-2(3H)-酮;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)-N-(三氟甲基磺酰基)乙酰胺;
5-(3-氯苯基)-6-(4-氯苯基)-3-((3-羟基-1H-吡唑-5-基)甲基)-3-甲基-1-(戊烷-3-基)哌啶-2-酮;
5-(3-氯苯基)-6-(4-氯苯基)-3-((3-羟基异噁唑-5-基)甲基)-3-甲基-1-(戊烷-3-基)哌啶-2-酮;
5-((5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)甲基)噁唑烷-2,4-二酮;
3-((5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)甲基)-1,2,4-噁二唑-5(4H)-酮;
3-((5-(3-氯苯基)-6-(4-氯苯基)-1-异丙基-3-甲基-2-氧代哌啶-3-基)甲基)-1,2,4-噁二唑-5(4H)-酮;
3-((5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)甲基)-1,2,4-噻二唑-5(4H)-酮;
3-((5-(3-氯苯基)-6-(4-氯苯基)-1-异丙基-3-甲基-2-氧代哌啶-3-基)甲基)-1,2,4-噻二唑-5(4H)-酮;
3-((1H-四唑-5-基)甲基)-5-(3-氯苯基)-6-(4-氯苯基)-1-异丙基-3-甲基哌啶-2-酮;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-2-氧代-1-(戊烷-3-基)哌啶-3-基)乙酸;
5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-3-(甲基磺酰基甲基)-1-(戊烷-3-基)哌啶-2-酮;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(3-环丙基-1,2,4-噁二唑-5-基)丙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-吗啉代丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1-(2,2,2-三氟乙基氨基)丁烷-2-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(2,2-二甲基吗啉代)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(2,6-二甲基吗啉代)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(4-(环丙基磺酰基)哌嗪-1-基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(4-(甲基磺酰基)哌嗪-1-基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(1-(1-(4-乙酰基哌嗪-1-基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(4-(环丙烷羰基)哌嗪-1-基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
3-((5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-吗啉代丁烷-2-基)-2-氧代哌啶-3-基)甲基)-1,2,4-噁二唑-5(4H)-酮;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(5,5-二甲基-2-氧代噁唑烷-3-基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(1-(1-(叔丁基氨基)-1-氧代丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2,3-二羟基环戊基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1'-(2,2,2-三氟乙基)-1,3'-联哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(3-羟基环戊基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(四氢-2H-吡喃-3-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(吡嗪-2-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-甲基-1H-吡唑-4-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(嘧啶-4-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-氯嘧啶-4-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(嘧啶-2-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(3-甲基吡啶-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(4-甲基吡啶-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(二环丙基甲基)-3-甲基-2-氧代哌啶-3-基)乙酸;
(4-(3-氯苯基)-3-(4-氯苯基)-1,1-二氧化-2-(2-丙基)-1,2-噻嗪烷-6-基)乙酸;
(4-(3-氯苯基)-3-(4-氯苯基)-6-甲基-1,1-二氧化-2-(2-丙基)-1,2-噻嗪烷-6-基)乙酸;
2-(5-(3-氯苯基)-6-(5-氯吡啶-2-基)-3-甲基-1-(1-吗啉代丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(5-氯吡啶-2-基)-3-甲基-2-氧代-1-(戊烷-3-基)哌啶-3-基)乙酸;
2-(1-(1-叔丁氧基-1-氧代丁烷-2-基)-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;或
2-(1-(1-叔丁氧基-1-氧代丁烷-2-基)-6-(4-氯苯基)-5-(4-氯吡啶-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸。
9.一种选自以下的化合物,或其药学上可接受的盐:
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)丙酸;
2-(3-((1H-四唑-5-基)甲基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-1-基)丁酸叔丁酯;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(甲基磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(5-氧代己烷-3-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(5-羟基-5-甲基己烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(6,6,6-三氟代-5-羟基-5-甲基己烷-3-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(N-甲基甲基磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(5-环丙基-6,6,6-三氟代-5-羟基己烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(6-羟基-6-甲基庚烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(6,6,6-三氟代-5,5-二羟基己烷-3-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(7,7,7-三氟代-6-羟基-6-甲基庚烷-3-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(7-羟基-7-甲基辛烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(N-环丙基甲基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(6,6,6-三氟代-5-羟基己烷-3-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(5-羟基己烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1-(N-(2,2,2-三氟乙基)甲基磺酰氨基)丁烷-2-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(5-羟基-4,5-二甲基己烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(5-氰基-5-甲基己烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(2-氧代戊烷-3-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-羟基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-甲氧基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-羟基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-羟基-2-甲基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(4-羟基己烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-甲氧基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1,1,1-三氟代-2-羟基-2-甲基戊烷-3-