CN111295382B - 作为法尼酯x受体调节剂的桥联双环化合物 - Google Patents
作为法尼酯x受体调节剂的桥联双环化合物 Download PDFInfo
- Publication number
- CN111295382B CN111295382B CN201880070852.4A CN201880070852A CN111295382B CN 111295382 B CN111295382 B CN 111295382B CN 201880070852 A CN201880070852 A CN 201880070852A CN 111295382 B CN111295382 B CN 111295382B
- Authority
- CN
- China
- Prior art keywords
- methoxy
- cyclopropyl
- isoxazol
- oct
- bicyclo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- -1 farnesyl ester Chemical class 0.000 title claims abstract description 410
- 125000002619 bicyclic group Chemical group 0.000 title description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 301
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 66
- 150000003839 salts Chemical class 0.000 claims abstract description 55
- 208000035475 disorder Diseases 0.000 claims abstract description 42
- 238000011282 treatment Methods 0.000 claims abstract description 27
- 206010016654 Fibrosis Diseases 0.000 claims abstract description 25
- 230000004761 fibrosis Effects 0.000 claims abstract description 23
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 23
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 17
- 201000011510 cancer Diseases 0.000 claims abstract description 11
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 8
- 230000001575 pathological effect Effects 0.000 claims abstract description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 60
- 125000000217 alkyl group Chemical group 0.000 claims description 54
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 43
- 239000003814 drug Substances 0.000 claims description 40
- 238000006467 substitution reaction Methods 0.000 claims description 35
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 32
- 229910052799 carbon Inorganic materials 0.000 claims description 31
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 25
- 125000004076 pyridyl group Chemical group 0.000 claims description 24
- DMPZJACLHDWUFS-UHFFFAOYSA-N 1,3-benzothiazole-6-carboxylic acid Chemical compound OC(=O)C1=CC=C2N=CSC2=C1 DMPZJACLHDWUFS-UHFFFAOYSA-N 0.000 claims description 22
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 22
- 229910052731 fluorine Inorganic materials 0.000 claims description 21
- 125000003566 oxetanyl group Chemical group 0.000 claims description 20
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 20
- 125000005605 benzo group Chemical group 0.000 claims description 16
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims description 16
- 125000000335 thiazolyl group Chemical group 0.000 claims description 15
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 14
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 13
- 125000002757 morpholinyl group Chemical group 0.000 claims description 13
- 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims description 12
- 239000005711 Benzoic acid Substances 0.000 claims description 12
- 235000010233 benzoic acid Nutrition 0.000 claims description 12
- 239000003937 drug carrier Substances 0.000 claims description 12
- 125000004193 piperazinyl group Chemical group 0.000 claims description 12
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 12
- 125000002393 azetidinyl group Chemical group 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 11
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 claims description 9
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 9
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 9
- 208000033222 Biliary cirrhosis primary Diseases 0.000 claims description 8
- 208000012654 Primary biliary cholangitis Diseases 0.000 claims description 8
- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 claims description 8
- 208000036971 interstitial lung disease 2 Diseases 0.000 claims description 8
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 8
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 claims description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 7
- 125000002971 oxazolyl group Chemical group 0.000 claims description 7
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 7
- 125000002883 imidazolyl group Chemical group 0.000 claims description 6
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 6
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
- 125000001041 indolyl group Chemical group 0.000 claims description 5
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 5
- 208000010157 sclerosing cholangitis Diseases 0.000 claims description 5
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- 206010004664 Biliary fibrosis Diseases 0.000 claims description 4
- 206010023421 Kidney fibrosis Diseases 0.000 claims description 4
- 208000020832 chronic kidney disease Diseases 0.000 claims description 4
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 125000003386 piperidinyl group Chemical group 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
- 125000001425 triazolyl group Chemical group 0.000 claims description 4
- KNOCEIYOPWHYEO-UHFFFAOYSA-N 1-[[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methyl]pyrazole-4-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)CN1N=CC(=C1)C(=O)O KNOCEIYOPWHYEO-UHFFFAOYSA-N 0.000 claims description 3
- HYRHTCHZQGGIKB-UHFFFAOYSA-N 2-[2-[[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]pyridin-4-yl]acetic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC1=NC=CC(=C1)CC(=O)O HYRHTCHZQGGIKB-UHFFFAOYSA-N 0.000 claims description 3
- VDWVQQGOPBOGRE-UHFFFAOYSA-N 2-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]quinazoline-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)C1=NC2=CC=C(C=C2C=N1)C(=O)O VDWVQQGOPBOGRE-UHFFFAOYSA-N 0.000 claims description 3
- BQZVTXZADJYSTG-UHFFFAOYSA-N 2-[5-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]acetic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)C1=NC(=NO1)CC(=O)O BQZVTXZADJYSTG-UHFFFAOYSA-N 0.000 claims description 3
- NAXDZGAMYZVHKL-UHFFFAOYSA-N 2-[5-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]pyridine-4-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)C1=NC(=NO1)C=1C=C(C(=O)O)C=CN=1 NAXDZGAMYZVHKL-UHFFFAOYSA-N 0.000 claims description 3
- FIAVPVDRQOFMTF-MDZDMXLPSA-N 3-[(E)-2-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethenyl]benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)/C=C/C=1C=C(C(=O)O)C=CC=1 FIAVPVDRQOFMTF-MDZDMXLPSA-N 0.000 claims description 3
- TUHGQIBMTUQNRU-UHFFFAOYSA-N 3-[2-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-2-hydroxyethyl]benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)C(CC=1C=C(C(=O)O)C=CC=1)O TUHGQIBMTUQNRU-UHFFFAOYSA-N 0.000 claims description 3
- XUKKVJLGZVCGLP-UHFFFAOYSA-N 3-[2-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)C#CC=1C=C(C(=O)O)C=CC=1 XUKKVJLGZVCGLP-UHFFFAOYSA-N 0.000 claims description 3
- MWOZFTAXBUAODT-UHFFFAOYSA-N 3-[5-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]-2,6-difluorobenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)C1=NC(=NO1)C=1C(=C(C(=O)O)C(=CC=1)F)F MWOZFTAXBUAODT-UHFFFAOYSA-N 0.000 claims description 3
- ZSVDAFBKKBTVNK-UHFFFAOYSA-N 3-[5-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]-2-fluorobenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)C1=NC(=NO1)C=1C(=C(C(=O)O)C=CC=1)F ZSVDAFBKKBTVNK-UHFFFAOYSA-N 0.000 claims description 3
- MCNALCXWQXEAJX-UHFFFAOYSA-N 3-[5-[4-[[5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1)OC(F)(F)F)COC12CCC(CC1)(CC2)C1=NC(=NO1)C=1C=C(C(=O)O)C=CC=1 MCNALCXWQXEAJX-UHFFFAOYSA-N 0.000 claims description 3
- HJHBACFCTKJTOW-UHFFFAOYSA-N 3-[5-[4-[[5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,3,4-thiadiazol-2-yl]benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1)OC(F)(F)F)COC12CCC(CC1)(CC2)C1=NN=C(S1)C=1C=C(C(=O)O)C=CC=1 HJHBACFCTKJTOW-UHFFFAOYSA-N 0.000 claims description 3
- LYUQTVQFXODQEH-UHFFFAOYSA-N 3-[[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-hydroxymethyl]-4-fluorobenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)C(C=1C=C(C(=O)O)C=CC=1F)O LYUQTVQFXODQEH-UHFFFAOYSA-N 0.000 claims description 3
- ZRVBOYFDBQSGOI-UHFFFAOYSA-N 4-[3-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-5-yl]pyridine-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)C1=NOC(=N1)C1=CC(=NC=C1)C(=O)O ZRVBOYFDBQSGOI-UHFFFAOYSA-N 0.000 claims description 3
- CMPUCDNLNFAGBQ-UHFFFAOYSA-N 4-[3-[4-[[5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-5-yl]benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1)C(F)(F)F)COC12CCC(CC1)(CC2)C1=NOC(=N1)C1=CC=C(C(=O)O)C=C1 CMPUCDNLNFAGBQ-UHFFFAOYSA-N 0.000 claims description 3
- AJQUFYGEEBGKRH-UHFFFAOYSA-N 4-[5-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]pyridine-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)C1=NC(=NO1)C1=CC(=NC=C1)C(=O)O AJQUFYGEEBGKRH-UHFFFAOYSA-N 0.000 claims description 3
- AJHHQPYCALNQJL-UHFFFAOYSA-N 4-[5-[4-[[5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1)OC(F)(F)F)COC12CCC(CC1)(CC2)C1=NC(=NO1)C1=CC=C(C(=O)O)C=C1 AJHHQPYCALNQJL-UHFFFAOYSA-N 0.000 claims description 3
- BHBFVDMFPOJDNC-UHFFFAOYSA-N 5-[3-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-5-yl]-2-methylpyrazole-3-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)C1=NOC(=N1)C1=NN(C(=C1)C(=O)O)C BHBFVDMFPOJDNC-UHFFFAOYSA-N 0.000 claims description 3
- LCSVEGBYCMYDKD-UHFFFAOYSA-N 5-[5-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]-2-methoxybenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)C1=NC(=NO1)C=1C=CC(=C(C(=O)O)C=1)OC LCSVEGBYCMYDKD-UHFFFAOYSA-N 0.000 claims description 3
- BXIKWFBTWHVRFY-UHFFFAOYSA-N 5-[5-[4-[[5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]-2-methoxybenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1)OC(F)(F)F)COC12CCC(CC1)(CC2)C1=NC(=NO1)C=1C=CC(=C(C(=O)O)C=1)OC BXIKWFBTWHVRFY-UHFFFAOYSA-N 0.000 claims description 3
- VVYCSMMIVOYHDI-UHFFFAOYSA-N 5-[5-[4-[[5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]pyridine-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1)OC(F)(F)F)COC12CCC(CC1)(CC2)C1=NC(=NO1)C=1C=CC(=NC=1)C(=O)O VVYCSMMIVOYHDI-UHFFFAOYSA-N 0.000 claims description 3
- MRAAWNFQBGUXFU-UHFFFAOYSA-N 5-[5-[4-[[5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]pyridine-3-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1)C(F)(F)F)COC12CCC(CC1)(CC2)C1=NC(=NO1)C=1C=NC=C(C(=O)O)C=1 MRAAWNFQBGUXFU-UHFFFAOYSA-N 0.000 claims description 3
- VISHNRLBZQHURE-UHFFFAOYSA-N 5-cyclopropyl-3-(2,6-dichlorophenyl)-4-[[4-[[3-(2H-tetrazol-5-yl)phenoxy]methyl]-1-bicyclo[2.2.2]octanyl]oxymethyl]-1,2-oxazole Chemical compound N=1NN=NC=1C=1C=C(OCC23CCC(CC2)(CC3)OCC=2C(=NOC=2C2CC2)C2=C(C=CC=C2Cl)Cl)C=CC=1 VISHNRLBZQHURE-UHFFFAOYSA-N 0.000 claims description 3
- QYMHJEPSMXHZIG-ZHACJKMWSA-N 5-cyclopropyl-4-[[4-[(E)-2-[3-(2H-tetrazol-5-yl)phenyl]ethenyl]-1-bicyclo[2.2.2]octanyl]oxymethyl]-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazole Chemical compound N1N=NN=C1C=1C=C(/C=C/C23CCC(CC2)(CC3)OCC=2C(=NOC=2C2CC2)C2=C(C=CC=C2)OC(F)(F)F)C=CC=1 QYMHJEPSMXHZIG-ZHACJKMWSA-N 0.000 claims description 3
- QDCSPAMDZWYZGW-UHFFFAOYSA-N 6-[3-[4-[[5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-5-yl]pyridine-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1)C(F)(F)F)COC12CCC(CC1)(CC2)C1=NOC(=N1)C1=CC=CC(=N1)C(=O)O QDCSPAMDZWYZGW-UHFFFAOYSA-N 0.000 claims description 3
- LXOJWNYSHPQEMU-UHFFFAOYSA-N 6-[5-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]pyridine-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)C1=NC(=NO1)C1=CC=CC(=N1)C(=O)O LXOJWNYSHPQEMU-UHFFFAOYSA-N 0.000 claims description 3
- FCASJJSUWLUYHQ-UHFFFAOYSA-N 6-[5-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]pyridine-3-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)C1=NC(=NO1)C1=NC=C(C(=O)O)C=C1 FCASJJSUWLUYHQ-UHFFFAOYSA-N 0.000 claims description 3
- OVWVWBRVVVSXMN-UHFFFAOYSA-N 6-[[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]quinoline-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC=1C=C2C=CC(=NC2=CC=1)C(=O)O OVWVWBRVVVSXMN-UHFFFAOYSA-N 0.000 claims description 3
- 206010008609 Cholangitis sclerosing Diseases 0.000 claims description 3
- 230000001587 cholestatic effect Effects 0.000 claims description 3
- VZFUCHSFHOYXIS-UHFFFAOYSA-N cycloheptane carboxylic acid Natural products OC(=O)C1CCCCCC1 VZFUCHSFHOYXIS-UHFFFAOYSA-N 0.000 claims description 3
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 201000000742 primary sclerosing cholangitis Diseases 0.000 claims description 3
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 3
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 3
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 2
- 230000002503 metabolic effect Effects 0.000 claims description 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 2
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 2
- ORSZGLLQNYSMNO-UHFFFAOYSA-N 1,3-benzothiazole-7-carboxylic acid Chemical compound OC(=O)C1=CC=CC2=C1SC=N2 ORSZGLLQNYSMNO-UHFFFAOYSA-N 0.000 claims 24
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims 6
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 claims 6
- MSKHYVHBBFEAMY-BQYQJAHWSA-N 2-[4-[(E)-2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethenyl]phenyl]acetic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)/C=C/C1=CC=C(C=C1)CC(=O)O MSKHYVHBBFEAMY-BQYQJAHWSA-N 0.000 claims 4
- VXXJEQJGJCXXES-UHFFFAOYSA-N 3-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]-2-methoxybenzoic acid Chemical compound COC1=C(C=CC=C1C(O)=O)C#CC12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 VXXJEQJGJCXXES-UHFFFAOYSA-N 0.000 claims 4
- PVGLYQXOHNMBFM-UHFFFAOYSA-N 3-[5-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]-2-methoxybenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)C1=NC(=NO1)C=1C(=C(C(=O)O)C=CC=1)OC PVGLYQXOHNMBFM-UHFFFAOYSA-N 0.000 claims 4
- FVHPLBPMZJNGCZ-UHFFFAOYSA-N 3-[[4-[2-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]ethenyl]bicyclo[2.2.2]octane-1-carbonyl]amino]benzoic acid Chemical compound OC(=O)C1=CC=CC(NC(=O)C23CCC(CC2)(CC3)C=CC2=C(ON=C2C2=C(Cl)C=CC=C2Cl)C2CC2)=C1 FVHPLBPMZJNGCZ-UHFFFAOYSA-N 0.000 claims 4
- QNCUSMLZWUPDEV-UHFFFAOYSA-N 4-[5-[4-[2-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]ethenyl]-1-bicyclo[2.2.1]heptanyl]-1,2,4-oxadiazol-3-yl]benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)C=CC12CCC(CC1)(C2)C1=NC(=NO1)C1=CC=C(C(=O)O)C=C1 QNCUSMLZWUPDEV-UHFFFAOYSA-N 0.000 claims 4
- OEFRRNDOWOKWSE-UHFFFAOYSA-N 4-[5-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]-6-cyclopropyloxypyridine-2-carboxylic acid Chemical compound C1(CC1)OC1=CC(=CC(=N1)C(=O)O)C1=NOC(=N1)C12CCC(CC1)(CC2)OCC=1C(=NOC=1C1CC1)C1=C(C=NC=C1Cl)Cl OEFRRNDOWOKWSE-UHFFFAOYSA-N 0.000 claims 4
- YCAPXSMYWUQRGA-UHFFFAOYSA-N 4-[5-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]-6-methoxypyridine-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)C1=NC(=NO1)C1=CC(=NC(=C1)OC)C(=O)O YCAPXSMYWUQRGA-UHFFFAOYSA-N 0.000 claims 4
- OMMFZYRVNFAUHZ-UHFFFAOYSA-N 7-[[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-2-carboxylic acid Chemical compound OC(=O)C1=CN2CCN(CC34CCC(CC3)(CC4)OCC3=C(ON=C3C3=C(Cl)C=CC=C3Cl)C3CC3)CC2=N1 OMMFZYRVNFAUHZ-UHFFFAOYSA-N 0.000 claims 4
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims 4
- FRNTUFQKHQMLSE-UHFFFAOYSA-N 1,3-benzoxazole-6-carboxylic acid Chemical compound OC(=O)C1=CC=C2N=COC2=C1 FRNTUFQKHQMLSE-UHFFFAOYSA-N 0.000 claims 2
- NDMFETHQFUOIQX-UHFFFAOYSA-N 1-(3-chloropropyl)imidazolidin-2-one Chemical compound ClCCCN1CCNC1=O NDMFETHQFUOIQX-UHFFFAOYSA-N 0.000 claims 2
- YNUYDKHIIIRLKZ-UHFFFAOYSA-N 1-(azetidin-1-yl)-7-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]isoquinoline-3-carboxylic acid Chemical compound OC(=O)C1=CC2=C(C=C(C=C2)C#CC23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)C(=N1)N1CCC1 YNUYDKHIIIRLKZ-UHFFFAOYSA-N 0.000 claims 2
- UASJWEHTQXRDCF-UHFFFAOYSA-N 1-(cyclopropylamino)-7-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]isoquinoline-3-carboxylic acid Chemical compound OC(=O)C1=CC2=C(C=C(C=C2)C#CC23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)C(NC2CC2)=N1 UASJWEHTQXRDCF-UHFFFAOYSA-N 0.000 claims 2
- MIKSITSFBHXCLH-UHFFFAOYSA-N 1-[3-[[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-hydroxymethyl]phenyl]cyclopropane-1-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)C(C=1C=C(C=CC=1)C1(CC1)C(=O)O)O MIKSITSFBHXCLH-UHFFFAOYSA-N 0.000 claims 2
- OAYASYFORALBMA-UHFFFAOYSA-N 1-[5-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]cyclopropane-1-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)C1=NC(=NO1)C1(CC1)C(=O)O OAYASYFORALBMA-UHFFFAOYSA-N 0.000 claims 2
- DLKATGBZWZVTLK-UHFFFAOYSA-N 1-anilino-7-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]isoquinoline-3-carboxylic acid Chemical compound OC(=O)C1=CC2=C(C=C(C=C2)C#CC23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)C(NC2=CC=CC=C2)=N1 DLKATGBZWZVTLK-UHFFFAOYSA-N 0.000 claims 2
- COKATMFAAIHOFX-CMDGGOBGSA-N 1-cyclobutyloxy-7-[(E)-2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethenyl]isoquinoline-3-carboxylic acid Chemical compound OC(=O)C1=CC2=C(C=C(\C=C\C34CCC(CC3)(CC4)OCC3=C(ON=C3C3=C(Cl)C=NC=C3Cl)C3CC3)C=C2)C(OC2CCC2)=N1 COKATMFAAIHOFX-CMDGGOBGSA-N 0.000 claims 2
- QVJYKNGWBFDKHY-MDZDMXLPSA-N 1-cyclopentyloxy-7-[(E)-2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethenyl]isoquinoline-3-carboxylic acid Chemical compound OC(=O)C1=CC2=C(C=C(\C=C\C34CCC(CC3)(CC4)OCC3=C(ON=C3C3=C(Cl)C=NC=C3Cl)C3CC3)C=C2)C(OC2CCCC2)=N1 QVJYKNGWBFDKHY-MDZDMXLPSA-N 0.000 claims 2
- MBGAXGKHADNKCF-UHFFFAOYSA-N 1-cyclopropyl-5-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]pyrazole-3-carboxylic acid Chemical compound OC(=O)C1=NN(C2CC2)C(OCC23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)=C1 MBGAXGKHADNKCF-UHFFFAOYSA-N 0.000 claims 2
- VZFHILQNKSNOBP-UHFFFAOYSA-N 2-[1-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]bicyclo[2.2.2]octane-1-carbonyl]piperidin-4-yl]acetic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)C(=O)N1CCC(CC1)CC(=O)O VZFHILQNKSNOBP-UHFFFAOYSA-N 0.000 claims 2
- NSSYCGXGDFDAML-UHFFFAOYSA-N 2-[2-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]pyridine-4-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)C#CC=1C=C(C(=O)O)C=CN=1 NSSYCGXGDFDAML-UHFFFAOYSA-N 0.000 claims 2
- XXCHIJLFLLIORN-UHFFFAOYSA-N 2-[2-[[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]phenyl]acetic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC1=C(C=CC=C1)CC(=O)O XXCHIJLFLLIORN-UHFFFAOYSA-N 0.000 claims 2
- GMOMKEOJVFSVDE-UHFFFAOYSA-N 2-[2-[[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methylamino]-4-methyl-1,3-thiazol-5-yl]acetic acid Chemical compound Cc1nc(NCC23CCC(CC2)(CC3)OCc2c(onc2-c2c(Cl)cccc2Cl)C2CC2)sc1CC(O)=O GMOMKEOJVFSVDE-UHFFFAOYSA-N 0.000 claims 2
- OYYYXAPLNZADQI-VOTSOKGWSA-N 2-[3-[(E)-2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethenyl]phenyl]acetic acid Chemical compound OC(=O)CC1=CC=CC(\C=C\C23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)=C1 OYYYXAPLNZADQI-VOTSOKGWSA-N 0.000 claims 2
- FGCVFKBIRAIUQW-UHFFFAOYSA-N 2-[3-[[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]phenyl]acetic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC=1C=C(C=CC=1)CC(=O)O FGCVFKBIRAIUQW-UHFFFAOYSA-N 0.000 claims 2
- GASIPMLUHJGRDS-UHFFFAOYSA-N 2-[3-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-5-ethylpyrazol-1-yl]acetic acid Chemical compound CCC1=CC(OCC23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)=NN1CC(O)=O GASIPMLUHJGRDS-UHFFFAOYSA-N 0.000 claims 2
- LPZUOUFFLBGESV-UHFFFAOYSA-N 2-[3-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methylamino]pyrazol-1-yl]acetic acid Chemical compound OC(=O)Cn1ccc(NCC23CCC(CC2)(CC3)OCc2c(onc2-c2c(Cl)cncc2Cl)C2CC2)n1 LPZUOUFFLBGESV-UHFFFAOYSA-N 0.000 claims 2
- KXMVLIDXEPLILP-AATRIKPKSA-N 2-[4-[(E)-2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethenyl]-2-fluorophenyl]acetic acid Chemical compound OC(=O)CC1=CC=C(\C=C\C23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)C=C1F KXMVLIDXEPLILP-AATRIKPKSA-N 0.000 claims 2
- TWLKAAFQTSOUNU-AATRIKPKSA-N 2-[4-[(E)-2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethenyl]-3-(trifluoromethyl)phenyl]acetic acid Chemical compound OC(=O)Cc1ccc(\C=C\C23CCC(CC2)(CC3)OCc2c(onc2-c2c(Cl)cncc2Cl)C2CC2)c(c1)C(F)(F)F TWLKAAFQTSOUNU-AATRIKPKSA-N 0.000 claims 2
- MZKGPWOMKIOYOR-AATRIKPKSA-N 2-[4-[(E)-2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethenyl]-3-fluorophenoxy]acetic acid Chemical compound OC(=O)COC1=CC(F)=C(\C=C\C23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)C=C1 MZKGPWOMKIOYOR-AATRIKPKSA-N 0.000 claims 2
- MJQZKZWQWOSOOH-AATRIKPKSA-N 2-[4-[(E)-2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethenyl]-3-fluorophenyl]acetic acid Chemical compound OC(=O)CC1=CC(F)=C(\C=C\C23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)C=C1 MJQZKZWQWOSOOH-AATRIKPKSA-N 0.000 claims 2
- JMHHCBCASLRABU-BQYQJAHWSA-N 2-[4-[(E)-2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethenyl]phenyl]-1,3-thiazole-4-carboxylic acid Chemical compound OC(=O)C1=CSC(=N1)C1=CC=C(\C=C\C23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)C=C1 JMHHCBCASLRABU-BQYQJAHWSA-N 0.000 claims 2
- PIYJSXJPHLJSDL-MDZDMXLPSA-N 2-[4-[(E)-2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethenyl]phenyl]-N,N-dimethylacetamide Chemical compound CN(C)C(=O)CC1=CC=C(\C=C\C23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)C=C1 PIYJSXJPHLJSDL-MDZDMXLPSA-N 0.000 claims 2
- XFLKGOONVOYBFA-HWKANZROSA-N 2-[4-[(E)-2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethenyl]pyridin-2-yl]oxyacetic acid Chemical compound OC(=O)COC1=NC=CC(\C=C\C23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)=C1 XFLKGOONVOYBFA-HWKANZROSA-N 0.000 claims 2
- PTJCDGHSTQTFSN-ONEGZZNKSA-N 2-[4-[(E)-2-[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]ethenyl]-1-bicyclo[2.2.2]octanyl]-1,3-thiazole-4-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)/C=C/C12CCC(CC1)(CC2)C=1SC=C(N=1)C(=O)O PTJCDGHSTQTFSN-ONEGZZNKSA-N 0.000 claims 2
- JQQWRDCKPWBLAV-SNAWJCMRSA-N 2-[4-[(E)-2-[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]ethenyl]-1-bicyclo[2.2.2]octanyl]-4-methyl-1,3-thiazole-5-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)/C=C/C12CCC(CC1)(CC2)C=1SC(=C(N=1)C)C(=O)O JQQWRDCKPWBLAV-SNAWJCMRSA-N 0.000 claims 2
- AFIOBOUXPNRWNF-UHFFFAOYSA-N 2-[4-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]-2-fluorophenyl]acetic acid Chemical compound OC(=O)CC1=CC=C(C=C1F)C#CC12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 AFIOBOUXPNRWNF-UHFFFAOYSA-N 0.000 claims 2
- SIGZLXFDGVPTJK-UHFFFAOYSA-N 2-[4-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]-3-(trifluoromethyl)phenyl]acetic acid Chemical compound OC(=O)Cc1ccc(C#CC23CCC(CC2)(CC3)OCc2c(onc2-c2c(Cl)cncc2Cl)C2CC2)c(c1)C(F)(F)F SIGZLXFDGVPTJK-UHFFFAOYSA-N 0.000 claims 2
- KZXVHNOKQURXGC-UHFFFAOYSA-N 2-[4-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]-3-fluorophenoxy]acetic acid Chemical compound OC(=O)COC1=CC=C(C#CC23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)C(F)=C1 KZXVHNOKQURXGC-UHFFFAOYSA-N 0.000 claims 2
- IVTUQNIKNGOFTD-UHFFFAOYSA-N 2-[4-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]pyridin-2-yl]oxyacetic acid Chemical compound OC(=O)COC1=NC=CC(=C1)C#CC12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 IVTUQNIKNGOFTD-UHFFFAOYSA-N 0.000 claims 2
- LIEOVZYAUKNHAY-ZHACJKMWSA-N 2-[4-[4-[(E)-2-[3-(3-chloro-5-methoxypyridin-4-yl)-5-cyclopropyl-1,2-oxazol-4-yl]ethenyl]-2-oxabicyclo[2.2.2]octan-1-yl]phenyl]-2-methylpropanoic acid Chemical compound ClC=1C=NC=C(C=1C1=NOC(=C1/C=C/C12COC(CC1)(CC2)C1=CC=C(C=C1)C(C(=O)O)(C)C)C1CC1)OC LIEOVZYAUKNHAY-ZHACJKMWSA-N 0.000 claims 2
- CPKXHKXPTHGMTF-MDZDMXLPSA-N 2-[4-[4-[(E)-2-[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]ethenyl]-2-oxabicyclo[2.2.2]octan-1-yl]phenyl]-2-methylpropanamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)/C=C/C12COC(CC1)(CC2)C1=CC=C(C=C1)C(C(=O)N)(C)C CPKXHKXPTHGMTF-MDZDMXLPSA-N 0.000 claims 2
- BBRVOIKJMGPGMD-MDZDMXLPSA-N 2-[4-[4-[(E)-2-[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]ethenyl]-2-oxabicyclo[2.2.2]octan-1-yl]phenyl]-2-methylpropanenitrile Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)/C=C/C12COC(CC1)(CC2)C1=CC=C(C=C1)C(C#N)(C)C BBRVOIKJMGPGMD-MDZDMXLPSA-N 0.000 claims 2
- FIAJPGJMSLFDKL-MDZDMXLPSA-N 2-[4-[4-[(E)-2-[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]ethenyl]-2-oxabicyclo[2.2.2]octan-1-yl]phenyl]-2-methylpropanoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)/C=C/C12COC(CC1)(CC2)C1=CC=C(C=C1)C(C(=O)O)(C)C FIAJPGJMSLFDKL-MDZDMXLPSA-N 0.000 claims 2
- IRHZURAXYGPNPQ-BUHFOSPRSA-N 2-[4-[4-[(E)-2-[5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl]ethenyl]-2-oxabicyclo[2.2.2]octan-1-yl]phenyl]-2-methylpropanamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1)C(F)(F)F)/C=C/C12COC(CC1)(CC2)C1=CC=C(C=C1)C(C(=O)N)(C)C IRHZURAXYGPNPQ-BUHFOSPRSA-N 0.000 claims 2
- YSZGMJHOCCDXMA-BUHFOSPRSA-N 2-[4-[4-[(E)-2-[5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl]ethenyl]-2-oxabicyclo[2.2.2]octan-1-yl]phenyl]-2-methylpropanenitrile Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1)C(F)(F)F)/C=C/C12COC(CC1)(CC2)C1=CC=C(C=C1)C(C#N)(C)C YSZGMJHOCCDXMA-BUHFOSPRSA-N 0.000 claims 2
- LTXMRHLVRKYATJ-BUHFOSPRSA-N 2-[4-[4-[(E)-2-[5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl]ethenyl]-2-oxabicyclo[2.2.2]octan-1-yl]phenyl]-2-methylpropanoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1)C(F)(F)F)/C=C/C12COC(CC1)(CC2)C1=CC=C(C=C1)C(C(=O)O)(C)C LTXMRHLVRKYATJ-BUHFOSPRSA-N 0.000 claims 2
- SJQJDPIBWCASQW-UHFFFAOYSA-N 2-[4-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]phenoxy]propanoic acid Chemical compound CC(OC1=CC=C(OCC23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)C=C1)C(O)=O SJQJDPIBWCASQW-UHFFFAOYSA-N 0.000 claims 2
- FNMVSJWDWYCICG-UHFFFAOYSA-N 2-[4-[[5-cyclopropyl-3-(2,2-difluoro-1-methylcyclopropyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]quinoline-5-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1(C(C1)(F)F)C)COC12CCC(CC1)(CC2)C1=NC=2C=CC=C(C=2C=C1)C(=O)O FNMVSJWDWYCICG-UHFFFAOYSA-N 0.000 claims 2
- CFLWZKKOSLLPFS-UHFFFAOYSA-N 2-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]pyridine-4-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)C=1C=C(C(=O)O)C=CN=1 CFLWZKKOSLLPFS-UHFFFAOYSA-N 0.000 claims 2
- WGPXBGGTZUUQQC-UHFFFAOYSA-N 2-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]quinoline-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)C1=NC2=CC=C(C=C2C=C1)C(=O)O WGPXBGGTZUUQQC-UHFFFAOYSA-N 0.000 claims 2
- GXWUJQPIBXQGMQ-UHFFFAOYSA-N 2-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]bicyclo[2.2.2]octane-1-carbonyl]-3,4-dihydro-1H-isoquinoline-5-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)C(=O)N1CC=2C=CC=C(C=2CC1)C(=O)O GXWUJQPIBXQGMQ-UHFFFAOYSA-N 0.000 claims 2
- WLLQLLQIMFKEHZ-UHFFFAOYSA-N 2-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]bicyclo[2.2.2]octane-1-carbonyl]-3,4-dihydro-1H-isoquinoline-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)C(=O)N1CC2=CC=C(C=C2CC1)C(=O)O WLLQLLQIMFKEHZ-UHFFFAOYSA-N 0.000 claims 2
- ZBRXAPRGIYZWBP-UHFFFAOYSA-N 2-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]bicyclo[2.2.2]octane-1-carbonyl]-3,4-dihydro-1H-isoquinoline-8-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)C(=O)N1CC2=C(C=CC=C2CC1)C(=O)O ZBRXAPRGIYZWBP-UHFFFAOYSA-N 0.000 claims 2
- SGUJKFFAWLLIGZ-UHFFFAOYSA-N 2-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxymethyl]-1-bicyclo[2.2.2]octanyl]-1,3-oxazole-4-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COCC12CCC(CC1)(CC2)C=1OC=C(N=1)C(=O)O SGUJKFFAWLLIGZ-UHFFFAOYSA-N 0.000 claims 2
- PNYIICMNDMXEGB-UHFFFAOYSA-N 2-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxymethyl]-1-bicyclo[2.2.2]octanyl]-1,3-thiazole-4-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COCC12CCC(CC1)(CC2)C=1SC=C(N=1)C(=O)O PNYIICMNDMXEGB-UHFFFAOYSA-N 0.000 claims 2
- CYCLZAVSVDDBDM-UHFFFAOYSA-N 2-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxymethyl]-1-bicyclo[2.2.2]octanyl]-4-methyl-1,3-thiazole-5-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COCC12CCC(CC1)(CC2)C=1SC(=C(N=1)C)C(=O)O CYCLZAVSVDDBDM-UHFFFAOYSA-N 0.000 claims 2
- YXVSTHAINMSHLT-UHFFFAOYSA-N 2-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxymethyl]-2-oxabicyclo[2.2.2]octan-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound OC(=O)C1=CSC(=N1)C12CCC(COCC3=C(ON=C3C3=C(Cl)C=CC=C3Cl)C3CC3)(CC1)CO2 YXVSTHAINMSHLT-UHFFFAOYSA-N 0.000 claims 2
- BGRBSSFDFYXYPH-UHFFFAOYSA-N 2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-5-(trifluoromethyl)quinoline-7-carboxylic acid Chemical compound OC(=O)C1=CC2=C(C=CC(=N2)C23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)C(=C1)C(F)(F)F BGRBSSFDFYXYPH-UHFFFAOYSA-N 0.000 claims 2
- VZLGSTKSUYAQNZ-UHFFFAOYSA-N 2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-6-methoxyquinoline-5-carboxylic acid Chemical compound COC1=C(C(O)=O)C2=C(C=C1)N=C(C=C2)C12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 VZLGSTKSUYAQNZ-UHFFFAOYSA-N 0.000 claims 2
- WZDQHEVIWLCSLF-UHFFFAOYSA-N 2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-7-(trifluoromethyl)quinoline-5-carboxylic acid Chemical compound OC(=O)C1=CC(=CC2=C1C=CC(=N2)C12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1)C(F)(F)F WZDQHEVIWLCSLF-UHFFFAOYSA-N 0.000 claims 2
- FKBKIWNUCUBWAN-UHFFFAOYSA-N 2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-8-(2-hydroxy-2-methylpropoxy)quinoline-5-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)C1=NC=2C(=CC=C(C=2C=C1)C(=O)O)OCC(C)(C)O FKBKIWNUCUBWAN-UHFFFAOYSA-N 0.000 claims 2
- KUDDWIOSXRMZPP-UHFFFAOYSA-N 2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-8-(3-methoxypropoxy)quinoline-6-carboxylic acid Chemical compound COCCCOC1=CC(=CC2=C1N=C(C=C2)C12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1)C(O)=O KUDDWIOSXRMZPP-UHFFFAOYSA-N 0.000 claims 2
- ISQFLTCJDFBHHA-UHFFFAOYSA-N 2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-8-(4-methylpiperazin-1-yl)quinoline-5-carboxylic acid Chemical compound CN1CCN(CC1)C1=CC=C(C(O)=O)C2=CC=C(N=C12)C12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 ISQFLTCJDFBHHA-UHFFFAOYSA-N 0.000 claims 2
- YULOLRRJARARHD-UHFFFAOYSA-N 2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-8-(cyclopropylmethoxy)quinoline-5-carboxylic acid Chemical compound OC(=O)C1=CC=C(OCC2CC2)C2=NC(=CC=C12)C12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 YULOLRRJARARHD-UHFFFAOYSA-N 0.000 claims 2
- MTNUKQZXOCAOIR-UHFFFAOYSA-N 2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-8-(oxan-4-yloxy)quinoline-5-carboxylic acid Chemical compound OC(=O)C1=CC=C(OC2CCOCC2)C2=NC(=CC=C12)C12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 MTNUKQZXOCAOIR-UHFFFAOYSA-N 0.000 claims 2
- AXJWXWHTELKSOZ-UHFFFAOYSA-N 2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-8-(oxetan-3-yloxy)quinoline-5-carboxylic acid Chemical compound OC(=O)C1=CC=C(OC2COC2)C2=NC(=CC=C12)C12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 AXJWXWHTELKSOZ-UHFFFAOYSA-N 0.000 claims 2
- FHBSBBXQLLGBBP-UHFFFAOYSA-N 2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-8-(oxetan-3-yloxy)quinoline-6-carboxylic acid Chemical compound OC(=O)C1=CC2=C(N=C(C=C2)C23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)C(OC2COC2)=C1 FHBSBBXQLLGBBP-UHFFFAOYSA-N 0.000 claims 2
- MEPPIPGTOKSMRR-UHFFFAOYSA-N 2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-8-(oxolan-3-yloxy)quinoline-6-carboxylic acid Chemical compound OC(=O)C1=CC2=C(N=C(C=C2)C23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)C(OC2CCOC2)=C1 MEPPIPGTOKSMRR-UHFFFAOYSA-N 0.000 claims 2
- OIRVTLYUXMHOIV-UHFFFAOYSA-N 2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-8-(trifluoromethyl)quinoline-5-carboxylic acid Chemical compound OC(=O)C1=CC=C(C2=NC(=CC=C12)C12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1)C(F)(F)F OIRVTLYUXMHOIV-UHFFFAOYSA-N 0.000 claims 2
- PGZFNBBQFNMPQR-UHFFFAOYSA-N 2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-8-(trifluoromethyl)quinoline-6-carboxylic acid Chemical compound OC(=O)C1=CC2=CC=C(N=C2C(=C1)C(F)(F)F)C12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 PGZFNBBQFNMPQR-UHFFFAOYSA-N 0.000 claims 2
- WPYWIOPLTFLQGN-UHFFFAOYSA-N 2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-8-fluoroquinoline-6-carboxylic acid Chemical compound OC(=O)C1=CC2=CC=C(N=C2C(F)=C1)C12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 WPYWIOPLTFLQGN-UHFFFAOYSA-N 0.000 claims 2
- SIRVQDTVVSUCLG-UHFFFAOYSA-N 2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-8-hydroxyquinoline-5-carboxylic acid Chemical compound OC(=O)C1=CC=C(O)C2=NC(=CC=C12)C12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 SIRVQDTVVSUCLG-UHFFFAOYSA-N 0.000 claims 2
- OXVJUKFVDFFXMA-UHFFFAOYSA-N 2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-8-methoxyquinoline-5-carboxylic acid Chemical compound COC1=CC=C(C(O)=O)C2=CC=C(N=C12)C12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 OXVJUKFVDFFXMA-UHFFFAOYSA-N 0.000 claims 2
- OOMFPJKYLUBFCO-UHFFFAOYSA-N 2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-8-methylquinoline-5-carboxylic acid Chemical compound CC1=CC=C(C(O)=O)C2=CC=C(N=C12)C12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 OOMFPJKYLUBFCO-UHFFFAOYSA-N 0.000 claims 2
- FLZAXVLXEIAVEY-UHFFFAOYSA-N 2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-8-morpholin-4-ylquinoline-5-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)C1=NC=2C(=CC=C(C=2C=C1)C(=O)O)N1CCOCC1 FLZAXVLXEIAVEY-UHFFFAOYSA-N 0.000 claims 2
- GQZQHOANKCWOCK-UHFFFAOYSA-N 2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-8-morpholin-4-ylquinoline-6-carboxylic acid Chemical compound OC(=O)C1=CC2=C(N=C(C=C2)C23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)C(=C1)N1CCOCC1 GQZQHOANKCWOCK-UHFFFAOYSA-N 0.000 claims 2
- PMEZLPBEMUVZTI-UHFFFAOYSA-N 2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-8-propan-2-yloxyquinoline-5-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)C1=NC=2C(=CC=C(C=2C=C1)C(=O)O)OC(C)C PMEZLPBEMUVZTI-UHFFFAOYSA-N 0.000 claims 2
- WAMGLBALJXEOHI-UHFFFAOYSA-N 2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-8-pyrrolidin-1-ylquinoline-5-carboxylic acid Chemical compound OC(=O)C1=CC=C(N2CCCC2)C2=NC(=CC=C12)C12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 WAMGLBALJXEOHI-UHFFFAOYSA-N 0.000 claims 2
- UDSKFKJXXCUHST-UHFFFAOYSA-N 2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]quinoline-5-carboxylic acid Chemical compound OC(=O)C1=CC=CC2=NC(=CC=C12)C12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 UDSKFKJXXCUHST-UHFFFAOYSA-N 0.000 claims 2
- QMYDZSITTJBTTH-UHFFFAOYSA-N 2-[4-[[5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]quinazoline-6-carboxylic acid Chemical compound OC(=O)C1=CC2=C(C=C1)N=C(N=C2)C12CCC(CC1)(CC2)OCC1=C(ON=C1C1=CC=CC=C1OC(F)(F)F)C1CC1 QMYDZSITTJBTTH-UHFFFAOYSA-N 0.000 claims 2
- ZNYYFNOKZWCJII-UHFFFAOYSA-N 2-[4-[[5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl]methoxymethyl]-2-oxabicyclo[2.2.2]octan-1-yl]-1,3-thiazole-4-carboxylic acid Chemical compound OC(=O)C1=CSC(=N1)C12CCC(COCC3=C(ON=C3C3=C(OC(F)(F)F)C=CC=C3)C3CC3)(CC1)CO2 ZNYYFNOKZWCJII-UHFFFAOYSA-N 0.000 claims 2
- CLJMUWUBOGWZGS-AATRIKPKSA-N 2-[5-[(E)-2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethenyl]pyridin-2-yl]acetic acid Chemical compound OC(=O)CC1=CC=C(\C=C\C23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)C=N1 CLJMUWUBOGWZGS-AATRIKPKSA-N 0.000 claims 2
- DLRBUARSOFLKGN-AATRIKPKSA-N 2-[5-[(E)-2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethenyl]pyridin-2-yl]oxyacetic acid Chemical compound OC(=O)COC1=CC=C(\C=C\C23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)C=N1 DLRBUARSOFLKGN-AATRIKPKSA-N 0.000 claims 2
- QVGDSDQMNKCFLT-UHFFFAOYSA-N 2-[5-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]cyclopropane-1-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)C1=NC(=NO1)C1C(C1)C(=O)O QVGDSDQMNKCFLT-UHFFFAOYSA-N 0.000 claims 2
- MTBVJYHELGSHOV-UHFFFAOYSA-N 2-[5-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]cyclopropane-1-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)C1=NC(=NO1)C1C(C1)C(=O)O MTBVJYHELGSHOV-UHFFFAOYSA-N 0.000 claims 2
- ALUZIFDFSMWCNQ-BQYQJAHWSA-N 2-[[4-[(E)-2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethenyl]phenyl]methoxy]acetic acid Chemical compound OC(=O)COCC1=CC=C(\C=C\C23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)C=C1 ALUZIFDFSMWCNQ-BQYQJAHWSA-N 0.000 claims 2
- NZNFNUOIGFQZFF-UHFFFAOYSA-N 2-[[4-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]phenyl]methoxy]acetic acid Chemical compound OC(=O)COCC1=CC=C(C=C1)C#CC12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 NZNFNUOIGFQZFF-UHFFFAOYSA-N 0.000 claims 2
- APCNPQASXSVHHU-UHFFFAOYSA-N 2-[[4-[[3-(3-chloro-5-methoxypyridin-4-yl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-4-methoxyquinoline-6-carboxylic acid Chemical compound ClC=1C=NC=C(C=1C1=NOC(=C1COC12CCC(CC1)(CC2)COC1=NC2=CC=C(C=C2C(=C1)OC)C(=O)O)C1CC1)OC APCNPQASXSVHHU-UHFFFAOYSA-N 0.000 claims 2
- BIBKQUNGQCLUJX-UHFFFAOYSA-N 2-[[4-[[3-(3-chloro-5-methoxypyridin-4-yl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-8-cyclopropylquinoline-6-carboxylic acid Chemical compound ClC=1C=NC=C(C=1C1=NOC(=C1COC12CCC(CC1)(CC2)COC1=NC2=C(C=C(C=C2C=C1)C(=O)O)C1CC1)C1CC1)OC BIBKQUNGQCLUJX-UHFFFAOYSA-N 0.000 claims 2
- XZPJFFTVOYYYDS-UHFFFAOYSA-N 2-[[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]pyridine-4-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC=1C=C(C(=O)O)C=CN=1 XZPJFFTVOYYYDS-UHFFFAOYSA-N 0.000 claims 2
- AKARZHRKWSJNCE-UHFFFAOYSA-N 2-[[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]pyrimidine-4-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC1=NC=CC(=N1)C(=O)O AKARZHRKWSJNCE-UHFFFAOYSA-N 0.000 claims 2
- LQWJTXSONPLUMD-UHFFFAOYSA-N 2-[[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methyl]-3,4-dihydro-1H-isoquinoline-7-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)CN1CC2=CC(=CC=C2CC1)C(=O)O LQWJTXSONPLUMD-UHFFFAOYSA-N 0.000 claims 2
- PAOITBRBSLDZKC-UHFFFAOYSA-N 2-[[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxymethyl]-1-bicyclo[2.2.2]octanyl]methoxy]-1,3-thiazole-4-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COCC12CCC(CC1)(CC2)COC=1SC=C(N=1)C(=O)O PAOITBRBSLDZKC-UHFFFAOYSA-N 0.000 claims 2
- DFWMAUFKEPCZOJ-UHFFFAOYSA-N 2-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-1,3-thiazole-4-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC=1SC=C(N=1)C(=O)O DFWMAUFKEPCZOJ-UHFFFAOYSA-N 0.000 claims 2
- SSEYHKOQIGHGPR-UHFFFAOYSA-N 2-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-4-(trifluoromethyl)-1,3-thiazole-5-carboxylic acid Chemical compound OC(=O)C1=C(N=C(OCC23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)S1)C(F)(F)F SSEYHKOQIGHGPR-UHFFFAOYSA-N 0.000 claims 2
- VDJQPWHDAUTVIX-UHFFFAOYSA-N 2-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-4-methyl-1,3-thiazole-5-carboxylic acid Chemical compound CC1=C(SC(OCC23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)=N1)C(O)=O VDJQPWHDAUTVIX-UHFFFAOYSA-N 0.000 claims 2
- HYFNLAKDEHXKCP-UHFFFAOYSA-N 2-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-8-methoxyquinoline-5-carboxylic acid Chemical compound COC1=CC=C(C(O)=O)C2=C1N=C(OCC13CCC(CC1)(CC3)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1)C=C2 HYFNLAKDEHXKCP-UHFFFAOYSA-N 0.000 claims 2
- YLRPVGNOQAKVMP-UHFFFAOYSA-N 2-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-8-methoxyquinoline-6-carboxylic acid Chemical compound COC1=CC(=CC2=CC=C(OCC34CCC(CC3)(CC4)OCC3=C(ON=C3C3=C(Cl)C=NC=C3Cl)C3CC3)N=C12)C(O)=O YLRPVGNOQAKVMP-UHFFFAOYSA-N 0.000 claims 2
- HMGRJAXOGQJXPW-UHFFFAOYSA-N 2-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]quinoline-5-carboxylic acid Chemical compound OC(=O)C1=CC=CC2=C1C=CC(OCC13CCC(CC1)(CC3)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1)=N2 HMGRJAXOGQJXPW-UHFFFAOYSA-N 0.000 claims 2
- PLHOKKPKPZKPEH-UHFFFAOYSA-N 2-[[5-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]pyridin-2-yl]methoxy]acetic acid Chemical compound OC(=O)COCC1=CC=C(C=N1)C#CC12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 PLHOKKPKPZKPEH-UHFFFAOYSA-N 0.000 claims 2
- ARGJZKHOYUFENQ-UHFFFAOYSA-N 2-[[6-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]pyridin-3-yl]methoxy]acetic acid Chemical compound OC(=O)COCC1=CC=C(N=C1)C#CC12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 ARGJZKHOYUFENQ-UHFFFAOYSA-N 0.000 claims 2
- BBABMYPSSZSIBI-UHFFFAOYSA-N 2-[[[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]bicyclo[2.2.2]octane-1-carbonyl]-methylamino]methyl]benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)C(=O)N(C)CC1=C(C(=O)O)C=CC=C1 BBABMYPSSZSIBI-UHFFFAOYSA-N 0.000 claims 2
- TYOXRISAXXIVAF-UHFFFAOYSA-N 2-[[[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]bicyclo[2.2.2]octane-1-carbonyl]amino]methyl]benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)C(=O)NCC1=C(C(=O)O)C=CC=C1 TYOXRISAXXIVAF-UHFFFAOYSA-N 0.000 claims 2
- RQRIGFGPOOOHHM-UHFFFAOYSA-N 2-chloro-3-[[4-[2-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]ethenyl]bicyclo[2.2.2]octane-1-carbonyl]amino]benzoic acid Chemical compound OC(=O)C1=CC=CC(NC(=O)C23CCC(CC2)(CC3)C=CC2=C(ON=C2C2=C(Cl)C=CC=C2Cl)C2CC2)=C1Cl RQRIGFGPOOOHHM-UHFFFAOYSA-N 0.000 claims 2
- QHILBULUBUBURK-UHFFFAOYSA-N 2-chloro-3-[[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxymethyl]bicyclo[2.2.2]octane-1-carbonyl]amino]benzoic acid Chemical compound OC(=O)C1=CC=CC(NC(=O)C23CCC(COCC4=C(ON=C4C4=C(Cl)C=CC=C4Cl)C4CC4)(CC2)CC3)=C1Cl QHILBULUBUBURK-UHFFFAOYSA-N 0.000 claims 2
- DMTLWRBTDNMMPU-UHFFFAOYSA-N 2-cyclopropyl-5-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]pyrazole-3-carboxylic acid Chemical compound OC(=O)C1=CC(OCC23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)=NN1C1CC1 DMTLWRBTDNMMPU-UHFFFAOYSA-N 0.000 claims 2
- DMWLBOPLZYJGPT-UHFFFAOYSA-N 3-(trifluoromethyl)pyridine-2-carboxylic acid Chemical compound OC(=O)C1=NC=CC=C1C(F)(F)F DMWLBOPLZYJGPT-UHFFFAOYSA-N 0.000 claims 2
- CFTBAAHLIFHVOM-MDZDMXLPSA-N 3-[(E)-2-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxymethyl]-2-oxabicyclo[2.2.2]octan-1-yl]ethenyl]benzoic acid Chemical compound OC(=O)C1=CC(\C=C\C23CCC(COCC4=C(ON=C4C4=C(Cl)C=CC=C4Cl)C4CC4)(CC2)CO3)=CC=C1 CFTBAAHLIFHVOM-MDZDMXLPSA-N 0.000 claims 2
- AKVMQXXDYKOSQK-ZHACJKMWSA-N 3-[(E)-2-[4-[[5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethenyl]benzoic acid Chemical compound OC(=O)C1=CC=CC(\C=C\C23CCC(CC2)(CC3)OCC2=C(ON=C2C2=CC=CC=C2OC(F)(F)F)C2CC2)=C1 AKVMQXXDYKOSQK-ZHACJKMWSA-N 0.000 claims 2
- LTCWVJLNFQOLIZ-ZHACJKMWSA-N 3-[(E)-2-[4-[[5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl]methoxymethyl]-2-oxabicyclo[2.2.2]octan-1-yl]ethenyl]benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1)OC(F)(F)F)COCC12COC(CC1)(CC2)/C=C/C=1C=C(C(=O)O)C=CC=1 LTCWVJLNFQOLIZ-ZHACJKMWSA-N 0.000 claims 2
- NQMFSFLXPUEVTD-UHFFFAOYSA-N 3-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]-1-methylindole-6-carboxylic acid Chemical compound CN1C=C(C#CC23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)C2=CC=C(C=C12)C(O)=O NQMFSFLXPUEVTD-UHFFFAOYSA-N 0.000 claims 2
- WKCWRPFFAKBFQJ-UHFFFAOYSA-N 3-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]-5-(methoxymethyl)benzoic acid Chemical compound COCC1=CC(=CC(=C1)C(O)=O)C#CC12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 WKCWRPFFAKBFQJ-UHFFFAOYSA-N 0.000 claims 2
- ABDUJJAYDHOSBU-UHFFFAOYSA-N 3-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]-5-(trifluoromethoxy)benzoic acid Chemical compound OC(=O)C1=CC(OC(F)(F)F)=CC(=C1)C#CC12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 ABDUJJAYDHOSBU-UHFFFAOYSA-N 0.000 claims 2
- PTHUMIAEZRHECP-UHFFFAOYSA-N 3-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]-5-(trifluoromethyl)benzoic acid Chemical compound OC(=O)C1=CC(=CC(=C1)C#CC12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1)C(F)(F)F PTHUMIAEZRHECP-UHFFFAOYSA-N 0.000 claims 2
- MIFSNPMXFRVBMY-UHFFFAOYSA-N 3-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]-5-methoxybenzoic acid Chemical compound COC1=CC(=CC(=C1)C(O)=O)C#CC12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 MIFSNPMXFRVBMY-UHFFFAOYSA-N 0.000 claims 2
- UHLIVNBWVKYELG-UHFFFAOYSA-N 3-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]-5-propan-2-yloxybenzoic acid Chemical compound CC(C)OC1=CC(=CC(=C1)C(O)=O)C#CC12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 UHLIVNBWVKYELG-UHFFFAOYSA-N 0.000 claims 2
- PZINQWGJMRPHLK-UHFFFAOYSA-N 3-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]-6-(trifluoromethyl)imidazo[1,2-a]pyridine-8-carboxylic acid Chemical compound OC(=O)c1cc(cn2c(cnc12)C#CC12CCC(CC1)(CC2)OCc1c(onc1-c1c(Cl)cncc1Cl)C1CC1)C(F)(F)F PZINQWGJMRPHLK-UHFFFAOYSA-N 0.000 claims 2
- CTQGXEMFWKWLOG-UHFFFAOYSA-N 3-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]-6-ethylimidazo[1,2-a]pyridine-8-carboxylic acid Chemical compound CCC1=CN2C(=CN=C2C(=C1)C(O)=O)C#CC12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 CTQGXEMFWKWLOG-UHFFFAOYSA-N 0.000 claims 2
- WPGMGJQJZMZVPU-UHFFFAOYSA-N 3-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]-6-fluoroimidazo[1,2-a]pyridine-8-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)C#CC1=CN=C2N1C=C(C=C2C(=O)O)F WPGMGJQJZMZVPU-UHFFFAOYSA-N 0.000 claims 2
- HTHOEVYGLIKVHB-UHFFFAOYSA-N 3-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]imidazo[1,2-a]pyridine-7-carboxylic acid Chemical compound OC(=O)C1=CC2=NC=C(C#CC34CCC(CC3)(CC4)OCC3=C(ON=C3C3=C(Cl)C=NC=C3Cl)C3CC3)N2C=C1 HTHOEVYGLIKVHB-UHFFFAOYSA-N 0.000 claims 2
- MAAOAVJEYBCDTN-UHFFFAOYSA-N 3-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]imidazo[1,2-a]pyridine-8-carboxylic acid Chemical compound OC(=O)C1=CC=CN2C(=CN=C12)C#CC12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 MAAOAVJEYBCDTN-UHFFFAOYSA-N 0.000 claims 2
- KOEWDFJNXGFEPL-CMDGGOBGSA-N 3-[3-[(E)-2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethenyl]phenyl]propanoic acid Chemical compound OC(=O)CCC1=CC=CC(\C=C\C23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)=C1 KOEWDFJNXGFEPL-CMDGGOBGSA-N 0.000 claims 2
- VMFAKWFEPOEJNC-UHFFFAOYSA-N 3-[3-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-5-yl]benzoic acid Chemical compound OC(=O)C1=CC=CC(=C1)C1=NC(=NO1)C12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=CC=C1Cl)C1CC1 VMFAKWFEPOEJNC-UHFFFAOYSA-N 0.000 claims 2
- OFRLZPLBXIKXMQ-UHFFFAOYSA-N 3-[3-[4-[[5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-5-yl]benzoic acid Chemical compound OC(=O)C1=CC=CC(=C1)C1=NC(=NO1)C12CCC(CC1)(CC2)OCC1=C(ON=C1C1=CC=CC=C1OC(F)(F)F)C1CC1 OFRLZPLBXIKXMQ-UHFFFAOYSA-N 0.000 claims 2
- BXWKZOMMLRAZKI-BQYQJAHWSA-N 3-[4-[(E)-2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethenyl]-2-fluorophenyl]propanoic acid Chemical compound OC(=O)CCC1=CC=C(\C=C\C23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)C=C1F BXWKZOMMLRAZKI-BQYQJAHWSA-N 0.000 claims 2
- VDIYTACMJVFXCG-MDZDMXLPSA-N 3-[4-[(E)-2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethenyl]phenyl]propanoic acid Chemical compound OC(=O)CCC1=CC=C(\C=C\C23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)C=C1 VDIYTACMJVFXCG-MDZDMXLPSA-N 0.000 claims 2
- AFJADHPEJPDHJM-ONEGZZNKSA-N 3-[4-[(E)-2-[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]ethenyl]-2-oxabicyclo[2.2.2]octan-1-yl]-5-(trifluoromethyl)benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)/C=C/C12COC(CC1)(CC2)C=1C=C(C(=O)O)C=C(C=1)C(F)(F)F AFJADHPEJPDHJM-ONEGZZNKSA-N 0.000 claims 2
- LLTLKVNZUINLLD-UHFFFAOYSA-N 3-[4-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]phenyl]propanoic acid Chemical compound OC(=O)CCC1=CC=C(C=C1)C#CC12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 LLTLKVNZUINLLD-UHFFFAOYSA-N 0.000 claims 2
- WPNCTCCEACQUDU-UHFFFAOYSA-N 3-[4-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]triazol-1-yl]benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)C=1N=NN(C=1)C=1C=C(C(=O)O)C=CC=1 WPNCTCCEACQUDU-UHFFFAOYSA-N 0.000 claims 2
- LADYWUOKVAOOOU-UHFFFAOYSA-N 3-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxymethyl]-2-oxabicyclo[2.2.2]octan-1-yl]benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COCC12COC(CC1)(CC2)C=1C=C(C(=O)O)C=CC=1 LADYWUOKVAOOOU-UHFFFAOYSA-N 0.000 claims 2
- WHVBWQWYTWCBEJ-UHFFFAOYSA-N 3-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxymethyl]-2-oxabicyclo[2.2.2]octan-1-yl]-5-(trifluoromethyl)benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COCC12COC(CC1)(CC2)C=1C=C(C(=O)O)C=C(C=1)C(F)(F)F WHVBWQWYTWCBEJ-UHFFFAOYSA-N 0.000 claims 2
- WIPJOIYNJSLXMU-UHFFFAOYSA-N 3-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxymethyl]-2-oxabicyclo[2.2.2]octan-1-yl]-5-(trifluoromethyl)benzonitrile Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COCC12COC(CC1)(CC2)C=1C=C(C#N)C=C(C=1)C(F)(F)F WIPJOIYNJSLXMU-UHFFFAOYSA-N 0.000 claims 2
- BONYTGCCCNCUJZ-UHFFFAOYSA-N 3-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxymethyl]-2-oxabicyclo[2.2.2]octan-1-yl]benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COCC12COC(CC1)(CC2)C=1C=C(C(=O)O)C=CC=1 BONYTGCCCNCUJZ-UHFFFAOYSA-N 0.000 claims 2
- ONZMWFFNQYDXJQ-UHFFFAOYSA-N 3-[4-[[5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl]methoxymethyl]-2-oxabicyclo[2.2.2]octan-1-yl]benzoic acid Chemical compound OC(=O)c1cccc(c1)C12CCC(COCc3c(onc3-c3ccccc3OC(F)(F)F)C3CC3)(CC1)CO2 ONZMWFFNQYDXJQ-UHFFFAOYSA-N 0.000 claims 2
- XXFYVQVCAJTJGU-BQYQJAHWSA-N 3-[5-[(E)-2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethenyl]-2-(2,2-difluoroethoxy)phenyl]propanoic acid Chemical compound OC(=O)CCC1=C(OCC(F)F)C=CC(\C=C\C23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)=C1 XXFYVQVCAJTJGU-BQYQJAHWSA-N 0.000 claims 2
- FDIVVUVFFKKSSI-CMDGGOBGSA-N 3-[5-[(E)-2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethenyl]-2-methoxyphenyl]propanoic acid Chemical compound COC1=C(CCC(O)=O)C=C(\C=C\C23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)C=C1 FDIVVUVFFKKSSI-CMDGGOBGSA-N 0.000 claims 2
- XIGOVDCLOGUVQA-ONEGZZNKSA-N 3-[5-[1-[(E)-2-[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]ethenyl]-2-oxabicyclo[2.2.2]octan-4-yl]-1,2,4-oxadiazol-3-yl]-5-(difluoromethoxy)benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)/C=C/C12OCC(CC1)(CC2)C1=NC(=NO1)C=1C=C(C(=O)O)C=C(C=1)OC(F)F XIGOVDCLOGUVQA-ONEGZZNKSA-N 0.000 claims 2
- YARVRPUCGDCJPU-ONEGZZNKSA-N 3-[5-[1-[(E)-2-[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]ethenyl]-2-oxabicyclo[2.2.2]octan-4-yl]-1,2,4-oxadiazol-3-yl]-5-(trifluoromethyl)benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)/C=C/C12OCC(CC1)(CC2)C1=NC(=NO1)C=1C=C(C(=O)O)C=C(C=1)C(F)(F)F YARVRPUCGDCJPU-ONEGZZNKSA-N 0.000 claims 2
- UANNOFSEVOTJGC-VOTSOKGWSA-N 3-[5-[1-[(E)-2-[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]ethenyl]-2-oxabicyclo[2.2.2]octan-4-yl]-1,2,4-oxadiazol-3-yl]benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)/C=C/C12OCC(CC1)(CC2)C1=NC(=NO1)C=1C=C(C(=O)O)C=CC=1 UANNOFSEVOTJGC-VOTSOKGWSA-N 0.000 claims 2
- HXULRUBKXIGJRK-UHFFFAOYSA-N 3-[5-[3-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxymethyl]-1-bicyclo[1.1.1]pentanyl]-1,2,4-oxadiazol-3-yl]benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COCC12CC(C1)(C2)C1=NC(=NO1)C=1C=C(C(=O)O)C=CC=1 HXULRUBKXIGJRK-UHFFFAOYSA-N 0.000 claims 2
- KEMMFMRNABRZSZ-MDZDMXLPSA-N 3-[5-[4-[(E)-2-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]ethenyl]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]benzoic acid Chemical compound OC(=O)C1=CC=CC(=C1)C1=NOC(=N1)C12CCC(CC1)(CC2)\C=C\C1=C(ON=C1C1=C(Cl)C=CC=C1Cl)C1CC1 KEMMFMRNABRZSZ-MDZDMXLPSA-N 0.000 claims 2
- ZBLAVCXWEDBPGW-BQYQJAHWSA-N 3-[5-[4-[(E)-2-[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]ethenyl]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]-2-methoxybenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)/C=C/C12CCC(CC1)(CC2)C1=NC(=NO1)C=1C(=C(C(=O)O)C=CC=1)OC ZBLAVCXWEDBPGW-BQYQJAHWSA-N 0.000 claims 2
- KCKINKDKHFRCCF-ONEGZZNKSA-N 3-[5-[4-[(E)-2-[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]ethenyl]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]-5-(trifluoromethyl)benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)/C=C/C12CCC(CC1)(CC2)C1=NC(=NO1)C=1C=C(C(=O)O)C=C(C=1)C(F)(F)F KCKINKDKHFRCCF-ONEGZZNKSA-N 0.000 claims 2
- XRQLLCDZAFIYMP-ONEGZZNKSA-N 3-[5-[4-[(E)-2-[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]ethenyl]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]-5-fluorobenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)/C=C/C12CCC(CC1)(CC2)C1=NC(=NO1)C=1C=C(C(=O)O)C=C(C=1)F XRQLLCDZAFIYMP-ONEGZZNKSA-N 0.000 claims 2
- NPLRKCYKCYMSBD-VOTSOKGWSA-N 3-[5-[4-[(E)-2-[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]ethenyl]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)/C=C/C12CCC(CC1)(CC2)C1=NC(=NO1)C=1C=C(C(=O)O)C=CC=1 NPLRKCYKCYMSBD-VOTSOKGWSA-N 0.000 claims 2
- FMXVWPLZYUWSRH-ONEGZZNKSA-N 3-[5-[4-[(E)-2-[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]ethenyl]-2-oxabicyclo[2.2.2]octan-1-yl]-1,2,4-oxadiazol-3-yl]-5-(difluoromethoxy)benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)/C=C/C12COC(CC1)(CC2)C1=NC(=NO1)C=1C=C(C(=O)O)C=C(C=1)OC(F)F FMXVWPLZYUWSRH-ONEGZZNKSA-N 0.000 claims 2
- VFLGTLCZFLXKHK-UHFFFAOYSA-N 3-[5-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]benzoic acid Chemical compound OC(=O)C1=CC=CC(=C1)C1=NOC(=N1)C12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=CC=C1Cl)C1CC1 VFLGTLCZFLXKHK-UHFFFAOYSA-N 0.000 claims 2
- NADGBATYYSICMD-UHFFFAOYSA-N 3-[5-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,3,4-thiadiazol-2-yl]benzoic acid Chemical compound OC(=O)C1=CC=CC(=C1)C1=NN=C(S1)C12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=CC=C1Cl)C1CC1 NADGBATYYSICMD-UHFFFAOYSA-N 0.000 claims 2
- STNYJQLDNCURKZ-UHFFFAOYSA-N 3-[5-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-oxabicyclo[2.2.2]octan-1-yl]-1,2,4-oxadiazol-3-yl]benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12COC(CC1)(CC2)C1=NC(=NO1)C=1C=C(C(=O)O)C=CC=1 STNYJQLDNCURKZ-UHFFFAOYSA-N 0.000 claims 2
- KPNRGTCZVFGEMY-UHFFFAOYSA-N 3-[5-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxymethyl]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COCC12CCC(CC1)(CC2)C1=NC(=NO1)C=1C=C(C(=O)O)C=CC=1 KPNRGTCZVFGEMY-UHFFFAOYSA-N 0.000 claims 2
- OJDZFOAVUNYLCO-UHFFFAOYSA-N 3-[5-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxymethyl]cuban-1-yl]-1,2,4-oxadiazol-3-yl]benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COCC12C3C4C5(C(C14)C2C53)C1=NC(=NO1)C=1C=C(C(=O)O)C=CC=1 OJDZFOAVUNYLCO-UHFFFAOYSA-N 0.000 claims 2
- JCMOMIMABYTFMJ-UHFFFAOYSA-N 3-[5-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)triazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]benzoic acid Chemical compound OC(=O)C1=CC=CC(=C1)C1=NOC(=N1)C12CCC(CC1)(CC2)OCC1=C(N=NN1C1=C(Cl)C=CC=C1Cl)C1CC1 JCMOMIMABYTFMJ-UHFFFAOYSA-N 0.000 claims 2
- GFCMFCLCFCZIBJ-UHFFFAOYSA-N 3-[5-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]-2,5-dimethoxybenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)C1=NC(=NO1)C=1C(=C(C(=O)O)C=C(C=1)OC)OC GFCMFCLCFCZIBJ-UHFFFAOYSA-N 0.000 claims 2
- LIQADTAOIWSMRQ-UHFFFAOYSA-N 3-[5-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]-2,6-difluorobenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)C1=NC(=NO1)C=1C(=C(C(=O)O)C(=CC=1)F)F LIQADTAOIWSMRQ-UHFFFAOYSA-N 0.000 claims 2
- KMTRQYIVCJCUDB-UHFFFAOYSA-N 3-[5-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]-2-fluoro-5-methoxybenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)C1=NC(=NO1)C=1C(=C(C(=O)O)C=C(C=1)OC)F KMTRQYIVCJCUDB-UHFFFAOYSA-N 0.000 claims 2
- XSBQAINLOLSXCK-UHFFFAOYSA-N 3-[5-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]-2-fluoro-6-methoxybenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)C1=NC(=NO1)C=1C(=C(C(=O)O)C(=CC=1)OC)F XSBQAINLOLSXCK-UHFFFAOYSA-N 0.000 claims 2
- BZODDLTWRLDJFC-UHFFFAOYSA-N 3-[5-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]-4-fluorobenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)C1=NC(=NO1)C=1C=C(C(=O)O)C=CC=1F BZODDLTWRLDJFC-UHFFFAOYSA-N 0.000 claims 2
- AZXOSCPIMLOMEF-UHFFFAOYSA-N 3-[5-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]-4-methoxybenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)C1=NC(=NO1)C=1C=C(C(=O)O)C=CC=1OC AZXOSCPIMLOMEF-UHFFFAOYSA-N 0.000 claims 2
- SQJSAFXWLCRMII-UHFFFAOYSA-N 3-[5-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]-5-(trifluoromethyl)benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)C1=NC(=NO1)C=1C=C(C(=O)O)C=C(C=1)C(F)(F)F SQJSAFXWLCRMII-UHFFFAOYSA-N 0.000 claims 2
- URSGZIHPVYJOGW-UHFFFAOYSA-N 3-[5-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]-5-fluoro-2-methoxybenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)C1=NC(=NO1)C=1C(=C(C(=O)O)C=C(C=1)F)OC URSGZIHPVYJOGW-UHFFFAOYSA-N 0.000 claims 2
- DROAEAYQUOSWBU-UHFFFAOYSA-N 3-[5-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]-5-methoxybenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)C1=NC(=NO1)C=1C=C(C(=O)O)C=C(C=1)OC DROAEAYQUOSWBU-UHFFFAOYSA-N 0.000 claims 2
- ZNYPZGSPXJORTF-UHFFFAOYSA-N 3-[5-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]-5-propan-2-yloxybenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)C1=NC(=NO1)C=1C=C(C(=O)O)C=C(C=1)OC(C)C ZNYPZGSPXJORTF-UHFFFAOYSA-N 0.000 claims 2
- HFVDBDMXBCHOML-UHFFFAOYSA-N 3-[5-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)C1=NC(=NO1)C=1C=C(C(=O)O)C=CC=1 HFVDBDMXBCHOML-UHFFFAOYSA-N 0.000 claims 2
- SKGHKCOLDJYBOG-UHFFFAOYSA-N 3-[5-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-2-oxabicyclo[2.2.2]octan-1-yl]-1,2,4-oxadiazol-3-yl]benzoic acid Chemical compound OC(=O)C1=CC=CC(=C1)C1=NOC(=N1)C12CCC(CC1)(CO2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 SKGHKCOLDJYBOG-UHFFFAOYSA-N 0.000 claims 2
- NLWIZKXHMCCCIF-UHFFFAOYSA-N 3-[5-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxymethyl]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]-4-fluorobenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COCC12CCC(CC1)(CC2)C1=NC(=NO1)C=1C=C(C(=O)O)C=CC=1F NLWIZKXHMCCCIF-UHFFFAOYSA-N 0.000 claims 2
- NPJLZPMCBSKGOG-UHFFFAOYSA-N 3-[5-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxymethyl]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]-4-methoxybenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COCC12CCC(CC1)(CC2)C1=NC(=NO1)C=1C=C(C(=O)O)C=CC=1OC NPJLZPMCBSKGOG-UHFFFAOYSA-N 0.000 claims 2
- ANMWGNOVKKRRFP-UHFFFAOYSA-N 3-[5-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxymethyl]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]-5-(trifluoromethyl)benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COCC12CCC(CC1)(CC2)C1=NC(=NO1)C=1C=C(C(=O)O)C=C(C=1)C(F)(F)F ANMWGNOVKKRRFP-UHFFFAOYSA-N 0.000 claims 2
- KJTHTTUKYWWIQM-UHFFFAOYSA-N 3-[5-[4-[[5-cyclopropyl-3-(3-fluoropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1)F)COC12CCC(CC1)(CC2)C1=NC(=NO1)C=1C=C(C(=O)O)C=CC=1 KJTHTTUKYWWIQM-UHFFFAOYSA-N 0.000 claims 2
- LBBDHXMSNKMXDO-UHFFFAOYSA-N 3-[5-[4-[[5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl]methoxy]-2-oxabicyclo[2.2.2]octan-1-yl]-1,2,4-oxadiazol-3-yl]benzoic acid Chemical compound OC(=O)c1cccc(c1)-c1noc(n1)C12CCC(CC1)(CO2)OCc1c(onc1-c1ccccc1OC(F)(F)F)C1CC1 LBBDHXMSNKMXDO-UHFFFAOYSA-N 0.000 claims 2
- XNZYEKZZXTWURN-UHFFFAOYSA-N 3-[5-[4-[[5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl]methoxymethyl]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]benzoic acid Chemical compound OC(=O)C1=CC=CC(=C1)C1=NOC(=N1)C12CCC(COCC3=C(ON=C3C3=CC=CC=C3OC(F)(F)F)C3CC3)(CC1)CC2 XNZYEKZZXTWURN-UHFFFAOYSA-N 0.000 claims 2
- OXRWPZWNYCYSBJ-UHFFFAOYSA-N 3-[5-[4-[[5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl]methoxymethyl]-2-oxabicyclo[2.2.2]octan-1-yl]-1,2,4-oxadiazol-3-yl]benzoic acid Chemical compound OC(=O)C1=CC(=CC=C1)C1=NOC(=N1)C12CCC(COCC3=C(ON=C3C3=C(OC(F)(F)F)C=CC=C3)C3CC3)(CC1)CO2 OXRWPZWNYCYSBJ-UHFFFAOYSA-N 0.000 claims 2
- YGCYIHIJUANYDQ-UHFFFAOYSA-N 3-[5-[4-[[5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]benzoic acid Chemical compound OC(=O)C1=CC=CC(=C1)C1=NOC(=N1)C12CCC(CC1)(CC2)OCC1=C(ON=C1C1=CC=CC=C1C(F)(F)F)C1CC1 YGCYIHIJUANYDQ-UHFFFAOYSA-N 0.000 claims 2
- JKMJWOGBGIGBGG-UHFFFAOYSA-N 3-[5-[4-[[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]amino]methyl]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)NCC12CCC(CC1)(CC2)C1=NC(=NO1)C=1C=C(C(=O)O)C=CC=1 JKMJWOGBGIGBGG-UHFFFAOYSA-N 0.000 claims 2
- BEZJHWZWAKSINQ-ONEGZZNKSA-N 3-[[1-[(E)-2-[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]ethenyl]-2-oxabicyclo[2.2.2]octan-4-yl]methoxy]-5-(trifluoromethyl)benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)/C=C/C12OCC(CC1)(CC2)COC=1C=C(C(=O)O)C=C(C=1)C(F)(F)F BEZJHWZWAKSINQ-ONEGZZNKSA-N 0.000 claims 2
- ONWQWNAGOWVHNP-SNAWJCMRSA-N 3-[[1-[(E)-2-[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]ethenyl]-2-oxabicyclo[2.2.2]octan-4-yl]methoxy]-5-methoxybenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)/C=C/C12OCC(CC1)(CC2)COC=1C=C(C(=O)O)C=C(C=1)OC ONWQWNAGOWVHNP-SNAWJCMRSA-N 0.000 claims 2
- HZNGYNGVHCVLAK-ONEGZZNKSA-N 3-[[4-[(E)-2-[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]ethenyl]-1-bicyclo[2.2.2]octanyl]methoxy]-5-(difluoromethoxy)benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)/C=C/C12CCC(CC1)(CC2)COC=1C=C(C(=O)O)C=C(C=1)OC(F)F HZNGYNGVHCVLAK-ONEGZZNKSA-N 0.000 claims 2
- CZMNMNVOPADVKJ-ONEGZZNKSA-N 3-[[4-[(E)-2-[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]ethenyl]-1-bicyclo[2.2.2]octanyl]methoxy]-5-(trifluoromethyl)benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)/C=C/C12CCC(CC1)(CC2)COC=1C=C(C(=O)O)C=C(C=1)C(F)(F)F CZMNMNVOPADVKJ-ONEGZZNKSA-N 0.000 claims 2
- IMLVEAAHUYIFPM-SNAWJCMRSA-N 3-[[4-[(E)-2-[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]ethenyl]-1-bicyclo[2.2.2]octanyl]methoxy]-5-methoxybenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)/C=C/C12CCC(CC1)(CC2)COC=1C=C(C(=O)O)C=C(C=1)OC IMLVEAAHUYIFPM-SNAWJCMRSA-N 0.000 claims 2
- NBHZLZHPSJMQHW-ONEGZZNKSA-N 3-[[4-[(E)-2-[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]ethenyl]-2-oxabicyclo[2.2.2]octan-1-yl]methoxy]-5-(difluoromethoxy)benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)/C=C/C12COC(CC1)(CC2)COC=1C=C(C(=O)O)C=C(C=1)OC(F)F NBHZLZHPSJMQHW-ONEGZZNKSA-N 0.000 claims 2
- HUAVBMOTFSPSCQ-SNAWJCMRSA-N 3-[[4-[(E)-2-[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]ethenyl]-2-oxabicyclo[2.2.2]octan-1-yl]methoxy]-5-methoxybenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)/C=C/C12COC(CC1)(CC2)COC=1C=C(C(=O)O)C=C(C=1)OC HUAVBMOTFSPSCQ-SNAWJCMRSA-N 0.000 claims 2
- FXBUHUFGIZNKAY-UHFFFAOYSA-N 3-[[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-2-fluorobenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC=1C(=C(C(=O)O)C=CC=1)F FXBUHUFGIZNKAY-UHFFFAOYSA-N 0.000 claims 2
- SVXNWHRRXDBJAY-UHFFFAOYSA-N 3-[[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-2-methylbenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC=1C(=C(C(=O)O)C=CC=1)C SVXNWHRRXDBJAY-UHFFFAOYSA-N 0.000 claims 2
- GDCAJVAYZJYLTR-UHFFFAOYSA-N 3-[[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-4-fluorobenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC=1C=C(C(=O)O)C=CC=1F GDCAJVAYZJYLTR-UHFFFAOYSA-N 0.000 claims 2
- UOTYJVXOVGITDR-UHFFFAOYSA-N 3-[[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-5-fluorobenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC=1C=C(C(=O)O)C=C(C=1)F UOTYJVXOVGITDR-UHFFFAOYSA-N 0.000 claims 2
- QWCKCBLCIJXSPP-UHFFFAOYSA-N 3-[[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC=1C=C(C(=O)O)C=CC=1 QWCKCBLCIJXSPP-UHFFFAOYSA-N 0.000 claims 2
- BWCRCWHVDZGJSG-UHFFFAOYSA-N 3-[[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]benzonitrile Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC=1C=C(C#N)C=CC=1 BWCRCWHVDZGJSG-UHFFFAOYSA-N 0.000 claims 2
- KRFRLPRRZHLQDL-UHFFFAOYSA-N 3-[[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxymethyl]-1-bicyclo[2.2.2]octanyl]methoxy]benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COCC12CCC(CC1)(CC2)COC=1C=C(C(=O)O)C=CC=1 KRFRLPRRZHLQDL-UHFFFAOYSA-N 0.000 claims 2
- CGGZGXALPDLUCC-UHFFFAOYSA-N 3-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-4-fluorobenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC=1C=C(C(=O)O)C=CC=1F CGGZGXALPDLUCC-UHFFFAOYSA-N 0.000 claims 2
- QLPYOMGYYAPNTB-UHFFFAOYSA-N 3-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-5-(trifluoromethyl)benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC=1C=C(C(=O)O)C=C(C=1)C(F)(F)F QLPYOMGYYAPNTB-UHFFFAOYSA-N 0.000 claims 2
- VNVBDQOPTQKPNV-UHFFFAOYSA-N 3-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-5-fluorobenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC=1C=C(C(=O)O)C=C(C=1)F VNVBDQOPTQKPNV-UHFFFAOYSA-N 0.000 claims 2
- KQFKBSJNVWRFDY-UHFFFAOYSA-N 3-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-5-methoxybenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC=1C=C(C(=O)O)C=C(C=1)OC KQFKBSJNVWRFDY-UHFFFAOYSA-N 0.000 claims 2
- WCGLTFMYGMEKEM-UHFFFAOYSA-N 3-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-5-methylbenzoic acid Chemical compound CC1=CC(=CC(OCC23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)=C1)C(O)=O WCGLTFMYGMEKEM-UHFFFAOYSA-N 0.000 claims 2
- WLSQQQFVCWASFK-UHFFFAOYSA-N 3-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-5-propan-2-yloxybenzoic acid Chemical compound CC(C)OC1=CC(=CC(OCC23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)=C1)C(O)=O WLSQQQFVCWASFK-UHFFFAOYSA-N 0.000 claims 2
- ITHXHZGUFHHOMA-UHFFFAOYSA-N 3-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxymethyl]benzoic acid Chemical compound OC(=O)C1=CC=CC(COCC23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)=C1 ITHXHZGUFHHOMA-UHFFFAOYSA-N 0.000 claims 2
- XJPBANNKNSFKOE-UHFFFAOYSA-N 3-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]bicyclo[2.2.2]octane-1-carbonyl]amino]-5-(trifluoromethyl)benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)C(=O)NC=1C=C(C(=O)O)C=C(C=1)C(F)(F)F XJPBANNKNSFKOE-UHFFFAOYSA-N 0.000 claims 2
- NYAOHXSBAWQFOZ-UHFFFAOYSA-N 3-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxymethyl]-1-bicyclo[2.2.2]octanyl]methoxy]-5-(trifluoromethyl)benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COCC12CCC(CC1)(CC2)COC=1C=C(C(=O)O)C=C(C=1)C(F)(F)F NYAOHXSBAWQFOZ-UHFFFAOYSA-N 0.000 claims 2
- XIZRNZVRNRWSFT-UHFFFAOYSA-N 3-[[[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]bicyclo[2.2.2]octane-1-carbonyl]amino]methyl]benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)C(=O)NCC=1C=C(C(=O)O)C=CC=1 XIZRNZVRNRWSFT-UHFFFAOYSA-N 0.000 claims 2
- ZPFDGMFKVKTCSJ-UHFFFAOYSA-N 3-chloro-4-[[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxymethyl]bicyclo[2.2.2]octane-1-carbonyl]amino]benzoic acid Chemical compound ClC=1C=C(C(=O)O)C=CC=1NC(=O)C12CCC(CC1)(CC2)COCC=1C(=NOC=1C1CC1)C1=C(C=CC=C1Cl)Cl ZPFDGMFKVKTCSJ-UHFFFAOYSA-N 0.000 claims 2
- RIFGMDROEVYTMA-UHFFFAOYSA-N 3-chloro-4-[[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxymethyl]bicyclo[2.2.2]octane-1-carbothioyl]amino]benzoic acid Chemical compound ClC=1C=C(C(=O)O)C=CC=1NC(=S)C12CCC(CC1)(CC2)COCC=1C(=NOC=1C1CC1)C1=C(C=CC=C1Cl)Cl RIFGMDROEVYTMA-UHFFFAOYSA-N 0.000 claims 2
- RVNRQGDQWVLPNS-UHFFFAOYSA-N 3-cyclobutyloxy-5-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]pyridine-2-carboxylic acid Chemical compound OC(=O)C1=C(OC2CCC2)C=C(OCC23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)C=N1 RVNRQGDQWVLPNS-UHFFFAOYSA-N 0.000 claims 2
- MMYAZTHOHJSTKC-UHFFFAOYSA-N 4-(1-chloro-3-hydroxypropan-2-yl)oxy-6-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]quinoline-2-carboxylic acid Chemical compound ClCC(CO)OC1=CC(=NC2=CC=C(C=C12)OCC12CCC(CC1)(CC2)OCC=1C(=NOC=1C1CC1)C1=C(C=NC=C1Cl)Cl)C(=O)O MMYAZTHOHJSTKC-UHFFFAOYSA-N 0.000 claims 2
- FGMDFCILNHZMHB-UHFFFAOYSA-N 4-(cyclobutylmethoxy)-6-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]quinoline-2-carboxylic acid Chemical compound OC(=O)C1=NC2=CC=C(OCC34CCC(CC3)(CC4)OCC3=C(ON=C3C3=C(Cl)C=NC=C3Cl)C3CC3)C=C2C(OCC2CCC2)=C1 FGMDFCILNHZMHB-UHFFFAOYSA-N 0.000 claims 2
- MWGLJKWWPIPPFU-BQYQJAHWSA-N 4-[(E)-2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethenyl]-1-methylindole-2-carboxylic acid Chemical compound CN1C(=CC2=C(\C=C\C34CCC(CC3)(CC4)OCC3=C(ON=C3C3=C(Cl)C=NC=C3Cl)C3CC3)C=CC=C12)C(O)=O MWGLJKWWPIPPFU-BQYQJAHWSA-N 0.000 claims 2
- RSTHOGFJRGIBNW-BQYQJAHWSA-N 4-[(E)-2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethenyl]benzoic acid Chemical compound OC(=O)C1=CC=C(\C=C\C23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)C=C1 RSTHOGFJRGIBNW-BQYQJAHWSA-N 0.000 claims 2
- MCGUGGTZDFCMEC-HWKANZROSA-N 4-[(E)-2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethenyl]pyridine-2-carboxylic acid Chemical compound OC(=O)C1=NC=CC(\C=C\C23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)=C1 MCGUGGTZDFCMEC-HWKANZROSA-N 0.000 claims 2
- RSRQPPUCNAFDTM-UHFFFAOYSA-N 4-[2-(chloromethyl)-3-hydroxypropoxy]-6-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]quinoline-2-carboxylic acid Chemical compound OCC(CCl)COC1=CC(=NC2=CC=C(OCC34CCC(CC3)(CC4)OCC3=C(ON=C3C3=C(Cl)C=NC=C3Cl)C3CC3)C=C12)C(O)=O RSRQPPUCNAFDTM-UHFFFAOYSA-N 0.000 claims 2
- GIWJDTCXTLGCDY-UHFFFAOYSA-N 4-[3-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-5-yl]benzoic acid Chemical compound OC(=O)C1=CC=C(C=C1)C1=NC(=NO1)C12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=CC=C1Cl)C1CC1 GIWJDTCXTLGCDY-UHFFFAOYSA-N 0.000 claims 2
- PZVQMSBIHKPIAA-UHFFFAOYSA-N 4-[3-[4-[[5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-5-yl]benzoic acid Chemical compound OC(=O)C1=CC=C(C=C1)C1=NC(=NO1)C12CCC(CC1)(CC2)OCC1=C(ON=C1C1=CC=CC=C1OC(F)(F)F)C1CC1 PZVQMSBIHKPIAA-UHFFFAOYSA-N 0.000 claims 2
- WMURSFMOBYNJQS-UHFFFAOYSA-N 4-[3-[4-[[5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-5-yl]pyridine-2-carboxylic acid Chemical compound OC(=O)C1=NC=CC(=C1)C1=NC(=NO1)C12CCC(CC1)(CC2)OCC1=C(ON=C1C1=CC=CC=C1OC(F)(F)F)C1CC1 WMURSFMOBYNJQS-UHFFFAOYSA-N 0.000 claims 2
- HTWAKCUDAAATHL-UHFFFAOYSA-N 4-[3-[4-[[5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-5-yl]pyridine-2-carboxylic acid Chemical compound OC(=O)C1=NC=CC(=C1)C1=NC(=NO1)C12CCC(CC1)(CC2)OCC1=C(ON=C1C1=CC=CC=C1C(F)(F)F)C1CC1 HTWAKCUDAAATHL-UHFFFAOYSA-N 0.000 claims 2
- XILBTPSGOHLEDS-ZHACJKMWSA-N 4-[4-[(E)-2-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]ethenyl]-2-oxabicyclo[2.2.2]octan-1-yl]benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)/C=C/C12COC(CC1)(CC2)C1=CC=C(C(=O)O)C=C1 XILBTPSGOHLEDS-ZHACJKMWSA-N 0.000 claims 2
- VUCYMPFZYDVGKQ-BQYQJAHWSA-N 4-[4-[(E)-2-[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]ethenyl]-2-oxabicyclo[2.2.2]octan-1-yl]benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)/C=C/C12COC(CC1)(CC2)C1=CC=C(C(=O)O)C=C1 VUCYMPFZYDVGKQ-BQYQJAHWSA-N 0.000 claims 2
- YIYQGXGZPYLUAG-UHFFFAOYSA-N 4-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxymethyl]-1-bicyclo[2.2.2]octanyl]benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COCC12CCC(CC1)(CC2)C1=CC=C(C(=O)O)C=C1 YIYQGXGZPYLUAG-UHFFFAOYSA-N 0.000 claims 2
- OARCYHJFTQEWHN-UHFFFAOYSA-N 4-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxymethyl]-2-oxabicyclo[2.2.2]octan-1-yl]benzoic acid Chemical compound OC(=O)C1=CC=C(C=C1)C12CCC(COCC3=C(ON=C3C3=C(Cl)C=CC=C3Cl)C3CC3)(CC1)CO2 OARCYHJFTQEWHN-UHFFFAOYSA-N 0.000 claims 2
- WEIJCVCCSSGFFL-UHFFFAOYSA-N 4-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-8-(trifluoromethyl)quinoline-6-carboxylic acid Chemical compound OC(=O)C1=CC2=C(N=CC=C2C23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)C(=C1)C(F)(F)F WEIJCVCCSSGFFL-UHFFFAOYSA-N 0.000 claims 2
- FCHMBRXQZPIBEH-UHFFFAOYSA-N 4-[4-[[5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl]methoxymethyl]-2-oxabicyclo[2.2.2]octan-1-yl]benzoic acid Chemical compound OC(=O)c1ccc(cc1)C12CCC(COCc3c(onc3-c3ccccc3OC(F)(F)F)C3CC3)(CC1)CO2 FCHMBRXQZPIBEH-UHFFFAOYSA-N 0.000 claims 2
- AEJICVPURLCZSH-UHFFFAOYSA-N 4-[4-[[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]amino]methyl]-2-oxabicyclo[2.2.2]octan-1-yl]benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)NCC12COC(CC1)(CC2)C1=CC=C(C(=O)O)C=C1 AEJICVPURLCZSH-UHFFFAOYSA-N 0.000 claims 2
- GVCAYIGNIXIVFE-ZHACJKMWSA-N 4-[5-[4-[(E)-2-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]ethenyl]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]benzoic acid Chemical compound OC(=O)C1=CC=C(C=C1)C1=NOC(=N1)C12CCC(CC1)(CC2)\C=C\C1=C(ON=C1C1=C(Cl)C=CC=C1Cl)C1CC1 GVCAYIGNIXIVFE-ZHACJKMWSA-N 0.000 claims 2
- GVCAYIGNIXIVFE-KHPPLWFESA-N 4-[5-[4-[(Z)-2-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]ethenyl]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]benzoic acid Chemical compound OC(=O)C1=CC=C(C=C1)C1=NOC(=N1)C12CCC(CC1)(CC2)\C=C/C1=C(ON=C1C1=C(Cl)C=CC=C1Cl)C1CC1 GVCAYIGNIXIVFE-KHPPLWFESA-N 0.000 claims 2
- CMRFXFLXJJYIOY-UHFFFAOYSA-N 4-[5-[4-[[3-(4-chloro-2-methylpyrazol-3-yl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]-6-methoxypyridine-2-carboxylic acid Chemical compound ClC=1C=NN(C=1C1=NOC(=C1COC12CCC(CC1)(CC2)C1=NC(=NO1)C1=CC(=NC(=C1)OC)C(=O)O)C1CC1)C CMRFXFLXJJYIOY-UHFFFAOYSA-N 0.000 claims 2
- FOFXFNYIVXFEAT-UHFFFAOYSA-N 4-[5-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]benzoic acid Chemical compound OC(=O)C1=CC=C(C=C1)C1=NOC(=N1)C12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=CC=C1Cl)C1CC1 FOFXFNYIVXFEAT-UHFFFAOYSA-N 0.000 claims 2
- GWDLVBWIPFNXBN-UHFFFAOYSA-N 4-[5-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-oxabicyclo[2.2.2]octan-1-yl]-1,2,4-oxadiazol-3-yl]benzoic acid Chemical compound OC(=O)C1=CC=C(C=C1)C1=NOC(=N1)C12CCC(CC1)(CO2)OCC1=C(ON=C1C1=C(Cl)C=CC=C1Cl)C1CC1 GWDLVBWIPFNXBN-UHFFFAOYSA-N 0.000 claims 2
- MWORYOAEBQFXDR-UHFFFAOYSA-N 4-[5-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxymethyl]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]benzoic acid Chemical compound OC(=O)C1=CC=C(C=C1)C1=NOC(=N1)C12CCC(COCC3=C(ON=C3C3=C(Cl)C=CC=C3Cl)C3CC3)(CC1)CC2 MWORYOAEBQFXDR-UHFFFAOYSA-N 0.000 claims 2
- MLGMMJBEJLQBQE-UHFFFAOYSA-N 4-[5-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxymethyl]-2-oxabicyclo[2.2.2]octan-1-yl]-1,2,4-oxadiazol-3-yl]benzoic acid Chemical compound OC(=O)C1=CC=C(C=C1)C1=NOC(=N1)C12CCC(COCC3=C(ON=C3C3=C(Cl)C=CC=C3Cl)C3CC3)(CC1)CO2 MLGMMJBEJLQBQE-UHFFFAOYSA-N 0.000 claims 2
- BLWSFOHIXSETRP-UHFFFAOYSA-N 4-[5-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)triazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]benzoic acid Chemical compound OC(=O)C1=CC=C(C=C1)C1=NOC(=N1)C12CCC(CC1)(CC2)OCC1=C(N=NN1C1=C(Cl)C=CC=C1Cl)C1CC1 BLWSFOHIXSETRP-UHFFFAOYSA-N 0.000 claims 2
- GCLGNJFXKDPAQS-UHFFFAOYSA-N 4-[5-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]-6-propan-2-yloxypyridine-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)C1=NC(=NO1)C1=CC(=NC(=C1)OC(C)C)C(=O)O GCLGNJFXKDPAQS-UHFFFAOYSA-N 0.000 claims 2
- ROQSCVHIZWPAQX-UHFFFAOYSA-N 4-[5-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-2-oxabicyclo[2.2.2]octan-1-yl]-1,2,4-oxadiazol-3-yl]benzoic acid Chemical compound OC(=O)C1=CC=C(C=C1)C1=NOC(=N1)C12CCC(CC1)(CO2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 ROQSCVHIZWPAQX-UHFFFAOYSA-N 0.000 claims 2
- OPWPEQHRUFBAMC-UHFFFAOYSA-N 4-[5-[4-[[5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]pyridine-2-carboxylic acid Chemical compound OC(=O)C1=NC=CC(=C1)C1=NOC(=N1)C12CCC(CC1)(CC2)OCC1=C(ON=C1C1=CC=CC=C1OC(F)(F)F)C1CC1 OPWPEQHRUFBAMC-UHFFFAOYSA-N 0.000 claims 2
- WMFDVCAPMHVISM-UHFFFAOYSA-N 4-[5-[4-[[5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl]methoxy]-2-oxabicyclo[2.2.2]octan-1-yl]-1,2,4-oxadiazol-3-yl]benzoic acid Chemical compound OC(=O)C1=CC=C(C=C1)C1=NOC(=N1)C12CCC(CC1)(CO2)OCC1=C(ON=C1C1=C(OC(F)(F)F)C=CC=C1)C1CC1 WMFDVCAPMHVISM-UHFFFAOYSA-N 0.000 claims 2
- IDWDGORIBPSEQT-UHFFFAOYSA-N 4-[5-[4-[[5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl]methoxymethyl]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]benzoic acid Chemical compound OC(=O)C1=CC=C(C=C1)C1=NOC(=N1)C12CCC(COCC3=C(ON=C3C3=CC=CC=C3OC(F)(F)F)C3CC3)(CC1)CC2 IDWDGORIBPSEQT-UHFFFAOYSA-N 0.000 claims 2
- JEXYEJHTRXRUMP-UHFFFAOYSA-N 4-[5-[4-[[5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]benzoic acid Chemical compound OC(=O)C1=CC=C(C=C1)C1=NOC(=N1)C12CCC(CC1)(CC2)OCC1=C(ON=C1C1=CC=CC=C1C(F)(F)F)C1CC1 JEXYEJHTRXRUMP-UHFFFAOYSA-N 0.000 claims 2
- OEHBBTWYSFNXKA-UHFFFAOYSA-N 4-[5-[4-[[5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]pyridine-2-carboxylic acid Chemical compound OC(=O)C1=NC=CC(=C1)C1=NOC(=N1)C12CCC(CC1)(CC2)OCC1=C(ON=C1C1=CC=CC=C1C(F)(F)F)C1CC1 OEHBBTWYSFNXKA-UHFFFAOYSA-N 0.000 claims 2
- SIFRMFSRTSVHJF-UHFFFAOYSA-N 4-[5-[4-[[5-propan-2-yl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]benzoic acid Chemical compound CC(C)C1=C(COC23CCC(CC2)(CC3)C2=NC(=NO2)C2=CC=C(C=C2)C(O)=O)C(=NO1)C1=CC=CC=C1OC(F)(F)F SIFRMFSRTSVHJF-UHFFFAOYSA-N 0.000 claims 2
- GWVFONNDXDMUIX-UHFFFAOYSA-N 4-[5-[4-[[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]amino]methyl]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]benzoic acid Chemical compound OC(=O)C1=CC=C(C=C1)C1=NOC(=N1)C12CCC(CNC3=C(ON=C3C3=C(Cl)C=CC=C3Cl)C3CC3)(CC1)CC2 GWVFONNDXDMUIX-UHFFFAOYSA-N 0.000 claims 2
- JGWDGYNZEHNIKF-VOTSOKGWSA-N 4-[[4-[(E)-2-[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]ethenyl]-1-bicyclo[2.2.2]octanyl]methoxy]-3-methoxybenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)/C=C/C12CCC(CC1)(CC2)COC1=C(C=C(C(=O)O)C=C1)OC JGWDGYNZEHNIKF-VOTSOKGWSA-N 0.000 claims 2
- RFEIIXLAOOMNFT-SNAWJCMRSA-N 4-[[4-[(E)-2-[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]ethenyl]-1-bicyclo[2.2.2]octanyl]methoxy]-8-fluoro-2-methylquinoline-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)/C=C/C12CCC(CC1)(CC2)COC1=CC(=NC2=C(C=C(C=C12)C(=O)O)F)C RFEIIXLAOOMNFT-SNAWJCMRSA-N 0.000 claims 2
- QUKDBOMNJLPTSZ-UHFFFAOYSA-N 4-[[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-hydroxymethyl]-3-fluorobenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)C(C1=C(C=C(C(=O)O)C=C1)F)O QUKDBOMNJLPTSZ-UHFFFAOYSA-N 0.000 claims 2
- BJPAPGXPJJWCSW-UHFFFAOYSA-N 4-[[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-hydroxymethyl]quinoline-7-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)C(C1=CC=NC2=CC(=CC=C12)C(=O)O)O BJPAPGXPJJWCSW-UHFFFAOYSA-N 0.000 claims 2
- PWFHKZKKGCMAME-UHFFFAOYSA-N 4-[[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC1=CC=C(C(=O)O)C=C1 PWFHKZKKGCMAME-UHFFFAOYSA-N 0.000 claims 2
- QQGPZJBHNOXQIW-UHFFFAOYSA-N 4-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-2-methoxybenzoic acid Chemical compound COC1=C(C=CC(OCC23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)=C1)C(O)=O QQGPZJBHNOXQIW-UHFFFAOYSA-N 0.000 claims 2
- ARFRUQUUKHDZFT-UHFFFAOYSA-N 4-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-3-(trifluoromethyl)benzoic acid Chemical compound OC(=O)C1=CC(=C(OCC23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)C=C1)C(F)(F)F ARFRUQUUKHDZFT-UHFFFAOYSA-N 0.000 claims 2
- AFCCCYPAVZDHFQ-UHFFFAOYSA-N 4-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-3-fluorobenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC1=C(C=C(C(=O)O)C=C1)F AFCCCYPAVZDHFQ-UHFFFAOYSA-N 0.000 claims 2
- UXTOVNAWKRFEQM-UHFFFAOYSA-N 4-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]isoquinoline-1-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC1=CN=C(C2=CC=CC=C12)C(=O)O UXTOVNAWKRFEQM-UHFFFAOYSA-N 0.000 claims 2
- FQIZYXUKQARSKS-UHFFFAOYSA-N 4-[[4-[[5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]isoquinoline-1-carboxylic acid Chemical compound OC(=O)C1=C2C=CC=CC2=C(OCC23CCC(CC2)(CC3)OCC2=C(ON=C2C2=CC=CC=C2C(F)(F)F)C2CC2)C=N1 FQIZYXUKQARSKS-UHFFFAOYSA-N 0.000 claims 2
- MDNDHAAVHUUPEM-UHFFFAOYSA-N 4-[[[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]bicyclo[2.2.2]octane-1-carbonyl]amino]methyl]benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)C(=O)NCC1=CC=C(C(=O)O)C=C1 MDNDHAAVHUUPEM-UHFFFAOYSA-N 0.000 claims 2
- FPODYWBPWRTPBY-UHFFFAOYSA-N 4-cyclobutyloxy-6-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]quinoline-2-carboxylic acid Chemical compound OC(=O)C1=NC2=C(C=C(C=C2)C#CC23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)C(OC2CCC2)=C1 FPODYWBPWRTPBY-UHFFFAOYSA-N 0.000 claims 2
- KSGCZEYUPFFYGI-UHFFFAOYSA-N 4-cyclobutyloxy-6-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-8-fluoroquinoline-2-carboxylic acid Chemical compound C1(CCC1)OC1=CC(=NC2=C(C=C(C=C12)OCC12CCC(CC1)(CC2)OCC=1C(=NOC=1C1CC1)C1=C(C=NC=C1Cl)Cl)F)C(=O)O KSGCZEYUPFFYGI-UHFFFAOYSA-N 0.000 claims 2
- AIOLYNAVGXTJAS-UHFFFAOYSA-N 4-cyclobutyloxy-6-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]quinoline-2-carboxylic acid Chemical compound OC(=O)C1=NC2=CC=C(OCC34CCC(CC3)(CC4)OCC3=C(ON=C3C3=C(Cl)C=NC=C3Cl)C3CC3)C=C2C(OC2CCC2)=C1 AIOLYNAVGXTJAS-UHFFFAOYSA-N 0.000 claims 2
- KZNMJSLLSRSUOV-MDZDMXLPSA-N 4-cyclopentyloxy-6-[(E)-2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethenyl]quinoline-2-carboxylic acid Chemical compound OC(=O)C1=NC2=C(C=C(\C=C\C34CCC(CC3)(CC4)OCC3=C(ON=C3C3=C(Cl)C=NC=C3Cl)C3CC3)C=C2)C(OC2CCCC2)=C1 KZNMJSLLSRSUOV-MDZDMXLPSA-N 0.000 claims 2
- RPJVJLNMEAKYTJ-UHFFFAOYSA-N 4-cyclopropyl-6-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]quinoline-2-carboxylic acid Chemical compound C1(CC1)C1=CC(=NC2=CC=C(C=C12)OCC12CCC(CC1)(CC2)OCC=1C(=NOC=1C1CC1)C1=C(C=NC=C1Cl)Cl)C(=O)O RPJVJLNMEAKYTJ-UHFFFAOYSA-N 0.000 claims 2
- ZZVZUHIALJOOAG-ONEGZZNKSA-N 5-[(E)-2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethenyl]pyridine-3-carboxylic acid Chemical compound OC(=O)C1=CN=CC(\C=C\C23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)=C1 ZZVZUHIALJOOAG-ONEGZZNKSA-N 0.000 claims 2
- HMOFYJHMANKUQJ-UHFFFAOYSA-N 5-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]-1H-indazole-7-carboxylic acid Chemical compound OC(=O)C1=C2NN=CC2=CC(=C1)C#CC12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 HMOFYJHMANKUQJ-UHFFFAOYSA-N 0.000 claims 2
- KUSMNRGZYMYFLR-UHFFFAOYSA-N 5-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]-2-methoxybenzoic acid Chemical compound COC1=C(C=C(C=C1)C#CC12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1)C(O)=O KUSMNRGZYMYFLR-UHFFFAOYSA-N 0.000 claims 2
- WLIMYGZPVUOUPU-UHFFFAOYSA-N 5-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]-3-methylpyridine-2-carboxylic acid Chemical compound CC1=CC(=CN=C1C(O)=O)C#CC12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 WLIMYGZPVUOUPU-UHFFFAOYSA-N 0.000 claims 2
- TXZNQMHNBYFICC-UHFFFAOYSA-N 5-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]-4-methylpyridine-2-carboxylic acid Chemical compound CC1=CC(=NC=C1C#CC12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1)C(O)=O TXZNQMHNBYFICC-UHFFFAOYSA-N 0.000 claims 2
- YDLTVBMEPKCJNY-UHFFFAOYSA-N 5-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]-6-(3-fluoroazetidin-1-yl)pyridine-3-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)C#CC=1C(=NC=C(C(=O)O)C=1)N1CC(C1)F YDLTVBMEPKCJNY-UHFFFAOYSA-N 0.000 claims 2
- AVBJOMCHKWSEJJ-UHFFFAOYSA-N 5-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]-6-(4-methylpiperazin-1-yl)pyridine-3-carboxylic acid Chemical compound CN1CCN(CC1)C1=NC=C(C=C1C#CC12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1)C(O)=O AVBJOMCHKWSEJJ-UHFFFAOYSA-N 0.000 claims 2
- QFWMXSJSFILRBU-UHFFFAOYSA-N 5-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]-6-methoxypyridine-3-carboxylic acid Chemical compound COC1=NC=C(C=C1C#CC12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1)C(O)=O QFWMXSJSFILRBU-UHFFFAOYSA-N 0.000 claims 2
- BVRVONYNOJFEIX-UHFFFAOYSA-N 5-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]pyrazine-2-carboxylic acid Chemical compound OC(=O)C1=NC=C(N=C1)C#CC12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 BVRVONYNOJFEIX-UHFFFAOYSA-N 0.000 claims 2
- AMOBTAXYXRZTCM-UHFFFAOYSA-N 5-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]pyrazolo[1,5-a]pyridine-3-carboxylic acid Chemical compound OC(=O)C1=C2C=C(C=CN2N=C1)C#CC12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 AMOBTAXYXRZTCM-UHFFFAOYSA-N 0.000 claims 2
- RWXJVDQCJRWGRT-UHFFFAOYSA-N 5-[3-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-5-yl]-2-methoxybenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)C1=NOC(=N1)C=1C=CC(=C(C(=O)O)C=1)OC RWXJVDQCJRWGRT-UHFFFAOYSA-N 0.000 claims 2
- UTSCVCPBMKAODD-UHFFFAOYSA-N 5-[4-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,3-oxazol-2-yl]-2-methoxybenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)C=1N=C(OC=1)C=1C=CC(=C(C(=O)O)C=1)OC UTSCVCPBMKAODD-UHFFFAOYSA-N 0.000 claims 2
- UJUBDXMUXAZMJA-UHFFFAOYSA-N 5-[4-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,3-thiazol-2-yl]-2-methoxybenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)C=1N=C(SC=1)C=1C=CC(=C(C(=O)O)C=1)OC UJUBDXMUXAZMJA-UHFFFAOYSA-N 0.000 claims 2
- JDAOYDDDSNTGHH-UHFFFAOYSA-N 5-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazole-3-carboxamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)C1=NC(=NO1)C(=O)N JDAOYDDDSNTGHH-UHFFFAOYSA-N 0.000 claims 2
- RSRGOYBWOBFVLU-UHFFFAOYSA-N 5-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxymethyl]-2-oxabicyclo[2.2.2]octan-1-yl]-2-fluorobenzoic acid Chemical compound OC(=O)C1=C(F)C=CC(=C1)C12CCC(COCC3=C(ON=C3C3=C(Cl)C=CC=C3Cl)C3CC3)(CC1)CO2 RSRGOYBWOBFVLU-UHFFFAOYSA-N 0.000 claims 2
- YMCZNWCHVOBTPB-UHFFFAOYSA-N 5-[4-[[5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl]methoxymethyl]-2-oxabicyclo[2.2.2]octan-1-yl]-2-fluorobenzoic acid Chemical compound OC(=O)c1cc(ccc1F)C12CCC(COCc3c(onc3-c3ccccc3OC(F)(F)F)C3CC3)(CC1)CO2 YMCZNWCHVOBTPB-UHFFFAOYSA-N 0.000 claims 2
- IPLOHDZNTRTGLB-VOTSOKGWSA-N 5-[5-[1-[(E)-2-[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]ethenyl]-2-oxabicyclo[2.2.2]octan-4-yl]-1,2,4-oxadiazol-3-yl]-2-methoxybenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)/C=C/C12OCC(CC1)(CC2)C1=NC(=NO1)C=1C=CC(=C(C(=O)O)C=1)OC IPLOHDZNTRTGLB-VOTSOKGWSA-N 0.000 claims 2
- IRIFQDKBNFFKJY-AATRIKPKSA-N 5-[5-[4-[(E)-2-[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]ethenyl]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]-2-(difluoromethoxy)benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)/C=C/C12CCC(CC1)(CC2)C1=NC(=NO1)C=1C=CC(=C(C(=O)O)C=1)OC(F)F IRIFQDKBNFFKJY-AATRIKPKSA-N 0.000 claims 2
- GIFYBJNFLVLYDG-VOTSOKGWSA-N 5-[5-[4-[(E)-2-[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]ethenyl]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]-2-methoxybenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)/C=C/C12CCC(CC1)(CC2)C1=NC(=NO1)C=1C=CC(=C(C(=O)O)C=1)OC GIFYBJNFLVLYDG-VOTSOKGWSA-N 0.000 claims 2
- BSRCTFQJGQGIBJ-CMDGGOBGSA-N 5-[5-[4-[(E)-2-[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]ethenyl]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]-N-cyclopropylsulfonyl-2-methoxybenzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)/C=C/C12CCC(CC1)(CC2)C1=NC(=NO1)C=1C=CC(=C(C(=O)NS(=O)(=O)C2CC2)C=1)OC BSRCTFQJGQGIBJ-CMDGGOBGSA-N 0.000 claims 2
- KDNBDLXGONOLQD-VOTSOKGWSA-N 5-[5-[4-[(E)-2-[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]ethenyl]-2-oxabicyclo[2.2.2]octan-1-yl]-1,2,4-oxadiazol-3-yl]-2-methoxybenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)/C=C/C12COC(CC1)(CC2)C1=NC(=NO1)C=1C=CC(=C(C(=O)O)C=1)OC KDNBDLXGONOLQD-VOTSOKGWSA-N 0.000 claims 2
- BLTHHBGIZDYSGE-UHFFFAOYSA-N 5-[5-[4-[[3-(4-chloro-2-methylpyrazol-3-yl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]-2-methoxybenzoic acid Chemical compound ClC=1C=NN(C=1C1=NOC(=C1COC12CCC(CC1)(CC2)C1=NC(=NO1)C=1C=CC(=C(C(=O)O)C=1)OC)C1CC1)C BLTHHBGIZDYSGE-UHFFFAOYSA-N 0.000 claims 2
- DIEZEEGCLMMFQD-UHFFFAOYSA-N 5-[5-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]-2-methoxybenzoic acid Chemical compound COC1=C(C=C(C=C1)C1=NOC(=N1)C12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=CC=C1Cl)C1CC1)C(O)=O DIEZEEGCLMMFQD-UHFFFAOYSA-N 0.000 claims 2
- ZXZIQBCDKQBELO-UHFFFAOYSA-N 5-[5-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]pyridine-2-carboxylic acid Chemical compound OC(=O)C1=NC=C(C=C1)C1=NOC(=N1)C12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=CC=C1Cl)C1CC1 ZXZIQBCDKQBELO-UHFFFAOYSA-N 0.000 claims 2
- QRLMUZGBVACLIR-UHFFFAOYSA-N 5-[5-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]pyridine-3-carboxylic acid Chemical compound OC(=O)C1=CN=CC(=C1)C1=NOC(=N1)C12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=CC=C1Cl)C1CC1 QRLMUZGBVACLIR-UHFFFAOYSA-N 0.000 claims 2
- NJHGZVVWFOCOIT-UHFFFAOYSA-N 5-[5-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-oxabicyclo[2.2.2]octan-1-yl]-1,2,4-oxadiazol-3-yl]-2-fluorobenzoic acid Chemical compound OC(=O)C1=C(F)C=CC(=C1)C1=NOC(=N1)C12CCC(CC1)(CO2)OCC1=C(ON=C1C1=C(Cl)C=CC=C1Cl)C1CC1 NJHGZVVWFOCOIT-UHFFFAOYSA-N 0.000 claims 2
- LCCVQASEJONYNN-UHFFFAOYSA-N 5-[5-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]-2,3-dimethoxybenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)C1=NC(=NO1)C=1C=C(C(=C(C(=O)O)C=1)OC)OC LCCVQASEJONYNN-UHFFFAOYSA-N 0.000 claims 2
- XOIYZDBLHCTKEX-UHFFFAOYSA-N 5-[5-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]-2-fluoro-3-methoxybenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)C1=NC(=NO1)C=1C=C(C(=C(C(=O)O)C=1)F)OC XOIYZDBLHCTKEX-UHFFFAOYSA-N 0.000 claims 2
- PXMMCIJJPZGEDM-UHFFFAOYSA-N 5-[5-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]-2-fluorobenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)C1=NC(=NO1)C=1C=CC(=C(C(=O)O)C=1)F PXMMCIJJPZGEDM-UHFFFAOYSA-N 0.000 claims 2
- NLNAQGCGEJRVNM-UHFFFAOYSA-N 5-[5-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]-2-methoxybenzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)C1=NC(=NO1)C=1C=CC(=C(C(=O)N)C=1)OC NLNAQGCGEJRVNM-UHFFFAOYSA-N 0.000 claims 2
- OLQGSCLODSDUHN-UHFFFAOYSA-N 5-[5-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]-2-methoxypyridine-3-carboxylic acid Chemical compound COC1=NC=C(C=C1C(O)=O)C1=NOC(=N1)C12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 OLQGSCLODSDUHN-UHFFFAOYSA-N 0.000 claims 2
- FKIOEQDWVYUFPH-UHFFFAOYSA-N 5-[5-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]-2-propan-2-yloxybenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)C1=NC(=NO1)C=1C=CC(=C(C(=O)O)C=1)OC(C)C FKIOEQDWVYUFPH-UHFFFAOYSA-N 0.000 claims 2
- ZVYCIBWSDREYGY-UHFFFAOYSA-N 5-[5-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]-3-fluoro-2-methoxybenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)C1=NC(=NO1)C=1C=C(C(=C(C(=O)O)C=1)OC)F ZVYCIBWSDREYGY-UHFFFAOYSA-N 0.000 claims 2
- IAFBSDYCVALMRX-UHFFFAOYSA-N 5-[5-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1H-imidazol-2-yl]-2-methoxybenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)C=1N=C(NC=1)C=1C=CC(=C(C(=O)O)C=1)OC IAFBSDYCVALMRX-UHFFFAOYSA-N 0.000 claims 2
- DWZYVFYSQDDYMA-UHFFFAOYSA-N 5-[5-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-2-oxabicyclo[2.2.2]octan-1-yl]-1,2,4-oxadiazol-3-yl]-2-methoxybenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12COC(CC1)(CC2)C1=NC(=NO1)C=1C=CC(=C(C(=O)O)C=1)OC DWZYVFYSQDDYMA-UHFFFAOYSA-N 0.000 claims 2
- WTNPWTUTRJHPAM-UHFFFAOYSA-N 5-[5-[4-[[5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]pyridine-3-carboxylic acid Chemical compound OC(=O)C1=CN=CC(=C1)C1=NOC(=N1)C12CCC(CC1)(CC2)OCC1=C(ON=C1C1=CC=CC=C1OC(F)(F)F)C1CC1 WTNPWTUTRJHPAM-UHFFFAOYSA-N 0.000 claims 2
- YCGGCEABKZAAJT-UHFFFAOYSA-N 5-[5-[4-[[5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]-2-methoxybenzoic acid Chemical compound COC1=C(C=C(C=C1)C1=NOC(=N1)C12CCC(CC1)(CC2)OCC1=C(ON=C1C1=CC=CC=C1C(F)(F)F)C1CC1)C(O)=O YCGGCEABKZAAJT-UHFFFAOYSA-N 0.000 claims 2
- ULQXKUPCZCEAAN-UHFFFAOYSA-N 5-[5-[4-[[5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]pyridine-2-carboxylic acid Chemical compound OC(=O)C1=NC=C(C=C1)C1=NOC(=N1)C12CCC(CC1)(CC2)OCC1=C(ON=C1C1=CC=CC=C1C(F)(F)F)C1CC1 ULQXKUPCZCEAAN-UHFFFAOYSA-N 0.000 claims 2
- LMRCIZRWNVSOGK-UHFFFAOYSA-N 5-[[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-2-fluorobenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC=1C=CC(=C(C(=O)O)C=1)F LMRCIZRWNVSOGK-UHFFFAOYSA-N 0.000 claims 2
- ABFMZSZMWTXJCO-UHFFFAOYSA-N 5-[[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]pyridine-3-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC=1C=NC=C(C(=O)O)C=1 ABFMZSZMWTXJCO-UHFFFAOYSA-N 0.000 claims 2
- CMMRGCPKNDCTPD-UHFFFAOYSA-N 5-[[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methylamino]-2-methylpyrazole-3-carboxylic acid Chemical compound Cn1nc(NCC23CCC(CC2)(CC3)OCc2c(onc2-c2c(Cl)cccc2Cl)C2CC2)cc1C(O)=O CMMRGCPKNDCTPD-UHFFFAOYSA-N 0.000 claims 2
- XBNVIGFWWMLPML-UHFFFAOYSA-N 5-[[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methylamino]pyridine-3-carboxylic acid Chemical compound OC(=O)c1cncc(NCC23CCC(CC2)(CC3)OCc2c(onc2-c2c(Cl)cccc2Cl)C2CC2)c1 XBNVIGFWWMLPML-UHFFFAOYSA-N 0.000 claims 2
- XZNNOPZSBQJCQR-UHFFFAOYSA-N 5-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-1-ethyl-4-fluoropyrazole-3-carboxylic acid Chemical compound CCN1N=C(C(O)=O)C(F)=C1OCC12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 XZNNOPZSBQJCQR-UHFFFAOYSA-N 0.000 claims 2
- NWGNUPKHTNBRHW-UHFFFAOYSA-N 5-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-1-ethylpyrazole-3-carboxylic acid Chemical compound CCN1N=C(C=C1OCC12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1)C(O)=O NWGNUPKHTNBRHW-UHFFFAOYSA-N 0.000 claims 2
- ONYOCMBSPOTMDK-UHFFFAOYSA-N 5-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-1-methylpyrazole-3-carboxylic acid Chemical compound CN1N=C(C=C1OCC12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1)C(O)=O ONYOCMBSPOTMDK-UHFFFAOYSA-N 0.000 claims 2
- QXFCVSGVIHMYJM-UHFFFAOYSA-N 5-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-2,4-dimethylpyrazole-3-carboxylic acid Chemical compound CN1N=C(OCC23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)C(C)=C1C(O)=O QXFCVSGVIHMYJM-UHFFFAOYSA-N 0.000 claims 2
- OTCIKYBWJGVFDZ-UHFFFAOYSA-N 5-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-2-(cyclopropylmethyl)-4-fluoropyrazole-3-carboxylic acid Chemical compound OC(=O)C1=C(F)C(OCC23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)=NN1CC1CC1 OTCIKYBWJGVFDZ-UHFFFAOYSA-N 0.000 claims 2
- GFAHBVBVQXMMOO-UHFFFAOYSA-N 5-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-2-(cyclopropylmethyl)-4-methylpyrazole-3-carboxylic acid Chemical compound CC1=C(N(CC2CC2)N=C1OCC12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1)C(O)=O GFAHBVBVQXMMOO-UHFFFAOYSA-N 0.000 claims 2
- SOQZOLPXBTWPRC-UHFFFAOYSA-N 5-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-2-(cyclopropylmethyl)pyrazole-3-carboxylic acid Chemical compound OC(=O)C1=CC(OCC23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)=NN1CC1CC1 SOQZOLPXBTWPRC-UHFFFAOYSA-N 0.000 claims 2
- PUKKTSYWAPQYSF-UHFFFAOYSA-N 5-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-2-ethyl-4-methylpyrazole-3-carboxylic acid Chemical compound CCN1N=C(OCC23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)C(C)=C1C(O)=O PUKKTSYWAPQYSF-UHFFFAOYSA-N 0.000 claims 2
- TWQDLGSODLDKLH-UHFFFAOYSA-N 5-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-2-ethylpyrazole-3-carboxylic acid Chemical compound CCN1N=C(OCC23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)C=C1C(O)=O TWQDLGSODLDKLH-UHFFFAOYSA-N 0.000 claims 2
- BDMBFJYSCVHMGG-UHFFFAOYSA-N 5-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-2-fluorobenzoic acid Chemical compound OC(=O)C1=CC(OCC23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)=CC=C1F BDMBFJYSCVHMGG-UHFFFAOYSA-N 0.000 claims 2
- ZIMSWRDTSMLLEI-UHFFFAOYSA-N 5-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-2-methylpyrazole-3-carboxylic acid Chemical compound CN1N=C(OCC23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)C=C1C(O)=O ZIMSWRDTSMLLEI-UHFFFAOYSA-N 0.000 claims 2
- DXJIDCXCBNRCAX-UHFFFAOYSA-N 5-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-3-(1,1-difluoroethyl)pyridine-2-carboxylic acid Chemical compound CC(F)(F)C1=C(N=CC(OCC23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)=C1)C(O)=O DXJIDCXCBNRCAX-UHFFFAOYSA-N 0.000 claims 2
- DLMNWXCTCNZVLS-UHFFFAOYSA-N 5-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-3-(2-methoxyethoxy)pyridine-2-carboxylic acid Chemical compound COCCOC1=C(N=CC(OCC23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)=C1)C(O)=O DLMNWXCTCNZVLS-UHFFFAOYSA-N 0.000 claims 2
- PYAADOMRMGVDPC-UHFFFAOYSA-N 5-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-3-(cyclopropylmethoxy)pyridine-2-carboxylic acid Chemical compound OC(=O)C1=C(OCC2CC2)C=C(OCC23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)C=N1 PYAADOMRMGVDPC-UHFFFAOYSA-N 0.000 claims 2
- KNJSJIQZZCMTMQ-UHFFFAOYSA-N 5-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-3-(methoxymethyl)pyridine-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC=1C=C(C(=NC=1)C(=O)O)COC KNJSJIQZZCMTMQ-UHFFFAOYSA-N 0.000 claims 2
- DFJRNGSOAMODNW-UHFFFAOYSA-N 5-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-3-(trifluoromethyl)pyridine-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC=1C=C(C(=NC=1)C(=O)O)C(F)(F)F DFJRNGSOAMODNW-UHFFFAOYSA-N 0.000 claims 2
- BRCIBDPAOCHJJV-UHFFFAOYSA-N 5-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-3-cyclopropyloxypyridine-2-carboxylic acid Chemical compound OC(=O)C1=C(OC2CC2)C=C(OCC23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)C=N1 BRCIBDPAOCHJJV-UHFFFAOYSA-N 0.000 claims 2
- JJLQSTCTEGETJB-UHFFFAOYSA-N 5-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-3-ethoxypyridine-2-carboxamide Chemical compound CCOC1=C(N=CC(OCC23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)=C1)C(N)=O JJLQSTCTEGETJB-UHFFFAOYSA-N 0.000 claims 2
- CJSIRNJGHHRFIU-UHFFFAOYSA-N 5-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-3-ethoxypyridine-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC=1C=C(C(=NC=1)C(=O)O)OCC CJSIRNJGHHRFIU-UHFFFAOYSA-N 0.000 claims 2
- ZHPQPBOLIUCJQY-UHFFFAOYSA-N 5-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-3-methoxypyridine-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC=1C=C(C(=NC=1)C(=O)O)OC ZHPQPBOLIUCJQY-UHFFFAOYSA-N 0.000 claims 2
- YVJKQRJAVRTJTD-UHFFFAOYSA-N 5-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-3-methylpyridine-2-carboxamide Chemical compound CC1=C(N=CC(OCC23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)=C1)C(N)=O YVJKQRJAVRTJTD-UHFFFAOYSA-N 0.000 claims 2
- RKLAKDFPMMYWJC-UHFFFAOYSA-N 5-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-3-methylpyridine-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC=1C=C(C(=NC=1)C(=O)O)C RKLAKDFPMMYWJC-UHFFFAOYSA-N 0.000 claims 2
- GAOJINMGTKCGQC-UHFFFAOYSA-N 5-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-3-propan-2-yloxypyridine-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC=1C=C(C(=NC=1)C(=O)O)OC(C)C GAOJINMGTKCGQC-UHFFFAOYSA-N 0.000 claims 2
- NDUJNEHQDYWIJJ-UHFFFAOYSA-N 5-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-4-methyl-2-(oxetan-3-ylmethyl)pyrazole-3-carboxylic acid Chemical compound CC1=C(N(CC2COC2)N=C1OCC12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1)C(O)=O NDUJNEHQDYWIJJ-UHFFFAOYSA-N 0.000 claims 2
- YREQNBLIVBLKFB-UHFFFAOYSA-N 5-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-4-methyl-2-propan-2-ylpyrazole-3-carboxylic acid Chemical compound CC(C)N1N=C(OCC23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)C(C)=C1C(O)=O YREQNBLIVBLKFB-UHFFFAOYSA-N 0.000 claims 2
- NIXOPQWMHLWRJT-UHFFFAOYSA-N 5-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]pyridine-2-carboxylic acid Chemical compound OC(=O)C1=CC=C(OCC23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)C=N1 NIXOPQWMHLWRJT-UHFFFAOYSA-N 0.000 claims 2
- RCUKLBOMCGLIRX-UHFFFAOYSA-N 5-[[4-[[5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-3-ethoxypyridine-2-carboxamide Chemical compound CCOC1=C(N=CC(OCC23CCC(CC2)(CC3)OCC2=C(ON=C2C2=CC=CC=C2C(F)(F)F)C2CC2)=C1)C(N)=O RCUKLBOMCGLIRX-UHFFFAOYSA-N 0.000 claims 2
- SFATYYDKFQXOFL-UHFFFAOYSA-N 5-[[4-[[5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-3-ethoxypyridine-2-carboxylic acid Chemical compound CCOC1=C(N=CC(OCC23CCC(CC2)(CC3)OCC2=C(ON=C2C2=CC=CC=C2C(F)(F)F)C2CC2)=C1)C(O)=O SFATYYDKFQXOFL-UHFFFAOYSA-N 0.000 claims 2
- WPEGGCDSUBAHHX-UHFFFAOYSA-N 5-cyclopropyl-3-(2,6-dichlorophenyl)-4-[[1-[3-(2H-tetrazol-5-yl)phenyl]-2-oxabicyclo[2.2.2]octan-4-yl]methoxymethyl]-1,2-oxazole Chemical compound N1N=NN=C1C=1C=C(C=CC=1)C12OCC(CC1)(CC2)COCC=1C(=NOC=1C1CC1)C1=C(C=CC=C1Cl)Cl WPEGGCDSUBAHHX-UHFFFAOYSA-N 0.000 claims 2
- UAISDRDPOMMDTE-BQYQJAHWSA-N 5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-4-[[4-[(E)-2-[4-(2H-tetrazol-5-ylmethyl)phenyl]ethenyl]-1-bicyclo[2.2.2]octanyl]oxymethyl]-1,2-oxazole Chemical compound ClC1=CN=CC(Cl)=C1C1=NOC(C2CC2)=C1COC12CCC(CC1)(CC2)\C=C\C1=CC=C(CC2=NNN=N2)C=C1 UAISDRDPOMMDTE-BQYQJAHWSA-N 0.000 claims 2
- OTPPXGVHWDQPCH-UHFFFAOYSA-N 6-(azetidin-1-yl)-5-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]pyridine-3-carboxylic acid Chemical compound OC(=O)C1=CN=C(N2CCC2)C(=C1)C#CC12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 OTPPXGVHWDQPCH-UHFFFAOYSA-N 0.000 claims 2
- STEFUOFHVMYJLH-VOTSOKGWSA-N 6-[(E)-2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethenyl]-1-methylindole-2-carboxylic acid Chemical compound CN1C(=CC2=C1C=C(\C=C\C13CCC(CC1)(CC3)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1)C=C2)C(O)=O STEFUOFHVMYJLH-VOTSOKGWSA-N 0.000 claims 2
- IHHXTFZSKFIHQX-BQYQJAHWSA-N 6-[(E)-2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethenyl]-4-ethoxyquinoline-2-carboxylic acid Chemical compound CCOC1=CC(=NC2=C1C=C(\C=C\C13CCC(CC1)(CC3)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1)C=C2)C(O)=O IHHXTFZSKFIHQX-BQYQJAHWSA-N 0.000 claims 2
- OCBYPFJVLBHLAY-VOTSOKGWSA-N 6-[(E)-2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethenyl]-4-methoxyquinazoline-2-carboxylic acid Chemical compound COC1=NC(=NC2=C1C=C(\C=C\C13CCC(CC1)(CC3)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1)C=C2)C(O)=O OCBYPFJVLBHLAY-VOTSOKGWSA-N 0.000 claims 2
- XMHVVIZKDIEWNV-BQYQJAHWSA-N 6-[(E)-2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethenyl]-4-propan-2-yloxyquinoline-2-carboxylic acid Chemical compound CC(C)OC1=CC(=NC2=C1C=C(\C=C\C13CCC(CC1)(CC3)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1)C=C2)C(O)=O XMHVVIZKDIEWNV-BQYQJAHWSA-N 0.000 claims 2
- CQRYVQKGTVZFLZ-AATRIKPKSA-N 6-[(E)-2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethenyl]imidazo[1,2-a]pyridine-3-carboxylic acid Chemical compound OC(=O)C1=CN=C2C=CC(\C=C\C34CCC(CC3)(CC4)OCC3=C(ON=C3C3=C(Cl)C=NC=C3Cl)C3CC3)=CN12 CQRYVQKGTVZFLZ-AATRIKPKSA-N 0.000 claims 2
- JYRFKQFUBIKIRL-BQYQJAHWSA-N 6-[(E)-2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethenyl]quinoline-2-carboxylic acid Chemical compound OC(=O)C1=NC2=C(C=C1)C=C(\C=C\C13CCC(CC1)(CC3)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1)C=C2 JYRFKQFUBIKIRL-BQYQJAHWSA-N 0.000 claims 2
- OHJIDDZOPJSSLT-UHFFFAOYSA-N 6-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethyl]-4-(trifluoromethyl)quinoline-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)CCC=1C=C2C(=CC(=NC2=CC=1)C(=O)O)C(F)(F)F OHJIDDZOPJSSLT-UHFFFAOYSA-N 0.000 claims 2
- KUVGDRNPGBBSQX-UHFFFAOYSA-N 6-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethyl]-4-propan-2-yloxyquinoline-2-carboxylic acid Chemical compound CC(C)OC1=CC(=NC2=C1C=C(CCC13CCC(CC1)(CC3)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1)C=C2)C(O)=O KUVGDRNPGBBSQX-UHFFFAOYSA-N 0.000 claims 2
- KGHFOIQKADFXOR-UHFFFAOYSA-N 6-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethyl]quinoline-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)CCC=1C=C2C=CC(=NC2=CC=1)C(=O)O KGHFOIQKADFXOR-UHFFFAOYSA-N 0.000 claims 2
- FISSJEHGGPTWRB-UHFFFAOYSA-N 6-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]-1-(3-methoxypropoxy)isoquinoline-3-carboxylic acid Chemical compound COCCCOC1=NC(=CC2=CC(=CC=C12)C#CC12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1)C(O)=O FISSJEHGGPTWRB-UHFFFAOYSA-N 0.000 claims 2
- QUCCUFPTCRJMDF-UHFFFAOYSA-N 6-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]-1-(4-methylpiperazin-1-yl)isoquinoline-3-carboxylic acid Chemical compound CN1CCN(CC1)C1=NC(=CC2=CC(=CC=C12)C#CC12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1)C(O)=O QUCCUFPTCRJMDF-UHFFFAOYSA-N 0.000 claims 2
- VGLMCUAPQNXBMX-UHFFFAOYSA-N 6-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]-1-methylpyrrolo[2,3-b]pyridine-3-carboxylic acid Chemical compound CN1C=C(C(O)=O)C2=CC=C(N=C12)C#CC12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 VGLMCUAPQNXBMX-UHFFFAOYSA-N 0.000 claims 2
- FACWXGBOTJWNEG-UHFFFAOYSA-N 6-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]-1-morpholin-4-ylisoquinoline-3-carboxylic acid Chemical compound OC(=O)C1=CC2=CC(=CC=C2C(=N1)N1CCOCC1)C#CC12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 FACWXGBOTJWNEG-UHFFFAOYSA-N 0.000 claims 2
- UWVTWSJJCWMSBX-UHFFFAOYSA-N 6-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]-1H-indazole-4-carboxylic acid Chemical compound OC(=O)c1cc(cc2[nH]ncc12)C#CC12CCC(CC1)(CC2)OCc1c(onc1-c1c(Cl)cncc1Cl)C1CC1 UWVTWSJJCWMSBX-UHFFFAOYSA-N 0.000 claims 2
- FVZHZZXEIXDCAU-UHFFFAOYSA-N 6-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]-1H-indole-4-carboxylic acid Chemical compound OC(=O)c1cc(cc2[nH]ccc12)C#CC12CCC(CC1)(CC2)OCc1c(onc1-c1c(Cl)cncc1Cl)C1CC1 FVZHZZXEIXDCAU-UHFFFAOYSA-N 0.000 claims 2
- XJTSSGUDXBLJOX-UHFFFAOYSA-N 6-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]-2-methylpyridine-3-carboxylic acid Chemical compound CC1=NC(=CC=C1C(O)=O)C#CC12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 XJTSSGUDXBLJOX-UHFFFAOYSA-N 0.000 claims 2
- IJOYJGSRLYNGHX-UHFFFAOYSA-N 6-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]-4-(difluoromethoxy)quinoline-2-carboxylic acid Chemical compound OC(=O)C1=NC2=C(C=C(C=C2)C#CC23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)C(OC(F)F)=C1 IJOYJGSRLYNGHX-UHFFFAOYSA-N 0.000 claims 2
- FCWPHZAWBUUALF-UHFFFAOYSA-N 6-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]-4-(trifluoromethyl)pyridine-3-carboxylic acid Chemical compound OC(=O)C1=CN=C(C=C1C(F)(F)F)C#CC12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 FCWPHZAWBUUALF-UHFFFAOYSA-N 0.000 claims 2
- UNSXJCDEVKZFJC-UHFFFAOYSA-N 6-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]-4-(trifluoromethyl)quinoline-2-carboxylic acid Chemical compound C1=2C(=CC(=NC1=CC=C(C#CC13CCC(CC1)(OCC=1C(C4=C(Cl)C=NC=C4Cl)=NOC=1C1CC1)CC3)C=2)C(=O)O)C(F)(F)F UNSXJCDEVKZFJC-UHFFFAOYSA-N 0.000 claims 2
- HMZNRSPTDAWOQF-UHFFFAOYSA-N 6-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]-4-methoxy-N,N-dimethylquinoline-2-carboxamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)C#CC=1C=C2C(=CC(=NC2=CC=1)C(=O)N(C)C)OC HMZNRSPTDAWOQF-UHFFFAOYSA-N 0.000 claims 2
- BPUYJUCMMUUXKG-UHFFFAOYSA-N 6-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]-4-methoxypyridine-2-carboxylic acid Chemical compound COC1=CC(=NC(=C1)C(O)=O)C#CC12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 BPUYJUCMMUUXKG-UHFFFAOYSA-N 0.000 claims 2
- BZPWHHFXRALUHJ-UHFFFAOYSA-N 6-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]-4-methoxyquinoline-2-carboxylic acid Chemical compound COC1=CC(=NC2=C1C=C(C=C2)C#CC12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1)C(O)=O BZPWHHFXRALUHJ-UHFFFAOYSA-N 0.000 claims 2
- BFOLGAJGUQFTOJ-UHFFFAOYSA-N 6-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]-4-propan-2-yloxyquinoline-2-carboxylic acid Chemical compound CC(C)OC1=CC(=NC2=C1C=C(C=C2)C#CC12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1)C(O)=O BFOLGAJGUQFTOJ-UHFFFAOYSA-N 0.000 claims 2
- BENHBDMPSKAHBL-UHFFFAOYSA-N 6-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]-5-fluoropyridine-3-carboxylic acid Chemical compound OC(=O)C1=CN=C(C#CC23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)C(F)=C1 BENHBDMPSKAHBL-UHFFFAOYSA-N 0.000 claims 2
- OUAGUFBGXYYMER-UHFFFAOYSA-N 6-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]imidazo[1,2-a]pyridine-8-carboxylic acid Chemical compound OC(=O)C1=CC(=CN2C=CN=C12)C#CC12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 OUAGUFBGXYYMER-UHFFFAOYSA-N 0.000 claims 2
- DVDFNRLZPAAJID-UHFFFAOYSA-N 6-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]pyridazine-3-carboxylic acid Chemical compound OC(=O)C1=CC=C(N=N1)C#CC12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 DVDFNRLZPAAJID-UHFFFAOYSA-N 0.000 claims 2
- KNOVNWAKJBUTEO-UHFFFAOYSA-N 6-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]quinoline-2-carboxylic acid Chemical compound OC(=O)C1=NC2=CC=C(C=C2C=C1)C#CC12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 KNOVNWAKJBUTEO-UHFFFAOYSA-N 0.000 claims 2
- VBGZNCZTIODECK-UHFFFAOYSA-N 6-[3-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-5-yl]pyridine-2-carboxylic acid Chemical compound OC(=O)C1=CC=CC(=N1)C1=NC(=NO1)C12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=CC=C1Cl)C1CC1 VBGZNCZTIODECK-UHFFFAOYSA-N 0.000 claims 2
- UZGHOHSXZJBXCY-UHFFFAOYSA-N 6-[3-[4-[[5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-5-yl]pyridine-2-carboxylic acid Chemical compound OC(=O)C1=CC=CC(=N1)C1=NC(=NO1)C12CCC(CC1)(CC2)OCC1=C(ON=C1C1=CC=CC=C1OC(F)(F)F)C1CC1 UZGHOHSXZJBXCY-UHFFFAOYSA-N 0.000 claims 2
- MJHFNWJSCIZWMS-UHFFFAOYSA-N 6-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1-methylpyrrolo[2,3-b]pyridine-3-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)C1=CC=C2C(=N1)N(C=C2C(=O)O)C MJHFNWJSCIZWMS-UHFFFAOYSA-N 0.000 claims 2
- XIQUUUJGRSAHID-UHFFFAOYSA-N 6-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]pyridine-3-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)C1=NC=C(C(=O)O)C=C1 XIQUUUJGRSAHID-UHFFFAOYSA-N 0.000 claims 2
- LWZWXVPIBBUZCS-UHFFFAOYSA-N 6-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,5-naphthyridine-2-carboxylic acid Chemical compound OC(=O)C1=NC2=C(C=C1)N=C(C=C2)C12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 LWZWXVPIBBUZCS-UHFFFAOYSA-N 0.000 claims 2
- JUOLNUVICVSFOF-UHFFFAOYSA-N 6-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1-ethylpyrazolo[3,4-b]pyridine-3-carboxylic acid Chemical compound CCN1N=C(C(O)=O)C2=CC=C(N=C12)C12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 JUOLNUVICVSFOF-UHFFFAOYSA-N 0.000 claims 2
- URZCSQZZYMCUTH-UHFFFAOYSA-N 6-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1-methylpyrazolo[3,4-b]pyridine-3-carboxylic acid Chemical compound CN1N=C(C(O)=O)C2=CC=C(N=C12)C12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 URZCSQZZYMCUTH-UHFFFAOYSA-N 0.000 claims 2
- DHOWRLMYESJZOE-UHFFFAOYSA-N 6-[5-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]-3-methoxypyridine-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)C1=NC(=NO1)C1=CC=C(C(=N1)C(=O)O)OC DHOWRLMYESJZOE-UHFFFAOYSA-N 0.000 claims 2
- XFNUKWLRGXKOHH-UHFFFAOYSA-N 6-[5-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]pyridine-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)C1=NC(=NO1)C1=CC=CC(=N1)C(=O)O XFNUKWLRGXKOHH-UHFFFAOYSA-N 0.000 claims 2
- CMJQZWWRGNZDMC-UHFFFAOYSA-N 6-[5-[4-[[5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]pyridine-2-carboxylic acid Chemical compound OC(=O)C1=CC=CC(=N1)C1=NOC(=N1)C12CCC(CC1)(CC2)OCC1=C(ON=C1C1=CC=CC=C1OC(F)(F)F)C1CC1 CMJQZWWRGNZDMC-UHFFFAOYSA-N 0.000 claims 2
- DZPUBFBGNVJPJQ-UHFFFAOYSA-N 6-[5-[4-[[5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]pyridine-2-carboxylic acid Chemical compound OC(=O)C1=CC=CC(=N1)C1=NOC(=N1)C12CCC(CC1)(CC2)OCC1=C(ON=C1C1=CC=CC=C1C(F)(F)F)C1CC1 DZPUBFBGNVJPJQ-UHFFFAOYSA-N 0.000 claims 2
- BKXWRZWBBNJDEN-AATRIKPKSA-N 6-[[1-[(E)-2-[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]ethenyl]-2-oxabicyclo[2.2.2]octan-4-yl]methoxy]-4-(difluoromethoxy)quinoline-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)/C=C/C12OCC(CC1)(CC2)COC=1C=C2C(=CC(=NC2=CC=1)C(=O)O)OC(F)F BKXWRZWBBNJDEN-AATRIKPKSA-N 0.000 claims 2
- WPNTWEJXPJOBCX-AATRIKPKSA-N 6-[[4-[(E)-2-[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]ethenyl]-1-bicyclo[2.2.2]octanyl]methoxy]-4-(difluoromethoxy)quinoline-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)/C=C/C12CCC(CC1)(CC2)COC=1C=C2C(=CC(=NC2=CC=1)C(=O)O)OC(F)F WPNTWEJXPJOBCX-AATRIKPKSA-N 0.000 claims 2
- HNOMCMXRVKWLGX-AATRIKPKSA-N 6-[[4-[(E)-2-[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]ethenyl]-1-bicyclo[2.2.2]octanyl]methoxy]-4-(trifluoromethyl)quinoline-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)/C=C/C12CCC(CC1)(CC2)COC=1C=C2C(=CC(=NC2=CC=1)C(=O)O)C(F)(F)F HNOMCMXRVKWLGX-AATRIKPKSA-N 0.000 claims 2
- MNPFGEKQMZWWBS-VOTSOKGWSA-N 6-[[4-[(E)-2-[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]ethenyl]-1-bicyclo[2.2.2]octanyl]methoxy]-4-methoxyquinoline-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)/C=C/C12CCC(CC1)(CC2)COC=1C=C2C(=CC(=NC2=CC=1)C(=O)O)OC MNPFGEKQMZWWBS-VOTSOKGWSA-N 0.000 claims 2
- OLNJPPKBVNVFQV-AATRIKPKSA-N 6-[[4-[(E)-2-[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]ethenyl]-2-oxabicyclo[2.2.2]octan-1-yl]methoxy]-4-(trifluoromethyl)quinoline-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)/C=C/C12COC(CC1)(CC2)COC=1C=C2C(=CC(=NC2=CC=1)C(=O)O)C(F)(F)F OLNJPPKBVNVFQV-AATRIKPKSA-N 0.000 claims 2
- CPHUJZRRSSSESC-BQYQJAHWSA-N 6-[[4-[(E)-2-[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]ethenyl]-2-oxabicyclo[2.2.2]octan-1-yl]methoxy]-4-propan-2-yloxyquinoline-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)/C=C/C12COC(CC1)(CC2)COC=1C=C2C(=CC(=NC2=CC=1)C(=O)O)OC(C)C CPHUJZRRSSSESC-BQYQJAHWSA-N 0.000 claims 2
- JKPLCBNWFFIWTP-UHFFFAOYSA-N 6-[[4-[[3-(3-chloro-5-methoxypyridin-4-yl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-3-methylpyridine-2-carboxylic acid Chemical compound ClC=1C=NC=C(C=1C1=NOC(=C1COC12CCC(CC1)(CC2)COC1=CC=C(C(=N1)C(=O)O)C)C1CC1)OC JKPLCBNWFFIWTP-UHFFFAOYSA-N 0.000 claims 2
- LKBUNXXRBNUZIG-UHFFFAOYSA-N 6-[[4-[[3-(3-chloro-5-methoxypyridin-4-yl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-4-methylpyridine-3-carboxylic acid Chemical compound ClC=1C=NC=C(C=1C1=NOC(=C1COC12CCC(CC1)(CC2)COC1=NC=C(C(=O)O)C(=C1)C)C1CC1)OC LKBUNXXRBNUZIG-UHFFFAOYSA-N 0.000 claims 2
- TZAKSOREWJSVGG-UHFFFAOYSA-N 6-[[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-hydroxymethyl]naphthalene-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)C(C=1C=C2C=CC(=CC2=CC=1)C(=O)O)O TZAKSOREWJSVGG-UHFFFAOYSA-N 0.000 claims 2
- QNGXXBUVPJMLSB-UHFFFAOYSA-N 6-[[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-1-methylindole-3-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC1=CC=C2C(=CN(C2=C1)C)C(=O)O QNGXXBUVPJMLSB-UHFFFAOYSA-N 0.000 claims 2
- LLFVOWYCDQTFOQ-UHFFFAOYSA-N 6-[[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-4-(trifluoromethyl)quinoline-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC=1C=C2C(=CC(=NC2=CC=1)C(=O)O)C(F)(F)F LLFVOWYCDQTFOQ-UHFFFAOYSA-N 0.000 claims 2