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酰胺;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-(甲基磺酰基)乙酰胺;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-(3-羟基丙基)乙酰胺;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-(2-羟基乙基)乙酰胺;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-羟基乙酰胺;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-甲氧基乙酰胺;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-(2,3-二羟基丙基)乙酰胺;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-(2,3-二羟基丙基)乙酰胺;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-氰基乙酰胺;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-(2-(二甲基氨基)乙基)乙酰胺;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)-N-(3,4-二羟基丁基)乙酰胺;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(环丙烷磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)丙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-(环丙烷磺酰氨基)戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(2-(1-甲基乙基磺酰氨基)戊烷-3-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(N-甲基环丙烷磺酰氨基)-1-氧代丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(新戊基氨基)-1-氧代丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(4,4-二甲基-4,5-二氢噁唑-2-基)丙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1-(N-(2,2,2-三氟乙基)乙酰氨基)丁烷-2-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(1,1-二甲基乙基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(N,2-二甲基丙烷-2-基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(1-甲基乙基磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(N-乙基丙烷-2-基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-羟基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1-(三氟甲基磺酰氨基)丁烷-2-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(4-氯苯基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(4-甲基苯基磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(2-氯苯基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(2-甲基苯基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(4-甲氧基苯基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(苯基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(1-甲基环丙烷磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(1,1-二氧化苯并[d]异噻唑-2(3H)-基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(3,3-二甲基-1,1-二氧化苯并[d]异噻唑-2(3H)-基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1-(吡啶-3-磺酰氨基)丁烷-2-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(4-氰基苯基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(3-氰基苯基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1-(吡啶-2-磺酰氨基)丁烷-2-基)哌啶-3-基)乙酸
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(N,1-二甲基环丙烷磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
3-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)丙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲氧基-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(6-甲基-4-氧代庚烷-3-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(乙基磺酰基)戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(异丙基磺酰基)戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(环丙基甲基磺酰基)戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1-(2-氧代吡咯烷-1-基)丁烷-2-基)哌啶-3-基)乙酸;
2-(1-(1-(2-氧杂-5-氮杂二环[2.2.1]庚烷-5-基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(3-甲基吗啉代)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(硫代吗啉代-1,1-二氧化物)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(3,3-二氟氮杂环丁烷-1-基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(1-(1-(8-氧杂-3-氮杂二环[3.2.1]辛烷-3-基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(3,3-二甲基吗啉代)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(3-羟基-3-(三氟甲基)氮杂环丁烷-1-基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(甲基(氧杂环丁烷-3-基)氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1-(2-氧代噁唑烷-3-基)丁烷-2-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1-(2-氧代吡啶-1(2H)-基)丁烷-2-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1-(2-氧代-5-(三氟甲基)吡啶-1(2H)-基)丁烷-2-基)哌啶-3-基)乙酸;
3-烯丙基-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(吡啶-3-基氧基)丁烷-2-基)哌啶-2-酮;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1-(四氢呋喃-2-基)丙基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1-(5-氧代四氢呋喃-2-基)丙基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1-(四氢-2H-吡喃-2-基)丙基)哌啶-3-基)乙酸;
2-(1-(1-(苯并[d]噻唑-2-基)丙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(3-甲基异噁唑-5-基)丙基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(6-氯吡啶-2-基)丙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1-(吡啶-2-基)丙基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1-(吡啶-2-基)丁基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-环丙基-1-(吡啶-2-基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1-(吡啶-3-基)丙基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1-(吡嗪-2-基)丙基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1-(嘧啶-2-基)丙基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(6-甲基吡啶-2-基)丙基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1-(吡啶-4-基)丙基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1-(6-(三氟甲基)吡啶-2-基)丙基)哌啶-3-基)乙酸;