- JVJQBNMFLWJKGS-UHFFFAOYSA-N 6-[[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]pyrazine-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC1=CN=CC(=N1)C(=O)O JVJQBNMFLWJKGS-UHFFFAOYSA-N 0.000 claims 2
- XCNAMCFSOUZOFB-UHFFFAOYSA-N 6-[[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]pyridine-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC1=CC=CC(=N1)C(=O)O XCNAMCFSOUZOFB-UHFFFAOYSA-N 0.000 claims 2
- KPBJBOHVGKQDTP-UHFFFAOYSA-N 6-[[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]pyridine-3-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC1=NC=C(C(=O)O)C=C1 KPBJBOHVGKQDTP-UHFFFAOYSA-N 0.000 claims 2
- VMPROHZLTYVFOR-UHFFFAOYSA-N 6-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-1,5-naphthyridine-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC=1N=C2C=CC(=NC2=CC=1)C(=O)O VMPROHZLTYVFOR-UHFFFAOYSA-N 0.000 claims 2
- YWKIRXJMCGIMOM-UHFFFAOYSA-N 6-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-1-methylindole-3-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC1=CC=C2C(=CN(C2=C1)C)C(=O)O YWKIRXJMCGIMOM-UHFFFAOYSA-N 0.000 claims 2
- JEJMNPWJFXSVTN-UHFFFAOYSA-N 6-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-4-(2-methylpropoxy)quinoline-2-carboxylic acid Chemical compound CC(C)COC1=CC(=NC2=CC=C(OCC34CCC(CC3)(CC4)OCC3=C(ON=C3C3=C(Cl)C=NC=C3Cl)C3CC3)C=C12)C(O)=O JEJMNPWJFXSVTN-UHFFFAOYSA-N 0.000 claims 2
- GODFICYVBREPEH-UHFFFAOYSA-N 6-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-4-(3-methoxyazetidin-1-yl)quinoline-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC=1C=C2C(=CC(=NC2=CC=1)C(=O)O)N1CC(C1)OC GODFICYVBREPEH-UHFFFAOYSA-N 0.000 claims 2
- LEQOJNMSKIRROL-UHFFFAOYSA-N 6-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-4-(cyclopropylmethoxy)-7-fluoroquinoline-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC=1C=C2C(=CC(=NC2=CC=1F)C(=O)O)OCC1CC1 LEQOJNMSKIRROL-UHFFFAOYSA-N 0.000 claims 2
- AFPROGJJEKEZEQ-UHFFFAOYSA-N 6-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-4-(cyclopropylmethoxy)quinoline-2-carboxylic acid Chemical compound OC(=O)C1=NC2=CC=C(OCC34CCC(CC3)(CC4)OCC3=C(ON=C3C3=C(Cl)C=NC=C3Cl)C3CC3)C=C2C(OCC2CC2)=C1 AFPROGJJEKEZEQ-UHFFFAOYSA-N 0.000 claims 2
- HQGPWGYDCIJFKC-UHFFFAOYSA-N 6-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-4-(difluoromethoxy)quinoline-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC=1C=C2C(=CC(=NC2=CC=1)C(=O)O)OC(F)F HQGPWGYDCIJFKC-UHFFFAOYSA-N 0.000 claims 2
- KRUFBCCMOLEMGI-UHFFFAOYSA-N 6-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-4-(oxetan-3-ylmethoxy)quinoline-2-carboxylic acid Chemical compound OC(=O)C1=NC2=CC=C(OCC34CCC(CC3)(CC4)OCC3=C(ON=C3C3=C(Cl)C=NC=C3Cl)C3CC3)C=C2C(OCC2COC2)=C1 KRUFBCCMOLEMGI-UHFFFAOYSA-N 0.000 claims 2
- NJSGVLUIYNRMLB-UHFFFAOYSA-N 6-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-4-(oxetan-3-yloxy)quinoline-2-carboxylic acid Chemical compound OC(=O)C1=NC2=CC=C(OCC34CCC(CC3)(CC4)OCC3=C(ON=C3C3=C(Cl)C=NC=C3Cl)C3CC3)C=C2C(OC2COC2)=C1 NJSGVLUIYNRMLB-UHFFFAOYSA-N 0.000 claims 2
- NXVPVIBWFNWSDO-UHFFFAOYSA-N 6-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-4-(trifluoromethyl)pyridine-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC1=CC(=CC(=N1)C(=O)O)C(F)(F)F NXVPVIBWFNWSDO-UHFFFAOYSA-N 0.000 claims 2
- SSSWRKXUHQHDEW-UHFFFAOYSA-N 6-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-4-(trifluoromethyl)pyridine-3-carboxylic acid Chemical compound OC(=O)C1=C(C=C(OCC23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)N=C1)C(F)(F)F SSSWRKXUHQHDEW-UHFFFAOYSA-N 0.000 claims 2
- PPEDFXXWSUZXSG-UHFFFAOYSA-N 6-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-4-(trifluoromethyl)quinoline-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC=1C=C2C(=CC(=NC2=CC=1)C(=O)O)C(F)(F)F PPEDFXXWSUZXSG-UHFFFAOYSA-N 0.000 claims 2
- IBPDZMRFYXTMIG-UHFFFAOYSA-N 6-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-4-ethoxy-7-fluoroquinoline-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC=1C=C2C(=CC(=NC2=CC=1F)C(=O)O)OCC IBPDZMRFYXTMIG-UHFFFAOYSA-N 0.000 claims 2
- MHIBKXCBYXMDST-UHFFFAOYSA-N 6-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-4-ethoxy-8-fluoroquinoline-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC=1C=C2C(=CC(=NC2=C(C=1)F)C(=O)O)OCC MHIBKXCBYXMDST-UHFFFAOYSA-N 0.000 claims 2
- SROOWOWZERCJKU-UHFFFAOYSA-N 6-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-4-ethoxyquinoline-2-carboxylic acid Chemical compound CCOC1=CC(=NC2=CC=C(OCC34CCC(CC3)(CC4)OCC3=C(ON=C3C3=C(Cl)C=NC=C3Cl)C3CC3)C=C12)C(O)=O SROOWOWZERCJKU-UHFFFAOYSA-N 0.000 claims 2
- GTKZANGPNBCQCM-UHFFFAOYSA-N 6-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-4-ethylquinoline-2-carboxylic acid Chemical compound CCC1=CC(=NC2=CC=C(OCC34CCC(CC3)(CC4)OCC3=C(ON=C3C3=C(Cl)C=NC=C3Cl)C3CC3)C=C12)C(O)=O GTKZANGPNBCQCM-UHFFFAOYSA-N 0.000 claims 2
- XHXAGNNTFOAPQP-UHFFFAOYSA-N 6-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-4-methoxypyridine-2-carboxylic acid Chemical compound COC1=CC(OCC23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)=NC(=C1)C(O)=O XHXAGNNTFOAPQP-UHFFFAOYSA-N 0.000 claims 2
- SINTWJMSZIZWDB-UHFFFAOYSA-N 6-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-4-methoxypyridine-3-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC1=NC=C(C(=O)O)C(=C1)OC SINTWJMSZIZWDB-UHFFFAOYSA-N 0.000 claims 2
- IDHYHTJHJDQQJC-UHFFFAOYSA-N 6-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-4-methoxyquinoline-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC=1C=C2C(=CC(=NC2=CC=1)C(=O)O)OC IDHYHTJHJDQQJC-UHFFFAOYSA-N 0.000 claims 2
- SYYLCGIHANJJDM-UHFFFAOYSA-N 6-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-4-methylsulfonylquinoline-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC=1C=C2C(=CC(=NC2=CC=1)C(=O)O)S(=O)(=O)C SYYLCGIHANJJDM-UHFFFAOYSA-N 0.000 claims 2
- UQPVNESMQGSVPN-UHFFFAOYSA-N 6-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-4-oxo-1H-quinoline-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC=1C=C2C(=CC(=NC2=CC=1)C(=O)O)O UQPVNESMQGSVPN-UHFFFAOYSA-N 0.000 claims 2
- KGVLTKTXRFHOQF-UHFFFAOYSA-N 6-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-4-propan-2-yloxyquinoline-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC=1C=C2C(=CC(=NC2=CC=1)C(=O)O)OC(C)C KGVLTKTXRFHOQF-UHFFFAOYSA-N 0.000 claims 2
- QJRZPTBGIRHTPX-UHFFFAOYSA-N 6-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-4-propylquinoline-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC=1C=C2C(=CC(=NC2=CC=1)C(=O)O)CCC QJRZPTBGIRHTPX-UHFFFAOYSA-N 0.000 claims 2
- BQPMJMLIAHSHRG-UHFFFAOYSA-N 6-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-5-(trifluoromethyl)pyridine-3-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC1=NC=C(C(=O)O)C=C1C(F)(F)F BQPMJMLIAHSHRG-UHFFFAOYSA-N 0.000 claims 2
- DTEBNIMQQGDJEM-UHFFFAOYSA-N 6-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-5-fluoropyridine-3-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC1=NC=C(C(=O)O)C=C1F DTEBNIMQQGDJEM-UHFFFAOYSA-N 0.000 claims 2
- JYAHYSPNAAVSLZ-UHFFFAOYSA-N 6-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-8-fluoro-4-(oxetan-3-yloxy)quinoline-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC=1C=C2C(=CC(=NC2=C(C=1)F)C(=O)O)OC1COC1 JYAHYSPNAAVSLZ-UHFFFAOYSA-N 0.000 claims 2
- CAKHNNKSADIIGV-UHFFFAOYSA-N 6-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-8-fluoro-4-methoxyquinoline-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC=1C=C2C(=CC(=NC2=C(C=1)F)C(=O)O)OC CAKHNNKSADIIGV-UHFFFAOYSA-N 0.000 claims 2
- WUEHDPQNJKMDJS-UHFFFAOYSA-N 6-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-8-fluoro-4-methylquinoline-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC=1C=C2C(=CC(=NC2=C(C=1)F)C(=O)O)C WUEHDPQNJKMDJS-UHFFFAOYSA-N 0.000 claims 2
- MBYZYARPQUOHDN-UHFFFAOYSA-N 6-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-8-fluoro-4-propan-2-yloxyquinoline-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC=1C=C2C(=CC(=NC2=C(C=1)F)C(=O)O)OC(C)C MBYZYARPQUOHDN-UHFFFAOYSA-N 0.000 claims 2
- OWWQJHFEDXHNQR-UHFFFAOYSA-N 6-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-8-fluoro-4-propylquinoline-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC=1C=C2C(=CC(=NC2=C(C=1)F)C(=O)O)CCC OWWQJHFEDXHNQR-UHFFFAOYSA-N 0.000 claims 2
- FZEXMBSEHOHXAE-UHFFFAOYSA-N 6-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]imidazo[1,2-b]pyridazine-3-carbonitrile Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC=1C=CC=2N(N=1)C(=CN=2)C#N FZEXMBSEHOHXAE-UHFFFAOYSA-N 0.000 claims 2
- TZUHLNVGYYTVSF-UHFFFAOYSA-N 6-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]imidazo[1,2-b]pyridazine-3-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC=1C=CC=2N(N=1)C(=CN=2)C(=O)O TZUHLNVGYYTVSF-UHFFFAOYSA-N 0.000 claims 2
- MBQCELYAKCNSLA-UHFFFAOYSA-N 6-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]pyridine-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC1=CC=CC(=N1)C(=O)O MBQCELYAKCNSLA-UHFFFAOYSA-N 0.000 claims 2
- HKLCQDDOPWQVSB-UHFFFAOYSA-N 6-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]quinoline-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)COC=1C=C2C=CC(=NC2=CC=1)C(=O)O HKLCQDDOPWQVSB-UHFFFAOYSA-N 0.000 claims 2
- FFHAOOKVOPSHCO-UHFFFAOYSA-N 6-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxymethyl]-4-(trifluoromethyl)pyridine-2-carboxylic acid Chemical compound OC(=O)C1=NC(COCC23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)=CC(=C1)C(F)(F)F FFHAOOKVOPSHCO-UHFFFAOYSA-N 0.000 claims 2
- OYPJXVNKEXEFGZ-UHFFFAOYSA-N 6-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-2-oxabicyclo[2.2.2]octan-1-yl]methoxy]-4-(difluoromethoxy)quinoline-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12COC(CC1)(CC2)COC=1C=C2C(=CC(=NC2=CC=1)C(=O)O)OC(F)F OYPJXVNKEXEFGZ-UHFFFAOYSA-N 0.000 claims 2
- GMWOGVFLSCQHJC-UHFFFAOYSA-N 6-[[4-[[5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-4-(trifluoromethyl)quinoline-2-carboxylic acid Chemical compound OC(=O)C1=NC2=CC=C(OCC34CCC(CC3)(CC4)OCC3=C(ON=C3C3=CC=CC=C3C(F)(F)F)C3CC3)C=C2C(=C1)C(F)(F)F GMWOGVFLSCQHJC-UHFFFAOYSA-N 0.000 claims 2
- VIJZTGRVAYCBSJ-UHFFFAOYSA-N 6-[[4-[[5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-4-methoxyquinoline-2-carboxylic acid Chemical compound COC1=CC(=NC2=CC=C(OCC34CCC(CC3)(CC4)OCC3=C(ON=C3C3=CC=CC=C3C(F)(F)F)C3CC3)C=C12)C(O)=O VIJZTGRVAYCBSJ-UHFFFAOYSA-N 0.000 claims 2
- AMXXRXOALPXPBH-UHFFFAOYSA-N 6-cyclobutyloxy-4-[5-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]pyridine-2-carboxylic acid Chemical compound C1(CCC1)OC1=CC(=CC(=N1)C(=O)O)C1=NOC(=N1)C12CCC(CC1)(CC2)OCC=1C(=NOC=1C1CC1)C1=C(C=NC=C1Cl)Cl AMXXRXOALPXPBH-UHFFFAOYSA-N 0.000 claims 2
- MCRKSMWUNWGFAU-AATRIKPKSA-N 7-[(E)-2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethenyl]-1-(3-fluoroazetidin-1-yl)isoquinoline-3-carboxylic acid Chemical compound OC(=O)C1=CC2=C(C=C(\C=C\C34CCC(CC3)(CC4)OCC3=C(ON=C3C3=C(Cl)C=NC=C3Cl)C3CC3)C=C2)C(=N1)N1CC(F)C1 MCRKSMWUNWGFAU-AATRIKPKSA-N 0.000 claims 2
- FABVVWZJGKTMKZ-AATRIKPKSA-N 7-[(E)-2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethenyl]-1-(3-hydroxyazetidin-1-yl)isoquinoline-3-carboxylic acid Chemical compound OC1CN(C1)C1=NC(=CC2=C1C=C(\C=C\C13CCC(CC1)(CC3)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1)C=C2)C(O)=O FABVVWZJGKTMKZ-AATRIKPKSA-N 0.000 claims 2
- TYJGIQVKKHAZHS-VOTSOKGWSA-N 7-[(E)-2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethenyl]-1-(3-methoxyazetidin-1-yl)isoquinoline-3-carboxylic acid Chemical compound COC1CN(C1)C1=NC(=CC2=C1C=C(\C=C\C13CCC(CC1)(CC3)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1)C=C2)C(O)=O TYJGIQVKKHAZHS-VOTSOKGWSA-N 0.000 claims 2
- ZAVPYEOKYCLCSH-BQYQJAHWSA-N 7-[(E)-2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethenyl]-1-(3-methoxypropoxy)isoquinoline-3-carboxylic acid Chemical compound COCCCOC1=NC(=CC2=C1C=C(\C=C\C13CCC(CC1)(CC3)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1)C=C2)C(O)=O ZAVPYEOKYCLCSH-BQYQJAHWSA-N 0.000 claims 2
- VFEBUNAVRGTMPU-AATRIKPKSA-N 7-[(E)-2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethenyl]-1-[3-(hydroxymethyl)azetidin-1-yl]isoquinoline-3-carboxylic acid Chemical compound OCC1CN(C1)C1=NC(=CC2=C1C=C(\C=C\C13CCC(CC1)(CC3)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1)C=C2)C(O)=O VFEBUNAVRGTMPU-AATRIKPKSA-N 0.000 claims 2
- MZBGAKNKNVCBPG-BQYQJAHWSA-N 7-[(E)-2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethenyl]-1-cyclopropyloxyisoquinoline-3-carboxylic acid Chemical compound OC(=O)C1=CC2=C(C=C(\C=C\C34CCC(CC3)(CC4)OCC3=C(ON=C3C3=C(Cl)C=NC=C3Cl)C3CC3)C=C2)C(OC2CC2)=N1 MZBGAKNKNVCBPG-BQYQJAHWSA-N 0.000 claims 2
- PHXBORMTXKNQBY-BQYQJAHWSA-N 7-[(E)-2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethenyl]-1-ethoxyisoquinoline-3-carboxylic acid Chemical compound CCOC1=NC(=CC2=C1C=C(\C=C\C13CCC(CC1)(CC3)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1)C=C2)C(O)=O PHXBORMTXKNQBY-BQYQJAHWSA-N 0.000 claims 2
- QHDRAKFSJWHEJN-VOTSOKGWSA-N 7-[(E)-2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethenyl]-1-methoxyisoquinoline-3-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)/C=C/C1=CC=C2C=C(N=C(C2=C1)OC)C(=O)O QHDRAKFSJWHEJN-VOTSOKGWSA-N 0.000 claims 2
- LNKFLVYZFNTXSH-AATRIKPKSA-N 7-[(E)-2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethenyl]-1-morpholin-4-ylisoquinoline-3-carboxylic acid Chemical compound OC(=O)C1=CC2=C(C=C(\C=C\C34CCC(CC3)(CC4)OCC3=C(ON=C3C3=C(Cl)C=NC=C3Cl)C3CC3)C=C2)C(=N1)N1CCOCC1 LNKFLVYZFNTXSH-AATRIKPKSA-N 0.000 claims 2
- ZYODQZJZOOPZDO-HWKANZROSA-N 7-[(E)-2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethenyl]imidazo[1,2-a]pyridine-3-carboxylic acid Chemical compound OC(=O)C1=CN=C2C=C(\C=C\C34CCC(CC3)(CC4)OCC3=C(ON=C3C3=C(Cl)C=NC=C3Cl)C3CC3)C=CN12 ZYODQZJZOOPZDO-HWKANZROSA-N 0.000 claims 2
- GZPUGVNZOVCVCT-UHFFFAOYSA-N 7-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]-1-(2-pyrrolidin-1-ylethoxy)isoquinoline-3-carboxylic acid Chemical compound OC(=O)C1=CC2=C(C=C(C=C2)C#CC23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)C(OCCN2CCCC2)=N1 GZPUGVNZOVCVCT-UHFFFAOYSA-N 0.000 claims 2
- HCUVUOYNAMYMGZ-UHFFFAOYSA-N 7-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]-1-(3-fluoroazetidin-1-yl)isoquinoline-3-carboxylic acid Chemical compound OC(=O)C1=CC2=C(C=C(C=C2)C#CC23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)C(=N1)N1CC(F)C1 HCUVUOYNAMYMGZ-UHFFFAOYSA-N 0.000 claims 2
- DAQIIRPVWHWLAI-UHFFFAOYSA-N 7-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]-1-(3-hydroxyazetidin-1-yl)isoquinoline-3-carboxylic acid Chemical compound OC1CN(C1)C1=NC(=CC2=C1C=C(C=C2)C#CC12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1)C(O)=O DAQIIRPVWHWLAI-UHFFFAOYSA-N 0.000 claims 2
- RMRNPIYWZQJVSA-UHFFFAOYSA-N 7-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]-1-(3-hydroxypyrrolidin-1-yl)isoquinoline-3-carboxylic acid Chemical compound OC1CCN(C1)C1=NC(=CC2=C1C=C(C=C2)C#CC12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1)C(O)=O RMRNPIYWZQJVSA-UHFFFAOYSA-N 0.000 claims 2
- OIPCKFACUTZLCI-UHFFFAOYSA-N 7-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]-1-[3-(dimethylamino)azetidin-1-yl]isoquinoline-3-carboxylic acid Chemical compound CN(C)C1CN(C1)C1=NC(=CC2=C1C=C(C=C2)C#CC12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1)C(O)=O OIPCKFACUTZLCI-UHFFFAOYSA-N 0.000 claims 2
- UUIOGVRAZSXXNM-UHFFFAOYSA-N 7-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]-1-methoxyisoquinoline-3-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=NC=C1Cl)Cl)COC12CCC(CC1)(CC2)C#CC1=CC=C2C=C(N=C(C2=C1)OC)C(=O)O UUIOGVRAZSXXNM-UHFFFAOYSA-N 0.000 claims 2
- YTFFITIOBXGTDI-UHFFFAOYSA-N 7-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]-1-morpholin-4-ylisoquinoline-3-carboxylic acid Chemical compound OC(=O)C1=CC2=C(C=C(C=C2)C#CC23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)C(=N1)N1CCOCC1 YTFFITIOBXGTDI-UHFFFAOYSA-N 0.000 claims 2
- WEDCERDTHIVAIY-UHFFFAOYSA-N 7-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]-1-piperazin-1-ylisoquinoline-3-carboxylic acid Chemical compound OC(=O)C1=CC2=C(C=C(C=C2)C#CC23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)C(=N1)N1CCNCC1 WEDCERDTHIVAIY-UHFFFAOYSA-N 0.000 claims 2
- UJBZFBGSKXDOMB-UHFFFAOYSA-N 7-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]imidazo[1,2-a]pyridine-2-carboxylic acid Chemical compound OC(=O)C1=CN2C=CC(=CC2=N1)C#CC12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 UJBZFBGSKXDOMB-UHFFFAOYSA-N 0.000 claims 2
- TVMKOQXOKATKAL-UHFFFAOYSA-N 7-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-1-ethoxyisoquinoline-3-carboxylic acid Chemical compound CCOC1=NC(=CC2=CC=C(OCC34CCC(CC3)(CC4)OCC3=C(ON=C3C3=C(Cl)C=NC=C3Cl)C3CC3)C=C12)C(O)=O TVMKOQXOKATKAL-UHFFFAOYSA-N 0.000 claims 2
- SUAVWWBKNLTFBI-UHFFFAOYSA-N 7-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]-1-ethylisoquinoline-3-carboxylic acid Chemical compound CCC1=NC(=CC2=CC=C(OCC34CCC(CC3)(CC4)OCC3=C(ON=C3C3=C(Cl)C=NC=C3Cl)C3CC3)C=C12)C(O)=O SUAVWWBKNLTFBI-UHFFFAOYSA-N 0.000 claims 2
- FDHGGOLHSWEJMP-UHFFFAOYSA-N 7-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]isoquinoline-3-carboxylic acid Chemical compound OC(=O)C1=CC2=CC=C(OCC34CCC(CC3)(CC4)OCC3=C(ON=C3C3=C(Cl)C=NC=C3Cl)C3CC3)C=C2C=N1 FDHGGOLHSWEJMP-UHFFFAOYSA-N 0.000 claims 2
- ROWGGXHYZOKNRE-UHFFFAOYSA-N 7-chloro-1-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]isoquinoline-3-carboxylic acid Chemical compound OC(=O)C1=NC(C#CC23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)=C2C=C(Cl)C=CC2=C1 ROWGGXHYZOKNRE-UHFFFAOYSA-N 0.000 claims 2
- UIWMZEUVMWOTNT-UHFFFAOYSA-N 8-[2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethynyl]quinoline-5-carboxylic acid Chemical compound OC(=O)C1=C2C=CC=NC2=C(C=C1)C#CC12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 UIWMZEUVMWOTNT-UHFFFAOYSA-N 0.000 claims 2
- YGXWIWKYJUSMQH-UHFFFAOYSA-N 8-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]quinoline-5-carboxylic acid Chemical compound OC(=O)C1=C2C=CC=NC2=C(OCC23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)C=C1 YGXWIWKYJUSMQH-UHFFFAOYSA-N 0.000 claims 2
- SAOIVFMCMRLOPD-UHFFFAOYSA-N 8-[[4-[[5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]quinoline-5-carboxylic acid Chemical compound OC(=O)C1=C2C=CC=NC2=C(OCC23CCC(CC2)(CC3)OCC2=C(ON=C2C2=CC=CC=C2C(F)(F)F)C2CC2)C=C1 SAOIVFMCMRLOPD-UHFFFAOYSA-N 0.000 claims 2
- QTKLZFBAUPDCBN-UHFFFAOYSA-N 8-chloro-2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-6-methoxyquinoline-5-carboxylic acid Chemical compound COC1=C(C(O)=O)C2=C(N=C(C=C2)C23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)C(Cl)=C1 QTKLZFBAUPDCBN-UHFFFAOYSA-N 0.000 claims 2
- SPIMLZZZZRKZIC-UHFFFAOYSA-N 8-chloro-2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-6-propan-2-yloxyquinoline-5-carboxylic acid Chemical compound CC(C)OC1=C(C(O)=O)C2=C(N=C(C=C2)C23CCC(CC2)(CC3)OCC2=C(ON=C2C2=C(Cl)C=NC=C2Cl)C2CC2)C(Cl)=C1 SPIMLZZZZRKZIC-UHFFFAOYSA-N 0.000 claims 2
- YPWDJYRSYDWICV-UHFFFAOYSA-N 8-chloro-6-cyclobutyloxy-2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]quinoline-5-carboxylic acid Chemical compound OC(=O)C1=C(OC2CCC2)C=C(Cl)C2=C1C=CC(=N2)C12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 YPWDJYRSYDWICV-UHFFFAOYSA-N 0.000 claims 2
- CDXOPRYHQWXKBA-UHFFFAOYSA-N 8-cyano-2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]quinoline-5-carboxylic acid Chemical compound C(#N)C1=CC=C(C=2C=CC(=NC1=2)C12CCC(CC1)(CC2)OCC=1C(=NOC=1C1CC1)C1=C(C=NC=C1Cl)Cl)C(=O)O CDXOPRYHQWXKBA-UHFFFAOYSA-N 0.000 claims 2
- MZEPUGKXGDBXTQ-UHFFFAOYSA-N 8-cyclobutyloxy-2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]quinoline-5-carboxylic acid Chemical compound OC(=O)C1=CC=C(OC2CCC2)C2=NC(=CC=C12)C12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 MZEPUGKXGDBXTQ-UHFFFAOYSA-N 0.000 claims 2
- KSQYXXHEKGGTCB-UHFFFAOYSA-N 8-cyclobutyloxy-2-[[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methoxy]quinoline-5-carboxylic acid Chemical compound C1(CCC1)OC1=CC=C(C=2C=CC(=NC1=2)OCC12CCC(CC1)(CC2)OCC=1C(=NOC=1C1CC1)C1=C(C=NC=C1Cl)Cl)C(=O)O KSQYXXHEKGGTCB-UHFFFAOYSA-N 0.000 claims 2
- WAMNDRORUJZBBV-UHFFFAOYSA-N 8-cyclopentyloxy-2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]quinoline-5-carboxylic acid Chemical compound OC(=O)C1=CC=C(OC2CCCC2)C2=NC(=CC=C12)C12CCC(CC1)(CC2)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1 WAMNDRORUJZBBV-UHFFFAOYSA-N 0.000 claims 2
- JPOQQUGIOXZHPJ-UHFFFAOYSA-N 8-cyclopropyl-2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]quinoline-5-carboxylic acid Chemical compound C1(CC1)C1=CC=C(C=2C=CC(=NC1=2)C12CCC(CC1)(CC2)OCC=1C(=NOC=1C1CC1)C1=C(C=NC=C1Cl)Cl)C(=O)O JPOQQUGIOXZHPJ-UHFFFAOYSA-N 0.000 claims 2
- GZBSUNIYGVGJSU-UHFFFAOYSA-N [5-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]methanol Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)C1=NC(=NO1)CO GZBSUNIYGVGJSU-UHFFFAOYSA-N 0.000 claims 2
- VDFSIQSDJNIOOD-UHFFFAOYSA-N methyl 3-[5-[4-[2-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]ethenyl]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]benzoate Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)C=CC12CCC(CC1)(CC2)C1=NC(=NO1)C=1C=C(C(=O)OC)C=CC=1 VDFSIQSDJNIOOD-UHFFFAOYSA-N 0.000 claims 2
- 235000001968 nicotinic acid Nutrition 0.000 claims 2
- 239000011664 nicotinic acid Substances 0.000 claims 2
- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 claims 2
- HRSDPDBQVZHCRC-UHFFFAOYSA-N pyrazolo[1,5-a]pyridine-3-carboxylic acid Chemical compound C1=CC=CC2=C(C(=O)O)C=NN21 HRSDPDBQVZHCRC-UHFFFAOYSA-N 0.000 claims 2
- LOAUVZALPPNFOQ-UHFFFAOYSA-N quinaldic acid Chemical compound C1=CC=CC2=NC(C(=O)O)=CC=C21 LOAUVZALPPNFOQ-UHFFFAOYSA-N 0.000 claims 2
- QRDZFPUVLYEQTA-UHFFFAOYSA-N quinoline-8-carboxylic acid Chemical compound C1=CN=C2C(C(=O)O)=CC=CC2=C1 QRDZFPUVLYEQTA-UHFFFAOYSA-N 0.000 claims 2
- HFUUIPMSPWIDDU-VOTSOKGWSA-N 7-[(E)-2-[4-[[5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethenyl]-1-(4-methylpiperazin-1-yl)isoquinoline-3-carboxylic acid Chemical compound CN1CCN(CC1)C1=NC(=CC2=C1C=C(\C=C\C13CCC(CC1)(CC3)OCC1=C(ON=C1C1=C(Cl)C=NC=C1Cl)C1CC1)C=C2)C(O)=O HFUUIPMSPWIDDU-VOTSOKGWSA-N 0.000 claims 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 140
- 239000012453 solvate Substances 0.000 abstract description 28
- 201000010099 disease Diseases 0.000 abstract description 23
- 230000000694 effects Effects 0.000 abstract description 16
- 239000000556 agonist Substances 0.000 abstract description 5
- 230000008482 dysregulation Effects 0.000 abstract description 3
- 208000001132 Osteoporosis Diseases 0.000 abstract 1
- 206010052779 Transplant rejections Diseases 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 210
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 127
- 238000006243 chemical reaction Methods 0.000 description 113
- 238000005481 NMR spectroscopy Methods 0.000 description 111
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 110
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 106
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 98
- 230000015572 biosynthetic process Effects 0.000 description 79
- 238000002360 preparation method Methods 0.000 description 77
- 238000003786 synthesis reaction Methods 0.000 description 75
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 67
- 102100038495 Bile acid receptor Human genes 0.000 description 66
- 101000603876 Homo sapiens Bile acid receptor Proteins 0.000 description 66
- 239000000203 mixture Substances 0.000 description 65
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 61
- 239000007787 solid Substances 0.000 description 55
- 125000003118 aryl group Chemical group 0.000 description 52
- 239000002253 acid Substances 0.000 description 48
- 235000019439 ethyl acetate Nutrition 0.000 description 48
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 47
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 46
- 125000001072 heteroaryl group Chemical group 0.000 description 46
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 45
- 239000002904 solvent Substances 0.000 description 45
- 239000012043 crude product Substances 0.000 description 44
- 239000012071 phase Substances 0.000 description 44
- 125000000623 heterocyclic group Chemical group 0.000 description 42
- 125000004432 carbon atom Chemical group C* 0.000 description 41
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 40
- 229910052757 nitrogen Inorganic materials 0.000 description 40
- 238000003818 flash chromatography Methods 0.000 description 38
- 239000000047 product Substances 0.000 description 37
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 36
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- 239000000741 silica gel Substances 0.000 description 33
- 229910002027 silica gel Inorganic materials 0.000 description 33
- 239000002585 base Substances 0.000 description 32
- 239000011541 reaction mixture Substances 0.000 description 32
- 239000011734 sodium Substances 0.000 description 31
- 229910052717 sulfur Inorganic materials 0.000 description 31
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 30
- 229910052760 oxygen Inorganic materials 0.000 description 29
- 239000000243 solution Substances 0.000 description 29
- 239000012267 brine Substances 0.000 description 28
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 28
- 229940124597 therapeutic agent Drugs 0.000 description 28
- 239000000460 chlorine Substances 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
- 239000003153 chemical reaction reagent Substances 0.000 description 25
- 239000012074 organic phase Substances 0.000 description 25
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 24
- 238000002953 preparative HPLC Methods 0.000 description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 125000003545 alkoxy group Chemical group 0.000 description 21
- 125000002947 alkylene group Chemical group 0.000 description 21
- 125000000753 cycloalkyl group Chemical group 0.000 description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 20
- 150000002148 esters Chemical class 0.000 description 20
- 239000002245 particle Substances 0.000 description 20
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 19
- 125000001188 haloalkyl group Chemical group 0.000 description 19
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 19
- 239000007858 starting material Substances 0.000 description 19
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 18
- 239000005695 Ammonium acetate Substances 0.000 description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 235000019257 ammonium acetate Nutrition 0.000 description 18
- 229940043376 ammonium acetate Drugs 0.000 description 18
- 125000005842 heteroatom Chemical group 0.000 description 18
- 125000001424 substituent group Chemical group 0.000 description 18
- 125000004103 aminoalkyl group Chemical group 0.000 description 17
- 125000004452 carbocyclyl group Chemical group 0.000 description 17
- 229910052736 halogen Inorganic materials 0.000 description 17
- 239000003112 inhibitor Substances 0.000 description 17
- 238000003756 stirring Methods 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- 239000007864 aqueous solution Substances 0.000 description 16
- 150000002367 halogens Chemical class 0.000 description 16
- 229910052739 hydrogen Inorganic materials 0.000 description 16
- 230000007062 hydrolysis Effects 0.000 description 16
- 238000006460 hydrolysis reaction Methods 0.000 description 16
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 16
- 239000000651 prodrug Substances 0.000 description 16
- 229940002612 prodrug Drugs 0.000 description 16
- 150000001721 carbon Chemical group 0.000 description 15
- 239000003880 polar aprotic solvent Substances 0.000 description 15
- PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 14
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 14
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 14
- 125000004438 haloalkoxy group Chemical group 0.000 description 14
- 239000000126 substance Substances 0.000 description 14
- 125000004429 atom Chemical group 0.000 description 13
- 239000000706 filtrate Substances 0.000 description 13
- 239000001257 hydrogen Substances 0.000 description 13
- 125000004433 nitrogen atom Chemical group N* 0.000 description 13
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 12
- 239000004480 active ingredient Substances 0.000 description 12
- 125000003710 aryl alkyl group Chemical group 0.000 description 12
- 235000015165 citric acid Nutrition 0.000 description 12
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 11
- 125000004093 cyano group Chemical group *C#N 0.000 description 11
- 229940121360 farnesoid X receptor (fxr) agonists Drugs 0.000 description 11
- 239000000463 material Substances 0.000 description 11
- UWKQJZCTQGMHKD-UHFFFAOYSA-N 2,6-di-tert-butylpyridine Chemical compound CC(C)(C)C1=CC=CC(C(C)(C)C)=N1 UWKQJZCTQGMHKD-UHFFFAOYSA-N 0.000 description 10
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 description 10
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 10
- 150000001299 aldehydes Chemical class 0.000 description 10
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 10
- 125000002950 monocyclic group Chemical group 0.000 description 10
- 239000003921 oil Substances 0.000 description 10
- 235000019198 oils Nutrition 0.000 description 10
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 10
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 125000003282 alkyl amino group Chemical group 0.000 description 9
- 239000007822 coupling agent Substances 0.000 description 9
- 230000003176 fibrotic effect Effects 0.000 description 9
- 125000004994 halo alkoxy alkyl group Chemical group 0.000 description 9
- 125000004404 heteroalkyl group Chemical group 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 8
- 241000282414 Homo sapiens Species 0.000 description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
- 230000002378 acidificating effect Effects 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 8
- NEHMKBQYUWJMIP-DICFDUPASA-N chloro(dideuterio)methane Chemical compound [2H]C([2H])Cl NEHMKBQYUWJMIP-DICFDUPASA-N 0.000 description 8
- 150000004820 halides Chemical class 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 230000002062 proliferating effect Effects 0.000 description 8
- 108090000623 proteins and genes Proteins 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- 238000007363 ring formation reaction Methods 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 7
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 7
- KRGFOUGVZFEEBW-UHFFFAOYSA-N [5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methanol Chemical compound OCC1=C(C2CC2)ON=C1C1=C(Cl)C=CC=C1Cl KRGFOUGVZFEEBW-UHFFFAOYSA-N 0.000 description 7
- 125000001931 aliphatic group Chemical group 0.000 description 7
- 125000004419 alkynylene group Chemical group 0.000 description 7
- 235000019416 cholic acid Nutrition 0.000 description 7
- 239000013058 crude material Substances 0.000 description 7
- 238000009472 formulation Methods 0.000 description 7
- 210000001035 gastrointestinal tract Anatomy 0.000 description 7
- 150000002825 nitriles Chemical class 0.000 description 7
- 125000004043 oxo group Chemical group O=* 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 6
- 239000004380 Cholic acid Substances 0.000 description 6
- 125000004414 alkyl thio group Chemical group 0.000 description 6
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 6
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 6
- 229960002471 cholic acid Drugs 0.000 description 6
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 6
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 230000014509 gene expression Effects 0.000 description 6
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 6
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 6
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 6
- 229910052740 iodine Inorganic materials 0.000 description 6
- 210000004185 liver Anatomy 0.000 description 6
- 150000004702 methyl esters Chemical class 0.000 description 6
- 125000003367 polycyclic group Chemical group 0.000 description 6
- 102000005962 receptors Human genes 0.000 description 6
- 108020003175 receptors Proteins 0.000 description 6
- 239000000377 silicon dioxide Substances 0.000 description 6
- 241000894007 species Species 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 238000002560 therapeutic procedure Methods 0.000 description 6
- 125000001544 thienyl group Chemical group 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 6
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 description 5
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 5
- BBVIDBNAYOIXOE-UHFFFAOYSA-N 1,2,4-oxadiazole Chemical compound C=1N=CON=1 BBVIDBNAYOIXOE-UHFFFAOYSA-N 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- OZAPTPNKBQTRMG-UHFFFAOYSA-N [5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl]methanol Chemical compound OCC1=C(C2CC2)ON=C1C1=CC=CC=C1C(F)(F)F OZAPTPNKBQTRMG-UHFFFAOYSA-N 0.000 description 5
- 125000003342 alkenyl group Chemical group 0.000 description 5
- 125000004450 alkenylene group Chemical group 0.000 description 5
- 125000003277 amino group Chemical group 0.000 description 5
- 229910021529 ammonia Inorganic materials 0.000 description 5
- 125000004104 aryloxy group Chemical group 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 5
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 5
- 239000003613 bile acid Substances 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- 125000002837 carbocyclic group Chemical group 0.000 description 5
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 5
- 238000012512 characterization method Methods 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- CZKMPDNXOGQMFW-UHFFFAOYSA-N chloro(triethyl)germane Chemical compound CC[Ge](Cl)(CC)CC CZKMPDNXOGQMFW-UHFFFAOYSA-N 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 208000006454 hepatitis Diseases 0.000 description 5
- 150000002430 hydrocarbons Chemical class 0.000 description 5
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 5
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical group CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 5
- 230000003647 oxidation Effects 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- 125000004430 oxygen atom Chemical group O* 0.000 description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 150000003254 radicals Chemical group 0.000 description 5
- QRUBYZBWAOOHSV-UHFFFAOYSA-M silver trifluoromethanesulfonate Chemical compound [Ag+].[O-]S(=O)(=O)C(F)(F)F QRUBYZBWAOOHSV-UHFFFAOYSA-M 0.000 description 5
- 238000010189 synthetic method Methods 0.000 description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 4
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 description 4
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 4
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 4
- 102000003816 Interleukin-13 Human genes 0.000 description 4
- 108090000176 Interleukin-13 Proteins 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 4
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- 229960000548 alemtuzumab Drugs 0.000 description 4
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 4
- 125000000304 alkynyl group Chemical group 0.000 description 4
- 125000002102 aryl alkyloxo group Chemical group 0.000 description 4
- 239000012298 atmosphere Substances 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- 238000001023 centrifugal evaporation Methods 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 4
- 208000033679 diabetic kidney disease Diseases 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 125000002541 furyl group Chemical group 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 4
- 208000002551 irritable bowel syndrome Diseases 0.000 description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 4
- CYEBJEDOHLIWNP-UHFFFAOYSA-N methanethioamide Chemical compound NC=S CYEBJEDOHLIWNP-UHFFFAOYSA-N 0.000 description 4
- 125000000160 oxazolidinyl group Chemical group 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 description 4
- 229920003023 plastic Polymers 0.000 description 4
- 239000004033 plastic Substances 0.000 description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 4
- 125000004434 sulfur atom Chemical group 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- 125000004306 triazinyl group Chemical group 0.000 description 4
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 4
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 4
- DMDRLTJRQCKPLQ-UHFFFAOYSA-N 2-(2-aminophenyl)benzenethiol Chemical class NC1=CC=CC=C1C1=CC=CC=C1S DMDRLTJRQCKPLQ-UHFFFAOYSA-N 0.000 description 3
- GJPIPLPHQGHOOY-UHFFFAOYSA-N 4-(3,5-difluorobenzoyl)oxybicyclo[2.2.2]octane-1-carboxylic acid Chemical compound OC(=O)C12CCC(CC1)(CC2)OC(=O)c1cc(F)cc(F)c1 GJPIPLPHQGHOOY-UHFFFAOYSA-N 0.000 description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- 239000004475 Arginine Substances 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 3
- 208000032928 Dyslipidaemia Diseases 0.000 description 3
- 229930183217 Genin Natural products 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 3
- 208000017170 Lipid metabolism disease Diseases 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 102000007399 Nuclear hormone receptor Human genes 0.000 description 3
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 206010035226 Plasma cell myeloma Diseases 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 241000283984 Rodentia Species 0.000 description 3
- 229910004298 SiO 2 Inorganic materials 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 239000012317 TBTU Substances 0.000 description 3
- YJPRZVHHSVCUIU-UHFFFAOYSA-N [5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl]methanol Chemical compound OCC1=C(C2CC2)ON=C1C1=CC=CC=C1OC(F)(F)F YJPRZVHHSVCUIU-UHFFFAOYSA-N 0.000 description 3
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 3
- 125000002015 acyclic group Chemical group 0.000 description 3
- 125000003368 amide group Chemical group 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 3
- 125000005110 aryl thio group Chemical group 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 3
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 125000005884 carbocyclylalkyl group Chemical group 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- NLUNLVTVUDIHFE-UHFFFAOYSA-N cyclooctylcyclooctane Chemical compound C1CCCCCCC1C1CCCCCCC1 NLUNLVTVUDIHFE-UHFFFAOYSA-N 0.000 description 3
- 239000002702 enteric coating Substances 0.000 description 3
- 238000009505 enteric coating Methods 0.000 description 3
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 3
- 239000006260 foam Substances 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 125000003147 glycosyl group Chemical group 0.000 description 3
- 230000002440 hepatic effect Effects 0.000 description 3
- 125000005553 heteroaryloxy group Chemical group 0.000 description 3
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
- 125000002632 imidazolidinyl group Chemical group 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 230000002757 inflammatory effect Effects 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 125000000842 isoxazolyl group Chemical group 0.000 description 3
- 208000017169 kidney disease Diseases 0.000 description 3
- 208000032839 leukemia Diseases 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- ZZQHNCFQLQSTAS-UHFFFAOYSA-N methyl bicyclo[2.2.2]octane-4-carboxylate Chemical compound C1CC2CCC1(C(=O)OC)CC2 ZZQHNCFQLQSTAS-UHFFFAOYSA-N 0.000 description 3
- AKRYBBWYDSDZHG-UHFFFAOYSA-N nitrosobis(2-oxopropyl)amine Chemical compound CC(=O)CN(N=O)CC(C)=O AKRYBBWYDSDZHG-UHFFFAOYSA-N 0.000 description 3
- 239000007800 oxidant agent Substances 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 239000000123 paper Substances 0.000 description 3
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 238000004611 spectroscopical analysis Methods 0.000 description 3
- 238000013268 sustained release Methods 0.000 description 3
- 239000012730 sustained-release form Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 230000009466 transformation Effects 0.000 description 3
- 238000000844 transformation Methods 0.000 description 3
- 238000002054 transplantation Methods 0.000 description 3
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 2
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 2
- TWYYFYNJOJGNFP-CUXYNZQBSA-N (2s,4r,5s,6s)-2-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-2-carbamoyl-4-[[(e,4s,6s)-4,6-dimethyloct-2-enoyl]oxymethyl]-5-hydroxy-1,3-dioxane-4,5,6-tricarboxylic acid Chemical compound O1[C@H](C(O)=O)[C@](C(O)=O)(O)[C@](COC(=O)/C=C/[C@@H](C)C[C@@H](C)CC)(C(O)=O)O[C@]1(C(N)=O)CCC(=C)[C@@H](OC(C)=O)[C@H](C)CC1=CC=CC=C1 TWYYFYNJOJGNFP-CUXYNZQBSA-N 0.000 description 2
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 2
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 2
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 description 2
- FKASFBLJDCHBNZ-UHFFFAOYSA-N 1,3,4-oxadiazole Chemical compound C1=NN=CO1 FKASFBLJDCHBNZ-UHFFFAOYSA-N 0.000 description 2
- MBIZXFATKUQOOA-UHFFFAOYSA-N 1,3,4-thiadiazole Chemical compound C1=NN=CS1 MBIZXFATKUQOOA-UHFFFAOYSA-N 0.000 description 2
- WYRRTJKOMZONQO-UHFFFAOYSA-N 1,3-benzothiazole-6-carbonitrile Chemical compound N#CC1=CC=C2N=CSC2=C1 WYRRTJKOMZONQO-UHFFFAOYSA-N 0.000 description 2
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 description 2
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 2
- 125000005955 1H-indazolyl group Chemical group 0.000 description 2
- ZZWWXIBKLBMSCS-FQEVSTJZSA-N 2-[1-[(2r)-2-(2-methoxyphenyl)-2-(oxan-4-yloxy)ethyl]-5-methyl-6-(1,3-oxazol-2-yl)-2,4-dioxothieno[2,3-d]pyrimidin-3-yl]-2-methylpropanoic acid Chemical compound COC1=CC=CC=C1[C@@H](OC1CCOCC1)CN1C(=O)N(C(C)(C)C(O)=O)C(=O)C2=C1SC(C=1OC=CN=1)=C2C ZZWWXIBKLBMSCS-FQEVSTJZSA-N 0.000 description 2
- CDAWCLOXVUBKRW-UHFFFAOYSA-N 2-aminophenol Chemical class NC1=CC=CC=C1O CDAWCLOXVUBKRW-UHFFFAOYSA-N 0.000 description 2
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 2
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 2
- WNEODWDFDXWOLU-QHCPKHFHSA-N 3-[3-(hydroxymethyl)-4-[1-methyl-5-[[5-[(2s)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl]amino]-6-oxopyridin-3-yl]pyridin-2-yl]-7,7-dimethyl-1,2,6,8-tetrahydrocyclopenta[3,4]pyrrolo[3,5-b]pyrazin-4-one Chemical compound C([C@@H](N(CC1)C=2C=NC(NC=3C(N(C)C=C(C=3)C=3C(=C(N4C(C5=CC=6CC(C)(C)CC=6N5CC4)=O)N=CC=3)CO)=O)=CC=2)C)N1C1COC1 WNEODWDFDXWOLU-QHCPKHFHSA-N 0.000 description 2
- MTYFJFMXUMMQDL-UHFFFAOYSA-N 3-cyano-2-fluorobenzoic acid Chemical compound OC(=O)C1=CC=CC(C#N)=C1F MTYFJFMXUMMQDL-UHFFFAOYSA-N 0.000 description 2
- PNZIYSWKRBYITO-UHFFFAOYSA-N 4-(bromomethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole Chemical compound ClC1=CC=CC(Cl)=C1C1=NOC(C2CC2)=C1CBr PNZIYSWKRBYITO-UHFFFAOYSA-N 0.000 description 2
- DEZDVAAAZZONAM-UHFFFAOYSA-N 4-(bromomethyl)-5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazole Chemical compound FC(F)(F)OC1=CC=CC=C1C1=NOC(C2CC2)=C1CBr DEZDVAAAZZONAM-UHFFFAOYSA-N 0.000 description 2
- MXDAYVCCPKGPOE-UHFFFAOYSA-N 4-amino-3-sulfanylbenzonitrile Chemical compound NC1=CC=C(C#N)C=C1S MXDAYVCCPKGPOE-UHFFFAOYSA-N 0.000 description 2
- AEMUWTWTDIUOLJ-UHFFFAOYSA-N 4-iodobicyclo[2.2.2]octane-1-carboxylic acid Chemical compound C1CC2(I)CCC1(C(=O)O)CC2 AEMUWTWTDIUOLJ-UHFFFAOYSA-N 0.000 description 2
- REIDAMBAPLIATC-UHFFFAOYSA-N 4-methoxycarbonylbenzoic acid Chemical compound COC(=O)C1=CC=C(C(O)=O)C=C1 REIDAMBAPLIATC-UHFFFAOYSA-N 0.000 description 2
- KBZVAQVEHVGIEI-UHFFFAOYSA-N 4-methoxycarbonylbicyclo[2.2.2]octane-1-carboxylic acid Chemical compound C1CC2(C(O)=O)CCC1(C(=O)OC)CC2 KBZVAQVEHVGIEI-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- 125000002373 5 membered heterocyclic group Chemical group 0.000 description 2
- HIHOEGPXVVKJPP-JTQLQIEISA-N 5-fluoro-2-[[(1s)-1-(5-fluoropyridin-2-yl)ethyl]amino]-6-[(5-methyl-1h-pyrazol-3-yl)amino]pyridine-3-carbonitrile Chemical compound N([C@@H](C)C=1N=CC(F)=CC=1)C(C(=CC=1F)C#N)=NC=1NC=1C=C(C)NN=1 HIHOEGPXVVKJPP-JTQLQIEISA-N 0.000 description 2
- 125000006163 5-membered heteroaryl group Chemical group 0.000 description 2
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 2
- VWIOMFMPIVMLIR-UHFFFAOYSA-N 6-methoxycarbonylpyridine-2-carboxylic acid Chemical compound COC(=O)C1=CC=CC(C(O)=O)=N1 VWIOMFMPIVMLIR-UHFFFAOYSA-N 0.000 description 2
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 102100031151 C-C chemokine receptor type 2 Human genes 0.000 description 2
- 101710149815 C-C chemokine receptor type 2 Proteins 0.000 description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 2
- 229930186147 Cephalosporin Natural products 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 206010008635 Cholestasis Diseases 0.000 description 2
- 206010008909 Chronic Hepatitis Diseases 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 2
- 238000006969 Curtius rearrangement reaction Methods 0.000 description 2
- 238000006646 Dess-Martin oxidation reaction Methods 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- 102100021977 Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 Human genes 0.000 description 2
- 108050004000 Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 Proteins 0.000 description 2
- 208000004930 Fatty Liver Diseases 0.000 description 2
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 2
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 208000010412 Glaucoma Diseases 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 206010022489 Insulin Resistance Diseases 0.000 description 2
- 102000004388 Interleukin-4 Human genes 0.000 description 2
- 108090000978 Interleukin-4 Proteins 0.000 description 2
- 208000029523 Interstitial Lung disease Diseases 0.000 description 2
- 108010055717 JNK Mitogen-Activated Protein Kinases Proteins 0.000 description 2
- 208000007766 Kaposi sarcoma Diseases 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 102100027159 Membrane primary amine oxidase Human genes 0.000 description 2
- 101710132836 Membrane primary amine oxidase Proteins 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 102100033127 Mitogen-activated protein kinase kinase kinase 5 Human genes 0.000 description 2
- 101710164337 Mitogen-activated protein kinase kinase kinase 5 Proteins 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 2
- 150000001204 N-oxides Chemical class 0.000 description 2
- 208000008589 Obesity Diseases 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 2
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 2
- 208000002158 Proliferative Vitreoretinopathy Diseases 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical class N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 102000034527 Retinoid X Receptors Human genes 0.000 description 2
- 108010038912 Retinoid X Receptors Proteins 0.000 description 2
- 206010038934 Retinopathy proliferative Diseases 0.000 description 2
- GIIZNNXWQWCKIB-UHFFFAOYSA-N Serevent Chemical compound C1=C(O)C(CO)=CC(C(O)CNCCCCCCOCCCCC=2C=CC=CC=2)=C1 GIIZNNXWQWCKIB-UHFFFAOYSA-N 0.000 description 2
- 206010050207 Skin fibrosis Diseases 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000005864 Sulphur Substances 0.000 description 2
- 201000009594 Systemic Scleroderma Diseases 0.000 description 2
- 206010042953 Systemic sclerosis Diseases 0.000 description 2
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 2
- KKEYFWRCBNTPAC-UHFFFAOYSA-N Terephthalic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 2
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 2
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 2
- AVEFYMQJQVLLQC-UHFFFAOYSA-N [4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methanol Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)CO AVEFYMQJQVLLQC-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 231100000354 acute hepatitis Toxicity 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 2
- 206010064930 age-related macular degeneration Diseases 0.000 description 2
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 description 2
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 2
- 150000001345 alkine derivatives Chemical class 0.000 description 2
- 125000005083 alkoxyalkoxy group Chemical group 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 150000003973 alkyl amines Chemical class 0.000 description 2
- 150000001351 alkyl iodides Chemical class 0.000 description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 125000001691 aryl alkyl amino group Chemical group 0.000 description 2
- 125000001769 aryl amino group Chemical group 0.000 description 2
- 125000004658 aryl carbonyl amino group Chemical group 0.000 description 2
- 125000005129 aryl carbonyl group Chemical group 0.000 description 2
- 125000005135 aryl sulfinyl group Chemical group 0.000 description 2
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 description 2
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 description 2
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 2
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 2
- 239000012964 benzotriazole Substances 0.000 description 2
- PUNFICOCZAPAJV-UHFFFAOYSA-N bicyclo[2.2.2]octane-4-carboxylic acid Chemical compound C1CC2CCC1(C(=O)O)CC2 PUNFICOCZAPAJV-UHFFFAOYSA-N 0.000 description 2
- 239000012867 bioactive agent Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- ZOAIGCHJWKDIPJ-UHFFFAOYSA-M caesium acetate Chemical compound [Cs+].CC([O-])=O ZOAIGCHJWKDIPJ-UHFFFAOYSA-M 0.000 description 2
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 239000011111 cardboard Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 229940124587 cephalosporin Drugs 0.000 description 2
- 150000001780 cephalosporins Chemical class 0.000 description 2
- SFZULDYEOVSIKM-UHFFFAOYSA-N chembl321317 Chemical compound C1=CC(C(=N)NO)=CC=C1C1=CC=C(C=2C=CC(=CC=2)C(=N)NO)O1 SFZULDYEOVSIKM-UHFFFAOYSA-N 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 231100000359 cholestasis Toxicity 0.000 description 2
- 230000007870 cholestasis Effects 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 description 2
- 230000007882 cirrhosis Effects 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 210000001072 colon Anatomy 0.000 description 2
- 239000013066 combination product Substances 0.000 description 2
- 229940127555 combination product Drugs 0.000 description 2
- 239000002131 composite material Substances 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 125000000392 cycloalkenyl group Chemical group 0.000 description 2
- 125000000000 cycloalkoxy group Chemical group 0.000 description 2
- 125000006310 cycloalkyl amino group Chemical group 0.000 description 2
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 2
- 230000007850 degeneration Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- NUJBTXFFJUGENN-UHFFFAOYSA-N ethyl 3,4-diaminobenzoate Chemical compound CCOC(=O)C1=CC=C(N)C(N)=C1 NUJBTXFFJUGENN-UHFFFAOYSA-N 0.000 description 2
- 229940126864 fibroblast growth factor Drugs 0.000 description 2
- 206010016629 fibroma Diseases 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 210000000232 gallbladder Anatomy 0.000 description 2
- 239000003292 glue Substances 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 125000004992 haloalkylamino group Chemical group 0.000 description 2
- 125000004474 heteroalkylene group Chemical group 0.000 description 2
- 125000005114 heteroarylalkoxy group Chemical group 0.000 description 2
- 125000005844 heterocyclyloxy group Chemical group 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 125000004857 imidazopyridinyl group Chemical group N1C(=NC2=C1C=CC=N2)* 0.000 description 2
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 239000007972 injectable composition Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 229940028885 interleukin-4 Drugs 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001786 isothiazolyl group Chemical group 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 2
- 208000002780 macular degeneration Diseases 0.000 description 2
- 159000000003 magnesium salts Chemical class 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- PIXOBZFOAGWQGO-UHFFFAOYSA-N methyl 5-cyano-2-methoxybenzoate Chemical compound COC(=O)C1=CC(C#N)=CC=C1OC PIXOBZFOAGWQGO-UHFFFAOYSA-N 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 2
- YNBADRVTZLEFNH-UHFFFAOYSA-N methyl nicotinate Chemical compound COC(=O)C1=CC=CN=C1 YNBADRVTZLEFNH-UHFFFAOYSA-N 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 201000000050 myeloid neoplasm Diseases 0.000 description 2
- 210000002850 nasal mucosa Anatomy 0.000 description 2
- 208000021971 neovascular inflammatory vitreoretinopathy Diseases 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 229960003301 nivolumab Drugs 0.000 description 2
- 201000004071 non-specific interstitial pneumonia Diseases 0.000 description 2
- 235000020824 obesity Nutrition 0.000 description 2
- 229960002450 ofatumumab Drugs 0.000 description 2
- 210000001672 ovary Anatomy 0.000 description 2
- 125000004095 oxindolyl group Chemical group N1(C(CC2=CC=CC=C12)=O)* 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 229960002621 pembrolizumab Drugs 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- 238000010647 peptide synthesis reaction Methods 0.000 description 2
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 150000002989 phenols Chemical class 0.000 description 2
- 150000004714 phosphonium salts Chemical class 0.000 description 2
- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- KASDHRXLYQOAKZ-ZPSXYTITSA-N pimecrolimus Chemical compound C/C([C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@]2(O)O[C@@H]([C@H](C[C@H]2C)OC)[C@@H](OC)C[C@@H](C)C/C(C)=C/[C@H](C(C[C@H](O)[C@H]1C)=O)CC)=C\[C@@H]1CC[C@@H](Cl)[C@H](OC)C1 KASDHRXLYQOAKZ-ZPSXYTITSA-N 0.000 description 2
- 229960005330 pimecrolimus Drugs 0.000 description 2
- 229960005095 pioglitazone Drugs 0.000 description 2
- 235000011056 potassium acetate Nutrition 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 150000003140 primary amides Chemical class 0.000 description 2
- 230000006785 proliferative vitreoretinopathy Effects 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 2
- 238000010926 purge Methods 0.000 description 2
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 2
- 150000003222 pyridines Chemical class 0.000 description 2
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 201000002793 renal fibrosis Diseases 0.000 description 2
- 238000004007 reversed phase HPLC Methods 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 125000006413 ring segment Chemical group 0.000 description 2
- 229960004641 rituximab Drugs 0.000 description 2
- 229960002052 salbutamol Drugs 0.000 description 2
- 229960004017 salmeterol Drugs 0.000 description 2
- YIDDLAAKOYYGJG-UHFFFAOYSA-N selonsertib Chemical compound CC(C)N1C=NN=C1C1=CC=CC(NC(=O)C=2C(=CC(C)=C(C=2)N2C=C(N=C2)C2CC2)F)=N1 YIDDLAAKOYYGJG-UHFFFAOYSA-N 0.000 description 2
- 229950003181 selonsertib Drugs 0.000 description 2
- PEGQOIGYZLJMIB-UHFFFAOYSA-N setogepram Chemical compound CCCCCC1=CC=CC(CC(O)=O)=C1 PEGQOIGYZLJMIB-UHFFFAOYSA-N 0.000 description 2
- BNRNXUUZRGQAQC-UHFFFAOYSA-N sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 description 2
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 2
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 2
- 229960002930 sirolimus Drugs 0.000 description 2
- 210000000813 small intestine Anatomy 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 230000000087 stabilizing effect Effects 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 229940124530 sulfonamide Drugs 0.000 description 2
- 150000003456 sulfonamides Chemical class 0.000 description 2
- 238000004808 supercritical fluid chromatography Methods 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 229960001967 tacrolimus Drugs 0.000 description 2
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 2
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 2
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 2
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 2
- 125000004525 thiadiazinyl group Chemical group S1NN=C(C=C1)* 0.000 description 2
- 150000003573 thiols Chemical class 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 2
- SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 description 2
- ONDSBJMLAHVLMI-UHFFFAOYSA-N trimethylsilyldiazomethane Chemical compound C[Si](C)(C)[CH-][N+]#N ONDSBJMLAHVLMI-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 238000003828 vacuum filtration Methods 0.000 description 2
- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 description 1
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- OUPXSLGGCPUZJJ-SARDKLJWSA-N (2s)-2-[[(2s)-1-[(2s)-6-amino-2-[[(2s)-1-[(2s)-2-amino-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-n-[(2s)-5-amino-1-[[(2s)-1-[[(2s)-1-[[2-[[(2s)-1-[[(2s)-1-amino-4-methylsulfonyl-1-oxobutan-2-y Chemical compound C([C@@H](C(=O)N(C)CC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCS(C)(=O)=O)C(N)=O)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 OUPXSLGGCPUZJJ-SARDKLJWSA-N 0.000 description 1
- LJIOTBMDLVHTBO-CUYJMHBOSA-N (2s)-2-amino-n-[(1r,2r)-1-cyano-2-[4-[4-(4-methylpiperazin-1-yl)sulfonylphenyl]phenyl]cyclopropyl]butanamide Chemical compound CC[C@H](N)C(=O)N[C@]1(C#N)C[C@@H]1C1=CC=C(C=2C=CC(=CC=2)S(=O)(=O)N2CCN(C)CC2)C=C1 LJIOTBMDLVHTBO-CUYJMHBOSA-N 0.000 description 1
- AEMPUAWUDAMJBV-QFIPXVFZSA-N (2s)-4-(4-methylphenyl)-5-(2h-tetrazol-5-yl)-2-[4-(4,4,4-trifluorobutoxy)phenyl]-2-(trifluoromethyl)-1,3-dihydropyridin-6-one Chemical compound C1=CC(C)=CC=C1C(C[C@](NC1=O)(C=2C=CC(OCCCC(F)(F)F)=CC=2)C(F)(F)F)=C1C1=NN=NN1 AEMPUAWUDAMJBV-QFIPXVFZSA-N 0.000 description 1
- LDQKDRLEMKIYMC-XMMPIXPASA-N (3R)-1'-(9-anthrylcarbonyl)-3-(morpholin-4-ylcarbonyl)-1,4'-bipiperidine Chemical compound O=C([C@H]1CN(CCC1)C1CCN(CC1)C(=O)C=1C2=CC=CC=C2C=C2C=CC=CC2=1)N1CCOCC1 LDQKDRLEMKIYMC-XMMPIXPASA-N 0.000 description 1
- RUDATBOHQWOJDD-UHFFFAOYSA-N (3beta,5beta,7alpha)-3,7-Dihydroxycholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 RUDATBOHQWOJDD-UHFFFAOYSA-N 0.000 description 1
- FOLCUFKJHSQMEL-BIXPGCQOSA-N (4-butylcyclohexyl) N-[(2S)-4-methyl-1-oxo-1-[[(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]amino]pentan-2-yl]carbamate Chemical compound CCCCC1CCC(CC1)OC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C[C@@H]2CCNC2=O)C=O FOLCUFKJHSQMEL-BIXPGCQOSA-N 0.000 description 1
- YCHYFHOSGQABSW-RTBURBONSA-N (6ar,10ar)-1-hydroxy-6,6-dimethyl-3-(2-methyloctan-2-yl)-6a,7,10,10a-tetrahydrobenzo[c]chromene-9-carboxylic acid Chemical compound C1C(C(O)=O)=CC[C@H]2C(C)(C)OC3=CC(C(C)(C)CCCCCC)=CC(O)=C3[C@@H]21 YCHYFHOSGQABSW-RTBURBONSA-N 0.000 description 1
- QOLHWXNSCZGWHK-BWBORTOCSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-(11-phenoxyundecylcarbamoyloxy)-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@@H]([C@@H](OC(=O)NCCCCCCCCCCCOC=3C=CC=CC=3)C(O1)(C(O)=O)C(O)(C(O2)C(O)=O)C(O)=O)O)C1=CC=CC=C1 QOLHWXNSCZGWHK-BWBORTOCSA-N 0.000 description 1
- VGNCBRNRHXEODV-XXVHXNRLSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-6-dodecoxy-4,7-dihydroxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@H](O)[C@H](C(O2)(C(O)=O)C(O)(C(O1)C(O)=O)C(O)=O)OCCCCCCCCCCCC)C1=CC=CC=C1 VGNCBRNRHXEODV-XXVHXNRLSA-N 0.000 description 1
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 1
- 125000006832 (C1-C10) alkylene group Chemical group 0.000 description 1
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 description 1
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- WEYFZKRRQZYAJI-SNAWJCMRSA-N (e)-3-(3-cyanophenyl)prop-2-enoic acid Chemical compound OC(=O)\C=C\C1=CC=CC(C#N)=C1 WEYFZKRRQZYAJI-SNAWJCMRSA-N 0.000 description 1
- FIARMZDBEGVMLV-UHFFFAOYSA-N 1,1,2,2,2-pentafluoroethanolate Chemical group [O-]C(F)(F)C(F)(F)F FIARMZDBEGVMLV-UHFFFAOYSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical group CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- 125000004605 1,2,3,4-tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000004607 1,2,3,4-tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000004502 1,2,3-oxadiazolyl group Chemical group 0.000 description 1
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 description 1
- 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 description 1
- 125000004514 1,2,4-thiadiazolyl group Chemical group 0.000 description 1
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 description 1
- 125000004506 1,2,5-oxadiazolyl group Chemical group 0.000 description 1
- 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- VMLKTERJLVWEJJ-UHFFFAOYSA-N 1,5-naphthyridine Chemical class C1=CC=NC2=CC=CN=C21 VMLKTERJLVWEJJ-UHFFFAOYSA-N 0.000 description 1
- CPVMAYNPSFMOGK-UHFFFAOYSA-N 1-(hydroxymethyl)bicyclo[2.2.2]octane-4-carboxylic acid Chemical compound C1CC2(C(O)=O)CCC1(CO)CC2 CPVMAYNPSFMOGK-UHFFFAOYSA-N 0.000 description 1
- GQBRZBHEPUQRPL-LJQANCHMSA-N 1-[4-[4-[3-methyl-4-[[(1r)-1-phenylethoxy]carbonylamino]-1,2-oxazol-5-yl]phenyl]phenyl]cyclopropane-1-carboxylic acid Chemical compound O([C@H](C)C=1C=CC=CC=1)C(=O)NC=1C(C)=NOC=1C(C=C1)=CC=C1C(C=C1)=CC=C1C1(C(O)=O)CC1 GQBRZBHEPUQRPL-LJQANCHMSA-N 0.000 description 1
- HSWKIPCBJSMQFA-UHFFFAOYSA-N 1-butoxybutane;tin Chemical compound [Sn].CCCCOCCCC HSWKIPCBJSMQFA-UHFFFAOYSA-N 0.000 description 1
- 125000006432 1-methyl cyclopropyl group Chemical group [H]C([H])([H])C1(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- RAXXELZNTBOGNW-MQIHXRCWSA-N 1h-imidazole Chemical compound C1=C[15NH]C=[15N]1 RAXXELZNTBOGNW-MQIHXRCWSA-N 0.000 description 1
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- CJLZUKCACMUYFP-GOSISDBHSA-N 2-[(5R)-4-[2-[3-(3-methylbutanoyloxy)phenyl]acetyl]-8-(trifluoromethyl)-1,2,3,5-tetrahydropyrido[2,3-e][1,4]diazepin-5-yl]acetic acid Chemical compound CC(C)CC(=O)OC1=CC=CC(CC(=O)N2[C@@H](C3=CC=C(N=C3NCC2)C(F)(F)F)CC(O)=O)=C1 CJLZUKCACMUYFP-GOSISDBHSA-N 0.000 description 1
- KZSKGLFYQAYZCO-UHFFFAOYSA-N 2-[3-[2-chloro-4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]phenyl]-3-hydroxyazetidin-1-yl]pyridine-4-carboxylic acid Chemical compound OC(=O)C1=CC=NC(N2CC(O)(C2)C=2C(=CC(OCC=3C(=NOC=3C3CC3)C=3C(=CC=CC=3Cl)Cl)=CC=2)Cl)=C1 KZSKGLFYQAYZCO-UHFFFAOYSA-N 0.000 description 1
- RYWCQJDEHXJHRI-XJMXIVSISA-N 2-[3-[5-[6-[3-[3-(carboxymethyl)phenyl]-4-[(2r,3s,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyphenyl]hexyl]-2-[(2r,3s,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyphenyl]phenyl]acetic acid Chemical compound O[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC(C(=C1)C=2C=C(CC(O)=O)C=CC=2)=CC=C1CCCCCCC(C=C1C=2C=C(CC(O)=O)C=CC=2)=CC=C1O[C@@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 RYWCQJDEHXJHRI-XJMXIVSISA-N 0.000 description 1
- BVAHPPKGOOJSPU-UHFFFAOYSA-N 2-[[5-chloro-2-[(5-methyl-2-propan-2-ylpyrazol-3-yl)amino]pyridin-4-yl]amino]-n-methoxybenzamide Chemical compound CONC(=O)C1=CC=CC=C1NC1=CC(NC=2N(N=C(C)C=2)C(C)C)=NC=C1Cl BVAHPPKGOOJSPU-UHFFFAOYSA-N 0.000 description 1
- 101710186725 2-acylglycerol O-acyltransferase 2 Proteins 0.000 description 1
- PUAQLLVFLMYYJJ-UHFFFAOYSA-N 2-aminopropiophenone Chemical compound CC(N)C(=O)C1=CC=CC=C1 PUAQLLVFLMYYJJ-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- VCBFAUSKNYAKJZ-UHFFFAOYSA-N 2-chloro-3-oxobutanoic acid Chemical compound CC(=O)C(Cl)C(O)=O VCBFAUSKNYAKJZ-UHFFFAOYSA-N 0.000 description 1
- AKCRQHGQIJBRMN-UHFFFAOYSA-N 2-chloroaniline Chemical class NC1=CC=CC=C1Cl AKCRQHGQIJBRMN-UHFFFAOYSA-N 0.000 description 1
- 125000006040 2-hexenyl group Chemical group 0.000 description 1
- MAFJOMAYYKSZOS-UHFFFAOYSA-N 2-methoxycarbonylpyridine-4-carboxylic acid Chemical compound COC(=O)C1=CC(C(O)=O)=CC=N1 MAFJOMAYYKSZOS-UHFFFAOYSA-N 0.000 description 1
- 125000006022 2-methyl-2-propenyl group Chemical group 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000006024 2-pentenyl group Chemical group 0.000 description 1
- KRTGJZMJJVEKRX-UHFFFAOYSA-N 2-phenylethan-1-yl Chemical group [CH2]CC1=CC=CC=C1 KRTGJZMJJVEKRX-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 1
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 1
- 125000004011 3 membered carbocyclic group Chemical group 0.000 description 1
- GONAVIHGXFBTOZ-UHFFFAOYSA-M 3,5-difluorobenzoate Chemical compound [O-]C(=O)C1=CC(F)=CC(F)=C1 GONAVIHGXFBTOZ-UHFFFAOYSA-M 0.000 description 1
- GONAVIHGXFBTOZ-UHFFFAOYSA-N 3,5-difluorobenzoic acid Chemical compound OC(=O)C1=CC(F)=CC(F)=C1 GONAVIHGXFBTOZ-UHFFFAOYSA-N 0.000 description 1
- ZLSOONVQLWLPMF-UHFFFAOYSA-M 3-(3,8-diamino-6-phenylphenanthridin-5-ium-5-yl)propyl-diethyl-methylazanium;dibromide Chemical compound [Br-].[Br-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 ZLSOONVQLWLPMF-UHFFFAOYSA-M 0.000 description 1
- YFJXQKGQZGVBHT-SNAWJCMRSA-N 3-[(E)-2-(4-hydroxy-1-bicyclo[2.2.2]octanyl)ethenyl]benzonitrile Chemical compound OC12CCC(CC1)(CC2)/C=C/C=1C=C(C#N)C=CC=1 YFJXQKGQZGVBHT-SNAWJCMRSA-N 0.000 description 1
- HUAACMFHYZDFDX-ZHACJKMWSA-N 3-[(E)-2-[4-[[5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]ethenyl]benzonitrile Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1)OC(F)(F)F)COC12CCC(CC1)(CC2)/C=C/C=1C=C(C#N)C=CC=1 HUAACMFHYZDFDX-ZHACJKMWSA-N 0.000 description 1
- BFWJNSGEBQVPJR-UHFFFAOYSA-N 3-[3-[4-[[5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-5-yl]benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1)C(F)(F)F)COC12CCC(CC1)(CC2)C1=NOC(=N1)C=1C=C(C(=O)O)C=CC=1 BFWJNSGEBQVPJR-UHFFFAOYSA-N 0.000 description 1
- PXVJVPSOOURVKX-UHFFFAOYSA-N 3-[5-[4-[[5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,3,4-oxadiazol-2-yl]benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1)OC(F)(F)F)COC12CCC(CC1)(CC2)C1=NN=C(O1)C=1C=C(C(=O)O)C=CC=1 PXVJVPSOOURVKX-UHFFFAOYSA-N 0.000 description 1
- JKCYKISVUIVZCS-UHFFFAOYSA-N 3-bromo-4-fluorobenzonitrile Chemical compound FC1=CC=C(C#N)C=C1Br JKCYKISVUIVZCS-UHFFFAOYSA-N 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- OJCKPWOBQFQMAA-UHFFFAOYSA-N 3-cyano-2,6-difluorobenzoic acid Chemical compound OC(=O)C1=C(F)C=CC(C#N)=C1F OJCKPWOBQFQMAA-UHFFFAOYSA-N 0.000 description 1
- 125000006041 3-hexenyl group Chemical group 0.000 description 1
- WMZNGTSLFSJHMZ-UHFFFAOYSA-N 3-methoxycarbonylbenzoic acid Chemical compound COC(=O)C1=CC=CC(C(O)=O)=C1 WMZNGTSLFSJHMZ-UHFFFAOYSA-N 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000001845 4 membered carbocyclic group Chemical group 0.000 description 1
- 125000001963 4 membered heterocyclic group Chemical group 0.000 description 1
- SILUQQCQOHFTGS-UHFFFAOYSA-N 4-(bromomethyl)-5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazole Chemical compound BrCC=1C(=NOC=1C1CC1)C1=C(C=CC=C1)C(F)(F)F SILUQQCQOHFTGS-UHFFFAOYSA-N 0.000 description 1
- MCFBUIIRFZBRCU-UHFFFAOYSA-N 4-[1-[5-[6-(trifluoromethyl)-1h-benzimidazol-2-yl]pyridin-2-yl]piperidin-4-yl]oxycyclohexane-1-carboxylic acid Chemical compound C1CC(C(=O)O)CCC1OC1CCN(C=2N=CC(=CC=2)C=2NC3=CC(=CC=C3N=2)C(F)(F)F)CC1 MCFBUIIRFZBRCU-UHFFFAOYSA-N 0.000 description 1
- WCDLCPLAAKUJNY-UHFFFAOYSA-N 4-[4-[3-(1h-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl]phenyl]morpholine Chemical compound C1COCCN1C1=CC=C(C2=CN3N=CC(=C3N=C2)C2=CNN=C2)C=C1 WCDLCPLAAKUJNY-UHFFFAOYSA-N 0.000 description 1
- 125000006042 4-hexenyl group Chemical group 0.000 description 1
- IGVRWPVSNYOJHJ-UHFFFAOYSA-N 4-iodobicyclo[2.2.2]octane-1-carbonitrile Chemical compound C1CC2(C#N)CCC1(I)CC2 IGVRWPVSNYOJHJ-UHFFFAOYSA-N 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000003119 4-methyl-3-pentenyl group Chemical group [H]\C(=C(/C([H])([H])[H])C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000002471 4H-quinolizinyl group Chemical group C=1(C=CCN2C=CC=CC12)* 0.000 description 1
- 125000001054 5 membered carbocyclic group Chemical group 0.000 description 1
- 125000004608 5,6,7,8-tetrahydroquinolinyl group Chemical group N1=C(C=CC=2CCCCC12)* 0.000 description 1
- JRVUMRYYCKYECS-UHFFFAOYSA-N 5-[5-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]-1,2,4-oxadiazol-3-yl]-2-fluorobenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC12CCC(CC1)(CC2)C1=NC(=NO1)C=1C=CC(=C(C(=O)O)C=1)F JRVUMRYYCKYECS-UHFFFAOYSA-N 0.000 description 1
- UQXVUTYCTZULCD-UHFFFAOYSA-N 5-cyano-2-fluorobenzoic acid Chemical compound OC(=O)C1=CC(C#N)=CC=C1F UQXVUTYCTZULCD-UHFFFAOYSA-N 0.000 description 1
- 125000006043 5-hexenyl group Chemical group 0.000 description 1
- 125000004008 6 membered carbocyclic group Chemical group 0.000 description 1
- 125000003341 7 membered heterocyclic group Chemical group 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 125000005330 8 membered heterocyclic group Chemical group 0.000 description 1
- 208000007082 Alcoholic Fatty Liver Diseases 0.000 description 1
- 102100024296 Alpha-1,6-mannosyl-glycoprotein 2-beta-N-acetylglucosaminyltransferase Human genes 0.000 description 1
- 241000937413 Axia Species 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 208000009299 Benign Mucous Membrane Pemphigoid Diseases 0.000 description 1
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 1
- 206010004659 Biliary cirrhosis Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 1
- 102000001902 CC Chemokines Human genes 0.000 description 1
- 108010040471 CC Chemokines Proteins 0.000 description 1
- 101100296726 Caenorhabditis elegans pde-5 gene Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- 102000011727 Caspases Human genes 0.000 description 1
- 108010076667 Caspases Proteins 0.000 description 1
- 206010008111 Cerebral haemorrhage Diseases 0.000 description 1
- 208000008964 Chemical and Drug Induced Liver Injury Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- AEMZEDNMNLIDSL-YGCVIUNWSA-N Cl.CC(C)(C)NC(=O)C1=CC=C(OC\C(CN)=C\F)C=C1 Chemical compound Cl.CC(C)(C)NC(=O)C1=CC=C(OC\C(CN)=C\F)C=C1 AEMZEDNMNLIDSL-YGCVIUNWSA-N 0.000 description 1
- 229940126559 Compound 4e Drugs 0.000 description 1
- 102000015225 Connective Tissue Growth Factor Human genes 0.000 description 1
- 108010039419 Connective Tissue Growth Factor Proteins 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- JVHXJTBJCFBINQ-ADAARDCZSA-N Dapagliflozin Chemical compound C1=CC(OCC)=CC=C1CC1=CC([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)=CC=C1Cl JVHXJTBJCFBINQ-ADAARDCZSA-N 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010012689 Diabetic retinopathy Diseases 0.000 description 1
- NTURVSFTOYPGON-UHFFFAOYSA-N Dihydroquinazoline Chemical compound C1=CC=C2C=NCNC2=C1 NTURVSFTOYPGON-UHFFFAOYSA-N 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- 206010072268 Drug-induced liver injury Diseases 0.000 description 1
- XPOQHMRABVBWPR-UHFFFAOYSA-N Efavirenz Natural products O1C(=O)NC2=CC=C(Cl)C=C2C1(C(F)(F)F)C#CC1CC1 XPOQHMRABVBWPR-UHFFFAOYSA-N 0.000 description 1
- 229940118365 Endothelin receptor antagonist Drugs 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 229940124783 FAK inhibitor Drugs 0.000 description 1
- 229940125634 FPR2 agonist Drugs 0.000 description 1
- 229920002430 Fibre-reinforced plastic Polymers 0.000 description 1
- 101710153363 Fibroblast growth factor 15 Proteins 0.000 description 1
- 108090000376 Fibroblast growth factor 21 Proteins 0.000 description 1
- 102000003973 Fibroblast growth factor 21 Human genes 0.000 description 1
- 208000007212 Foot-and-Mouth Disease Diseases 0.000 description 1
- 241000710198 Foot-and-mouth disease virus Species 0.000 description 1
- 108010001517 Galectin 3 Proteins 0.000 description 1
- 102100039558 Galectin-3 Human genes 0.000 description 1
- 229940089838 Glucagon-like peptide 1 receptor agonist Drugs 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 206010019663 Hepatic failure Diseases 0.000 description 1
- 101000966782 Homo sapiens Lysophosphatidic acid receptor 1 Proteins 0.000 description 1
- 101001043352 Homo sapiens Lysyl oxidase homolog 2 Proteins 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 108010023610 IL13-PE38 Proteins 0.000 description 1
- 208000010159 IgA glomerulonephritis Diseases 0.000 description 1
- 206010021263 IgA nephropathy Diseases 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- 208000003618 Intervertebral Disc Displacement Diseases 0.000 description 1
- 208000002260 Keloid Diseases 0.000 description 1
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 108010014552 LY2405319 Proteins 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- YSDQQAXHVYUZIW-QCIJIYAXSA-N Liraglutide Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)CC[C@H](NC(=O)CCCCCCCCCCCCCCC)C(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=C(O)C=C1 YSDQQAXHVYUZIW-QCIJIYAXSA-N 0.000 description 1
- 108010019598 Liraglutide Proteins 0.000 description 1
- 208000005777 Lupus Nephritis Diseases 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 102000004137 Lysophosphatidic Acid Receptors Human genes 0.000 description 1
- 108090000642 Lysophosphatidic Acid Receptors Proteins 0.000 description 1
- 102100040607 Lysophosphatidic acid receptor 1 Human genes 0.000 description 1
- 102100021948 Lysyl oxidase homolog 2 Human genes 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 206010027406 Mesothelioma Diseases 0.000 description 1
- 208000001145 Metabolic Syndrome Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 241000736262 Microbiota Species 0.000 description 1
- 238000006751 Mitsunobu reaction Methods 0.000 description 1
- UCHDWCPVSPXUMX-TZIWLTJVSA-N Montelukast Chemical compound CC(C)(O)C1=CC=CC=C1CC[C@H](C=1C=C(\C=C\C=2N=C3C=C(Cl)C=CC3=CC=2)C=CC=1)SCC1(CC(O)=O)CC1 UCHDWCPVSPXUMX-TZIWLTJVSA-N 0.000 description 1
- 208000012192 Mucous membrane pemphigoid Diseases 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 1
- RATDFIOSZONOPC-UHFFFAOYSA-N N'-hydroxy-4-iodobicyclo[2.2.2]octane-1-carboximidamide Chemical compound O\N=C(/N)\C12CCC(CC1)(CC2)I RATDFIOSZONOPC-UHFFFAOYSA-N 0.000 description 1
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
- 108010082699 NADPH Oxidase 4 Proteins 0.000 description 1
- 102100021872 NADPH oxidase 4 Human genes 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- ZNSPHKJFQDEABI-NZQKXSOJSA-N Nc1nc(O[C@H](c2ccc(Cl)cc2-c2ccccc2)C(F)(F)F)cc(n1)N1CCC2(CN[C@@H](C2)C(O)=O)CC1 Chemical compound Nc1nc(O[C@H](c2ccc(Cl)cc2-c2ccccc2)C(F)(F)F)cc(n1)N1CCC2(CN[C@@H](C2)C(O)=O)CC1 ZNSPHKJFQDEABI-NZQKXSOJSA-N 0.000 description 1
- 208000000693 Neurogenic Urinary Bladder Diseases 0.000 description 1
- 206010029279 Neurogenic bladder Diseases 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 208000027771 Obstructive airways disease Diseases 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- 208000012868 Overgrowth Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 108700027412 Pegbelfermin Proteins 0.000 description 1
- 206010034277 Pemphigoid Diseases 0.000 description 1
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 description 1
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 208000032056 Radiation Fibrosis Syndrome Diseases 0.000 description 1
- 108091005682 Receptor kinases Proteins 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 108091027981 Response element Proteins 0.000 description 1
- 229940125907 SJ995973 Drugs 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 201000010208 Seminoma Diseases 0.000 description 1
- 238000006223 Seyferth-Gilbert homologation reaction Methods 0.000 description 1
- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 238000006859 Swern oxidation reaction Methods 0.000 description 1
- 108091005735 TGF-beta receptors Proteins 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 241000534944 Thia Species 0.000 description 1
- 241000838698 Togo Species 0.000 description 1
- 102000016715 Transforming Growth Factor beta Receptors Human genes 0.000 description 1
- 108700019146 Transgenes Proteins 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 102000011016 Type 5 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 1
- 108010037581 Type 5 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 1
- 206010046798 Uterine leiomyoma Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- OEXHQOGQTVQTAT-BZQJJPTISA-N [(1s,5r)-8-methyl-8-propan-2-yl-8-azoniabicyclo[3.2.1]octan-3-yl] 3-hydroxy-2-phenylpropanoate Chemical compound C([C@H]1CC[C@@H](C2)[N+]1(C)C(C)C)C2OC(=O)C(CO)C1=CC=CC=C1 OEXHQOGQTVQTAT-BZQJJPTISA-N 0.000 description 1
- NELWQUQCCZMRPB-UBPLGANQSA-N [(2r,3r,4r,5r)-4-acetyloxy-5-(4-amino-5-ethenyl-2-oxopyrimidin-1-yl)-2-methyloxolan-3-yl] acetate Chemical compound CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1N1C(=O)N=C(N)C(C=C)=C1 NELWQUQCCZMRPB-UBPLGANQSA-N 0.000 description 1
- OZIUPHNKJFMRMQ-UHFFFAOYSA-N [4-[[5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl]methoxy]-1-bicyclo[2.2.2]octanyl]methanol Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1)OC(F)(F)F)COC12CCC(CC1)(CC2)CO OZIUPHNKJFMRMQ-UHFFFAOYSA-N 0.000 description 1
- CPJZYYFKLNQGQU-UHFFFAOYSA-N [5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)-1,2-oxazol-4-yl]methanol Chemical compound OCC=1C(C=2C(=CN=CC=2Cl)Cl)=NOC=1C1CC1 CPJZYYFKLNQGQU-UHFFFAOYSA-N 0.000 description 1
- CKUAXEQHGKSLHN-UHFFFAOYSA-N [C].[N] Chemical group [C].[N] CKUAXEQHGKSLHN-UHFFFAOYSA-N 0.000 description 1
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 229940121373 acetyl-coa carboxylase inhibitor Drugs 0.000 description 1
- 229960004308 acetylcysteine Drugs 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 210000004100 adrenal gland Anatomy 0.000 description 1
- 239000000614 adrenergic beta-2 receptor agonist Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000001270 agonistic effect Effects 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 208000026594 alcoholic fatty liver disease Diseases 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910001413 alkali metal ion Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 229910001420 alkaline earth metal ion Inorganic materials 0.000 description 1
- 125000005236 alkanoylamino group Chemical group 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 125000000278 alkyl amino alkyl group Chemical group 0.000 description 1
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 description 1
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 description 1
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 description 1
- 150000005215 alkyl ethers Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000003510 anti-fibrotic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 235000009697 arginine Nutrition 0.000 description 1
- 125000005018 aryl alkenyl group Chemical group 0.000 description 1
- 125000004659 aryl alkyl thio group Chemical group 0.000 description 1
- 125000005100 aryl amino carbonyl group Chemical group 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- 125000005160 aryl oxy alkyl group Chemical group 0.000 description 1
- 125000004657 aryl sulfonyl amino group Chemical group 0.000 description 1
- 125000005164 aryl thioalkyl group Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 229960003852 atezolizumab Drugs 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- HKVFISRIUUGTIB-UHFFFAOYSA-O azanium;cerium;nitrate Chemical compound [NH4+].[Ce].[O-][N+]([O-])=O HKVFISRIUUGTIB-UHFFFAOYSA-O 0.000 description 1
- 210000004082 barrier epithelial cell Anatomy 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- BNBQRQQYDMDJAH-UHFFFAOYSA-N benzodioxan Chemical compound C1=CC=C2OCCOC2=C1 BNBQRQQYDMDJAH-UHFFFAOYSA-N 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004935 benzoxazolinyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- PUJDIJCNWFYVJX-UHFFFAOYSA-N benzyl carbamate Chemical compound NC(=O)OCC1=CC=CC=C1 PUJDIJCNWFYVJX-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- MKCBRYIXFFGIKN-UHFFFAOYSA-N bicyclo[1.1.1]pentane Chemical group C1C2CC1C2 MKCBRYIXFFGIKN-UHFFFAOYSA-N 0.000 description 1
- VEPYQCZRVLNDBC-UHFFFAOYSA-N bicyclo[2.2.2]octan-3-one Chemical group C1CC2C(=O)CC1CC2 VEPYQCZRVLNDBC-UHFFFAOYSA-N 0.000 description 1
- MPLAMJZRRHSDCU-UHFFFAOYSA-N bicyclo[2.2.2]octane-4-carbaldehyde Chemical compound C1CC2CCC1(C=O)CC2 MPLAMJZRRHSDCU-UHFFFAOYSA-N 0.000 description 1
- ISPHHZHLSLZHMD-UHFFFAOYSA-N bicyclo[2.2.2]octane-4-carbonitrile Chemical compound C1CC2CCC1(C#N)CC2 ISPHHZHLSLZHMD-UHFFFAOYSA-N 0.000 description 1
- 150000001602 bicycloalkyls Chemical group 0.000 description 1
- 210000000941 bile Anatomy 0.000 description 1
- 210000000013 bile duct Anatomy 0.000 description 1
- 210000003445 biliary tract Anatomy 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 125000004623 carbolinyl group Chemical group 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000009787 cardiac fibrosis Effects 0.000 description 1
- 238000005266 casting Methods 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- PNDKCRDVVKJPKG-WHERJAGFSA-N cenicriviroc Chemical compound C1=CC(OCCOCCCC)=CC=C1C1=CC=C(N(CC(C)C)CCC\C(=C/2)C(=O)NC=3C=CC(=CC=3)[S@@](=O)CC=3N(C=NC=3)CCC)C\2=C1 PNDKCRDVVKJPKG-WHERJAGFSA-N 0.000 description 1
- 229950011033 cenicriviroc Drugs 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- AEULIVPVIDOLIN-UHFFFAOYSA-N cep-11981 Chemical compound C1=C2C3=C4CNC(=O)C4=C4C5=CN(C)N=C5CCC4=C3N(CC(C)C)C2=CC=C1NC1=NC=CC=N1 AEULIVPVIDOLIN-UHFFFAOYSA-N 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 210000003679 cervix uteri Anatomy 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 230000035605 chemotaxis Effects 0.000 description 1
- RUDATBOHQWOJDD-BSWAIDMHSA-N chenodeoxycholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-BSWAIDMHSA-N 0.000 description 1
- 229960001091 chenodeoxycholic acid Drugs 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 1
- 229940106681 chloroacetic acid Drugs 0.000 description 1
- 208000006990 cholangiocarcinoma Diseases 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 239000002812 cholic acid derivative Substances 0.000 description 1
- 150000001842 cholic acids Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- QZHPTGXQGDFGEN-UHFFFAOYSA-N chromene Chemical compound C1=CC=C2C=C[CH]OC2=C1 QZHPTGXQGDFGEN-UHFFFAOYSA-N 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 201000010002 cicatricial pemphigoid Diseases 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N cinnamic acid group Chemical class C(C=CC1=CC=CC=C1)(=O)O WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 229950010810 cintredekin besudotox Drugs 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 229940127206 compound 14d Drugs 0.000 description 1
- 229940125876 compound 15a Drugs 0.000 description 1
- 229940125872 compound 4d Drugs 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- JZCCFEFSEZPSOG-UHFFFAOYSA-L copper(II) sulfate pentahydrate Chemical compound O.O.O.O.O.[Cu+2].[O-]S([O-])(=O)=O JZCCFEFSEZPSOG-UHFFFAOYSA-L 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 238000006880 cross-coupling reaction Methods 0.000 description 1
- TXWRERCHRDBNLG-UHFFFAOYSA-N cubane Chemical compound C12C3C4C1C1C4C3C12 TXWRERCHRDBNLG-UHFFFAOYSA-N 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 1
- 125000001047 cyclobutenyl group Chemical group C1(=CCC1)* 0.000 description 1
- XSYZCZPCBXYQTE-UHFFFAOYSA-N cyclodecylcyclodecane Chemical compound C1CCCCCCCCC1C1CCCCCCCCC1 XSYZCZPCBXYQTE-UHFFFAOYSA-N 0.000 description 1
- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000522 cyclooctenyl group Chemical group C1(=CCCCCCC1)* 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 229960003834 dapagliflozin Drugs 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 125000004856 decahydroquinolinyl group Chemical group N1(CCCC2CCCCC12)* 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- XXTZHYXQVWRADW-UHFFFAOYSA-N diazomethanone Chemical compound [N]N=C=O XXTZHYXQVWRADW-UHFFFAOYSA-N 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical compound [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 description 1
- 150000001991 dicarboxylic acids Chemical class 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 102000038379 digestive enzymes Human genes 0.000 description 1
- 108091007734 digestive enzymes Proteins 0.000 description 1
- 125000005047 dihydroimidazolyl group Chemical group N1(CNC=C1)* 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 201000008865 drug-induced hepatitis Diseases 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- XPOQHMRABVBWPR-ZDUSSCGKSA-N efavirenz Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)O1)C(F)(F)F)#CC1CC1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 0.000 description 1
- 229960003804 efavirenz Drugs 0.000 description 1
- 239000012039 electrophile Substances 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000013931 endocrine signaling Effects 0.000 description 1
- 210000004696 endometrium Anatomy 0.000 description 1
- 239000002308 endothelin receptor antagonist Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 210000003979 eosinophil Anatomy 0.000 description 1
- 230000004890 epithelial barrier function Effects 0.000 description 1
- 229940011399 escin Drugs 0.000 description 1
- 229930186222 escin Natural products 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- CSRGAOFBAGYDHR-UHFFFAOYSA-N ethyl 2-(2-fluoropyridin-4-yl)acetate Chemical compound CCOC(=O)CC1=CC=NC(F)=C1 CSRGAOFBAGYDHR-UHFFFAOYSA-N 0.000 description 1
- VICYTAYPKBLQFB-UHFFFAOYSA-N ethyl 3-bromo-2-oxopropanoate Chemical compound CCOC(=O)C(=O)CBr VICYTAYPKBLQFB-UHFFFAOYSA-N 0.000 description 1
- RUCQPHRTDATAOE-UHFFFAOYSA-N ethyl 4-[(Z)-N'-hydroxycarbamimidoyl]pyridine-2-carboxylate Chemical compound CCOC(=O)c1cc(ccn1)C(=N)NO RUCQPHRTDATAOE-UHFFFAOYSA-N 0.000 description 1
- SPGMDXDPJKEDGC-UHFFFAOYSA-N ethyl 4-amino-3-fluorobenzoate Chemical compound CCOC(=O)C1=CC=C(N)C(F)=C1 SPGMDXDPJKEDGC-UHFFFAOYSA-N 0.000 description 1
- YJZQRRZEDGIEFC-UHFFFAOYSA-N ethyl 4-cyanopyridine-2-carboxylate Chemical compound CCOC(=O)C1=CC(C#N)=CC=N1 YJZQRRZEDGIEFC-UHFFFAOYSA-N 0.000 description 1
- BCANRKMLDXLWMP-UHFFFAOYSA-N ethyl 5-cyano-2-fluorobenzoate Chemical compound CCOC(=O)C1=CC(C#N)=CC=C1F BCANRKMLDXLWMP-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 208000010706 fatty liver disease Diseases 0.000 description 1
- 239000011151 fibre-reinforced plastic Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 229940126374 fipaxalparant Drugs 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000003709 fluoroalkyl group Chemical group 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 229960002714 fluticasone Drugs 0.000 description 1
- MGNNYOODZCAHBA-GQKYHHCASA-N fluticasone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(O)[C@@]2(C)C[C@@H]1O MGNNYOODZCAHBA-GQKYHHCASA-N 0.000 description 1
- 201000005206 focal segmental glomerulosclerosis Diseases 0.000 description 1
- 231100000854 focal segmental glomerulosclerosis Toxicity 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 210000004392 genitalia Anatomy 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000014101 glucose homeostasis Effects 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000004995 haloalkylthio group Chemical group 0.000 description 1
- LVASCWIMLIKXLA-LSDHHAIUSA-N halofuginone Chemical compound O[C@@H]1CCCN[C@H]1CC(=O)CN1C(=O)C2=CC(Cl)=C(Br)C=C2N=C1 LVASCWIMLIKXLA-LSDHHAIUSA-N 0.000 description 1
- 229950010152 halofuginone Drugs 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 125000006343 heptafluoro propyl group Chemical group 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004447 heteroarylalkenyl group Chemical group 0.000 description 1
- 125000005368 heteroarylthio group Chemical group 0.000 description 1
- 125000004366 heterocycloalkenyl group Chemical group 0.000 description 1
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005980 hexynyl group Chemical group 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- RCBVKBFIWMOMHF-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical compound C1=CC=NC=C1.C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O RCBVKBFIWMOMHF-UHFFFAOYSA-L 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000010952 in-situ formation Methods 0.000 description 1
- 125000004926 indolenyl group Chemical group 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 108010021309 integrin beta6 Proteins 0.000 description 1
- 229940125798 integrin inhibitor Drugs 0.000 description 1
- 229960003130 interferon gamma Drugs 0.000 description 1
- 210000004347 intestinal mucosa Anatomy 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 230000026045 iodination Effects 0.000 description 1
- 238000006192 iodination reaction Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229960005386 ipilimumab Drugs 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 description 1
- 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 0.000 description 1
- 125000003384 isochromanyl group Chemical group C1(OCCC2=CC=CC=C12)* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000005438 isoindazolyl group Chemical group 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 210000001117 keloid Anatomy 0.000 description 1
- 208000011379 keloid formation Diseases 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 238000011813 knockout mouse model Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- ACKFDYCQCBEDNU-UHFFFAOYSA-J lead(2+);tetraacetate Chemical compound [Pb+2].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O ACKFDYCQCBEDNU-UHFFFAOYSA-J 0.000 description 1
- 201000010260 leiomyoma Diseases 0.000 description 1
- 229940065725 leukotriene receptor antagonists for obstructive airway diseases Drugs 0.000 description 1
- 239000003199 leukotriene receptor blocking agent Substances 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 229960002701 liraglutide Drugs 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- 229910000103 lithium hydride Inorganic materials 0.000 description 1
- 238000012317 liver biopsy Methods 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 231100000835 liver failure Toxicity 0.000 description 1
- 208000007903 liver failure Diseases 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 208000018191 liver inflammation Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 235000018977 lysine Nutrition 0.000 description 1
- JGCMEBMXRHSZKX-UHFFFAOYSA-N macitentan Chemical compound C=1C=C(Br)C=CC=1C=1C(NS(=O)(=O)NCCC)=NC=NC=1OCCOC1=NC=C(Br)C=N1 JGCMEBMXRHSZKX-UHFFFAOYSA-N 0.000 description 1
- 229960001039 macitentan Drugs 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- OJXOOFXUHZAXLO-UHFFFAOYSA-M magnesium;1-bromo-3-methanidylbenzene;bromide Chemical compound [Mg+2].[Br-].[CH2-]C1=CC=CC(Br)=C1 OJXOOFXUHZAXLO-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- MMIPFLVOWGHZQD-UHFFFAOYSA-N manganese(3+) Chemical compound [Mn+3] MMIPFLVOWGHZQD-UHFFFAOYSA-N 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- OXQRLBFDJMSRMM-NKWVEPMBSA-N methyl (1s,3r)-3-hydroxycyclohexane-1-carboxylate Chemical compound COC(=O)[C@H]1CCC[C@@H](O)C1 OXQRLBFDJMSRMM-NKWVEPMBSA-N 0.000 description 1
- ORVHMLCJEKDDAX-UHFFFAOYSA-N methyl 2-cyanopyridine-4-carboxylate Chemical compound COC(=O)C1=CC=NC(C#N)=C1 ORVHMLCJEKDDAX-UHFFFAOYSA-N 0.000 description 1
- NPXOIGSBRLCOSD-UHFFFAOYSA-N methyl 3-iodobenzoate Chemical compound COC(=O)C1=CC=CC(I)=C1 NPXOIGSBRLCOSD-UHFFFAOYSA-N 0.000 description 1
- IGHWNCLZGNNKBN-UHFFFAOYSA-N methyl 4-[(e)-n'-hydroxycarbamimidoyl]benzoate Chemical compound COC(=O)C1=CC=C(C(\N)=N/O)C=C1 IGHWNCLZGNNKBN-UHFFFAOYSA-N 0.000 description 1
- SMRMKBCUMBETPV-UHFFFAOYSA-N methyl 4-amino-3-(aminomethyl)benzoate dihydrochloride Chemical compound Cl.Cl.COC(=O)c1ccc(N)c(CN)c1 SMRMKBCUMBETPV-UHFFFAOYSA-N 0.000 description 1
- RLUVYUFWNPLVPL-UHFFFAOYSA-N methyl 5-cyanopyridine-3-carboxylate Chemical compound COC(=O)C1=CN=CC(C#N)=C1 RLUVYUFWNPLVPL-UHFFFAOYSA-N 0.000 description 1
- RWTWEJPTYZWMEY-UHFFFAOYSA-N methyl 6-cyanopyridine-2-carboxylate Chemical compound COC(=O)C1=CC=CC(C#N)=N1 RWTWEJPTYZWMEY-UHFFFAOYSA-N 0.000 description 1
- JLJVETNNBYVBKA-UHFFFAOYSA-N methyl 6-hydroxyquinoline-2-carboxylate Chemical compound C1=C(O)C=CC2=NC(C(=O)OC)=CC=C21 JLJVETNNBYVBKA-UHFFFAOYSA-N 0.000 description 1
- CILJSZLWPHTUIP-UHFFFAOYSA-N methyl quinoline-2-carboxylate Chemical compound C1=CC=CC2=NC(C(=O)OC)=CC=C21 CILJSZLWPHTUIP-UHFFFAOYSA-N 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 229960005127 montelukast Drugs 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- 230000004682 mucosal barrier function Effects 0.000 description 1
- 239000003149 muscarinic antagonist Substances 0.000 description 1
- 206010028537 myelofibrosis Diseases 0.000 description 1
- ZUHZZVMEUAUWHY-UHFFFAOYSA-N n,n-dimethylpropan-1-amine Chemical compound CCCN(C)C ZUHZZVMEUAUWHY-UHFFFAOYSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- XZMHJYWMCRQSSI-UHFFFAOYSA-N n-[5-[2-(3-acetylanilino)-1,3-thiazol-4-yl]-4-methyl-1,3-thiazol-2-yl]benzamide Chemical compound CC(=O)C1=CC=CC(NC=2SC=C(N=2)C2=C(N=C(NC(=O)C=3C=CC=CC=3)S2)C)=C1 XZMHJYWMCRQSSI-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 210000003739 neck Anatomy 0.000 description 1
- 230000001338 necrotic effect Effects 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000009826 neoplastic cell growth Effects 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- XZXHXSATPCNXJR-ZIADKAODSA-N nintedanib Chemical compound O=C1NC2=CC(C(=O)OC)=CC=C2\C1=C(C=1C=CC=CC=1)\NC(C=C1)=CC=C1N(C)C(=O)CN1CCN(C)CC1 XZXHXSATPCNXJR-ZIADKAODSA-N 0.000 description 1
- 229960004378 nintedanib Drugs 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- FBUKVWPVBMHYJY-UHFFFAOYSA-N nonanoic acid Chemical compound CCCCCCCCC(O)=O FBUKVWPVBMHYJY-UHFFFAOYSA-N 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000005016 nuclear Overhauser enhanced spectroscopy Methods 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 108020004017 nuclear receptors Proteins 0.000 description 1
- 102000027507 nuclear receptors type II Human genes 0.000 description 1
- 108091008686 nuclear receptors type II Proteins 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- ZXERDUOLZKYMJM-ZWECCWDJSA-N obeticholic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)CCC(O)=O)CC[C@H]21 ZXERDUOLZKYMJM-ZWECCWDJSA-N 0.000 description 1
- 229960001601 obeticholic acid Drugs 0.000 description 1
- 125000004930 octahydroisoquinolinyl group Chemical group C1(NCCC2CCCC=C12)* 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- ACSQLTBPYZSGBA-GMXVVIOVSA-N olorinab Chemical compound C([C@@H]1C[C@@H]1C=12)C=1C(C(=O)N[C@H](CO)C(C)(C)C)=NN2C1=C[N+]([O-])=CC=N1 ACSQLTBPYZSGBA-GMXVVIOVSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- PFGVNLZDWRZPJW-OPAMFIHVSA-N otamixaban Chemical compound C([C@@H](C(=O)OC)[C@@H](C)NC(=O)C=1C=CC(=CC=1)C=1C=C[N+]([O-])=CC=1)C1=CC=CC(C(N)=N)=C1 PFGVNLZDWRZPJW-OPAMFIHVSA-N 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 230000014306 paracrine signaling Effects 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000006611 pharmacological activation Effects 0.000 description 1
- 210000003800 pharynx Anatomy 0.000 description 1
- 125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 description 1
- 125000004625 phenanthrolinyl group Chemical group N1=C(C=CC2=CC=C3C=CC=NC3=C12)* 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000004928 piperidonyl group Chemical group 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 125000004591 piperonyl group Chemical group C(C1=CC=2OCOC2C=C1)* 0.000 description 1
- ISWRGOKTTBVCFA-UHFFFAOYSA-N pirfenidone Chemical compound C1=C(C)C=CC(=O)N1C1=CC=CC=C1 ISWRGOKTTBVCFA-UHFFFAOYSA-N 0.000 description 1
- 229960003073 pirfenidone Drugs 0.000 description 1
- 229920000548 poly(silane) polymer Polymers 0.000 description 1
- 125000006684 polyhaloalkyl group Polymers 0.000 description 1
- 150000004033 porphyrin derivatives Chemical class 0.000 description 1
- 208000007232 portal hypertension Diseases 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 150000003246 quinazolines Chemical class 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 238000007347 radical substitution reaction Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 231100000272 reduced body weight Toxicity 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- TZSZZENYCISATO-WIOPSUGQSA-N rodatristat Chemical compound CCOC(=O)[C@@H]1CC2(CN1)CCN(CC2)c1cc(O[C@H](c2ccc(Cl)cc2-c2ccccc2)C(F)(F)F)nc(N)n1 TZSZZENYCISATO-WIOPSUGQSA-N 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- MRWFZSLZNUJVQW-DEOSSOPVSA-N saroglitazar Chemical compound C1=CC(C[C@H](OCC)C(O)=O)=CC=C1OCCN1C(C=2C=CC(SC)=CC=2)=CC=C1C MRWFZSLZNUJVQW-DEOSSOPVSA-N 0.000 description 1
- 229950006544 saroglitazar Drugs 0.000 description 1
- 231100000241 scar Toxicity 0.000 description 1
- 230000037390 scarring Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 150000003334 secondary amides Chemical class 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000008299 semisolid dosage form Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- RGYQPQARIQKJKH-UHFFFAOYSA-N setanaxib Chemical compound CN(C)C1=CC=CC(C2=C3C(=O)N(C=4C(=CC=CC=4)Cl)NC3=CC(=O)N2C)=C1 RGYQPQARIQKJKH-UHFFFAOYSA-N 0.000 description 1
- 229960003310 sildenafil Drugs 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 229950009513 simtuzumab Drugs 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 description 1
- 229960002218 sodium chlorite Drugs 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- VGTPCRGMBIAPIM-UHFFFAOYSA-M sodium thiocyanate Chemical compound [Na+].[S-]C#N VGTPCRGMBIAPIM-UHFFFAOYSA-M 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- JEZLFWXSKCTMPN-ILCIQDJASA-M sodium;2-[(2s,3r,4e,6e,10e,12s)-13-(4-fluorophenoxy)-2,3,12-trihydroxytrideca-4,6,10-trien-8-ynoxy]acetate Chemical compound [Na+].[O-]C(=O)COC[C@H](O)[C@H](O)/C=C/C=C/C#C/C=C/[C@H](O)COC1=CC=C(F)C=C1 JEZLFWXSKCTMPN-ILCIQDJASA-M 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 206010062261 spinal cord neoplasm Diseases 0.000 description 1
- 208000005198 spinal stenosis Diseases 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000002466 tachykinin receptor agonist Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- FRACPXUHUTXLCX-BELIEFIBSA-N tert-butyl N-{1-[(1S)-1-{[(1R,2S)-1-(benzylcarbamoyl)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-2-cyclopropylethyl]-2-oxopyridin-3-yl}carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=CN(C1=O)[C@@H](CC2CC2)C(=O)N[C@@H](C[C@@H]3CCNC3=O)[C@H](C(=O)NCC4=CC=CC=C4)O FRACPXUHUTXLCX-BELIEFIBSA-N 0.000 description 1
- XBXCNNQPRYLIDE-UHFFFAOYSA-N tert-butylcarbamic acid Chemical compound CC(C)(C)NC(O)=O XBXCNNQPRYLIDE-UHFFFAOYSA-N 0.000 description 1
- 150000003511 tertiary amides Chemical class 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 125000004627 thianthrenyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3SC12)* 0.000 description 1
- 125000005309 thioalkoxy group Chemical group 0.000 description 1
- 125000004001 thioalkyl group Chemical group 0.000 description 1
- 125000005403 thiohaloalkoxy group Chemical group 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- LERNTVKEWCAPOY-DZZGSBJMSA-N tiotropium Chemical compound O([C@H]1C[C@@H]2[N+]([C@H](C1)[C@@H]1[C@H]2O1)(C)C)C(=O)C(O)(C=1SC=CC=1)C1=CC=CS1 LERNTVKEWCAPOY-DZZGSBJMSA-N 0.000 description 1
- 229940110309 tiotropium Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 229960005294 triamcinolone Drugs 0.000 description 1
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical group CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- ZMCBYSBVJIMENC-UHFFFAOYSA-N tricaine Chemical compound CCOC(=O)C1=CC=CC(N)=C1 ZMCBYSBVJIMENC-UHFFFAOYSA-N 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 1
- TVLNGWSWPKIYAO-UHFFFAOYSA-N tris(2-diphenylphosphanylethyl)phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(CCP(C=1C=CC=CC=1)C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 TVLNGWSWPKIYAO-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 125000005500 uronium group Chemical group 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4245—Oxadiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/428—Thiazoles condensed with carbocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
本发明提供式(I)化合物或其立体异构体、互变异构体或药学上可接受的盐或溶剂合物,其中所有变量如本文中所定义。这些化合物调节法尼酯X受体(FXR)的活性,例如作为激动剂。本发明还涉及包含这些化合物的药物组合物,及使用所述化合物和药物组合物治疗与FXR调节异常相关的疾病、病症或病状,诸如病理性纤维化、移植排斥、癌症、骨质疏松和炎性病症的方法。
Description
交叉引用
本申请要求2017年11月1日提交的美国临时申请第62/580,075号的权益,该申请以全文引用的方式并入本文中。
技术领域
本发明一般涉及适用作法尼酯X受体(farnesoid X receptor;FXR)调节剂的化合物、包含此类化合物的药物组合物,以及其在治疗中的用途,尤其用于治疗或预防FXR调节剂适用的疾病、病症和病状。
背景技术
FXR或NR1H4(核受体亚家族1,H组,成员4)是一种可以配体依赖性方式活化特定靶基因表达的核受体。FXR表达于人体内肝脏中,整个胃肠道、结肠、卵巢、肾上腺、肾脏中,以及胆囊和胆管树中。FXR与类视黄素X受体(RXR)形成杂二聚体,且与靶基因中的特定反应元件结合以调节基因转录(B.M.Forman等人,Cell 1995;81:687;W.Seol等人,Mol.Endocrinol.1995;9:72)。FXR/RXR杂二聚体通常与由单核苷酸间隔开的共有六核苷酸序列(AGGTCA)(即IR-1序列)的反向重复序列结合。FXR的相关生理配体为胆酸,包括鹅去氧胆酸及其牛磺酸缀合物(D.J.Parks等人,Science 1999;284:1365;M.Makishima等人,Science 1999;284:1362)。FXR活化调节多种基因的表达,该多种基因编码胆酸合成、流入和流出肝脏及肠道所涉及的酶和转运蛋白,从而引起负反馈回路中的总内源性胆酸的净减少。FXR通过上调细胞因子成纤维细胞生长因子15(啮齿动物)或19(灵长类动物)的表达而参与旁分泌和内分泌信号传导,其还可促进胆酸浓度的调节(Holt等人,Genes Dev.2003;17:1581;Inagaki等人,Cell Metab 2005;2:217)。因此,FXR被认为是胆酸内稳定的主调节因子。
FXR激动剂的一个用途是用于治疗胆酸调节异常的疾病,包括胆汁郁积性疾病(例如,原发性胆汁性肝硬化和原发性硬化性胆管炎),其可导致纤维化、肝硬化、胆管癌、肝细胞癌、肝功能衰竭和死亡。虽然肝脏中的胆酸浓度升高具有不利影响,但胆酸还影响小肠的微生物群和完整性。人类或啮齿类动物的胆汁流动阻塞造成肠道细菌增殖和粘膜损伤,其可导致细菌穿过粘膜屏障的易位和全身性感染(Berg,Trends Microbiol.1995;3:149-154)。缺乏FXR的小鼠的回肠细菌量增加且上皮屏障受损,同时肠道FXR的活化在预防细菌过度生长和维持肠道上皮的完整性中起重要作用(Inagaki等人,Proc Natl Acad Sci2006;103:3920-3925)。随时间推移,FXR敲除小鼠自发演变成肝细胞癌,且此情形可通过选择性地重新活化肠道中的FXR而消除(Degirolamo等人,Hepatology 61:161-170)。用小分子激动剂药理学活化FXR或在肠道中转基因表达FXR可使胆酸浓度正常,降低肝胆管中的细胞增殖,以及减少啮齿动物胆汁郁积模型中的炎性细胞浸润、坏死区域和肝纤维化(Liu等人,J.Clin.Invest.2003;112:1678-1687;Modica等人,Gastroenterology.2012;142:355-365)。在临床前胆汁郁积模型中观测到的这些有益效应中的一些已转移至人类患者,且FXR激动剂奥贝胆酸(OCA或OCALIVATM)已经批准用于治疗原发性胆汁性肝硬化(https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm503964.htm)。
除了控制胆酸内稳定以外,FXR激动剂还调节数百种基因的肝脏表达,所述基因编码胆固醇和脂质代谢和转运、葡萄糖内稳定、炎症、趋化性和细胞凋亡以及其他途径所涉及的蛋白(Zhan等人,PLoS One 2014;9:e105930;Ijssennagger等人,J Hepatol 2016;64:1158-1166)。根据对基因表达的这些广泛影响,还已在纤维化、癌症、炎性疾病和代谢障碍的临床前模型中研究FXR激动剂,所述代谢障碍包括血脂异常、肥胖症、2型糖尿病、非酒精性脂肪肝病(NAFLD)和代谢综合征(Crawley,Expert Opin.Ther.Patents 2010;20:1047-1057)。
还在人类临床试验中研究FXR激动剂用于治疗NAFLD(脂肪肝病的更晚期形式)、非酒精性脂肪变性肝炎(NASH)及相关并发症。NAFLD为现今全世界慢性肝病的最常见病因之一(Vernon等人,Aliment Pharmacol Ther 2011;34:274-285)。患上NAFLD的风险因素包括肥胖、2型糖尿病(T2DM)、胰岛素抗性、高血压和血脂异常。在患有NAFLD的T2DM患者的6周临床试验中,FXR激动剂OCA在统计学上显著改善胰岛素敏感度且减轻体重,由此展现对这些风险因素中的一些的有益效应(Mudaliar等人,Gastroenterology 2013;145:574-582)。NASH是NAFLD的最严重和进行性形式,且包括以下组织学表现:肝脏脂肪变性、发炎和伴随细胞外纤维化量改变的气球样变性(ballooning degeneration)(Sanyal等人,Hepatology2015;61:1392-1405)。在患有NASH的患者的72周临床试验中,OCA在统计学上显著改善肝脏脂肪变性、小叶发炎、肝细胞气球样变和纤维化,如通过肝脏活检体的组织学分析所评估(Neuschwander-Tetri等人,Lancet 2015;385:956-965)。鉴于NASH是美国肝细胞癌(HCC)和肝脏移植的第二主要病因,这些数据还表明FXR激动剂在临床结果方面展现益处的潜力(Wong等人,Hepatology 2014;59:2188-2195)。
本发明提供用于治疗有需要的患者的与法尼酯X受体(FXR)活性相关的疾病、病症或病状的新颖化合物。
发明内容
在一个方面,本发明提供可用作FXR调节剂的式(I)、式(IIa)和式(IIb)化合物以及其亚属和种,包括其立体异构体、互变异构体、药学上可接受的盐和溶剂合物。
在另一方面,本发明还提供用于制备本发明化合物的方法和中间体。
在另一方面,本发明还提供药物组合物,其包含药学上可接受的载体和至少一种本发明化合物或其立体异构体、互变异构体、药学上可接受的盐或溶剂合物。
在另一方面,本发明化合物可单独或与一或多种其他治疗剂组合用于治疗。
本发明化合物可用于治疗该患者的与法尼酯X受体(FXR)活性相关的疾病、病症或病状,其是通过向该患者给药治疗有效量的化合物或其立体异构体、互变异构体或药学上可接受的盐或溶剂合物。该疾病、病症或病状可与病理性纤维化有关。本发明化合物可单独使用,与一或多种本发明化合物组合使用,或与一或多种(例如一至两种)其他治疗剂组合使用。
本发明化合物可作为单一药物或与其他药物组合用于治疗选自以下的疾病、病症或病状:非酒精性脂肪变性肝炎(NASH)、非酒精性脂肪肝病(NAFLD)、慢性肾病、糖尿病性肾病、原发性硬化性胆管炎(PSC)和原发性胆汁性肝硬化症(PBC)。本发明化合物可作为单一药物或与其他药物组合用于治疗特发性肺纤维化(IPF)。
本发明化合物可用于制造用以治疗需要此类治疗的患者的疾病、病症或病状的药物。
本发明的其他特征和有点将自以下描述和权利要求书显而易知。
具体实施方式
本申请提供式(I)化合物,包括其所有立体异构体、溶剂合物、前药和药学上可接受的盐和溶剂合物形式。本申请还提供含有至少一种式(I)化合物或其立体异构体、互变异构体或药学上可接受的盐或溶剂合物且任选含有至少一种其他治疗剂的药物组合物。另外,本申请提供用于治疗患有FXR调节性疾病或病症的患者的方法,该疾病或病症诸如胆纤维化、肝纤维化、肾纤维化、非酒精性脂肪肝病(NAFLD)、非酒精性脂肪性肝炎(NASH)、原发性硬化性胆管炎(PSC)、原发性胆汁性肝硬化症(PBC)和胰纤维化,该方法是通过向需要此类治疗的患者给药治疗有效量的本发明化合物或其立体异构体、互变异构体或药学上可接受的盐或溶剂合物,且任选组合给药至少一种其他治疗剂。
I.本发明化合物
在一个实施方案中,本发明提供一种式(I)化合物:
或其立体异构体、互变异构体或药学上可接受的盐或溶剂合物;其中
X1和X4各自独立地为C或N;
X2和X3各自独立地为CR3、N、NR4、O或S;
虚线圆表示由X1、X2、X3、X4和碳原子形成的芳环;
E1和E3各自独立地为共价键、O、S、N、NR6、CR5或CR5aR5b;
E2为O、S、N、NR8、CR7或CR7aR7b;其中(E1与E2)或(E3与E2)形成单键或双键;其限制条件为:(1)(E1与E2)和(E3与E2)之间的键不都为双键;和(2)E1、E2和E3中至多一者为O、S、N或NR8;
虚线为任选的共价键;“任选”意指存在或不存在共价键;
B环为5元至8元桥联环烷基或环杂烷基;且与L1或Z的连接点为碳原子;且环烷基和环杂烷基中的每个独立地包括(但不限于)单环、双环、多环和桥联环系统;
L1为共价键、O、S、NR16、-C(S)NH-、C1-3亚烷基、C1-3亚杂烷基、C2-4亚烯基、C2-4亚炔基、芳基或含有1至4个独立地选自N、O和S的杂原子的5元至6元杂芳基;其中该亚烷基、亚杂烷基、芳基和杂芳基各自独立地经0至3个R9取代;举例而言,该5元至6元杂芳基包括(但不限于)噁二唑、噻二唑、三唑、吡唑、咪唑、异噻唑、噻唑、噁唑、异噁唑、吡咯、呋喃、噻吩、吡喃、吡啶、哒嗪、嘧啶和吡嗪;
Z为6元至10元芳基、5元至10元杂芳基、3元至10元碳环基或4元至10元杂环基,其中该芳基、杂芳基、碳环基和杂环基独立地经0至5个R10取代;
L2各自独立地为共价键、O、S、NR17、C1-3亚烷基或C1-3亚杂烷基,其中该亚烷基和亚杂烷基独立地经0至3个R11取代;
RX为-(CR12aR12b)e-RZ或-Ο(CR12aR12b)e-RZ;
e为0或1;
RZ选自-CN、-OH、-C(O)OR13、-C(O)NR14aR14b、
Re为C1-6烷基、C3-6环烷基、卤烷基、羟基烷基、氨基烷基、烷氧基烷基、卤烷氧基烷基或苯基;
R1为C1-6烷基、C3-5环烷基或C4-6杂环基,其中该烷基、环烷基和杂环基各自独立地经0至3个R15取代;
R2为6元至10元芳基、5元至10元杂芳基、3元至10元碳环基或4元至10元杂环基,其中该芳基、杂芳基、碳环基和杂环基独立地经0至5个R16取代;
R3和R7各自独立地为氢、卤素、氰基、羟基、氨基、C1-6烷基、烷基氨基、卤烷基、羟基烷基、氨基烷基、烷氧基烷基、卤烷氧基烷基、烷氧基或卤烷氧基;
R4、R6、R8、R16和R17各自独立地为氢、C1-6烷基、卤烷基、羟基烷基、氨基烷基、烷氧基烷基或卤烷氧基烷基;
R5为氢、C1-6烷基、卤烷基、羟基烷基、氨基烷基、烷氧基烷基或卤烷氧基烷基;
R5a、R5b、R7a和R7b各自独立地为氢、卤素、氰基、羟基、氨基、C1-6烷基、烷基氨基、卤烷基、羟基烷基、氨基烷基、烷氧基烷基、卤烷氧基烷基、烷氧基或卤烷氧基;
R9和R11各自独立地为卤素、氧代、氰基、羟基、氨基、C1-6烷基、C3-6环烷基、C4-6杂环基、烷基氨基、卤烷基、羟基烷基、氨基烷基、烷氧基烷基、卤烷氧基烷基、烷氧基或卤烷氧基;
a为整数0、1、2或3;
R10和R16各自独立地为卤素、氰基、羟基、氨基、氧代、-ORa、-SRa、=S、-NRcRc、=NH、=N-OH、=NRa、=N-ORa、-NO2、-S(O)2Ra、-S(O)2NHRb、-S(O)2NRcRc、-S(O)2ORb、-OS(O)2Rb、-OS(O)2ORb、-P(O)(ORb)(ORb)、-C(O)Rb、-C(NRb)Rb、-C(O)ORb、-C(O)NRcRc、-C(NRb)NRcRc、-OC(O)Rb、-NRbC(O)Rb、-OC(O)ORb、-NRbC(O)ORb、-OC(O)NRcRc、-NRbC(O)NRcRc、-NRbC(NRb)Rb、-NRbC(NRb)NRcRc、C1-6烷基、C1-6卤烷基、芳基、芳基烷基、杂芳基、碳环基或杂环基;其中单独或作为另一基团的一部分的烷基、芳基、杂芳基、碳环基和杂环基各自独立地经0至5个Rd取代;
Ra选自C1-6烷基、卤烷基、羟基烷基、氨基烷基、烷氧基烷基、卤烷氧基烷基、芳基、芳基烷基、杂芳基、杂芳基烷基、碳环基、碳环基烷基、杂环基和杂环基烷基;
Rb各自独立地为氢或Ra;
Rc各自独立地为Rb,或替代地两个Rc和与其所键合的氮原子一起形成4元、5元、6元或7元杂环基;
Rd各自独立地选自Ra、烷氧基、卤烷氧基、烷基氨基、环烷基氨基、杂环基氨基、卤烷基、羟基烷基、氨基烷基、环烷氧基、杂环基氧基、卤烷氧基、烷氧基烷氧基、卤烷基氨基、烷氧基烷基氨基、卤烷氧基烷基氨基、芳基氨基、芳烷基氨基、芳基氧基、芳烷基氧基、杂芳基氧基、杂芳基烷基氧基、烷基硫基、卤素、氰基、羟基、氨基、氧代、-ORa、-SRa、=S、-NRcRc、=NH、=N-OH、=NRa、=N-ORa、-NO2、-S(O)2Ra、-S(O)2NHRb、-S(O)2NRcRc、-S(O)2ORb、-OS(O)2Rb、-OS(O)2ORb、-P(O)(ORb)(ORb)、-C(O)Rb、-C(NRb)Rb、-C(O)ORb、-C(O)NRcRc、-C(NRb)NRcRc、-OC(O)Rb、-NRbC(O)Rb、-OC(O)ORb、-NRbC(O)ORb、-NRbC(O)NRcRc、-NRbC(NRb)Rb和-NRbC(NRb)NRcRc;
R12a和R12b各自独立地为氢、卤素、氰基、羟基、氨基、C1-6烷基、烷基氨基、卤烷基、羟基烷基、氨基烷基、烷氧基烷基、卤烷氧基烷基、烷氧基或卤烷氧基;或替代地R12a和R12b和与其所连接的一或多个原子一起形成3元或4元碳环或杂环;
R13为氢、C1-10烷基或糖基;
R14a和R14b各自独立地为氢、C1-6烷基、卤烷基、羟基烷基、氨基烷基、烷氧基烷基、卤烷氧基烷基、烷氧基或卤烷氧基;且
R15为氢、卤素、氰基、羟基、氨基、C1-6烷基、烷基氨基、卤烷基、羟基烷基、氨基烷基、烷氧基烷基、卤烷氧基烷基、烷氧基或卤烷氧基。
在式(I)的任一前述实施方案中,X2为N或NR4。
在式(I)的任一前述实施方案中,与E3或E2的连接点还为碳原子。
在式(I)的任一前述实施方案中,B环为选自以下的部分:
在式(I)的任一前述实施方案中,
部分为选自/>的环部分。
在式(I)的任一前述实施方案中,E1、E2和E3一起形成选自以下的部分:
在式(I)的任一前述实施方案中,L1为共价键、
在式(I)的任一前述实施方案中,Z为苯基、3元至7元环烷基、4元至10元环杂烷基或5元至10元杂芳基,其中该苯基、环烷基、环杂烷基和杂芳基独立地经0至5个R10取代,其中R8与上文所定义相同。
在式(I)的任一前述实施方案中,-Z-RX选自
其中Z部分进一步经0至3个R10取代,且R10与上文所定义相同。
在式(I)的任一前述实施方案中,R1为C1-3烷基或C3-5环烷基。
在式(I)的任一前述实施方案中,R2为苯基或6元杂芳基,其中该苯基和杂芳基独立地经0至3个R10取代。
在式(I)的任一前述实施方案中,L2为共价键。
在式(I)的任一前述实施方案中,RX为-C(O)OH、-CH2C(O)OH、-C(O)OCH3、-CH2C(O)OCH3、-C(O)NH-S(O)2-CH3或四唑基。
在本发明的一个实施方案中,式(I)化合物由式(IIa)或式(IIb)表示:
其中
X1为C或N;
X2和X3各自独立地为CH、N、O或S;
E1和E3各自独立地为共价键、O、S、N、NH、CH或CH2;
E2为O、S、N、NH、CH或CH2;其中(E1与E2)或(E3与E2)形成单键或双键;其限制条件为:(1)(E1与E2)和(E3与E2)之间的键不都为双键;和(2)E1、E2和E3中的至少一个不为O、S、N或NH;
Y为O、S、NH或CH2;
m、n和p各自独立地为0或1;
L1为共价键、C1-3亚烷基、C1-3亚杂烷基、C2-4亚烯基、C2-4亚炔基或含有1至3个独立地选自N、O和S的杂原子的5元至6元杂芳基;其中该亚烷基、亚杂烷基、芳基和杂芳基独立地经0至3个R9取代;
Z为苯基或5元至10元杂芳基,其中该苯基和杂芳基独立地经0至3个R10取代;
RX为-C(O)OH;
R1为C1-6烷基或C3-5环烷基,其中该烷基或环烷基经0至3个R15取代;
R2为苯基或6元杂芳基,其中该苯基或杂芳基经0至3个R16取代;且
R9、R10、R15和R16与上文所定义相同。
在式(IIa)或式(IIb)的任一前述实施方案中,m、n和p为1;且Y为O或CH2。
在式(IIa)或式(IIb)的任一前述实施方案中,Y为CH2;且L1为含有1至3个独立地选自N、O和S的杂原子的5元至6元杂芳基,且Z为苯基或6元杂芳基;或替代地,L1为共价键,且Z为5元至10元杂芳基;或替代地,L1为C1-3亚烷基、C1-3亚杂烷基或C2-4亚炔基,且Z为苯基或5元至10元杂芳基;其中该苯基和杂芳基各自独立地经0至3个R9取代。
在式(IIa)或式(IIb)的任一前述实施方案中,Y为O;且L1为含有1至3个独立地选自N、O和S的杂原子的5元至6元杂芳基,且Z为苯基或6元杂芳基;或替代地,L1为共价键,且Z为5元至10元杂芳基;或替代地,L1为C1-3亚杂烷基或C2-4亚炔基,且Z为苯基或5元至10元杂芳基;其中该苯基和杂芳基各自独立地经0至3个R9取代。
在式(IIa)或式(IIb)的任一前述实施方案中,
部分为选自/>的环部分。
在式(IIa)或式(IIb)的任一前述实施方案中,E1、E2和E3一起形成选自以下的部分:
在式(IIa)或式(IIb)的任一前述实施方案中,L1为共价键或
在式(IIa)或式(IIb)的任一前述实施方案中,Z为苯基、5元或6元单环杂芳基或8元至10元双环杂芳基,其中该苯基或杂芳基独立地经0至3个R10取代。
在式(I)、式(IIa)或式(IIb)的一个实施方案中,X1为C。
在式(I)、式(IIa)或式(IIb)的一个实施方案中,X2为N。
在式(I)、式(IIa)或式(IIb)的一个实施方案中,X3为O。
在式(I)的一个实施方案中,X4为C。
在式(I)的一个实施方案中,X1为C且X4为C。
在式(I)、式(IIa)或式(IIb)的一个实施方案中,X2和X3中的一个为N,且X2和X3中的另一个为O。
在式(I)、式(IIa)或式(IIb)的一个实施方案中,X2为N且X3为O。
在式(I)、式(IIa)或式(IIb)的一个实施方案中,X2为O且X3为N。
在式(I)、式(IIa)或式(IIb)的一个实施方案中,X1为C;X2为N;且X3为O。
在式(I)的一个实施方案中,X1为C;X2和X3中的一个为N,且X2和X3中的另一个为O;且X4为C。
在式(I)的一个实施方案中,X1为C;X2为N;X3为O;且X4为C。
在式(I)的一个实施方案中,X1为C;X2为O;X3为N;且X4为C。
在式(I)、式(IIa)或式(IIb)的一个实施方案中,X1为N;X2为N;且X3为N。
在式(I)的一个实施方案中,E1、E2和E3一起形成选自 的部分。
在式(I)的一个实施方案中,E1、E2和E3一起形成选自 的部分。
在式(I)、式(IIa)或式(IIb)的一个实施方案中,R1为环丙基。
在式(I)、式(IIa)或式(IIb)的一个实施方案中,R2为苯基或吡啶基,其各自经零至2个R16取代。
在式(I)、式(IIa)或式(IIb)的一个实施方案中,R2为经零至2个R16取代的苯基。
在式(I)、式(IIa)或式(IIb)的一个实施方案中,R2为经零至2个R16取代的吡啶基。
在式(I)、式(IIa)或式(IIb)的一个实施方案中,各R16独立地为F、Cl、-CH3、-CF3、-OCH3或-OCF3。
在式(I)的一个实施方案中,L2为共价键。
在式(I)、式(IIa)或式(IIb)的一个实施方案中,B环为选自 的部分。
在式(I)、式(IIa)或式(IIb)的一个实施方案中,B环为选自的部分。
在式(I)、式(IIa)或式(IIb)的一个实施方案中,B环为
在式(I)、式(IIa)或式(IIb)的一个实施方案中,B环为选自的部分。
在式(I)、式(IIa)或式(IIb)的一个实施方案中,B环为
在式(I)、式(IIa)或式(IIb)的一个实施方案中,B环为
在式(I)、式(IIa)或式(IIb)的一个实施方案中,L1为共价键、
在式(I)、式(IIa)或式(IIb)的一个实施方案中,L1为共价键。
在式(I)、式(IIa)或式(IIb)的一个实施方案中,L1为:
在式(I)、式(IIa)或式(IIb)的一个实施方案中,L1为:
在式(I)、式(IIa)或式(IIb)的一个实施方案中,Z为苯基、吡唑基、噻唑基、噁二唑基、吡啶基、吲哚基、吲唑基、苯并[d]噻唑基、咪唑并[1,2-a]吡啶基、喹啉基或异喹啉基,其各自经零至2个R10取代。
在式(I)、式(IIa)或式(IIb)的一个实施方案中,Z为苯基、吡啶基、苯并[d]噻唑基、喹啉基或异喹啉基,其各自经零至2个R10取代。
在式(I)、式(IIa)或式(IIb)的一个实施方案中,Z为经零至2个R10取代的苯基。
在式(I)、式(IIa)或式(IIb)的一个实施方案中,Z为经零至2个R10取代的吡啶基。
在式(I)、式(IIa)或式(IIb)的一个实施方案中,Z为经零至2个R10取代的苯并[d]噻唑基。
在式(I)、式(IIa)或式(IIb)的一个实施方案中,Z为喹啉基或异喹啉基,其各自经零至2个R10取代。
在式(I)、式(IIa)或式(IIb)的一个实施方案中,Z为经零至2个R10取代的喹啉基。
在式(I)、式(IIa)或式(IIb)的一个实施方案中,Z为经零至2个R10取代的异喹啉基。
在式(I)、式(IIa)或式(IIb)的一个实施方案中,各R10独立地为F、Cl、-OH、-CN、-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2、-CHF2、-CF3、-CF2CH3、-CH2OCH3、-OCH3、-OCH2CH3、-OCH(CH3)2、-OCHF2、-OCF3、-OCH2CHF2、-OCH2CF3、-OCH2C(CH3)2OH、-OCH2CH2OCH3、-OCH2CH2CH2OCH3、-OCH(CH2Cl)(CH2OH)、-OCH2CH(CH2Cl)(CH2OH)、-O(C3-5环烷基)、-N(CH3)2、-S(O)2CH3、-CH2(环丙基)、-CH2(氧杂环丁烷基)、-OCH2(环丙基)、-NH(环丙基)、-NH(苯基)、-O(氧杂环丁烷基)、-O(四氢呋喃基)、-O(四氢吡喃基)、-OCH2(环丙基)、-OCH2(环丁基)、-OCH2(氧杂环丁烷基)、-OCH2CH2(吡咯烷基)、环丙基、氮杂环丁烷基、(羟基甲基)氮杂环丁烷基、氟氮杂环丁烷基、(二甲基氨基)氮杂环丁烷基、甲氧基氮杂环丁烷基、羟基氮杂环丁烷基、吗啉基、哌嗪基、甲基哌嗪基、羟基哌啶基、吡咯烷基或羟基吡咯烷基。
在式(I)、式(IIa)或式(IIb)的一个实施方案中,各R10独立地为F、Cl、-OH、-CN、-CH3、-CH2CH3、-CHF2、-CF3、-OCH3、-OCH2CH3、-OCH(CH3)2、-OCHF2、-OCF3、-OCH2CHF2、-OCH2CF3、-O(C3-5环烷基)、-N(CH3)2、-S(O)2CH3、-CH2(环丙基)、-CH2(氧杂环丁烷基)、-OCH2(环丙基)、-NH(环丙基)、-NH(苯基)、-O(氧杂环丁烷基)、-O(四氢呋喃基)、-O(四氢吡喃基)、-OCH2(环丙基)、-OCH2(环丁基)、-OCH2(氧杂环丁烷基)、环丙基、氮杂环丁烷基、(羟基甲基)氮杂环丁烷基、氟氮杂环丁烷基、(二甲基氨基)氮杂环丁烷基、甲氧基氮杂环丁烷基、羟基氮杂环丁烷基、吗啉基、哌嗪基、甲基哌嗪基、羟基哌啶基、吡咯烷基或羟基吡咯烷基。
在式(I)、式(IIa)或式(IIb)的一个实施方案中,各R10独立地为-O(C3-5环烷基)、-CH2(环丙基)、-CH2(氧杂环丁烷基)、-OCH2(环丙基)、-NH(环丙基)、-NH(苯基)、-O(氧杂环丁烷基)、-O(四氢呋喃基)、-O(四氢吡喃基)、-OCH2(环丙基)、-OCH2(环丁基)、-OCH2(氧杂环丁烷基)、-OCH2CH2(吡咯烷基)、环丙基、氮杂环丁烷基、(羟基甲基)氮杂环丁烷基、氟氮杂环丁烷基、(二甲基氨基)氮杂环丁烷基、甲氧基氮杂环丁烷基、羟基氮杂环丁烷基、吗啉基、哌嗪基、甲基哌嗪基、羟基哌啶基、吡咯烷基或羟基吡咯烷基。
在式(I)、式(IIa)或式(IIb)的一个实施方案中,Rx为-C(O)OH、-CH2C(O)OH或
在式(I)、式(IIa)或式(IIb)的一个实施方案中,Rx为-C(O)OH或-CH2C(O)OH。
在式(I)、式(IIa)或式(IIb)的一个实施方案中,Rx为-C(O)OH。
在式(I)、式(IIa)或式(IIb)的一个实施方案中,Rx为
在式(I)的一个实施方案中,a为零或1。
在式(I)的一个实施方案中,a为零。
在式(I)的一个实施方案中,X1为C;X2为N;X3为O;X4为C;R1为环丙基;L2为共价键;R2为苯基或吡啶基,其各自经零至2个R16取代;E1、E2和E3一起形成选自的部分;且B环为选自/> 的部分。
在式(I)、式(IIa)或式(IIb)的一个实施方案中,L1为共价键、 B环为/>且Z为苯基、吡啶基、苯并[d]噻唑基、喹啉基或异喹啉基,其各自经零至2个R10取代;Rx为-C(O)OH、-CH2C(O)OH或/>且各R10独立地为F、Cl、-OH、-CN、-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2、-CHF2、-CF3、-CF2CH3、-CH2OCH3、-OCH3、-OCH2CH3、-OCH(CH3)2、-OCHF2、-OCF3、-OCH2CHF2、-OCH2CF3、-OCH2C(CH3)2OH、-OCH2CH2OCH3、-OCH2CH2CH2OCH3、-OCH(CH2Cl)(CH2OH)、-OCH2CH(CH2Cl)(CH2OH)、-O(C3-5环烷基)、-N(CH3)2、-S(O)2CH3、-CH2(环丙基)、-CH2(氧杂环丁烷基)、-OCH2(环丙基)、-NH(环丙基)、-NH(苯基)、-O(氧杂环丁烷基)、-O(四氢呋喃基)、-O(四氢吡喃基)、-OCH2(环丙基)、-OCH2(环丁基)、-OCH2(氧杂环丁烷基)、-OCH2CH2(吡咯烷基)、环丙基、氮杂环丁烷基、(羟基甲基)氮杂环丁烷基、氟氮杂环丁烷基、(二甲基氨基)氮杂环丁烷基、甲氧基氮杂环丁烷基、羟基氮杂环丁烷基、吗啉基、哌嗪基、甲基哌嗪基、羟基哌啶基、吡咯烷基或羟基吡咯烷基。
一个实施方案提供一种式(I)化合物或其立体异构体、互变异构体或药学上可接受的盐或溶剂合物;其中:
X1为C;X2为N;X3为O;X4为C;
R1为环丙基;
L2为共价键;
R2为苯基或吡啶基,其各自经零至2个R16取代;
各R16独立地为F、Cl、-CH3、-CF3、-OCH3或-OCF3;
E1、E2和E3一起形成选自的部分;
B环为
a为0;
L1为共价键、
Z为苯基、吡啶基、苯并[d]噻唑基、喹啉基或异喹啉基,其各自经零至2个R10取代;
Rx为-C(O)OH、-CH2C(O)OH或且
各R10独立地为F、Cl、-OH、-CN、-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2、-CHF2、-CF3、-CF2CH3、-CH2OCH3、-OCH3、-OCH2CH3、-OCH(CH3)2、-OCHF2、-OCF3、-OCH2CHF2、-OCH2CF3、-OCH2C(CH3)2OH、-OCH2CH2OCH3、-OCH2CH2CH2OCH3、-OCH(CH2Cl)(CH2OH)、-OCH2CH(CH2Cl)(CH2OH)、-O(C3-5环烷基)、-N(CH3)2、-S(O)2CH3、-CH2(环丙基)、-CH2(氧杂环丁烷基)、-OCH2(环丙基)、-NH(环丙基)、-NH(苯基)、-O(氧杂环丁烷基)、-O(四氢呋喃基)、-O(四氢吡喃基)、-OCH2(环丙基)、-OCH2(环丁基)、-OCH2(氧杂环丁烷基)、-OCH2CH2(吡咯烷基)、环丙基、氮杂环丁烷基、(羟基甲基)氮杂环丁烷基、氟氮杂环丁烷基、(二甲基氨基)氮杂环丁烷基、甲氧基氮杂环丁烷基、羟基氮杂环丁烷基、吗啉基、哌嗪基、甲基哌嗪基、羟基哌啶基、吡咯烷基或羟基吡咯烷基。
一个实施方案提供一种式(I)化合物或其立体异构体、互变异构体或药学上可接受的盐或溶剂合物;其中:
X1为C;X2为N;X3为O;X4为C;
R1为环丙基;
L2为共价键;
R2为苯基或吡啶基,其各自经零至2个R16取代;
各R16独立地为F、Cl、-CH3、-CF3、-OCH3或-OCF3;
E1、E2和E3一起形成选自的部分;
B环为
a为0;
L1为
Z为苯基、吡啶基、苯并[d]噻唑基、喹啉基或异喹啉基,其各自经零至2个R10取代;
Rx为-C(O)OH、-CH2C(O)OH或且
各R10独立地为F、Cl、-OH、-CN、-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2、-CHF2、-CF3、-CF2CH3、-CH2OCH3、-OCH3、-OCH2CH3、-OCH(CH3)2、-OCHF2、-OCF3、-OCH2CHF2、-OCH2CF3、-OCH2C(CH3)2OH、-OCH2CH2OCH3、-OCH2CH2CH2OCH3、-OCH(CH2Cl)(CH2OH)、-OCH2CH(CH2Cl)(CH2OH)、-O(C3-5环烷基)、-N(CH3)2、-S(O)2CH3、-CH2(环丙基)、-CH2(氧杂环丁烷基)、-OCH2(环丙基)、-NH(环丙基)、-NH(苯基)、-O(氧杂环丁烷基)、-O(四氢呋喃基)、-O(四氢吡喃基)、-OCH2(环丙基)、-OCH2(环丁基)、-OCH2(氧杂环丁烷基)、-OCH2CH2(吡咯烷基)、环丙基、氮杂环丁烷基、(羟基甲基)氮杂环丁烷基、氟氮杂环丁烷基、(二甲基氨基)氮杂环丁烷基、甲氧基氮杂环丁烷基、羟基氮杂环丁烷基、吗啉基、哌嗪基、甲基哌嗪基、羟基哌啶基、吡咯烷基或羟基吡咯烷基。
一个实施方案提供一种式(I)化合物或其立体异构体、互变异构体或药学上可接受的盐或溶剂合物;其中:
X1为C;X2为N;X3为O;X4为C;
R1为环丙基;
L2为共价键;
R2为苯基或吡啶基,其各自经零至2个R16取代;
各R16独立地为F、Cl、-CH3、-CF3、-OCH3或-OCF3;
E1、E2和E3一起形成选自的部分;
B环为
a为0;
L1为
Z为苯基、喹啉基或异喹啉基,其各自经零至2个R10取代;
Rx为-C(O)OH;且
各R10独立地为F、Cl、-OH、-CN、-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2、-CHF2、-CF3、-CF2CH3、-CH2OCH3、-OCH3、-OCH2CH3、-OCH(CH3)2、-OCHF2、-OCF3、-OCH2CHF2、-OCH2CF3、-O(C3-5环烷基)、-N(CH3)2、-S(O)2CH3、-CH2(环丙基)、-CH2(氧杂环丁烷基)、-OCH2(环丙基)、-NH(环丙基)、-NH(苯基)、-O(氧杂环丁烷基)、-O(四氢呋喃基)、-O(四氢吡喃基)、-OCH2(环丙基)、-OCH2(环丁基)、-OCH2(氧杂环丁烷基)、-OCH2CH2(吡咯烷基)、环丙基、氮杂环丁烷基、(羟基甲基)氮杂环丁烷基、氟氮杂环丁烷基、(二甲基氨基)氮杂环丁烷基、甲氧基氮杂环丁烷基、羟基氮杂环丁烷基、吗啉基、哌嗪基、甲基哌嗪基、羟基哌啶基、吡咯烷基或羟基吡咯烷基。
一个实施方案提供一种式(I)化合物或其立体异构体、互变异构体或药学上可接受的盐或溶剂合物;其中:
X1为C;X2为N;X3为O;X4为C;
R1为环丙基;
L2为共价键;
R2为吡啶基,其各自经零至2个R16取代;
各R16独立地为F、Cl、-CH3、-CF3、-OCH3或-OCF3;
E1、E2和E3一起形成选自的部分;
B环为
a为0;
L1为
Z为苯基、喹啉基或异喹啉基,其各自经零至2个R10取代;
Rx为-C(O)OH;且
各R10独立地为F、Cl、-OH、-CN、-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2、-CHF2、-CF3、-CF2CH3、-CH2OCH3、-OCH3、-OCH2CH3、-OCH(CH3)2、-OCHF2、-OCF3、-OCH2CHF2、-OCH2CF3、-O(C3-5环烷基)、-N(CH3)2、-S(O)2CH3、-CH2(环丙基)、-CH2(氧杂环丁烷基)、-OCH2(环丙基)、-NH(环丙基)、-NH(苯基)、-O(氧杂环丁烷基)、-O(四氢呋喃基)、-O(四氢吡喃基)、-OCH2(环丙基)、-OCH2(环丁基)、-OCH2(氧杂环丁烷基)、-OCH2CH2(吡咯烷基)、环丙基、氮杂环丁烷基、(羟基甲基)氮杂环丁烷基、氟氮杂环丁烷基、(二甲基氨基)氮杂环丁烷基、甲氧基氮杂环丁烷基、羟基氮杂环丁烷基、吗啉基、哌嗪基、甲基哌嗪基、羟基哌啶基、吡咯烷基或羟基吡咯烷基。