2-(1-(1-(6-溴吡啶-2-基)丙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1-(噻唑-2-基)丙基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(6-(2-羟基丙烷-2-基)吡啶-2-基)丙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(6-环丙基吡啶-2-基)丙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(3,3,3-三氟代-1-(吡啶-2-基)丙基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(2-甲基-1-(吡啶-2-基)丙基)-2-氧代哌啶-3-基)乙酸;
3-((1H-四唑-5-基)甲基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(戊烷-3-基)哌啶-2-酮;
5-(3-氯苯基)-6-(4-氯苯基)-3-(2,3-二羟基丙基)-1-(2-羟基戊烷-3-基)-3-甲基哌啶-2-酮;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-羟基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)环丙烷羧酸;
2-(1-(2-(叔丁氧基)-1-环丙基-2-氧代乙基)-5-(3-氯苯基)-6-(4-氯苯基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-乙氧基-2-氧代乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-羟基乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-羟基丁基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(N-甲基环丙烷磺酰氨基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-(环丙烷磺酰氨基)-1-环丙基乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(乙基磺酰氨基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(N-甲基环丙烷磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-羟基丙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(1-甲基乙基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(N-甲基环丙烷磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-羟基-4-甲基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;或
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(环丙基(吡啶-2-基)甲基)-3-甲基-2-氧代哌啶-3-基)乙酸。
10.一种选自以下的化合物,或其药学上可接受的盐:
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2S,3S)-2-羟基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2R,3S)-2-羟基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二甲基乙基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N,2-二甲基丙烷-2-基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N,1-二甲基环丙烷磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-甲基环丙烷磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((1S,2R)-1-环丙基-2-羟基丙基)-3-甲基-2-氧代哌啶-3-基)乙酸;或
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((1S,2S)-1-环丙基-2-羟基丙基)-3-甲基-2-氧代哌啶-3-基)乙酸。
11.一种选自以下的化合物,或其药学上可接受的盐:
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-羟基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-羟基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(1,1-二甲基乙基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(N,2-二甲基丙烷-2-基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(N,1-二甲基环丙烷磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(N-甲基环丙烷磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;或
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-羟基丙基)-3-甲基-2-氧代哌啶-3-基)乙酸。
12.一种选自以下的化合物,或其药学上可接受的盐:
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(噻吩-2-磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-甲基噻吩-2-磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-(5-氯噻吩-2-磺酰氨基)-1-环丙基乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-2-(5-氯代-N-甲基噻吩-2-磺酰氨基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-(二氟甲基)-2-甲基丙烷-2-基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-(二氟甲基)乙基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-(二氟甲基)环丙烷磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
1-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-(环丙烷磺酰氨基)-1-环丙基乙基)-3-甲基-2-氧代哌啶-3-基)环丙烷羧酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-(2-氟苯基)乙基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-(2-氟苯基)甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-苯基环丙烷磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-苯基乙基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(乙基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-(3-氟苯基)乙基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-(N-(2-氰基苯基)甲基磺酰氨基)-1-环丙基乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(丙基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-苯基甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-(N-(3-氰基苯基)甲基磺酰氨基)-1-环丙基乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-(吡啶-3-基)甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-(噻吩-2-基甲基)甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-(3-甲氧基苄基)甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(苯基甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(吡啶-2-基甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(吡啶-3-基甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-(吡啶-2-基)甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-乙基甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-异丙基甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