一个实施方案提供一种式(I)化合物或其立体异构体、互变异构体或药学上可接受的盐或溶剂合物;其中该化合物选自:
在一个实施方案中,本发明尤其提供选自如本说明书中所描述的任一实施例的化合物或其立体异构体、互变异构体或药学上可接受的盐或溶剂合物。
II.药物组合物、治疗用途和组合
在另一实施方案中,本发明提供一种组合物,其包含至少一种本发明化合物或其立体异构体、互变异构体或药学上可接受的盐或溶剂合物。
在另一实施方案中,本发明提供一种药物组合物,其包含药学上可接受的载体和至少一种本发明化合物或其立体异构体、互变异构体或药学上可接受的盐或溶剂合物。
在另一实施方案中,本发明提供一种药物组合物,其包含药学上可接受的载体和治疗有效量的至少一种本发明化合物或其立体异构体、互变异构体或药学上可接受的盐或溶剂合物。
在另一实施方案中,本发明提供一种用于制备本发明化合物的方法。
在另一实施方案中,本发明提供一种用于制备本发明化合物的中间体。
在另一实施方案中,本发明提供一种如上文所定义的药物组合物,其进一步包含一或多种其他治疗剂。
在另一实施方案中,本发明提供一种用于治疗需要此类治疗的患者的与胆酸调节异常相关的疾病、病症或病状的方法,且该方法包括向该患者给药治疗有效量的本发明化合物或其立体异构体、互变异构体或药学上可接受的盐或溶剂合物。
在另一实施方案中,本发明提供一种用于治疗需要此类治疗的患者的与法尼酯X受体(FXR)活性相关的疾病、病症或病状的方法,其包括向该患者给药治疗有效量的本发明化合物或其立体异构体、互变异构体或药学上可接受的盐或溶剂合物。
在另一实施方案中,本发明提供一种用于治疗该疾病、病症或病状的方法,其包括单独或任选与另一本发明化合物和/或至少一种其他类型的治疗剂组合地向需要此类治疗的患者给药治疗有效量的至少一种本发明化合物。
在另一实施方案中,本发明提供一种用于在患者中引发法尼酯X受体(FXR)激动效应的方法,其包括向该患者给药治疗有效量的本发明化合物或其立体异构体、互变异构体或药学上可接受的盐或溶剂合物。
在一些实施方案中,该疾病、病症或病状与FXR功能障碍相关,包括病理性纤维化、癌症、炎性病症、代谢性或胆汁郁积性病症。
在一些实施方案中,该疾病、病症或病状与纤维化相关,包括肝纤维化、胆纤维化、肾纤维化、心脏纤维化、皮肤纤维化、眼纤维化和胰纤维化。
在其他实施方案中,该疾病、病症或病状与细胞增殖性病症相关,诸如癌症。在一些实施方案中,癌症包括实体肿瘤生长或瘤形成。在其他实施方案中,癌症包括肿瘤转移。在一些实施方案中,癌症为肝脏、胆囊、小肠、大肠、肾脏、前列腺、膀胱、血液、骨头、大脑、乳房、中枢神经系统、子宫颈、结肠、子宫内膜、食道、生殖器、泌尿生殖道、头部、喉、肺部、肌肉组织、颈部、口腔粘膜或鼻粘膜、卵巢、胰脏、皮肤、脾、胃、睾丸或甲状腺的癌症。在其他实施方案中,癌症为癌瘤、肉瘤、淋巴瘤、白血病、黑素瘤、间皮瘤、多发性骨髓瘤或精原细胞瘤。
可根据本发明预防、调节或治疗的与FXR活性相关的疾病、病症或病状的实例包括(但不限于)移植注射、纤维化病症(例如肝纤维化、肾纤维化)、炎性病症(例如急性肝炎、慢性肝炎、非酒精性脂肪变性肝炎(NASH)、肠易激综合征(IBS)、炎性肠病(IBD))以及细胞增殖性病症(例如癌症、骨髓瘤、纤维瘤、肝细胞癌、结肠直肠癌、前列腺癌、白血病、卡波西肉瘤、实体肿瘤)。
适合通过本发明化合物预防或治疗的纤维化病症、炎性病症以及细胞增殖性病症包括(但不限于)非酒精性脂肪肝病(NAFLD)、酒精性或非酒精性脂肪变性肝炎(NASH)、急性肝炎、慢性肝炎、肝硬化、原发性胆汁性肝硬化、原发性硬化性胆管炎、药物诱发性肝炎、胆汁性肝硬化、门静脉高血压、再生障碍、肝脏机能减退、肝血流紊乱(hepatic blood flowdisorder)、肾病变、肠易激综合征(IBS)、炎性肠病(IBD)、胰腺分泌异常、良性前列腺增生、神经病性膀胱疾病、糖尿病性肾病变、病灶性节段性肾小球硬化、IgA肾病变、药物或移植诱发的肾病变、自身免疫肾病变、狼疮性肾炎、肝纤维化、肾纤维化、慢性肾病(CKD)、糖尿病性肾病(DKD)、皮肤纤维化、瘢痕瘤、全身性硬化症、硬皮病、病毒诱发的纤维化、特发性肺纤维化(IPF)、间质性肺病、非特异性间质性肺炎(NSIP)、寻常性间质性肺炎(UIP)、放射诱发的纤维化、家族性肺纤维化、气道纤维化、慢性阻塞性肺病(COPD)、脊髓肿瘤、椎间盘突出、椎管狭窄症、心力衰竭、心脏纤维化、血管纤维化、血管周围纤维化、口蹄疫、癌症、骨髓瘤、纤维瘤、肝细胞癌、结肠直肠癌、前列腺癌、白血病、慢性淋巴细胞性白血病、卡波西肉瘤、实体肿瘤、脑梗塞、脑出血、神经痛、周边神经病变、年龄相关黄斑变性(AMD)、青光眼、眼纤维化、角膜瘢痕、糖尿病性视网膜病变、增殖性玻璃体视网膜病变(PVR)、瘢痕性类天疱疮、青光眼滤过手术瘢痕、克罗恩病或全身性红斑狼疮症;由创伤愈合异常引起的瘢痕瘤形成;器官移植之后出现的纤维化、骨髓纤维化和类纤维瘤。在一个实施方案中,本发明提供一种用于治疗纤维化病症、炎性病症或细胞增殖性病症的方法,其包括单独或任选与另一本发明化合物和/或至少一种其他类型的治疗剂组合地向需要此类治疗的患者给药治疗有效量的至少一种本发明化合物。
在另一实施方案中,本发明提供一种用于疗法的本发明化合物。
在另一实施方案中,本发明提供一种用于疗法的本发明化合物,该疗法用于治疗其纤维化病症、炎性病症或细胞增殖性病症。
在另一实施方案中,本发明还提供本发明化合物用于制造用以治疗其纤维化病症、炎性病症或细胞增殖性病症的药物的用途。
在另一实施方案中,本发明提供一种用于治疗纤维化病症、炎性病症或细胞增殖性病症的方法,其包括向有需要的患者给药治疗有效量的第一和第二治疗剂,其中该第一治疗剂为本发明化合物。
在另一实施方案中,本发明提供同时、分开或依序用于疗法中的本发明化合物与其他治疗剂的组合制剂。
在另一实施方案中,本发明提供同时、分开或依序用于治疗纤维化病症、炎性病症或细胞增殖性病症的本发明化合物与其他治疗剂的组合制剂。
本发明化合物可与一或多种其他治疗剂组合使用,该其他治疗剂诸如一或多种抗纤维化治疗剂和/或抗炎治疗剂。
在一个实施方案中,用于组合药物组合物或组合方法或组合用途中的其他治疗剂选自一或多种(优选一至三种)以下治疗剂:TGFβ受体抑制剂(例如,高伦替布(galunisertib));TGFβ合成抑制剂(例如,吡非尼酮(pirfenidone));血管内皮生长因子(VEGF)、血小板源生长因子(PDGF)和成纤维细胞生长因子(FGF)受体激酶的抑制剂(例如,尼达尼布(nintedanib));人源化抗αVβ6整合素单克隆抗体(例如,3G9);人类重组正五聚素蛋白-2;重组人类血清淀粉样蛋白P;针对TGFβ-1、TGFβ-2和TGFβ-3的重组人类抗体;内皮素受体拮抗剂(例如,马西替坦(macitentan));干扰素γ;c-Jun氨基末端激酶(JNK)抑制剂(例如,4-[[9-[(3S)-四氢-3-呋喃基]-8-[(2,4,6-三氟苯基)氨基]-9H-嘌呤-2-基]氨基]-反-环己醇);3-戊基苯乙酸(PBI-4050);含有锰(III)的经四取代卟啉衍生物;靶向嗜酸性粒细胞趋化因子-2的单克隆抗体;白介素-13(IL-13)抗体(例如,雷布瑞奇单抗(lebrikizumab)、塔罗金单抗(tralokinumab));靶向白介素4(IL-4)和白介素13(IL-13)的双特异性抗体;NK1速激肽受体激动剂(例如,Sar9、Met(O2)11-P物质);辛曲德开贝舒托(Cintredekin Besudotox);针对结缔组织生长因子的人类重组DNA源性IgG1κ单克隆抗体;和选择性用于CC-趋化因子配体2的全人类IgG1κ抗体(例如,卡鲁单抗(carlumab)、CCX140);抗氧化剂(例如,N-乙酰半胱氨酸);磷酸二酯酶5(PDE5)抑制剂(例如,西地那非(sildenafil));用于治疗阻塞性气道疾病的药物,诸如毒蕈碱拮抗剂(例如,噻托铵(tiotropium)、溴化丙托铵(ipatropium bromide));肾上腺素能β2激动剂(例如,沙丁胺醇(salbutamol)、沙美特罗(salmeterol));皮质类固醇(例如,曲安西龙(triamcinolone)、地塞米松(dexamethasone)、氟替卡松(fluticasone));免疫抑制剂(例如,他克莫司(tacrolimus)、雷帕霉素(rapamycin)、吡美莫司(pimecrolimus));和可用于治疗纤维化病状(诸如肝纤维化、胆纤维化和肾纤维化)、非酒精性脂肪肝病(NALFD)、非酒精性脂肪性肝炎(NASH)、心脏纤维化、特发性肺纤维化(IPF)和全身性硬化症的治疗剂。可用于治疗此类纤维化病状的治疗剂包括(但不限于)FXR激动剂(例如,OCA、GS-9674和LJN452);LOXL2抑制剂(例如,辛图珠单抗(simtuzumab));LPA1拮抗剂(例如,BMS-986020和SAR 100842);PPAR调节剂(例如,埃菲卟喏(elafibrinor)、吡格列酮(pioglitazone)和沙格列让(saroglitazar)、IVA337);SSAO/VAP-1抑制剂(例如,PXS-4728A和SZE5302);ASK-1抑制剂(例如,GS-4997或胜龙塞替(selonsertib));ACC抑制剂(例如,CP-640186和NDI-010976或GS-0976);FGF21模拟物(例如,LY2405319和BMS-986036);半胱天冬酶抑制剂(例如,恩利卡生(emricasan));NOX4抑制剂(例如,GKT137831);MGAT2抑制剂(例如,BMS-963272);αV整合素抑制剂(例如,阿吐珠单抗(abituzumab));和胆酸/脂肪酸缀合物(例如,阿雷美罗(aramchol))。本发明的各种实施方案的FXR激动剂还可与一或多种治疗剂组合使用,该一或多种治疗剂诸如CCR2/5抑制剂(例如,森尼韦若(cenicriviroc));半乳糖凝集素-3抑制剂(例如,TD-139、GR-MD-02);白三烯受体拮抗剂(例如,泰鲁斯特(tipelukast)、孟鲁司特(montelukast));SGLT2抑制剂(例如,达格列净(dapagliflozin)、瑞格列净(remogliflozin));GLP-1受体激动剂(例如,利拉鲁肽(liraglutide)和司美鲁肽(semaglutide));FAK抑制剂(例如,GSK-2256098);CB1反向激动剂(例如,JD-5037);CB2激动剂(例如,APD-371和JBT-101);自分泌运动因子抑制剂(例如,GLPG1690);脯氨酰基t-RNA合成酶抑制剂(例如,卤夫酮(halofugenone));FPR2激动剂(例如,ZK-994);和THR激动剂(例如,MGL:3196)。在另一实施方案中,用于组合药物组合物或组合方法或组合用途中的其他治疗剂选自一或多种(欧璇一至三种)免疫肿瘤剂,诸如阿仑单抗(Alemtuzumab)、阿特珠单抗(Atezolizumab)、伊匹单抗(Ipilimumab)、纳武单抗(Nivolumab)、奥伐木单抗(Ofatumumab)、派姆单抗(Pembrolizumab)和利妥昔单抗(Rituximab)。
本发明化合物可通过任何适合手段给药以用于任一种本文所描述用途中,例如:口服给药,诸如片剂、胶囊(其各自包括持续释放或定时释放制剂)、丸剂、散剂、颗粒、酏剂、酊剂、悬浮液、糖浆和乳液;舌下给药;经颊给药;肠胃外给药,诸如皮下、静脉内、肌内或胸骨内注射,或输注技术(例如,呈无菌可注射水溶液或非水溶液或悬浮液的形式);经鼻给药,包括给药至鼻粘膜,诸如通过吸入喷雾;局部给药,诸如以乳膏或软膏的形式;或经直肠给药,诸如以栓剂形式。其可单独给药,但一般将与基于所选给药途径和标准药学实践选择的药物载体一起给药。
术语“药物组合物”意指包含本发明化合物与至少一种其他药学上可接受的载体的组合的组合物。“药学上可接受的载体”是指本领域中公认用于向动物(尤其哺乳动物)递送生物活性剂的介质,取决于给药模式的性质和剂型,包括(即)佐剂、赋形剂或媒介物,诸如稀释剂、防腐剂、填充剂、流动调节剂、崩解剂、湿润剂、乳化剂、悬浮剂、甜味剂、调味剂、芳香剂、抗细菌剂、抗真菌剂、润滑剂和分散剂。药学上可接受的载体根据本领域普通技术人员范围内的多个因素调配。这些因素包括(但不限于):所调配的活性剂的类型和性质;向其给药含该药物的组合物的受试者;组合物的预期给药途径;以及所靶向的治疗适应症。药学上可接受的载体包括水性和非水性液体介质,以及各种固体和半固体剂型。除活性剂以外,此类载体可包括多种不同成分和添加剂,此类额外成分出于本领域普通技术人员已知的多种原因(例如使活性剂、粘合剂稳定等)包括于制剂中。药学上可接受的适合载体和涉及其选择的因素的描述见于多种可容易获得的来源中,诸如Remington's PharmaceuticalSciences,第18版(1990)。
如本文所使用,术语“治疗(treating/treatment)”是指通过使用本发明的化合物或组合物获得有益或期望结果(包括临床结果)的方法。出于本发明的目的,有益或期望的临床结果包括(但不限于)以下中的一或多种:降低由疾病、病症或病状引起的一或多种症状的严重程度和/或频率;降低疾病、病症或病状的程度或使疾病、病症或病状消退;使疾病、病症或病状稳定(例如预防或延迟疾病、病症或病状的恶化);延迟或减慢疾病、病症或病状的进展;改善疾病、病症或病状状态;减少治疗疾病、病症或病状所需的一或多种其他药物的剂量;和/或提高生活质量。
本发明化合物的给药方案将当然取决于已知因素而变化,诸如特定药物的药效学特征及其给药模式和途径;接受者的物种、年龄、性别、健康状况、医学病状和体重;症状的性质和程度;同时发生的治疗的种类;治疗频率;给药途径、患者的肾功能和肝功能以及所需作用。
通过一般指导,各活性成分在用于指定作用时的每日口服剂量将介于每天约0.01至约5000mg之间,优选每天约0.01至约1000mg之间,且最优选每天约0.01至约250mg之间范围内。静脉内给药时,在恒定速率输注期间最优选剂量将在每分钟约0.01至约10mg/kg的范围内。本发明化合物可以单次日剂量给药,或每日总剂量可分成每天两次、三次或四次给药。
化合物通常以与针对预期给药形式(例如口服片剂、胶囊、酏剂和糖浆)适当选择且与常规药学实践相符的适合药物稀释剂、赋形剂或载体(在本文中统称为药物载体)的共混物形式给药。
适合于给药的剂型(药物组合物)可含有每剂量单位约0.1毫克至约2000毫克的活性成分。在这些药物组合物中,活性成分通常将以按该组合物的总重量计约0.1-95重量%的量存在。
用于口服给药的典型胶囊含有至少一种本发明化合物(250mg)、乳糖(75mg)和硬脂酸镁(15mg)。混合物通过60目筛且装入1号明胶胶囊中。
通过将至少一种本发明化合物(250mg)无菌置入小瓶中,无菌冷冻-干燥和密封来制造典型可注射制剂。对于使用,将小瓶的内容物与2mL生理盐水混合以得到可注射制剂。
本发明在其范畴内包括药物组合物,该药物组合物包含单独或与药物载体组合的治疗有效量的至少一种本发明化合物作为活性成分。任选地,本发明化合物可单独、与本发明的其他化合物组合或与一或多种(优选一至三种)其他治疗剂组合使用,该其他治疗剂例如ASK-1抑制剂、CCR2/5拮抗剂、自分泌运动因子抑制剂、LPA1受体拮抗剂或其他药学活性物质。
以上其他治疗剂与本发明化合物组合使用时可以例如Physicians'DeskReference(如上文所陈述的专利中)中所指示的量或另外由本领域普通技术人员确定的量使用。
尤其当以单个剂量单元形式提供时,组合的活性成分之间可能存在化学相互作用。因此,当本发明化合物和第二治疗剂以单一剂量单位组合时,尽管活性成分以单一剂量单位组合,但仍对其进行调配,使活性成分之间的物理接触降至最低(即降低)。举例而言,一种活性成分可包覆肠溶包衣。通过对活性成分中的一种包覆肠溶包衣,不仅可使组合的活性成分之间的接触降至最低,而且可控制这些组分中的一种在胃肠道中的释放,使得这些组分中的一种不在胃中释放,而是在肠中释放。活性成分中的一种还可包覆有这样的物质:其影响在整个胃肠道中持续释放,且还用以使组合的活性成分之间的物理接触降至最低。此外,持久释放的组分可额外包覆肠溶包衣使得该组分的释放仅在肠道中发生。另一方法将涉及组合产物的调配,其中一种组分包覆有持续和/或肠释放聚合物,且另一组分还包覆有诸如低粘度级别的羟丙基甲基纤维素(HPMC)的聚合物或本领域已知的其他适合物质,以进一步分离活性组分。聚合物包衣用以形成与另一组分的相互作用的额外屏障。
这些以及其他方法使本发明的组合产物的组分之间的接触降至最低,本领域技术人员将容易显而易知是在单个剂型中给药还是以各别形式通过相同方式同时给药,只要与本发明相符。
本发明化合物可单独或与一或多种(优选一至三种)其他治疗剂组合给药。“组合给药”或“组合疗法”意指同时向所治疗的哺乳动物给药本发明化合物和一或多种(优选一至三种)其他治疗剂。当组合给药时,各组分可同时给药或以任何顺序依序在不同时间点给药。因此,各组分可单独但时间上充分接近地给药,以便提供所需治疗性效应。
本发明化合物还可用作涉及FXR激动剂的测试或测定中的标准或参考化合物,例如作为质量标准或对照。此类化合物可提供于例如用于涉及FXR激动剂活性的药物研究的市售试剂盒中。举例而言,本发明化合物可在测定中用作参考物以使其已知活性与具有未知活性的化合物相比较。这将确保实验者正确进行测定且提供比较基础,当测试化合物为参考化合物的衍生物时尤其如此。当开发新测定法或方案时,本发明化合物可用于测试其有效性。
本发明还涵盖制品。如本文中所使用,制品意欲包括(但不限于)试剂盒和包装。本发明的制品包含:(a)第一容器;(b)位于该第一容器内的药物组合物,其中该组合物包含:第一治疗剂,其包含本发明化合物或其药学上可接受的盐形式;和(c)药品说明书,其陈述该药物组合物可用于治疗血脂异常及其后遗症。在另一实施方案中,该药品说明书陈述该药物组合物可与第二治疗剂组合(如上文所定义)用于治疗纤维化及其后遗症。制品可进一步包含:(d)第二容器,其中组分(a)和(b)位于第二容器中,且组分(c)位于第二容器内或外。位于第一和第二容器内意指各别容器将物品保持于其边界内。
第一容器为用于容纳药物组合物的盛器。该容器可用于制造、储存、运送和/或零售/批发。第一容器意欲涵盖瓶子、罐、小瓶、烧瓶、注射器、试管(例如用于乳膏制剂)或用以制备、容纳、存储或分配药物产品的任何其他容器。
第二容器为用于容纳第一容器和任选的药品说明书的容器。第二容器的实例包括(但不限于)盒子(例如卡纸板或塑料)、板条箱、纸盒、袋(例如纸袋或塑料袋)、小袋和大袋。药品说明书可经由胶带、胶、U形钉或另一附着方法物理附着于第一容器的外部,或其可留在第二容器内部而不借助于任何物理手段附着于第一容器。或者,包装说明书位于第二容器外部上。当位于第二容器的外部上时,药品说明书优选经胶带、胶、U形钉或另一附着方法物理附着。或者,其可与第二容器外部相邻或接触但不物理附着。
药品说明书为叙述与第一容器内的药物组合物有关的信息的标记、标签、标记物等。所述信息通常将由管控出售制品的地区的监管机构(例如美国食品与药物管理局)决定。优选地,包装说明书具体叙述药物组合物已获批的适应症。包装说明书可由任何材料制成,个人可从上面读取其中或其上所含的信息。优选地,药品说明书为上面已形成(例如印刷或涂覆)所要信息的可印刷材料(例如纸、塑料、卡纸板、箔、粘着剂背衬纸或塑料等)。
III.定义
在整个说明书和随附权利要求书中,既定化学式或名称应涵盖其所有立体异构体和光学异构体及外消旋物(若此类异构体存在)。除非另外指明,否则所有手性(对映异构体和非对映异构体)和外消旋形式属于本发明的范畴内。化合物中还可存在C=C双键、C=N双键、环系统等的多种几何异构体,且所有此类稳定异构体均涵盖于本发明中。本发明化合物的顺式和反式(或E型和Z型)几何异构体已描述且可以异构体混合物形式或以经分离的异构体形式分离。本发明化合物可以光学活性或外消旋形式分离。光学活性形式可通过拆分外消旋形式或通过自光学活性起始物质合成来制备。用于制备本发明化合物的所有方法及其中制备的中间体视为本发明的一部分。制备对映异构或非对映异构产物时,其可通过常规方法分离,例如通过色谱或分步结晶加以分离。取决于方法条件,本发明的最终产物以游离(中性)形式或盐形式获得。这些最终产物的游离形式与盐皆属于本发明的范畴。若有此需要,可将化合物的一种形式转化成另一种形式。游离碱或酸可转化成盐;盐可转化成游离化合物或另一种盐;本发明的异构体化合物的混合物可分离成个别异构体。呈游离形式的本发明化合物及其盐可以多种互变异构体形式存在,其中氢原子转置至分子的其他部分且分子中的原子之间的化学键因此重排。应理解,所有互变异构形式只要可能存在则均包括于本发明内。如本文中所使用,“本发明化合物”或“本发明的化合物”意指式(I)、式(IIa)和式(IIb)中的任一者所涵盖的一或多种化合物或其立体异构体、互变异构体或药学上可接受的盐或溶剂合物。
如本文中所使用,术语“烷基”或“亚烷基”意欲包括具有指定数目个碳原子的支链和直链饱和脂族烃基。“烷基”表示单价饱和脂族基(诸如乙基),而“亚烷基”表示二价饱和脂族基(诸如亚乙基)。举例而言,“C1至C10烷基”或“C1-10烷基”意欲包括C1、C2、C3、C4、C5、C6、C7、C8、C9和C10烷基。“C1至C10亚烷基”或“C1-10亚烷基”意欲包括C1、C2、C3、C4、C5、C6、C7、C8、C9和C10亚烷基。另外,举例而言,“C1至C6烷基”或“C1-6烷基”表示具有1至6个碳原子的烷基;且“C1至C6亚烷基”或“C1-6亚烷基”表示具有1至6个碳原子的亚烷基。烷基可不经取代或经取代,其中至少一个氢经另一化学基团替换。烷基的实例包括(但不限于)甲基(Me)、乙基(Et)、丙基(例如正丙基和异丙基)、丁基(例如正丁基、异丁基、叔丁基)和戊基(例如正戊基、异戊基、新戊基)。当使用“C0烷基”或“C0亚烷基”时,其意欲表示直接键。
除非另有指示,否则如本文中单独或作为另一基团的一部分所使用的术语“低碳数烷基”包括含有1至8个碳原子的直链和支链烃,且如本文中单独或作为另一基团的一部分所使用的术语“烷基”和“烷”包括在正链中含有1至20个碳原子,优选1至10个碳原子,更优选1至8个碳原子的直链和支链烃,诸如甲基、乙基、丙基、异丙基、丁基、叔丁基、异丁基、戊基、己基、异己基、庚基、4,4-二甲基戊基、辛基、2,2,4-三甲基戊基、壬基、癸基、十一烷基、十二烷基、其各种支链异构体等。
“杂烷基”是指其中一或多个碳原子已由杂原子(诸如O、N或S)替换的烷基。举例而言,若烷基的与母分子连接的碳原子经杂原子(例如,O、N或S)替换,则所得杂烷基分别为烷氧基(例如-OCH3等)、烷基氨基(例如-NHCH3、-N(CH3)2等)或硫基烷基(例如-SCH3)。若烷基的未与母分子连接的非末端碳原子经杂原子(例如,O、N或S)替换,则所得杂烷基分别为烷基醚(例如-CH2CH2-O-CH3等)、烷基氨基烷基(例如-CH2NHCH3、-CH2N(CH3)2等)或硫基烷基醚(例如-CH2-S-CH3)。若烷基的末端碳原子经杂原子(例如,O、N或S)替换,则所得杂烷基分别为羟基烷基(例如-CH2CH2-OH)、氨基烷基(例如-CH2NH2)或烷基硫醇基(例如-CH2CH2-SH)。杂烷基可具有例如1至20个碳原子、1至10个碳原子或1至6个碳原子。C1-C6杂烷基意指具有1至6个碳原子的杂烷基。
“烯基”或“亚烯基”意欲包括具有指定数目个碳原子和一或多个、优选一至两个碳-碳双键的直链或支链构型的烃链,其中碳-碳双键可存在于沿着链的任何稳定点处。“烯基”表示单价基团,而“亚烯基”表示二价基团。举例而言,“C2至C6烯基”或“C2-6烯基”(或亚烯基)意欲包括C2、C3、C4、C5和C6烯基。烯基的实例包括(但不限于)乙烯基、1-丙烯基、2-丙烯基、2-丁烯基、3-丁烯基、2-戊烯基、3-戊烯基、4-戊烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、2-甲基-2-丙烯基和4-甲基-3-戊烯基。
“炔基”或“亚炔基”意欲包括具有一或多个、优选一至三个碳-碳三键的直链或支链构型的烃链,其中碳-碳三键可存在于沿着链的任何稳定点处。“炔基”表示单价基团,而“亚炔基”表示二价基团。举例而言,“C2至C6炔基”或“C2-6炔基”(或亚炔基)意欲包括C2、C3、C4、C5和C6炔基;诸如乙炔基、丙炔基、丁炔基、戊炔基和己炔基。
如本文中所使用,“芳基烷基”(也称为芳烷基)、“杂芳基烷基”、“碳环基烷基”或“杂环基烷基”是指其中键合至碳原子(通常为末端或sp3碳原子)的氢原子中的一个分别经芳基、杂芳基、碳环基或杂环基替换的非环状烷基。典型芳基烷基包括(但不限于)苯甲基、2-苯基乙-1-基、萘基甲基、2-萘基乙-1-基、萘并苯甲基、2-萘并苯基乙-1-基等。芳基烷基、杂芳基烷基、碳环基烷基或杂环基烷基可包含4至20个碳原子和0至5个杂原子,例如烷基部分可含有1至6个碳原子。
如本文所用,术语“苯甲基”是指一个氢原子经苯基替换的甲基,其中所述苯基可任选经1至5个基团、优选1至3个基团OH、OCH3、Cl、F、Br、I、CN、NO2、NH2、N(CH3)H、N(CH3)2、CF3、OCF3、C(=O)CH3、SCH3、S(=O)CH3、S(=O)2CH3、CH3、CH2CH3、CO2H和CO2CH3取代。“苯甲基”还可由式“Bn”表示。
术语“低碳数烷氧基”、“烷氧基”或“烷基氧基”、“芳基氧基”或“芳烷基氧基”是指连接至氧原子的上述烷基、芳烷基或芳基中的任一者。“C1至C6烷氧基”或“C1-6烷氧基”(或烷基氧基)意欲包括C1、C2、C3、C4、C5和C6烷氧基。烷氧基的实例包括(但不限于)甲氧基、乙氧基、丙氧基(例如正丙氧基和异丙氧基)和叔丁氧基。类似地,“低碳数烷基硫基”、“烷基硫基”、“硫基烷氧基”、“芳基硫基”或“芳烷基硫基”表示经由硫桥连接的具有指定数目个碳原子的如上文所定义的烷基、芳基或芳烷基;例如甲基-S-和乙基-S-。
如本文中单独或作为另一基团的一部分所使用的术语“烷酰基”或“烷基羰基”是指连接至羰基的烷基。举例而言,烷基羰基可由烷基-C(O)-表示。“C1至C6烷基羰基”(或烷基羰基)意欲包括C1、C2、C3、C4、C5和C6烷基-C(O)-基团。
如本文中单独或作为另一基团的一部分所使用的术语“烷基磺酰基”或“磺酰胺”是指连接至磺酰基的烷基或氨基。举例而言,烷基磺酰基可由-S(O)2R'表示,而磺酰胺可由-S(O)2NRcRd表示。R'为C1至C6烷基;且Rc和Rd与下文关于“氨基”所定义相同。
如本文中单独或作为另一基团的一部分所使用的术语“氨基甲酸酯”是指连接至酰氨基的氧。举例而言,氨基甲酸酯可由N(RcRd)-C(O)-O-表示,且Rc和Rd与下文关于“氨基”所定义相同。
如本文中单独或作为另一基团的一部分所使用的术语“酰氨基”是指连接至羰基的氨基。举例而言,酰氨基可由N(RcRd)-C(O)-表示,且Rc和Rd与下文关于“氨基”所定义相同。
术语“氨基”经定义为-NRc1Rc2,其中Rc1和Rc2独立地为H或C1-6烷基;或替代地,Rc1和Rc2和与其所连接的原子一起形成3元至8元杂环,其任选经一或多个选自卤素、氰基、羟基、氨基、氧代、C1-6烷基、烷氧基和氨基烷基的基团取代。当Rc1或Rc2(或两者)为C1-6烷基时,氨基也可被称作烷基氨基。烷基氨基的实例包括(但不限于)-NH2、甲基氨基、乙基氨基、丙基氨基、异丙基氨基等。
术语“氨基烷基”是指氢原子中的一个经氨基替换的烷基。举例而言,氨基烷基可由N(Rc1Rc2)-亚烷基-表示。“C1至C6”或“C1-6”氨基烷基(或氨基烷基)意欲包括C1、C2、C3、C4、C5和C6氨基烷基。
如本文中单独或作为另一基团的一部分所使用的术语“卤素”或“卤基”是指氯、溴、氟和碘,其中优选为氯或氟。
“卤烷基”意欲包括经一或多个卤素取代的具有指定数目个碳原子的支链和直链饱和脂族烃基。“C1至C6卤烷基”或“C1-6卤烷基”(或卤烷基)意欲包括C1、C2、C3、C4、C5和C6卤烷基。卤烷基的实例包括(但不限于)氟甲基、二氟甲基、三氟甲基、三氯甲基、五氟乙基、五氯乙基、2,2,2-三氟乙基、七氟丙基和七氯丙基。卤烷基的实例还包括“氟烷基”,其意欲包括经1个或多个氟原子取代的具有指定数目个碳原子的支链和直链饱和脂族烃基。如本文中所使用的术语“多卤烷基”是指包括2至9个,优选2至5个卤素取代基(诸如F或Cl,优选F)的如上文所定义的“烷基”,诸如多氟烷基,例如CF3CH2、CF3或CF3CF2CH2。
“卤烷氧基”或“卤烷基氧基”表示经由氧桥连接的具有指定数目个碳原子的如上文所定义的卤烷基。举例而言,“C1至C6卤烷氧基”或“C1-6卤烷氧基”意欲包括C1、C2、C3、C4、C5和C6卤烷氧基。卤烷氧基的实例包括(但不限于)三氟甲氧基、2,2,2-三氟乙氧基和五氟乙氧基。类似地,“卤烷基硫基”或“硫基卤烷氧基”表示经由硫桥连接的具有指定数目个碳原子的如上文所定义的卤烷基;例如三氟甲基-S-和五氟乙基-S-。如本文所使用的术语“多卤烷氧基”是指包括2至9个,优选2至5个卤素取代基(诸如F或Cl,优选F)的如上文所定义的“烷氧基”或“烷基氧基”,诸如多氟烷氧基,例如CF3CH2O、CF3O或CF3CF2CH2O。
“羟基烷基”意欲包括经1个或多个羟基(OH)取代的具有指定数目个碳原子的支链和直链饱和脂族烃基。“C1至C6羟基烷基”(或羟基烷基)意欲包括C1、C2、C3、C4、C5和C6羟基烷基。
术语“环烷基”是指环化烷基,包括单环、双环或多环环系统。“C3至C7环烷基”或“C3-7环烷基”意欲包括C3、C4、C5、C6和C7环烷基。环烷基的实例包括(但不限于)环丙基、环丁基、环戊基、环己基和降崁基。“环烷基”定义中包括支链环烷基,诸如1-甲基环丙基和2-甲基环丙基。
术语“环杂烷基”是指环化杂烷基,包括单环、双环或多环环系统。“C3至C7环杂烷基”或“C3-7环杂烷基”意欲包括C3、C4、C5、C6和C7环杂烷基。环杂烷基的实例包括(但不限于)氧杂环丁烷基、四氢呋喃基、四氢吡喃基、氮杂环丁烷基、吡咯烷基、哌啶基、吗啉基和哌嗪基。“环杂烷基”的定义中包括支链环杂烷基,诸如哌啶基甲基、哌嗪基甲基、吗啉基甲基、吡啶基甲基、吡嗪基甲基、嘧啶基甲基和吡嗪基甲基。
如本文中所使用,术语“氮杂环基”是指在环中含有一或多个氮原子的环杂烷基。氮杂环基的实例包括(但不限于)吡咯烷基、哌啶基、吗啉基和哌嗪基。
如本文中所使用,“碳环”、“碳环基”或“碳环状”意欲意指任何稳定的3、4、5、6、7或8元单环或5、6、7、8、9、10、11、12或13元多环(包括双环或三环)烃环,其中任一者可为饱和或部分不饱和的。即,术语“碳环”、“碳环基”或“碳环状”包括(但不限于)环烷基和环烯基。此类碳环的实例包括(但不限于)环丙基、环丁基、环丁烯基、环戊基、环戊烯基、环己基、环庚烯基、环庚基、环庚烯基、金刚烷基、环辛基、环辛烯基、环辛二烯基、[3.3.0]二环辛烷、[4.3.0]二环壬烷、[4.4.0]二环癸烷(十氢萘)、[2.2.2]二环辛烷、芴基、茚满基、金刚烷基和四氢萘基(萘满)。如上文所示,桥联环还包括于碳环定义中(例如[2.2.2]二环辛烷)。除非另外规定,否则优选碳环为环丙基、环丁基、环戊基、环己基、茚满基和四氢萘基。当一或多个,优选一至三个碳原子连接两个不相邻碳原子时,产生桥联环。优选桥为一或两个碳原子。应指出,一个桥总是将单环转变成三环。当环桥联时,该环中所述取代基也可存在于桥上。
此外,如本文中单独或作为另一基团的一部分所使用的术语“碳环基”(包括“环烷基”和“环烯基”)包括含有1至3个环的饱和或部分不饱和(含有1或2个双键)环烃基,包括单环烷基、双环烷基和三环烷基,其含有形成环的总共3至20个碳原子,优选形成环的3至10个碳原子或3至6个碳原子,且其可与1或2个如关于芳基所描述的芳环稠合,包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环癸基和环十二基、环己烯基、
所述基团中的任一种可任选经1至4个取代基取代,该取代基诸如卤素、烷基、烷氧基、羟基、芳基、芳基氧基、芳基烷基、环烷基、烷基酰氨基、烷酰基氨基、氧代、酰基、芳基羰基氨基、硝基、氰基、硫醇和/或烷硫基和/或烷基取代基中的任一种。
如本文中所使用,术语“双环碳环”或“双环碳环基”意欲指含有两个稠合环且由碳原子组成的稳定9元或10元碳环环系统。在两个稠合环中,一个环为稠合至第二环的苯并环;且第二环为饱和或部分不饱和的5元或6元碳环。双环碳环基可在产生稳定结构的任何碳原子处连接至其侧基。若所得化合物稳定,则本文中所描述的双环碳环基可在任何碳上经取代。双环碳环基的实例为(但不限于)1,2-二氢萘基、1,2,3,4-四氢萘基和二氢茚基。
如本文中所使用,如本文中单独或作为另一基团的一部分所使用的术语“芳基”是指单环或多环(包括双环和三环)芳族烃,包括例如苯基、萘基、蒽基和菲基。芳基部分是已知的且描述于例如Lewis,R.J.,编,Hawley's Condensed Chemical Dictionary,第13版,John Wiley&Sons,Inc.,New York(1997)中。在一个实施方案中,术语“芳基”表示在环部分中含有6至10个碳原子的单环和双环芳族基团(诸如苯基或萘基,包括1-萘基和2-萘基)。举例而言,“C6或C10芳基”或“C6-10芳基”是指苯基和萘基。除非另外说明,否则“芳基”、“C6或C10芳基”、“C6-10芳基”或“芳族残基”可未经取代或经选自以下的1至5个基团,优选1至3个基团取代:-OH、-OCH3、F、Cl、Br、I、-CN、-NO2、-NH2、-N(CH3)H、-N(CH3)2、-CF3、-OCF3、-C(O)CH3、-SCH3、-S(O)CH3、-S(O)2CH3、-CH3、-CH2CH3、-CO2H和-CO2CH3。
如本文中所使用,术语“杂环”、“杂环基”或“杂环状基团”意欲意指稳定的3、4、5、6或7元单环或5、6、7、8、9、10、11、12、13或14元多环(包括双环和三环)杂环,其为饱和或部分不饱和的,且含有碳原子和1、2、3或4个独立地选自N、O和S的杂原子;且包括其中上文所定义杂环中的任一种与碳环或芳基(例如苯)环稠合的任何多环基团。即,术语“杂环”、“杂环基”或“杂环状基团”包括非芳环系统,诸如杂环烷基和杂环烯基。氮和硫杂原子可任选经氧化(即,N→O和S(O)p,其中p为0、1或2)。氮原子可经取代或未经取代(即,N或NR,其中R为H或另一取代基(若经定义))。杂环可在产生稳定结构的任何杂原子或碳原子处连接至其侧基。若所得化合物稳定,则本文中所描述的杂环可在碳原子或氮原子上经取代。杂环中的氮可任选经季铵化。当杂环中S和O原子的总数超过1时,则这些杂原子优选彼此不相邻。杂环中的S和O原子的总数优选不超过1。杂环基的实例包括(但不限于)氮杂环丁烷基、哌嗪基、哌啶基、哌啶酮基、胡椒基、吡喃基、吗啉基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、吗啉基、二氢呋喃并[2,3-b]四氢呋喃。
如本文中所使用,术语“双环杂环”或“双环杂环基”意欲指稳定的9元或10元杂环系统,其含有两个稠合环且由碳原子和1、2、3或4个独立地选自N、O和S的杂原子组成。在两个稠合环中,一个环为5元或6元单环芳环,其包含5元杂芳基环、6元杂芳基环或苯并环,各自稠合至第二环。第二环为5元或6元单环,其为饱和、部分不饱和或不饱和的且包含5元杂环、6元杂环或碳环(限制条件为若第二环为碳环,则第一环不为苯并环)。
双环杂环基可在产生稳定结构的任何杂原子或碳原子处连接至其侧基。若所得化合物稳定,则本文所描述的双环杂环基可在碳原子或氮原子上经取代。当杂环中S和O原子的总数超过1时,则这些杂原子优选彼此不相邻。杂环中的S和O原子的总数优选不超过1。双环杂环基的实例为(但不限于)1,2,3,4-四氢喹啉基、1,2,3,4-四氢异喹啉基、5,6,7,8-四氢-喹啉基、2,3-二氢-苯并呋喃基、色满基、1,2,3,4-四氢-喹喔啉基和1,2,3,4-四氢-喹唑啉基。
桥联环也包括于杂环的定义中。当一或多个,优选一至三个原子(即,C、O、N或S)连接两个不相邻碳或氮原子时,形成桥联环。桥联环的实例包括(但不限于)一个碳原子、两个碳原子、一个氮原子、两个氮原子和一个碳-氮基团。应指出,一个桥总是将单环转变成三环。当环桥联时,该环中所述取代基也可存在于桥上。
如本文中所使用,术语“杂芳基”意欲意指稳定的单环和多环(包括双环和三环)芳族烃,其包括至少一个杂原子环成员,诸如硫、氧或氮。杂芳基包括(但不限于)吡啶基、嘧啶基、吡嗪基、哒嗪基、三嗪基、呋喃基、喹啉基、异喹啉基、噻吩基、咪唑基、噻唑基、吲哚基、吡咯基、噁唑基、苯并呋喃基、苯并噻吩基、苯并噻唑基、异噁唑基、吡唑基、三唑基、四唑基、吲唑基、1,2,4-噻二唑基、异噻唑基、嘌呤基、咔唑基、苯并咪唑基、吲哚啉基、苯并二氧杂环戊基和苯并二噁烷。杂芳基经取代或未经取代。氮原子经取代或未经取代(即,N或NR,其中R为H或另一取代基(若经定义))。氮和硫杂原子可任选经氧化(即,N→O和S(O)p,其中p为0、1或2)。
杂芳基的实例包括(但不限于)吖啶基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并硫代呋喃基、苯并噻吩基、苯并噁唑基、苯并噁唑啉基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异噁唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、色满基、色烯基、噌啉基、十氢喹啉基、2H,6H-1,5,2-二噻嗪基、呋喃基、咪唑烷基、二氢咪唑基、咪唑基、1H-吲唑基、咪唑并吡啶基、吲哚烯基、吲哚啉基、吲嗪基、吲哚基、3H-吲哚基、靛红酰基、异苯并呋喃基、异色满基、异吲唑基、异吲哚啉基、异吲哚基、异喹啉基、异噻唑基、异噻唑并吡啶基、异噁唑基、异噁唑并吡啶基、亚甲基二氧基苯基、二氮杂萘基、八氢异喹啉基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、噁唑烷基、噁唑基、噁唑并吡啶基、噁唑烷基、蝶啶基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪基、吩噻嗪基、吩噁噻基、吩噁嗪基、酞嗪基、喋啶基、嘌呤基、吡嗪基、吡唑烷基、吡唑啉基、吡唑并吡啶基、吡唑基、哒嗪基、吡啶并噁唑基、吡啶并咪唑基、吡啶并噻唑基、吡啶基、嘧啶基、吡咯烷基、吡咯啉基、2-吡咯烷酮基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四唑基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、噻吩基、噻唑并吡啶基、噻吩并噻唑基、噻吩并噁唑基、噻吩并咪唑基、噻吩基、三嗪基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基和呫吨基。
5元至10元杂芳基的实例包括(但不限于)吡啶基、呋喃基、噻吩基、吡唑基、咪唑基、咪唑烷基、吲哚基、四唑基、异噁唑基、噁唑基、噁二唑基、噁唑烷基、噻二嗪基、噻二唑基、噻唑基、三嗪基、三唑基、苯并咪唑基、1H-吲唑基、苯并呋喃基、苯并硫代呋喃基、苯并四唑基、苯并三唑基、苯并异噁唑基、苯并噁唑基、羟吲哚基、苯并噁唑啉基、苯并噻唑基、苯并异噻唑基、靛红酰基、异喹啉基、八氢异喹啉基、异噁唑并吡啶基、喹唑啉基、喹啉基、异噻唑并吡啶基、噻唑并吡啶基、噁唑并吡啶基、咪唑并吡啶基和吡唑并吡啶基。5元至6元杂环的实例包括(但不限于)吡啶基、呋喃基、噻吩基、吡咯基、吡唑基、吡嗪基、咪唑基、咪唑烷基、吲哚基、四唑基、异噁唑基、噁唑基、噁二唑基、噁唑烷基、噻二嗪基、噻二唑基、噻唑基、三嗪基和三唑基。
除非另有指示,否则“碳环基”或“杂环基”包括一至三个与碳环或杂环稠合的其他环,诸如芳基、环烷基、杂芳基或环杂烷基环,例如
且可任选经由可用碳原子经1、2或3个选自以下的基团取代:氢、卤素、卤烷基、烷基、卤烷基、烷氧基、卤烷氧基、烯基、三氟甲基、三氟甲氧基、炔基、环烷基-烷基、环杂烷基、环杂烷基烷基、芳基、杂芳基、芳基烷基、芳基氧基、芳基氧基烷基、芳基烷氧基、烷氧基羰基、芳基羰基、芳基烯基、氨基羰基芳基、芳基硫基、芳基亚磺酰基、芳基偶氮、杂芳基烷基、杂芳基烯基、杂芳基杂芳基、杂芳基氧基、羟基、硝基、氰基、硫醇、烷硫基、芳基硫基、杂芳基硫基、芳基硫基烷基、烷氧基芳基硫基、烷基羰基、芳基羰基、烷基氨基羰基、芳基氨基羰基、烷氧基羰基、氨基羰基、烷基羰基氧基、芳基羰基氧基、烷基羰基氨基、芳基羰基氨基、芳基亚磺酰基、芳基亚磺酰基烷基、芳基磺酰基氨基和芳基砜氨基羰基和/或本文中阐述的烷基取代基中的任一种。
当术语烷基、烯基、炔基、环烷基、碳环基、杂环基、芳基和杂芳基中的任一种作为另一基团的一部分使用时,碳原子数和环成员与术语本身中所定义相同。举例而言,烷氧基、卤烷氧基、烷基氨基、卤烷基、羟基烷基、氨基烷基、卤烷氧基、烷氧基烷氧基、卤烷基氨基、烷氧基烷基氨基、卤烷氧基烷基氨基、烷基硫基等各自独立地含有与关于术语“烷基”所定义相同的碳原子数,诸如1至4个碳原子、1至6个碳原子、1至10个碳原子等。类似地,环烷氧基、杂环基氧基、环烷基氨基、杂环基氨基、芳烷基氨基、芳基氨基、芳基氧基、芳烷基氧基、杂芳基氧基、杂芳基烷基氧基等各自独立地含有与关于术语“环烷基”、“杂环基”、“芳基”和“杂芳基”所定义相同的环成员,诸如3元至6元、4元至7元、6元至10元、5元至10元、5元或6元等。
根据本领域使用的惯例,如结构式中所使用的指向粗线的键,诸如描绘作为部分或取代基与核心或主链结构的连接点的键。
根据本领域使用的惯例,结构式中的波浪或弯曲键,诸如用于描绘X'、Y'和Z'所连接的碳原子的立体对称中心,且意欲在单一图式中表示两种对映异构体。即,具有诸如波浪键的结构式分别表示对映异构体中的每一种,诸如/>以及其外消旋混合物。当波浪或完全键连接至双键(诸如C=C或C=N)部分时,其包括顺式或反式(或E和Z)几何异构体或其混合物。
应理解在本文中,若碳环或杂环部分可经由不同环原子键合或以其他方式连接至指定底物而未标示特定连接点,则所有可能点均是预期点,无论是经由碳原子还是经由例如三价氮原子。举例而言,术语“吡啶基”意指2-吡啶基、3-吡啶基或4-吡啶基,术语“噻吩基”意指2-噻吩基或3-噻吩基等。
当展示连至取代基的键与连接环中的两个原子的键交叉时,则此取代基可键合至该环上的任何原子。若所列取代基未指示此取代基键和至指定式化合物的其余部分的原子,则此取代基可经由此取代基中的任何原子键合。取代基和/或变量的组合仅在此类组合产生稳定化合物时为容许的。
本领域技术人员将认识到,应选择本发明化合物的取代基及其他部分以提供足够稳定的化合物,从而提供药学可用化合物,其可调配成可接受地稳定的药物组合物。预期具有此类稳定性的本发明化合物属于本发明的范畴内。
术语“抗衡离子”用于表示带负电的物质,诸如氯离子、溴离子、氢氧根、乙酸根和硫酸根。术语“金属离子”是指碱金属离子,诸如钠、钾或锂;和碱土金属离子,诸如镁和钙;以及锌和铝。
如本文中所提及,术语“经取代”意指至少一个(连接至碳原子或杂原子的)氢原子经非氢基团替换,其限制条件为维持常价且取代产生稳定化合物。当取代基为氧代(即=O)时,则替换原子上的2个氢。氧代取代基不存在于芳族部分上。当称环系统(例如碳环或杂环)经羰基或双键取代时,其意指该羰基或双键成为环的部分(即,在环内)。如本文所使用的环双键为在两个相邻环原子之间所形成的双键(例如,C=C、C=N或N=N)。关于烷基、环烷基、杂烷基、环杂烷基、亚烷基、芳基、芳基烷基、杂芳基、杂芳基烷基、碳环基和杂环基的术语“经取代”分别意指其中连接至碳原子或杂原子的一或多个氢原子各自独立地经一或多个非氢取代基替换的烷基、环烷基、杂烷基、环杂烷基、亚烷基、芳基、芳基烷基、杂芳基、杂芳基烷基、碳环基和杂环基。
在本发明化合物上存在氮原子(例如胺)的情况下,这些氮原子可通过用氧化剂(例如mCPBA和/或过氧化氢)处理而转化成N-氧化物,得到本发明其他化合物。因此,所展示和所要求保护的氮原子视为涵盖所展示的氮及其N-氧化物(N→O)衍生物。
当任何变量在化合物的任何组分或式中出现多于一次时,其在每次出现时的定义独立于其在其他每次出现时的定义。因此,举例而言,若展示基团经0、1、2或3个R基团取代,则所述基团在其经0个R基团取代时未经取代,或经至多三个R基团取代,且R在每次出现时独立地根据R的定义加以选择。
此外,取代基和/或变量的组合为容许的,只要此类组合产生稳定化合物。
如本文所使用,术语“互变异构体”是指化合物的两种或更多种异构体中的每一种,这些异构体一起平衡存在,且由于分子内的原子或基团的电子迁移而容易互换。举例而言,本领域技术人员将容易理解,1,2,3-三唑以如上文所定义的两种互变异构形式存在:
因此,本发明意欲涵盖所有可能的互变异构体,即使在结构仅描绘其中的一个时也是如此。
短语“药学上可接受”在本文中用于指在合理医学判断范畴内,适用于与人类和动物的组织接触而无过度毒性、刺激、过敏反应和/或其他问题或并发症、与合理益处/风险比相称的那些化合物、材料、组合物和/或剂型。
本发明化合物可以盐形式存在,其也在本发明的范畴内。优选药学上可接受的盐。如本文所使用,“药学上可接受的盐”是指所公开的化合物的衍生物,其中母体化合物通过制得其酸盐或碱盐而改质。本发明的药学上可接受的盐可由含有碱性或酸性部分的母体化合物通过常规化学方法合成。一般而言,此类盐可通过使这些化合物的游离酸或碱形式与化学计量量的适当碱或酸在水中或在有机溶剂中或在两者的混合物中反应来制备;一般而言,优选非水性介质(如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈)。适合盐的清单见于Remington's Pharmaceutical Sciences,第18版,Mack Publishing Company,Easton,PA(1990)中,其公开内容在此以引用的方式并入。
若本发明化合物具有例如至少一个碱性中心,则其可形式酸加成盐。这些酸加成盐通过以下酸形成,例如:强无机酸,诸如矿物酸,例如硫酸、磷酸或氢卤酸;有机羧酸,诸如具有1至4个碳原子的烷羧酸(例如乙酸),其未经取代或经例如卤素取代(如氯乙酸),诸如饱和或不饱和的二羧酸,例如草酸、丙二酸、琥珀酸、马来酸、富马酸、邻苯二甲酸或对苯二甲酸,诸如羟基羧酸,例如抗坏血酸、乙醇酸、乳酸、苹果酸、酒石酸或柠檬酸,诸如氨基酸(例如天冬氨酸或谷氨酸或赖氨酸或精氨酸)或苯甲酸;或有机磺酸,诸如(C1-C4)烷基或芳基磺酸,其未经取代或经例如卤素取代,例如甲基磺酸或对甲苯磺酸。对应的酸加成盐视需要还可形成为具有其他存在的碱性中心。具有至少一个酸性基团(例如COOH)的本发明化合物还可与碱形成盐。与碱形成的适合盐为例如金属盐,诸如碱金属盐或碱土金属盐,例如钠、钾或镁盐;或与氨或有机胺的盐,诸如吗啉、硫代吗啉、哌啶、吡咯烷、单-、二-或三-低碳数烷基胺,例如乙基、叔丁基、二乙基、二异丙基、三乙基、三丁基或二甲基-丙基胺,或单、二或三羟基低碳数烷基胺,例如单、二或三乙醇胺。可进一步形成对应的内盐。还包括不适合用于药物用途但可用于例如分离或纯化式(I)的游离化合物或其药学上可接受的盐的盐。
含有碱性基团的式(I)化合物的优选盐包括单盐酸盐、硫酸氢盐、甲磺酸盐、磷酸盐、硝酸盐或乙酸盐。
含有酸性基团的式(I)化合物的优选盐包括钠、钾和镁盐及药学上可接受的有机胺。
另外,本发明的化合物可具有前药形式。将在体内转化以提供生物活性剂的任何化合物为本发明的范畴和精神内的前药。如本文所使用的术语“前药”涵盖基于羧酸残基的前药(即“前药酯”)和基于精氨酸模拟物部分的前药(即“精氨酸模拟物的前药”)。此类前药优选口服给药,因为许多情况下水解主要在消化酶的影响下发生。在酯本身具有活性的情况下或在水解发生于血液中的那些情况下,可使用肠胃外给药。
本发明化合物含有羧基,其可形成在生理上可水解的酯,这些酯通过在体内水解得到本发明化合物本身而充当前药(即“前药酯”)。本发明化合物的生理上可水解的酯的实例包括C1至C6烷基、C1至C6烷基苯甲基、4-甲氧基苯甲基、茚满基、酞酰基、甲氧基甲基、C1-6烷酰氧基-C1-6烷基(例如乙酰氧基甲基、特戊酰氧基甲基或丙酰氧基甲基)、C1至C6烷氧基羰氧基-C1至C6烷基(例如甲氧基羰基氧基甲基或乙氧基羰基氧基甲基、甘氨酰基氧基甲基、苯基甘氨酰基氧基甲基、(5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)-甲基),和用于例如青霉素(penicillin)和头孢菌素(cephalosporin)技术中的其他已知的生理上可水解的酯。此类酯可通过本领域已知的常规技术来制备。“前药酯”可通过采用本领域技术人员已知的步骤使本发明化合物的羧酸部分与烷基或芳基醇、卤化物或磺酸酯反应而形成。此外,前药的各种形式为本领域已知的。关于此类前药衍生物的实例,参见:
Bundgaard,H.编,Design of Prodrugs,Elsevier(1985)和Widder,K.等人编,Methods in Enzymology,112:309-396,Academic Press(1985);
Bundgaard,H.,第5章,“Design and Application of Prodrugs”,Krosgaard-Larsen,P.等人编,A Textbook of Drug Design and Development,第113-191页,HarwoodAcademic Publishers(1991);
Bundgaard,H.,Adv.Drug Deliv.Rev.,8:1-38(1992);
Bundgaard,H.等人,J.Pharm.Sci.,77:285(1988);和
Kakeya,N.等人,Chem.Pharm.Bull.,32:692(1984)。
前药制备在本领域已知且描述于例如King,F.D.,编,Medicinal Chemistry:Principles and Practice,The Royal Society of Chemistry,Cambridge,UK(1994);Testa,B.等人,Hydrolysis in Drug and Prodrug Metabolism.Chemistry,Biochemistryand Enzymology,VCHAand Wiley-VCH,Zurich,Switzerland(2003);Wermuth,C.G.,编,ThePractice of Medicinal Chemistry,Academic Press,San Diego,CA(1999);Rautio,J.等人,Nature Review Drug Discovery,17,559-587,(2018)。
本发明意欲包括存在于本发明化合物中的原子的所有同位素。同位素包括原子数相同但质量数不同的那些原子。借助于一般实例但非限制性地,氢的同位素包括氘(符号D或2H)和氚(符号T或3H)。碳的同位素包括13C和14C。本发明的同位素标记化合物可一般通过本领域技术人员已知的常规技术或通过类似于本文所述的方法,使用适当同位素标记试剂代替另外使用的非标记试剂来制备。此类化合物具有多种潜在用途,例如作为测定潜在药物化合物结合至靶蛋白或受体的能力的标准品和试剂或用于使体内或体外结合至生物受体的本发明化合物成像。
“稳定化合物”和“稳定结构”意欲指示足够稳固能经受自反应混合物分离至适用纯度且调配成有效治疗剂的化合物。优选地,本发明化合物不含有N-卤素、S(O)2H或S(O)H基团。
术语“溶剂合物”意指本发明化合物与一或多个溶剂分子(不论有机或无机)的物理缔合。该物理缔合包括氢键。溶剂合物中的溶剂分子可以有序排列和/或无序排列而存在。溶剂合物可包含化学计量或非化学计量的量的溶剂分子。“溶剂合物”涵盖溶液相和可分离的溶剂合物两者。示例性溶剂合物包括(但不限于)水合物、乙醇化物、甲醇化物和异丙醇化物。溶剂化方法一般是本领域已知的。
术语“糖基”意指通过自环状形式的单糖且引申开来自低碳数寡糖移除半缩醛羟基而获得的单价自由基或取代基部分。在一个实施方案中,糖基具有以下结构:
如本文中所使用的缩写定义如下:“1×”为一次,“2×”为两次,“3×”为三次,“℃”为摄氏度,“eq”为当量,“g”为克,“mg”为毫克,“L”为升,“mL”为毫升,“μL”为微升,“N”为当量浓度,“M”为摩尔浓度,“mmol”为毫摩尔,“min”为分钟,“h”为小时,“rt”为室温,“RBF”为圆底烧瓶,“atm”为氛围,“psi”为磅/平方英寸,“conc.”为浓缩,“RCM”为关环转换,“sat”或“sat'd”为饱和,“SFC”为超临界流体色谱,“MW”为分子量,“mp”为熔点,“ee”为对映异构过量,“MS”或“Mass Spec”为质谱法,“ESI”为电喷雾电离质谱,“HR”为高分辨,“HRMS”为高分辨质谱,“LCMS”为液相色谱质谱法,“HPLC”为高压液相色谱,“RP HPLC”为反相HPLC,“TLC”或“tlc”为薄层色谱,“NMR”为核磁共振光谱,“nOe”为核奥氏效应光谱(nuclearOverhauser effect spectroscopy),“1H”为质子,“δ”为德尔塔(delta),“s”为单峰,“d”为二重峰,“t”为三重峰,“q”为四重峰,“m”为多重峰,“br”为宽峰,“Hz”为赫兹(hertz),且“α”、“β”、“R”、“S”、“E”和“Z”为本领域技术人员常见的立体化学标示。
缩写
以下缩写用于方案、实施例及本文他处:
AcOH=乙酸
AIBN=偶氮二异丁腈
BOP=(苯并三唑-1-基氧基)三(二甲基氨基)鏻鎓六氟磷酸盐
CDI=1,1'-羰基二咪唑
Cs2CO3=碳酸铯
DCE=二氯乙烷
DCM=CH2Cl2=二氯甲烷
DDQ=2,3-二氯-5,6-二氰基-1,4-苯醌
DIBAL-H=二异丁基氢化铝
DIEA=许尼希碱(Hunig's base)=N,N-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
DMP=戴斯-马丁高碘烷
DMSO=二甲基亚砜
DPPA=二苯基磷酰基叠氮化物
dppf=1,1'-双(二苯基膦基)二茂铁
EDC=1-乙基-3-(3-二甲基氨基丙基)碳二亚胺
EtOAc=乙酸乙酯
EtOH=乙醇
HATU=1-[双(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物六氟磷酸盐
HBTU=N,N,N',N'-四甲基-O-(1H-苯并三唑-1-基)脲鎓六氟磷酸盐
HCl=盐酸
HOBT=羟基苯并三唑
H2SO4=硫酸
K2CO3=碳酸钾
K2HPO4=磷酸氢二钾
KMnO4=高锰酸钾
KOH=氢氧化钾
KOtBu=叔丁醇钾
LAH=氢化锂铝
mCPBA=间氯过氧苯甲酸
MeCN=乙腈
MeOH=甲醇
MgSO4=硫酸镁
Na2CO3=碳酸钠
NaBH4=硼氢化钠
NaHCO3=碳酸氢钠
NBS=N-溴琥珀酰亚胺
NCS=N-氯琥珀酰亚胺
NH4Cl=氯化铵
NMP=N-甲基-2-吡咯烷酮
PCC=氯铬酸吡啶鎓
Pd2(dba)3=三(二苯亚甲基丙酮)二钯(0)
Pd(dppf)Cl2·CH2Cl2加合物=[1,1'-双(二苯基膦基)二茂铁]二氯钯(II)与二氯甲烷的络合物
Pd(PPh3)4=四(三苯基膦)钯(0)
PDC=重铬酸吡啶鎓
PE=石油醚
Ph3P=三苯基膦
PyBOP=(苯并三唑-1-基氧基)三吡咯烷鏻鎓六氟磷酸盐
SiO2=二氧化硅
T3P=丙基膦酸酐
TBTU=O-(苯并三唑-1-基)-N,N,N',N'-四甲脲鎓四氟硼酸盐
TEA=Et3N=三乙胺
TFA=三氟乙酸
THF=四氢呋喃
Xantphos=4,5-双(二苯基膦基)-9,9-二甲基呫吨
IV.制备方法
本发明化合物可使用下文所描述的方法以及合成有机化学技术中已知的合成方法或本领域技术人员所理解的变化形式,以有机合成领域技术人员已知的多种方式制备。优选方法包括(但不限于)下文所描述的那些方法。本文所述的所有参考文献均在此以全文引用的方式并入。反应在适于所采用的试剂和材料且适于实现转化的溶剂或溶剂混合物中进行。有机合成领域技术人员应理解,分子上存在的官能团应与所提议的转化相符。有时此将需要作出判断以修改合成步骤次序或选择一种特定方法方案而非另一种,从而获得所需的本发明化合物。对与反应条件相容的取代基的限制对于本领域技术人员将为显而易见的,且于是必须使用替代方法。还将认识到,在本领域中,任何合成途径的规划中的另一主要考虑因素为审慎选择用于保护本发明所述化合物中存在的反应性官能团的保护基。可适用于制备本发明化合物的合成方法的特别有用概要可见于Larock,R.C.,ComprehensiveOrganic Transformations,VCH,New York(1989)中。
本发明化合物可使用此部分中所描述的反应和技术来制备。反应在适于所用试剂和材料且适于实现转化的溶剂中进行。而且,在下述合成方法的说明中,应理解所提出的所有反应条件(包括溶剂、反应氛围、反应温度、实验持续时间和处理程序)均选择为本领域技术人员应容易识别的该反应的标准条件。有机合成领域技术人员应理解,所公布分子各个部分上所存在的官能团必须与所提出的试剂和反应物相容。并非落入给定类别内的所有式(I)化合物均可与一些所描述方法中需要的一些反应条件相容。本领域技术人员将显而易知对与反应条件相容的取代基的此类限制,且必须使用替代方法。可适用于制备本发明化合物的合成方法的特别有用概要可见于Larock,R.C.,Comprehensive OrganicTransformations,VCH,New York(1989)中。
通用方案
由式(I)、式(IIa)、式(IIb)表示的本发明化合物或其任何亚属或种可根据下述方案1至18中所示的通用路线制备。
方案1
方案1描述式I-A(式I的子集)化合物的合成,其中:L1=5元杂芳环。Z=6元芳环或5元至10元杂芳环。
本领域普通技术人员可容易使用许多且沿用已久的操作来制备杂芳基甲醇化合物1d,代表性实例见于WO 2012/087519(Tully,D.C.等人)、WO 2009/012125(Genin,M.J.等人)和WO 2008/051942(Navas,F.等人)中。
起始物质4-(甲氧基羰基)双环[2.2.2]辛烷-1-甲酸1a可商购,或可由本领域普通技术人员已知的步骤来制备(Kiesman W.F.等人WO 2001/034610)。酸1a可经由典型汉斯狄克反应(Hunsdieker reaction)碘化(Al Hussainy,R.等人J.Med.Chem.2011,54,3480-3491),或替代地经由J.Am.Chem.Soc.1999,121,1936-1944中所描述的光化学应用方法碘化(参见Kuduva,S.S.等人;photochemical iodination of bridgehead cubane)。甲酯与碱金属氢氧化物碱的后续水解可提供酸1b。
杂环形成(L1)。本领域普通技术人员可使用许多已确立方法将化合物1b的羧酸部分转化成各种杂环(L1),所述方法包括(但不限于)以下各者:
L1=1,2,4-噁二唑(Z=3-芳基或3-杂芳基)(L1在1,2,4-噁二唑的5位置处连接至双环[2.2.2]辛烷环)。酸1b可在室温,于极性非质子溶剂(例如,甲苯、THF、1,4-二噁烷)中,使用常用酰胺键偶联剂(例如,CDI、BOP、EDC)与各种芳基(或杂芳基)酰胺肟偶联。所得非环状中间体随后可在高温(60℃至110℃)环化成1,2,4-噁二唑。酰胺肟可由对应的芳基(或杂芳基)腈与羟胺反应而合成(参见Hirawat,S.等人WO 2006/110483;制备酰胺肟的通用操作)。
L1=1,3,4-噁二唑(Z=5-芳基或5-杂芳基)或L1=1,3,4-噻二唑(Z=5-芳基或5-杂芳基)(L1在1,3,4-噁(噻)二唑的2位置处连接至双环[2.2.2]辛烷环)。酸1b可在极性非质子溶剂(例如,DMF、MeCN)中使用典型酰胺键偶联剂(例如,EDC、PyBOP、T3P)而与3-(肼羰基)苯甲酸甲酯(Bradner,J.E.等人WO2014/071247)偶联。非环状酰肼中间体可随后分别使用4-甲苯磺酸(Stabile,P.等人Tetrahedron Lett.2010,51,4801-4805)或五硫化磷(Yoshida,S.等人Org.Process Res.Dev.2013,17,1252-1260)而环化成1,3,4-噁二唑或1,3,4-噻二唑。
L1=噁唑或噻唑(Z=2-芳基或2-杂芳基)(L1在噁唑或噻唑的4位置处连接至双环[2.2.2]辛烷环)。酸1b可经活化,以由本领域普通技术人员在介于-30℃至25℃之间的温度,于极性非质子溶剂(例如,DCM、THF)中使用任何数目种试剂(例如,亚硫酰氯、草酰氯)进行酰化。经活化酸中间体可在介于-5℃至5℃之间的温度,于极性非质子溶剂(例如,乙醚、THF、DCM)中与三甲基硅烷基重氮甲烷反应。重氮酮可在酸性条件(HCl)下水解,产生2-氯乙烷中间体。可通过2-氯乙烷部分与芳基或杂芳基伯甲酰胺(或硫甲酰胺)在高温(175℃,密封)于醚溶剂(1,4-二噁烷)中的后续反应来实现至噁唑或噻唑的环化。
L1=1H-咪唑(Z=2-芳基或2-杂芳基)(L1在1H-咪唑的4位置处连接至双环[2.2.2]辛烷环)。可通过芳基或杂芳基脒与针对L1=噁唑或噻唑(见上文)的合成所描述的2-氯乙烷中间体的反应来实现至1H-咪唑的环化。偶联反应可在高温(60℃至105℃)于醚溶剂(例如,THF、1,4-二噁烷)中进行。本领域普通技术人员可通过众多所报道方法中的任一种来制备芳基或杂芳基脒。一种此类方法是通过对应的芳基或杂芳基腈与氨进行反应(“Preparation of amidine salts by reaction of nitriles with ammonium salts inthe presence of ammonia”,Schaefer,F.C.等人J.Org.Chem.1962,27,1255-1258)。
碘化物1c可在三氟甲磺酸银和碱(例如,吡啶、2,6-二甲基吡啶、2,6-二-叔丁基吡啶)存在下经醇1d替换。使用典型碱金属氢氧化物碱使酯R(R=Me、Et或其他适合的烷基取代基)水解可得到式I-A化合物。
方案2
方案2描述化合物1c(参见方案1)的替代合成,其中:L1=1,2,4-噁二唑。Z=5-芳基或5-杂芳基。L1在1,2,4-噁二唑的3位置处连接至双环[2.2.2]辛烷环。
酸1b可经活化,以由本领域普通技术人员在介于-30℃至0℃之间的温度,于极性非质子溶剂(例如,DCM、THF)中使用任何数目种试剂(例如,亚硫酰氯、草酰氯、氯甲酸甲酯或氯甲酸乙酯)进行酰化。经活化的酸中间体可与氨或铵(例如,NH3(g)、NH4Cl)反应,产生伯酰胺2a。酰胺2a可使用脱水剂(例如,氧氯化磷、五氧化二磷、三氟乙酸酐)转化成腈2b。腈2b可使用羟胺转化成酰胺肟2c(参见Hirawat,S.等人WO 2006/110483;腈转化成酰胺肟的通用操作),随后在极性非质子溶剂(例如,甲苯、THF、1,4-二噁烷)中使用典型酰胺键偶联剂(例如,CDI、BOP、EDC)与各种芳基或杂芳基酸偶联。可在高温(60℃至100℃)进行环化,以形成化合物1c。可使用方案1中所描述的方法将1c转化成式I-A化合物。
方案3
方案3描述化合物1c(方案1)的替代合成,其中:L1=共价键。Z=5元至10元杂芳环。Z在杂芳基的2位置处连接至双环[2.2.2]辛烷环。
杂环形成.本领域普通技术人员可使用许多已知且沿用已久的方法将化合物1b的羧酸部分转化成各种杂环,所述方法包括(但不限于)以下各种:
苯并噻唑.方法A:酸1b可在极性非质子溶剂(例如,DCE、THF)中,使用常用酰胺键偶联剂(例如,BOP、T3P、EDC)与经取代的2-氨基苯硫酚(通常参见Chedekel,M.R.等人Synth.Commun.1980,10,167-173;各种2-氨基苯硫酚的合成)偶联。偶联反应可在高温(60℃至80℃)进行,由此实现环化苯并噻唑的原位形成。
方法B:替代地,酸1b可使用典型的酰胺键偶联剂(例如,T3P、BOP),或通过活化酸1b以使用任何数目种常见试剂(例如,草酰氯、亚硫酰氯、氧氯化磷)进行酰化,而与经取代的2-氯苯胺(广泛商业可获得性)偶联。可在高温(120℃)用劳森试剂(Lawesson'sreagent)处理所得甲酰胺,以实现甲酰胺至硫甲酰胺的转化。可在高温(130℃),于极性非质子溶剂(例如,DMF、NMP)中用氢化钠进行处理而实现至苯并噻唑的环化。
苯并噁唑.酸1b可在极性非质子溶剂(例如,DMF、THF)中,使用常见酰胺键偶联剂(例如,BOP、EDC)而与经取代的2-氨基苯酚(广泛商业可获得性)偶联。可在催化量的酸(对甲苯磺酸)存在下,在高温(115℃)实现环化。
1H-苯并咪唑.酸1b可在极性非质子溶剂(例如,DMF、NMP)中使用常见酰胺键偶联剂(例如,TBTU、T3P、PyBOP)与3,4-二氨基苯甲酸乙酯偶联,随后在高温(115℃)在酸性条件(纯AcOH)下环化成苯并咪唑。
喹唑啉.酸1b可在极性非质子溶剂(例如,MeCN、THF)中使用酰胺键偶联剂(例如,HBTU、EDC、PyBOP)与4-氨基-3-(氨基甲基)苯甲酸酯二盐酸盐(Pascal,R.等人Eur.J.Org.Chem.2000,22,3755-3761)偶联。可在高温(115℃)在酸性条件(纯AcOH)下实现环化。可使用诸如DDQ的氧化剂将所得二氢喹唑啉中间体氧化成喹唑啉。
噻唑.酸1b可经活化,以由本领域普通技术人员在介于-30℃至0℃之间的温度,于极性非质子溶剂(例如,THF、甲苯)中使用任何数目种试剂(例如,亚硫酰氯、草酰氯、氯甲酸甲酯或氯甲酸乙酯)进行酰化。经活化的酸中间体可与氨或铵(例如,NH3(g)、NH4Cl)反应,产生伯酰胺,可在高温(60℃至120℃)用劳森试剂处理该伯酰胺以实现甲酰胺至硫甲酰胺的转化。硫甲酰胺可随后通过在高温(60℃至100℃)与各种亲电试剂(例如,3-溴-2-氧代丙酸、2-氯乙酰乙酸乙酯)反应而环化成噻唑。
化合物1c可使用方案1中所描述的方法与化合物1d反应,得到式I-A化合物。
方案4
方案4描述获得式I-A(式I的子集)化合物的替代合成路线,其中:L1=共价键。Z=9元至10元杂芳环。
可根据方案1中所描述的方法合成化合物4a。在三氟甲磺酸银和碱(例如,吡啶、2,6-二甲基吡啶、2,6-二-叔丁基吡啶)存在下用醇1d替换碘化物化合物4a,可得到化合物4b。可使用典型碱金属氢氧化物碱使酯4b水解,且所得酸可通过方案1中所描述的方法转化成碘化合物4c。应用Togo,H.等人所描述的方法(“Radical alkylation of heteroaromaticbases with polysilane compounds”,Bull.Chem.Soc.Jpn.1994,67,2522-2527),化合物4c可在自由基引发剂(AIBN)存在下经历至含氮杂芳族化合物4d(例如,经取代的吡啶、喹啉、1,5-二氮杂萘等)的自由基取代,得到化合物4e。使用典型碱金属氢氧化物碱使酯R(R=Me、Et或其他适合的烷基取代基)水解可得到式I-A化合物。
方案5
方案5描述式I-B(式I的子集)化合物的合成,其中:Z=6元至10元芳环或5元至10元杂芳环。
本领域普通技术人员可用常用还原剂(例如,LAH、DIBAL-H、NaBH4)容易地将羧酸酯4b转化成醇5a。就此转化而言的典型溶剂包括氯化溶剂或醚溶剂(例如,DCM、醚、THF、1,4-二噁烷),且温度可在-78℃至100℃之间变化。
醚化.存在许多将产生式I-B化合物的由醇5a形成醚键的方法,包括但不限于以下方法:
SNAr反应.醇5a可与经2-卤素取代的吡啶(或其他含氮杂环)进行SNAr反应。此转化通常通过碱(诸如碳酸盐、胺、氢化物、硅烷胺、醇盐和烷基锂)在碱性条件下进行。使用诸如氯化溶剂或醚溶剂(例如,DCM、THF、1,4-二噁烷)的非质子性溶剂,且温度可在-78℃至120℃之间变化。
SN2反应.另外,醇5a可转化成卤化物。用于卤化的典型试剂包括PPh3/四溴化碳、溴、三溴化磷、三氯化磷和甲磺酰氯。通常使用非质子性的氯化溶剂或醚溶剂(例如,DCM、四氯化碳、THF),且温度可在0℃至100℃之间变化。卤化物可在与上文针对SNAr反应所描述类似的碱性条件下,经由SN2反应而与各种酚反应。
光延反应.构建醚键的替代方法是通过使醇5a经由光延反应与各种酚反应(“TheMitsunobu reaction in the 21st century”,Fletcher,S.Org.Chem.Front.2015,2,739-752)。
最后,使用典型碱金属氢氧化物碱使化合物5b的酯R(R=Me、Et或其他适合的烷基取代基)水解,可得到式I-B化合物。
方案6
方案6描述式I-C(式I的子集)化合物的合成,其中:Z=6元至10元芳环或5元至10元杂芳环。
本领域普通技术人员可使用典型氧化条件(例如,戴斯-马丁高碘烷、斯文氧化反应(Swern oxidation)、PDC或PCC)将化合物5a(方案5)氧化成醛6a。醛6a可在碱性条件(例如,K2CO3、KOtBu)下与1-重氮-2-氧代丙基膦酸二甲酯6b反应,得到炔烃6c(参见Seyferth,D.等人J.Org.Chem.1971,36,1379-1386;Seyferth-Gilbert同系化)。炔烃6c可在典型Sonogashira条件(Sonogashira,K.J.Organomet.Chem.2002,653,46-49)下与芳基或杂芳基卤化物6d(X=Cl、Br、I)偶联,得到化合物6e。使用典型碱金属氢氧化物碱使酯R(R=Me、Et或其他适合的烷基取代基)水解可得到式I-C化合物。
方案7
方案7描述式I-D(式I的子集)化合物的合成,其中:Z=6元芳环或5元至10元杂芳环。
化合物6c(方案6)可在铜催化剂(例如,碘化铜(I)、硫酸铜(II)五水合物)存在下经由“点击”化学与各种芳基或杂芳基叠氮化物7a反应(“ClickChemistry:DiverseChemical Function from a Few Good Reactions”,Kolb,H.C.;Finn,M.G.;Sharpless,K.B.Angew.Chem.Int.Ed.2001,40,2004-2021),产生1H-1,2,3三唑。使用典型碱金属氢氧化物碱使酯R(R=Me、Et或其他适合的烷基取代基)水解可得到式I-D化合物。
方案8
方案8描述式I-E(式I的子集)化合物的合成,其中:Z=6元芳环或5元至10元杂芳环。
可在低温(0℃至-78℃),于醚溶剂(例如,醚、THF、1,4-二噁烷)中使用烷基锂试剂(例如,正丁基锂、叔丁基锂)实现化合物8a的锂-卤素交换。所得芳基锂物质可与醛6a反应,得到中间体8b。可在高温(60℃至100℃)使用典型碱金属氢氧化物碱使腈8b水解,得到式I-E化合物。
方案9
方案9描述式I-F(式I的子集)化合物的合成,其中:Z=6元芳环或5元至10元杂芳环。
本领域普通技术人员可容易地通过酯4b(方案4)的水解来制备酸9a。应用Mai,W.-P.等人所描述的方法(“Cu/Ag-catalyzed double decarboxylative cross-couplingreaction between cinnamic acids and aliphatic acids in aqueous solution”,RSCAdvances,2013,3,19264-19267),酸9a可与反式-芳基(或杂芳基)丙烯酸9b反应,得到化合物9c。可在高温(60℃至100℃)使用典型碱金属氢氧化物碱使腈9c水解,得到式I-F化合物。
方案10
方案10描述式I-G(式I的子集)化合物的合成,其中-C(=O)-N-Z-键可包含仲或叔酰胺。
本领域普通技术人员可在极性非质子溶剂(例如,DCM、THF、DMF)存在下,在使用或不使用催化剂(例如,DMAP、HOBT)的情况下,使用常用酰胺键偶联剂(例如,EDC、PyBOP、CDI)使酸9a与各种伯或仲胺10a反应。使用典型碱金属氢氧化物碱使酯R(R=Me、Et或其他适合的烷基取代基)水解可得到式I-G化合物。
方案11
方案11描述式I-A(式I的子集)化合物的替代合成方法。
可根据WO 2014/159802(Shi,Y.等人)中所描述的操作制备起始物质4-((3,5-二氟苯甲酰基)氧基)双环[2.2.2]辛烷-1-甲酸11a。可根据方案1至10中所描述的方法由酸11a实现L1-Z形成。甲醇钠可用于在酯R(R=Me、Et或其他适合的烷基取代基)存在下使3,5-二氟苯甲酸酯化合物11b选择性裂解,得到化合物11c。本领域普通技术人员可容易使用许多且沿用已久的操作来制备杂芳基甲基卤化物11d(X=Cl、Br、I),代表性实例见于WO2012/087519(Tully,D.C.等人)、WO 2009/012125(Genin,M.J.等人)和WO 2008/051942(Navas,F.等人)中。使用WO 2014/159802(Shi,Y.等人)中所描述的通用操作,醇11c可在三氟甲磺酸银和碱(例如,吡啶、2,6-二甲基吡啶、2,6-二-叔丁基吡啶)存在下经卤化物11d烷基化。使用典型碱金属氢氧化物碱使酯R(R=Me、Et或其他适合的烷基取代基)水解可得到式I-A化合物。
方案12
方案12描述式I-H(式I的子集)化合物的合成。
本领域普通技术人员可遵循WO 2001/034610(Kiesman W.F.等人)中所描述的操作来制备起始物质4-(羟基甲基)双环[2.2.2]辛烷-1-甲酸12a。可根据方案1至10中所描述的方法由酸12a实现L1-Z形成。所得醇12b可通过方案11中所描述的方法与卤化物11d反应,得到式I-H化合物。
方案13
方案13描述式I-I(式I的子集)化合物的合成。
本领域普通技术人员可容易使用许多且沿用已久的操作来制备杂芳基羧酸化合物13a,代表性实例见于WO 2012/087519(Tully,D.C.等人)、WO 2009/012125(Genin,M.J.等人)和WO 2008/051942(Navas,F.等人)中。可根据US 2015/0133428(Velaparthi,U.等人)中所描述的操作制备醛13d。
酸13a可在高温(85℃),在叔丁醇存在下与二苯基磷酰基叠氮化物(DPPA)(“Newconvenient reagent for a modified Curtius reaction and for peptidesynthesis”,Shioiri,T.等人J.Am.Chem.Soc.1972,94,6203-6205)反应,产生氨基甲酸叔丁酯化合物13b。在酸性条件(例如,TFA、HCl)下去除保护基,可得到胺13c。胺13c可在极性质子溶剂(例如,MeOH、EtOH)和还原剂(例如,氰基硼氢化钠、三乙酰氧基硼氢化钠)存在下与醛13d进行还原胺化,其中温度在0℃与80℃之间变化。使用典型碱金属氢氧化物碱使甲酯进行后续水解,可得到酸13e。可根据方案1至10中所描述的方法由酸13e实现L1-Z形成。使用典型碱金属氢氧化物碱使酯R(R=Me、Et或其他适合的烷基取代基)水解可得到式I-I化合物。
方案14
方案14描述式I-J、式I-K和式I-L(式I的子集)化合物的合成。
可通过PCT国际申请2010/127975(Jakob-Roetne,R.等人)中所描述的方法由杂芳基甲基卤化物11d(方案11)制备鏻盐14a。本领域普通技术人员可容易地通过11d在高温(100℃至160℃)与亚磷酸三乙酯反应来制备膦酸酯14b。可在-78℃与60℃之间的温度,于醚溶剂(例如,THF、1,4-二噁烷)中,在碱(例如,双(三甲基硅烷基)氨基锂、KOtBu、氢化钠)存在下用鏻盐14a或膦酸酯14b使醛13d烯化。使用氢氧化物碱使甲酯水解,可得到酸14c。可根据方案1至10中所描述的方法由酸14c实现L1-Z形成,得到化合物14d。使用典型碱金属氢氧化物碱使酯R(R=Me、Et或其他适合的烷基取代基)水解可得到式I-J化合物。本领域普通技术人员可使用常用纯化方法(例如,硅胶快速柱色谱、反相制备型HPLC)将式I-J化合物分离成反式和顺式异构体,分别得到式I-K和式I-L化合物。
方案15
方案15描述式I-M(式I的子集)化合物的合成。
可根据Singh,S.B.等人所描述的方法(ACS Med.Chem.Lett.2014,5,609-614)合成化合物15a。可在醚溶剂(例如,THF、1,4-二噁烷)中用烷基锂试剂(例如,正丁基锂、叔丁基锂)使化合物15b去质子化,其中温度在-78℃与0℃之间变化。所得烷基锂物质可与酮15a反应,形成中间体15c。可在高温(70℃),在典型碱金属氢氧化物碱存在下实现甲苯磺酸酯15c的分子内环化,形成氧代双环[2.2.2]辛烷环化合物15d。本领域普通技术人员可使用任何数目种试剂(例如,NCS、Hg(ClO4)2、DDQ)实现硫缩醛脱保护,得到醛,可通过使用典型氧化剂(亚氯酸钠、PCC或PDC、KMnO4)将该醛氧化成酸。该酸随后可通过与烷基碘(例如,碘甲烷)反应而酯化,得到化合物15e。甲苯磺酸酯15e可在高温(120℃)于极性非质子溶剂(例如,DMF、NMP)中经常用乙酸盐(例如,乙酸铯、乙酸钾)替换,得到化合物15f。乙酸酯15f在酸性条件(HCl)下进行后续水解,接着使用常规氧化条件(例如,PCC或PDC、斯文氧化条件)氧化所得醇,可得到酸15g。酸15g可在10℃与120℃之间变化的温度,在苯甲醇存在下与二苯基磷酰基叠氮化物(DPPA)(“New convenient reagent for a modified Curtius reactionand for peptide synthesis”,Shioiri,T.等人J.Am.Chem.Soc.1972,94,6203-6205)反应,产生苯甲基氨基甲酸酯化合物15h。使用常用碱金属氢氧化物碱使甲酯水解,接着在钯催化剂(钯/碳)存在下使氨基甲酸苯甲酯氢化,可得到胺15i。使用亚硝酸钠使胺重氮化,接着用碱金属氢氧化物碱使重氮物质水解,可得到化合物15j。可根据方案1至10中所描述的方法由酸15j实现L1-Z形成,得到化合物15k。所得醇15k可通过方案11中所描述的方法与卤化物11d反应,得到式I-M化合物。
方案16
方案16描述式I-N和式I-O(式I的子集)化合物的合成。
可通过使用典型碱金属氢氧化物碱使化合物15f(方案15)酯水解而制备化合物16a。可根据方案1至10中所描述的方法由酸16a实现L1-Z形成。醇16b可使用方案11中所描述的方法与卤化物11d反应,得到式I-N化合物。替代地,可使用方案6中所描述的方法将化合物16b氧化成醛16c。醛16b可使用方案14中所描述的方法与14a或14b反应,得到式I-O化合物。本领域普通技术人员可使用常用纯化方法(例如,硅胶快速柱色谱、反相制备型HPLC)将式I-O化合物分离成反式和顺式异构体。
方案17
方案17描述化合物16a的替代合成,其中:L1=共价键。Z=6元至10元芳环。
本领域普通技术人员可使用许多已知且沿用已久的方法将芳基卤化物17a(X=Cl、Br、I)转化成格林纳试剂(Grignard reagent)(“The Grignard reagent:Preparation,structure,and some reactions”,Orchin,M.J.Chem.Educ.,1989,66,586)。所得格林纳试剂可在-78℃至25℃之间的温度,于醚溶剂(例如,醚、THF、1,4-二噁烷)中与酮15a反应,得到17b。中间体17b可在高温(70℃)在典型碱金属氢氧化物碱存在下环化,且随后经烷基碘(例如,碘甲烷、碘乙烷)重新酯化,形成氧代双环[2.2.2]辛烷环化合物17c。甲苯磺酸酯17c可在高温(120℃),于极性非质子溶剂(例如,DMF、NMP)中经常用的乙酸盐(例如,乙酸铯、乙酸钾)替换。可用甲醇钠使所得乙酸酯水解,得到醇16a。可使用方案16中所描述的方法将16a转化成式I-N和式I-O化合物。
方案18
方案18描述式I-P(式I的子集)化合物的合成,其中:B=双环[1.1.1]戊烷或1,4-经取代立方烷。
可通过甲酯前体的水解制备酸18a。这些甲酯前体是可商购的,或可通过本领域普通技术人员使用已知方法获得:3-(羟基甲基)双环[1.1.1]戊烷-1-甲酸甲酯(Goh,Y.L.等人ACS Med.Chem.Lett.2017,8,516-520);或(1r,2R,3R,4s,5s,6S,7S,8r)-4-(羟基甲基)立方烷-1-甲酸甲酯(Curry,K.等人WO 99/54280)。可根据方案1至10中所描述的方法由酸18a实现L1-Z形成。所得醇18b可通过方案11中所描述的方法与卤化物11d反应,得到式I-P化合物。
实施例
提供以下实施例作为说明,作为本发明的部分范围和特定实施方案,且不欲限制本发明的范围。除非另外指示,否则缩写和化学符号具有其常见和惯用含义。除非另外指示,否则本文所述化合物已使用本文公开的方案和其他方法制备、分离和表征或可使用其制备。
视需要,反应在干燥氮气(或氩气)的氛围下进行。对于无水反应,使用来自EM的溶剂。对于其他反应,利用试剂级或HPLC级溶剂。除非另外说明,否则所有商购试剂按原样使用。
NMR(核磁共振)谱通常在指定溶剂中在Bruker或JEOL 400MHz和500MHz仪器上获得。用溶剂共振作为内标,四甲基硅烷的所有化学位移以ppm为单位报道。1HNMR光谱数据通常报道如下:化学位移、多重性(s=单峰,br s=宽单峰,d=二重峰,dd=双二重峰,t=三重峰,q=四重峰,sep=七重峰,m=多重峰,app=明显)、偶合常数(Hz)和积分。
实施例
提供以下实施例作为说明,作为本发明的部分范围和特定实施方案,且不欲限制本发明的范围。除非另外指示,否则缩写和化学符号具有其常见和惯用含义。除非另外指示,否则本文所述化合物已使用本文公开的方案和其他方法制备、分离和表征或可使用其制备。
视需要,反应在干燥氮气(或氩气)的氛围下进行。对于无水反应,使用来自EM的溶剂。对于其他反应,利用试剂级或HPLC级溶剂。除非另外说明,否则所有商购试剂按原样使用。
NMR(核磁共振)谱通常在指定溶剂中在Bruker或JEOL 400MHz和500MHz仪器上获得。用溶剂共振作为内标,四甲基硅烷的所有化学位移以ppm为单位报道。1HNMR光谱数据通常报道如下:化学位移、多重性(s=单峰,br s=宽单峰,d=二重峰,dd=双二重峰,t=三重峰,q=四重峰,sep=七重峰,m=多重峰,app=明显)、偶合常数(Hz)和积分。
实施例1
3-(5-(4-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸
步骤A.中间体1A.3,5-二氟苯甲酸4-(3-(3-(甲氧基羰基)苯基)-1,2,4-噁二唑-5-基)双环[2.2.2]辛-1-基酯的制备
向25mL梨形烧瓶中添加4-((3,5-二氟苯甲酰基)氧基)双环[2.2.2]辛烷-1-甲酸(0.20g,0.65mmol)(Shi,Y.等人WO 2014/159802)和DCM(2mL)。向该混合物中一次性添加CDI(0.16g,0.97mmol),此时观察到气体逸出。搅拌反应物1h,随后添加(Z)-3-(N'-羟基甲脒基)苯甲酸甲酯(0.23g,1.2mmol)(Tung,R.D.WO 2016/073545)。在N2下搅拌18h之后,浓缩溶剂,将残余物溶解于甲苯(5mL)中且在回流下搅拌反应物。3h后,使混合物冷却,浓缩溶剂且将残余物溶解于EtOAc(50mL)中。将有机相用盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过快速柱色谱(24g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至20%B;流速=24mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈淡黄色油状物的标题化合物(0.29g,0.62mmol,96%产率)。1H NMR(400MHz,氯仿-d)δ8.75(t,J=1.5Hz,1H),8.28(d,J=7.7Hz,1H),8.20(d,J=8.1Hz,1H),7.59(t,J=7.8Hz,1H),7.55-7.48(m,2H),7.07-6.98(m,1H),3.99(s,3H),2.33(s,14H)。MS(ESI)469(M+H)。
步骤B.中间体1B.3-(5-(4-羟基双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸甲酯的制备
向250mL圆底烧瓶中添加中间体1A(0.29g,0.62mmol)、MeOH(6mL)、THF(12mL)和甲醇钠(0.25mL,1.2mmol)(5N于MeOH中)。在N2下搅拌1h后,将反应物用5%柠檬酸(水溶液)淬灭,进一步用水(50mL)稀释且用EtOAc(2×25mL)萃取。将有机相合并,用盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过快速柱色谱(24g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=24mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈无色油状物的标题化合物(0.16g,0.47mmol,76%产率)。1H NMR(400MHz,氯仿-d)δ8.74(t,J=1.4Hz,1H),8.27(d,J=7.9Hz,1H),8.19(d,J=7.9Hz,1H),7.63-7.54(m,1H),3.98(s,3H),2.28-2.20(m,6H),1.88-1.80(m,6H)。MS(ESI)329(M+H)。
步骤C.中间体1C.3-(5-(4-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸甲酯的制备
向50mL圆底烧瓶中添加中间体1B(0.050g,0.15mmol)、三氟甲烷磺酸银(0.24g,0.91mmol)、2,6-二-叔丁基吡啶(0.20mL,0.91mmol)和DCM(2mL)。将混合物冷却至0℃,且添加4-(溴甲基)-5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑(0.083g,0.23mmol)。在N2下搅拌18h后,过滤混合物,且通过快速柱色谱(24g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=24mL/min)纯化所得滤液。将纯级分合并、浓缩且在真空中干燥,得到呈无色油状物的标题化合物(0.029g,0.048mmol,31%产率)。1H NMR(400MHz,甲醇-d4)δ8.66(s,1H),8.27-8.23(m,1H),8.19-8.14(m,1H),7.63-7.56(m,3H),7.50-7.42(m,2H),4.30-4.28(m,2H),3.96(s,3H),3.35-3.31(m,1H),2.19-2.12(m,6H),1.78-1.71(m,6H),1.22-1.12(m,4H)。MS(ESI)610(M+H)。
步骤D.实施例1
向20mL梨形烧瓶中添加中间体1C(0.020g,0.033mmol)、MeOH(1mL)和1M NaOH(水溶液)(0.33mL,0.33mmol)。搅拌18h后,将混合物用1M HCl(水溶液)(20mL)稀释且用EtOAc(2×10mL)萃取。将有机相合并,用盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过制备型HPLC(柱:XBridge C18,19×200mm,5μm颗粒;流动相A:5:95的乙腈:水/10mM乙酸铵;流动相B:95:5的乙腈:水/10mM乙酸铵;梯度:25-100%B经15分钟,接着在100%B下保持5分钟;流速:20mL/min)纯化粗产物。将含有期望产物的级分合并、浓缩且在真空中干燥,得到标题化合物(0.017g,0.029mmol,88%产率)。1H NMR(500MHz,DMSO-d6)δ8.64-8.40(m,1H),8.20-8.03(m,2H),7.71-7.63(m,2H),7.63-7.58(m,1H),7.58-7.48(m,2H),4.20(s,2H),2.31-2.22(m,1H),2.10-1.99(m,6H),1.64(br d,J=7.3Hz,6H),1.20-1.09(m,4H)。FXR EC50(nM)=110。MS(ESI)596(M+H)。
实施例2
4-(5-(4-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸
步骤A.中间体2A.3,5-二氟苯甲酸4-(3-(4-(甲氧基羰基)苯基)-1,2,4-噁二唑-5-基)双环[2.2.2]辛-1-基酯的制备
根据针对中间体1A的合成所描述的方法,适当时代入(Z)-4-(N'-羟基甲脒基)苯甲酸甲酯(Tale,R.H.等人J.Chem.Pharm.Res.,2011,3,496-505)来制备标题化合物:(0.33g,0.70mmol,87%产率,白色固体)。1H NMR(400MHz,氯仿-d)δ8.20-8.13(m,4H),7.56-7.47(m,2H),7.07-6.97(m,1H),3.98(s,3H),2.32(br d,J=1.3Hz,12H)。MS(ESI)469(M+H)。
步骤B.中间体2B.4-(5-(4-羟基双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸甲酯的制备
根据针对中间体1B的合成所描述的方法,适当时代入中间体2A来制备标题化合物:(0.19g,0.58mmol,82%产率,灰白色固体)。1H NMR(500MHz,二氯甲烷-d2)δ8.17(d,J=0.8Hz,4H),3.97(s,3H),2.29-2.18(m,6H),1.89-1.78(m,6H)。MS(ESI)329(M+H)。
步骤C.中间体2C.4-(5-(4-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸甲酯的制备
根据针对中间体1C的合成所描述的方法,适当时代入中间体2B来制备标题化合物:(0.027g,0.044mmol,31%产率,淡黄色油状物)。1H NMR(500MHz,DMSO-d6)δ8.17-8.07(m,4H),7.71-7.65(m,1H),7.65-7.61(m,1H),7.60-7.54(m,2H),4.21(s,2H),3.89(s,3H),2.33-2.24(m,1H),2.05(br s,6H),1.65(br d,J=7.6Hz,6H),1.17-1.11(m,2H),1.10-1.03(m,2H)。MS(ESI)610(M+H)。
步骤D.实施例2
根据针对实施例1的合成(步骤D)所描述的方法,适当时代入中间体2C来制备标题化合物:(17mg,0.028mmol,80%产率)。1H NMR(500MHz,DMSO-d6)δ8.07(br s,4H),7.71-7.66(m,1H),7.65-7.61(m,1H),7.60-7.52(m,2H),4.21(s,2H),2.32-2.24(m,1H),2.06(brs,6H),1.71-1.58(m,6H),1.22-1.03(m,5H)。FXR EC50(nM)=170。MS(ESI)596(M+H)。
实施例3
4-(5-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-N-(甲基磺酰基)苯甲酰胺
向20mL闪烁瓶中添加实施例28(0.017g,0.029mmol)、甲磺酰胺(5.6mg,0.059mmol)、DMAP(7.2mg,0.059mmol)和DMF(1mL)。向该混合物中添加EDC(0.011g,0.059mmol)并搅拌反应物。2h后,过滤反应物,且通过制备型HPLC(柱:waters Xbridge c-18,19×200mm,5μm颗粒;流动相A:5:95的乙腈:水+0.1%三氟乙酸;流动相B:95:5的乙腈:水+0.1%三氟乙酸;梯度:45-90%B经20分钟,接着在100%B下保持5分钟;流速:20mL/min)纯化粗产物。将含有期望产物的级分合并、浓缩且在真空中干燥,得到标题化合物(0.0095g,0.014mmol,49%产率)。1H NMR(500MHz,DMSO-d6)δ8.11-8.06(m,2H),8.05-8.00(m,2H),7.65-7.60(m,2H),7.59-7.53(m,1H),4.19(s,2H),3.19(s,3H),2.32-2.25(m,1H),2.01(br d,J=8.2Hz,6H),1.59-1.48(m,6H),1.19-1.12(m,2H),1.11-1.05(m,2H)。FXREC50(nM)=890。MS(ESI)596(M+H)。
实施例4
5-(5-(4-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-2-甲氧基苯甲酸
步骤A.中间体4A.4-碘双环[2.2.2]辛烷-1-甲酸甲酯的制备
向500mL梨形烧瓶中添加4-(甲氧基羰基)双环[2.2.2]辛烷-1-甲酸(1.0g,4.7mmol)、氯苯(200mL)、四乙酸铅(2.7g,6.1mmol),接着添加碘(2.6g,10mmol)。在N2下在80℃搅拌反应物,且用蓝色LED(Kessil)照射。在2.5h之后,将反应物冷却、过滤,且用DCM洗涤滤饼。浓缩经合并的滤液,且通过快速柱色谱(120g硅胶滤筒;A=己烷,B=EtOAc;30min梯度;0%B至10%B;流速=80mL/min)纯化粗产物(产物具有UV活性;TLC Rf=0.5;4:1的己烷:EtOAc)。将纯级分合并、浓缩且在真空中干燥,得到呈白色固体状的标题化合物(1.3g,4.4mmol,92%产率)。1H NMR(400MHz,氯仿-d)δ3.65(s,3H),2.61-2.31(m,6H),2.04-1.84(m,6H)。
步骤B.中间体4B.4-碘双环[2.2.2]辛烷-1-甲酸的制备
向100mL梨形烧瓶中添加中间体4A(1.3g,4.4mmol)、1M NaOH(水溶液)(31mL,31mmol)和THF(30mL)。搅拌18h后,将反应物用5%柠檬酸(水溶液)(150mL)稀释且用EtOAc(2×75mL)萃取。将有机相合并,用盐水洗涤,经Na2SO4干燥,过滤且浓缩。将产物在真空中干燥,得到呈白色固体状的标题化合物(1.2g,4.28mmol,98%产率)。1H NMR(500MHz,甲醇-d4)δ2.57-2.34(m,6H),2.10-1.86(m,6H)。
步骤C.中间体4C.(Z)-5-(N'-羟基甲脒基)-2-甲氧基苯甲酸甲酯的制备
向100mL梨形烧瓶中添加5-氰基-2-甲氧基苯甲酸甲酯(0.23g,1.2mmol)、羟胺盐酸盐(0.42g,6.0mmol)、MeOH(12mL)和TEA(0.84mL,6.0mmol)。搅拌18h后,浓缩溶剂且将残余物溶解于EtOAc(150mL)中。将有机相用盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过快速柱色谱(80g硅胶滤筒;A=己烷,B=EtOAc;25min梯度;0%B至100%B;流速=60mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈白色固体状的标题化合物(0.252g,1.124mmol,93%产率)。1H NMR(400MHz,DMSO-d6)δ9.55(s,1H),7.98(d,J=2.2Hz,1H),7.87-7.78(m,1H),7.16(d,J=8.8Hz,1H),5.82(s,2H),3.85(s,3H),3.80(s,3H)。MS(ESI)225(M+H)。
步骤D.中间体4D.5-(5-(4-碘双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-2-甲氧基苯甲酸甲酯的制备
步骤1:向100mL梨形烧瓶中添加中间体4B(0.21g,0.75mmol)和DCM(3mL)。向该混合物中一次性添加CDI(0.18g,1.1mmol),此时观察到气体逸出。搅拌15min后,添加中间体4C(0.25g,1.1mmol),且在N2下搅拌反应物18h。
步骤2:浓缩溶剂且将残余物溶解于甲苯(5mL)中,并且在回流下搅拌。5h后,使反应物冷却并浓缩溶剂。将残余物溶解于EtOAc(50mL)中,用盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过快速柱色谱(24g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至20%B;流速=24mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈白色固体状的标题化合物(0.30g,0.64mmol,85%产率)。1H NMR(500MHz,氯仿-d)δ8.64-8.47(m,1H),8.35-8.14(m,1H),7.44-7.23(m,1H),7.21-7.01(m,1H),3.99(s,3H),3.94(s,3H),2.79-2.57(m,6H),2.36-2.16(m,6H)。MS(ESI)469(M+H)。
步骤E.实施例4
步骤1.向装备有压力释放盖的20mL闪烁瓶中添加中间体4D(0.05g,0.11mmol)、(5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲醇(0.096g,0.32mmol)、三氟甲烷磺酸银(0.22g,0.85mmol)和2,6-二-叔丁基吡啶(0.48mL,2.1mmol)。用氮气冲洗容器,加盖,且在80℃搅拌18h。将反应物冷却,用DCM:MeOH(1:1;4mL)稀释,滤出固体且浓缩滤液。将残余物经由SiO2塞过滤,首先用己烷接着用EtOAc洗脱,收集粗产物。浓缩滤液且残余物用于下一步骤。
步骤2:将上文步骤1的产物溶解于1M NaOH(水溶液)(10mL)和THF(10mL)中,且在45℃搅拌。1h后,将反应物冷却,用5%柠檬酸(水溶液)(50mL)稀释且用EtOAc(2×25mL)萃取。将有机相合并,用盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过制备型HPLC(柱:XBridgeC18,19×200mm,5μm颗粒;流动相A:5:95的乙腈:水+0.1%三氟乙酸;流动相B:95:5的乙腈:水+0.1%三氟乙酸;梯度:57-82%B经20分钟,接着在100%B下保持2分钟;流速:20mL/min)纯化粗产物。将含有期望产物的级分合并、浓缩且在真空中干燥,得到标题化合物(13mg,0.021mmol,19%产率)。1H NMR(500MHz,DMSO-d6)δ8.21(s,1H),8.10-8.04(m,1H),7.71-7.65(m,1H),7.61(s,1H),7.56(br s,2H),7.29(d,J=8.9Hz,1H),4.21(s,2H),3.89(s,3H),2.31-2.23(m,1H),2.07-2.00(m,6H),1.68-1.59(m,6H),1.17-1.10(m,2H),1.10-1.03(m,2H)。FXR EC50(nM)=110。MS(ESI)626(M+H)。
实施例6
2-(4-((5-环丙基-3-(2-(三氟甲基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)苯并[d]噻唑-6-甲酸
步骤A.中间体6A.3,5-二氟苯甲酸4-(6-氰基苯并[d]噻唑-2-基)双环[2.2.2]辛-1-基酯的制备
向装备有压力释放盖的20mL闪烁瓶中添加4-((3,5-二氟苯甲酰基)氧基)双环[2.2.2]辛烷-1-甲酸(0.3g,0.97mmol)、4-氨基-3-巯基苯甲腈(0.17g,1.2mmol)(通常参见Chedekel,M.R.等人Synth.Commun.1980,10,167-173;各种2-氨基苯硫酚的合成)、吡啶(0.24mL,2.9mmol)和DCE(4mL)。向该混合物中添加T3P(1.4mL,2.4mmol)(于EtOAc中的50%w/v溶液),且将小瓶加盖并在80℃搅拌均质溶液。18h后,观察到淡黄色析出物。使反应物冷却,浓缩溶剂,且通过快速柱色谱(40g硅胶滤筒;A=己烷,B=EtOAc;20min梯度;0%B至100%B;流速=24mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈淡黄色固体状的标题化合物(0.39g,0.92mmol,95%产率)。1H NMR(400MHz,氯仿-d)δ8.26-8.19(m,1H),8.08-8.03(m,1H),7.77-7.70(m,1H),7.56-7.47(m,2H),7.06-6.99(m,1H),2.40-2.27(m,12H)。MS(ESI)425(M+H)。
步骤B.中间体6B.2-(4-羟基双环[2.2.2]辛-1-基)苯并[d]噻唑-6-甲腈的制备
向100mL梨形烧瓶中添加中间体6A(0.39g,0.92mmol)、THF(9mL)和MeOH(9mL)。向该混合物中添加甲醇钠(0.37mL,1.8mmol)(于THF中的5N溶液)并搅拌反应物。1h后,将反应物用水(50mL)稀释,用5%柠檬酸(水溶液)酸化且用EtOAc(2×25mL)萃取。将有机相合并,用盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过快速柱色谱(40g硅胶滤筒;A=己烷,B=EtOAc;20min梯度;0%B至60%B;流速=40mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈淡黄色固体状的标题化合物(0.35g,0.92mmol,75%产率)。1H NMR(500MHz,甲醇-d4)δ8.44(d,J=1.1Hz,1H),8.06(d,J=8.3Hz,1H),7.80(dd,J=8.4,1.5Hz,1H),2.28-2.18(m,6H),1.87-1.83(m,6H)。MS(ESI)285(M+H)。
步骤C.实施例6
步骤1.向50mL小瓶中添加中间体6B(0.11g,0.30mmol)、三氟甲烷磺酸银(0.46g,1.8mmol)、2,6-二-叔丁基吡啶(0.39mL,1.8mmol)和THF(6mL)。用N2冲洗容器且使其冷却至0℃。向该混合物中添加4-(溴甲基)-5-环丙基-3-(2-(三氟甲基)苯基)异噁唑(0.16g,0.45mmol),再次用N2冲洗容器,且在rt搅拌混合物。48h后,过滤反应物且浓缩滤液。通过快速柱色谱(40g硅胶滤筒;A=己烷,B=EtOAc;25min梯度;0%B至100%B;流速=40mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥。该物质不经表征即用于下一步骤。
步骤2:将上文步骤1的产物溶解于MeOH(5mL)、THF(5mL)和1M NaOH(水溶液)(5mL)中。在90℃搅拌18h后,将反应物冷却,用5%柠檬酸(水溶液)(50mL)稀释且用EtOAc(2×25mL)萃取。将有机相合并,用盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过制备型HPLC(柱:XBridge C18,19×200mm,5μm颗粒;流动相A:5:95的乙腈:水+0.1%三氟乙酸;流动相B:95:5的乙腈:水+0.1%三氟乙酸;梯度:40-80%B经24分钟,接着在100%B下保持5分钟;流速:20mL/min)纯化粗产物。将含有期望产物的级分合并、浓缩且在真空中干燥,得到标题化合物(2.4mg,4.1μmol,1%产率)。1H NMR(500MHz,DMSO-d6)δ8.65(s,1H),8.00(s,1H),7.98-7.94(m,1H),7.92(d,J=7.6Hz,1H),7.82(br d,J=7.3Hz,1H),7.77(br d,J=7.6Hz,1H),7.57(d,J=7.3Hz,1H),4.14(s,2H),2.31-2.24(m,1H),2.07-1.96(m,6H),1.59(br s,6H),1.16-1.11(m,2H),1.10-1.04(m,2H)。FXR EC50(nM)=4200。MS(ESI)569(M+H)。
实施例7
(E)-3-(2-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)苯甲酸
步骤A.中间体7A.3,5-二氟苯甲酸(E)-4-(3-氰基苯乙烯基)双环[2.2.2]辛-1-基酯的制备
向25mL梨形烧瓶中添加4-((3,5-二氟苯甲酰基)氧基)双环[2.2.2]辛烷-1-甲酸(0.27g,0.87mmol)、(E)-3-(3-氰基苯基)丙烯酸(0.10g,0.58mmol)、铜粉(1.8mg,0.029mmol)、硝酸银(0.020g,0.12mmol)、过硫酸钾(0.16g,0.56mmol)、乙腈(2mL)和水(2mL)。为反应烧瓶装备回流冷凝器,且在90℃搅拌混合物,打开盖子且与空气相通。18h后,将反应物冷却,用水(50mL)稀释且用EtOAc(2×25mL)萃取。将有机相合并,用盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过快速柱色谱(40g硅胶滤筒;A=己烷,B=EtOAc;30min梯度;0%B至50%B;流速=40mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈淡黄色油状物的标题化合物(98mg,0.25mmol,43%产率)。1H NMR(400MHz,氯仿-d)δ7.66-7.62(m,1H),7.59-7.54(m,1H),7.54-7.47(m,3H),7.45-7.38(m,1H),7.04-6.97(m,1H),6.31-6.17(m,2H),2.28-2.18(m,6H),1.90-1.82(m,6H)。MS(ESI)394(M+H)。
步骤B.中间体7B.(E)-3-(2-(4-羟基双环[2.2.2]辛-1-基)乙烯基)苯甲腈的制备
向250mL圆底烧瓶中添加中间体7A(0.36g,0.92mmol)、MeOH(10mL)、THF(10mL)和甲醇钠(0.37mL,1.8mmol)(5M于MeOH中)。在N2下搅拌反应物。1h后,将反应物用5%柠檬酸(水溶液)淬灭,用水(50mL)稀释且用EtOAc(2×25mL)萃取。将有机相合并,用盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过快速柱色谱(24g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=24mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈灰白色固体状的标题化合物(0.21g,0.83mmol,91%产率)。1H NMR(500MHz,氯仿-d)δ7.65-7.61(m,1H),7.59-7.54(m,1H),7.52-7.47(m,1H),7.44-7.37(m,1H),6.30-6.16(m,2H)。MS(ESI)254(M+H)。
步骤C.实施例7
根据针对实施例6的合成(步骤C)所描述的方法,通过使中间体7B与4-(溴甲基)-5-环丙基-3-(2,6-二氯苯基)异噁唑反应来制备标题化合物:(2.4mg,4.5μmol,2%产率)。1H NMR(500MHz,DMSO-d6)δ8.02-7.94(m,1H),7.87-7.81(m,1H),7.69-7.65(m,1H),7.64-7.59(m,1H),7.58-7.53(m,1H),7.50-7.43(m,1H),7.38-7.29(m,1H),6.26-6.18(m,2H),4.14(s,2H),2.27(br s,1H),1.63-1.52(m,6H),1.44-1.34(m,6H),1.13(br d,J=8.2Hz,2H),1.06(br d,J=2.7Hz,2H)。FXR EC50(nM)=150。MS(ESI)539(M+H)。
实施例8
(E)-4-(((4-(3-(1H-四唑-5-基)苯乙烯基)双环[2.2.2]辛-1-基)氧基)甲基)-5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑
步骤A.中间体8A.(E)-3-(2-(4-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)苯甲腈的制备
向100mL圆底烧瓶中添加中间体7B(0.15g,0.59mmol)、三氟甲烷磺酸银(0.91g,3.6mmol)、2,6-二-叔丁基吡啶(0.78mL,3.6mmol)和DCM(8mL)。用N2冲洗混合物且使其冷却至0℃。向该混合物中添加4-(溴甲基)-5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑(0.32g,0.89mmol),且再次用N2冲洗容器并搅拌。18h后,将混合物用DCM:MeOH(4mL;1:1)稀释,过滤,且浓缩滤液。通过快速柱色谱(24g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至50%B;流速=24mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈无色残余物的标题化合物(0.060g,0.11mmol,19%产率)。1H NMR(400MHz,氯仿-d)δ7.54-7.48(m,2H),7.47-7.35(m,3H),7.34-7.21(m,3H),6.09(d,J=3.7Hz,2H),4.18(s,2H),2.12-2.00(m,1H),1.59(br d,J=5.3Hz,12H),1.17-1.11(m,2H),1.04-0.97(m,2H)。MS(ESI)535(M+H)。
步骤B.实施例8
向装备有压力释放盖的20mL闪烁瓶中添加中间体8A(0.060g,0.11mmol)、甲苯(5mL)、氧化(二丁基)锡(0.028g,0.11mmol)和叠氮基三甲基硅烷(0.13g,1.1mmol)。将容器加盖且在100℃搅拌。18h后,将反应物冷却,用EtOAc(50mL)稀释,且用溶解于水(50mL)中的硝酸铈铵(0.68g,1.2mmol)缓慢淬灭。搅拌混合物10min,分离各层且用EtOAc(20mL)萃取水相。将有机相合并,用盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过制备型HPLC(柱:XBridgeC18,19×200mm,5μm颗粒;流动相A:5:95的乙腈:水+0.1%三氟乙酸;流动相B:95:5的乙腈:水+0.1%三氟乙酸;梯度:60-85%B经25分钟,接着在85%B下保持2分钟;流速:20mL/min)纯化粗产物。将含有期望产物的级分合并、浓缩且在真空中干燥,得到标题化合物(4.7mg,8.0μmol,7%产率)。1H NMR(500MHz,DMSO-d6)δ8.07-7.97(m,1H),7.87-7.79(m,1H),7.70-7.64(m,1H),7.64-7.58(m,1H),7.58-7.48(m,4H),6.38-6.21(m,2H),2.30-2.20(m,1H),1.63(br d,J=8.8Hz,6H),1.54(br d,J=8.0Hz,5H),1.18-1.10(m,2H),1.09-1.02(m,2H)。FXR EC50(nM)=380。MS(ESI)578(M+H)。
实施例9
6-(5-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)吡啶-3-甲酸
步骤A.中间体9A.6-(5-(4-碘双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)吡啶-3-甲酸甲酯的制备
根据针对中间体4D的合成所描述的方法,以中间体4B开始且适当时代入(Z)-6-(N'-羟基甲脒基)吡啶-3-甲酸甲酯(Ho,J.Z.等人WO 2001/079261)来制备标题化合物:(0.085g,0.19mmol,19%产率,无色油状物)。1H NMR(500MHz,氯仿-d)δ9.38(s,1H),8.47(dd,J=8.3,1.9Hz,1H),8.22(d,J=8.3Hz,1H),4.02(s,3H),2.69-2.55(m,6H),2.28-2.20(m,6H)。MS(ESI)440(M+H)。
步骤B.实施例9
根据针对实施例4的合成(步骤E)所描述的方法,通过使中间体9A与(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲醇反应来制备标题化合物:(12mg,0.020mmol,22%产率)。1HNMR(500MHz,DMSO-d6)δ9.27-9.05(m,1H),8.50-8.32(m,1H),8.18-7.98(m,1H),7.67-7.60(m,2H),7.60-7.54(m,1H),4.21-4.14(m,2H),2.34-2.26(m,1H),2.05-1.96(m,6H),1.54-1.45(m,6H),1.19-1.12(m,2H),1.11-1.04(m,2H)。FXR EC50(nM)=950。MS(ESI)582(M+H)。
实施例10
2-(5-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)吡啶-4-甲酸
步骤A.中间体10A.(Z)-2-(N'-羟基甲脒基)吡啶-4-甲酸甲酯的制备
根据针对中间体4C的合成所描述的方法,使用2-氰基吡啶-4-甲酸甲酯作为起始物质来制备标题化合物:(0.51g,2.6mmol,85%产率,白色固体)。1H NMR(500MHz,甲醇-d4)δ11.06-11.06(m,1H),8.75(d,J=5.2Hz,1H),8.50-8.35(m,1H),7.95-7.80(m,1H),3.98(s,3H)。MS(ESI)196(M+H)。
步骤B.中间体10B.2-(5-(4-((3,5-二氟苯甲酰基)氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)吡啶-4-甲酸甲酯的制备
根据针对中间体1A的合成所描述的方法,适当时代入中间体10A来制备标题化合物:(0.14g,0.30mmol,31%产率,白色固体)。1H NMR(500MHz,THF)δ7.07(d,J=5.0Hz,1H),6.71(s,1H),6.14(dd,J=5.0,1.7Hz,1H),5.75-5.65(m,2H),5.49-5.37(m,1H),2.14(s,3H),0.57-0.46(m,12H)。MS(ESI)470(M+H)。
步骤C.中间体10C.2-(5-(4-羟基双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)吡啶-4-甲酸甲酯的制备
根据针对中间体1B的合成所描述的方法制备标题化合物:(0.097g,0.30mmol,99%产率,无色油状物)。1H NMR(500MHz,甲醇-d4)δ8.93-8.87(m,1H),8.65-8.57(m,1H),8.13-8.05(m,1H),2.95(s,3H),2.29-2.19(m,6H),1.88-1.78(m,6H)。MS(ESI)330(M+H)。
步骤D.实施例10
根据针对实施例1的合成(步骤C和D)所描述的方法,通过使中间体10C与4-(溴甲基)-5-环丙基-3-(2,6-二氯苯基)异噁唑反应来制备标题化合物:(0.026g,0.045mmol,15%产率)。1H NMR(500MHz,DMSO-d6)δ8.85-8.77(m,1H),8.40-8.32(m,1H),7.97-7.88(m,1H),7.66-7.60(m,2H),7.60-7.52(m,1H),4.22-4.12(m,2H),2.35-2.23(m,1H),2.04-1.95(m,6H),1.56-1.42(m,6H),1.15(br s,2H),1.10-1.03(m,2H)。FXR EC50(nM)=2700。MS(ESI)582(M+H)。
实施例11
5-(5-(4-((5-环丙基-3-(2-(三氟甲基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)吡啶-3-甲酸
步骤A.中间体11A.(Z)-5-(N'-羟基甲脒基)吡啶-3-甲酸甲酯的制备
根据针对中间体4C的合成所描述的方法,使用5-氰基吡啶-3-甲酸甲酯作为起始物质来制备标题化合物:(1.2g,6.1mmol,98%产率,白色固体)。1H NMR(400MHz,DMSO-d6)δ10.06-9.92(m,1H),9.15-9.00(m,2H),8.61-8.43(m,1H),6.19-6.02(m,2H),3.92(s,3H)。MS(ESI)196(M+H)。
步骤B.中间体11B.5-(5-(4-碘双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)吡啶-3-甲酸甲酯的制备
根据针对中间体4D的合成所描述的方法,以中间体4B开始且适当时代入中间体11A来制备标题化合物:(0.59g,1.3mmol,94%产率,白色固体)。1H NMR(500MHz,二氯甲烷-d2)δ9.43(d,J=1.9Hz,1H),9.32(d,J=1.9Hz,1H),8.90(t,J=2.1Hz,1H),4.01(s,3H),2.68-2.58(m,6H),2.30-2.19(m,6H)。MS(ESI)330(M+H)。
步骤C.实施例11
根据针对实施例4的合成(步骤E)所描述的方法,通过使中间体11B与(5-环丙基-3-(2-(三氟甲基)苯基)异噁唑-4-基)甲醇反应来制备标题化合物:(49mg,0.083mmol,73%产率)。1H NMR(500MHz,DMSO-d6)δ9.33-9.27(m,1H),9.26-9.18(m,1H),8.73-8.63(m,1H),7.95-7.89(m,1H),7.86-7.81(m,1H),7.79-7.73(m,1H),7.60-7.51(m,1H),4.13(s,2H),2.32-2.24(m,1H),2.07-1.97(m,6H),1.62-1.51(m,6H),1.17-1.11(m,2H),1.09-1.03(m,2H)。FXR EC50(nM)=2900。MS(ESI)581(M+H)。
实施例12
5-(5-(4-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)吡啶-2-甲酸
步骤A.中间体12A.5-(5-(4-碘双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)吡啶-2-甲酸甲酯的制备
根据针对中间体4D的合成所描述的方法,以中间体4B开始且适当时代入(Z)-5-(N'-羟基甲脒基)吡啶-2-甲酸甲酯(Quattropani,A.等人WO 2010/100142)来制备标题化合物:(0.43g,0.98mmol,69%产率,白色固体)。1H NMR(500MHz,二氯甲烷-d2)δ9.37(d,J=1.4Hz,1H),8.54-8.46(m,1H),8.28-8.20(m,1H),4.03(s,3H),2.69-2.60(m,6H),2.29-2.20(m,6H)。MS(ESI)330(M+H)。
步骤B.实施例12
根据针对实施例4的合成(步骤E)所描述的方法,通过使中间体12A与(5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲醇反应来制备标题化合物:(15mg,0.024mmol,21%产率)。1H NMR(500MHz,DMSO-d6)δ9.16(br s,1H),8.42(br d,J=7.6Hz,1H),8.20-8.08(m,1H),7.71-7.65(m,1H),7.64-7.60(m,1H),7.59-7.50(m,2H),4.21(s,2H),2.29-2.23(m,1H),2.09-2.01(m,6H),1.69-1.59(m,6H),1.18-1.11(m,2H),1.06(br d,J=2.7Hz,2H)。FXR EC50(nM)=1200。MS(ESI)597(M+H)。
实施例13
6-(5-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)吡啶-2-甲酸
步骤A.中间体13A.(Z)-6-(N'-羟基甲脒基)吡啶-2-甲酸甲酯的制备
根据针对中间体4C的合成所描述的方法,使用6-氰基吡啶-2-甲酸甲酯作为起始物质来制备标题化合物:(1.1g,5.5mmol,89%产率,白色固体)。1H NMR(500MHz,DMSO-d6)δ10.16-10.09(m,1H),8.12-8.06(m,2H),8.05-7.97(m,1H),5.93-5.78(m,2H),3.92(s,3H)。MS(ESI)196(M+H)。
步骤B.中间体13B.6-(5-(4-碘双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)吡啶-2-甲酸甲酯的制备
根据针对中间体4D的合成所描述的方法,以中间体4B开始且适当时代入中间体13A来制备标题化合物:(0.23g,0.52mmol,54%产率,白色固体)。1H NMR(500MHz,二氯甲烷-d2)δ8.32-8.23(m,2H),8.07-8.01(m,1H),4.05(s,3H),2.70-2.60(m,6H),2.32-2.24(m,6H)。MS(ESI)330(M+H)。
步骤C.实施例13
根据针对实施例4的合成(步骤E)所描述的方法,通过使中间体13B与(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲醇反应来制备标题化合物:(17mg,0.029mmol,32%产率)。1H NMR(500MHz,DMSO-d6)δ8.16-7.99(m,3H),7.66-7.55(m,3H),4.24-4.14(m,2H),2.32-2.22(m,1H),2.03(br s,6H),1.52(br s,6H),1.19-1.12(m,2H),1.11-1.05(m,2H)。FXR EC50(nM)=270。MS(ESI)582(M+H)。
实施例14
4-(5-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)吡啶-2-甲酸
步骤A.中间体14A.(Z)-4-(N'-羟基甲脒基)吡啶-2-甲酸乙酯的制备
根据针对中间体4C的合成所描述的方法,使用4-氰基吡啶-2-甲酸乙酯作为起始物质来制备标题化合物:(0.30g,1.4mmol,100%产率,白色固体)。1H NMR(400MHz,DMSO-d6)δ10.23-10.16(m,1H),8.77-8.69(m,1H),8.39-8.30(m,1H),7.92-7.81(m,1H),6.21-6.09(m,2H),4.52-4.26(m,2H),1.35(t,J=7.2Hz,3H)。MS(ESI)210(M+H)。
步骤B.中间体14B.4-(5-(4-碘双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)吡啶-2-甲酸乙酯的制备
根据针对中间体4D的合成所描述的方法,以中间体4B开始且适当时代入中间体14A来制备标题化合物:(0.34g,0.75mmol,78%产率,白色固体)。1H NMR(500MHz,二氯甲烷-d2)δ8.92-8.86(m,1H),8.72-8.67(m,1H),8.15-8.08(m,1H),4.50(d,J=7.2Hz,2H),2.71-2.55(m,6H),2.29-2.20(m,6H),1.48(t,J=7.2Hz,3H)。MS(ESI)454(M+H)。
步骤C.实施例14
根据针对实施例4的合成(步骤E)所描述的方法,通过使中间体14B与(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲醇反应来制备标题化合物:(6.8mg,0.012mmol,13%产率)。1H NMR(500MHz,DMSO-d6)δ8.91-8.80(m,1H),8.50-8.41(m,1H),8.08-7.98(m,1H),7.69-7.61(m,2H),7.61-7.51(m,1H),4.18(s,2H),2.35-2.26(m,1H),2.06-1.98(m,6H),1.56-1.47(m,6H),1.18-1.12(m,2H),1.11-1.06(m,2H)。FXR EC50(nM)=130。MS(ESI)582(M+H)。
实施例15
2-(4-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-4-氟苯并[d]噻唑-6-甲酸
步骤A.中间体15A.2-氨基-4-氟苯并[d]噻唑-6-甲酸乙酯的制备
向200mL梨形烧瓶中添加4-氨基-3-氟苯甲酸乙酯(3.7g,20mmol)、硫氰酸钠(6.5g,80mmol)和冰AcOH(25mL)。将反应物冷却至约0℃。在5分钟的时间段内向该混合物中添加溶解于冰AcOH(5mL)中的溴(1mL)。在30℃搅拌混合物48h。使反应物冷却,通过真空过滤移除固体,且用DCM(2×10mL)洗涤滤饼。浓缩滤液,在水(50mL)中稀释残余物,且添加浓NH4OH直至pH约为9为止(约5mL)。搅拌悬浮液2h,并通过真空过滤收集固体产物,且用水(3×10mL)洗涤滤饼。将产物在真空中干燥,得到呈黄色固体状的标题化合物(3.0g,12mmol,62%产率)。1H NMR(400MHz,DMSO-d6)δ8.35-8.00(m,2H),7.57(dd,J=11.4,1.5Hz,1H),4.30(q,J=7.1Hz,2H),1.32(t,J=7.0Hz,3H)。MS(ESI)241(M+H)。
步骤B.中间体15B.4-氟苯并[d]噻唑-6-甲酸乙酯的制备
向250mL圆底烧瓶中添加中间体15A(1.5g,6.2mmol)、THF(20mL),接着添加亚硝酸异戊酯(2.5mL,19mmol)。在N2下在回流下搅拌悬浮液2h,使其冷却至rt并搅拌18h。浓缩溶剂,且通过快速柱色谱(40g硅胶滤筒;A=己烷,B=EtOAc;20min梯度;0%B至100%B;流速=40mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈淡黄色固体状的标题化合物(1.0g,4.6mmol,74%产率)。1H NMR(400MHz,氯仿-d)δ9.17(d,J=0.7Hz,1H),8.52(d,J=1.1Hz,1H),7.91(dd,J=10.6,1.3Hz,1H),4.46(d,J=7.0Hz,2H),1.46(t,J=7.2Hz,4H)。MS(ESI)226(M+H)。
步骤C.中间体15C.4-氟苯并[d]噻唑-6-甲酸的制备
向250mL圆底烧瓶中添加中间体15B(1.0g,4.6mmol)、THF(23mL),接着添加1MNaOH(水溶液)(23mL,23mmol)。搅拌反应物18h,且用5%柠檬酸(水溶液)(100mL)稀释。用EtOAc(2×50mL)萃取悬浮液。将有机相合并,用盐水洗涤,经Na2SO4干燥,过滤且浓缩。将产物在真空中干燥,得到呈淡黄色固体状的标题化合物(0.90g,4.6mmol,99%产率)。1H NMR(500MHz,DMSO-d6)δ13.62-12.50(br s,1H),9.62(s,1H),8.68(d,J=1.4Hz,1H),7.82(dd,J=11.3,1.4Hz,1H)。MS(ESI)198(M+H)。
步骤D.中间体15D.4-氟苯并[d]噻唑-6-甲酸叔丁酯的制备
向250mL圆底烧瓶中添加中间体15C(0.90g,4.6mmol)和叔丁醇(11mL)。向反应物中添加溶解于THF(11mL)中的(Z)-N,N'-二异丙基氨基甲酸叔丁酯(9.2g,46mmol)(Mathias,L.J.Synthesis 1979,1979,561-576)。搅拌18h后,过滤反应物且浓缩滤液。通过快速柱色谱(40g硅胶滤筒;A=己烷,B=EtOAc;20min梯度;0%B至50%B;流速=40mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈黄褐色固体状的标题化合物(0.75g,3.0mmol,65%产率)。1H NMR(400MHz,氯仿-d)δ9.17-9.12(m,1H),8.47-8.41(m,1H),7.89-7.81(m,1H),1.66(s,11H)。MS(ESI)254(M+H)。
步骤E.中间体15E.4-氨基-3-氟-5-巯基苯甲酸叔丁酯的制备
向100mL梨形烧瓶中添加中间体15D(0.75g,3.0mmol)、95%EtOH(水溶液)(10mL)和水合肼(6.4mL,100mmol)。搅拌反应物2.5h,浓缩溶剂,且通过快速柱色谱(24g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=24mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈淡黄色油状物的标题化合物(0.38g,1.5mmol,52%产率)。1HNMR(500MHz,氯仿-d)δ7.88-7.83(m,1H),7.61-7.55(m,1H),4.67-4.53(m,2H),3.14-2.95(m,1H),1.59(s,9H)。MS(ESI)244(M+H)。
步骤F.中间体15F.4-氟-2-(4-碘双环[2.2.2]辛-1-基)苯并[d]噻唑-6-甲酸叔丁酯的制备
向100mL梨形烧瓶中添加中间体15E(0.35g,1.3mmol)、中间体4B(0.46g,1.5mmol)、吡啶(0.30mL,3.8mmol)和DCE(8mL)。向该混合物中添加T3P(1.9mL,3.1mmol)(于EtOAc中的50%w/v溶液),且在N2下在80℃搅拌反应物5h。浓缩溶剂,且通过快速柱色谱(40g硅胶滤筒;A=己烷,B=EtOAc;20min梯度;0%B至100%B;流速=40mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈淡黄色固体状的标题化合物(0.17g,0.35mmol,28%产率)。1H NMR(500MHz,二氯甲烷-d2)δ8.35(d,J=1.4Hz,1H),7.84-7.72(m,1H),2.70-2.62(m,6H),2.30-2.21(m,6H),1.64(s,9H)。MS(ESI)488(M+H)。
步骤G.实施例15
步骤1:向装备有压力释放盖的2打兰(dram)小瓶中添加中间体15F(0.030g,0.062mmol)、(5-环丙基-3-(2-(三氟甲基)苯基)异噁唑-4-基)甲醇(0.055g,0.19mmol)、三氟甲烷磺酸银(0.13g,0.49mmol)和2,6-二-叔丁基吡啶(0.28mL,1.2mmol)。用N2冲洗容器,加盖,且在80℃搅拌。18h后,将反应物冷却,用DCM/MeOH稀释,过滤且浓缩滤液。将残余物经由SiO2塞过滤,首先用己烷接着用EtOAc洗脱,收集粗产物。浓缩滤液且粗残余物用于下一步骤。
步骤2:将上文步骤1的产物溶解于KOH(5mL)(2M于MeOH中)和THF(5mL)中并搅拌。2h后,将反应物用5%柠檬酸(水溶液)(50mL)稀释且用EtOAc(2×25mL)萃取。将有机相合并,用盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过制备型HPLC(柱:XBridge C18,19×200mm,5μm颗粒;流动相A:5:95的乙腈:水/10mM乙酸铵;流动相B:95:5的乙腈:水/10mM乙酸铵;梯度:30-70%B经20分钟,接着在100%B下保持4分钟;流速:20mL/min)纯化粗产物。将含有期望产物的级分合并、浓缩且在真空中干燥,得到标题化合物(1.4mg,2.3μmol,4%产率)。1HNMR(500MHz,DMSO-d6)δ8.44-8.31(m,1H),7.77-7.61(m,3H),7.57(br t,J=6.7Hz,2H),4.23(s,2H),2.31-2.27(m,1H),2.07(br s,6H),1.68(br d,J=7.3Hz,6H),1.17-1.11(m,2H),1.10-1.04(m,2H)。FXR EC50(nM)=210。MS(ESI)603(M+H)。