(1-甲基乙基磺酰氨基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-(环丁烷磺酰氨基)-1-环丙基乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-(环戊烷磺酰氨基)-1-环丙基乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-3-甲基-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环丙烷磺酰氨基)-3-甲基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(乙基磺酰氨基)-3-甲基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环丁烷磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N-乙基环丁烷磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(苯基磺酰基)丁烷-2-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(甲基磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-(丙基磺酰基)丁烷-2-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(异丁基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-((环丙基甲基)磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-((环丁基甲基)磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环戊基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(氧杂环丁烷-3-基磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(((3-甲基氧杂环丁烷-3-基)甲基)磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-((S)-1-((四氢-2H-吡喃-4-基)磺酰基)丁烷-2-基)哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-((2-羟基-2-甲基丙基)磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-1-((R)-仲丁基磺酰基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-1-((S)-仲丁基磺酰基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-(环戊基磺酰基)-1-环丙基乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(((3-甲基氧杂环丁烷-3-基)甲基)磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(苯基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(邻甲苯基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-((2-氯苯基)磺酰基)-1-环丙基乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-((4-氯苯基)磺酰基)-1-环丙基乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-((4-氟苯基)磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(吡啶-4-基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-2-((2-氯代-4-氟苯基)磺酰基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-((环丙基甲基)磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-((2,2,2-三氟乙基)磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-((三氟甲基)磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(苯基磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-((2-氯苯基)磺酰基)-1-环丙基乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-((2-氟苯基)磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-((3-氟苯基)磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-((4-氟苯基)磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(丙基磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-2-(丁基磺酰基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(异戊基磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-(环戊基磺酰基)-1-环丙基乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-(环己基磺酰基)-1-环丙基乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(甲基磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-3-甲基-1-((2,2,2-三氟乙基)磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-1-(叔丁基磺酰基)-3-甲基丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-3-甲基-1-(甲基磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(乙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环丙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(异丙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-1-(叔丁基磺酰基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环丁基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-1-((S)-1-(乙基磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-1-((S)-1-(异丙基磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-1-(叔丁基磺酰基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环丁基磺酰基)丁烷-2-基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(环丙基磺酰基)丁烷-2-基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(乙基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(异丙基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-2-(叔丁基磺酰基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-2-(环丁基磺酰基)-1-环丙基乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(环丙基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(甲基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(叔戊基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-((2,4-二氟苯基)磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(乙基磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(异丙基磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-2-(叔丁基磺酰基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(环丙基磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(乙基磺酰基)-3-甲基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-3,3-二甲基-1-(甲基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(乙基磺酰基)-3,3-二甲基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(异丙基磺酰基)-3,3-二甲基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(戊烷-3-基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-((S)-异丙基亚磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-((R)-异丙基亚磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((2S,3S)-2-(甲基磺酰基)戊烷-3-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((2R,3S)-2-(甲基磺酰基)戊烷-3-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2S,3S)-2-(乙基磺酰基)戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2R,3S)-2-(乙基磺酰基)戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-(氧杂环丁烷-3-基)氨磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-((3-甲基氧杂环丁烷-3-基)甲基)氨磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-(氧杂环丁烷-3-基甲基)氨磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-2-(N-(叔丁基)氨磺酰基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-甲基氨磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N,N-二甲基氨磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-异丙基氨磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(吗啉代磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(哌啶-1-基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(吡咯烷-1-基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-2-(氮杂环丁烷-1-基磺酰基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-((N,N-二甲基氨磺酰基)氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-((N,N-二甲基氨磺酰基)(甲基)氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(3-甲基-2,5-二氧代咪唑烷-1-基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(3,4,4-三甲基-2,5-二氧代咪唑烷-1-基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(4,4-二甲基-2,5-二氧代咪唑烷-1-基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(3-异丙基-2,2-二氧化-4-氧代-3,4-二氢-1H-苯并[c][1,2,6]噻二嗪-1-基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-1-基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯代-4-氟苯基)-6-(4-氯苯基)-1-异丙基-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-异丙基-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3S,5R,6S)-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-异丙基-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-((S)-1-(乙基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(N-甲基乙基磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-(甲基磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-((S)-1-(乙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-((S)-1-(环丙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-1-(叔丁基磺酰基)丁烷-2-基)-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-((S)-1-(异丙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-6-(4-氯苯基)-5-(5-氯吡啶-3-基)-1-((S)-1-(环丙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-1-(叔丁基磺酰基)丁烷-2-基)-6-(4-氯苯基)-5-(5-氯吡啶-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-6-(4-氯苯基)-5-(5-氯吡啶-3-基)-1-((S)-1-(环丙烷磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-6-(4-氯苯基)-5-(5-氯吡啶-3-基)-3-甲基-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(5-氯吡啶-2-基)-1-((S)-1-(乙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-((S)-吗啉-2-基)丙基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((S)-1-((R)-吗啉-2-基)丙基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((R)-1-((S)-吗啉-2-基)丙基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((R)-1-((R)-吗啉-2-基)丙基)-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((R)-1-((R)-吗啉-2-基)丙基)-2-氧代哌啶-3-基)乙酸;
或2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-((R)-1-((S)-吗啉-2-基)丙基)-2-氧代哌啶-3-基)乙酸;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-3-(2-吗啉代乙基)-2-氧代哌啶-3-基)乙酸;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-(2-(1,1-二氧化硫代吗啉代)乙基)-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代-3-(2-(吡咯烷-1-基)乙基)哌啶-3-基)乙酸;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-3-(2-(二甲基氨基)乙基)-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-3-(2-吗啉代乙基)-2-氧代哌啶-3-基)乙酰胺;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-3-(2-吗啉代乙基)-2-氧代哌啶-3-基)乙酰胺;
(1R,3S,6S,7R)-7-(3-氯苯基)-6-(4-氯苯基)-5-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-4-氧代-5-氮杂螺[2.5]辛烷-1-羧酸;
(3S,6S,7R)-7-(3-氯苯基)-6-(4-氯苯基)-5-((S)-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-4-氧代-5-氮杂螺[2.5]辛烷-1-羧酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2S,3S)-1,2-二羟基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2R,3S)-1,2-二羟基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2R,3S)-1,2-二羟基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((2S,3S)-1,2-二羟基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((1S,2S)-1-环丙基-1-羟基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((1R,2S)-1-环丙基-1-羟基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-异丙基-6-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-异丙基-6-甲基-2-氧代哌啶-3-基)乙酸;
(3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-((6-甲氧基吡啶-2-基)甲基)哌啶-2-酮;
(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-((6-甲氧基吡啶-2-基)甲基)哌啶-2-酮;