实施例16
2-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-4-氟苯并[d]噻唑-6-甲酸
步骤A.中间体16A.4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛烷-1-甲酸甲酯的制备
向25mL圆底烧瓶中添加中间体4A(280mg,0.97mmol)、(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲醇,接着添加2,6-二-叔丁基吡啶(2.6mL,12mmol)和三氟甲烷磺酸银(2.0mg,7.7mmol)。在80℃搅拌反应物4h,使其冷却至rt且用DCM/MeOH(20mL;1:1)稀释。过滤所得悬浮液,用DCM(10mL)洗涤滤饼,且浓缩滤液。通过快速柱色谱(40g硅胶滤筒;A=己烷,B=EtOAc;20min梯度;0%B至100%B;流速=40mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈白色固体状的标题化合物(250mg,0.56mmol,58%产率)。1H NMR(500MHz,氯仿-d)δ7.46-7.39(m,2H),7.38-7.32(m,1H),4.18(s,2H),3.63(s,3H),2.18-2.08(m,1H),1.91-1.78(m,6H),1.55-1.42(m,6H),1.30-1.22(m,2H),1.15-1.07(m,2H)。MS(ESI)451(M+H)。
步骤B.中间体16B.4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛烷-1-甲酸的制备
向100mL梨形烧瓶中添加中间体16A(150mg,0.22mmol)、1M NaOH(水溶液)(2.2mL,2.2mmol)和THF(2mL)。在40℃搅拌反应物18h,之后使反应物冷却,用5%柠檬酸(水溶液)(50mL)稀释且用EtOAc(2×25mL)萃取。将有机相合并,用盐水洗涤,经Na2SO4干燥,过滤且浓缩。将产物在真空中干燥,得到呈白色固体状的标题化合物(110mg,0.19mmol,87%产率)。1H NMR(400MHz,甲醇-d4)δ7.57-7.46(m,3H),4.86(s,2H),2.28-2.19(m,1H),1.87-1.79(m,6H),1.51-1.43(m,6H),1.20-1.14(m,4H)。MS(ESI)437(M+H)。
步骤C.实施例16
步骤1:向100mL梨形烧瓶中添加中间体16B(110mg,0.19mmol)、中间体15E(100mg,0.42mmol)、吡啶(0.046mL,0.57mmol)和DCE(2mL)。向该混合物中添加T3P(0.28mL,0.47mmol)(于EtOAc中的50%w/v溶液),且在N2下在80℃搅拌反应物。18h后,使反应物冷却,浓缩溶剂且通过快速柱色谱(12g硅胶滤筒;A=DCM,B=EtOAc;20min梯度;0%B至10%B;流速=12mL/min)纯化粗产物。将纯级分合并且浓缩。残余物不经表征即用于下一步骤。
将上文步骤1的产物溶解于KOH(5mL)(2M于MeOH中)和THF(5mL)中并搅拌。1.5h后,用水(50mL)稀释反应物,且通过旋转蒸发共沸移除MeOH。用5%柠檬酸(水溶液)酸化所得水层,且用EtOAc(2×25mL)萃取水相。将有机相合并,用盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过制备型HPLC(柱:XBridge C18,19×200mm,5μm颗粒;流动相A:5:95的乙腈:水/10mM乙酸铵;流动相B:95:5的乙腈:水/10mM乙酸铵;梯度:24-64%B经22分钟,接着在100%B下保持4分钟;流速:20mL/min)纯化粗产物。将含有期望产物的级分合并、浓缩且在真空中干燥,得到标题化合物(37mg,0.062mmol,33%产率)。1H NMR(500MHz,DMSO-d6)δ8.55-8.50(m,1H),7.78-7.73(m,1H),7.67-7.62(m,2H),7.62-7.56(m,1H),4.20(s,2H),2.35-2.28(m,1H),2.07-1.98(m,6H),1.57-1.49(m,6H),1.19-1.13(m,2H),1.12-1.06(m,2H)。FXR EC50(nM)=36。MS(ESI)588(M+H)。
实施例17
2-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1H-苯并[d]咪唑-5-甲酸
步骤A.中间体17A.3-氨基-4-(4-碘双环[2.2.2]辛烷-1-甲酰氨基)苯甲酸乙酯的制备
向20mL闪烁瓶中添加中间体4B(0.30g,1.1mmol)、3,4-二氨基苯甲酸乙酯(0.29g,1.6mmol)、DMAP(0.26g,2.1mmol),接着添加DMF(5mL)。向该混合物中添加EDC(0.41g,2.1mmol),且将小瓶加盖并搅拌18h。反应物用水(50mL)稀释且用EtOAc(2×25mL)萃取。将有机相合并,用盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过快速柱色谱(40g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=40mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈淡黄色油状物的标题化合物(0.17g,0.38mmol,36%产率)。1HNMR(500MHz,甲醇-d4)δ7.73-7.68(m,1H),7.68-7.63(m,1H),6.87-6.77(m,1H),4.37-4.25(m,2H),2.60-2.51(m,6H),2.13-2.05(m,6H),1.42-1.32(m,3H)。MS(ESI)443(M+H)。
步骤B.中间体17B.2-(4-碘双环[2.2.2]辛-1-基)-1H-苯并[d]咪唑-5-甲酸乙酯的制备
向100mL圆底烧瓶中添加中间体17A(0.17g,0.38mmol)和冰AcOH(8mL)。在N2下在115℃搅拌反应物。18h后,使反应物冷却,浓缩溶剂且通过快速柱色谱(40g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=40mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈黄褐色固体状的标题化合物(0.16g,0.38mmol,98%产率)。1HNMR(400MHz,甲醇-d4)δ8.34-8.11(m,1H),7.94-7.87(m,1H),7.66-7.43(m,1H),4.42-4.36(m,2H),2.68-2.58(m,6H),2.19(br d,J=8.1Hz,6H),1.41(t,J=7.2Hz,3H)。MS(ESI)425(M+H)。
步骤C.实施例17
根据针对实施例4的合成(步骤E)所描述的方法,通过使中间体17B与(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲醇反应来制备标题化合物:(24mg,0.043mmol,37%产率)。1H NMR(500MHz,DMSO-d6)δ8.17-7.95(m,1H),7.82-7.71(m,1H),7.64(s,2H),7.62-7.56(m,1H),7.55-7.41(m,1H),4.23-4.16(m,2H),2.35-2.27(m,1H),2.00-1.92(m,6H),1.54-1.44(m,6H),1.18-1.13(m,2H),1.12-1.05(m,2H)。FXR EC50(nM)=2700。MS(ESI)553(M+H)。
实施例18
3-(5-(4-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,3,4-噁二唑-2-基)苯甲酸
步骤A.中间体18A.3-(5-(4-碘双环[2.2.2]辛-1-基)-1,3,4-噁二唑-2-基)苯甲酸甲酯的制备
向中间体4B(0.24g,0.84mmol)、3-(肼羰基)苯甲酸甲酯(0.16g,0.84mmol)(Bradner,J.E.等人WO 2014/071247)和DIEA(0.44mL,2.5mmol)于MeCN(10mL)中的混合物中添加TBTU(0.30g,0.92mmol)。搅拌2h后,依次添加DIEA(0.29mL,1.7mmol)、对甲苯磺酰氯(0.48g,2.5mmol),且在N2下搅拌所得反应混合物。18h后,将混合物用1M K2HPO4(水溶液)(50mL)稀释且用EtOAc(2×25mL)萃取。将有机相合并,用盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过快速柱色谱(40g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=40mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈白色固体状的标题化合物(0.063g,0.14mmol,17%产率)。1H NMR(500MHz,二氯甲烷-d2)δ8.69-8.60(m,1H),8.31-8.19(m,2H),7.69-7.60(m,1H),3.99(s,3H),2.70-2.61(m,6H),2.24(br d,J=8.3Hz,6H)。MS(ESI)439(M+H)。
步骤B.实施例18
根据针对实施例4的合成(步骤E)所描述的方法,通过使中间体18A与(5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲醇反应来制备标题化合物:(19mg,0.033mmol,47%产率)。1H NMR(500MHz,DMSO-d6)δ8.48-8.42(m,1H),8.19-8.11(m,2H),7.73-7.66(m,2H),7.66-7.61(m,1H),7.60-7.52(m,2H),4.22(s,2H),2.32-2.24(m,1H),2.08-1.99(m,6H),1.69-1.59(m,6H),1.17-1.11(m,2H),1.10-1.03(m,2H)。FXR EC50(nM)=1100。MS(ESI)596(M+H)。
实施例19
3-(5-(4-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,3,4-噻二唑-2-基)苯甲酸
步骤A.中间体19A.3-(5-(4-碘双环[2.2.2]辛-1-基)-1,3,4-噻二唑-2-基)苯甲酸甲酯的制备
步骤1:向中间体4B(0.24g,0.84mmol)、3-(肼羰基)苯甲酸甲酯(0.16g,0.84mmol)(Bradner,J.E.等人WO 2014/071247)、TEA(0.18mL,1.3mmol)和HOBT(0.039g,0.25mmol)于DMF(6mL)中的混合物中添加EDC(0.24g,1.3mmol),并搅拌所得混合物。2h后,将反应物用水(50mL)稀释且用EtOAc(2×25mL)萃取。将有机相合并,用盐水洗涤,经Na2SO4干燥,过滤且浓缩。将残余物在真空中干燥,且不经表征即用于下一步骤。
步骤2:将步骤1的产物溶解于THF(5mL)中,添加五硫化磷(0.48g,2.2mmol),且在50℃搅拌反应物。18h后,使反应物冷却,过滤,且浓缩滤液。通过快速柱色谱(40g硅胶滤筒;A=己烷,B=EtOAc;20min梯度;0%B至60%B;流速=40mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈白色固体状的标题化合物(60mg,0.13mmol,16%产率)。1HNMR(400MHz,二氯甲烷-d2)δ8.41(t,J=1.5Hz,1H),8.05(td,J=7.9,1.4Hz,2H),7.48(t,J=7.8Hz,1H),3.85(s,3H),2.58-2.50(m,6H),2.17-2.05(m,6H)。MS(ESI)455(M+H)。
步骤B.实施例19
根据针对实施例4的合成(步骤E)所描述的方法,通过使中间体19A与(5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲醇反应来制备标题化合物:(4.1mg,0.0067mmol,10%产率)。1H NMR(500MHz,DMSO-d6)δ8.40(br s,1H),8.08(br t,J=9.0Hz,2H),7.71-7.60(m,3H),7.56(br t,J=7.0Hz,2H),4.21(s,2H),2.31-2.24(m,1H),2.08-1.99(m,6H),1.71-1.59(m,6H),1.18-1.10(m,2H),1.09-1.03(m,2H)。FXR EC50(nM)=1700。MS(ESI)612(M+H)。
实施例20
3-(3-(4-((5-环丙基-3-(2-(三氟甲基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-5-基)苯甲酸
步骤A.中间体20A.4-碘双环[2.2.2]辛烷-1-甲腈的制备
步骤1:向250mL圆底烧瓶中添加中间体4B(0.56g,2.0mmol)、THF(20mL)和TEA(0.42mL,3.0mmol)。将混合物冷却至-30℃,随后逐滴添加氯甲酸乙酯(0.23mL,2.4mmol)。在-30℃搅拌混合物1h。过滤反应物,用额外量的冰冷THF(15mL)洗涤烧瓶和滤饼,且将反应物冷却至-20℃。
步骤2:将上文所产生的混合物冷却至-20℃,且使氨气散布在混合物中,持续10min。在该温度搅拌40min后,浓缩溶剂,且残余物不经纯化或表征即用于下一步骤。
步骤3:将上文的残余物溶解于THF(12mL)中,添加吡啶(0.53mL,6.6mmol),且将混合物冷却至0℃。向该混合物中添加三氟乙酸酐(0.57mL,4.0mmol),且在该温度搅拌反应物2h。向该混合物中添加MeOH(5mL)和1M K2HPO4(水溶液)(5mL),并搅拌30min。将混合物用水(100mL)稀释且用EtOAc(2×50mL)萃取。将有机相合并,用1M HCl(水溶液)、盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过快速柱色谱(40g硅胶滤筒;A=己烷,B=EtOAc;20min梯度;0%B至50%B;流速=40mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈白色固体状的标题化合物(0.37g,1.4mmol,71%产率)。1H NMR(500MHz,氯仿-d)δ2.56-2.46(m,6H),2.14-2.04(m,6H)。
步骤B.中间体20B.(Z)-N'-羟基-4-碘双环[2.2.2]辛烷-1-甲脒的制备
向100mL梨形烧瓶中添加中间体20A(0.37g,1.4mmol)、羟胺盐酸盐(0.49g,7.1mmol)、MeOH(14mL)和TEA(0.99mL,7.1mmol)。在回流下搅拌反应物18h。将反应物冷却,用水(200mL)稀释且用EtOAc(2×100mL)萃取。将有机相合并,经Na2SO4干燥,过滤且浓缩。将产物在真空中干燥,得到呈白色固体状的标题化合物(0.40g,1.4mmol,96%产率)。1H NMR(500MHz,氯仿-d)δ7.26-7.14(br s,1H),4.55-4.33(br s,2H),2.51(br d,J=8.3Hz,6H),1.93-1.85(m,6H)。
步骤C.中间体20C.3-(3-(4-碘双环[2.2.2]辛-1-基)-1,2,4-噁二唑-5-基)苯甲酸甲酯的制备
步骤1:向100mL梨形烧瓶中添加3-(甲氧基羰基)苯甲酸(0.14g,0.75mmol)和DCM(4mL)。向该混合物中一次性添加CDI(0.13g,0.82mmol),此时观察到气体逸出。搅拌反应物30min,添加中间体20B(0.20g,0.68mmol),且在N2下搅拌反应物。
步骤2:浓缩溶剂且将残余物溶解于甲苯(5mL)中,并且在回流下搅拌。2h后,使反应物冷却,浓缩溶剂且通过快速柱色谱(40g硅胶滤筒;A=己烷,B=EtOAc;20min梯度;0%B至50%B;流速=40mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈白色固体状的标题化合物(0.25g,0.57mmol,84%产率)。1H NMR(500MHz,氯仿-d)δ8.80-8.75(m,1H),8.33-8.24(m,2H),7.67-7.60(m,1H),4.00(s,3H),2.67-2.58(m,6H),2.23-2.13(m,6H)。MS(ESI)439(M+H)。
步骤D.实施例20
根据针对实施例4的合成(步骤E)所描述的方法,通过使中间体20C与(5-环丙基-3-(2-(三氟甲基)苯基)异噁唑-4-基)甲醇反应来制备标题化合物:(27mg,0.047,41%产率)。1H NMR(500MHz,DMSO-d6)δ8.59-8.54(m,1H),8.29-8.25(m,1H),8.24-8.20(m,1H),7.93-7.88(m,1H),7.85-7.80(m,1H),7.79-7.72(m,2H),7.59-7.53(m,1H),4.21(s,2H),2.33-2.21(m,1H),2.04-1.91(m,6H),1.64-1.51(m,6H),1.15(br d,J=2.3Hz,2H),1.10-1.05(m,2H)。FXR EC50(nM)=510。MS(ESI)580(M+H)。
实施例21
4-(3-(4-((5-环丙基-3-(2-(三氟甲基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-5-基)苯甲酸
步骤A.中间体21A.4-(3-(4-碘双环[2.2.2]辛-1-基)-1,2,4-噁二唑-5-基)苯甲酸甲酯的制备
根据针对中间体20C的合成所描述的方法,通过使中间体20B与4-(甲氧基羰基)苯甲酸反应来制备标题化合物:(240mg,0.55mmol,81%产率,白色固体)。1H NMR(500MHz,氯仿-d)δ8.25-8.15(m,4H),3.99(s,3H),2.68-2.58(m,6H),2.23-2.13(m,6H)。MS(ESI)439(M+H)。
步骤B.实施例21
根据针对实施例4的合成(步骤E)所描述的方法,通过使中间体21A与(5-环丙基-3-(2-(三氟甲基)苯基)异噁唑-4-基)甲醇反应来制备标题化合物:(41mg,0.070mmol,60%产率)。1H NMR(500MHz,DMSO-d6)δ8.13(s,4H),7.93-7.88(m,1H),7.85-7.79(m,1H),7.79-7.73(m,1H),7.58-7.53(m,1H),4.21(s,2H),2.30-2.24(m,1H),2.02-1.93(m,6H),1.62-1.53(m,6H),1.16-1.11(m,2H),1.10-1.05(m,2H)。FXR EC50(nM)=880。MS(ESI)580(M+H)。
实施例22
4-(3-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-5-基)吡啶-2-甲酸
步骤A.中间体22A.4-(3-(4-碘双环[2.2.2]辛-1-基)-1,2,4-噁二唑-5-基)吡啶-2-甲酸甲酯的制备
根据针对中间体20C的合成所描述的方法,通过使中间体20B与2-(甲氧基羰基)吡啶-4-甲酸反应来制备标题化合物:(0.25g,0.57mmol,76%产率,白色固体)。1H NMR(500MHz,氯仿-d)δ8.39-8.31(m,2H),8.12-8.06(m,1H),4.07(s,3H),2.66-2.60(m,6H),2.22-2.16(m,6H)。MS(ESI)440(M+H)。
步骤B.实施例22
根据针对实施例4的合成(步骤E)所描述的方法,通过使中间体22A与(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲醇反应来制备标题化合物:(2.4mg,0.0041,4%产率)。1H NMR(500MHz,DMSO-d6)δ9.02-8.94(m,1H),8.54-8.45(m,1H),8.23-8.15(m,1H),7.68-7.62(m,2H),7.61-7.54(m,1H),4.19(s,2H),2.35-2.27(m,1H),1.98-1.88(m,6H),1.56-1.44(m,6H),1.18-1.12(m,2H),1.11-1.06(m,2H)。FXR EC50(nM)=210。MS(ESI)582(M+H)。
实施例23
6-(3-(4-((5-环丙基-3-(2-(三氟甲基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-5-基)吡啶-2-甲酸
步骤A.中间体23A.6-(3-(4-碘双环[2.2.2]辛-1-基)-1,2,4-噁二唑-5-基)吡啶-2-甲酸甲酯的制备
根据针对中间体20C的合成所描述的方法,通过使中间体20B与6-(甲氧基羰基)吡啶-2-甲酸反应来制备标题化合物:(0.24g,0.55mmol,73%产率,白色固体)。1H NMR(500MHz,氯仿-d)δ9.03-8.97(m,1H),8.82-8.76(m,1H),8.18-8.12(m,1H),4.10(s,3H),2.67-2.60(m,6H),2.22-2.13(m,6H)。MS(ESI)440(M+H)。
步骤B.实施例23
根据针对实施例4的合成(步骤E)所描述的方法,通过使中间体22A与(5-环丙基-3-(2-(三氟甲基)苯基)异噁唑-4-基)甲醇反应来制备标题化合物:(12mg,0.020mmol,17%产率)。1H NMR(500MHz,DMSO-d6)δ8.37-8.31(m,1H),8.29-8.19(m,2H),7.94-7.90(m,1H),7.86-7.80(m,1H),7.80-7.74(m,1H),7.59-7.54(m,1H),4.14(s,2H),2.31-2.24(m,1H),2.02-1.90(m,6H),1.61-1.51(m,6H),1.17-1.12(m,2H),1.08(br d,J=2.7Hz,2H)。FXREC50(nM)=2800。MS(ESI)581(M+H)。
实施例24
2-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)喹唑啉-6-甲酸
步骤A.中间体24A.4-氨基-3-((4-碘双环[2.2.2]辛烷-1-甲酰氨基)甲基)苯甲酸甲酯的制备
向50mL圆底烧瓶中添加中间体4B(0.19g,0.69mmol)、MeCN(7mL)和HBTU(0.31g,0.83mmol)。搅拌30min后,添加4-氨基-3-(氨基甲基)苯甲酸甲酯二盐酸盐(0.26g,0.69mmol)(Pascal,R.等人Eur.J.Org.Chem.2000,22,3755-3761)和DIEA(0.48mL,2.8mmol)溶解于MeCN(3mL)中的溶液,且在N2下搅拌反应物。2h后,浓缩溶剂,且通过快速柱色谱(40g硅胶滤筒;A=己烷,B=EtOAc;20min梯度;0%B至100%B;流速=40mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈淡黄色固体状的标题化合物(0.29g,0.66mmol,95%产率)。1H NMR(400MHz,氯仿-d)δ7.81-7.77(m,1H),7.76-7.73(m,1H),6.63-6.56(m,1H),5.85-5.73(m,1H),4.94-4.84(m,2H),3.87(s,3H),2.53-2.45(m,6H),1.95-1.86(m,6H)。MS(ESI)443(M+H)。
步骤B.中间体24B.2-(4-碘双环[2.2.2]辛-1-基)-3,4-二氢喹唑啉-6-甲酸甲酯的制备
向50mL圆底烧瓶中添加中间体24A(0.29g,0.66mmol)和冰AcOH(7mL)。在回流下搅拌混合物。18h后,将反应物冷却、浓缩,将残余物溶解于MeOH(5mL)中且用1M K2HPO4(水溶液)(50mL)稀释。用EtOAc(2×25mL)萃取所得悬浮液,将有机相合并,用盐水洗涤,经Na2SO4干燥,过滤且浓缩。将产物在真空中干燥,得到呈淡黄色固体状的标题化合物(0.24g,0.57mmol,86%产率)。1H NMR(500MHz,甲醇-d4)δ7.79(d,J=8.3Hz,1H),7.62(s,1H),6.96(d,J=8.3Hz,1H),4.54(s,2H),3.87(s,3H),2.57-2.52(m,6H),1.99(br s,6H)。MS(ESI)425(M+H)。
步骤C.中间体24C.2-(4-碘双环[2.2.2]辛-1-基)喹唑啉-6-甲酸甲酯的制备
向25mL圆底烧瓶中添加中间体24B(0.24g,0.57mmol)、THF(6mL)和DDQ(0.13g,0.57mmol)。在N2下搅拌反应物25分钟,之后将反应物分配至1M K2HPO4(水溶液)(75mL)中且用EtOAc(2×50mL)萃取。将有机相合并,用盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过快速柱色谱(24g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至70%B;流速=24mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈淡黄色油状物的标题化合物(0.17g,0.40mmol,71%产率)。1H NMR(500MHz,氯仿-d)δ9.44-9.42(m,1H),8.69-8.63(m,1H),8.51-8.43(m,1H),8.05-7.98(m,1H),4.03(s,3H),2.72-2.64(m,6H),2.34-2.24(m,6H)。MS(ESI)423(M+H)。
步骤D.实施例24
根据针对实施例4的合成(步骤E)所描述的方法,通过使中间体24C与(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲醇反应来制备标题化合物:(41mg,0.072mmol,60%产率)。1H NMR(500MHz,DMSO-d6)δ9.64(s,1H),8.71-8.65(m,1H),8.44-8.34(m,1H),7.96-7.91(m,1H),7.64(s,2H),7.61-7.57(m,1H),4.20(s,2H),2.35-2.27(m,1H),2.07-1.99(m,6H),1.56-1.45(m,6H),1.19-1.13(m,2H),1.10-1.05(m,2H)。FXR EC50(nM)=250。MS(ESI)565(M+H)。
根据本文中其他处所描述的方法,使用适当起始物质、试剂和条件来制备表1中的以下实施例。
表1
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
实施例64
5-(5-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-2-氟苯甲酸
/>
步骤A.中间体64A.5-氰基-2-氟苯甲酸乙酯的制备
向5-氰基-2-氟苯甲酸(0.50g,3.0mmol)于EtOH(20mL)中的溶液中添加亚硫酰氯(0.51mL,7.0mmol)。在65℃搅拌混合物。18h后,使反应物冷却,浓缩溶剂且通过快速柱色谱(40g硅胶滤筒,A=己烷,B=EtOAc;25min梯度;0%B至25%B,流速=40mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈白色固体状的标题化合物(0.50g,2.6mmol,85%产率)。1H NMR(500MHz,氯仿-d)δ8.29(dd,J=6.6,2.2Hz,1H),7.82(ddd,J=8.6,4.3,2.2Hz,1H),7.36-7.21(m,1H),4.44(q,J=7.2Hz,2H),1.42(t,J=7.2Hz,3H)。MS(ESI)194(M+H)。
步骤B.中间体64B.(Z)-2-氟-5-(N'-羟基甲脒基)苯甲酸乙酯的制备
根据针对中间体4C的合成所描述的方法,使用中间体64A作为起始物质来制备标题化合物:(0.51g,2.3mmol,88%产率,浅黄色固体)。1H NMR(500MHz,DMSO-d6)δ9.77(s,1H),8.19(dd,J=7.2,2.5Hz,1H),7.92(ddd,J=8.7,4.5,2.5Hz,1H),7.36(dd,J=10.6,8.7Hz,1H),5.95(s,2H),4.33(q,J=7.1Hz,2H),1.32(t,J=7.2Hz,3H)。MS(ESI)227(M+H)。
步骤C.实施例64
步骤1:向中间体16B(33mg,0.076mmol)、中间体64B(17mg,0.076mmol)和BOP(37mg,0.083mmol)于DMF(0.10mL)中的溶液中添加TEA(32μL,0.23mmol),且在N2下在80℃搅拌反应物。18h后,使反应物冷却,用EtOAc稀释,用10%氯化锂(水溶液)、水和盐水洗涤。有机相经无水Na2SO4干燥,过滤且浓缩。粗残余物不经进一步纯化或表征即用于下一步骤。
步骤2:将上文步骤1的产物溶解于1M NaOH(水溶液)(1.5mL)和THF(1.5mL)中,且在室温搅拌。7h后,用5%柠檬酸(水溶液)酸化反应物,且用EtOAc(2×)萃取水相。将有机相合并,用盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过制备型HPLC(柱:XBridge C18,19×200mm,5μm颗粒;流动相A:5:95的乙腈:水/10mM乙酸铵;流动相B:95:5的乙腈:水/10mM乙酸铵;梯度:28-68%B经20分钟,接着在100%B下保持4分钟;流速:20mL/min)纯化粗产物。将含有期望产物的级分合并、浓缩且在真空中干燥,得到标题化合物(15mg,0.023mmol,30%产率)。1H NMR(500MHz,DMSO-d6)δ8.48-8.20(m,1H),8.03(br d,J=7.9Hz,1H),7.66-7.59(m,2H),7.59-7.53(m,1H),7.46(br s,1H),4.16(s,2H),2.35-2.21(m,1H),2.04-1.93(m,6H),1.59-1.40(m,6H),1.13(br d,J=8.2Hz,2H),1.06(br d,J=3.1Hz,2H)。FXR EC50(nM)=140。MS(ESI)598(M+H)。
实施例66
4-(((4-(6-(1H-四唑-5-基)苯并[d]噻唑-2-基)双环[2.2.2]辛-1-基)氧基)甲基)-5-环丙基-3-(2,6-二氯苯基)异噁唑
步骤A.中间体66A.2-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)苯并[d]噻唑-6-甲腈的制备
根据针对实施例16的合成(步骤C)所描述的方法,通过使中间体16B与4-氨基-3-巯基苯甲腈(通常参见Chedekel,M.R.等人Synth.Commun.1980,10,167-173)反应来制备标题化合物:(17mg,0.031mmol,30%产率,白色固体)。1H NMR(500MHz,氯仿-d)δ8.21-8.12(m,1H),8.00(d,J=8.5Hz,1H),7.69(dd,J=8.4,1.5Hz,1H),7.46-7.41(m,2H),7.37-7.31(m,1H),4.23(s,2H),2.32-1.95(m,7H),1.69-1.61(m,6H),1.29-1.20(m,2H),1.16-1.04(m,2H)。MS(ESI)550(M+H)。
步骤B.实施例66
在120℃搅拌中间体66A(17mg,0.031mmol)、叠氮化钠(12mg,0.18mmol)和氯化铵(9.8mg,0.18mmol)于NMP(0.21mL)中的溶液。18h后,使反应物冷却,用EtOAc稀释且用盐水洗涤。分离有机相,经无水Na2SO4干燥,过滤,且浓缩。通过制备型HPLC(柱:Phenomenex LunaAXIA5u C18 21.2×100mm;流动相B:90:10的MeOH:H2O/0.1%TFA;流动相A=10:90的MeOH:H2O/0.1%TFA;梯度:10-100%B经10min,接着在100%B下保持5min;流速:20mL/min)纯化粗产物。将含有期望产物的级分合并、浓缩且在真空中干燥,得到呈白色固体状的标题化合物(11mg,0.019mmol,61%产率)。1H NMR(500MHz,DMSO-d6)δ8.75(s,1H),8.14-8.03(m,2H),7.65(d,J=1.1Hz,1H),7.63(s,1H),7.60-7.55(m,1H),4.19(s,2H),2.33-2.26(m,1H),2.05-1.98(m,6H),1.56-1.49(m,6H),1.14(dt,J=8.3,3.0Hz,2H),1.10-1.04(m,2H)。FXREC50(nM)=390。MS(ESI)593(M+H)。
实施例68
3-(5-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-2,6-二氟苯甲酸
步骤A.中间体68A.3-氰基-2,6-二氟苯甲酸乙酯的制备
根据针对中间体64A的合成所描述的方法,使用3-氰基-2,6-二氟苯甲酸作为起始物质来制备标题化合物:(0.46g,2.2mmol,79%产率,白色固体)。1H NMR(500MHz,氯仿-d)δ7.89-7.64(m,1H),7.11(td,J=8.6,1.2Hz,1H),4.47(q,J=7.2Hz,2H),1.42(t,J=7.2Hz,3H)。MS(ESI)212(M+H)。
步骤B.中间体68B.(Z)-2,6-二氟-3-(N'-羟基甲脒基)苯甲酸乙酯的制备
根据针对中间体4C的合成所描述的方法,使用中间体68A作为起始物质来制备标题化合物:(0.2g,0.81mmol,38%产率,浅黄色固体)。1H NMR(500MHz,DMSO-d6)δ9.71(s,1H),7.68(td,J=8.4,6.6Hz,1H),7.31-7.14(m,1H),5.92(s,2H),4.38(q,J=7.2Hz,2H),1.31(t,J=7.2Hz,3H)。MS(ESI)245(M+H)。
步骤C.实施例68
根据针对实施例64的合成(步骤C)所描述的方法,通过使中间体68B与中间体16B反应来制备标题化合物:(24mg,0.037mmol,40%产率,灰白色固体)。1H NMR(500MHz,DMSO-d6)δ14.42-14.05(br.s,1H),8.11(td,J=8.4,6.3Hz,1H),7.65-7.61(m,2H),7.59-7.52(m,1H),7.41(t,J=8.8Hz,1H),4.18(s,2H),2.30(tt,J=8.3,5.2Hz,1H),2.07-1.92(m,6H),1.59-1.43(m,6H),1.14(dt,J=8.3,2.9Hz,2H),1.11-1.01(m,2H)。FXR EC50(nM)=250。MS(ESI)616(M+H)。
实施例69
5-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-2-甲氧基苯甲酸
/>
步骤A.中间体69A.4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛烷-1-甲酸甲酯的制备
向装备有压力释放盖的20mL闪烁瓶中添加中间体4A(0.47g,1.6mmol)、(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲醇(0.45g,1.6mmol)、三氟甲烷磺酸银(0.49g,1.9mmol)、2,6-二-叔丁基吡啶(0.70mL,3.2mmol)和DCE(2mL)。用N2冲洗容器,加盖,且在100℃搅拌1h。使反应物冷却,过滤且浓缩滤液。通过快速柱色谱(40g硅胶滤筒;A=己烷,B=EtOAc;19min梯度;0%B至70%B;流速=40mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈白色固体状的标题化合物(0.24g,0.52mmol,33%产率)。1H NMR(500MHz,氯仿-d)δ8.61(s,2H),4.20(s,2H),3.62(s,3H),2.08(tt,J=8.5,5.0Hz,1H),1.88-1.77(m,6H),1.48-1.40(m,6H),1.27-1.21(m,2H),1.16-1.08(m,2H)。MS(ESI)451(M+H)。
步骤B.中间体69B.4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛烷-1-甲酸的制备
在40℃搅拌中间体69A(240mg,0.52mmol)、1M NaOH(水溶液)(5.2mL,5.2mmol)于MeOH(4mL)和THF(1mL)中的溶液1h。使反应物冷却,浓缩溶剂,且将残余物用水(7.5mL)处理并用1M HCl(水溶液)酸化。过滤析出物,用水充分洗涤且在真空中干燥,得到呈白色固体状的标题化合物(180mg,0.41mmol,78%产率)。1H NMR(500MHz,DMSO-d6)δ12.01(s,1H),8.81(s,2H),4.19(s,2H),2.29(tt,J=8.4,5.1Hz,1H),1.75-1.62(m,6H),1.37-1.28(m,6H),1.14(dt,J=8.3,3.0Hz,2H),1.09-1.02(m,2H)。MS(ESI)437(M+H)。
步骤C.中间体69C.(Z)-5-(N'-羟基甲脒基)-2-甲氧基苯甲酸甲酯的制备
根据针对中间体4C的合成所描述的方法,使用5-氰基-2-甲氧基苯甲酸甲酯作为起始物质来制备标题化合物:(0.18g,0.78mmol,30%产率,灰白色固体)。1H NMR(500MHz,DMSO-d6)δ9.58-9.52(m,1H),7.99(d,J=2.5Hz,1H),7.83(dd,J=8.8,2.5Hz,1H),7.17(d,J=8.8Hz,1H),5.82(s,2H),3.85(s,3H),3.80(s,3H)。MS(ESI)225(M+H)。
步骤D.实施例69
根据针对实施例64的合成(步骤C)所描述的方法,通过使中间体69B与中间体69C反应来制备标题化合物:(40mg,0.061mmol,67%产率):1H NMR(500MHz,DMSO-d6)δ8.82(s,2H),8.13(d,J=1.5Hz,1H),8.01(dd,J=8.7,2.0Hz,1H),7.25(d,J=8.9Hz,1H),4.24(s,2H),3.86(s,3H),2.37-2.25(m,1H),2.02-1.96(m,6H),1.51-1.40(m,6H),1.26-1.13(m,2H),1.13-1.03(m,2H)。FXR EC50(nM)=56。MS(ESI)611(M+H)。
实施例70
3-(3-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-5-基)-1-甲基-1H-吡唑-5-甲酸
步骤A.中间体70A.4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛烷-1-甲腈的制备
根据针对中间体20A的合成所描述的方法,使用中间体16B作为起始物质来制备标题化合物:(57mg,0.14mmol,83%产率,白色固体)。1H NMR(500MHz,DMSO-d6)δ7.63-7.59(m,2H),7.58-7.51(m,1H),4.10(s,2H),2.32-2.20(m,1H),1.91-1.82(m,6H),1.41-1.32(m,6H),1.17-1.09(m,2H),1.08-1.00(m,2H)。FXR EC50(nM)=470。MS(ESI)417(M+H)。
步骤B.中间体70B.(Z)-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)-N'-羟基双环[2.2.2]辛烷-1-甲脒的制备
根据针对中间体4C的合成所描述的方法,使用中间体70A作为起始物质来制备标题化合物:(32mg,0.071mmol,92%产率,透明油状物)。1H NMR(500MHz,氯仿-d)δ7.45-7.38(m,2H),7.37-7.29(m,1H),4.46(br s,2H),4.17(s,2H),2.16-2.07(m,1H),1.83-1.69(m,6H),1.54-1.41(m,6H),1.26-1.21(m,2H),1.13-1.05(m,2H)。MS(ESI)450(M+H)。
步骤C.实施例70
根据针对实施例64的合成所描述的方法,通过使中间体70B与5-(甲氧基羰基)-1-甲基-1H-吡唑-3-甲酸反应来制备标题化合物:(5.1mg,0.088mmol,25%产率)。1H NMR(500MHz,DMSO-d6)δ7.63-7.58(m,2H),7.57-7.52(m,1H),7.31(s,1H),4.21-4.15(m,5H),2.31-2.22(m,1H),1.93-1.86(m,6H),1.53-1.44(m,6H),1.16-1.10(m,2H),1.08-1.01(m,2H)。FXR EC50(nM)=430。MS(ESI)584(M+H)。
实施例71
3-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-2-氟苯甲酸
步骤A.中间体71A.3-氰基-2-氟苯甲酸乙酯的制备
根据针对中间体64A的合成所描述的方法,使用3-氰基-2-氟苯甲酸作为起始物质来制备标题化合物:(0.55g,2.8mmol,93%产率,白色固体)。1H NMR(400MHz,DMSO-d6)δ8.24-8.08(m,2H),7.54(t,J=7.8Hz,1H),4.36(q,J=7.0Hz,2H),1.32(t,J=7.2Hz,3H)。MS(ESI)194(M+H)。
步骤B.中间体71B.(Z)-2-氟-3-(N'-羟基甲脒基)苯甲酸乙酯的制备
根据针对中间体4C的合成所描述的方法,使用中间体71A作为起始物质来制备标题化合物:(0.35g,1.6mmol,55%产率,白色固体)。1H NMR(500MHz,DMSO-d6)δ9.67(s,1H),7.92-7.84(m,1H),7.73-7.65(m,1H),7.32(t,J=7.7Hz,1H),5.90(s,2H),4.33(q,J=7.2Hz,2H),1.32(t,J=7.2Hz,3H)。MS(ESI)227(M+H)。
步骤C.实施例71
根据针对实施例64的合成(步骤C)所描述的方法,通过使中间体69B与中间体71B反应来制备标题化合物:(16mg,0.027mmol,59%产率):1H NMR(500MHz,DMSO-d6)δ8.84(s,2H),8.15(br t,J=6.4Hz,1H),8.05(br t,J=6.6Hz,1H),7.48(t,J=7.6Hz,1H),4.26(s,2H),2.38-2.28(m,1H),2.06-1.97(m,6H),1.56-1.41(m,6H),1.22-1.13(m,2H),1.11-1.00(m,2H)。FXR EC50(nM)=69。MS(ESI)599(M+H)。
实施例72
2-(5-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)乙酸
步骤1:向中间体16B(20mg,0.046mmol)、(E)-3-氨基-3-(羟亚氨基)丙酸叔丁酯(8.0mg,0.046mmol)和BOP(22mg,0.050mmol)于DMF(0.1mL)中的溶液中添加Et3N(0.019mL,0.14mmol)。将反应物在室温搅拌2h,且在80℃搅拌12h。使混合物冷却,用水稀释且用EtOAc(2×)萃取。经合并的有机层用10%氯化锂(水溶液)、盐水洗涤,经无水Na2SO4干燥,过滤且浓缩,得到呈黄褐色固体状的粗产物(26mg,0.045mmol,99%产率),其不经进一步纯化即用于下一步骤。MS(ESI)574(M+H)。
步骤2:向上文步骤1的产物(26mg,0.045mmol)中添加HCl(0.23mL,0.91mmol)(4M于1,4-二噁烷中)。在室温搅拌反应混合物18h且浓缩。通过制备型HPLC(柱:XBridge C18,19×200mm,5μm颗粒;流动相A:5:95的乙腈:水+0.1%三氟乙酸;流动相B:95:5的乙腈:水+0.1%三氟乙酸;梯度:30-70%B经20分钟,接着在100%B下保持4分钟;流速:20mL/min)纯化粗产物。将含有期望产物的级分合并、浓缩且在真空中干燥,得到标题化合物(0.90mg,1.7μmol,4%产率)。1H NMR(500MHz,DMSO-d6)δ7.64(br d,J=7.6Hz,2H),7.61-7.55(m,1H),4.17(s,2H),3.63(br s,2H),2.31(br s,1H),1.98-1.84(m,6H),1.48(br s,6H),1.19-1.11(m,2H),1.08(br s,2H)。FXR EC50(nM)=3100。MS(ESI)518(M+H)。
实施例76
1-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲基)-1H-吡唑-4-甲酸
步骤A.中间体76A.1-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲基)-1H-吡唑-4-甲酸乙酯的制备
在rt向中间体104A(20mg,0.047mmol)和1H-吡唑-4-甲酸乙酯(8.6mg,0.062mmol)于甲苯(0.2mL)中的溶液中添加氰基亚甲基三丁基磷烷(18mg,0.076mmol)。将反应物加热至100℃并搅拌。6h后,使反应物冷却,且通过快速柱色谱(4g硅胶滤筒;A=己烷,B=EtOAc;20min梯度;0%B至100%B;流速=4mL/min)纯化粗反应混合物。将纯级分合并、浓缩且在真空中干燥,得到呈浅棕色油状物的标题化合物(25mg,0.046mmol,97%产率)。MS(ESI)544(M+H)。
步骤B.实施例76
向中间体76A(25mg,0.046mmol)于MeOH(0.5mL)中的溶液中添加1M NaOH(水溶液)(0.23mL,0.23mmol)。在60℃搅拌反应混合物。1h后,使反应物冷却,且通过制备型HPLC(Phenomenex Luna AXIA 5u C18 21.2×100mm,10min梯度,15min运行,0%至100%溶剂B=90%MeOH-10%H2O-0.1%TFA,溶剂A=10%MeOH-90%H2O-0.1%TFA)纯化粗反应混合物。将期望级分浓缩且在真空中干燥,得到呈白色固体状的标题化合物(6.3mg,0.012mmol,26%产率)。1H NMR(500MHz,DMSO-d6)δ8.01-7.93(m,1H),7.67(s,1H),7.62-7.53(m,3H),4.11(s,2H),3.79(s,2H),2.30-2.23(m,1H),1.38-1.32(m,6H),1.32-1.24(m,6H),1.12(dt,J=8.5,2.9Hz,2H),1.08-1.02(m,2H)。FXR EC50(nM)=290。MS(ESI)516(M+H)。
实施例80
顺-3-((4-((5-环丙基-3-(2-三氟甲氧基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)环己烷甲酸
步骤A.中间体80A.4-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛烷-1-甲酸甲酯的制备
根据针对中间体16A的合成所描述的方法,适当时代入(5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲醇来制备标题化合物:(0.21g,0.45mmol,44%产率,无色油状物)。1H NMR(500MHz,氯仿-d)δ7.63-7.56(m,1H),7.55-7.50(m,1H),7.40(s,2H),4.23(s,2H),3.65(s,3H),2.16-2.10(m,1H),1.93-1.86(m,6H),1.67-1.59(m,6H),1.27-1.20(m,2H),1.13-1.07(m,2H)。
步骤B.中间体80B.(4-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲醇的制备
根据针对中间体104A的合成所描述的方法,使用中间体80A作为起始物质来制备标题化合物:(0.15g,0.35mmol,80%产率,无色油状物)。1H NMR(500MHz,氯仿-d)δ7.62-7.58(m,1H),7.55-7.49(m,1H),7.44-7.36(m,2H),4.24(s,2H),3.27(s,2H),2.18-2.11(m,1H),1.59(m,6H),1.54(m,6H),1.25-1.21(m,2H),1.12-1.08(m,2H)。
步骤C.中间体80C.4-((4-溴甲基)双环[2.2.2]辛-1-基氧基)甲基)-5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑的制备
向中间体80B(450mg,1.0mmol)于CH2Cl2(3mL)中的溶液中添加Ph3P(410mg,1.5mmol)。使反应物在冰浴中冷却,且逐份添加CBr4(510mg,1.5mmol)。搅拌2d后,浓缩溶剂且通过快速柱色谱(40g硅胶滤筒;A=己烷,B=EtOAc;25min梯度;0%B至30%B;流速=40mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈白色固体状的标题化合物(310mg,0.62mmol,60%产率)。1H NMR(500MHz,氯仿-d))δ7.61-7.54(m,1H),7.53-7.47(m,1H),7.42-7.33(m,2H),4.22(s,2H),3.17(s,2H),2.17-2.06(m,1H),1.59(s,12H),1.24-1.17(m,2H),1.11-1.04(m,2H)。MS(ESI)500.0(M+H)。
步骤D.实施例80
在室温向(1S,3R)-3-羟基环己烷-1-甲酸甲酯(63mg,0.40mmol)于无水NMP(0.5mL)中的溶液中添加KOtBu(27mg,0.24mmol)。5分钟后,添加中间体80C(40mg,0.080mmol)。在120℃搅拌反应物2h。冷却至室温后,通过逐滴添加1M HCl(水溶液)将反应物酸化至pH约3。将所得反应混合物用DMF稀释,且经由制备型HPLC(柱:XBridge C18,19×200mm,5μm颗粒;流动相A:5:95的乙腈:水/10mM乙酸铵;流动相B:95:5的乙腈:水/10mM乙酸铵;梯度:20-64%B经20分钟,接着在100%B下保持4分钟;流速:20mL/min)纯化。将含有期望产物的级分合并且经由离心蒸发干燥。该物质进一步经由制备型HPLC(柱:XBridge C18,19×200mm,5μm颗粒;流动相A:5:95的乙腈:水+0.1%三氟乙酸;流动相B:95:5的乙腈:水+0.1%三氟乙酸;梯度:31-71%B经20分钟,接着在100%B下保持4分钟;流速:20mL/min)纯化。将含有期望产物的级分合并、浓缩且在真空中干燥,得到标题化合物(8.2mg,17%产率)。1H NMR(500MHz,DMSO-d6)δ7.70-7.63(m,1H),7.59(br d,J=6.5Hz,1H),7.53(t,J=7.7Hz,2H),4.17(s,2H),3.65(s,2H),3.46-3.35(m,1H),2.31(tt,J=12.2,3.4Hz,1H),2.26-2.19(m,1H),2.05-1.99(m,1H),1.85-1.66(m,3H),1.53-1.42(m,12H),1.29-1.20(m,1H),1.20-1.15(m,1H),1.15-1.09(m,3H),1.07-1.00(m,3H)。FXR EC50(nM)=5100。MS(ESI)564(M+H)。
实施例85
3-((4-((5-环丙基-3-(2-三氟甲氧基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氨基)苯甲酸
向中间体80C(35mg,0.070mmol)和3-氨基苯甲酸乙酯(14mg,0.084mmol)于DMF(1mL)中的溶液中添加KOtBu(7.9mg,0.070mmol)。将反应物在室温搅拌4h,且在100℃搅拌1h。冷却至室温后,将反应混合物用H2O稀释且用EtOAc(3×)萃取。浓缩经合并的有机萃取物,且经由制备型HPLC(柱:XBridge C18,19×200mm,5μm颗粒;流动相A:5:95的乙腈:水/10mM乙酸铵;流动相B:95:5的乙腈:水/10mM乙酸铵;梯度:20-64%B经20分钟,接着在100%B下保持4分钟;流速:20mL/min)纯化粗物质。将含有期望产物的级分合并且经由离心蒸发干燥。该物质进一步经由制备型HPLC(柱:XBridge C18,19×200mm,5μm颗粒;流动相A:5:95的乙腈:水+0.1%三氟乙酸;流动相B:95:5的乙腈:水+0.1%三氟乙酸;梯度:31-71%B经20分钟,接着在100%B下保持4分钟;流速:20mL/min)纯化。将含有期望产物的级分合并、浓缩且在真空中干燥,得到标题化合物(8.1mg,21%产率)。1H NMR(500MHz,DMSO-d6)δ7.69-7.63(m,1H),7.62-7.57(m,1H),7.57-7.50(m,2H),7.18(s,1H),7.16-7.11(m,1H),7.11-7.07(m,1H),6.80(br d,J=7.3Hz,1H),4.16(s,2H),3.83(s,2H),2.29-2.19(m,1H),1.57-1.43(m,12H),1.15-1.08(m,2H),1.07-1.01(m,2H)。FXR EC50(nM)=610。MS(ESI)557(M+H)。
实施例89
4-((4-((3-(2H-四唑-5-基)苯氧基)甲基)双环[2.2.2]辛-1-基氧基)甲基)-5-环丙基-3-(2,6-二氯苯基)异噁唑
在100℃搅拌实施例88(19mg,0.036mmol)、二丁基锡酮(18mg,0.073mmol)和叠氮基三甲基硅烷(42mg,0.36mmol)于甲苯(0.5mL)中的混合物4h。冷却至室温后,将反应物用H2O稀释且用EtOAc(3×)萃取。浓缩经合并的有机萃取物,且经由制备型HPLC(柱:XBridgeC18,19×200mm,5μm颗粒;流动相A:5:95的乙腈:水/10mM乙酸铵;流动相B:95:5的乙腈:水/10mM乙酸铵;梯度:20-64%B经20分钟,接着在100%B下保持4分钟;流速:20mL/min)纯化粗物质。将含有期望产物的级分合并且经由离心蒸发干燥。该物质进一步经由制备型HPLC(柱:XBridge C18,19×200mm,5μm颗粒;流动相A:5:95的乙腈:水+0.1%三氟乙酸;流动相B:95:5的乙腈:水+0.1%三氟乙酸;梯度:31-71%B经20分钟,接着在100%B下保持4分钟;流速:20mL/min)纯化。将含有期望产物的级分合并、浓缩且在真空中干燥,得到标题化合物(4.1mg,0.0070mmol,19%产率)。1H NMR(500MHz,DMSO-d6)δ7.69-7.61(m,2H),7.59-7.51(m,2H),7.48(br s,1H),7.29(br t,J=7.9Hz,1H),6.89-6.81(m,1H),4.15(s,2H),3.57(s,2H),2.35-2.24(m,1H),1.65-1.47(m,6H),1.44-1.30(m,6H),1.18-1.10(m,2H),1.09-1.03(m,2H)。FXR EC50(nM)=120。MS(ESI)566(M+H)。
实施例104
2-(2-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)吡啶-4-基)乙酸
步骤A.中间体104A.(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲醇的制备
在-78℃向中间体16A(0.35g,0.78mmol)于THF(5mL)中的经搅拌溶液中逐滴添加氢化锂铝(0.39mL,0.78mmol)(于THF中的2M溶液)。在30min的时间段内使反应物缓慢升温至rt。使反应物冷却至0℃,且添加EtOAc和1M HCl(水溶液)并搅拌反应物30min。浓缩反应混合物且用EtOAc稀释。有机层用H2O洗涤,经MgSO4干燥,过滤且浓缩。通过快速柱色谱(24g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;10%B至100%B;流速=24mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈白色泡沫状的标题化合物(0.32g,0.76mmol,97%产率)。1H NMR(500MHz,氯仿-d)δ7.45-7.40(m,2H),7.39-7.32(m,1H),4.20(s,2H),3.23(s,2H),2.18-2.10(m,1H),1.47(s,12H),1.28-1.22(m,2H),1.17-1.07(m,2H)。MS(ESI)422.0(M+H)。
步骤B.中间体104B.2-(2-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)吡啶-4-基)乙酸乙酯的制备
向中间体104A(15mg,0.036mmol)于THF(1mL)中的经搅拌溶液中添加KOtBu(8.0mg,0.071mmol)。5min后,添加2-(2-氟吡啶-4-基)乙酸乙酯(9.8mg,0.053mmol),且在100℃搅拌反应物2h。使反应混合物冷却至rt,浓缩且用EtOAc稀释。有机层用饱和NaHCO3(水溶液)洗涤,经MgSO4干燥,过滤且浓缩。通过快速柱色谱(12g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至60%B;流速=12mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈透明液体状的标题化合物(10mg,0.017mmol,48%产率)。1H NMR(500MHz,氯仿-d)δ8.11(d,J=5.2Hz,1H),7.49-7.41(m,2H),7.38-7.35(m,1H),6.85-6.76(m,1H),6.65(d,J=7.2Hz,1H),4.38(q,J=7.2Hz,1H),4.18(s,2H),3.78-3.69(m,2H),3.56(d,J=2.8Hz,2H),2.22-2.07(m,2H),1.71-1.55(m,6H),1.53-1.46(m,6H),1.43-1.38(m,3H),1.30-1.23(m,2H),1.16-1.08(m,2H)。MS(ESI)585.2(M+H)。
步骤C.实施例104
向中间体104B(10mg,0.017mmol)于THF(1mL)中的经搅拌溶液中添加含单水合氢氧化锂(1.4mg,0.034mmol)的水(1mL)。在rt搅拌反应物3h。浓缩反应物,且经由制备型HPLC(柱:XBridge C18,19×200mm,5μm颗粒;流动相A:5:95的乙腈:水/10mM乙酸铵;流动相B:95:5的乙腈:水/10mM乙酸铵;梯度:20-64%B经20分钟,接着在100%B下保持4分钟;流速:20mL/min)纯化粗物质。将含有期望产物的级分合并且经由离心蒸发干燥。该物质进一步经由制备型HPLC(柱:XBridge C18,19×200mm,5μm颗粒;流动相A:5:95的乙腈:水+0.1%三氟乙酸;流动相B:95:5的乙腈:水+0.1%三氟乙酸;梯度:31-71%B经20分钟,接着在100%B下保持4分钟;流速:20mL/min)纯化。将含有期望产物的级分合并、浓缩且在真空中干燥,得到标题化合物(2.3mg,0.0041mmol,24%)。1H NMR(500MHz,DMSO-d6)δ8.02(d,J=5.2Hz,1H),7.68-7.60(m,2H),7.60-7.50(m,1H),6.85(d,J=4.9Hz,1H),6.67(s,1H),4.16(s,2H),3.82(s,2H),3.58(s,2H),2.28(td,J=8.4,4.6Hz,1H),1.58-1.42(m,6H),1.36(br d,J=8.5Hz,6H),1.14(br d,J=8.2Hz,2H),1.07(br d,J=2.7Hz,2H)。FXR EC50(nM)=210nM。MS(ESI)557.3(M+H)。
实施例105
6-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)喹啉-2-甲酸
步骤A.中间体105A.6-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)喹啉-2-甲酸甲酯的制备
向中间体104A(17mg,0.039mmol)和6-羟基喹啉-2-甲酸甲酯(12mg,0.059mmol)于1,4-二噁烷(1mL)中的经搅拌溶液中添加1,1'-(氮杂二羰基)二哌啶(20mg,0.078mmol)和三-正丁基膦(16mg,0.078mmol)。在80℃搅拌反应物16h。浓缩反应混合物且用EtOAc稀释。有机层用H2O洗涤,经MgSO4干燥,过滤且浓缩。通过快速柱色谱(12g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=12mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈透明液体状的标题化合物(20mg,0.033mmol,84%产率)。1H NMR(500MHz,氯仿-d)δ8.23-8.12(m,2H),7.48-7.39(m,3H),7.36(dd,J=8.9,7.3Hz,1H),7.29(s,1H),7.05(d,J=2.8Hz,1H),4.23(s,2H),4.09(s,3H),3.68(s,2H),2.18-2.10(m,1H),1.72-1.62(m,6H),1.60-1.50(m,6H),1.34-1.21(m,2H),1.11(td,J=8.0,2.8Hz,2H)。MS(ESI)607.0(M+H)。
步骤B.实施例105
根据针对实施例104的合成(步骤C)所描述的方法,使用中间体105A作为起始物质来制备标题化合物:(7.4mg,0.012mmol,38%产率,白色固体)。1H NMR(500MHz,DMSO-d6)δ8.31(br d,J=8.5Hz,1H),8.02(br t,J=8.4Hz,2H),7.71-7.62(m,2H),7.62-7.54(m,1H),7.43(br d,J=9.2Hz,1H),7.37(br s,1H),4.18(s,2H),3.71(s,2H),2.36-2.25(m,1H),1.57(br d,J=7.9Hz,6H),1.48-1.34(m,6H),1.20-1.11(m,2H),1.08(br d,J=2.7Hz,2H)。FXR EC50(nM)=76nM。MS(ESI)593.2(M+H)。
根据本文中其他处所描述的方法,使用适当起始物质、试剂和条件来制备表2中的以下实施例。
表2
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
实施例121
3-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)(羟基)甲基)-4-氟苯甲酸
步骤A.中间体121A.4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛烷-1-甲醛的制备
将草酰氯(0.15mL,1.7mmol)于CH2Cl2(9mL)中的溶液冷却至-78℃,且逐滴添加DMSO(0.28mL,3.9mmol)于CH2Cl2(4mL)中的溶液。搅拌反应混合物10min。缓慢添加中间体104A(0.55g,1.3mmol)于CH2Cl2中的溶液,且搅拌反应混合物30min。添加三乙胺(0.91mL,6.5mmol),且使反应混合物升温至rt并搅拌30min。将反应混合物用CH2Cl2稀释,用1M HCl(水溶液)、1M K2HPO4(水溶液)、盐水洗涤,干燥(MgSO4),过滤且浓缩。将产物在真空中干燥,得到呈灰白色固体状的标题化合物(0.54g,1.3mmol,99%产率)。1H NMR(400MHz,氯仿-d)δ9.41(s,1H),7.42(d,J=1.5Hz,1H),7.40(s,1H),7.37-7.31(m,1H),4.19(s,2H),2.11(tt,J=8.4,5.1Hz,1H),1.71-1.62(m,6H),1.54-1.46(m,6H),1.27-1.22(m,2H),1.14-1.07(m,2H)。MS(ESI)420(M+H)。
步骤B.中间体121B.3-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)(羟基)甲基)-4-氟苯甲腈的制备
在-78℃向3-溴-4-氟苯甲腈(0.027g,0.13mmol)于无水THF(0.56mL)中的溶液中添加正丁基锂(0.084mL,0.13mmol)(于THF中的1.6M溶液)。在-78℃搅拌反应混合物1h。经由插管逐滴添加中间体121A(0.028g,0.067mmol)于THF(0.11mL)中的溶液。在-78℃搅拌反应混合物1h。将反应物用水淬灭且升温至rt。将反应混合物用EtOAc稀释且用盐水洗涤。将有机层干燥(MgSO4)且浓缩。通过快速柱色谱(12g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;10%B至100%B;流速=12mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈无色玻璃状的标题化合物(0.022g,0.040mmol,59%产率)。1H NMR(400MHz,氯仿-d)δ7.74(dd,J=6.5,2.1Hz,1H),7.55(ddd,J=8.6,4.6,2.2Hz,1H),7.41-7.39(m,1H),7.38(d,J=0.7Hz,1H),7.35-7.29(m,1H),7.09(dd,J=9.4,8.7Hz,1H),4.70(d,J=3.3Hz,1H),4.13(s,2H),4.12-4.09(m,1H),2.13-2.07(m,1H),1.62-1.48(m,4H),1.40(br d,J=3.5Hz,8H),1.24-1.19(m,2H),1.12-1.03(m,2H)。MS(ESI)541(M+H)。
步骤C.实施例121
向中间体121B(0.022g,0.040mmol)于EtOH(0.40mL)中的溶液中添加6M NaOH(水溶液)(0.13mL,0.79mmol)。在压力小瓶中在110℃搅拌反应混合物18h。使反应混合物冷却,用1M HCl(水溶液)酸化且用EtOAc(3×)萃取。将合并的有机层干燥(MgSO4)且浓缩。通过制备型HPLC(柱:XBridge C18,19×200mm,5μm颗粒;流动相A:5:95的乙腈:水+0.1%三氟乙酸;流动相B:95:5的乙腈:水+0.1%三氟乙酸;梯度:38-78%B经20分钟,接着100%B保持4分钟;流速:20mL/min)纯化粗物质。将含有期望产物的级分合并、浓缩且在真空中干燥,得到标题化合物(0.018g,0.033mmol,82%产率)。1H NMR(500MHz,DMSO-d6)δ7.95(br d,J=5.1Hz,1H),7.84(td,J=5.4,2.3Hz,1H),7.60-7.55(m,2H),7.55-7.49(m,1H),7.20(t,J=9.2Hz,1H),4.47(br d,J=3.8Hz,1H),4.07(s,2H),2.28-2.18(m,1H),1.45(br d,J=4.9Hz,3H),1.36-1.17(m,9H),1.14-1.08(m,2H),1.05-1.01(m,2H)。FXR EC50(nM)=1500。MS(ESI)560(M+H)。
实施例122
2-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)(羟基)甲基)-4-氟苯并[d]噻唑-6-甲酸
步骤A.中间体122A.(6-溴-4-氟苯并[d]噻唑-2-基)(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲醇的制备
根据针对实施例121的合成(步骤B)所描述的方法,通过使中间体121A与2,6-二溴-4-氟苯并[d]噻唑反应来制备标题化合物:(0.030g,0.046mmol,69%产率)。1H NMR(500MHz,氯仿-d)δ7.80(d,J=0.8Hz,1H),7.39(s,1H),7.37(s,1H),7.35(dd,J=9.6,1.7Hz,1H),7.33-7.29(m,1H),4.67(d,J=4.4Hz,1H),4.15(s,2H),4.14-4.10(m,1H),2.13-2.07(m,1H),1.71-1.60(m,6H),1.44(br t,J=7.7Hz,6H),1.24-1.20(m,2H),1.11-1.04(m,2H)。MS(ESI)653(M+H)。
步骤B.中间体122B.2-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)(羟基)甲基)-4-氟苯并[d]噻唑-6-甲腈的制备
用氮气(3×)吹扫含有(6-溴-4-氟苯并[d]噻唑-2-基)(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲醇(0.030g,0.046mmol)、Xantphos(5.3mg,9.2μmol)、Pd2(dba)3(8.5mg,9.3μmol)和氰化锌(11mg,0.092mmol)的微波小瓶,且添加无水DMF(0.5mL)。在110℃(微波)照射反应混合物1.5h。将反应混合物用EtOAc稀释且用水(3×)洗涤。有机层用盐水洗涤,干燥(MgSO4)且浓缩。通过快速柱色谱(12g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;10%B至100%B;流速=12mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈无色泡沫状的标题化合物(0.021g,0.034mmol,75%产率)。1H NMR(400MHz,氯仿-d)δ8.02(d,J=0.9Hz,1H),7.45(dd,J=9.6,1.4Hz,1H),7.39(d,J=1.5Hz,1H),7.37(s,1H),7.34-7.28(m,1H),4.74(d,J=5.1Hz,1H),4.15(s,2H),4.14-4.10(m,1H),2.13-2.06(m,1H),1.74-1.58(m,6H),1.50-1.42(m,6H),1.25-1.18(m,2H),1.11-1.03(m,2H)。MS(ESI)598(M+H)。
步骤C.实施例122
根据针对实施例121的合成(步骤C)所描述的方法,使用中间体122B作为起始物质来制备标题化合物:(0.0049g,0.0079mmol,23%产率)。1H NMR(500MHz,DMSO-d6)δ8.25(dd,J=4.8,1.7Hz,1H),8.17(dd,J=7.4,1.7Hz,1H),7.53(br d,J=19.7Hz,2H),7.43(br d,J=3.9Hz,1H),7.10(dd,J=7.4,4.9Hz,1H),6.31(s,1H),6.02(br d,J=7.7Hz,1H),5.21(quin,J=7.0Hz,1H),3.98(sxt,J=7.8Hz,1H),2.60(d,J=4.7Hz,4H),2.48-2.41(m,1H),2.41-2.33(m,1H),2.31-2.23(m,1H),2.23-2.10(m,2H),1.93(br t,J=9.5Hz,2H),1.29-1.17(m,2H),1.01(d,J=6.3Hz,1H),0.86-0.73(m,2H)。FXR EC50(nM)=1000。MS(ESI)617(M+H)。
实施例127
3-(2-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-2-羟乙基)苯甲酸
步骤A.中间体127A.2-(3-溴苯基)-1-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙-1-醇的制备
根据针对实施例121的合成(步骤B)所描述的方法,通过使中间体121A与溴化(3-溴苯甲基)镁反应来制备标题化合物:(0.024g,0.040mmol,50%产率)。1H NMR(500MHz,氯仿-d)δ7.46-7.41(m,2H),7.40-7.31(m,3H),7.21-7.15(m,1H),7.14-7.10(m,1H),4.21(s,2H),4.18-4.12(m,1H),3.33(br d,J=10.7Hz,1H),2.77(br d,J=13.8Hz,1H),2.19-2.11(m,1H),1.52-1.45(m,6H),1.34-1.21(m,6H),1.16-1.06(m,3H),0.94-0.81(m,2H)。MS(ESI)592(M+H)。
步骤B.实施例127
在-78℃向中间体127A(0.024g,0.040mmol)于THF(0.40mL)中的溶液中添加正丁基锂(0.028mL,0.044mmol)(于THF中的1.6M溶液)。5min后,添加一整刮勺尖的新制碎干冰,且使反应混合物升温至rt。反应混合物用1M HCl(水溶液)酸化,且用EtOAc(3×)萃取。将合并的有机层干燥(MgSO4)且浓缩。通过制备型HPLC(柱:XBridge C18,19×200mm,5μm颗粒;流动相A:5:95的乙腈:水/10mM乙酸铵;流动相B:95:5的乙腈:水/10mM乙酸铵;梯度:19-59%B经20分钟,接着在100%B下保持4分钟;流速:20mL/min)纯化粗物质。将含有期望产物的级分合并、浓缩且在真空中干燥,得到标题化合物(0.013g,0.023mmol,57%产率)。1HNMR(500MHz,DMSO-d6)δ7.77(s,1H),7.74(br d,J=7.6Hz,1H),7.64(s,1H),7.63(s,1H),7.60-7.54(m,1H),7.43-7.38(m,1H),7.38-7.32(m,1H),4.14(s,2H),3.10(br d,J=8.5Hz,1H),2.72(br d,J=14.0Hz,1H),2.36-2.23(m,2H),1.54-1.37(m,6H),1.36-1.26(m,6H),1.19-1.11(m,2H),1.10-1.03(m,2H)。FXR EC50(nM)=280。MS(ESI)556(M+H)。
实施例130
3-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)苯甲酸
步骤A.中间体130A.5-环丙基-3-(2,6-二氯苯基)-4-(((4-乙炔基双环[2.2.2]辛-1-基)氧基)甲基)异噁唑的制备
向中间体121A(0.056g,0.13mmol)和K2CO3(0.037g,0.27mmol)的溶液中添加无水MeOH(0.5mL),且在rt搅拌混合物30min。经由注射器添加(1-重氮-2-氧代丙基)膦酸二甲酯(0.030g,0.16mmol),且搅拌反应混合物1h。将反应混合物用醚稀释,用1M K2HPO4(水溶液)洗涤,干燥(MgSO4),过滤且浓缩,得到呈灰白色泡沫状的标题化合物(0.054g,0.13mmol,99%产率),其不经进一步纯化即使用。1H NMR(500MHz,氯仿-d)δ7.43(d,J=0.8Hz,1H),7.42(s,1H),7.38-7.33(m,1H),4.16(s,2H),2.15-2.09(m,1H),2.07(s,1H),1.89-1.76(m,6H),1.53-1.41(m,6H),1.28-1.22(m,2H),1.15-1.06(m,2H)。MS(ESI)416(M+H)。
步骤B.中间体130B.3-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)苯甲酸甲酯的制备
用氮气吹扫含有碘化铜(I)(0.18mg,0.94μmol)和Pd(dppf)Cl2·CH2Cl2加合物(0.77mg,0.94μmol)的烧瓶。添加3-碘苯甲酸甲酯(0.015g,0.056mmol)和中间体130A(0.020g,0.047mmol)以及THF(0.37mL)和TEA(0.099mL)。在70℃搅拌反应混合物18h。将反应混合物用EtOAc稀释,过滤且浓缩。通过快速柱色谱(12g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;10%B至100%B;流速=12mL/min)纯化粗物质。将纯级分合并、浓缩且在真空中干燥,得到标题化合物(0.016g,0.029mmol,62%产率)。1H NMR(500MHz,氯仿-d)δ8.04-7.99(m,1H),7.94-7.89(m,1H),7.52-7.48(m,1H),7.43(d,J=0.8Hz,1H),7.41(s,1H),7.37-7.31(m,2H),4.17(s,2H),3.91(s,3H),2.12(tt,J=8.5,5.0Hz,1H),1.94-1.83(m,6H),1.54-1.45(m,6H),1.27-1.22(m,2H),1.14-1.06(m,2H)。MS(ESI)550(M+H)。
步骤C.实施例130
向中间体130B(0.016g,0.029mmol)于THF(0.29mL)中的溶液中添加1M NaOH(水溶液)(0.18mL,0.18mmol)和数滴MeOH。在70℃搅拌反应混合物2h。将反应混合物用1M HCl(水溶液)酸化且用EtOAc(3×)萃取。将合并的有机层干燥(MgSO4)且浓缩。通过制备型HPLC(柱:XBridge C18,19×200mm,5μm颗粒;流动相A:5:95的乙腈:水/10mM乙酸铵;流动相B:95:5的乙腈:水/10mM乙酸铵;梯度:26-66%B经20分钟,接着在100%B下保持4分钟;流速:20mL/min)纯化粗物质。将含有期望产物的级分合并、浓缩且在真空中干燥,得到标题化合物(15mg,0.029mmol,98%产率)。1H NMR(500MHz,DMSO-d6)δ7.87(br d,J=7.8Hz,1H),7.81(s,1H),7.65(s,1H),7.63(s,1H),7.60-7.55(m,1H),7.54(br d,J=7.7Hz,1H),7.50-7.42(m,1H),4.13(s,2H),2.34-2.24(m,1H),1.88-1.75(m,6H),1.47-1.34(m,6H),1.19-1.11(m,2H),1.10-1.03(m,2H)。FXR EC50(nM)=68。MS(ESI)536(M+H)。
实施例131
3-(4-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1H-1,2,3-三唑-1-基)苯甲酸
步骤A.中间体131A.3-(4-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1H-1,2,3-三唑-1-基)苯甲酸乙酯的制备
向压力小瓶中添加中间体130A(0.020g,0.048mmol)、3-叠氮苯甲酸乙酯(0.018g,0.096mmol)和碘化铜(I)(0.91mg,4.8μmol)。用氮气(3×)吹扫烧瓶,接着添加THF(0.48mL)和TEA(0.013mL,0.096mmol)。将反应混合物在50℃搅拌3h,且在rt搅拌18h。浓缩反应混合物,且通过快速柱色谱(12g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;10%B至100%B;流速=12mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈无色玻璃状的标题化合物(0.023g,0.038mmol,79%产率)。1H NMR(500MHz,氯仿-d)δ8.27(s,1H),8.09(d,J=7.7Hz,1H),7.99(dd,J=8.1,1.2Hz,1H),7.68(s,1H),7.59(t,J=7.8Hz,1H),7.46-7.40(m,2H),7.39-7.31(m,1H),4.43(q,J=7.1Hz,2H),4.23(s,2H),2.18-2.10(m,1H),2.04-1.94(m,6H),1.67-1.56(m,6H),1.43(t,J=7.2Hz,3H),1.28-1.23(m,2H),1.15-1.06(m,2H)。MS(ESI)607(M+H)。
步骤B.实施例131
根据针对实施例130的合成(步骤C)所描述的方法制备标题化合物:(20mg,0.034mmol,91%产率)。1H NMR(500MHz,DMSO-d6)δ8.61(s,1H),8.35(s,1H),8.07(br d,J=7.9Hz,1H),7.99(br d,J=7.6Hz,1H),7.68(t,J=7.9Hz,1H),7.65(s,1H),7.64(s,1H),7.61-7.55(m,1H),4.19(s,2H),2.35-2.25(m,1H),1.92-1.82(m,6H),1.55-1.40(m,6H),1.15(br d,J=8.2Hz,2H),1.11-1.04(m,2H)。FXR EC50(nM)=460。MS(ESI)579(M+H)。
实施例134
2-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)喹啉-6-甲酸
步骤A.中间体134A.3,5-二氟苯甲酸4-碘双环[2.2.2]辛-1-基酯的制备
向100mL梨形烧瓶中添加4-((3,5-二氟苯甲酰基)氧基)双环[2.2.2]辛烷-1-甲酸(200mg,0.65mmol)(Shi,Y.等人WO 2014/159802)、氯苯(26mL)、四乙酸铅(370mg,0.84mmol),接着添加碘(360mg,1.4mmol)。在N2下在80℃搅拌反应物,且用蓝色LED(Kessil)照射2.5h。过滤反应物且浓缩经合并的滤液。通过快速柱色谱(24g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=24mL/min)纯化产物。将纯级分合并、浓缩且在真空中干燥,得到呈无色油状物的标题化合物(220mg,0.55mmol,85%产率)。1H NMR(400MHz,氯仿-d)δ7.54-7.40(m,2H),7.08-6.88(m,1H),2.69-2.50(m,6H),2.34-2.19(m,6H)。
步骤B.中间体134B.2-(4-((3,5-二氟苯甲酰基)氧基)双环[2.2.2]辛-1-基)喹啉-6-甲酸甲酯的制备
在0℃向含有含喹啉-6-甲酸甲酯(17mg,0.89mmol)的乙醇(1.2mL)的密封反应容器中添加TFA(69μL,0.89mmol)。移除冰浴,添加中间体134A(140mg,0.36mmol)和三(三甲基硅烷基)硅烷(240μL,0.79mmol)。在90℃搅拌反应物直至混合物变均匀,之后添加AIBN(70mg,0.43mmol)。密封反应容器且在90℃搅拌16h。使反应物冷却,将其倒入1M K2HPO4(水性)溶液中且用EtOAc萃取。将有机相用盐水洗涤,经硫酸钠干燥并浓缩。通过快速柱色谱(24g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=24mL/min)纯化产物。将纯级分合并、浓缩且在真空中干燥,得到呈白色固体状的标题化合物(65mg,0.14mmol,40%产率)。1H NMR(400MHz,氯仿-d)δ8.60-8.49(m,1H),8.26(dd,J=8.8,2.0Hz,1H),8.20-8.13(m,1H),8.06(d,J=8.8Hz,1H),7.56-7.42(m,3H),7.06-6.89(m,1H),4.02-3.96(m,3H),2.40-2.18(m,12H)。MS(ESI)452(M+H)。
步骤C.中间体134C.2-(4-羟基双环[2.2.2]辛-1-基)喹啉-6-甲酸甲酯的制备
向含有中间体134B(80mg,0.18mmol)、THF(2mL)和MeOH(2mL)的小瓶中添加甲醇钠(66μL,0.35mmol)(5.4M于MeOH中)。将反应物在室温搅拌1h,用5%柠檬酸(水溶液)(10mL)稀释,且用EtOAc(2×25mL)萃取。合并有机层,用盐水洗涤,经硫酸钠干燥,过滤且浓缩。通过快速柱色谱(12g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=12mL/min)纯化产物。将纯级分合并、浓缩且在真空中干燥,得到呈白色固体状的标题化合物(19mg,0.061mmol,34%产率)。1H NMR(400MHz,氯仿-d)δ8.53(d,J=2.0Hz,1H),8.25(dd,J=8.8,2.0Hz,1H),8.15(d,J=8.6Hz,1H),8.05(d,J=8.8Hz,1H),7.65-7.47(m,1H),4.03-3.80(m,3H),2.30-2.09(m,6H),1.87-1.79(m,6H)。MS(ESI)312(M+H)。
步骤D.中间体134D.2-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)喹啉-6-甲酸甲酯的制备
向烧瓶中添加中间体134C(19mg,0.061mmol)、三氟甲烷磺酸银(94mg,0.37mmol)和2,6-二-叔丁基吡啶(81μL,0.37mmol)以及DCM(1.2mL)。将混合物冷却至0℃,添加4-(溴甲基)-5-环丙基-3-(2,6-二氯苯基)异噁唑(32mg,0.092mmol),且使反应物缓慢达至室温并搅拌7h。过滤且浓缩混合物。通过快速柱色谱(12g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=12mL/min)纯化产物。将纯级分合并、浓缩且在真空中干燥,得到呈无色油状物的标题化合物(11mg,0.019mmol,31%产率)。1H NMR(400MHz,氯仿-d)δ8.54-8.46(m,1H),8.24(dd,J=8.9,1.9Hz,1H),8.13(d,J=8.8Hz,1H),8.02(d,J=8.8Hz,1H),7.47-7.39(m,2H),7.38-7.28(m,2H),4.29-4.19(m,2H),3.98(s,3H),2.21-2.12(m,1H),2.10-1.98(m,6H),1.68-1.58(m,6H),1.30-1.22(m,2H),1.15-1.05(m,2H)。MS(ESI)577(M+H)。
步骤E.实施例134
根据针对实施例1的合成(步骤D)所描述的方法,以中间体134D为起始物质来制备标题化合物:(3.3mg,0.0060mmol,30%产率)。1H NMR(500MHz,DMSO-d6)δ8.54(s,1H),8.39(d,J=8.9Hz,1H),8.16(br d,J=8.9Hz,1H),7.94(d,J=8.9Hz,1H),7.67-7.56(m,4H),4.20(s,2H),2.31(br t,J=4.9Hz,1H),2.07-1.91(m,6H),1.56-1.43(m,6H),1.23-1.12(m,2H),1.08(br d,J=2.7Hz,2H)。FXR EC50(nM)=83。MS(ESI)563(M+H)。
实施例135
6-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1-甲基-1H-吡咯并[2,3-b]吡啶-3-甲酸
步骤A.中间体135A.5-环丙基-3-(2,6-二氯苯基)-4-(((4-碘双环[2.2.2]辛-1-基)氧基)甲基)异噁唑的制备
向小瓶中添加中间体16B(0.11g,0.25mmol)、氯苯(3mL)、四乙酸铅(0.15g,0.33mmol),接着添加碘(0.14g,0.56mmol)。在氮气下在80℃搅拌反应物,且用蓝色LED(Kessil)照射2h。使反应物冷却,过滤且用DCM洗涤滤饼。有机层用硫代硫酸钠、盐水洗涤,经硫酸钠干燥且浓缩。通过快速柱色谱(24g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=24mL/min)纯化产物。将纯级分合并、浓缩且在真空中干燥,得到呈白色固体状的标题化合物(100mg,0.20mmol,77%产率)。1H NMR(400MHz,氯仿-d)δ7.54-7.13(m,3H),2.55-2.34(m,6H),2.13-1.90(m,1H),1.66-1.44(m,6H),1.28-1.17(m,2H),1.11-0.98(m,2H)。MS(ESI)518(M+H)。
步骤B.中间体135B.6-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1-甲基-1H-吡咯并[2,3-b]吡啶-3-甲酸甲酯的制备
在0℃向含有含1-甲基-1H-吡咯并[2,3-b]吡啶-3-甲酸甲酯(37mg,0.19mmol)的乙醇(0.4mL)的密封反应容器中添加TFA(15μL,0.19mmol)。移除冰浴,且添加中间体135A(40mg,0.077mmol)和三(三甲基硅烷基)硅烷(52μL,0.17mmol)。在90℃搅拌混合物直至均匀,之后添加AIBN(15mg,0.093mmol)。在90℃搅拌反应物15h。使反应物冷却,将其倒入1MK2HPO4(水溶液)中,用EtOAc萃取,且有机相用盐水洗涤、经硫酸钠干燥并浓缩。通过快速柱色谱(12g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=12mL/min)纯化产物。将纯级分合并、浓缩且在真空中干燥,得到标题化合物(4.0mg,6.9μmol,9%产率)。MS(ESI)580(M+H)。
步骤C.实施例135
根据针对实施例1的合成(步骤D)所描述的方法,以中间体135B为起始物质来制备标题化合物:(1.7mg,0.0030mmol,42%产率)。1H NMR(500MHz,DMSO-d6)δ8.34-8.12(m,1H),7.76-7.62(m,1H),7.39-7.16(m,2H),7.13(br s,1H),7.03(br s,1H),4.20(s,2H),3.81(s,3H),2.32(br s,1H),2.01-1.79(m,6H),1.59-1.37(m,6H),1.21-1.12(m,2H),1.09(brd,J=2.9Hz,2H)。FXR EC50(nM)=9。MS(ESI)566(M+H)。
实施例139
2-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛烷-1-羰基)-1,2,3,4-四氢异喹啉-5-甲酸
步骤A.中间体139A.2-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛烷-1-羰基)-1,2,3,4-四氢异喹啉-5-甲酸乙酯的制备
向中间体16B(0.020g,0.050mmol)于DMF(0.23mL)中的溶液中添加HATU(0.020g,0.060mmol)。搅拌5min后,添加1,2,3,4-四氢异喹啉-5-甲酸乙酯(0.010g,0.060mmol)和休尼格氏碱(0.02mL,0.12mmol),且在rt搅拌反应混合物。18h后,将混合物用EtOAc稀释,且有机相用水和盐水洗涤、干燥(MgSO4)并浓缩。通过快速柱色谱(4g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=18mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到标题化合物(22mg,0.040mmol,77%产率)。MS(ESI)624(M+H)。1H NMR(500MHz,氯仿-d)δ7.84(br d,J=6.1Hz,1H),7.44(br d,J=7.7Hz,2H),7.40-7.33(m,1H),7.32-7.25(m,2H),4.74(br s,2H),4.37(q,J=6.9Hz,2H),4.20(s,2H),3.81(br s,2H),3.25(br s,2H),2.14(br d,J=4.4Hz,1H),1.97(br s,6H),1.90-1.82(m,1H),1.41(br t,J=6.9Hz,4H),1.34-1.21(m,5H),1.12(br d,J=6.1Hz,3H)。
步骤D.实施例139
向中间体139A(0.020g,0.040mmol)于THF(0.39mL)、MeOH(0.20mL)和水(0.20mL)中的溶液中添加单水合氢氧化锂(0.012g,0.28mmol)。在室温搅拌反应物18h,之后浓缩溶剂。通过制备型HPLC(柱:XBridge C18,19×200mm,5μm颗粒;流动相A:5:95的乙腈:水+0.1%三氟乙酸;流动相B:95:5的乙腈:水+0.1%三氟乙酸;梯度:40-80%B经20分钟,接着在100%B下保持3分钟;流速:20mL/min)纯化粗产物。将含有期望产物的级分合并、浓缩且在真空中干燥,得到标题化合物(0.017g,0.029mmol,88%产率)。1H NMR(500MHz,DMSO-d6)δ7.68-7.63(m,1H),7.60-7.55(m,2H),7.54-7.49(m,1H),7.35(br d,J=7.3Hz,1H),7.23(t,J=7.6Hz,1H),4.61(br s,2H),4.07(s,2H),3.68(br s,1H),3.01(br s,2H),2.28-2.19(m,1H),1.81-1.72(m,6H),1.39-1.30(m,6H),1.14-1.06(m,2H),1.02(br d,J=2.7Hz,2H),0.95(d,J=6.1Hz,1H)。FXR EC50(nM)=1400。MS(ESI)596(M+H)。
根据本文中其他处所描述的方法,使用适当起始物质、试剂和条件来制备表3中的以下实施例。
表3
/>
/>
/>
/>
/>
/>
/>
实施例151
3-(5-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸
步骤A.中间体151A.4-(5-(4-羟基甲基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸甲酯的制备
向25mL梨形烧瓶中添加含4-(羟基甲基)双环[2.2.2]辛烷-1-甲酸(160mg,0.85mmol)(Kiesman W.F.等人WO 2001/034610)和BOP(38mg,0.85mmol)的DMF(1mL),接着添加(Z)-3-(N'-羟基甲脒基)苯甲酸甲酯(Tung,R.D.WO 2016/073545)(150mg,0.77mmol)。在0℃向该混合物中添加Et3N(0.32mL,2.3mmol)。将反应混合物在rt搅拌2h,且在100℃搅拌4h。使反应物冷却,浓缩溶剂且将残余物溶解于EtOAc(50mL)中。将有机相用盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过快速柱色谱(24g硅胶柱;A=己烷,B=EtOAc;15min梯度;0%B至30%B;流速=24mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈淡黄色固体状的标题化合物(120mg,45%产率)。1H NMR(400MHz,DMSO-d6)δ=8.54(t,J=1.5Hz,1H),8.26(dt,J=7.8,1.5Hz,1H),8.16(dt,J=7.9,1.6Hz,1H),7.74(t,J=7.7Hz,1H),5.76(s,1H),4.46(t,J=5.5Hz,1H),3.99-3.85(m,3H),3.11(d,J=5.4Hz,2H),1.99(d,J=7.8Hz,6H),1.55-1.39(m,6H)。MS(ESI)343(M+H)。
步骤B.中间体151B.3-(5-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸甲酯的制备
向20mL闪烁瓶中添加中间体151A(50mg,0.15mmol)、2,6-二-叔丁基吡啶(0.12mL,0.51mmol)、无水DCM(1mL),接着添加三氟甲烷磺酸银(110mg,0.44mmol)。在0℃逐滴添加4-(溴甲基)-5-环丙基-3-(2,6-二氯苯基)异噁唑(150mg,0.44mmol)于DCM(1mL)中的溶液。在rt搅拌反应物12h,且用DCM:MeOH(1:1;4mL)稀释。滤出固体且浓缩滤液。将残余物经由SiO2塞过滤,首先用己烷接着用EtOAc洗脱,收集粗产物。浓缩滤液,且通过制备型HPLC(WatersXBridge C18,19×150mm,5μm颗粒;流动相A:10mM乙酸铵;流动相B:乙腈;梯度:45-95%B经25分钟,接着在100%B下保持5分钟;流速:15mL/min)纯化粗物质。将含有期望产物的级分合并、浓缩且在真空中干燥,得到标题化合物(13mg,14%产率)。1H NMR(400MHz,DMSO-d6)δ8.59-8.46(m,1H),8.24(dd,J=7.8,1.3Hz,1H),8.19-8.10(m,1H),7.80-7.69(m,1H),7.69-7.62(m,2H),7.61-7.50(m,1H),4.25(s,2H),3.91(s,3H),2.96(s,2H),2.38-2.22(m,1H),2.00-1.74(m,6H),1.42-1.21(m,6H),1.19-1.01(m,4H)。MS(ESI)608(M+H)。
步骤C.实施例151
在0℃向中间体151B(23mg,0.038mmol)于MeOH(1mL)中的经搅拌溶液中添加NaOH(7.6mg,0.19mmol)于H2O(0.5mL)中的溶液。使反应混合物升温至rt并搅拌。18h后,将混合物用5%柠檬酸(水溶液)(20mL)稀释且用EtOAc(2×25mL)萃取。将有机相合并,用盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过制备型HPLC(柱:Waters XBridge C18,19×150mm,5μm颗粒;流动相A:10mM乙酸铵;流动相B:乙腈;梯度:15-55%B经25分钟,接着在100%B下保持5分钟;流速:15mL/min)纯化粗物质。将含有期望产物的级分合并、浓缩且在真空中干燥,得到标题化合物(0.0096g,42%产率)。1H NMR(400MHz,DMSO-d6)δ8.58-8.48(m,1H),8.19(dt,J=7.7,1.4Hz,1H),8.12(dt,J=7.8,1.3Hz,1H),7.76-7.62(m,3H),7.62-7.50(m,1H),4.26(s,2H),2.97(s,2H),2.34-2.26(m,1H),1.97-1.79(m,6H),1.42-1.25(m,6H),1.20-1.02(m,4H)。FXR EC50(nM)=150。MS(ESI)594(M+H)。
实施例159
(E)-3-(5-(4-(2-(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸
步骤A.中间体159A.4-(羟基甲基)双环[2.2.2]辛烷-1-甲酸甲酯的制备
在0℃向4-(甲氧基羰基)双环[2.2.2]辛烷-1-甲酸(1.5g,7.1mmol)于THF(17mL)中的经搅拌溶液中添加甲硼烷二甲基硫醚络合物(2.0mL,21mmol)。使反应物升温至rt并搅拌。4h后,将反应混合物用MeOH(在冷却下经15min逐滴添加)淬灭且在rt搅拌2h。浓缩溶剂,且通过快速柱色谱(80g硅胶滤筒;A=PE,B=EtOAc;25min梯度;0%至50%B;流速=60mL/min;用KMnO4观测TLC)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈白色固体状的标题化合物(1.3g,6.6mmol,93%产率)。1H NMR(400MHz,DMSO-d6)δ3.56(s,3H),3.36(s,2H),3.05(s,1H),1.78-1.64(m,6H),1.37-1.27(m,6H)。
步骤B.中间体159B.4-甲酰基双环[2.2.2]辛烷-1-甲酸甲酯的制备
向中间体159A(0.10g,0.50mmol)于DCM(5mL)中的溶液中添加DMP(0.28g,0.66mmol),且在rt搅拌反应物。3h后,将反应物冷却至0℃,且谨慎地用饱和NaHCO3(水性)溶液(30mL)淬灭。分离各层,且用CH2Cl2(2×15mL)萃取水层。合并有机层,用盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过快速柱色谱(12g硅胶滤筒,A=PE,B=EtOAc;15min梯度;20%至100%B;流速=12mL/min;用KMnO4观测TLC)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈无色油状物的标题化合物(0.070g,0.34mmol,67%产率)。1H NMR(400MHz,氯仿-d)δ9.4(s,1H),3.66(s,3H),1.86-1.82(m,7H),1.69-1.66(m,5H)。
步骤C.中间体159C.溴化5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲基)三苯基鏻的制备
向4-(溴甲基)-5-环丙基-3-(2,6-二氯苯基)异噁唑(1.5g,4.3mmol)于甲苯(20mL)中的溶液中添加三苯膦(2.3g,8.6mmol),且在120℃搅拌所得混合物。24h后,使反应物冷却,过滤混合物且用甲苯洗涤固体产物,得到呈白色固体状的标题化合物(2.2g,3.5mmol,80%产率)。1H NMR(400MHz,DMSO-d6)δ7.88-7.80(m,3H),7.65-7.41(m,15H),4.93(d,J=14H,2H),1.76-1.66(m,1H),0.73-0.56(m,4H)。MS(ESI)528(M+H)。
步骤D.中间体159D.4-(2-(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)乙烯基)双环[2.2.2]辛烷-1-甲酸甲酯的制备
在-78℃向中间体159C(0.26g,0.43mmol)(与甲苯的新制共沸物)于THF(5mL)中的悬浮液中添加双(三甲基硅烷基)氨基锂(0.57mL,0.57mmol)(于THF中的1M溶液)。添加碱后,反应混合物的颜色变成黄色。将所得混合物在-78℃搅拌15min,且在rt搅拌30min,此时颜色变成深棕色。向上述混合物中逐滴添加含中间体159B(0.070g,0.36mmol)的THF(2mL),此时颜色变回黄色。在60℃搅拌反应混合物。6h后,使反应物冷却,用饱和NH4Cl(水溶液)(40mL)淬灭且用EtOAc(2×20mL)萃取。将有机相合并,用盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过快速柱色谱(12g硅胶滤筒,A=PE,B=EtOAc;15min梯度;0%至40%B;流速=12mL/min)纯化粗残余物。将纯级分合并、浓缩且在真空中干燥,得到呈无色残余物的标题化合物(0.045g,0.072mmol,20%产率)。1H NMR(400MHz,氯仿-d)δ7.42-7.34(m,3H),5.82(d,J=16.2Hz,1H),5.33(d,J=16.2Hz,1H),3.65(s,3H),1.78-1.66(m,7H),1.42-1.31(m,6H),1.22-1.12(m,4H)。MS(ESI)447(M+H)。产物以反/顺异构体的3:1混合物形式获得,其可不通过快速柱色谱分离。通过1H NMR基于特征质子的积分确定比率。
步骤E.中间体159E.4-(2-(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)乙烯基)双环[2.2.2]辛烷-1-甲酸的制备
将中间体159D(40mg,0.090mmol)溶解于MeOH(1mL)中。向该溶液中添加溶解于水(0.2mL)中的氢氧化钠(9.0mg,0.22mmol)。在75℃搅拌反应物。6h后,使反应物冷却,用水(10mL)稀释且用1.5M HCl酸化至pH约3。用EtOAc(2×10mL)萃取水相,且将有机相合并、经Na2SO4干燥,过滤并浓缩。将产物在真空中干燥,得到标题化合物(35mg,0.063mmol,70%产率),其不经进一步纯化或表征即用于后续步骤中。MS(ESI)432(M+H)。
步骤F.中间体159F.3-(5-(4-(2-(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸甲酯的制备
向中间体159E(20mg,0.046mmol)于DMF(1mL)中的经搅拌溶液中添加(Z)-3-(N'-羟基甲脒基)苯甲酸甲酯(Tung,R.D.WO 2016/073545)(9.0mg,0.046mmol)、BOP(23mg,0.051mmol)和三乙胺(0.019mL,0.14mmol)。将反应物在rt搅拌2h,且在100℃搅拌4h。使反应物冷却,浓缩溶剂。将残余物溶解于EtOAc(50mL)中,用盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过制备型HPLC(柱:Waters XBridge C18,19×150mm,5μm颗粒;流动相A:10mM乙酸铵;流动相B:乙腈;梯度:15-90%B经25分钟,接着在100%B下保持5分钟;流速:15mL/min)纯化粗物质。将含有期望产物的级分合并、浓缩且在真空中干燥,得到标题化合物(8.0mg,29%产率):1H NMR(400MHz,DMSO-d6)δ8.51(s,1H),8.24(d,J=7.1Hz,1H),8.15(d,J=7.8Hz,1H),7.78-7.49(m,4H),6.06(d,J=16.4Hz,1H),5.25(d,J=16.4Hz,1H),3.90(s,3H),2.43-2.34(m,1H),2.04-1.81(m,6H),1.51-1.36(m,6H),1.20-0.97(m,4H)。FXR EC50(nM)=4600。MS(ESI)590(M+H)。产物以约1:1比率的反/顺异构体混合物形式获得。通过1H NMR基于特征质子的积分确定比率。
步骤G.实施例159
根据针对实施例151的合成(步骤C)所描述的方法,适当时代入中间体159F来制备标题化合物。通过制备型HPLC(柱:Waters XBridge C18,19×150mm,5μm颗粒;流动相A:10mM乙酸铵;流动相B:乙腈;梯度:15-75%B经25分钟,接着在100%B下保持5分钟;流速:15mL/min)分离顺/反异构体,得到呈灰白色固体状的标题化合物(4.8mg,15%产率)。1HNMR(400MHz,DMSO-d6)δ8.51(s,1H),8.20(d,J=7.6Hz,1H),8.12(d,J=7.6Hz,1H),7.76-7.64(m,3H),7.64-7.54(m,1H),6.05(d,J=16.6Hz,1H),5.25(d,J=16.6Hz,1H),2.41-2.35(m,1H),2.03-1.86(m,6H),1.55-1.36(m,6H),1.21-0.98(m,4H)。FXR EC50(nM)=14。MS(ESI)576(M+H)。由此获得的产物主要为反式异构体,如通过1H NMR基于特征质子的积分所确定。下文将顺式异构体命名为实施例163。
实施例162
2-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛-1-基)噻唑-4-甲酸
步骤A.中间体162A.4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛烷-1-甲酸甲酯的制备
在0℃向20mL闪烁瓶中添加4-(羟基甲基)双环[2.2.2]辛烷-1-甲酸甲酯(200mg,1.0mmol)(Al Hussainy,R.等人Nucl.Med.Biol.2012,39,1068-1076)、2,6-二-叔丁基吡啶(0.91mL,4.0mmol)、无水DCM(2mL),接着添加三氟甲烷磺酸银(780mg,3.0mmol)。在0℃逐滴添加4-(溴甲基)-5-环丙基-3-(2,6-二氯苯基)异噁唑(1.1g,3.0mmol)于DCM(2mL)中的溶液。在rt搅拌反应物12h,且用DCM:MeOH(1:1;10mL)稀释。滤出固体且浓缩滤液。通过快速柱色谱(24g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至25%B;流速=24mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈淡黄色固体状的标题化合物(0.18g,35%产率)。MS(ESI)464(M+H)。
步骤B.中间体162B.4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛烷-1-甲酸的制备
向产物中间体162A(180mg,0.39mmol)于MeOH(4mL)中的经搅拌溶液中添加氢氧化钠(39mg,0.97mmol)于H2O(1mL)中的溶液。在70℃搅拌反应物4h,使其冷却,用5%柠檬酸(水溶液)(50mL)稀释且用EtOAc(2×25mL)萃取。将有机相合并,用盐水洗涤,经Na2SO4干燥,过滤,浓缩。将产物在真空中干燥,得到呈灰白色固体状的标题化合物(0.12g,67%产率)。1H NMR(400MHz,DMSO-d6)δ=11.94(s,1H),7.71-7.46(m,3H),4.22(s,2H),2.88(s,2H),2.37-2.23(m,1H),1.64-1.45(m,6H),1.24-1.00(m,10H)。
步骤C.中间体162C.4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛烷-1-甲酰胺的制备
向25mL梨形烧瓶中添加中间体162B(45mg,0.10mmol)、BOP(49mg,0.11mmol)和DMF(2mL)。向该混合物中添加Et3N(0.070mL,0.50mmol)和氯化铵(53mg,1.0mmol)。搅拌18h后,浓缩溶剂且将残余物溶解于EtOAc(50mL)中。将有机相用盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过制备型HPLC(柱:Waters XBridge C18,19×150mm,5μm颗粒;流动相A:10mM乙酸铵;流动相B:乙腈;梯度:15-55%B经20分钟,接着在100%B下保持5分钟;流速:15mL/min)纯化粗物质。将含有期望产物的级分合并、浓缩且在真空中干燥,得到标题化合物(10mg,22%产率)。1H NMR(400MHz,DMSO-d6)δ7.70-7.61(m,2H),7.60-7.47(m,1H),6.82(br s,1H),6.62(br s,1H),4.21(s,2H),2.88(s,2H),2.32-2.21(m,1H),1.60-1.37(m,6H),1.21-0.94(m,10H)。FXR EC50(nM)=180。MS(ESI)449(M+H)。
步骤D.中间体162D.4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛烷-1-硫代碳酰胺的制备
向中间体162C(55mg,0.12mmol)于THF(2mL)中的经搅拌溶液中添加劳森试剂(Lawesson's reagent)(50mg,0.12mmol),且在回流下搅拌反应混合物。2h后,将反应物冷却,用水(20mL)稀释且用EtOAc(2×25mL)萃取。将有机相合并,用盐水洗涤,经Na2SO4干燥,过滤且浓缩。将产物在真空中干燥,得到呈淡黄色固体状的标题化合物(0.045g,18%产率),其不经进一步纯化或表征即用于后续步骤中。MS(ESI)465(M+H)。
步骤E.实施例162
向中间体162D(40mg,0.086mmol)于1,4-二噁烷中的经搅拌溶液中添加3-溴-2-氧代丙酸(14mg,0.086mmol)。在90℃搅拌反应物。4h后,将反应物冷却,用5%柠檬酸(水溶液)(50mL)稀释且用EtOAc(2×25mL)萃取。将有机相合并,用盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过制备型HPLC(柱:Waters XBridge C18,19×150mm,5μm颗粒;流动相A:10mM乙酸铵;流动相B:乙腈;梯度:15-50%B经25分钟,接着在100%B下保持5分钟;流速:15mL/min)纯化粗物质。将含有期望产物的级分合并、浓缩且在真空中干燥,得到呈灰白色固体状的标题化合物(0.013g,27%产率)。1H NMR(400MHz,DMSO-d6)δ8.28(s,1H),7.71-7.60(m,2H),7.60-7.51(m,1H),4.25(s,2H),2.95(s,2H),2.33-2.25(m,1H),1.84-1.69(m,6H),1.37-1.20(m,6H),1.17-1.07(m,4H)。FXR EC50(nM)=1300。MS(ESI)533(M+H)。
实施例163
(Z)-3-(5-(4-(2-(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸
通过分离用于制备实施例159的步骤G中的反/顺异构体而获得标题化合物:(3.6mg,12%产率,灰白色固体)。1H NMR(400MHz,DMSO-d6)δ13.34(s,1H),8.51(br s,1H),8.19(d,J=8.1Hz,1H),8.11(br s,1H),7.76-7.59(m,3H),7.59-7.51(m,1H),5.82(d,J=12.2Hz,1H),5.63(d,J=12.2Hz,1H),2.13-2.07(m,1H),1.97-1.85(m,6H),1.62-1.51(m,6H),1.19-1.08(m,4H)。FXR EC50(nM)=211。MS(ESI)576(M+H)。由此获得的产物主要为顺式异构体,如通过1H NMR基于特征质子的积分所确定。上文将反式异构体命名为实施例159。
实施例166
3-(5-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)氨基)甲基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸。
步骤A.中间体166A.5-环丙基-3-(2,6-二氯苯基)异噁唑-4-甲酸的制备
向25mL梨形烧瓶中添加5-环丙基-3-(2,6-二氯苯基)异噁唑-4-甲酸甲酯(2.0g,6.1mmol)(Genin,M.J.等人WO 2009/012125)和EtOH(10mL)。将混合物冷却至0℃,接着添加1M NaOH(水溶液)(12mL,12mmol)。在80℃搅拌2h后,使反应物冷却且浓缩溶剂。将残余物溶解于EtOAc(50mL)中,用盐水洗涤,经Na2SO4干燥,过滤且浓缩。将产物在真空中干燥,得到呈白色固体状的标题化合物(1.8g,85%产率)。1H NMR(400MHz,DMSO-d6)δ=7.78-7.30(m,3H),2.96-2.81(m,1H),1.43-1.08(m,4H)。MS(ESI)=298(M+H)。
步骤B.中间体166B.(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)氨基甲酸叔丁酯的制备
向25mL梨形烧瓶中添加中间体166A(1.8g,5.9mmol)、Et3N(0.82mL,5.9mmol)和叔丁醇(20mL)。在5min的时间段内向该混合物中逐滴添加DPPA(1.3mL,5.9mmol)。在85℃搅拌反应物。12h后,使反应物冷却并浓缩溶剂。将残余物溶解于EtOAc(50mL)中,用盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过快速柱色谱(40g硅胶滤筒;A=己烷,B=EtOAc;25min梯度;0%B至30%B;流速=24mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈淡黄色固体状的标题化合物(1.3g,50%产率)。1H NMR(400MHz,DMSO-d6)δ=8.62(br.s.,1H),7.73-7.39(m,3H),2.23-1.99(m,1H),1.40-1.19(m,9H),1.14-0.79(m,4H)。MS(ESI)369(M+H)。
步骤C.中间体166C.5-环丙基-3-(2,6-二氯苯基)异噁唑-4-胺的制备
向25mL梨形烧瓶中添加含中间体166B(500mg,1.4mmol)的DCM(5mL)。在0℃向该混合物中添加TFA(1.0mL,14mmol)。使混合物升温至rt并搅拌。18h后,浓缩溶剂,且将残余物用饱和NaHCO3(水溶液)(250mL)稀释并用EtOAc(250mL)萃取。将有机相用盐水洗涤,经Na2SO4干燥,过滤且浓缩。将产物在真空中干燥,得到呈淡黄色固体状的标题化合物(230mg,50%产率)。1H NMR(400MHz,DMSO-d6)δ=7.68-7.49(m,3H),3.86(s,2H),2.18(s,1H),1.09-0.86(m,4H)。MS(ESI)=269(M+H)。
步骤D.中间体166D.4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)氨基)甲基)双环[2.2.2]辛烷-1-甲酸甲酯的制备
向25mL梨形烧瓶中添加中间体166C(200mg,0.74mmol)、中间体159B(150mg,0.74mmol)和MeOH(5mL)。将混合物冷却至0℃,接着添加冰AcOH(4.3μl,0.074mmol)。在80℃搅拌2h后,将反应物冷却至rt,接着添加氰基硼氢化钠(47mg,0.74mmol)。搅拌30min后,浓缩溶剂,且将残余物用饱和NaHCO3(水溶液)(25mL)稀释并用EtOAc(25mL)萃取。将有机相用盐水洗涤,经Na2SO4干燥,过滤且浓缩。将产物在真空中干燥,得到呈淡黄色固体状的标题化合物(300mg,75%产率)。MS(ESI)=449(M+H)。
步骤E.中间体166E.4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)氨基)甲基)双环[2.2.2]辛烷-1-甲酸的制备
向25mL梨形烧瓶中添加中间体166D(150mg,0.33mmol)、MeOH(2mL)和水(1mL)。向该混合物中添加氢氧化钠(33mg,0.83mmol)。在70℃搅拌4h后,将反应物冷却至rt,用1MHCl(水溶液)(50mL)酸化,且用EtOAc(2×25mL)萃取。将有机相合并,用盐水洗涤,经Na2SO4干燥,过滤且浓缩。将产物在真空中干燥,得到呈淡黄色固体状的标题化合物(90mg,43%产率)。1H NMR(400MHz,DMSO-d6)δ=11.92(s,1H),7.71-7.47(m,3H),4.10(q,J=5.1Hz,1H),3.51(t,J=7.3Hz,1H),3.17(s,2H),2.30-2.16(m,1H),1.63-1.50(m,6H),1.25-1.12(m,6H),1.10-0.90(m,4H)。MS(ESI)=435(M+H)。
步骤F.中间体166F.3-(5-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)氨基)甲基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸甲酯的制备
向中间体166E(20mg,0.046mmol)和(E)-3-(N'-羟基甲脒基)苯甲酸甲酯(8.9mg,0.046mmol)溶解于DMF(1mL)中的溶液中添加BOP(22mg,0.051mmol)和三乙胺(0.019mL,0.14mmol)。将反应物在rt搅拌2h,且在100℃搅拌4h。使反应物冷却,且用EtOAc(40mL)和水(10mL)稀释。分离各层,用EtOAc(2×20mL)萃取水层,且经合并的有机层用盐水洗涤,经MgSO4干燥,过滤且浓缩。通过制备型HPLC(柱:Waters XBridge C18,19×150mm,5μm颗粒;流动相A:10mM乙酸铵;流动相B:乙腈;梯度:15-45%B经25分钟,接着在100%B下保持5分钟;流速:15mL/min)纯化粗物质。将含有期望产物的级分合并、浓缩且在真空中干燥,得到呈淡黄色固体状的标题化合物(14mg,50%产率)。1H NMR(400MHz,DMSO-d6)δ8.51(t,J=1.5Hz,1H),8.24(d,J=7.8Hz,1H),8.15(d,J=8.1Hz,1H),7.72(t,J=7.8Hz,1H),7.68-7.61(m,2H),7.60-7.53(m,1H),3.91(s,3H),3.60(t,J=7.9Hz,1H),2.31-2.24(m,1H),2.00-1.78(m,6H),1.43-1.27(m,6H),1.12-1.04(m,2H),1.02-0.91(m,2H)。MS(ESI)593(M+H)。
步骤G.实施例166
根据针对实施例151的合成(步骤C)所描述的方法,适当时代入中间体166F来制备标题化合物:(0.012g,40%产率,灰白色固体)。1H NMR(400MHz,DMSO-d6)δ8.51(s,1H),8.16(d,J=8.1Hz,1H),8.11(d,J=7.1Hz,1H),7.76-7.60(m,3H),7.60-7.50(m,1H),3.60(brs,1H),3.3(s,2H),2.32-2.23(m,1H),1.99-1.78(m,6H),1.45-1.26(m,6H),1.12-1.03(m,2H),1.02-0.92(m,2H)。FXR EC50(nM)=580。MS(ESI)579(M+H)。
实施例168
2-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛-1-基)苯并[d]噻唑-6-甲酸
步骤A.中间体168A.3-氯-4-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛烷-1-硫代碳酰氨基)苯甲酸甲酯的制备
在rt向中间体170A(75mg,0.12mmol)于无水甲苯(1mL)中的经搅拌溶液中添加劳森试剂(25mg,0.061mmol)。在120℃搅拌18h后,使反应物冷却,用水(20mL)稀释且用EtOAc(2×25mL)萃取。将有机相合并,用盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过制备型HPLC(柱:Waters XBridge C18,19×150mm,5μm颗粒;流动相A:10mM乙酸铵;流动相B:乙腈;梯度:15-55%B经20分钟,接着在100%B下保持5分钟;流速:15mL/min)纯化粗物质。将含有期望产物的级分合并、浓缩且在真空中干燥,得到呈灰白色固体状的标题化合物(0.0034g,5%产率)。1H NMR(400MHz,DMSO-d6)δ10.65(s,1H),8.01(d,J=1.7Hz,1H),7.93(dd,J=8.2,1.6Hz,1H),7.64(d,J=7.6Hz,2H),7.60-7.52(m,1H),7.45(d,J=8.3Hz,1H),4.24(s,2H),3.87(s,3H),2.94(s,2H),2.33-2.24(m,1H),1.92-1.72(m,6H),1.34-1.18(m,6H),1.18-0.97(m,4H)。FXR EC50(nM)=4385。MS(ESI)619(M+H)。
步骤B.实施例168
向氢化钠(2.8mg,0.071mmol)(于矿物油中的60%分散物)于NMP(1mL)中的经搅拌溶液中添加中间体168A(30mg,0.047mmol)。在130℃搅拌3h后,使混合物冷却且将残余物溶解于乙醚(50mL)中。有机相用H2O、盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过制备型HPLC(柱:Waters XBridge C18,19×150mm,5μm颗粒;流动相A:10mM乙酸铵;流动相B:乙腈;梯度:15-45%B经25分钟,接着在100%B下保持5分钟;流速:15mL/min)纯化粗物质。将含有期望产物的级分合并、浓缩且在真空中干燥,得到呈灰白色固体状的标题化合物(0.0030g,10%产率)。1H NMR(400MHz,DMSO-d6)δ8.65(s,1H),8.10-7.91(m,2H),7.75-7.62(m,2H),7.61-7.52(m,1H),4.26(s,2H),2.97(s,2H),2.33-2.25(m,1H),1.94-1.74(m,6H),1.39-1.26(m,6H),1.18-1.06(m,4H)。FXR EC50(nM)=1200。MS(ESI)583(M+H)。
实施例170
3-氯-4-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛烷-1-甲酰氨基)苯甲酸
步骤A.中间体170A.3-氯-4-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛烷-1-甲酰氨基)苯甲酸甲酯的制备
向中间体162B(25mg,0.056mmol)于无水DCM(1mL)中的搅拌溶液中添加草酰氯(4.9μl,0.056mmol)。搅拌1h后,浓缩混合物且将残余物溶解于DCM(1mL)中。将混合物冷却至0℃,且添加DIEA(9.7μl,0.056mmol),接着逐滴添加溶解于DCM(1mL)中的4-氨基-3-氯苯甲酸甲酯(10mg,0.056mmol)。使反应物升温至rt并搅拌。18h后,浓缩溶剂,且将残余物溶解于EtOAc(50mL)中,用盐水洗涤,经Na2SO4干燥,过滤且浓缩。经由制备型HPLC(柱:WatersXBridge C18,19×150mm,5μm颗粒;流动相A:10mM乙酸铵;流动相B:乙腈;梯度:15-55%B经20分钟,接着在100%B下保持5分钟;流速:15mL/min)纯化粗物质。将含有期望产物的级分合并、浓缩且在真空中干燥,得到呈灰白色固体状的标题化合物(0.0020g,6%产率)。1HNMR(400MHz,DMSO-d6)δ8.86(s,1H),7.98(d,J=2.0Hz,1H),7.89(dd,J=8.6,2.0Hz,1H),7.83(d,J=8.3Hz,1H),7.69-7.61(m,2H),7.60-7.53(m,1H),4.24(s,2H),3.85(s,3H),2.93(s,2H),2.32-2.27(m,1H),1.76-1.65(m,6H),1.26-1.16(m,6H),1.16-1.07(m,4H)。FXR EC50(nM)=2400。MS(ESI)619(M+H)。
步骤B.实施例170
根据针对实施例151的合成(步骤C)所描述的方法,适当时代入中间体170A来制备标题化合物:(0.014g,55%产率,灰白色固体)。1H NMR(400MHz,DMSO-d6)δ8.83(s,1H),7.95(d,J=2.0Hz,1H),7.86(dd,J=8.3,2.0Hz,1H),7.78(d,J=8.3Hz,1H),7.69-7.61(m,2H),7.60-7.52(m,1H),4.28-4.21(m,2H),2.93(s,2H),2.34-2.28(m,1H),1.79-1.63(m,6H),1.26-1.17(m,6H),1.16-1.08(m,4H)。FXR EC50(nM)=636。MS(ESI)603(M+H)。
实施例171
3-氯-4-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛烷-1-硫代碳酰氨基)苯甲酸
根据针对实施例151的合成(步骤C)所描述的方法,适当时代入中间体168A来制备标题化合物:(0.0020g,10%产率,灰白色固体)。1H NMR(400MHz,DMSO-d6)δ10.59(br s,1H),7.95(s,1H),7.86(d,J=8.8Hz,1H),7.65(d,J=7.6Hz,2H),7.60-7.53(m,1H),7.33(d,J=8.6Hz,1H),4.24(s,2H),2.94(s,2H),2.32-2.30(m,1H),1.89-1.79(m,6H),1.25-1.22(m,6H),1.16-1.08(m,4H)。FXR EC50(nM)=4700。MS(ESI)620(M+H)。
实施例172
2-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛-1-基)苯并[d]噻唑-7-甲酸
步骤A.中间体172A.2-氯-3-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛烷-1-甲酰氨基)苯甲酸甲酯的制备
根据针对中间体170A的合成所描述的方法,适当时代入3-氨基-2-氯苯甲酸甲酯来制备标题化合物:(85mg,0.056mmol,25%)。MS(ESI)619(M+H)。
步骤B.中间体172B.2-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛-1-基)苯并[d]噻唑-7-甲酸甲酯的制备
向中间体172A(60mg,0.097mmol)于甲苯(1mL)中的溶液中添加劳森试剂(59mg,0.15mmol)。在120℃搅拌18h后,使反应物冷却,用水(20mL)稀释且用EtOAc(2×15mL)萃取。经合并的有机相用盐水洗涤,经Na2SO4干燥,过滤且浓缩,得到标题化合物(40mg,0.067mmol,69%),其不经进一步纯化或表征即用于后续步骤中。MS(ESI)597(M+H)。
步骤C.实施例172.