(3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-((6-羟基吡啶-2-基)甲基)哌啶-2-酮;
(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-((6-羟基吡啶-2-基)甲基)哌啶-2-酮;
(3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-((6-甲氧基吡啶-2-基)甲基)-3-甲基哌啶-2-酮;
(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-((6-甲氧基吡啶-2-基)甲基)-3-甲基哌啶-2-酮;
(3S,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-((6-羟基吡啶-2-基)甲基)-3-甲基哌啶-2-酮;
(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-((6-羟基吡啶-2-基)甲基)-3-甲基哌啶-2-酮;
(3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(乙基磺酰基)乙基)-3-(3-羟基-2-氧代丙基)-3-甲基哌啶-2-酮;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(二乙基氨基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-(二甲基氨基)-3-甲基-2-氧代哌啶-3-基)乙酸;或
(2S,3S,5S,6R,7aR,10aS)-6-(3-氯苯基)-5-(4-氯苯基)-3-乙基-2,7a-二甲基六氢呋喃并[2,3-b]噁唑并[3,2-a]吡啶-9(5H)-酮。
13.一种选自以下的化合物,或其药学上可接受的盐:
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(噻吩-2-磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(N-甲基噻吩-2-磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-(5-氯噻吩-2-磺酰氨基)-1-环丙基乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(1-(2-(5-氯代-N-甲基噻吩-2-磺酰氨基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(N-(二氟甲基)-2-甲基丙烷-2-基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(N-(二氟甲基)乙基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(N-(二氟甲基)环丙烷磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
1-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-(环丙烷磺酰氨基)-1-环丙基乙基)-3-甲基-2-氧代哌啶-3-基)环丙烷羧酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(N-(2-氟苯基)乙基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(N-(2-氟苯基)甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(N-苯基环丙烷磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(N-苯基乙基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(乙基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(N-(3-氟苯基)乙基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-(N-(2-氰基苯基)甲基磺酰氨基)-1-环丙基乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(丙基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(N-苯基甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-(N-(3-氰基苯基)甲基磺酰氨基)-1-环丙基乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(N-(吡啶-3-基)甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(N-(噻吩-2-基甲基)甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(N-(3-甲氧基苄基)甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(苯基甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(吡啶-2-基甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(吡啶-3-基甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(N-(吡啶-2-基)甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(N-乙基甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(N-异丙基甲基磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(1-甲基乙基磺酰氨基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-(环丁烷磺酰氨基)-1-环丙基乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-(环戊烷磺酰氨基)-1-环丙基乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(3-甲基-1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(环丙烷磺酰氨基)-3-甲基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(乙基磺酰氨基)-3-甲基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(环丁烷磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(N-乙基环丁烷磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1-(苯基磺酰基)丁烷-2-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(甲基磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1-(丙基磺酰基)丁烷-2-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(异丁基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-((环丙基甲基)磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-((环丁基甲基)磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(环戊基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(氧杂环丁烷-3-基磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(((3-甲基氧杂环丁烷-3-基)甲基)磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代-1-(1-((四氢-2H-吡喃-4-基)磺酰基)丁烷-2-基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-((2-羟基-2-甲基丙基)磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(1-(1-(-仲丁基磺酰基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-(环戊基磺酰基)-1-环丙基乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(((3-甲基氧杂环丁烷-3-基)甲基)磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(苯基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(邻甲苯基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-((2-氯苯基)磺酰基)-1-环丙基乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-((4-氯苯基)磺酰基)-1-环丙基乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-((4-氟苯基)磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(吡啶-4-基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(1-(2-((2-氯代-4-氟苯基)磺酰基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-((环丙基甲基)磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-((2,2,2-三氟乙基)磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-((三氟甲基)磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(苯基磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-((2-氯苯基)磺酰基)-1-环丙基乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-((2-氟苯基)磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-((3-氟苯基)磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-((4-氟苯基)磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(丙基磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-(1-(2-(丁基磺酰基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(异戊基磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-(环戊基磺酰基)-1-环丙基乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-(环己基磺酰基)-1-环丙基乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(甲基磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(3-甲基-1-((2,2,2-三氟乙基)磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(1-(1-(叔丁基磺酰基)-3-甲基丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(3-甲基-1-(甲基磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(乙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(环丙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(异丙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(1-(1-(叔丁基磺酰基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(环丁基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-1-(1-(乙基磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-1-(1-(异丙基磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(1-(1-(叔丁基磺酰基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(环丁基磺酰基)丁烷-2-基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(环丙基磺酰基)丁烷-2-基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(乙基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(异丙基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(1-(2-(叔丁基磺酰基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-(环丁基磺酰基)-1-环丙基乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(环丙基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(甲基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(叔戊基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-((2,4-二氟苯基)磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(乙基磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(异丙基磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-(1-((2-(叔丁基磺酰基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(环丙基磺酰基)乙基)-3-乙基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(乙基磺酰基)-3-甲基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(异丙基磺酰基)-3-甲基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(3,3-二甲基-1-(甲基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(乙基磺酰基)-3,3-二甲基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(异丙基磺酰基)-3,3-二甲基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(戊烷-3-基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(异丙基亚磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(2-(甲基磺酰基)戊烷-3-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(2-(乙基磺酰基)戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(N-(氧杂环丁烷-3-基)氨磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(N-((3-甲基氧杂环丁烷-3-基)甲基)氨磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(N-(氧杂环丁烷-3-基甲基)氨磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(1-(2-(N-(叔丁基)氨磺酰基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(N-甲基氨磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(N,N-二甲基氨磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(N-异丙基氨磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(吗啉代磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(哌啶-1-基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(吡咯烷-1-基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(1-(2-(氮杂环丁烷-1-基磺酰基)-1-环丙基乙基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-((N,N-二甲基氨磺酰基)氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-((N,N-二甲基氨磺酰基)(甲基)氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(3-甲基-2,5-二氧代咪唑烷-1-基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(3,4,4-三甲基-2,5-二氧代咪唑烷-1-基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(4,4-二甲基-2,5-二氧代咪唑烷-1-基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(3-异丙基-2,2-二氧化-4-氧代-3,4-二氢-1H-苯并[c][1,2,6]噻二嗪-1-基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-1-基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯代-4-氟苯基)-6-(4-氯苯基)-1-异丙基-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-异丙基-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-(1-(乙基磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-3-甲基-1-(1-(N-甲基乙基磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-3-甲基-1-(1-(甲基磺酰基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-(1-(乙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-(1-(环丙