根据针对实施例151的合成(步骤C)所描述的方法,适当时代入中间体172B来制备标题化合物:(0.013g,34%产率,灰白色固体)。1H NMR(400MHz,DMSO-d6)δ8.14(d,J=8.1Hz,1H),8.01(d,J=6.8Hz,1H),7.70-7.63(m,2H),7.62-7.51(m,2H),4.26(s,2H),2.97(s,2H),2.34-2.30(m,1H),1.95-1.82(m,6H),1.38-1.28(m,6H),1.18-1.08(m,4H)。FXREC50(nM)=89。MS(ESI)583(M+H)。
实施例174
4-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛-1-基)苯甲酸
步骤A.中间体174A.(4-(4-溴苯基)双环[2.2.2]辛-1-基)甲醇的制备
向25mL圆底烧瓶中添加溶解于DCM(5mL)中的4-(4-溴苯基)双环[2.2.2]辛烷-1-甲酸甲酯(0.65g,2.0mmol)(Velaparthi U.等人US 2015/0133428)。将溶液冷却至-78℃,且添加DIBAL-H(4.0mL,4.0mmol)(于DCM中的1M溶液)。将反应混合物在相同温度搅拌30min,且在rt搅拌2h。在0℃用1.5M HCl(水溶液)(20mL)淬灭混合物,分离各层且用EtOAc(20mL)萃取水相。将有机相合并,用盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过快速柱色谱(24g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至15%B;流速=24mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈黄色固体状的标题化合物(0.59g,99%产率)。1H NMR(300MHz,DMSO-d6)δ=7.55-7.38(m,2H),7.33-7.17(m,2H),4.35(t,J=5.3Hz,1H),3.08(d,J=5.3Hz,2H),1.84-1.63(m,5H),1.56-1.24(m,6H)。
步骤B.中间体174B.4-(((4-(4-溴苯基)双环[2.2.2]辛-1-基)甲氧基)甲基)-5-环丙基-3-(2,6-二氯苯基)异噁唑的制备
向20mL圆底烧瓶中添加含中间体174A(200mg,0.68mmol)和2,6-二-叔丁基吡啶(0.61mL,2.7mmol)的无水DCM(1mL)。将混合物冷却至0℃,添加三氟甲烷磺酸银(520mg,2.0mmol),接着逐滴添加含4-(溴甲基)-5-环丙基-3-(2,6-二氯苯基)异噁唑(710mg,2.0mmol)的DCM(2mL)。用N2冲洗反应物,且使其缓慢达至室温。搅拌18h后,用DCM:MeOH(1:1;4mL)稀释混合物,过滤且浓缩滤液。通过快速柱色谱(24g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至25%B;流速=24mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈无色残余物的标题化合物(0.13g,0.23mmol,34%产率)。1H NMR(400MHz,氯仿-d)δ=7.31(s,5H),7.09(d,J=8.0Hz,2H),4.32-4.23(m,2H),2.98(s,2H),1.76-1.66(m,7H),1.43-1.31(m,6H),1.30-1.22(m,2H),1.18-1.05(m,2H)。MS(ESI)561(M+H)。
步骤C.实施例174
步骤1:向装备有压力释放盖的2打兰小瓶中添加中间体174B(20mg,0.036mmol)、氰化铜(I)(9.6mg,0.11mmol)和无水DMF(1mL)。在150℃搅拌18h后,使反应物冷却且将其倒入冰水中。通过真空过滤收集所得析出物且将产物在真空中干燥,得到标题化合物(0.015g,30%产率)。MS(ESI)507(M+H)。
步骤2:将上文步骤1的产物溶解于EtOH:H2O(2mL,1:1)中,且添加5.9M KOH(水溶液)(0.066mL,0.39mmol)。在100℃搅拌8h后,将反应物冷却,用5%柠檬酸(水溶液)(50mL)稀释且用EtOAc(2×25mL)萃取。将有机相合并,用盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过制备型HPLC(柱:Waters XBridge C18,19×150mm,5μm颗粒;流动相A:10mM乙酸铵;流动相B:乙腈;梯度:25-85%B经20分钟,接着在100%B下保持5分钟;流速:15mL/min)纯化粗物质。将含有期望产物的级分合并、浓缩且在真空中干燥,得到标题化合物(0.0029mg,14%产率)。1H NMR(400MHz,DMSO-d6)δ7.95-7.73(m,J=8.1Hz,2H),7.69-7.49(m,3H),7.47-7.28(m,J=8.3Hz,2H),4.24(s,2H),2.94(s,2H),2.32-2.20(m,1H),1.78-1.50(m,6H),1.37-1.19(m,6H),1.17-1.00(m,4H)。FXR EC50(nM)=210。MS(ESI)526(M+H)。
实施例176
2-((4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛-1-基)甲氧基)噻唑-4-甲酸
步骤A.中间体176A.(4-(((5-环丙基-3-(2,6二氯苯基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛-1-基)甲醇的制备
在-78℃向中间体162A(200mg,0.43mmol)于THF(4mL)中的经搅拌溶液中添加DIBAL-H(1.1mL,1.1mmol)(于庚烷中的1M溶液)。使反应物升温至rt并搅拌。2h后,将混合物冷却至0℃且用1.5M HCl(水溶液)(50mL)淬灭。用EtOAc(2×25mL)萃取水相,且有机相经Na2SO4干燥、过滤并浓缩。通过快速柱色谱(12g硅胶筒;A=己烷,B=EtOAc;15min梯度;0%B至60%B;流速=12mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈白色固体的标题化合物(160mg,0.37mmol,85%产率)。1H NMR(400MHz,DMSO-d6)δ7.63-7.57(m,3H),4.21(s,1H),4.20(s,2H),2.97(d,J=5.60Hz,2H),2.86(s,2H),2.32-2.33(m,1H),1.20-1.09(m,16H)。MS(ESI)436(M+H)。
步骤B.实施例176
在0℃向中间体176A(30mg,0.069mmol)于DMF(0.5mL)中的经搅拌溶液中添加氢化钠(4.1mg,0.10mmol)(于矿物油中的60%分散物)。搅拌10min后,添加溶解于DMF(0.35mL)中的2-溴噻唑-4-甲酸甲酯(23mg,0.10mmol)。使反应混合物升温至rt并搅拌。18h后,浓缩反应物,将残余物用水(10mL)稀释,用1.5M HCl(水溶液)(pH约3)酸化且用EtOAc(3×20mL)萃取。合并的有机相经Na2SO4干燥,过滤且浓缩。通过制备型HPLC(柱:Waters XBridge C18,19×150mm,5μm颗粒;流动相A:10mM乙酸铵;流动相B:乙腈;梯度:10-35%B经25分钟,接着100%B保持5分钟;流速:15mL/min)纯化粗物质。将含有期望产物的级分合并、浓缩且在真空中干燥,得到标题化合物(1.4mg,2.4μmol,4%产率)。1H NMR(400MHz,DMSO-d6)δ7.74(s,1H),7.68-7.59(m,2H),7.59-7.47(m,1H),4.22(s,2H),4.01(s,2H),2.90(s,2H),2.32-2.22(m,1H),1.45-1.26(m,6H),1.22-1.02(m,10H)。FXR EC50(nM)=740。MS(ESI)563(M+H)。
实施例177
2-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛-1-基)噁唑-4-甲酸
步骤A.中间体177A.2-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛-1-基)噁唑-4-甲酸乙酯的制备
向中间体162C(35mg,0.078mmol)于THF(2mL)中的经搅拌溶液中添加NaHCO3(33mg,0.39mmol),接着添加溴丙酮酸乙酯(0.024mL,0.20mmol)。在80℃搅拌16h后,使反应混合物冷却并过滤。向滤液中添加三氟乙酸酐(0.13mL,0.94mmol)。搅拌2h后,将混合物用饱和NaHCO3(水溶液)(20mL)稀释且用EtOAc(2×20mL)萃取。将有机相合并,经Na2SO4干燥,过滤且浓缩,得到呈深色油状物的标题化合物(40mg,0.073mmol,94%产率)。MS(ESI)545(M+H)。
步骤B.实施例177
根据针对实施例151的合成(步骤C)所描述的方法,适当时代入中间体177A来制备标题化合物:(2.7mg,5.1μmol,7%产率)。1H NMR(400MHz,DMSO-d6)δ8.22(s,1H),7.70-7.61(m,2H),7.60-7.51(m,1H),4.25(s,2H),2.94(s,2H),2.29(d,J=8.2Hz,1H),1.80-1.63(m,6H),1.29-1.18(m,7H),1.16-1.04(m,4H)。FXR EC50(nM)=1800。MS(ESI)517(M+H)。
实施例178
2-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛-1-基)苯并[d]噁唑-6-甲酸
步骤A.中间体178A.4-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛烷-1-甲酰氨基)-3-羟基苯甲酸甲酯的制备
向中间体162B(60mg,0.13mmol)于DMF中的溶液中添加4-氨基-3-羟基苯甲酸甲酯(25mg,0.15mmol)、TEA(55μL,0.40mmol),接着添加BOP(65mg,0.15mmol)。搅拌4h后,将混合物用水(40mL)稀释且用EtOAc(2×25mL)萃取。将有机相合并,经Na2SO4干燥,过滤且浓缩,得到呈淡黄色油状物的标题化合物(50mg,0.083mmol,63%产率)。1H-NMR(400MHz,DMSO-d6)δ9.36(s,1H),7.66-7.50(m,4H),7.25-7.23(m,2H),4.24(s,2H),3.75(s,2H),3.72(s,3H),2.33-2.32(m,1H),1.82-1.78(m,6H),1.24-1.09(m,10H)。MS(ESI)599(M+H)。
步骤B.中间体178B.2-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛-1-基)苯并[d]噁唑-6-甲酸甲酯的制备
向中间体178A(50mg,0.083mmol)于甲苯(2mL)中的溶液中添加单水合对甲苯磺酸(16mg,0.083mmol)。在125℃搅拌18h后,使反应物冷却,浓缩且用EtOAc(20mL)稀释。有机相用饱和NaHCO3(水溶液)(2×10mL)、盐水(10mL)洗涤,经Na2SO4干燥,过滤且浓缩。将产物在真空中干燥,得到呈橙色油状物的标题化合物(40mg,0.069mmol,82%产率),其不经进一步纯化或表征即用于后续步骤中。MS(ESI)581(M+H)。
步骤C.实施例178
根据针对实施例151的合成(步骤C)所描述的方法,适当时代入中间体178B来制备标题化合物:(2.8mg,4.8μmol,8%产率)。1H NMR(400MHz,DMSO-d6)δ13.06(s,1H),8.13(s,1H),7.94(dd,J=8.3,1.5Hz,1H),7.74(d,J=8.3Hz,1H),7.68-7.61(m,2H),7.61-7.53(m,1H),4.26(s,2H),2.97(s,2H),2.32-2.25(m,1H),1.92-1.82(m,6H),1.34-1.20(m,6H),1.17-1.07(m,4H)。FXR EC50(nM)=910。MS(ESI)568(M+H)。
实施例179
2-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛-1-基)-4-甲基噻唑-5-甲酸
步骤A.中间体179A.2-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛-1-基)-4-甲基噻唑-5-甲酸乙酯的制备
向中间体162A(40mg,0.086mmol)于乙醇(1.5mL)中的经搅拌溶液中添加2-氯乙酰乙酸乙酯(16mg,0.095mmol)。在100℃搅拌18h后,使反应混合物冷却,用水(20mL)稀释且用EtOAc(2×20mL)萃取。经合并的有机相经Na2SO4干燥,过滤且浓缩。通过快速柱色谱(4g硅胶滤筒;A=己烷,B=EtOAc;10min梯度;0%B至60%B;流速=4mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈黄色液体状的标题化合物(15mg,0.026mmol,30%产率),其不经进一步纯化或表征即用于后续步骤中。MS(ESI)575(M+H)。
步骤B.实施例179
根据针对实施例151的合成(步骤C)所描述的方法,适当时代入中间体178B来制备标题化合物:(0.8mg,1.5μmol,7%产率)。1H NMR(400MHz,DMSO-d6)δ7.72-7.60(m,2H),7.59-7.48(m,1H),4.24(s,2H),2.93(s,2H),2.54(s,3H),2.32-2.25(m,1H),1.80-1.63(m,6H),1.33-1.19(m,6H),1.18-1.00(m,4H)。FXR EC50(nM)=560。MS(ESI)548(M+H)。
实施例180
(E)-2-(4-(2-(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)苯并[d]噻唑-6-甲酸
步骤A.中间体180A.3-氯-4-(4-(2-(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)乙烯基)双环[2.2.2]辛烷-1-甲酰氨基)苯甲酸甲酯的制备
向4-氨基-3-氯苯甲酸甲酯(25mg,0.14mmol)和中间体159E(50mg,0.10mmol)于DCM(2mL)中的溶液中添加吡啶(0.059mL,0.34mmol)。将混合物冷却至0℃,且添加氧氯化磷(39mg,0.26mmol)并在rt搅拌反应物。18h后,将混合物用DCM(20mL)稀释且用水(2×10mL)洗涤。将有机相合并,经Na2SO4干燥,过滤且浓缩。通过快速柱色谱(24g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至50%B;流速=40mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈无色残余物的标题化合物(0.045g,0.057mmol,55%产率)。1H NMR(400MHz,DMSO-d6)δ8.89(s,1H),7.97(s,1H),7.87-7.80(m,2H),7.68-7.62(m,3H),6.01(d,J=16.4Hz,1H),5.23(d,J=16.4Hz,1H),3.85(s,3H),1.81-1.77(m,7H),1.49-1.35(m,6H),1.26-1.08(m,4H)。MS(ESI)601(M+H)。
步骤B.中间体180B.3-氯-4-(4-(2-(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)乙烯基)双环[2.2.2]辛烷-1-硫代碳酰氨基)苯甲酸甲酯的制备
根据针对中间体168A的合成所描述的方法,适当时代入中间体180A来制备标题化合物:(30mg,0.049mmol,97%产率)。MS(ESI)617.0(M+H)。
步骤C.实施例180
根据针对实施例168的合成(步骤B)所描述的方法,适当时代入中间体180B来制备标题化合物。通过制备型HPLC(柱:Waters XBridge C18,19×150mm,5μm颗粒;流动相A:10mM乙酸铵;流动相B:乙腈;梯度:15-75%B经25分钟,接着在100%B下保持5分钟;流速:15mL/min)分离顺/反异构体,得到标题化合物(6.7mg,0.011mmol,19%产率)。1H NMR(400MHz,DMSO-d6)13.07(s,1H),8.66(d,J=1.0Hz,1H),8.07-7.91(m,2H),7.73-7.65(m,2H),7.64-7.56(m,1H),6.05(d,J=16.4Hz,1H),5.27(d,J=16.6Hz,1H),2.40-2.34(m,1H),2.03-1.89(m,6H),1.59-1.42(m,7H),1.21-1.13(m,2H),1.12-1.02(m,2H)。FXR EC50(nM)=43。MS(ESI)567.2(M+H)。由此获得的产物主要为反式异构体,如通过1H NMR基于特征质子的积分所确定。下文将顺式异构体命名为实施例181。
实施例181
(Z)-2-(4-(2-(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)苯并[d]噻唑-6-甲酸
通过分离用于制备实施例180的步骤C中的反/顺异构体而获得标题化合物:(2.1mg,3.6μmol,6%产率)。1H NMR(400MHz,DMSO-d6)δ8.65(s,1H),8.07-7.91(m,2H),7.74-7.62(m,2H),7.61-7.52(m,1H),5.81(d,J=12.2Hz,1H),5.63(d,J=12.5Hz,1H),2.13-2.04(m,1H),1.97-1.85(m,6H),1.65-1.50(m,6H),1.22-1.01(m,4H)。FXR EC50(nM)=780。MS(ESI)567.2(M+H)。由此获得的产物主要为顺式异构体,如通过1H NMR基于特征质子的积分所确定。上文将反式异构体命名为实施例180。
实施例182
(E)-2-(4-(2-(5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)苯并[d]噻唑-6-甲酸
步骤A.中间体182A.溴化5-环丙基-3-(2-三氟甲氧基苯基)异噁唑-4-基)甲基)三苯基鏻的制备
根据针对中间体159C的合成所描述的方法,适当时代入4-(溴甲基)-5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑来制备标题化合物:(1.2g,1.7mmol,87%产率,白色固体)。1H NMR(400MHz,DMSO-d6)δ7.84-7.80(m,3H),7.62-7.40(m,13H),7.39-7.28(m,3H),4.93(d,J=13.6H,2H),1.76-1.66(m,1H),0.73-0.56(m,4H)。MS(ESI)544.(M+H)。
步骤B.中间体182B.4-(2-(5-环丙基-3-(2-三氟甲氧基苯基)异噁唑-4-基)乙烯基)双环[2.2.2]辛烷-1-甲酸甲酯的制备
根据针对中间体159D的合成所描述的方法,适当时代入中间体182A来制备标题化合物:(0.22g,0.42mmol,55%产率)。产物以反/顺异构体的混合物形式获得。1H NMR(400MHz,DMSO-d6)δ7.58-7.52(m,4H),5.92-5.86(m,1H),5.54-5.51(m,1H),3.55(s,3H),1.76-1.11(m,17H)。MS(ESI)462(M+H)。
步骤C.中间体182C.4-(2-(5-环丙基-3-(2-三氟甲氧基苯基)异噁唑-4-基)乙烯基)双环[2.2.2]辛烷-1-甲酸的制备
根据针对中间体159E的合成所描述的方法,适当时代入中间体182B来制备标题化合物:(0.17g,0.38mmol,88%产率)。MS(ESI)448.5(M+H)。
步骤D.中间体182D.3-氯-4-(4-(2-(5-环丙基-3-(2-三氟甲氧基苯基)异噁唑-4-基)乙烯基)双环[2.2.2]辛烷-1-甲酰氨基)苯甲酸甲酯的制备
根据针对中间体170A的合成所描述的方法,适当时代入中间体182C来制备标题化合物:(25mg,0.018mmol,9%产率,白色固体)。1H NMR(400MHz,DMSO-d6)δ8.92-8.86(m,1H),7.97-7.92(m,1H),7.89-7.74(m,2H),7.56-7.52(m,3H),5.92-5.86(m,1H),5.58-5.54(m,1H),3.85(s,3H),1.85-1.11(m,17H)。MS(ESI)617(M+H)。
步骤E.中间体182E.3-氯-4-(4-(2-(5-环丙基-3-(2-三氟甲氧基苯基)异噁唑-4-基)乙烯基)双环[2.2.2]辛烷-1-硫代碳酰氨基)苯甲酸甲酯的制备
/>
根据针对中间体168A的合成所描述的方法,适当时代入中间体182D来制备标题化合物:(0.020g,0.032mmol,78%产率)。MS(ESI)631(M+H)。
步骤F.实施例182
根据针对实施例168的合成(步骤B)所描述的方法,适当时代入中间体182E来制备标题化合物:(2.0mg,3.3μmol,11%产率)。1H NMR(400MHz,DMSO-d6)δ8.65(d,J=1.0Hz,1H),7.99-7.96(m,2H),7.71-7.68(m,1H),7.57-7.55(m,3H),5.97(d,J=16.4Hz,1H),5.55(d,J=16.4Hz,1H),2.32-2.02(m,1H),2.00-1.96(m,6H),1.57-1.53(m,6H),1.17-1.13(m,4H)。FXR EC50(nM)=100。MS(ESI)581(M+H)。
实施例193
3-(5-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)-2-氧杂双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸
步骤A.中间体193A.(4-(1,3-二噻烷-2-基)-4-羟基环己烷-1,1-二基)双(亚甲基)双(苯磺酸4-甲酯)
在-78℃向1,3-二噻烷(4.6g,39mmol)于THF(90mL)中的搅拌溶液中逐滴添加正丁基锂(17mL,42mmol)(于己烷中的2.5M溶液)。使反应物缓慢升温至0℃,且在该温度搅拌1h。使反应混合物冷却至-78℃,且添加(4-氧代环己烷-1,1-二基)双(亚甲基)双(苯磺酸4-甲酯)(15g,32mmol)(ACS Med.Chem.Lett.2014,5,609-614)溶解于THF(60mL)中的溶液。使反应物升温至rt并搅拌。1h后,将混合物用饱和NH4Cl(水溶液)(400mL)淬灭且用EtOAc(2×200mL)萃取。将有机相合并,用盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过快速柱色谱(80g硅胶滤筒;A=CH3Cl,B=MeOH;25min梯度;0%B至7%B;流速=40mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈白色固体状的标题化合物(14g,20mmol,61%产率)。1H NMR(400MHz,DMSO-d6)δ7.73(dd,J=2.80,8.20Hz,4H),7.48(d,J=7.20Hz,4H),4.54(s,1H),4.05(s,1H),3.84(s,2H),3.67(s,2H),2.78-2.84(m,4H),2.42(s,6H),1.80-2.00(m,1H),1.50-1.70(m,1H),1.19-1.39(m,8H)。MS(ESI)587(M+H)。
步骤B.中间体193B.4-甲基苯磺酸(1-(1,3-二噻烷-2-基)-2-氧杂双环[2.2.2]辛-4-基)甲酯的制备
向中间体193A(3.2g,5.5mmol)于THF(100mL)中的经搅拌溶液中添加粉末状NaOH(0.65g,16mmol)。在回流下搅拌反应混合物。18h后,使反应物冷却并浓缩溶剂。残余物用水(50mL)稀释且用EtOAc(2×50mL)萃取。合并的有机层用盐水洗涤,经Na2SO4干燥,过滤且浓缩。将产物在真空中干燥,得到呈灰白色固体状的标题化合物(2.6g,4.5mmol,83%产率)。1H NMR(400MHz,DMSO-d6)δ7.78(d,J=8.40Hz,2H),7.49(d,J=8.00Hz,2H),4.17(s,1H),3.74(s,2H),3.48(s,2H),2.81-2.84(m,4H),2.34(s,3H),1.90-2.00(m,1H),1.85-1.87(m,2H),1.63-1.65(m,3H),1.42-1.51(m,4H)。MS(ESI)587(M+H)。
步骤C.中间体193C.4-甲基苯磺酸(1-甲酰基-2-氧杂双环[2.2.2]辛-4-基)甲酯的制备
向中间体193B(2.4g,5.8mmol)于DCM(100mL)和水(12mL)中的经搅拌溶液中添加NCS(2.7g,20mmol)。搅拌1h后,用水(150mL)和盐水洗涤反应混合物。有机相经Na2SO4干燥,过滤且浓缩。产物不经纯化即用于后续步骤中。1H NMR(400MHz,DMSO-d6)δ11.05(s,1H),7.78(d,J=8.00Hz,2H),7.49(d,J=8.00Hz,2H),3.78(s,2H),3.45(s,2H),2.45(s,3H),1.85-1.75(m,4H),1.49-1.42(m,4H)。
步骤D.中间体193D.4-((甲苯磺酰基氧基)甲基)-2-氧杂双环[2.2.2]辛烷-1-甲酸的制备
向中间体193C(2.4g,7.4mmol)于叔丁醇(72mL)中的溶液中添加2-甲基-2-丁烯(2.4mL,22mmol)。向该混合物中添加溶解于水(24mL)中的亚氯酸钠(3.4g,37mmol)和单水合磷酸二氢钠(8.9g,74mmol)。搅拌1h后,浓缩反应混合物,用水(50mL)稀释且用1.5M HCl(水性)溶液酸化。用EtOAc(2×50mL)萃取水相,将有机相合并、经Na2SO4干燥,过滤并浓缩。产物不经纯化即用于后续步骤中。MS(ESI)341(M+H)。
步骤E.中间体193E.4-((甲苯磺酰基氧基)甲基)-2-氧杂双环[2.2.2]辛烷-1-甲酸甲酯的制备
向中间体193D(2.8g,8.2mmol)于DMF(40mL)中的经搅拌溶液中添加K2CO3(2.3g,17mmol)。搅拌5min后,添加碘甲烷(1.0mL,17mmol)。30min后,浓缩溶剂且通过快速柱色谱(24g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至50%B;流速=24mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈棕色固体状的标题化合物(1.4g,3.9mmol,48%产率)。1H NMR(400MHz,DMSO-d6)δ7.78(d,J=8.40Hz,2H),7.49(d,J=8.00Hz,2H),3.76(s,2H),3.60(s,3H),3.55(s,2H),2.43(s,3H),1.82-1.89(m,4H),1.52-1.54(m,4H)。MS(ESI)355(M+H)。
步骤F.中间体193F.4-(乙酰氧基甲基)-2-氧杂双环[2.2.2]辛烷-1-甲酸甲酯的制备
向中间体193E(1.4g,4.0mmol)于DMF(20mL)中的经搅拌溶液中添加乙酸铯(1.9g,9.9mmol)。在120℃搅拌4h后,使反应物冷却且浓缩溶剂。残余物用水(50mL)稀释且用EtOAc(2×80mL)萃取。合并的有机层用盐水洗涤,经Na2SO4干燥,过滤且浓缩。将产物在真空中干燥,得到标题化合物(0.85g,3.5mmol,89%产率)。1H NMR(400MHz,DMSO-d6)δ3.76(s,3H),3.62(s,4H),2.02(s,3H),1.85-1.96(m,4H),1.50-1.70(m,4H)。
步骤G.中间体193G.4-(羟基甲基)-2-氧杂双环[2.2.2]辛烷-1-甲酸甲酯的制备
向中间体193F(0.85g,3.5mmol)中添加HCl(8.0mL,24mmol)(3M于MeOH中)且在rt搅拌。2h后,将反应混合物浓缩且与甲苯(2×20mL)共同蒸馏,得到呈棕色半固体状的标题化合物(0.68g,3.4mmol,97%产率)。1H NMR(400MHz,DMSO-d6)δ3.63(s,2H),3.63(s,3H),3.10(s,2H),1.80-1.94(m,4H),1.53-1.61(m,2H),1.42-1.49(m,2H)。
步骤H.中间体193H.1-(甲氧基羰基)-2-氧杂双环[2.2.2]辛烷-4-甲酸的制备
在0℃向中间体193G(680mg,3.4mmol)于DMF(10mL)中的经搅拌溶液中添加重铬酸吡啶鎓(450mg,12mmol)。使混合物升温至rt且在40℃搅拌。3h后,将反应混合物用水(50mL)稀释且用EtOAc(5×30mL)萃取。合并的有机层用盐水洗涤,经Na2SO4干燥,过滤且浓缩。将产物在真空中干燥,得到呈棕色固体状的标题化合物(580mg,2.7mmol,80%产率)。1H NMR(400MHz,DMSO-d6)δ12.50(s,1H),3.85(s,2H),3.62(s,3H),1.97-1.85(m,8H)。
步骤I.中间体193I.4-(((苯甲基氧基)羰基)氨基)-2-氧杂双环[2.2.2]辛烷-1-甲酸甲酯的制备
在10℃向中间体193H(580mg,2.7mmol)于甲苯(12mL)中的经搅拌溶液中添加DIEA(0.95mL,5.4mmol),接着逐滴添加DPPA(0.70mL,3.3mmol)。在回流下搅拌2h后,将混合物冷却至60℃且添加苯甲醇(0.56mL,5.4mmol)。在回流下继续搅拌。18h后,使混合物冷却且用EtOAc(30mL)稀释。将有机层用水(20mL)、盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过快速柱色谱(24g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至70%B;流速=24mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈棕色半固体状的标题化合物(400mg,1.3mmol,46%产率)。1H NMR(400MHz,DMSO-d6)δ7.31-7.38(m,5H),7.23(s,1H),5.75(s,2H),3.85(s,2H),3.61(s,3H),1.84-2.00(m,8H)。MS(ESI)320(M+H)。
步骤J.中间体193J.4-(((苯甲基氧基)羰基)氨基)-2-氧杂双环[2.2.2]辛烷-1-甲酸的制备
向中间体193I(400mg,1.3mmol)于MeOH(8mL)中的经搅拌溶液中添加含NaOH(130mg,3.1mmol)的水(1mL)。在75℃搅拌1h后,使反应混合物冷却并浓缩。将残余物用水(10mL)稀释且用EtOAc(10mL)洗涤。将水层用1.5M HCl(水性)溶液酸化(pH约2)且用EtOAc(2×25mL)萃取。合并的有机层用盐水洗涤,经Na2SO4干燥,过滤且浓缩。将产物在真空中干燥,得到呈棕色半固体状的标题化合物(340mg,1.1mmol,89%产率)。1H NMR(400MHz,DMSO-d6)δ7.29-7.38(m,5H),7.19(s,1H),4.96(s,2H),3.82(s,2H),1.81-1.99(m,8H)。MS(ESI)306(M+H)。
步骤K.中间体193K.4-氨基-2-氧杂双环[2.2.2]辛烷-1-甲酸盐酸盐的制备
向中间体193J(340mg,1.1mmol)于MeOH(5mL)中的经搅拌溶液中添加1.25M HCl(水溶液)(1.4mL,1.1mmol)。用N2吹扫并冲洗反应容器,接着添加钯/碳(120mg,0.11mmol)(10重量%负载,基质活性碳载体),并再次吹扫和冲洗容器。在氢气(1个大气压,气球)下搅拌反应物。4h后,过滤反应混合物,浓缩滤液且与甲苯(2×10mL)共同蒸馏,得到呈白色固体状的标题化合物(230mg,1.1mmol,99%产率)。1H NMR(400MHz,DMSO-d6)δ8.43(s,2H),3.80(s,2H),1.85-2.03(m,8H)。MS(ESI)172(M+H)。
步骤L.中间体193L.4-羟基-2-氧杂双环[2.2.2]辛烷-1-甲酸的制备
在0℃向中间体193K(250mg,1.5mmol)于AcOH(2mL,10%v/v)中的经搅拌溶液中逐滴添加溶解于水(1mL)中的亚硝酸钠(300mg,4.4mmol)。完成添加后,在65℃搅拌反应混合物。18h后,将反应混合物冷却至5℃,且逐滴添加KOH(740mg,13mmol)溶解于MeOH(0.8mL)中的溶液。在65℃搅拌4h后,使反应混合物冷却并浓缩。将残余物用水(10mL)稀释,用浓HCl酸化(pH约2)且用EtOAc(2×25mL)萃取。合并的有机层用盐水洗涤,经Na2SO4干燥,过滤且浓缩。将产物在真空中干燥,得到呈棕色半固体状的标题化合物(100mg,0.58mmol,39%产率)。1H NMR(400MHz,DMSO-d6)δ3.52(s,2H),1.91-1.97(m,4H),1.60-1.71(m,4H)。MS(ESI)171.0(M-H)。
步骤M.中间体193M.3-(5-(4-羟基-2-氧杂双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸甲酯的制备
向中间体193L(50mg,0.29mmol)于DMF(1mL)中的经搅拌溶液中添加TEA(0.12mL,0.87mmol)、3-(N'-羟基甲脒基)苯甲酸甲酯(110mg,0.58mmol),接着添加BOP(140mg,0.32mmol)。在rt搅拌30min后,将反应混合物加热且在100℃搅拌。2h后,使反应混合物冷却,浓缩,且残余物用水(10mL)稀释并用EtOAc(2×10mL)萃取。合并的有机相用水(20mL)、盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过快速柱色谱(12g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至70%B;流速=12mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈棕色半固体状的标题化合物(120mg,0.16mmol,53%产率)。MS(ESI)331(M+H)。
步骤N.中间体193N.3-(5-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)-2-氧杂双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸甲酯的制备
向中间体193M(50mg,0.15mmol)于DCM(1mL)中的经搅拌溶液中添加三氟甲烷磺酸银(120mg,0.45mmol),接着添加2,6-二-叔丁基吡啶(120mg,0.61mmol)。向该混合物中添加含4-(溴甲基)-5-环丙基-3-(2,6-二氯苯基)异噁唑(160mg,0.45mmol)的DCM(0.5mL),且在rt搅拌所得混合物。18h后,将反应混合物用DCM(15mL)稀释且经由硅藻土过滤。有机相用水(10mL)、盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过快速柱色谱(12g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至50%B;流速=12mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到标题化合物(50mg,0.041mmol,27%产率)。MS(ESI)596(M+H)。
步骤O.实施例193
根据针对实施例151的合成(步骤C)所描述的方法,适当时代入中间体193N来制备标题化合物:(8.0mg,0.014mmol,16%产率)。1H NMR(400MHz,甲醇-d4)δ8.66(s,1H),8.13-8.08(m,2H),7.60-7.51(m,4H),4.34(s,2H),3.65(s,2H),2.40-2.36(m,2H),2.30-2.23(m,3H),1.99-1.93(m,2H),1.71-1.67(m,2H),1.21-1.17(m,4H)。FXR EC50(nM)=26。MS(ESI)582(M+H)。
实施例194
(E)-4-(4-(2-(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)乙烯基)-2-氧杂双环[2.2.2]辛-1-基)苯甲酸
步骤A.中间体194A.4-(1-羟基-4,4-双((甲苯磺酰基氧基)甲基)环己基)苯甲酸甲酯的制备
在0℃向4-碘苯甲酸甲酯(1.8g,6.7mmol)于THF(10mL)中的经搅拌溶液中添加氯化异丙基镁(5.4mL,7.0mmol)。使混合物升温至5℃且搅拌10min。将反应混合物冷却至0℃,且逐滴添加(4-氧代环己烷-1,1-二基)双(亚甲基)双(苯磺酸4-甲酯)(2.5g,5.4mmol)(ACSMed.Chem.Lett.2014,5,609-614)于THF(5mL)中的溶液。使混合物升温至5℃并搅拌。1h后,将反应物用饱和NH4Cl(水溶液)(10mL)淬灭且用EtOAc(2×25mL)萃取。合并的有机相用水(10mL)、盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过快速柱色谱(24g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;25%B至50%B;流速=24mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈黄色固体状的标题化合物(2.7g,2.8mmol,52%产率)。MS(ESI)620(M+H+17)。
步骤B.中间体194B.4-(4-((甲苯磺酰基氧基)甲基)-2-氧杂双环[2.2.2]辛-1-基)苯甲酸的制备
向中间体194A(2.7g,4.5mmol)于THF(75mL)中的经搅拌溶液中添加粉末状NaOH(0.18g,4.5mmol)。在回流下搅拌混合物18h,冷却至rt且浓缩。残余物用水(50mL)稀释且用1.5M HCl(水溶液)酸化(pH约2),并用EtOAc(2×100mL)萃取。合并的有机相用盐水洗涤,经Na2SO4干燥,过滤且浓缩。将产物在真空中干燥,得到标题化合物(1.8g,4.3mmol,96%产率),其不经进一步纯化或表征即用于后续步骤中。MS(ESI)434(M+H+17)。
步骤C.中间体194C.4-(4-((甲苯磺酰基氧基)甲基)-2-氧杂双环[2.2.2]辛-1-基)苯甲酸甲酯的制备
向中间体194B(1.8g,4.3mmol)于DMF(20mL)中的经搅拌溶液中添加K2CO3(1.2g,8.6mmol)。搅拌10min后,添加碘甲烷(0.54mL,8.6mmol)。搅拌1h后,浓缩混合物,且通过快速柱色谱(24g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;25%B至100%B;流速=24mL/min)纯化粗物质。将纯级分合并、浓缩且在真空中干燥,得到呈白色固体状的标题化合物(1.0g,2.0mmol,47%产率)。MS(ESI)448(M+H+17)。
步骤D.中间体194D.4-(4-(乙酰氧基甲基)-2-氧杂双环[2.2.2]辛-1-基)苯甲酸甲酯的制备
向中间体194C(0.90g,2.1mmol)于DMF(10mL)中的经搅拌溶液中添加乙酸铯(1.0g,5.2mmol)。在120℃搅拌4h后,将反应混合物冷却至rt并浓缩。残余物用水(50mL)稀释且用EtOAc(2×80mL)萃取。合并的有机相用盐水洗涤,经Na2SO4干燥,过滤且浓缩。将产物在真空中干燥,得到呈棕色半固体状的标题化合物(660mg,1.6mmol,78%产率)。1H NMR(400MHz,DMSO-d6)δ7.90(dd,J=1.60,6.80Hz,2H),7.53(dd,J=1.60,6.80Hz,2H),3.84(s,3H),3.82(s,2H),2.84(s,2H),2.14-2.08(m,2H),2.04(s,3H),1.85-1.68(m,6H)。MS(ESI)319(M+H)。
步骤E.中间体194E.4-(4-(羟基甲基)-2-氧杂双环[2.2.2]辛-1-基)苯甲酸甲酯的制备
向中间体194D(660mg,2.1mmol)于MeOH(7mL)中的经搅拌溶液中添加甲醇钠(45mg,0.21mmol)(25%w/v于MeOH中)。搅拌1h后,将反应混合物用DCM(20mL)稀释,且用水(10mL)、盐水洗涤,经Na2SO4干燥,过滤且浓缩。将产物在真空中干燥,得到呈白色固体状的标题化合物(550mg,1.8mmol,88%产率)。1H NMR(400MHz,DMSO-d6)δ7.88(dd,J=2.00,5.20Hz,2H),7.53(dd,J=4.80,5.20Hz,2H),4.55-4.52(m,1H),3.83(s,3H),3.80(s,2H),3.17(s,1H),3.15(s,1H),2.11-2.05(m,2H),1.82-1.54(m,6H)。MS(ESI)277(M+H)。
步骤F.中间体194F.4-(4-甲酰基-2-氧杂双环[2.2.2]辛-1-基)苯甲酸甲酯的制备
在rt向中间体194E(200mg,0.72mmol)于DCM(4mL)中的经搅拌溶液中添加DMP(460mg,1.1mmol)。搅拌1h后,将反应混合物用DCM(15mL)稀释,且用10%NaHCO3(水性)溶液(2×25mL)、盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过快速柱色谱(24g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=24mL/min)纯化粗物质。将纯级分合并、浓缩且在真空中干燥,得到呈白色固体状的标题化合物(170mg,0.47mmol,65%产率)。1H NMR(400MHz,DMSO-d6)δ9.52(s,1H),7.92(d,J=8.40Hz,2H),7.55(d,J=8.00Hz,2H),4.02(s,2H),3.85(s,3H),2.18-2.15(m,2H),1.92-1.90(m,6H)。MS(ESI)275(M+H)。
步骤G.中间体194G.((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲基)膦酸二乙酯的制备
在160℃搅拌4-(溴甲基)-5-环丙基-3-(2,6-二氯苯基)异噁唑(2.0g,5.8mmol)于亚磷酸三乙酯(8mL,46mmol)中的溶液2.5h。使反应混合物冷却至rt,用水(50mL)稀释且用EtOAc(2×50mL)萃取。合并的有机相用盐水洗涤,经Na2SO4干燥,过滤且浓缩。向粗残余物中添加己烷(50mL)且搅拌5min。通过真空过滤收集所得析出物,用己烷(5mL)洗涤滤饼,且将固体产物在真空中干燥,得到呈白色固体状的标题化合物(1.9g,4.7mmol,82%产率)。1HNMR(400MHz,DMSO-d6)δ7.65-7.63(m,1H),7.59-7.55(m,2H),3.88-3.78(m,4H),2.89(d,J=20.40Hz,2H),2.36-2.32(m,1H),1.15-1.11(m,10H)。MS(ESI)404(M+H)。
步骤H.中间体194H.(E)-4-(4-(2-(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)乙烯基)-2-氧杂双环[2.2.2]辛-1-基)苯甲酸甲酯的制备
在-78℃向中间体194G(88mg,0.22mmol)于THF(1mL)中的经搅拌溶液中添加双(三甲基硅烷基)氨基锂(0.23mL,0.23mmol)(于THF中的1M溶液)。使混合物缓慢升温至0℃并搅拌。30min后,将反应物重新冷却至-78℃。向该混合物中添加中间体194F(40mg,0.15mmol)溶解于THF(0.5mL)中的溶液。使混合物缓慢升温至rt并搅拌。18h后,将反应混合物用饱和NH4Cl(水溶液)(10mL)淬灭且用EtOAc(2×20mL)萃取。合并的有机相用盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过快速柱色谱(12g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至70%B;流速=12mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈棕色半固体状的标题化合物(27mg,0.048mmol,33%产率)。1H NMR(400MHz,DMSO-d6)δ7.88(d,J=8.8Hz,2H),7.70-7.62(m,3H),7.49(d,J=8.4Hz,2H),6.14(d,J=16.8Hz,1H),5.16(d,J=16.4Hz,1H),3.83(s,3H),3.64(s,2H),2.09-2.04(m,3H),1.81-1.79(m,2H),1.63-1.61(m,4H),1.18-1.10(m,4H)。MS(ESI)524(M+H)。
步骤I.实施例194
根据针对实施例151的合成(步骤C)所描述的方法,适当时代入中间体194H来制备标题化合物:(11mg,0.022mmol,45%产率)。1H NMR(400MHz,DMSO-d6)δ12.80(br.s.,1H),7.86(d,J=8.3Hz,2H),7.69-7.67(m,2H),7.64-7.59(m,1H),7.46(d,J=8.3Hz,2H),6.13(d,J=16.4Hz,1H),5.17(d,J=16.4Hz,1H),3.64(s,2H),2.44-2.35(m,1H),2.16-1.99(m,2H),1.88-1.73(m,2H),1.69-1.52(m,4H),1.22-1.00(m,4H)。FXR EC50(nM)=34。MS(ESI)510(M+H)。
实施例195
3-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)-2-氧杂双环[2.2.2]辛-1-基)苯甲酸
步骤A.中间体195A.3-(1-羟基-4,4-双((甲苯磺酰基氧基)甲基)环己基)苯甲酸乙酯的制备.
根据针对中间体194A的合成所描述的方法,适当时代入3-碘苯甲酸乙酯来制备标题化合物:(1.4g,2.1mmol,48%产率,白色固体)。1H NMR(400MHz,DMSO-d6):δ8.00(s,1H),7.76-7.83(m,5H),7.44-7.51(m,6H),4.95(s,1H),4.33(q,J=7.2Hz,2H),4.04(s,2H),3.74(s,2H),2.44(s,3H),2.33(s,3H),1.58-1.61(m,2H),1.26-1.36(m,9H)。MS(ESI)634(M+18)。
步骤B.中间体195B.3-(4-((甲苯磺酰基氧基)甲基)-2-氧杂双环[2.2.2]辛-1-基)苯甲酸的制备.
根据针对中间体194B的合成所描述的方法,适当时代入中间体195A来制备标题化合物:(0.7g,1.7mmol,87%产率,棕色油状物)。1H NMR 400MHz,DMSO-d6:δ12.89(br s,1H),7.96(s,1H),7.77-7.95(m,3H),7.57-7.59(m,1H),7.49-7.51(m,2H),7.39-7.43(m,1H),3.83(s,2H),3.73(s,2H),2.44(s,3H),1.99-2.11(m,2H),1.79-1.91(m,2H),1.50-1.70(m,4H)。MS(ESI)434(M+18)。
步骤C.中间体195C.3-(4-((甲苯磺酰基氧基)甲基)-2-氧杂双环[2.2.2]辛-1-基)苯甲酸甲酯的制备
根据针对中间体194C的合成所描述的方法,适当时代入中间体195B来制备标题化合物:(820mg,1.9mmol,92%产率,淡黄色油状物)。1H NMR400MHz,DMSO-d6:δ7.97-7.98(m,1H),7.81-7.83(m,3H),7.61-7.63(m,1H),7.44-7.52(m,3H),3.80-3.84(m,5H),3.74(s,2H),2.44(s,3H),2.08-2.09(m,2H),1.79-1.80(m,2H),1.59-1.62(m,4H)。MS(ESI)448(M+18)。
步骤D.中间体195D.3-(4-(乙酰氧基甲基)-2-氧杂双环[2.2.2]辛-1-基)苯甲酸甲酯的制备.
根据针对中间体194D的合成所描述的方法,适当时代入中间体195C来制备标题化合物:(450mg,1.4mmol,87%产率)。1H NMR 400MHz,DMSO-d6:δ8.00-8.01(m,1H),7.80-7.83(m,1H),7.63-7.66(m,1H),7.44-7.48(m,1H),3.82-3.94(m,7H),2.09-2.13(m,2H),2.04(s,3H),1.83-1.86(m,2H),1.64-1.71(m,4H)。MS(ESI)336(M+18)。
步骤E.中间体195E.3-(4-(羟基甲基)-2-氧杂双环[2.2.2]辛-1-基)苯甲酸甲酯的制备.
根据针对中间体194E的合成(步骤D和E)所描述的方法,适当时代入中间体195D来制备标题化合物:(160mg,0.58mmol,61%产率,黄色蜡状物)。1H NMR(400MHz,DMSO-d6)δ8.00-8.01(m,1H),7.80-7.82(m,1H),7.63-7.65(m,1H),7.43-7.47(m,1H),4.53(t,J=5.60Hz,1H),3.81-3.86(m,5H),3.16(d,J=5.60Hz,2H),2.05-2.09(m,2H),1.78-1.82(m,2H),1.50-1.70(m,4H)。MS(ESI)294(M+18)。
步骤F.实施例195
在0至5℃向中间体195E(45mg,0.16mmol)于DMF(0.5mL)中的经搅拌溶液中添加氢化钠(9.8mg,0.24mmol)(于矿物油中的60%分散物)。在该温度搅拌10min后,添加4-(溴甲基)-5-环丙基-3-(2,6-二氯苯基)异噁唑(68mg,0.20mmol)。使反应物升温至rt并搅拌。18h后,浓缩混合物,用水(5mL)稀释,用1.5M HCl(水溶液)(0.5mL)酸化,且用EtOAc(2×5mL)萃取。合并的有机相用盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过制备型HPLC(柱:WatersXBridge C18,19×150mm,5μm颗粒;流动相A:10mM乙酸铵;流动相B:乙腈;梯度:10-45%B经25分钟,接着在100%B下保持5分钟;流速:15mL/min)纯化粗残余物。将纯级分合并、浓缩且在真空中干燥,得到标题化合物(2.0mg,3.8μmol,2%产率)。1H NMR(400MHz,DMSO-d6)δ7.94(s,1H),7.77(d,J=7.6Hz,1H),7.72-7.63(m,2H),7.62-7.47(m,2H),7.45-7.30(m,1H),4.25(s,2H),3.61(s,2H),3.02(s,2H),2.35-2.31(m,1H),2.06-1.92(m,2H),1.80-1.66(m,2H),1.55-1.31(m,4H),1.22-1.01(m,4H)。FXR EC50(nM)=47。MS(ESI)530(M+2)。
实施例197
(E)-3-(2-(4-(((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)甲基)-2-氧杂双环[2.2.2]辛-1-基)乙烯基)苯甲酸
步骤A.中间体197A.(E)-3-(2-(4-(乙酰氧基甲基)-2-氧杂双环[2.2.2]辛-1-基)乙烯基)苯甲酸乙酯的制备
向4-甲基苯磺酸(1-乙烯基-2-氧杂双环[2.2.2]辛-4-基)甲酯(60mg,0.19mmol)(ACS Med.Chem.Lett.,2014,5,609-614)于DMF(2mL)中的经搅拌溶液中添加3-溴苯甲酸乙酯(47mg,0.21mmol)、乙酸钾(46mg,0.47mmol)和溴化四丁基铵(60mg,0.19mmol)。用氮气吹扫反应混合物10min,之后添加四(三苯基膦)钯(0)(22mg,0.019mmol)。密封小瓶,且在110℃搅拌混合物。18h后,将反应混合物冷却至rt并浓缩。通过快速柱色谱(24g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至40%B;流速=24mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到标题化合物(50mg,0.13mmol,71%产率,无色半固体)。1H NMR(300MHz,氯仿-d)δ8.05(s,1H),7.89(d,J=7.80Hz,1H),7.53(d,J=8.10Hz,1H),7.39-7.34(m,1H),6.57(d,J=16.20Hz,1H),6.26(d,J=16.20Hz,1H),3.86(s,3H),3.82(s,2H),2.07(s,3H),2.07-1.61(m,6H),1.40-1.26(m,4H)。MS(ESI)359(M+H)。
步骤B.中间体197B.(E)-3-(2-(4-(羟基甲基)-2-氧杂双环[2.2.2]辛-1-基)乙烯基)苯甲酸甲酯的制备
根据针对中间体194E的合成(步骤D和E)所描述的方法,适当时代入中间体197A来制备呈无色半固体状的标题化合物:(30mg,0.063mmol,57%产率)。1H NMR(400MHz,DMSO-d6)δ7.95(s,1H),7.81-7.79(m,1H),7.70-7.68(m,1H),7.48-7.44(m,1H),6.55(d,J=16.00Hz,1H),6.34(d,J=16.00Hz,1H),4.50(s,1H),3.85(s,3H),3.69(s,2H),3.12(s,2H),1.82-1.78(m,4H),1.64-1.46(m,4H)。MS(ESI)303(M+H)。
步骤C.中间体197C.(E)-3-(2-(4-(((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)甲基)-2-氧杂双环[2.2.2]辛-1-基)乙烯基)苯甲酸甲酯的制备
根据针对中间体193N的合成所描述的方法,以中间体197B开始且适当时代入4-(溴甲基)-5-环丙基-3-(2-三氟甲氧基苯基)异噁唑来制备呈无色半固体状的标题化合物:(40mg,0.050mmol,30%产率)。MS(ESI)584(M+H)。
步骤D.实施例197
根据针对实施例151的合成(步骤C)所描述的方法,适当时代入中间体197C来制备标题化合物:(7.2mg,0.013mmol,21%产率)。1H NMR(400MHz,DMSO-d6)δ7.92(s,1H),7.77(d,J=8.00Hz,1H),7.68-7.66(m,1H),7.63-7.61(m,2H),7.57-7.55(m,2H),7.42(t,J=7.60Hz,1H),6.50(d,J=16.00Hz,1H),6.27(d,J=16.40Hz,1H),4.29(s,2H),3.49(s,2H),3.00(s,2H),2.32-2.30(m,1H),1.73-1.70(m,4H),1.44-1.34(m,4H),1.14-1.09(m,4H)。FXR EC50(nM)=90。MS(ESI)570(M+H)。
实施例203
4-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)氨基)甲基)-2-氧杂双环[2.2.2]辛-1-基)苯甲酸
步骤A.中间体203A.4-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)氨基)甲基)-2-氧杂双环[2.2.2]辛-1-基)苯甲酸甲酯的制备
向中间体166C(0.098g,0.37mmol)和中间体194F(0.1g,0.37mmol)于MeOH(3mL)中的经搅拌溶液中添加AcOH(0.042mL,0.73mmol),接着添加分子筛(10mg)。在60℃搅拌18h后,将混合物冷却至0℃,且添加氰基硼氢化钠(0.046g,0.73mmol)。使反应物升温至rt并搅拌。2h后,将混合物用水(20mL)淬灭且用EtOAc(2×25mL)萃取。合并的有机相用盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过制备型HPLC(柱:Waters XBridge C18,19×150mm,5μm颗粒;流动相A:10mM乙酸铵;流动相B:乙腈;梯度:25-90%B经20分钟,接着在100%B下保持5分钟;流速:15mL/min)纯化粗残余物。将含有期望产物的级分合并、浓缩且在真空中干燥,得到标题化合物(110mg,0.21mol,59%产率)。1H NMR(400MHz,DMSO-d6)δ7.88-7.86(m,2H),7.67-7.64(m,2H),7.61-7.55(m,1H),7.48-7.46(m,2H),3.82(s,3H),3.77(t,J=7.5Hz,1H),3.57(s,2H),2.51-2.53(m,2H),2.33-2.24(m,1H),2.08-1.94(m,2H),1.82-1.59(m,2H),1.56-1.30(m,4H),1.12-1.03(m,2H),1.02-0.89(m,2H)。FXR EC50(nM)=2800。MS(ESI)527(M+H)。
步骤B.实施例203
根据针对实施例151的合成(步骤C)所描述的方法,适当时代入中间体203A来制备标题化合物:(100mg,0.2mmol,95%产率)。1H NMR(400MHz,DMSO-d6)δ12.78(br.s.,1H),7.84(d,J=8.3Hz,2H),7.74-7.62(m,2H),7.62-7.53(m,1H),7.44(d,J=8.6Hz,2H),3.83-3.70(m,1H),3.57(s,2H),2.53(m,2H),2.32-2.22(m,1H),2.07-1.90(m,2H),1.71(m,2H),1.55-1.33(m,4H),1.14-1.03(m,2H),1.03-0.90(m,2H)。FXR EC50(nM)=420。MS(ESI)513(M+H)。
实施例208
4-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)氨基)甲基)-2-氧杂双环[2.2.2]辛-1-基)苯甲酰胺
向实施例203(30mg,0.058mmol)于DMF(2mL)中的经搅拌溶液中添加NH4Cl(9.4mg,0.18mmol)和TEA(0.024mL,0.18mmol)。向该混合物中添加BOP(28mg,0.064mmol),且在rt搅拌反应物。1h后,过滤反应物且浓缩滤液。经由制备型HPLC(柱:Waters XBridge C18,19×150mm,5μm颗粒;流动相A:10mM乙酸铵;流动相B:乙腈;梯度:15-55%B经25分钟,接着在100%B下保持5分钟;流速:15mL/min)纯化粗物质。将含有期望产物的级分合并、浓缩且在真空中干燥,得到标题化合物(2.7mg,5.3μmol,9%产率)。1H NMR(400MHz,DMSO-d6)δ7.87(br.s.,1H),7.81-7.71(m,2H),7.70-7.62(m,2H),7.61-7.49(m,1H),7.43-7.31(m,2H),7.25(br.s.,1H),3.76(t,J=7.5Hz,1H),3.57(s,2H),2.32-2.25(m,1H),2.06-1.90(m,2H),1.71(d,J=5.6Hz,2H),1.55-1.33(m,4H),1.14-1.05(m,2H),1.04-0.89(m,2H)。2H埋在溶剂峰下。FXR EC50(nM)=710。MS(ESI)512(M+H)。
实施例209
4-(5-(4-(((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)甲基)-2-氧杂双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸
步骤A.中间体209A.4-(((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)甲基)-2-氧杂双环[2.2.2]辛烷-1-甲酸甲酯的制备
根据针对中间体193N的合成所描述的方法,适当时代入中间体193G和4-(溴甲基)-5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑来制备标题化合物(70mg,0.13mmol,26%产率)。1H NMR(400MHz,DMSO-d6)δ7.70-7.52(m,4H),4.30(s,1H),4.28(s,1H),3.59(s,3H),3.42(s,2H),2.98(s,2H),2.31-2.27(m,1H),1.80-1.76(m,4H),1.42-1.26(m,4H),1.20-1.02(m,4H)。MS(ESI)482(M+H)。
步骤B.中间体209B.4-(((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)甲基)-2-氧杂双环[2.2.2]辛烷-1-甲酸的制备
/>
根据针对实施例151的合成(步骤C)所描述的方法,适当时代入中间体209A来制备标题化合物:(60mg,0.11mmol,73%产率)。1H NMR(400MHz,DMSO-d6)δ12.30(s,1H),7.67-7.54(m,4H),4.28(s,2H),3.42(s,2H),2.98(s,2H),2.30-2.29(m,1H),1.79-1.75(m,4H),1.39-1.24(m,4H),1.14-1.06(m,4H)。MS(ESI)468(M+H)。
步骤C.中间体209C.4-(5-(4-(((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)甲基)-2-氧杂双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸甲酯的制备
根据针对实施例193的合成(步骤M)所描述的方法,以中间体209B开始且适当时代入4-(N'-羟基甲脒基)苯甲酸甲酯来制备标题化合物。MS(ESI)626(M+H)。
步骤D.实施例209
根据针对实施例151的合成(步骤C)所描述的方法,适当时代入中间体209C来制备标题化合物:(3.6mg,5.6μmol,14%产率)。1H NMR(400MHz,DMSO-d6)δ8.10(s,4H),7.74-7.66(m,1H),7.65-7.60(m,1H),7.60-7.49(m,2H),4.32(s,2H),3.58(s,2H),3.06(s,2H),2.35-2.27(m,1H),2.18-2.20(m,2H),2.12-1.98(m,2H),1.65-1.38(m,4H),1.20-1.02(m,4H)。FXR EC50(nM)=470。MS(ESI)612(M+H)。
实施例210
3-(5-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)-2-氧杂双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸
步骤A.中间体210A.4-((甲苯磺酰基氧基)甲基)-2-氧杂双环[2.2.2]辛烷-1-甲酸的制备
向4-甲基苯磺酸(1-乙烯基-2-氧杂双环[2.2.2]辛-4-基)甲酯(0.46g,1.4mmol)(Singh,S.B.等人ACS Med.Chem.Lett.,2014,5,609-614)于四氯化碳(10mL)和MeCN(10mL)中的经搅拌溶液中添加含高碘酸钠(1.2g,5.7mmol)的水(15mL),接着添加氯化钌(III)水合物(0.016g,0.071mmol)。搅拌2h后,经由硅藻土过滤反应混合物,且用DCM(30mL)洗涤滤饼。将滤液用盐水洗涤,经硫酸钠干燥且浓缩,得到呈棕色半固体状的标题化合物(0.42g,1.2mmol,80%产率)。1H NMR(400MHz,DMSO-d6)δ12.44(s,1H),7.79(d,J=8.40Hz,2H),7.50(d,J=8.00Hz,2H),3.78(s,2H),3.55(s,2H),2.43(s,3H),2.00-1.78(m,4H),1.51-1.47(m,4H)。MS(ESI)358(M+H+17)。
步骤B.中间体210B.3-(5-(4-((甲苯磺酰基氧基)甲基)-2-氧杂双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸甲酯的制备
根据针对中间体1A的合成所描述的方法,适当时代入中间体210A来制备标题化合物:(50mg,0.085mmol,7%产率,棕色半固体)。1H NMR(400MHz,DMSO-d6)δ8.53(s,1H),8.30-8.15(m,2H),7.81(d,J=8.40Hz,2H),7.76-7.72(m,1H),7.51(d,J=8.00Hz,2H),3.91(s,3H),3.85(s,2H),3.73(s,2H),2.49(s,3H),2.32-2.13(m,4H),1.70-1.62(m,4H)。MS(ESI)499(M+H)。
步骤C.中间体210C.3-(5-(4-(乙酰氧基甲基)-2-氧杂双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸甲酯的制备
根据针对中间体194D的合成所描述的方法,适当时代入中间体210B来制备标题化合物:(25mg,0.060mmol,60%产率,棕色半固体)。1H NMR(400MHz,DMSO-d6)δ8.55-8.54(m,1H),8.28-8.16(m,2H),7.77-7.73(m,1H),3.91(s,3H),3.84(s,2H),3.83(s,2H),2.33-2.18(m,4H),2.05(s,3H),1.77-1.71(m,4H)。MS(ESI)387(M+H)。
步骤D.中间体210D.3-(5-(4-(羟基甲基)-2-氧杂双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸甲酯的制备
根据针对中间体194E的合成所描述的方法,适当时使用中间体210C来制备标题化合物(20mg,0.048mmol,93%产率)。1H NMR(400MHz,DMSO-d6)δ8.55-8.54(m,1H),8.26-8.16(m,2H),7.74-7.70(m,1H),4.60(s,1H),3.91(s,3H),3.80(s,2H),3.18(s,2H),2.33-2.11(m,4H),1.76-1.57(m,4H)。MS(ESI)345(M+H)。
步骤E.实施例210
根据针对实施例193的合成(步骤N和O)所描述的方法,适当时代入中间体210D来制备标题化合物:(6.1mg,10.0μmol,41%产率)。1H NMR(400MHz,DMSO-d6)δ8.53-8.52(m,1H),8.17-8.11(m,2H),7.69-7.57(m,4H),4.27(s,2H),3.60(s,2H),3.05(s,2H),2.34-2.32(m,1H),2.21-2.19(m,2H),2.09-2.06(m,2H),1.54-1.44(m,4H),1.18-1.10(m,4H)。FXR EC50(nM)=960。MS(ESI)596(M+H)。
实施例219
3-(5-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)-2-氧杂双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-5-氟苯甲酸
步骤A.中间体219A.4-羟基-2-氧杂双环[2.2.2]辛烷-1-甲酸甲酯的制备
向中间体193L(60mg,0.348mmol)于DMF(2mL)中的经搅拌溶液中添加K2CO3(72.2mg,0.523mmol),接着添加碘甲烷(0.033mL,0.523mmol)。搅拌2h后,浓缩反应混合物,残余物用水(10mL)稀释且用乙酸乙酯(2×10mL)萃取。合并的有机层经硫酸钠干燥且浓缩,得到呈棕色半固体状的标题化合物(65mg,0.25mmol,72%产率)。1H NMR(400MHz,DMSO-d6)δ4.82(s,1H),3.60(s,3H),3.36(s,2H),2.00-1.90(m,4H),1.70-1.50(m,4H)。MS(ESI)187(M+H)。
步骤B.中间体219B.4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)-2-氧杂双环[2.2.2]辛烷-1-甲酸甲酯的制备
根据针对中间体193N的合成所描述的方法,适当时代入中间体219A来制备标题化合物:(55mg,0.12mmol,26%产率)。1H NMR(400MHz,DMSO-d6)δ7.65-7.57(m,3H),4.20(s,2H),3.65(s,3H),3.31(s,2H),2.33-2.29(m,1H),1.91-1.88(m,4H),1.70-1.60(m,2H),1.45-1.30(m,2H),1.15-1.05(m,4H)。MS(ESI)452(M+H)。
步骤C.中间体219C.4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)-2-氧杂双环[2.2.2]辛烷-1-甲酸的制备
根据针对实施例151的合成(步骤C)所描述的方法,适当时代入中间体219B来制备标题化合物:(45mg,0.10mmol,92%产率)。MS(ESI)438(M+H)。
步骤D.实施例219
根据针对实施例64的合成(步骤C)所描述的方法,通过使中间体219C与(Z)-3-氟-5-(N'-羟基甲脒基)苯甲酸甲酯反应来制备标题化合物:(1.0mg,1.7μmol,7%产率)。1HNMR(400MHz,DMSO-d6)δ8.33(s,1H),7.83(br.s.,2H),7.71-7.53(m,2H),7.29(d,J=16.4Hz,1H),4.26(s,2H),3.51(s,2H),2.32-2.27(m,3H),2.19-2.15(m,2H),1.82(br.s.,2H),1.54(br.s.,2H),1.31-1.20(m,2H),1.15-1.08(m,2H)。FXR EC50(nM)=300。MS(ESI)600(M+H)。
实施例220
4-(((1-(3-(1H-四唑-5-基)苯基)-2-氧杂双环[2.2.2]辛-4-基)甲氧基)甲基)-5-环丙基-3-(2,6-二氯苯基)异噁唑
步骤A.中间体220A.3-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)-2-氧杂双环[2.2.2]辛-1-基)苯甲腈的制备
根据针对中间体20A的合成所描述的方法,适当时代入实施例195来制备标题化合物:(25mg,0.049mmol,65%产率)。MS(ESI)509(M+H)。
步骤B.实施例220
根据针对实施例8的合成(步骤B)所描述的方法,适当时代入中间体220A来制备标题化合物:(2.8mg,5.0μmol,10%产率)。1H NMR(400MHz,DMSO-d6)δ8.05(s,1H),7.86(d,J=5.6Hz,1H),7.72-7.61(m,2H),7.60-7.53(m,1H),7.53-7.39(m,2H),4.26(s,2H),3.64(s,2H),3.03(s,2H),2.37-2.26(m,1H),2.09-1.95(m,2H),1.85-1.67(m,2H),1.54-1.35(m,4H),1.21-1.04(m,4H)。FXR EC50(nM)=870。MS(ESI)552(M+H)。
实施例221
3-(5-((1r,4r)-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.1]庚-1-基)-1,2,4-噁二唑-3-基)苯甲酸
步骤A.中间体221A.3-(5-((1r,4r)-4-羟基双环[2.2.1]庚-1-基)-1,2,4-噁二唑-3-基)苯甲酸甲酯的制备
根据针对中间体151A的合成所描述的方法,适当时代入4-羟基双环[2.2.1]庚烷-1-甲酸(Brydon,B.等人WO2012/145569)来制备标题化合物:(0.030g,34%产率,白色固体)。1H NMR(400MHz,DMSO-d6)δ=8.53(s,1H),8.38-8.30(m,1H),8.28-8.22(m,1H),7.73(t,J=8Hz,1H),5.2(s,1H),3.91(s,3H),2.27-2.21(m,2H),1.98-1.62(m,8H)。MS(ESI)314(M+H)。
步骤B.中间体221B.3-(5-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸甲酯的制备
根据针对中间体151B的合成所描述的方法,适当时代入中间体221A来制备标题化合物:(0.020g,36%产率,淡黄色固体)。MS(ESI)580(M+H).