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(1-(1-(叔丁基磺酰基)丁烷-2-基)-5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯代-5-氟苯基)-6-(4-氯苯基)-1-(1-(异丙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(6-(4-氯苯基)-5-(5-氯吡啶-3-基)-1-(1-(环丙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(1-(1-(叔丁基磺酰基)丁烷-2-基)-6-(4-氯苯基)-5-(5-氯吡啶-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(6-(4-氯苯基)-5-(5-氯吡啶-3-基)-1-(1-(环丙烷磺酰氨基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(6-(4-氯苯基)-5-(5-氯吡啶-3-基)-3-甲基-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(5-氯吡啶-2-基)-1-(1-(乙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-1-(1-(吗啉-2-基)丙基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-3-(2-吗啉代乙基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-(2-(1,1-二氧化硫代吗啉代)乙基)-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代-3-(2-(吡咯烷-1-基)乙基)哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-3-(2-(二甲基氨基)乙基)-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-3-(2-吗啉代乙基)-2-氧代哌啶-3-基)乙酰胺;
7-(3-氯苯基)-6-(4-氯苯基)-5-(1-(N-甲基环丙烷磺酰氨基)丁烷-2-基)-4-氧代-5-氮杂螺[2.5]辛烷-1-羧酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1,2-二羟基戊烷-3-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-1-羟基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-异丙基-6-甲基-2-氧代哌啶-3-基)乙酸;
5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-((6-甲氧基吡啶-2-基)甲基)哌啶-2-酮;
5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-((6-羟基吡啶-2-基)甲基)哌啶-2-酮;
5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-((6-甲氧基吡啶-2-基)甲基)-3-甲基哌啶-2-酮;
5-(3-氯苯基)-6-(4-氯苯基)-1-(1-(1,1-二氧化异噻唑烷-2-基)丁烷-2-基)-3-((6-羟基吡啶-2-基)甲基)-3-甲基哌啶-2-酮;
(5-(3-氯苯基)-6-(4-氯苯基)-1-(1-环丙基-2-(乙基磺酰基)乙基)-3-(3-羟基-2-氧代丙基)-3-甲基哌啶-2-酮;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(二乙基氨基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(5-(3-氯苯基)-6-(4-氯苯基)-1-(二甲基氨基)-3-甲基-2-氧代哌啶-3-基)乙酸;或
6-(3-氯苯基)-5-(4-氯苯基)-3-乙基-2,7a-二甲基六氢呋喃并[2,3-b]噁唑并[3,2-a]吡啶-9(5H)-酮。
14.一种选自以下的化合物,或其药学上可接受的盐:
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(甲基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-1-((S)-1-(叔丁基磺酰基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(异丙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(异丙基磺酰基)-3,3-二甲基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(乙基磺酰基)-3-甲基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(乙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-环丙基-2-(N-苯基环丙烷磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;或
2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-((环丙基甲基)磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸。
15.一种选自以下的化合物,或其药学上可接受的盐:
2-(-5-(3-氯苯基)-6-(4-氯苯基)-1-(-1-环丙基-2-(甲基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(-5-(3-氯苯基)-6-(4-氯苯基)-1-(-1-(异丙基磺酰基)-3-甲基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(-1-(-1-(叔丁基磺酰基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(-5-(3-氯苯基)-6-(4-氯苯基)-1-(-1-(异丙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(-5-(3-氯苯基)-6-(4-氯苯基)-1-(-1-(异丙基磺酰基)-3,3-二甲基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(-5-(3-氯苯基)-6-(4-氯苯基)-1-(-1-(乙基磺酰基)-3-甲基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(-5-(3-氯苯基)-6-(4-氯苯基)-1-(-1-(乙基磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(-5-(3-氯苯基)-6-(4-氯苯基)-1-(-1-环丙基-2-(N-苯基环丙烷磺酰氨基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(-5-(3-氯苯基)-6-(4-氯苯基)-1-(-1-((环丙基甲基)磺酰基)丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸;
2-(-5-(3-氯苯基)-6-(4-氯苯基)-1-(-1-环丙基-2-(甲基磺酰基)乙基)-3-甲基-2-氧代哌啶-3-基)乙酸;或
2-(-1-(-1-(叔丁基磺酰基)丁烷-2-基)-5-(3-氯苯基)-6-(4-氯苯基)-3-甲基-2-氧代哌啶-3-基)乙酸。
16.一种药物组合物,其包含根据权利要求1至15中任一项所述的化合物,或其药学上可接受的盐,以及药学上可接受的赋形剂、稀释剂或载体。
17.权利要求1至15中任一项所述的化合物或其药学上可接受的盐在制备用于治疗需要所述治疗的受试者癌症的药物中的用途。
18.2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(异丙基磺酰基)-3-甲基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸或其药学上可接受的盐在制备用于治疗需要所述治疗的人受试者癌症的药物中的用途。
19.权利要求17和18中任一项的用途,其中所述癌症选自
(a)膀胱癌、乳腺癌、结肠癌、直肠癌、肾癌、肝癌、肺癌、食道癌、胆囊癌、卵巢癌、胰腺癌、胃癌、宫颈癌、甲状腺癌、前列腺癌和皮肤癌;
(b)急性淋巴细胞性白血病、急性成淋巴细胞性白血病、B-细胞淋巴瘤、T-细胞淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、毛细胞淋巴瘤和伯基特淋巴瘤;
(c)急性和慢性骨髓性白血病、骨髓发育不良综合征和前髓细胞白血病;
(d)纤维肉瘤、横纹肌肉瘤、软组织肉瘤和骨肉瘤;
(e)星形细胞瘤、成神经细胞瘤、胶质瘤和神经鞘瘤;
(f)黑素瘤、精原细胞瘤、畸胎瘤、骨肉瘤、着色性干皮病、角化棘皮瘤、甲状腺滤泡状癌、卡波西肉瘤、子宫内膜癌、头部和颈部癌、胶质母细胞瘤、恶性腹水,或造血系统癌症。
20.权利要求17和18中任一项的用途,其中所述癌症是淋巴谱系造血系统肿瘤。
21.权利要求17和18中任一项的用途,其中所述癌症是软组织肉瘤。
22.权利要求17和18中任一项的用途,其中所述癌症是乳腺癌。
23.权利要求17和18中任一项的用途,其中所述癌症是胶质母细胞瘤。
24.权利要求17和18中任一项的用途,其中所述癌症是急性骨髓性白血病。
25.权利要求17和18中任一项的用途,其中所述癌症是黑素瘤。
26.权利要求17和18中任一项的用途,其中所述癌症是骨髓发育不良综合征。
27.权利要求17和18中任一项的用途,其中所述癌症是慢性骨髓性白血病。
28.权利要求17和18中任一项的用途,其中所述癌症是脑肿瘤。
29.权利要求17和18中任一项的用途,其中所述癌症是前髓细胞白血病。
30.权利要求17和18中任一项的用途,其中所述癌症被鉴定为p53野生型。
31.权利要求17和18中任一项的用途,其中所述药物与放射治疗联合使用。
32.权利要求17和18中任一项的用途,其中所述癌症是白血病。
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