步骤C.实施例221
根据针对实施例151的合成(步骤C)所描述的方法,适当时代入中间体221B来制备标题化合物:(7.7mg,25%产率)。1H NMR(400MHz,DMSO-d6)δ8.51(s,1H),8.21(d,J=7.3Hz,1H),8.13(d,J=7.6Hz,1H),7.70(t,J=7.6Hz,1H),7.66-7.61(m,2H),7.60-7.54(m,1H),4.31(s,2H),2.35-2.32(s,1H),2.11-2.07(m,2H),1.94-1.90(m,2H),1.76-1.72(m,2H),1.66-1.62(m,2H),1.50-1.46(m,2H),1.17-1.12(m,2H),1.11-1.07(m,2H)。FXR EC50(nM)=300。MS(ESI)566(M+H)。
实施例226
4-(5-(4-(2-(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)乙烯基)双环[2.2.1]庚-1-基)-1,2,4-噁二唑-3-基)苯甲酸
步骤A.中间体226A.4-(2-(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)乙烯基)双环[2.2.1]庚烷-1-甲酸甲酯的制备
根据针对中间体159D的合成所描述的方法,适当时代入4-甲酰基双环[2.2.1]庚烷-1-甲酸甲酯(Velaparthi U.等人US 2015/0133428)来制备标题化合物:(0.18g,0.42mmol,54%产率)。1H NMR(400MHz,DMSO-d6)δ7.67-7.61(m,3H),6.12(d,J=16.4Hz,1H),5.56(d,J=16.4Hz,1H),3.60(s,3H),2.45-2.35(m,1H),1.91-1.78(m,2H),1.61-1.09(m,12H)。MS(ESI)432(M+H)。
步骤B.中间体226B.(1r,4r)-4-(2-(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)乙烯基)双环[2.2.1]庚烷-1-甲酸的制备
根据针对中间体159E的合成所描述的方法,适当时代入中间体226A来制备标题化合物:(0.090g,0.22mmol,58%产率)。1H NMR(400MHz,DMSO-d6)δ12.1(br s,1H),7.78-7.51(m,3H),6.12(d,J=16.4Hz,1H),5.55(d,J=16.4Hz,1H),2.42-2.36(m,1H),1.91-1.78(m,2H),1.61-1.09(m,12H)。MS(ESI)418(M+H)。产物以7:3比率的反/顺异构体混合物形式获得。通过1H NMR基于特征质子的积分确定比率。
步骤C.中间体226C.4-(5-(4-(2-(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)乙烯基)双环[2.2.1]庚-1-基)-1,2,4-噁二唑-3-基)苯甲酸甲酯的制备
根据针对中间体159F的合成所描述的方法,适当时代入中间体226B来制备标题化合物:(3.0mg,5.2μmol,22%产率)。1H NMR(400MHz,DMSO-d6)δ8.12(s,4H),7.70-7.53(m,3H),6.20(d,J=16.4Hz,1H),5.61(d,J=16.4Hz,1H),3.89(s,3H),2.44-2.35(m,1H),2.20-2.00(m,2H),1.97-1.78(m,2H),1.73(s,2H),1.71-1.54(m,2H),1.49(d,J=8.3Hz,2H),1.21-1.03(m,4H)。FXR EC50(nM)=2500。MS(ESI)576(M+H)。产物以5:1比率的反/顺异构体混合物形式获得。通过1H NMR基于特征质子的积分确定比率。
步骤D.实施例226
根据针对实施例151的合成(步骤C)所描述的方法,适当时代入中间体226C来制备标题化合物:(1.8mg,3.1μmol,5%产率)。1H NMR(400MHz,DMSO-d6)δ8.15-7.96(m,4H),7.75-7.49(m,3H),6.21(d,J=16.4Hz,1H),5.62(d,J=16.4Hz,1H),2.45-2.35(m,1H),2.21-2.00(m,2H),1.96-1.80(m,2H),1.79-1.55(m,4H),1.50(d,J=8.3Hz,2H),1.22-1.01(m,4H)。FXR EC50(nM)=420。MS(ESI)562(M+H)。产物以4:1比率的反/顺异构体混合物形式获得。通过1H NMR基于特征质子的积分确定比率。
根据本文中其他处所描述的方法,使用适当起始物质、试剂和条件来制备表4中的以下实施例。
表4
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
实施例234
5-(3-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-5-基)-2-甲氧基苯甲酸
步骤A.中间体234A.(Z)-4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)-N'-羟基双环[2.2.2]辛烷-1-甲脒的制备
根据针对中间体70A的合成所描述的方法,使用中间体69B作为起始物质来制备标题化合物:(23mg,0.051mmol,71%产率,透明油状物)。1H NMR(400MHz,氯仿-d)δ8.63-8.58(m,2H),4.45(br s,2H),4.22-4.18(m,2H),2.13-2.06(m,1H),1.80-1.73(m,6H),1.52-1.42(m,6H),1.26-1.22(m,2H),1.16-1.09(m,2H)。MS(ESI)451(M+H)。
步骤B.实施例234
根据针对实施例64的合成(步骤C)所描述的方法,通过使中间体234A与4-甲氧基-3-(甲氧基羰基)苯甲酸反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.82(s,2H),8.26(d,J=1.8Hz,1H),8.15(dd,J=8.9,1.8Hz,1H),7.33(d,J=8.9Hz,1H),4.24(s,2H),3.91(s,3H),2.36-2.25(m,1H),1.97-1.82(m,6H),1.50-1.40(m,6H),1.17-1.12(m,2H),1.10-1.05(m,2H)。FXR EC50(nM)=190。MS(ESI)611(M+H)。
实施例235
3-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-5-(三氟甲基)苯甲酸
步骤A.中间体235A.(Z)-3-(N'-羟基甲脒基)-5-(三氟甲基)苯甲酸甲酯的制备
根据针对中间体4C的合成所描述的方法,使用3-氰基-5-(三氟甲基)苯甲酸甲酯作为起始物质来制备标题化合物:(60mg,0.23mmol,97%产率,白色固体)。1H NMR(500MHz,DMSO-d6)δ10.02(s,1H),8.57(s,1H),8.27(s,1H),8.17(s,1H),6.16(s,2H),3.92(s,3H)。MS(ESI)263(M+H)。
步骤B.实施例235
根据针对实施例64的合成(步骤C)所描述的方法,通过使中间体69B与中间体235A反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.75(s,2H),8.67(br s,1H),8.34(s,1H),8.30(br s,1H),4.22(s,2H),2.29-2.20(m,1H),2.05-1.93(m,6H),1.52-1.43(m,6H),1.17-1.11(m,2H),1.05(br d,J=3.4Hz,2H)。FXR EC50(nM)=25。MS(ESI)649(M+H)。
实施例238
5-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-3-氟-2-甲氧基苯甲酸
/>
步骤A.中间体238A.5-溴-3-氟-2-甲氧基苯甲酸甲酯的制备
向5-溴-3-氟-2-羟基苯甲酸(0.50g,2.1mmol)和K2CO3(1.5g,11mmol)于DMF(12mL)中的0℃溶液中添加碘甲烷(0.40mL,6.4mmol)。在0℃搅拌1h后,使反应物升温至室温且搅拌另外5h。将反应混合物用水稀释且用DCM(3×)萃取。将合并的有机层用水、盐水洗涤,经无水Na2SO4干燥且浓缩。通过快速柱色谱(40g硅胶滤筒,A=己烷,B=EtOAc;12min梯度;0%B至25%B;流速=40mL/min)纯化粗产物。将纯级分浓缩且在真空中干燥,得到呈透明油状物的标题化合物(0.48g,1.8mmol,86%产率)。1H NMR(500MHz,氯仿-d)δ7.69(t,J=2.1Hz,1H),7.41(dd,J=10.2,2.5Hz,1H),3.98(d,J=1.4Hz,3H),3.93(s,3H)。MS(ESI)263(M+H)。
步骤B.中间体238B.5-氰基-3-氟-2-甲氧基苯甲酸甲酯的制备
在密封反应小瓶中,在120℃搅拌中间体238A(50mg,0.19mmol)和氰化铜(I)(21mg,0.23mmol)于DMF(1mL)中的混合物。18h后,使反应混合物冷却,用水稀释且用EtOAc(3×)萃取。将合并的有机层用盐水洗涤,经无水Na2SO4干燥且浓缩。通过快速柱色谱(12g硅胶滤筒,A=己烷,B=EtOAc;10min梯度;0%B至15%B;流速=30mL/min)纯化粗产物。将纯级分浓缩且在真空中干燥,得到呈黄褐色固体状的标题化合物(10mg,0.049mmol,26%产率)。1H NMR(400MHz,氯仿-d)δ7.88-7.83(m,1H),7.53(dd,J=10.8,2.2Hz,1H),4.10(d,J=2.9Hz,3H),3.95(s,3H)。MS(ESI)210(M+H)。
步骤C.中间体238C.(Z)-3-氟-5-(N'-羟基甲脒基)-2-甲氧基苯甲酸甲酯的制备
根据针对中间体4C的合成所描述的方法,使用中间体238B作为起始物质来制备呈灰白色固体状的标题化合物:(11.9mg,0.049mmol,100%产率)。MS(ESI)243(M+H)。
步骤D.实施例238
根据针对实施例64的合成(步骤C)所描述的方法,通过使中间体69B与中间体238C反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ13.67-13.29(br s,1H),8.83(s,2H),8.06(d,J=1.9Hz,1H),7.94(dd,J=11.6,2.2Hz,1H),4.25(s,2H),3.94(d,J=1.1Hz,3H),2.38-2.28(m,1H),2.02-1.96(m,6H),1.52-1.43(m,6H),1.15(dt,J=8.5,2.9Hz,2H),1.11-1.05(m,2H)。FXR EC50(nM)=21。MS(ESI)629(M+H)。
实施例239
3-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-5-甲氧基苯甲酸
步骤A.中间体239A.(Z)-3-(N'-羟基甲脒基)-5-甲氧基苯甲酸甲酯的制备
根据针对中间体4C的合成所描述的方法,使用3-氰基-5-甲氧基苯甲酸甲酯(Wensbo,D.等人WO 2004/014902)作为起始物质来制备标题化合物:(0.23g,1.0mmol,79%产率,白色固体)。1H NMR(400MHz,DMSO-d6)δ9.76(s,1H),7.91(t,J=1.5Hz,1H),7.49(dd,J=2.4,1.5Hz,1H),7.43(dd,J=2.5,1.4Hz,1H),5.93(s,2H),3.86(s,3H),3.84(s,3H)。MS(ESI)225(M+H)。
步骤B.实施例239
根据针对实施例64的合成(步骤C)所描述的方法,通过使中间体69B与中间体239A反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.82(s,2H),8.09(s,1H),7.62(br d,J=17.7Hz,2H),4.24(s,2H),3.87(s,3H),2.38-2.27(m,1H),2.05-1.93(m,6H),1.53-1.42(m,6H),1.18-1.14(m,2H),1.09(br d,J=2.7Hz,2H)。FXR EC50(nM)=79。MS(ESI)611(M+H)。
实施例240
5-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-2-甲氧基苯甲酰胺
根据针对中间体20A的合成(步骤1和2)所描述的方法,使用实施例69作为起始物质来制备标题化合物:(5.2mg,8.5μmol,21%产率,白色固体)。1H NMR(500MHz,氯仿-d)δ8.89(d,J=2.2Hz,1H),8.64(s,2H),8.20(dd,J=8.8,2.2Hz,1H),7.90(br s,1H),7.11(d,J=8.8Hz,1H),6.97(br s,1H),4.26(s,2H),4.07(s,3H),2.14-2.03(m,7H),1.63-1.54(m,6H),1.29-1.23(m,2H),1.18-1.08(m,2H)。FXR EC50(nM)=170。MS(ESI)610(M+H)。
实施例241
5-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-2-氟-3-甲氧基苯甲酸
步骤A.中间体241A.5-氰基-2-氟-3-甲氧基苯甲酸甲酯的制备
根据针对中间体238B的合成所描述的方法,使用5-溴-2-氟-3-甲氧基苯甲酸甲酯作为起始物质来制备标题化合物:(25mg,0.12mmol,32%产率,白色固体)。1H NMR(500MHz,氯仿-d)δ7.86-7.80(m,1H),7.34(dd,J=6.9,1.9Hz,1H),3.97(s,3H),3.96(s,3H)。MS(ESI)210(M+H)。
步骤B.中间体241B.(Z)-2-氟-5-(N'-羟基甲脒基)-3-甲氧基苯甲酸甲酯的制备
根据针对中间体4C的合成所描述的方法,使用中间体241A作为起始物质来制备标题化合物:(29mg,0.12mmol,98%产率,灰白色固体)。1H NMR(400MHz,DMSO-d6)δ9.75(s,1H),7.74(dd,J=5.9,2.0Hz,1H),7.65(dd,J=7.7,2.2Hz,1H),5.97(br s,2H),3.90(s,3H),3.86(s,3H)。MS(ESI)243(M+H)。
步骤C.实施例241
根据针对实施例64的合成(步骤C)所描述的方法,通过使中间体69B与中间体241B反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.79(s,2H),7.92(br d,J=4.3Hz,1H),7.74(br d,J=6.1Hz,1H),4.21(s,2H),3.91(s,3H),2.32-2.22(m,1H),2.00-1.92(m,6H),1.48-1.39(m,6H),1.14-1.08(m,2H),1.07-1.01(m,2H)。FXR EC50(nM)=130。MS(ESI)629(M+H)。
实施例242
4-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-2-(1H-四唑-5-基)酚
步骤A.中间体242A.5-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-2-甲氧基苯甲腈的制备
根据针对中间体20A的合成所描述的方法,使用实施例69作为起始物质来制备标题化合物:(9.1mg,0.015mmol,38%产率,白色固体)。1H NMR(400MHz,氯仿-d)δ8.63(s,2H),8.27(d,J=2.0Hz,1H),8.23(dd,J=8.9,2.1Hz,1H),7.06(d,J=9.0Hz,1H),4.26(s,2H),4.01(s,3H),2.09(dt,J=8.6,3.7Hz,7H),1.63-1.53(m,6H),1.34-1.23(m,2H),1.19-1.08(m,2H)。MS(ESI)592(M+H)。
步骤B.实施例242
在密封反应小瓶中,在120℃搅拌中间体242A(9.1mg,0.015mmol)、叠氮化钠(6.0mg,0.092mmol)和NH4Cl(4.9mg,0.092mmol)于NMP(0.15mL)中的溶液。18h后,添加另外的叠氮化钠(5.99mg,0.092mmol)和NH4Cl(4.9mg,0.092mmol),且在120℃继续搅拌。18h后,使反应物冷却,用EtOAc稀释且用盐水洗涤。有机层经无水Na2SO4干燥,过滤且浓缩。制备型HPLC(柱:Phenomenex Luna AXIA 5u C18 21.2×100mm;溶剂B=90%/10%的MeOH:H2O/0.1%TFA,溶剂A=10%/90%的MeOH:H2O/0.1%TFA;梯度:15%至100%溶剂B经10分钟,接着在100%B下保持5分钟;流速:20mL/min)纯化粗产物。将纯级分浓缩且在真空中干燥,得到呈白色固体状的标题化合物(3.4mg,5.4μmol,35%产率)。1H NMR(400MHz,DMSO-d6)δ8.84(s,2H),8.61(d,J=2.2Hz,1H),7.98(dd,J=8.6,2.2Hz,1H),7.21(d,J=8.8Hz,1H),4.25(s,2H),2.39-2.24(m,1H),2.06-1.96(m,6H),1.53-1.43(m,6H),1.17-1.13(m,2H),1.11-1.05(m,2H)。FXR EC50(nM)=1400。MS(ESI)621(M+H)。
实施例243
5-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-2,3-二甲氧基苯甲酸
步骤A.中间体243A.5-溴-2,3-二甲氧基苯甲酸乙酯的制备
根据针对中间体64A的合成所描述的方法,使用5-溴-2,3-二甲氧基苯甲酸作为起始物质来制备标题化合物:(0.53g,1.9mmol,96%产率,黄色油状物)。1H NMR(500MHz,氯仿-d)δ7.45(d,J=2.5Hz,1H),7.15(d,J=2.2Hz,1H),4.37(q,J=7.2Hz,2H),3.89(d,J=2.8Hz,6H),1.40(t,J=7.2Hz,3H)。MS(ESI)291(M+H)。
步骤B.中间体243B.5-氰基-2,3-二甲氧基苯甲酸乙酯的制备
根据针对中间体238B的合成所描述的方法,使用中间体243A作为起始物质来制备标题化合物:(57mg,0.24mmol,71%产率,灰白色固体)。1H NMR(500MHz,氯仿-d)δ7.66(d,J=1.9Hz,1H),7.25-7.22(m,1H),4.40(q,J=7.2Hz,2H),3.97(s,3H),3.93(s,3H),1.41(t,J=7.2Hz,3H)。MS(ESI)236(M+H)。
步骤C.中间体243C.(Z)-5-(N'-羟基甲脒基)-2,3-二甲氧基苯甲酸乙酯的制备
根据针对中间体4C的合成所描述的方法,使用中间体243B作为起始物质来制备标题化合物:(64mg,0.24mmol,99%产率,灰白色固体)。1H NMR(500MHz,DMSO-d6)δ9.66(s,1H),7.50(dd,J=10.7,1.9Hz,2H),5.88(s,2H),4.29(q,J=7.2Hz,2H),3.86(s,3H),3.77(s,3H),1.31(t,J=7.2Hz,3H)。MS(ESI)269(M+H)。
步骤D.实施例243
根据针对实施例64的合成(步骤C)所描述的方法,通过使中间体69B与中间体243C反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.77(s,2H),7.76(d,J=1.5Hz,1H),7.63(d,J=1.6Hz,1H),4.23(s,2H),3.89(s,3H),3.81(s,3H),2.33-2.22(m,1H),2.02-1.93(m,6H),1.54-1.42(m,6H),1.18-1.12(m,2H),1.10-1.00(m,2H)。FXR EC50(nM)=120。MS(ESI)641(M+H)。
实施例244
3-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-2-氟-5-甲氧基苯甲酸
步骤A.中间体244A.3-氰基-2-氟-5-甲氧基苯甲酸甲酯的制备
根据针对中间体238B的合成所描述的方法,使用3-溴-2-氟-5-甲氧基苯甲酸甲酯(Lu,L.等人WO 2016/134320)作为起始物质来制备标题化合物:(74mg,0.35mmol,70%产率,白色固体)。1H NMR(500MHz,DMSO-d6)δ7.86-7.80(m,1H),7.65(dd,J=5.8,3.3Hz,1H),3.89(s,3H),3.85(s,3H)。MS(ESI)210(M+H)。
步骤B.中间体244B.(Z)-2-氟-3-(N'-羟基甲脒基)-5-甲氧基苯甲酸甲酯的制备
根据针对中间体4C的合成所描述的方法,使用中间体244A作为起始物质来制备标题化合物:(67mg,0.28mmol,81%产率,白色固体)。1H NMR(500MHz,DMSO-d6)δ9.70(s,1H),7.34(dd,J=5.0,3.3Hz,1H),7.23(dd,J=5.1,3.4Hz,1H),5.89(s,2H),3.86(s,3H),3.80(s,3H)。MS(ESI)243(M+H)。
步骤C.实施例244
根据针对实施例64的合成(步骤C)所描述的方法,通过使中间体69B与中间体244B反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.83(s,2H),7.30(t,J=3.8Hz,1H),7.25(br d,J=4.5Hz,1H),4.25(s,2H),3.78(s,3H),2.37-2.25(m,1H),2.04-1.94(m,6H),1.53-1.43(m,6H),1.15(dt,J=8.1,3.0Hz,2H),1.12-1.04(m,2H)。FXR EC50(nM)=230。MS(ESI)629(M+H)。
实施例245
3-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-5-氟-2-甲氧基苯甲酸
步骤A.中间体245A.3-溴-5-氟-2-甲氧基苯甲酸甲酯的制备
根据针对中间体238A的合成所描述的方法,使用3-溴-5-氟-2-羟基苯甲酸(Xu,R.等人J.Med.Chem.2010,53,7035)作为起始物质来制备标题化合物:(0.16g,0.60mmol,56%产率,黄色油状物)。1H NMR(500MHz,甲醇-d4)δ7.64(dd,J=7.6,3.2Hz,1H),7.51(dd,J=8.4,3.2Hz,1H),3.92(s,3H),3.87(s,3H)。MS(ESI)263(M+H)。
步骤B.中间体245B.3-氰基-5-氟-2-甲氧基苯甲酸甲酯的制备
根据针对中间体238B的合成所描述的方法,使用中间体245A作为起始物质来制备标题化合物:(84mg,0.12mmol,68%产率,白色固体)。1H NMR(500MHz,DMSO-d6)δ8.11(dd,J=7.8,3.2Hz,1H),7.91(dd,J=8.5,3.3Hz,1H),3.93(s,3H),3.88(s,3H)。MS(ESI)210(M+H)。
步骤C.中间体245C.(Z)-5-氟-3-(N'-羟基甲脒基)-2-甲氧基苯甲酸甲酯的制备
根据针对中间体4C的合成所描述的方法,使用中间体245B作为起始物质来制备标题化合物:(88mg,0.36mmol,92%产率,浅黄色油状物)。1H NMR(500MHz,DMSO-d6)δ9.71-9.61(m,1H),7.52(dd,J=8.5,3.3Hz,1H),7.39(dd,J=8.8,3.3Hz,1H),5.84(br s,2H),3.85(s,3H),3.73(s,3H)。MS(ESI)243(M+H)。
步骤D.实施例245
根据针对实施例64的合成(步骤C)所描述的方法,通过使中间体69B与中间体245C反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.81(s,2H),7.75(dd,J=8.4,3.2Hz,1H),7.65(dd,J=8.2,3.1Hz,1H),4.23(s,2H),3.64(br s,3H),2.36-2.25(m,1H),2.03-1.90(m,6H),1.53-1.37(m,6H),1.20-1.12(m,2H),1.07(br d,J=2.4Hz,2H)。FXR EC50(nM)=46。MS(ESI)629(M+H)。
实施例246
3-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-2,5-二甲氧基苯甲酸
步骤A.中间体246A.3-氰基-2,5-二甲氧基苯甲酸甲酯的制备
根据针对中间体238B的合成所描述的方法,使用3-溴-2,5-二甲氧基苯甲酸甲酯(Miller,C.P.等人US 2006/0004087)作为起始物质来制备标题化合物:(38mg,0.17mmol,77%产率,白色固体)。1H NMR(500MHz,DMSO-d6)δ7.66(d,J=3.3Hz,1H),7.53(d,J=3.3Hz,1H),3.88(s,3H),3.87(s,3H),3.82(s,3H)。MS(ESI)222(M+H)。
步骤B.中间体246B.(Z)-3-(N'-羟基甲脒基)-2,5-二甲氧基苯甲酸甲酯的制备
根据针对中间体4C的合成所描述的方法,使用中间体246A作为起始物质来制备标题化合物:(40mg,0.16mmol,94%产率,白色固体)。1H NMR(500MHz,DMSO-d6)δ9.56(s,1H),7.19(d,J=3.3Hz,1H),7.10(d,J=3.3Hz,1H),5.76(s,2H),3.84(s,3H),3.76(s,3H),3.69(s,3H)。MS(ESI)255(M+H)。
步骤C.实施例246
根据针对实施例64的合成(步骤C)所描述的方法,通过使中间体69B与中间体246B反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.84(s,2H),7.42(d,J=3.1Hz,1H),7.32(br d,J=2.7Hz,1H),4.26(s,2H),3.80(s,3H),3.72(s,3H),2.36-2.30(m,1H),2.03-1.97(m,6H),1.52-1.45(m,6H),1.16(dt,J=8.2,2.9Hz,2H),1.10(br d,J=2.4Hz,2H)。FXR EC50(nM)=90。MS(ESI)641(M+H)。
实施例249
4-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)吡啶-2-甲酸
步骤A.中间体249A.(Z)-4-(N'-羟基甲脒基)吡啶-2-甲酸甲酯的制备
根据针对中间体4C的合成所描述的方法,使用4-氰基吡啶-2-甲酸甲酯作为起始物质来制备呈黄色固体状的标题化合物:(7.1mg,0.036mmol,100%产率)。MS(ESI)196(M+H)。
步骤B.实施例249
根据针对实施例64的合成(步骤C)所描述的方法,通过使中间体69B与中间体249A反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.88(br s,1H),8.82(s,2H),8.46(brs,1H),8.07(br s,1H),4.25(s,2H),2.36-2.27(m,1H),2.04-1.98(m,6H),1.53-1.43(m,6H),1.17(br d,J=7.9Hz,2H),1.09(br d,J=2.4Hz,2H)。FXR EC50(nM)=240。MS(ESI)582(M+H)。
实施例250
3-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-2-氟-6-甲氧基苯甲酸
步骤A.中间体250A.3-氰基-2-氟-6-甲氧基苯甲酸甲酯的制备
根据针对中间体238B的合成所描述的方法,使用3-溴-2-氟-6-甲氧基苯甲酸甲酯作为起始物质来制备标题化合物:(56mg,0.27mmol,57%产率,白色固体)。1H NMR(400MHz,DMSO-d6)δ8.07(dd,J=8.9,7.8Hz,1H),7.22(dd,J=9.0,0.7Hz,1H),3.94(s,3H),3.87(s,3H)。MS(ESI)210(M+H)。
步骤B.中间体250B.(Z)-2-氟-3-(N'-羟基甲脒基)-6-甲氧基苯甲酸甲酯的制备
根据针对中间体4C的合成所描述的方法,使用中间体250A作为起始物质来制备标题化合物:(63mg,0.26mmol,100%产率,黄色固体)。1H NMR(500MHz,DMSO-d6)δ9.58(s,1H),7.56(t,J=8.7Hz,1H),6.99(d,J=8.8Hz,1H),5.79(s,2H),3.84(d,J=0.8Hz,6H)。MS(ESI)243(M+H)。
步骤C.实施例250
根据针对实施例64的合成(步骤C)所描述的方法,通过使中间体69B与中间体250B反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.81(br s,2H),7.89(br t,J=8.7Hz,1H),7.07(br d,J=8.5Hz,1H),4.23(s,2H),3.88(s,3H),2.37-2.21(m,1H),2.00-1.88(m,6H),1.53-1.39(m,6H),1.15(br d,J=7.9Hz,2H),1.07(br d,J=2.1Hz,2H)。FXR EC50(nM)=730。MS(ESI)629(M+H)。
实施例251
3-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-5-异丙氧基苯甲酸
步骤A.中间体251A.(Z)-3-(N'-羟基甲脒基)-5-异丙氧基苯甲酸甲酯的制备
根据针对中间体4C的合成所描述的方法,使用3-氰基-5-异丙氧基苯甲酸甲酯作为起始物质来制备标题化合物:(68mg,0.27mmol,100%产率,透明油状物)。1H NMR(500MHz,DMSO-d6)δ9.75(s,1H),7.88(t,J=1.4Hz,1H),7.47-7.44(m,1H),7.41-7.37(m,1H),5.91(s,2H),4.70(dt,J=12.0,5.9Hz,1H),3.85(s,3H),1.29(s,3H),1.28(s,3H)。MS(ESI)253(M+H)。
步骤B.实施例251
根据针对实施例64的合成(步骤C)所描述的方法,通过使中间体69B与中间体251A反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.74(s,2H),8.03(s,1H),7.60(s,1H),7.55(s,1H),4.74-4.61(m,1H),4.21(s,2H),2.30-2.17(m,1H),2.01-1.92(m,6H),1.51-1.42(m,6H),1.28(d,J=6.0Hz,6H),1.17-1.11(m,2H),1.05(br d,J=2.6Hz,2H)。FXR EC50(nM)=16。MS(ESI)639(M+H)。
实施例252
5-(4-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)噁唑-2-基)-2-甲氧基苯甲酸
步骤A.中间体252A.4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛烷-1-甲酰氯的制备
向中间体69B(100mg,0.23mmol)于DCM(0.50mL)中的溶液中添加草酰氯(0.030mL,0.34mmol),接着添加DMF(1.7μL)。在室温搅拌18h后,浓缩溶剂,得到呈粗黄色油状物的标题化合物(100mg,0.23mmol,100%产率),其不经纯化即用于下一步骤中。MS(ESI)451(M-Cl+OMe+H)。
步骤B.中间体252B.1-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-2-重氮乙-1-酮的制备
向氧化钙(28mg,0.50mmol)于THF(1mL)和MeCN(1mL)中的0℃溶液中添加(三甲基硅烷基)重氮甲烷(0.23mL,0.46mmol)(2.0M于己烷中)。在0℃搅拌20min后,添加中间体252A(100mg,0.23mmol)于THF(0.10mL)和MeCN(0.10mL)中的溶液。使反应混合物缓慢升温至rt且搅拌18h。经由硅藻土垫过滤反应物,且浓缩滤液。通过快速柱色谱(4g硅胶滤筒,A=己烷,B=EtOAc;11min梯度;0%B至100%B;流速=18mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈浅黄色固体状的标题化合物(79mg,0.17mmol,75%产率)。1HNMR(500MHz,氯仿-d)δ8.61(s,2H),5.28(s,1H),4.20(s,2H),2.11-2.05(m,1H),1.78-1.71(m,6H),1.48-1.43(m,6H),1.27-1.22(m,2H),1.17-1.09(m,2H)。MS(ESI)461(M+H)。
步骤C.中间体252C.2-氯-1-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙-1-酮的制备
向中间体252B(79mg,0.17mmol)于DCM(2mL)中的0℃溶液中逐滴添加HCl(0.13mL,0.51mmol)(4M于1,4-二噁烷中)。在0℃搅拌30min后,浓缩溶剂。通过快速柱色谱(4g硅胶滤筒,A=己烷,B=EtOAc;11min梯度;0%B至75%B;流速=18mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈白色固体状的标题化合物(66mg,0.14mmol,82%产率)。1HNMR(400MHz,氯仿-d)δ8.61(s,2H),4.24(s,2H),4.22-4.19(m,1H),4.21(s,1H),2.13-2.00(m,1H),1.86-1.77(m,6H),1.52-1.45(m,6H),1.29-1.22(m,2H),1.17-1.08(m,2H)。MS(ESI)471(M+H)。
步骤D.中间体252D.5-氨甲酰基-2-甲氧基苯甲酸甲酯的制备
根据针对中间体20A的合成(步骤1和步骤2)所描述的方法,使用4-甲氧基-3-(甲氧基羰基)苯甲酸(Casagrande,C.等人EP 1270558)作为起始物质来制备标题化合物:(40mg,0.19mmol,62%产率,白色固体)。1H NMR(500MHz,DMSO-d6)δ8.19(d,J=2.2Hz,1H),8.06(dd,J=8.8,2.5Hz,1H),7.97(br s,1H),7.29(br s,1H),7.21(d,J=8.8Hz,1H),3.88(s,3H),3.81(s,3H)。MS(ESI)210(M+H)。
步骤E.中间体252E.5-(4-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)噁唑-2-基)-2-甲氧基苯甲酸甲酯的制备
向中间体252C(10mg,0.021mmol)于1,4-二噁烷(0.20mL)中的溶液中添加中间体252D(6.7mg,0.032mmol)。在密封反应小瓶中在175℃搅拌4h后,使反应物冷却至室温且浓缩。通过制备型HPLC(柱:Phenomenex Luna AXIA 5u C18 21.2×100mm,流动相A:10:90的甲醇:水/10-0.1%TFA;流动相B:90:10的甲醇:水/0.1%TFA;梯度:15-100%B经10分钟,接着在100%B下保持5分钟;流速:20mL/min)纯化粗产物。将含有期望产物的级分合并、浓缩且在真空中干燥,得到呈棕色固体状的标题化合物(8.3mg,0.013mmol,62%产率)。MS(ESI)624(M+H)。
步骤F.实施例252
将中间体252E(8.4mg,0.013mmol)溶解于THF(0.50mL)和1M NaOH(水溶液)(0.50mL)中,且在50℃搅拌。6.5h后,使反应物冷却至室温,用5%柠檬酸(水溶液)稀释且用EtOAc(2×)萃取。将经合并的有机层用盐水洗涤,经Na2SO4干燥且浓缩。通过制备型HPLC(柱:XBridge C18,19×200mm,5μm颗粒;流动相A:5:95的乙腈:水/10mM乙酸铵;流动相B:95:5的乙腈:水/10mM乙酸铵;梯度:25-65%B经20分钟,接着在100%B下保持4分钟;流速:20mL/min)纯化粗产物。将含有期望产物的级分合并、浓缩且在真空中干燥,得到标题化合物(2.9mg,4.7μmol,35%产率)。1H NMR(500MHz,DMSO-d6)δ8.74(s,2H),7.99(s,1H),7.87(br d,J=8.6Hz,1H),7.62(s,1H),7.12(d,J=8.8Hz,1H),4.21(s,2H),3.81(s,3H),2.29-2.17(m,1H),1.81-1.69(m,6H),1.47-1.35(m,6H),1.16-1.11(m,2H),1.09-1.00(m,2H)。FXR EC50(nM)=86。MS(ESI)610(M+H)。
实施例253
6-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-3-甲氧基吡啶-2-甲酸
步骤A.中间体253A.6-氰基-3-甲氧基吡啶-2-甲酸甲酯的制备
向6-溴-3-甲氧基吡啶-2-甲酸甲酯(50mg,0.20mmol)于NMP(1mL)中的经吹扫溶液中添加氰化锌(48mg,0.41mmol)和Pd(PPh3)4(12mg,10μmol)。在65℃搅拌22h后,使反应物冷却至室温,用EtOAc稀释且用水洗涤。有机层经无水Na2SO4干燥,过滤且浓缩。通过快速柱色谱(12g硅胶滤筒,A=己烷,B=EtOAc;11min梯度;0%B至100%B;流速=30mL/min)纯化粗产物。将纯级分浓缩且在真空中干燥,得到呈白色固体状的标题化合物(33mg,0.17mmol,86%产率)。1H NMR(400MHz,DMSO-d6)δ8.22(d,J=8.8Hz,1H),7.86(d,J=8.8Hz,1H),3.96(s,3H),3.87(s,3H)。MS(ESI)193(M+H)。
步骤B.中间体253B.(Z)-6-(N'-羟基甲脒基)-3-甲氧基吡啶-2-甲酸甲酯的制备
根据针对中间体4C的合成所描述的方法,使用中间体253A作为起始物质来制备标题化合物:(23mg,0.10mmol,61%产率,黄色固体)。1H NMR(500MHz,DMSO-d6)δ9.84(s,1H),7.96(d,J=9.1Hz,1H),7.69(d,J=9.1Hz,1H),5.69(s,2H),3.88(s,3H),3.86(s,3H)。MS(ESI)226(M+H)。
步骤C.实施例253
根据针对实施例64的合成(步骤C)所描述的方法,通过使中间体69B与中间体253B反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.83(s,2H),7.92(br s,1H),7.57(brd,J=8.2Hz,1H),4.25(s,2H),3.90-3.77(m,3H),2.32(br dd,J=8.2,4.9Hz,1H),2.00(brs,6H),1.48(br s,6H),1.17(br d,J=8.2Hz,2H),1.09(br d,J=2.7Hz,2H)。FXR EC50(nM)=740。MS(ESI)612(M+H)。
实施例254
5-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-2-(三氟甲基)苯甲酸
步骤A.中间体254A.(Z)-5-(N'-羟基甲脒基)-2-(三氟甲基)苯甲酸甲酯的制备
根据针对中间体4C的合成所描述的方法,使用5-氰基-2-(三氟甲基)苯甲酸甲酯作为起始物质来制备标题化合物:(69mg,0.26mmol,100%产率,透明油状物)。1H NMR(500MHz,DMSO-d6)δ10.04(s,1H),8.13(s,1H),8.03(d,J=8.3Hz,1H),7.89(d,J=8.3Hz,1H),6.07(s,2H),3.89(s,3H)。MS(ESI)263(M+H)。
步骤B.实施例254
根据针对实施例64的合成(步骤C)所描述的方法,通过使中间体69B与中间体254A反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.80(s,2H),8.03(s,1H),7.98(br d,J=8.2Hz,1H),7.79(br d,J=8.2Hz,1H),4.23(s,2H),2.34-2.25(m,1H),2.03-1.95(m,6H),1.51-1.41(m,6H),1.17-1.13(m,2H),1.07(br d,J=2.7Hz,2H)。FXR EC50(nM)=2000。MS(ESI)649(M+H)。
实施例255
5-(4-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)噻唑-2-基)-2-甲氧基苯甲酸
步骤A.中间体255A.5-硫代氨甲酰基-2-甲氧基苯甲酸甲酯的制备
向5-氰基-2-甲氧基苯甲酸甲酯(0.20g,1.1mmol)于THF(3mL)和水(1mL)中的溶液中添加二硫代磷酸二乙酯(0.21mL,1.3mmol)。在80℃搅拌反应物。17h后,使混合物冷却至室温且浓缩溶剂,得到黄色油状物。用EtOAc(25mL)稀释残余物,且通过真空过滤收集所得析出物并在真空中干燥,得到呈粗浅黄色固体状的标题化合物(0.12g,0.55mmol,53%产率),其不经进一步纯化即用于下一步骤中。1H NMR(500MHz,DMSO-d6)δ9.77(br s,1H),9.47(br s,1H),8.33(d,J=2.5Hz,1H),8.12(dd,J=8.8,2.5Hz,1H),7.19(d,J=8.8Hz,1H),3.88(s,3H),3.81(s,3H)。MS(ESI)226(M+H)。
步骤B.实施例255
根据针对实施例252的合成所描述的方法,适当时代入中间体255A来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.77(s,2H),8.03(br s,1H),7.99-7.80(m,1H),7.16(brd,J=8.9Hz,1H),7.09(s,1H),4.21(s,2H),3.79(s,3H),2.26(br s,1H),1.85-1.77(m,6H),1.44-1.33(m,6H),1.16-1.11(m,2H),1.04(br d,J=2.4Hz,2H)。FXR EC50(nM)=18。MS(ESI)626(M+H)。
实施例256
5-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-2-异丙氧基苯甲酸
步骤A.中间体256A.5-氰基-2-异丙氧基苯甲酸甲酯的制备
根据针对中间体238B的合成所描述的方法,使用5-溴-2-异丙氧基苯甲酸甲酯作为起始物质来制备标题化合物:(65mg,0.30mmol,54%产率,透明油状物)。1H NMR(500MHz,DMSO-d6)δ8.03(d,J=2.2Hz,1H),7.95(dd,J=8.8,2.2Hz,1H),7.36(d,J=8.8Hz,1H),4.83(dt,J=12.1,6.1Hz,1H),3.80(s,3H),1.30(s,3H),1.28(s,3H)。MS(ESI)220(M+H)。
步骤B.中间体256B.(Z)-5-(N'-羟基甲脒基)-2-异丙氧基苯甲酸甲酯的制备
根据针对中间体4C的合成所描述的方法,使用中间体256A作为起始物质来制备标题化合物:(67mg,0.27mmol,94%产率,白色固体)。1H NMR(500MHz,DMSO-d6)δ9.53(s,1H),7.93(d,J=2.5Hz,1H),7.77(dd,J=8.7,2.3Hz,1H),7.16(d,J=9.1Hz,1H),5.79(s,2H),4.68(dt,J=12.0,5.9Hz,1H),3.79(s,3H),1.28(s,3H),1.26(s,3H)。MS(ESI)253(M+H)。
步骤C.实施例256
根据针对实施例64的合成(步骤C)所描述的方法,通过使中间体69B与中间体256B反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.77(s,2H),8.13(s,1H),7.99(br d,J=8.8Hz,1H),7.26(br d,J=8.8Hz,1H),4.73(dt,J=11.9,6.0Hz,1H),4.23(s,2H),2.27(br s,1H),2.03-1.93(m,6H),1.53-1.42(m,6H),1.30(s,3H),1.29(s,3H),1.18-1.10(m,2H),1.10-1.02(m,2H)。FXR EC50(nM)=260。MS(ESI)639(M+H)。
实施例257
4-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-6-甲氧基吡啶-2-甲酸
步骤A.中间体257A.4-氰基-6-甲氧基吡啶-2-甲酸甲酯的制备
根据针对中间体20A的合成所描述的方法,使用2-甲氧基-6-(甲氧基羰基)吡啶-4-甲酸(Bilcer,G.M.等人WO 2012/054510)作为起始物质来制备标题化合物:(90mg,0.47mmol,76%产率,白色固体)。1H NMR(400MHz,DMSO-d6)δ7.99(d,J=1.1Hz,1H),7.72(d,J=1.1Hz,1H),3.96(s,3H),3.90(s,3H)。MS(ESI)193(M+H)。
步骤B.中间体257B.(Z)-4-(N'-羟基甲脒基)-6-甲氧基吡啶-2-甲酸甲酯的制备
根据针对中间体4C的合成所描述的方法,使用中间体257A作为起始物质来制备标题化合物:(81mg,0.36mmol,79%产率,白色固体)。1H NMR(500MHz,DMSO-d6)δ10.16(s,1H),8.01(d,J=1.1Hz,1H),7.33(d,J=1.4Hz,1H),6.09(s,2H),3.92(s,3H),3.87(s,3H)。MS(ESI)226(M+H)。
步骤C.实施例257
根据针对实施例64的合成(步骤C)所描述的方法,通过使中间体69B与中间体257B反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.81(s,2H),8.02(s,1H),7.30(s,1H),4.24(s,2H),3.93(s,3H),2.35-2.25(m,1H),2.03-1.94(m,6H),1.52-1.41(m,6H),1.15(brd,J=7.9Hz,2H),1.08(br d,J=2.7Hz,2H)。FXR EC50(nM)=79。MS(ESI)612(M+H)。
实施例258
4-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-6-异丙氧基吡啶-2-甲酸
步骤A.中间体258A.2-氯-6-异丙氧基吡啶-4-甲酸叔丁酯的制备
向2-氯-6-异丙氧基吡啶-4-甲酸(1.1g,5.0mmol)(Bolli,M.等人WO 2008/029371)和一缩二碳酸二叔丁酯(2.7mL,11mmol)于NMP(5mL)中的溶液中添加DMAP(0.61g,5.0mmol)。在室温搅拌2h后,反应物用水稀释且用EtOAc(3×)萃取。将合并的有机层用盐水洗涤,经无水Na2SO4干燥且浓缩。通过快速柱色谱(80g硅胶滤筒,A=己烷,B=EtOAc;20min梯度;0%B至5%B;流速=60mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈透明油状物的标题化合物(0.46g,1.7mmol,34%产率)。1H NMR(400MHz,氯仿-d)δ7.33(d,J=1.1Hz,1H),7.11(d,J=0.9Hz,1H),5.36-5.26(m,1H),1.58(s,9H),1.36(s,3H),1.35(s,3H)。MS(ESI)272(M+H)。
步骤B.中间体258B.6-异丙氧基吡啶-2,4-二甲酸4-(叔丁基)酯2-甲酯的制备
向中间体258A(0.33g,1.2mmol)和TEA(0.56mL,4.0mmol)于DMSO(3mL)和MeOH(3mL)中的溶液中添加乙酸钯(II)(0.030g,0.13mmol),接着添加dppf(0.075g,0.13mmol)。在80℃,在一氧化碳氛围(1个大气压,气球)下搅拌反应物9h。冷却至室温后,经由硅藻土垫过滤反应物且浓缩滤液,以移除MeOH。含有DMSO的残余物用水稀释且用EtOAc(3×)萃取。将合并的有机层用水、盐水洗涤,经无水Na2SO4干燥且浓缩。通过快速柱色谱(24g硅胶滤筒,A=己烷,B=EtOAc;10min梯度;0%B至15%B;流速=35mL/min)纯化粗产物。将纯级分浓缩且在真空中干燥,得到呈白色固体状的标题化合物(0.30g,1.0mmol,83%产率)。1H NMR(400MHz,DMSO-d6)δ7.91(d,J=1.3Hz,1H),7.32(d,J=1.3Hz,1H),5.39-5.30(m,1H),3.89(s,3H),1.56(s,9H),1.33(s,3H),1.31(s,3H)。MS(ESI)296(M+H)。
步骤C.中间体258C.2-异丙氧基-6-(甲氧基羰基)吡啶-4-甲酸的制备
向中间体258B(0.30g,1.0mmol)中添加TFA(2.8mL,36mmol),且在室温搅拌反应物3h。浓缩TFA,且将残余物在真空中干燥,得到呈粗灰白色固体状的标题化合物(0.23g,0.96mmol,96%产率),其不经纯化即用于下一步骤中。1H NMR(500MHz,DMSO-d6)δ13.88(brs,1H),7.97(d,J=1.1Hz,1H),7.33(s,1H),5.34(dt,J=12.4,6.2Hz,1H),3.89(s,3H),1.33(s,3H),1.32(s,3H)。MS(ESI)240(M+H)。
步骤D.中间体258D.4-氰基-6-异丙氧基吡啶-2-甲酸甲酯的制备
根据针对中间体20A的合成所描述的方法,使用中间体258C作为起始物质来制备标题化合物:(0.18g,0.83mmol,88%产率,白色固体)。1H NMR(500MHz,DMSO-d6)δ7.93(d,J=0.8Hz,1H),7.61(d,J=0.8Hz,1H),5.33(dt,J=12.4,6.2Hz,1H),3.89(s,3H),1.33(s,3H),1.32(s,3H)。MS(ESI)221(M+H)。
步骤E.中间体258E.(Z)-4-(N'-羟基甲脒基)-6-异丙氧基吡啶-2-甲酸甲酯的制备
根据针对中间体4C的合成所描述的方法,使用中间体258D作为起始物质来制备标题化合物:(74mg,0.29mmol,35%产率,白色固体)。1H NMR(500MHz,DMSO-d6)δ10.14(s,1H),7.96(d,J=1.4Hz,1H),7.29-7.19(m,1H),6.05(s,2H),5.40-5.19(m,1H),3.86(s,3H),1.32(s,3H),1.31(s,3H)。MS(ESI)254(M+H)。
步骤F.实施例258
根据针对实施例64的合成(步骤C)所描述的方法,通过使中间体69B与中间体257B反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ13.54-13.26(br s,1H),8.83(s,2H),8.06-8.01(m,1H),7.37(d,J=1.1Hz,1H),5.40(quin,J=6.1Hz,1H),4.25(s,2H),2.38-2.28(m,1H),2.03-1.95(m,6H),1.56-1.43(m,6H),1.34(s,3H),1.32(s,3H),1.15(dt,J=8.3,3.0Hz,2H),1.11-1.05(m,2H)。FXR EC50(nM)=8。MS(ESI)640(M+H)。
实施例259
5-(4-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1H-咪唑-2-基)-2-甲氧基苯甲酸
步骤A.中间体259A.5-甲脒基-2-甲氧基苯甲酸甲酯HCl的制备
步骤1:向5-氰基-2-甲氧基苯甲酸甲酯(250mg,1.3mmol)于MeOH(0.14mL)、水(0.029mL)和乙醚(0.16mL)中的0℃溶液中添加亚硫酰氯(0.095mL,1.3mmol)。使反应混合物缓慢升温至rt且搅拌。18h后,通过真空过滤收集所得析出物,用乙醚洗涤滤饼,且将产物在50℃真空干燥1h,得到用于下一步骤的粗白色固体。
步骤2:将上文步骤1的产物悬浮于MeOH(1mL)中,接着一次性添加氨(0.24mL,1.7mmol)(7M于MeOH中)。在室温搅拌24h后,浓缩溶剂且将残余物在真空中干燥,得到呈粗白色固体状的标题化合物(0.26g,1.1mmol,80%产率),其不经进一步纯化即用于下一步骤中。1H NMR(500MHz,DMSO-d6)δ9.40-8.94(m,4H),8.15(d,J=2.5Hz,1H),8.04(dd,J=8.9,2.3Hz,1H),7.40(d,J=9.1Hz,1H),3.94(s,3H),3.84(s,3H)。MS(ESI)209(M+H)。
步骤B.实施例259
步骤1:向中间体259A(5.2mg,0.021mmol)和碳酸氢钾(4.3mg,0.043mmol)于THF(0.10mL)和水(0.10mL)中的溶液中添加中间体252C(10mg,0.021mmol)。在密封反应小瓶中在65℃搅拌20h后,将反应混合物冷却至室温,用EtOAc稀释并过滤。浓缩滤液且粗残余物用于下一步骤。
步骤2:将上文步骤1的产物溶解于THF(0.50mL)和1M NaOH(水溶液)(0.50mL)中。在65℃搅拌3h后,使反应物冷却至室温,用5%柠檬酸(水溶液)稀释且用EtOAc萃取。有机层用水、盐水洗涤,经无水Na2SO4干燥且浓缩。通过制备型HPLC(柱:XBridge C18,200mm×19mm,5μm颗粒;流动相A:5:95的乙腈:水/10mM乙酸铵;流动相B:95:5的乙腈:水/10mM乙酸铵;梯度:在18%B下保持0分钟,18-58%B经20分钟,接着在100%B下保持4分钟;流速:20mL/min)纯化粗产物。将含有期望产物的级分合并、浓缩且在真空中干燥,得到标题化合物(4.3mg,7.1μmol,33%产率)。1H NMR(500MHz,DMSO-d6)δ8.78(s,2H),8.15(d,J=1.9Hz,1H),7.97(dd,J=8.7,1.9Hz,1H),7.15(d,J=8.8Hz,1H),6.65(s,1H),4.23(s,2H),3.84(s,3H),2.32-2.20(m,1H),1.87-1.71(m,6H),1.48-1.35(m,6H),1.18-1.12(m,2H),1.10-0.97(m,2H)。FXR EC50(nM)=5500。MS(ESI)609(M+H)。
实施例260
6-环丙氧基-4-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)吡啶-2-甲酸
步骤A中间体260A.2-氯-6-环丙氧基吡啶-4-甲腈的制备
向环丙醇(0.18mL,2.9mmol)于1,4-二噁烷(4mL)中的室温溶液中缓慢添加氢化钠(0.17g,4.3mmol)(于矿物油中的60%分散物)。搅拌10min后,添加2,6-二氯吡啶-4-甲腈(0.50g,2.9mmol),且在60℃搅拌反应混合物2.5h。冷却至室温后,将反应物用EtOAc稀释,用1M HCl(水溶液)和盐水洗涤。有机层经无水Na2SO4干燥且浓缩。通过快速柱色谱(40g硅胶滤筒,A=己烷,B=EtOAc;13min梯度;0%B至25%B;流速=40mL/min)纯化粗产物。将纯级分浓缩且在真空中干燥,得到呈浅黄色固体状的标题化合物(0.35g,1.8mmol,62%产率)。1H NMR(400MHz,DMSO-d6)δ7.71(d,J=1.1Hz,1H),7.49(d,J=1.1Hz,1H),4.24(tt,J=6.2,3.1Hz,1H),0.87-0.78(m,2H),0.78-0.68(m,2H)。MS(ESI)195(M+H)。
步骤B.中间体260B.4-氰基-6-环丙氧基吡啶-2-甲酸甲酯的制备
根据针对中间体258B的合成所描述的方法,使用中间体260A作为起始物质来制备标题化合物:(0.21g,0.96mmol,53%产率,白色固体)。1H NMR(500MHz,DMSO-d6)δ8.06-7.98(m,1H),7.74(d,J=0.8Hz,1H),4.34(tt,J=6.2,3.1Hz,1H),3.90(s,3H),0.88-0.81(m,2H),0.76-0.69(m,2H)。MS(ESI)219(M+H)。
步骤C.中间体260C.(Z)-6-环丙氧基-4-(N'-羟基甲脒基)吡啶-2-甲酸甲酯的制备
根据针对中间体4C的合成所描述的方法,使用中间体260B作为起始物质来制备标题化合物:(0.22mg,0.86mmol,91%产率,白色固体)。1H NMR(500MHz,DMSO-d6)δ10.17(s,1H),8.03(d,J=1.1Hz,1H),7.38(d,J=1.1Hz,1H),6.09(s,2H),4.35-4.26(m,1H),3.87(s,3H),0.85-0.76(m,2H),0.72-0.65(m,2H)。MS(ESI)252(M+H)。
步骤D.实施例260
根据针对实施例64的合成(步骤C)所描述的方法,通过使中间体69B与中间体260C反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.81(s,2H),8.08(s,1H),7.46(s,1H),4.38(br s,1H),4.24(s,2H),2.38-2.25(m,1H),2.05-1.93(m,6H),1.53-1.40(m,6H),1.19-1.14(m,2H),1.08(br d,J=2.7Hz,2H),0.81(br d,J=6.1Hz,2H),0.72(br s,2H)。FXR EC50(nM)=39。MS(ESI)638(M+H)。
实施例261
6-环丁氧基-4-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)吡啶-2-甲酸
步骤A.中间体261A.2-氯-6-环丁氧基吡啶-4-甲酸叔丁酯的制备
根据针对中间体258A的合成所描述的方法,使用2-氯-6-环丁氧基吡啶-4-甲酸(Bolli,M.H.等人Eur.J.Med.Chem.2016,115,326)作为起始物质来制备标题化合物:(0.33mg,1.2mmol,82%产率,透明油状物)。1H NMR(400MHz,DMSO-d6)δ7.35(d,J=1.1Hz,1H),7.10(d,J=0.9Hz,1H),5.10(dd,J=7.8,6.9Hz,1H),2.44-2.35(m,2H),2.13-2.01(m,2H),1.84-1.73(m,1H),1.72-1.60(m,1H),1.54(s,9H)。MS(ESI)284(M+H)。
步骤B.中间体261B.6-环丁氧基吡啶-2,4-二甲酸4-(叔丁基)酯2-甲酯的制备
根据针对中间体258B的合成所描述的方法,使用中间体261A作为起始物质来制备标题化合物:(0.28mg,0.91mmol,78%产率,白色固体)。1H NMR(500MHz,DMSO-d6)δ7.93(d,J=1.1Hz,1H),7.36(d,J=1.1Hz,1H),5.20(t,J=7.6Hz,1H),3.89(s,3H),2.47-2.37(m,2H),2.08(ddd,J=9.8,7.8,2.5Hz,2H),1.80(br d,J=9.9Hz,1H),1.73-1.62(m,1H),1.56(s,9H)。MS(ESI)308(M+H)。
步骤C.中间体261C.2-环丁氧基-6-(甲氧基羰基)吡啶-4-甲酸的制备
根据针对中间体258C的合成所描述的方法,使用中间体261B作为起始物质来制备标题化合物:(0.27mg,1.1mmol,119%产率,含有TFA的粗灰白色固体)。1H NMR(500MHz,DMSO-d6)δ14.26-13.31(m,1H),7.99(d,J=1.1Hz,1H),7.37(d,J=1.1Hz,1H),5.19(quin,J=7.4Hz,1H),3.89(s,3H),2.46-2.39(m,2H),2.19-2.02(m,2H),1.85-1.74(m,1H),1.71-1.63(m,1H)。MS(ESI)252(M+H)。
步骤D.中间体261D.4-氰基-6-环丁氧基吡啶-2-甲酸甲酯的制备
根据针对中间体20A的合成所描述的方法,使用中间体261C作为起始物质来制备标题化合物:(0.11g,0.48mmol,51%产率,白色固体)。1H NMR(500MHz,DMSO-d6)δ7.96(s,1H),7.65(s,1H),5.17(quin,J=7.4Hz,1H),3.89(s,3H),2.47-2.39(m,2H),2.14-2.03(m,2H),1.80(q,J=10.3Hz,1H),1.73-1.61(m,1H)。MS(ESI)233(M+H)。
步骤E.中间体261E.(Z)-6-环丁氧基-4-(N'-羟基甲脒基)吡啶-2-甲酸甲酯的制备
根据针对中间体4C的合成所描述的方法,使用中间体261D作为起始物质来制备标题化合物:(0.12g,0.46mmol,96%产率,白色固体)。1H NMR(500MHz,DMSO-d6)δ10.15(s,1H),7.98(d,J=1.1Hz,1H),7.28(d,J=1.1Hz,1H),6.07(s,2H),5.17(quin,J=7.4Hz,1H),3.86(s,3H),2.46-2.36(m,2H),2.15-1.99(m,2H),1.83-1.75(m,1H),1.72-1.60(m,1H)。MS(ESI)266(M+H)。
步骤F.实施例261
根据针对实施例64的合成(步骤C)所描述的方法,通过使中间体69B与中间体261E反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.78(s,2H),8.03(s,1H),7.35(s,1H),5.26(quin,J=7.3Hz,1H),4.24(s,2H),2.44(br d,J=7.2Hz,2H),2.33-2.23(m,1H),2.14-2.05(m,2H),2.04-1.95(m,6H),1.80(br d,J=9.8Hz,1H),1.70-1.60(m,1H),1.54-1.43(m,6H),1.21-1.12(m,2H),1.07(br d,J=2.5Hz,2H)。FXR EC50(nM)=36。MS(ESI)652(M+H)。
实施例262
4-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-6-(二甲基氨基)吡啶-2-甲酸
步骤A.中间体262A.4-氰基-6-(二甲基氨基)吡啶-2-甲酸甲酯的制备
根据针对中间体258B的合成所描述的方法,使用2-氯-6-(二甲基氨基)吡啶-4-甲腈(Fruttardo,F.等人WO 2014/135617)作为起始物质来制备标题化合物:(28mg,0.14mmol,66%产率,黄色固体)。1H NMR(500MHz,DMSO-d6)δ7.48-7.40(m,1H),7.37(d,J=0.8Hz,1H),3.85(s,3H),3.10(s,6H)。MS(ESI)206(M+H)。
步骤B.中间体262B.(Z)-6-(二甲基氨基)-4-(N'-羟基甲脒基)吡啶-2-甲酸甲酯的制备
根据针对中间体4C的合成所描述的方法,使用中间体262A作为起始物质来制备标题化合物:(30mg,0.12mmol,91%产率,黄色固体)。1H NMR(500MHz,DMSO-d6)δ9.96(s,1H),7.57(s,1H),7.10(s,1H),6.02(s,2H),3.83(s,3H),3.09(s,6H)。MS(ESI)239(M+H)。
步骤C.实施例262
根据针对实施例64的合成(步骤C)所描述的方法,通过使中间体69B与中间体262B反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.82(s,2H),7.65(s,1H),7.20(s,1H),4.24(s,2H),3.12(s,6H),2.37-2.24(m,1H),2.03-1.96(m,6H),1.50-1.40(m,6H),1.15(brd,J=8.2Hz,2H),1.08(br d,J=2.4Hz,2H)。FXR EC50(nM)=53。MS(ESI)625(M+H)。
实施例263
4-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-6-(2,2,2-三氟乙氧基)吡啶-2-甲酸
步骤A.中间体263A.4-氰基-6-(2,2,2-三氟乙氧基)吡啶-2-甲酸甲酯的制备
根据针对中间体258B的合成所描述的方法,使用2-氯-6-(2,2,2-三氟乙氧基)吡啶-4-甲腈(Arvela,R.等人WO 2012/152983)作为起始物质来制备标题化合物:(0.19g,0.74mmol,64%产率,白色固体)。1H NMR(500MHz,氯仿-d)δ7.99(d,J=0.8Hz,1H),7.33(d,J=0.8Hz,1H),4.90(q,J=8.3Hz,2H),4.01(s,3H)。MS(ESI)261(M+H)。
步骤B.中间体263B.(Z)-4-(N'-羟基甲脒基)-6-(2,2,2-三氟乙氧基)吡啶-2-甲酸甲酯的制备
根据针对中间体4C的合成所描述的方法,使用中间体263A作为起始物质来制备标题化合物:(69mg,0.24mmol,32%产率,白色固体)。1H NMR(500MHz,DMSO-d6)δ10.26(s,1H),8.13(d,J=1.1Hz,1H),7.51(d,J=0.8Hz,1H),6.14(s,2H),5.06(q,J=9.1Hz,2H),3.89(s,3H)。MS(ESI)294(M+H)。
步骤C.实施例263
根据针对实施例64的合成(步骤C)所描述的方法,通过使中间体69B与中间体263B反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.81(s,2H),8.15(s,1H),7.54(s,1H),5.13(q,J=8.9Hz,2H),4.24(s,2H),2.35-2.25(m,1H),2.03-1.95(m,6H),1.51-1.41(m,6H),1.19-1.12(m,2H),1.10-1.03(m,2H)。FXR EC50(nM)=95。MS(ESI)680(M+H)。
实施例264
4-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-6-(三氟甲基)吡啶-2-甲酸
步骤A.中间体264A.4-氰基-6-(三氟甲基)吡啶-2-甲酸甲酯的制备
根据针对中间体258B的合成所描述的方法,使用2-氯-6-(三氟甲基)吡啶-4-甲腈(Rodgers,J.D.等人WO 2012/068450)作为起始物质来制备标题化合物:(10mg,0.045mmol,42%产率,白色固体)。1H NMR(500MHz,氯仿-d)δ8.53(s,1H),8.09(s,1H),4.08(s,3H)。MS(ESI)231(M+H)。
步骤B.中间体264B.(Z)-4-(N'-羟基甲脒基)-6-(三氟甲基)吡啶-2-甲酸甲酯的制备
根据针对中间体4C的合成所描述的方法,使用中间体264A作为起始物质来制备标题化合物:(6.0mg,0.023mmol,51%产率,白色固体)。MS(ESI)264(M+H)。
步骤C.实施例264
根据针对实施例64的合成(步骤C)所描述的方法,通过使中间体69B与中间体264B反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.80(s,2H),8.58(br s,1H),8.27-8.13(m,1H),4.23(s,2H),2.33-2.23(m,1H),2.04-1.96(m,6H),1.49-1.41(m,6H),1.19-1.12(m,2H),1.09-1.03(m,2H)。FXR EC50(nM)=180。MS(ESI)650(M+H)。
实施例265
5-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-3-甲氧基吡啶-2-甲酸
步骤A.中间体265A.(Z)-5-(N'-羟基甲脒基)-3-甲氧基吡啶-2-甲酸甲酯的制备
根据针对中间体4C的合成所描述的方法,使用5-氰基-3-甲氧基吡啶-2-甲酸甲酯作为起始物质来制备标题化合物:(15mg,0.065mmol,100%产率,白色固体)。1H NMR(500MHz,氯仿-d)δ8.59(d,J=2.2Hz,1H),8.41-8.39(m,1H),4.84(br d,J=1.1Hz,2H),4.09(s,3H),3.92(s,3H)。MS(ESI)226(M+H)。
步骤B.实施例265
根据针对实施例64的合成(步骤C)所描述的方法,通过使中间体69B与中间体265A反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.81(s,2H),8.79(br d,J=2.1Hz,1H),8.43(br s,1H),4.23(s,2H),3.96(s,3H),2.34-2.25(m,1H),2.02-1.94(m,6H),1.50-1.40(m,6H),1.19-1.13(m,2H),1.10-1.01(m,2H)。FXR EC50(nM)=1500。MS(ESI)612(M+H)。
实施例266
2-(5-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)环丙烷-1-甲酸
步骤A.中间体266A.(Z)-2-(N'-羟基甲脒基)环丙烷-1-甲酸乙酯的制备
根据针对中间体4C的合成所描述的方法,使用2-氰基环丙烷-1-甲酸乙酯作为起始物质来制备标题化合物:(230mg,1.4mmol,95%产率,透明油状物)。1H NMR(500MHz,DMSO-d6)δ8.94(s,1H),5.43(br s,2H),4.16-3.99(m,2H),1.93-1.78(m,2H),1.30-1.23(m,1H),1.23-1.16(m,3H),1.15-1.09(m,1H)。MS(ESI)m/z 173(M+H)。
步骤B.实施例266
根据针对实施例64的合成(步骤C)所描述的方法,通过使中间体69B与中间体266A反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ7.64-7.60(m,2H),7.59-7.53(m,1H),4.15(s,2H),2.40-2.34(m,1H),2.33-2.24(m,1H),1.91-1.85(m,7H),1.49-1.39(m,7H),1.33-1.26(m,1H),1.16-1.09(m,2H),1.09-1.04(m,2H)。FXR EC50(nM)=720。MS(ESI)544(M+H)。
实施例267
5-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-3-(2H-四唑-5-基)-1,2,4-噁二唑
步骤A.中间体267A.5-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-甲腈的制备
根据针对中间体20A的合成(步骤3)所描述的方法,适当时代入实施例74来制备标题化合物:(9.6mg,0.020mmol,59%产率,白色固体)。1H NMR(500MHz,DMSO-d6)δ7.64-7.61(m,2H),7.59-7.54(m,1H),4.16(s,2H),2.33-2.24(m,1H),1.99-1.91(m,6H),1.51-1.45(m,6H),1.16-1.10(m,2H),1.09-1.05(m,2H)。MS(ESI)485(M+H)。
步骤B.实施例267
根据针对实施例66的合成(步骤B)所描述的方法,适当时代入中间体267A来制备标题化合物:(4.3mg,8.1μmol,56%产率,白色固体)。1H NMR(500MHz,DMSO-d6)δ7.71-7.62(m,2H),7.61-7.55(m,1H),4.19(s,2H),2.32(ddd,J=13.2,8.3,5.2Hz,1H),2.04-1.95(m,6H),1.57-1.43(m,6H),1.20-1.12(m,2H),1.12-1.03(m,2H)。FXR EC50(nM)=4400。MS(ESI)528(M+H)。
实施例272
2-(5-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲基)-1,2,4-噁二唑-3-基)环丙烷-1-甲酸
步骤A.中间体272A.2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙酸的制备
在60℃搅拌中间体69B(30mg,0.069mmol)于亚硫酰氯(5.0μl,0.069mmol)中的混合物2h,并浓缩。将残余物溶解于乙腈(0.6mL)中,且添加三甲基硅烷基重氮甲烷(0.041mL,0.082mmol)(0.5M于己烷中)。在rt搅拌混合物2h。向该混合物中添加三氟乙酸银(23mg,0.10mmol)、TEA(0.019mL,0.14mmol)和H2O(0.06mL)。在rt搅拌混合物20h,且过滤。浓缩滤液,得到呈黄色油状物的标题化合物(31mg,0.069mmol,100%产率),其不经进一步纯化即用于下一步骤中。MS(ESI)451(M+H)。
步骤B.实施例272
根据针对实施例64的合成(步骤C)所描述的方法,通过使中间体266A与中间体272A反应来制备标题化合物:1H NMR(500MHz,甲醇-d4)δ8.67(s,2H),4.26-4.19(m,2H),2.65-2.55(m,2H),2.51-2.41(m,1H),2.25-2.15(m,1H),2.06-1.99(m,1H),1.56-1.47(m,6H),1.47-1.39(m,6H),1.38-1.31(m,2H),1.19-1.11(m,4H)。EC50(nM)=400。MS(ESI)559(M+H)。
实施例273
5-(5-(4-((3-(4-氯-1-甲基-1H-吡唑-5-基)-5-环丙基异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-2-甲氧基苯甲酸
步骤A.中间体273A.(E)-4-氯-1-甲基-1H-吡唑-5-甲醛肟的制备
在0℃向羟胺盐酸盐(260mg,3.8mmol)于水(0.2mL)中的经搅拌悬浮液中逐滴添加3M NaOH(水溶液)(1.3mL,3.8mmol)。向该混合物中逐滴添加4-氯-1-甲基-1H-吡唑-5-甲醛(500mg,3.5mmol)于EtOH(4mL)中的溶液。在回流下搅拌反应物16h。使混合物冷却,浓缩EtOH,且剩余水层用水稀释并用EtOAc(2×)萃取。将有机相合并,用盐水洗涤,经Na2SO4干燥,过滤且浓缩,得到呈灰白色固体状的标题化合物(550mg,3.5mmol,100%产率),其不经进一步纯化即用于下一步骤中。MS(ESI)160(M+H)。
步骤B.中间体273B.(Z)-4-氯-N-羟基-1-甲基-1H-吡唑-5-甲酰亚氨基氯的制备
将中间体273A(530mg,3.3mmol)溶解于DMF(2.5mL)中且加热至40℃。在10min的时间段内逐份添加溶解于DMF(2mL)中的NCS(532mg,4.0mmol)。将反应物在40℃搅拌48h,接着在rt搅拌16h。将混合物倒入冰水中且用EtOAc萃取。用盐水洗涤有机物,且用EtOAc反萃取经合并的水层。合并的有机层经Na2SO4干燥,过滤且浓缩。通过快速柱色谱(40g硅胶滤筒,A=己烷,B=EtOAc;15min梯度;0%B至40%B;流速=40mL/min)纯化粗产物。将纯级分浓缩且在真空中干燥,得到呈白色固体状的标题化合物(430mg,2.2mmol,67%产率)。。MS(ESI)192(M+H)。
步骤C.中间体273C.3-(4-氯-1-甲基-1H-吡唑-5-基)-5-环丙基异噁唑-4-甲酸甲酯的制备
向3-环丙基-3-氧代丙酸甲酯(0.27mL,2.2mmol)中添加TEA(0.62mL,4.4mmol),且在室温搅拌所得澄清溶液15min。使反应混合物冷却至5℃。经10min向该溶液中添加溶解于EtOH(1mL)中的中间体273B(430mg,2.2mmol)(在添加期间,澄清溶液变成黄色/白色悬浮液)。在室温搅拌所得悬浮液2h。浓缩反应混合物,且所得残余物用H2O稀释且用EtOAc(2×)萃取。合并的有机相用盐水洗涤,经无水Na2SO4干燥,过滤且浓缩。通过快速柱色谱(40g硅胶滤筒,A=己烷,B=EtOAc;15min梯度;0%B至40%B;流速=40mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈白色固体状的标题化合物(320mg,1.1mmol,51%产率)。1H NMR(500MHz,氯仿-d)δ7.52(s,1H),3.83(s,3H),3.79-3.76(m,3H),2.91(s,1H),1.43-1.38(m,2H),1.34-1.27(m,2H)。(ESI)282(M+H)。
步骤D.中间体273D.(3-(4-氯-1-甲基-1H-吡唑-5-基)-5-环丙基异噁唑-4-基)甲醇的制备
将中间体273C(220mg,0.78mmol)溶解于DCM(5mL)中,且将其冷却至-10℃。逐滴添加DIBAL-H(2.0mL,2.0mmol)(于DCM中的1M溶液),同时维持内部反应温度低于-5℃(添加时间约为15分钟)。搅拌另外15min后,用EtOAc(0.5mL)淬灭反应物。用EtOAc(2mL)及饱和罗谢尔盐(Rochelle's salt)溶液(水溶液)(2mL)稀释混合物。用EtOAc(2×)萃取溶液,且将有机层合并、经Na2SO4干燥、过滤并浓缩。通过快速柱色谱(40g硅胶滤筒;A=DCM,B=MeOH;10min梯度;0%B至10%B;流速=40mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈白色固体状的标题化合物(190mg,0.73mmol,93%产率)。1H NMR(500MHz,氯仿-d)δ7.49(s,1H),4.54(s,2H),3.81(s,3H),2.28-2.15(m,1H),1.28-1.21(m,2H),1.18-1.12(m,2H)。MS(ESI)254(M+H)。
步骤E.中间体273E.4-((3-(4-氯-1-甲基-1H-吡唑-5-基)-5-环丙基异噁唑-4-基)甲氧基)双环[2.2.2]辛烷-1-甲酸甲酯的制备
向中间体273D(180mg,0.71mmol)和中间体4A(210mg,0.71mmol)于DCE(0.70mL)中的溶液中添加三氟甲烷磺酸银(220mg,0.85mmol)和2,6-二-叔丁基吡啶(0.23mL,1.1mmol)。在100℃搅拌反应物1h。使反应混合物冷却,过滤且浓缩。通过快速柱色谱(40g硅胶滤筒,A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=40mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈透明油状物的标题化合物(180mg,0.43mmol,60%产率)。1H NMR(500MHz,氯仿-d)δ7.44-7.40(m,1H),4.16(s,2H),3.72(s,3H),3.54(s,3H),2.06(tt,J=8.5,5.0Hz,1H),1.83-1.77(m,6H),1.55-1.48(m,6H),1.16-1.11(m,2H),1.07-0.94(m,2H)。MS(ESI)420(M+H)。
步骤E.中间体273F.4-((3-(4-氯-1-甲基-1H-吡唑-5-基)-5-环丙基异噁唑-4-基)甲氧基)双环[2.2.2]辛烷-1-甲酸的制备
在rt搅拌中间体273E(180mg,0.43mmol)和1M NaOH(水溶液)(4.3mL,4.3mmol)于MeOH(3mL)和THF(1mL)中的混合物2h。浓缩有机溶剂,且用1M HCl(水溶液)(5mL)酸化剩余水相。通过真空过滤收集析出物,且在真空中干燥,得到呈白色固体状的标题化合物(170mg,0.42mmol,98%产率),其不经进一步纯化即用于下一步骤中。MS(ESI)406(M+H)。
步骤F.实施例273
根据针对实施例64的合成(步骤C)所描述的方法,通过使中间体69B与中间体273F反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ7.96-7.90(m,1H),7.86-7.80(m,1H),7.79-7.74(m,1H),7.16-7.01(m,1H),4.25(s,2H),3.80(s,3H),3.72(s,3H),2.38-2.29(m,2H),2.12-2.00(m,6H),1.68-1.55(m,6H),1.20-1.13(m,2H),1.13-1.07(m,2H)。EC50(nM)=3300。MS(ESI)580(M+H)。
根据本文中其他处所描述的方法,使用适当起始物质、试剂和条件来制备表5中的以下实施例。
表5
/>
/>
/>
/>
实施例276
4-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-3-氟苯甲酸
步骤A.中间体276A.(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲醇的制备
/>
根据针对中间体16A和中间体104A的合成所描述的组合方法,适当时代入(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲醇来制备标题化合物:1H NMR(500MHz,氯仿-d)δ8.62(s,2H),4.23(s,2H),3.24(d,J=5.5Hz,2H),2.18-2.08(m,1H),1.53-1.40(m,12H),1.34-1.23(m,2H),1.20-1.09(m,2H)。MS(ESI)423.0(M+H)。
步骤B.中间体276B.4-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-3-氟苯甲酸甲酯的制备
将中间体276A(34mg,0.080mmol)、3-氟-4-羟基苯甲酸甲酯(11mg,0.067mmol)、Ph3P(17mg,0.064mmol)和(E)-二氮烯-1,2-二甲酸二异丙酯(0.013mL,0.064mmol)溶解于THF(0.5mL)中,且在密封小瓶中在100℃搅拌。1h后,将混合物冷却至rt,且浓缩溶剂。通过快速柱色谱(12g硅胶滤筒,A=己烷,B=EtOAc;15min梯度;0%B至60%B;流速=40mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈透明液体状的标题化合物(24mg,0.042mmol,62%产率)。MS(ESI)575.0(M+H)。
步骤C.实施例276
根据针对实施例104的合成(步骤C)所描述的方法,使用中间体276B作为起始物质来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.82(s,2H),7.96-7.48(m,2H),7.20(br s,1H),4.21(s,2H),3.67(s,2H),2.36-2.25(m,1H),1.50(br d,J=7.9Hz,6H),1.40-1.30(m,6H),1.17-1.12(m,2H),1.10-1.05(m,2H)。FXR EC50(nM)=170。MS(ESI)561(M+H)。
实施例278
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-5-(三氟甲基)吡啶-3-甲酰胺
步骤A.中间体278A.4-(((4-((5-溴-3-(三氟甲基)吡啶-2-基)氧基)甲基)双环[2.2.2]辛-1-基)氧基)甲基)-5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑的制备
/>
根据针对实施例276的合成(步骤B和C)所描述的方法,通过使中间体276A与5-溴-3-(三氟甲基)吡啶-2-醇反应来制备标题化合物:1H NMR(500MHz,氯仿-d)δ8.61(s,2H),8.30(d,J=2.4Hz,1H),7.93(d,J=2.4Hz,1H),4.22(s,2H),3.94(s,2H),2.18-2.00(m,1H),1.67-1.54(m,6H),1.53-1.40(m,6H),1.33-1.21(m,2H),1.18-1.07(m,2H)。MS(ESI)645.9(M+H)。
步骤B.中间体278B.6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-5-(三氟甲基)吡啶-3-甲腈的制备
用氮气(3×)吹扫含有中间体278A(42mg,0.065mmol)、Xantphos(7.5mg,0.013mmol)、Pd2(dba)3(12mg,0.013mmol)和氰化锌(7.6mg,0.065mmol)的压力反应小瓶。添加无水DMF(0.5mL)并将小瓶加盖,且在70℃搅拌混合物。3h后,使反应物冷却至室温,用水稀释且用EtOAc(2×)萃取。合并的有机萃取物用盐水洗涤,干燥(Na2SO4),过滤且浓缩。通过快速柱色谱(12g硅胶滤筒,A=己烷,B=EtOAc;15min梯度;0%B至30%B;流速=12mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈灰白色泡沫状的标题化合物(20mg,0.034mmol,52%产率)。MS(ESI)593.1(M+H)。
步骤C.实施例278
将中间体278B(20mg,0.034mmol)溶解于EtOH(1mL)中,且添加5M NaOH(水溶液)(0.1mL,0.5mmol)。在100℃搅拌反应物3h。使反应混合物冷却,浓缩,且用1M HCl(水溶液)酸化。用EtOAc(3×)萃取水层。浓缩经合并的有机层。经由制备型HPLC(柱:XBridge C18,19×200mm,5μm颗粒;流动相A:5:95的乙腈:水+0.1%三氟乙酸;流动相B:95:5的乙腈:水+0.1%三氟乙酸;梯度:53-76%B经25分钟,接着在100%B下保持2分钟;流速:20mL/min)纯化粗物质。将含有期望产物的级分合并、浓缩且在真空中干燥,得到标题化合物(8.0mg,39%产率):1H NMR(500MHz,DMSO-d6)δ8.91-8.85(m,1H),8.81(s,2H),8.34(s,1H),4.21(s,2H),4.05(s,2H),2.35-2.23(m,1H),1.58-1.44(m,6H),1.40-1.29(m,6H),1.19-1.11(m,2H),1.10-1.03(m,2H)。FXR EC50(nM)=620。MS(ESI)611(M+H)。
实施例279
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-5-(三氟甲基)吡啶-3-甲酸
在实施例278的纯化(步骤C)期间分离标题化合物:(7.6mg,36%产率)。1H NMR(500MHz,DMSO-d6)δ8.85(s,1H),8.82(s,2H),8.46(s,1H),4.21(s,2H),4.03(s,2H),2.34-2.26(m,1H),1.55-1.46(m,6H),1.38-1.3(m,6H),1.18-1.12(m,2H),1.10-1.03(m,2H)。FXREC50(nM)=190。MS(ESI)612(M+H)。
实施例280
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-(三氟甲基)吡啶-2-甲酸
步骤A.中间体280A.2-(甲氧基羰基)-4-(三氟甲基)吡啶1-氧化物的制备
在rt搅拌4-(三氟甲基)吡啶-2-甲酸乙酯(300mg,1.4mmol)、过氧化脲(260mg,2.7mmol)和三氟乙酸酐(0.39mL,2.7mmol)于DCM(6mL)中的溶液16h。滤出固体且浓缩滤液。通过快速柱色谱(24g硅胶滤筒,A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=24mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈白色泡沫状的标题化合物(300mg,1.3mmol,93%产率)。MS(ESI)235.9(M+H)。
步骤B.中间体280B.6-氯-4-(三氟甲基)吡啶-2-甲酸甲酯的制备
在回流下搅拌中间体280A(300mg,1.3mmol)于氧氯化磷(3mL,32mmol)中的悬浮液30min。在冷却至rt后,将反应混合物倒入冰中,用浓氢氧化铵碱化且用DCM(3×)萃取。合并的有机萃取物用盐水洗涤,干燥(MgSO4),过滤且浓缩。通过快速柱色谱(24g硅胶滤筒,A=己烷,B=EtOAc;15min梯度;0%B至30%B;流速=24mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈无色油状物的标题化合物(180mg,0.70mmol,55%产率)。1H NMR(500MHz,氯仿-d)δ8.25(s,1H),7.75(s,1H),4.52(q,J=7.1Hz,2H),1.46(t,J=7.0Hz,3H)。MS(ESI)254(M+H)。
步骤C.实施例280
根据针对实施例104的合成所描述的方法,通过使中间体276A与中间体280B反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.77(s,2H),7.71(s,1H),7.24(s,1H),4.21(s,2H),3.99(s,2H),2.31-2,21(m,1H),1.60-1.45(m,6H),1.43-1.30(m,6H),1.19-1.11(m,3H),1.09-1.01(m,2H)。FXR EC50(nM)=23。MS(ESI)612(M+H)。
实施例282
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-甲氧基喹啉-2-甲酸
步骤A.中间体282A.6-溴-4-甲氧基喹啉-2-甲酸甲酯的制备
向6-溴-4-羟基喹啉-2-甲酸甲酯(0.6g,2.1mmol)于乙腈(5mL)中的经搅拌溶液中添加碘甲烷(0.20mL,3.2mmol)和K2CO3(0.44g,3.2mmol)。在60℃搅拌反应物3h。浓缩反应混合物且用EtOAc稀释。有机层用盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过快速柱色谱(24g硅胶滤筒,A=己烷,B=EtOAc;15min梯度;0%B至70%B;流速=24mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈灰白色固体状的标题化合物(530mg,1.8mmol,84%产率)。
步骤B.中间体282B.4-甲氧基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)喹啉-2-甲酸甲酯的制备
将中间体282A(530mg,1.8mmol)、4,4,4',4',5,5,5',5'-八甲基-2,2'-二(1,3,2-二氧硼戊烷)(590mg,2.3mmol)和乙酸钾(530mg,5.4mmol)于1,4-二噁烷(8mL)中的搅拌混合物用氮气冲洗2min。向该混合物中添加Pd(dppf)Cl2·CH2Cl2加合物(290mg,0.36mmol),且在90℃搅拌反应物3h。在冷却至rt后,反应混合物用水稀释且用乙酸乙酯(2×)萃取。合并有机层,用盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过快速柱色谱(24g硅胶滤筒,A=己烷,B=EtOAc;15min梯度;0%B至70%B;流速=24mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈白色泡沫状的标题化合物(270mg,0.77mmol,43%产率)。
步骤C.中间体282C.6-羟基-4-甲氧基喹啉-2-甲酸甲酯的制备
向中间体282B(270mg,0.77mmol)于THF(4mL)中的经搅拌0℃溶液中添加1M NaOH(水溶液)(1.5mL,1.5mmol),接着添加30%H2O2(水溶液)(0.24mL,2.4mmol)。在0℃搅拌反应物10min。反应物用EtOAc稀释且用10%Na2SO3(水溶液)淬灭,并用水和盐水洗涤。用EtOAc反萃取经合并的水层。合并有机层,用盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过快速柱色谱(24g硅胶滤筒,A=己烷,B=EtOAc;15min梯度;0%B至60%B;流速=24mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈白色固体状的标题化合物(150mg,0.65mmol,84%产率)。
步骤D.实施例282
根据针对实施例276的合成(步骤B和C)所描述的方法,通过使中间体276A与中间体282C反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.80(s,2H),7.99(s,1H),7.52(s,1H),7.43(dd,J=9.2,2.4Hz,1H),7.35(d,J=2.1Hz,1H),4.22(s,2H),4.09(s,3H),3.68(s,2H),2.35-2.23(m,1H),1.60-1.49(m,6H),1.40-1.28(m,6H),1.19-1.11(m,2H),1.09-1.03(m,2H)。FXR EC50(nM)=60。MS(ESI)624(M+H)。
实施例284
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-(二氟甲氧基)喹啉-2-甲酸
步骤A.中间体284A.6-溴-4-(二氟甲氧基)喹啉-2-甲酸甲酯的制备
在0℃向Cs2CO3(980mg,3.0mmol)于DMF(5mL)中的经搅拌溶液中添加6-溴-4-羟基喹啉-2-甲酸甲酯(280mg,1.0mmol)和氯二氟乙酸钠(460mg,3.0mmol)。在80℃搅拌反应物30min。使反应混合物冷却至室温后,添加水(25mL)。搅拌所得悬浮液1h。通过真空过滤收集固体,且用水(2×5mL)洗涤滤饼。收集固体产物且在真空中干燥,得到呈白色固体状的标题化合物(280mg,0.81mmol,81%产率)。1H NMR(400MHz,氯仿-d)δ8.38(d,J=2.20Hz,1H),8.16(d,J=9.02Hz,1H),7.91(dd,J=2.20,9.24Hz,1H),7.85(t,J=1.10Hz,1H),6.61-7.17(m,1H),4.09(s,3H)。MS(ESI)333.9(M+H)。
步骤B.中间体284B.6-羟基-4-(二氟甲氧基)喹啉-2-甲酸甲酯的制备
根据针对中间体282C的合成(步骤B和C)所描述的方法,使用中间体284A作为起始物质来制备标题化合物:1H NMR(500MHz,氯仿-d)δ8.70(s,1H),8.15(d,J=9.00Hz,1H),7.73(d,J=2.20Hz,1H),7.46(t,J=1.10Hz,1H),7.34(dd,J=2.20,9.20Hz,1H),6.61-7.17(m,1H),4.09(s,3H)。MS(ESI)269.9(M+H)。
步骤C.实施例284
根据针对实施例276的合成(步骤B和C)所描述的方法,通过使中间体276A与中间体284B反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.81(s,2H),8.07(br d,J=9.2Hz,1H),7.76(s,1H),7.73(t,J=70Hz,1H),7.56-7.47(m,1H),7.29(br s,1H),4.22(s,2H),3.73(s,2H),2.35-2.23(m,1H),1.64-1.49(m,6H),1.43-1.30(m,6H),1.22-1.11(m,2H),1.10-1.03(m,2H)。FXR EC50(nM)=8。MS(ESI)660(M+H)。
实施例285
5-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-3-(三氟甲基)吡啶-2-甲酸
步骤A.中间体285A.5-羟基-3-(三氟甲基)吡啶-2-甲酸甲酯的制备
根据针对中间体282C的合成(步骤B和C)所描述的方法,使用5-溴-3-(三氟甲基)吡啶-2-甲酸甲酯作为起始物质来制备标题化合物:1H NMR(500MHz,氯仿-d)δ8.41(d,J=2.5Hz,1H),7.59(d,J=2.5Hz,1H),3.99(s,3H)。MS(ESI)221.9(M+H)。
步骤B.实施例285
根据针对实施例276的合成(步骤B和C)所描述的方法,通过使中间体276A与中间体285A反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.84-8.77(m,2H),8.44(br s,1H),7.65(d,J=2.1Hz,1H),4.21(s,2H),3.75(s,2H),2.34-2.24(m,1H),1.59-1.47(m,6H),1.41-1.28(m,6H),1.20-1.11(m,2H),1.11-1.02(m,2H)。FXR EC50(nM)=130。MS(ESI)612(M+H)。
实施例291
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-(三氟甲基)喹啉-2-甲酰胺
向实施例105(40mg,0.060mmol)于DCM(1mL)中的溶液中添加2,4,6-三丙基-1,3,5,2,4,6三氧杂三磷杂环己烷-2,4,6-三氧化物(0.071mL,0.24mmol)和休尼格氏碱(0.042mL,0.24mmol)。搅拌混合物15min,接着添加氯化铵(13mg,0.24mmol)。搅拌16h后,反应物用DCM稀释且用H2O洗涤。浓缩有机层。经由制备型HPLC(柱:XBridge C18,19×200mm,5μm颗粒;流动相A:5:95的乙腈:水+0.1%三氟乙酸;流动相B:95:5的乙腈:水+0.1%三氟乙酸;梯度:50-75%B经25分钟,接着在100%B下保持2分钟;流速:20mL/min)纯化粗物质。将含有期望产物的级分合并、浓缩且在真空中干燥,得到标题化合物:(29mg,0.043mmol,72%产率)。1H NMR(500MHz,DMSO-d6)δ8.82(s,2H),8.34(s,2H),8.18(d,J=9.2Hz,1H),7.88(brs,1H),7.65(dd,J=9.2,2.1Hz,1H),7.25(br s,1H),4.22(s,2H),3.74(s,2H),2.36-2.26(m,1H),1.64-1.52(m,6H),1.43-1.30(m,6H),1.18-1.12(m,2H),1.10-1.01(m,2H)。FXREC50(nM)=230。MS(ESI)661(M+H)。
实施例292
4-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)异喹啉-1-甲酸
步骤A.中间体292A.4-羟基异喹啉-1-甲酸甲酯的制备
根据针对中间体282C的合成(步骤B和C)所描述的方法,使用溴异喹啉-1-甲酸甲酯作为起始物质来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ11.51-11.23(m,1H),8.78-8.61(m,1H),8.32-8.19(m,1H),8.15(s,1H),7.84-7.62(m,2H),3.92(s,3H)。MS(ESI)204.0(M+H)。
步骤B.实施例292
根据针对实施例276的合成(步骤B和C)所描述的方法,通过使中间体276A与中间体292A反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.80-8.73(m,2H),8.20(br d,J=7.9Hz,1H),8.11(br s,1H),8.05-8.05(m,1H),7.86-7.79(m,1H),7.79-7.72(m,1H),4.20(s,1H),3.77(br s,2H),2.31-2.20(m,1H),1.64-1.52(m,6H),1.43-1.30(m,6H),1.18-1.12(m,2H),1.10-1.01(m,2H)。FXR EC50(nM)=9。MS(ESI)594(M+H)。
实施例293
5-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-3-(甲氧基甲基)吡啶-2-甲酸
步骤A.中间体293A.5-溴-3-(溴甲基)吡啶-2-甲酸甲酯的制备
在90℃搅拌5-溴-3-甲基吡啶-2-甲酸甲酯(450mg,2.0mmol)、NBS(350mg,2.0mmol)和AIBN(32mg,0.20mmol)于四氯化碳(10mL)中的混合物。18h后,使反应物冷却至rt,过滤,且用四氯化碳洗涤固体。合并的有机层用饱和NaHCO3(水溶液)、盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过快速柱色谱(40g硅胶滤筒,A=己烷,B=EtOAc;15min梯度;0%B至60%B;流速=40mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈灰白色泡沫状的标题化合物(400mg,1.3mmol,66%产率)。MS(ESI)307.8(M+H)。
步骤B.中间体293B.5-溴-3-(甲氧基甲基)吡啶-2-甲酸甲酯的制备
向中间体293A(380mg,1.2mmol)于MeOH(3mL)中的经搅拌溶液中添加甲醇钠(2.7mL,1.4mmol)(0.5M于MeOH中)。搅拌反应物20min。浓缩反应物且将残余物溶解于DCM中。有机层用水洗涤,经Na2SO4干燥,过滤且浓缩。通过快速柱色谱(24g硅胶滤筒,A=己烷,B=EtOAc;15min梯度;0%B至80%B;流速=24mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈白色泡沫状的标题化合物(140mg,0.52mmol,42%产率)。1H NMR(500MHz,氯仿-d)δ8.67(d,J=2.2Hz,1H),8.30-8.28(m,1H),4.86(s,2H),3.99(s,3H),3.52(s,3H)。MS(ESI)259.9(M+H)。
步骤C.中间体293C.5-羟基-3-(甲氧基甲基)吡啶-2-甲酸甲酯的制备
根据针对中间体282C的合成(步骤B和C)所描述的方法,使用中间体293B作为起始物质来制备标题化合物:1H NMR(500MHz,氯仿-d)δ9.50(s,1H),8.17(d,J=2.2Hz,1H),7.81-7.78(m,1H),4.90(s,2H),3.99(s,3H),3.52(s,3H)。MS(ESI)197.9(M+H)。
步骤D.实施例293
根据针对实施例276的合成(步骤B和C)所描述的方法,通过使中间体276A与中间体293C反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.76(s,2H),8.20-8.12(m,1H),7.41(br s,1H),4.70(br s,2H),4.19(s,2H),3.83-3.61(m,2H),3.34(s,3H),2.31-2.20(m,1H),1.56-1.45(m,6H),1.36-1.27(m,6H),1.16-1.09(m,2H),1.08-0.99(m,2H)。FXREC50(nM)=16。MS(ESI)588(M+H)。
实施例294
5-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-3-乙氧基吡啶-2-甲酸
步骤A.中间体294A.5-溴-3-乙氧基吡啶-2-甲腈的制备
向5-溴-3-硝基吡啶-2-甲腈(1.0g,4.4mmol)于EtOH(12mL)中的悬浮液中添加乙醇钠(1.6mL,4.4mmol)(21%w/v于EtOH中)。搅拌反应物2min。浓缩反应混合物且用EtOAc稀释。有机层用H2O洗涤,经MgSO4干燥,过滤且浓缩。通过快速柱色谱(40g硅胶滤筒,A=己烷,B=EtOAc;15min梯度;0%B至50%B;流速=40mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈米色固体状的标题化合物(670mg,3.0mmol,67%产率)。1H NMR(500MHz,氯仿-d)δ8.33(d,J=1.9Hz,1H),7.50(d,J=1.7Hz,1H),4.20(q,J=7.1Hz,2H),1.53(t,J=7.0Hz,3H)。MS(ESI)227.0(M+H)。
步骤B.中间体294B.5-羟基-3-乙氧基吡啶-2-甲腈的制备
根据针对中间体282C的合成(步骤B和C)所描述的方法,使用中间体294A作为起始物质来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ11.44-11.00(m,1H),7.84(d,J=2.2Hz,1H),6.99(d,J=2.2Hz,1H),4.17(q,J=7.0Hz,2H),1.36(t,J=7.0Hz,3H)。MS(ESI)165.0(M+H)。
步骤C.实施例294
根据针对中间体276B和实施例278的合成(步骤C)所描述的组合方法,通过使中间体276A与中间体294B反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.81(s,2H),7.81(br s,1H),7.05(br s,1H),4.21(s,2H),4.10(br d,J=7.0Hz,2H),3.68(br s,1H),2.34-2.25(m,1H),1.56-1.45(m,6H),1.42-1.26(m,9H),1.23-1.11(m,2H),1.10-1.05(m,2H)。FXR EC50(nM)=32。MS(ESI)588(M+H)。
实施例298
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-1,5-二氮杂萘-2-甲酸
步骤A.中间体298A.2-氯-6-((4-甲氧基苯甲基)氧基)-1,5-二氮杂萘的制备
向(4-甲氧基苯基)甲醇(140mg,1.0mmol)于NMP(8mL)中的溶液中逐份添加氢化钠(40mg,1.0mmol)(于矿物油中的60%分散物)。搅拌15min后,添加2,6-二氯-1,5-二氮杂萘(200mg,1.0mmol)。搅拌30min后,反应物用饱和NH4Cl(水溶液)淬灭且用EtOAc(3×)萃取。合并的有机萃取物用盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过快速柱色谱(24g硅胶滤筒,A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=24mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈白色泡沫状的标题化合物(230mg,0.75mmol,75%产率)。1H NMR(500MHz,氯仿-d)δ8.16-8.06(m,2H),7.54(d,J=8.5Hz,1H),7.45(d,J=8.5Hz,2H),7.17(d,J=8.8Hz,1H),6.94(d,J=8.5Hz,2H),5.47(s,2H),3.83(s,3H)。MS(ESI)301.0(M+H)。
步骤B.中间体298B.6-((4-甲氧基苯甲基)氧基)-1,5-二氮杂萘-2-甲酸甲酯的制备
向中间体298A(230mg,0.75mmol)于MeOH(12mL)中的悬浮液中添加Pd(dppf)Cl2·CH2Cl2加合物(55mg,0.075mmol),接着添加Et3N(0.21mL,1.50mmol)。在85℃在一氧化碳氛围(40-50psi)下搅拌反应物。16h后,将反应混合物冷却至rt,经由硅藻土过滤且浓缩滤液。通过快速柱色谱(24g硅胶滤筒,A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=24mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈白色泡沫状的标题化合物(180mg,0.55mmol,74%产率)。1H NMR(500MHz,氯仿-d)δ8.42-8.34(m,2H),8.27(d,J=8.8Hz,1H),7.47(d,J=8.8Hz,2H),7.21(d,J=9.1Hz,1H),6.94(d,J=8.5Hz,2H),5.51(s,2H),4.09(s,3H),3.83(s,3H)。MS(ESI)325.0(M+H)。
步骤C.中间体298C.6-羟基-1,5-二氮杂萘-2-甲酸甲酯的制备
用氮气吹扫并冲洗中间体298B(120mg,0.37mmol)于EtOAc(2mL)和EtOH(7mL)中的经搅拌溶液。向该混合物中添加钯/碳(90mg,0.085mmol)(10重量%负载,基质活性碳载体),且再次用氮气吹扫和冲洗混合物。在氢气(1个大气压,气球)下搅拌反应物。1.5h后,过滤反应混合物且浓缩滤液。通过快速柱色谱(12g硅胶滤筒,A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=12mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈白色固体状的标题化合物(53mg,0.26mmol,70%产率)。1H NMR(500MHz,甲醇-d4)δ8.25(d,J=8.5Hz,1H),8.11(d,J=9.9Hz,1H),7.84(d,J=8.5Hz,1H),6.93(d,J=9.6Hz,1H),4.01(s,3H)。MS(ESI)204.9(M+H)。
步骤D.实施例298
根据针对实施例276的合成(步骤B和C)所描述的方法,通过使中间体276A与中间体298C反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.81(s,2H),8.34(br d,J=8.9Hz,1H),8.21(s,2H),7.29(br d,J=9.2Hz,1H),4.22(s,2H),4.04(s,2H),2.34-2.21(m,1H),1.62-1.48(m,6H),1.43-1.30(m,6H),1.19-1.11(m,2H),1.10-1.05(m,2H)。FXREC50(nM)=63。MS(ESI)595(M+H)。
实施例300
5-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-3-(2,2,2-三氟乙氧基)吡啶-2-甲酸
步骤A.中间体300A.5-溴-3-(2,2,2-三氟乙氧基)吡啶-2-甲腈的制备
向5-溴-3-硝基吡啶-2-甲腈(0.34g,1.5mmol)和2,2,2-三氟乙-1-醇(1.5g,15mmol)的经搅拌溶液中添加5M NaOH(水溶液)(1.5mL,7.5mmol)。在60℃搅拌反应混合物。10min后,使混合物冷却,浓缩且用EtOAc稀释。有机层用1M HCl(水溶液)洗涤,经MgSO4干燥,过滤且浓缩。通过快速柱色谱(24g硅胶滤筒,A=己烷,B=EtOAc;15min梯度;0%B至70%B;流速=24mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈浅黄色固体状的标题化合物(170mg,0.59mmol,39%产率)。1H NMR(500MHz,氯仿-d)δ8.33(d,J=1.9Hz,1H),7.50(d,J=1.7Hz,1H),4.48(q,J=7.9Hz,2H)。MS(ESI)280.9(M+H)。
步骤B.中间体300B.5-羟基-3-(2,2,2-三氟乙氧基)吡啶-2-甲腈的制备
根据针对中间体335B的合成所描述的方法,使用中间体300A作为起始物质来制备标题化合物(115mg,0.527mmol,90%产率):1H NMR(500MHz,氯仿-d)δ8.05(d,J=2.2Hz,1H),7.27(s,1H),6.87(d,J=1.9Hz,1H),4.50(q,J=7.9Hz,2H)。MS(ESI)218.9(M+H)。
步骤C.实施例300
根据针对中间体276B和实施例278的合成(步骤C)所描述的组合方法,通过使中间体276A与中间体300B反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.77(s,2H),7.93(d,J=1.5Hz,1H),7.20(s,1H),4.80(q,J=8.5Hz,2H),4.20(s,2H),3.70(br s,2H),2.31-2.20(m,1H),1.57-1.44(m,6H),1.39-1.28(m,6H),1.20-1.10(m,2H),1.08-1.00(m,2H)。FXR EC50(nM)=57。MS(ESI)642(M+H)。
实施例301
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-甲氧基吡啶-3-甲酸
步骤A.中间体301A.叔丁基-6-氯-4-甲氧基吡啶-3-甲酸酯的制备
根据针对中间体321A的合成所描述的方法,使用6-氯-4-甲氧基吡啶-3-甲酸作为起始物质来制备标题化合物:(160mg,36%产率)。1H NMR(500MHz,氯仿-d)δ8.68(s,1H),6.90(s,1H),3.96(s,3H),1.58(s,9H)。MS(ESI)243.9(M+H)。
步骤B.实施例301
步骤1:向中间体276A(80mg,0.19mmol)于无水THF(1mL)中的溶液中添加KOtBu(32mg,0.28mmol)。搅拌5min后,添加中间体301A(55mg,0.23mmol)。搅拌5min后,反应物用饱和NH4Cl(水溶液)淬灭,用水稀释且用EtOAc(3×)萃取。经合并的有机层用盐水洗涤,干燥(Na2SO4)且浓缩。通过快速柱色谱(12g硅胶滤筒,A=己烷,B=EtOAc;15min梯度;0%B至60%B;流速=12mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈透明液体状的叔丁酯中间体(30mg,0.048mmol,25%产率)。
步骤2:将步骤1的产物(30mg,0.048mmol)溶解于1,4-二噁烷(1mL)和1M HCl(水溶液)(0.48mL,0.48mmol)中。在100℃搅拌反应物。30min后,使反应混合物冷却并浓缩。通过制备型HPLC(柱:XBridge C18,30×200mm,5μm颗粒;流动相A:5:95的乙腈:水/10mM乙酸铵;流动相B:95:5的乙腈:水/10mM乙酸铵;梯度:26-66%B经20分钟,接着在100%B下保持2分钟;流速:45mL/min)纯化粗物质。将含有期望产物的级分合并、浓缩且在真空中干燥,得到标题化合物(2.7mg,10%产率)。1H NMR(500MHz,DMSO-d6)δ8.83(s,2H),8.13(s,1H),6.26(s,1H),4.23(s,2H),3.84(s,2H),3.77(s,3H),2.35-2.28(m,1H),1.57-1.44(m,6H),1.39-1.28(m,6H),1.20-1.10(m,2H),1.08-1.00(m,2H)。FXR EC50(nM)=42。MS(ESI)574(M+H)。
实施例303
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-8-氟-4-甲氧基喹啉-2-甲酸
步骤A.中间体303A.2-((4-(苯甲基氧基)-2-氟苯基)氨基)马来酸二甲酯的制备
向4-(苯甲基氧基)-2-氟苯胺(1.5g,6.9mmol)于MeOH(20mL)中的溶液中添加丁-2-炔二酸二甲酯(1.3g,9.0mmol)。搅拌5min后,浓缩反应物。通过快速柱色谱(120g硅胶滤筒,A=己烷,B=EtOAc;30min梯度;0%B至50%B;流速=80mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈黄色液体状的标题化合物(1.5g,4.0mmol,58%产率)。1H NMR(500MHz,氯仿-d)δ9.44(s,1H),7.45-7.31(m,5H),6.90(t,J=8.9Hz,1H),6.74(dd,J=12.2,2.6Hz,1H),6.69(dd,J=8.8,1.7Hz,1H),5.46(s,1H),5.02(s,2H),3.86(s,1H),3.75(s,3H),3.71(s,3H)。MS(ESI)360.0(M+H)。
步骤B.中间体303B.6-(苯甲基氧基)-8-氟-4-氧代-1,4-二氢喹啉-2-甲酸甲酯的制备
在回流下搅拌中间体303A(1.4g,4.0mmol)和二苯醚(9mL)的反应混合物。30min后,反应物冷却至rt且用己烷(120mL)稀释,此时形成胶状固体。倾析母液。通过快速柱色谱(120g硅胶滤筒,A=己烷,B=EtOAc;30min梯度;0%B至100%B;流速=80mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈米色固体状的标题化合物(0.85g,2.6mmol,65%产率)。1H NMR(500MHz,氯仿-d)δ9.20-9.04(m,1H),7.62(d,J=2.2Hz,1H),7.49-7.45(m,2H),7.42(t,J=7.3Hz,2H),7.39-7.34(m,1H),7.18(dd,J=11.7,2.6Hz,1H),6.96(d,J=1.9Hz,1H),5.17(s,2H),4.06(s,3H)。MS(ESI)328.1(M+H)。
步骤C.中间体303C.6-(苯甲基氧基)-8-氟-4-甲氧基喹啉-2-甲酸甲酯的制备
向中间体303B(90mg,0.28mmol)于乙腈(3mL)中的经搅拌溶液中添加碘甲烷(0.051mL,0.83mmol)和K2CO3(110mg,0.83mmol)。在60℃搅拌反应物。1h后,使反应混合物冷却,浓缩且用EtOAc稀释。有机层用饱和NaHCO3(水溶液)洗涤,经MgSO4干燥,过滤且浓缩。通过快速柱色谱(12g硅胶滤筒,A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=12mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈浅黄色固体状的标题化合物(86mg,0.25mmol,92%产率)。1H NMR(500MHz,氯仿-d)δ7.64-7.61(m,1H),7.51-7.47(m,2H),7.46-7.41(m,2H),7.40-7.35(m,2H),7.25-7.18(m,1H),5.23-5.18(m,2H),4.13(s,3H),4.06(s,3H)。MS(ESI)342.0(M+H)。
步骤D.中间体303D.8-氟-6-羟基-4-甲氧基喹啉-2-甲酸甲酯的制备
根据针对中间体324C的合成所描述的方法,使用中间体303C作为起始物质来制备标题化合物:1H NMR(500MHz,甲醇-d4)δ7.57-7.51(m,1H),7.23(br s,1H),7.09(br d,J=11.8Hz,1H),4.11(s,3H),4.01(s,3H)。MS(ESI)252.0(M+H)。
步骤E.实施例303
根据针对实施例276的合成(步骤B和C)所描述的方法,通过使中间体276A与中间体303D反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.78(s,2H),7.55(s,1H),7.31(br d,J=11.9Hz,1H),7.20(br s,1H),4.22(s,2H),4.09(s,3H),3.71(s,2H),2.36-2.22(m,1H),1.61-1.52(m,6H),1.42-1.32(m,6H),1.19-1.12(m,2H),1.10-1.04(m,2H)。FXREC50(nM)=24。MS(ESI)642(M+H)。
实施例304
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-8-氟-4-异丙氧基喹啉-2-甲酸
步骤A.中间体304A.8-氟-6-羟基-4-异丙氧基喹啉-2-甲酸甲酯的制备
根据针对中间体303D的合成(步骤C和D)所描述的方法,使用中间体303B和2-碘丙烷作为起始物质来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ11.58-10.15(m,1H),7.49(s,1H),7.30-6.93(m,2H),5.58-4.83(m,1H),3.92(s,3H),1.42(d,J=6.1Hz,6H)。MS(ESI)280.0(M+H)。
步骤B.实施例304
根据针对实施例276的合成(步骤B和C)所描述的方法,通过使中间体276A与中间体304A反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.81(s,2H),7.52(s,1H),7.42-7.30(m,1H),7.16(br s,1H),5.00(dt,J=11.8,5.8Hz,1H),4.21(s,2H),3.68(s,2H),2.35-2.22(m,1H),1.58-1.49(m,6H),1.41(d,J=6.1Hz,6H),1.37-1.28(m,6H),1.19-1.12(m,2H),1.09-1.02(m,2H)。FXR EC50(nM)=11。MS(ESI)670(M+H)。
实施例306
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-乙氧基-8-氟喹啉-2-甲酸
步骤A.中间体306A.8-氟-6-羟基-4-乙氧基喹啉-2-甲酸甲酯的制备
根据针对中间体303D的合成(步骤C和D)所描述的方法,使用中间体303B和碘乙烷作为起始物质来制备标题化合物:1H NMR(400MHz,DMSO-d6)δ10.75(brs,1H),7.48(s,1H),7.33-7.11(m,2H),4.36(q,J=6.8Hz,2H),3.92(s,3H),1.48(t,J=6.9Hz,3H)。MS(ESI)266.0(M+H)。
步骤B.实施例306
根据针对实施例276的合成(步骤B和C)所描述的方法,通过使中间体276A与中间体306A反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.78(s,2H),7.52(d,J=4.2Hz,1H),7.33(br s,1H),7.20(br s,1H),4.38(q,J=6.5Hz,2H),4.22(s,2H),3.70(br s,2H),2.33-2.22(m,1H),1.63-1.52(m,6H),1.48(br t,J=6.5Hz,3H),1.43-1.33(m,6H),1.19-1.11(m,2H),1.10-1.03(m,2H)。FXR EC50(nM)=11。MS(ESI)656(M+H)。
实施例307
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-8-氟-4-甲基喹啉-2-甲酸
步骤A.中间体307A.6-(苯甲基氧基)-4-氯-8-氟喹啉-2-甲酸甲酯的制备
向中间体303B(320mg,0.96mmol)于DCM(8mL)中的经搅拌溶液中添加草酰氯(0.33mL,3.9mmol)和DMF(1滴)。在55℃搅拌反应物。1h后,使混合物冷却,浓缩且用EtOAc稀释。有机层用饱和NaHCO3(水溶液)洗涤,经MgSO4干燥,过滤且浓缩。通过快速柱色谱(12g硅胶滤筒,A=己烷,B=EtOAc;15min梯度;0%B至70%B;流速=12mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈浅黄色固体状的标题化合物(290mg,0.84mmol,87%产率)。MS(ESI)346.0(M+H)。
步骤B.中间体307B.8-氟-6-羟基-4-甲基喹啉-2-甲酸甲酯的制备
根据针对中间体324C的合成(步骤B和C)所描述的方法,使用中间体307A和甲基硼酸作为起始物质来制备标题化合物:1H NMR(400MHz,DMSO-d6)δ10.81(brs,1H),7.96(s,1H),7.24(dd,J=12.1,2.4Hz,1H),7.11(d,J=1.8Hz,1H),3.92(s,3H),2.63(s,3H)。MS(ESI)236.0(M+H)。
步骤C.实施例307
根据针对实施例276的合成(步骤B和C)所描述的方法,通过使中间体276A与中间体307B反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.77(s,2H),7.93(br s,1H),7.29(br s,1H),7.14(br s,1H),4.22(s,2H),3.75(br s,2H),2.65(s,3H),2.30-2.22(m,1H),1.63-1.52(m,6H),1.43-1.33(m,6H),1.19-1.11(m,2H),1.10-1.03(m,2H)。FXR EC50(nM)=20。MS(ESI)626(M+H)。
实施例308
4-环丁氧基-6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-8-氟喹啉-2-甲酸
步骤A.中间体308A.4-环丁氧基-8-氟-6-羟基喹啉-2-甲酸甲酯的制备
根据针对中间体303D的合成(步骤C和D)所描述的方法,使用中间体303B和溴环丁烷作为起始物质来制备标题化合物:1H NMR(400MHz,DMSO-d6)δ7.32(s,1H),7.25-7.19(m,2H),5.12-5.03(m,1H),3.92(s,3H),2.62-2.52(m,2H),2.27-2.13(m,2H),1.96-1.67(m,2H)。MS(ESI)292.1(M+H)。
步骤B.实施例308
根据针对实施例276的合成(步骤B和C)所描述的方法,通过使中间体276A与中间体308A反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.77(s,2H),7.35(s,1H),7.30(br d,J=11.3Hz,1H),7.20(br s,1H),5.05(br t,J=6.8Hz,1H),4.22(s,2H),3.71(s,2H),2.60-2.52(m,2H),2.32-2.17(m,3H),1.88(q,J=9.9Hz,1H),1.81-1.71(m,1H),1.60-1.52(m,6H),1.42-1.34(m,6H),1.19-1.11(m,2H),1.09-1.03(m,2H)。FXR EC50(nM)=12。MS(ESI)682(M+H)。
实施例309
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-8-氟-4-丙基喹啉-2-甲酸
步骤A.中间体309A.8-氟-6-羟基-4-丙基喹啉-2-甲酸甲酯的制备
根据针对中间体324C的合成(步骤B和C)所描述的方法,使用中间体307A和丙基硼酸作为起始物质来制备标题化合物:1H NMR(500MHz,氯仿-d)δ8.15-7.95(m,1H),7.22-7.09(m,2H),4.05(s,3H),3.07-2.95(m,2H),1.86-1.75(m,2H),1.06(t,J=7.3Hz,3H)。MS(ESI)264.0(M+H)。
步骤B.实施例309
根据针对实施例276的合成(步骤B和C)所描述的方法,通过使中间体276A与中间体309A反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.77(s,2H),7.92(s,1H),7.31(br d,J=10.9Hz,1H),7.18(br s,1H),4.21(s,2H),3.75(s,2H),3.03(br t,J=7.3Hz,2H),2.31-2.18(m,1H),1.80-1.67(m,2H),1.64-1.52(m,6H),1.44-1.33(m,6H),1.19-1.11(m,2H),1.10-1.01(m,2H),0.95(t,J=7.3Hz,3H)。FXR EC50(nM)=13。MS(ESI)654(M+H)。
实施例311
4-环丙基-6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-8-氟喹啉-2-甲酸
步骤A.中间体311A.4-环丙基-8-氟-6-羟基喹啉-2-甲酸甲酯的制备
根据针对中间体324C的合成(步骤B和C)所描述的方法,使用中间体307A和环丙基硼酸作为起始物质来制备标题化合物:1H NMR(400MHz,DMSO-d6)δ7.92(s,1H),7.66(s,1H),7.44(d,J=2.0Hz,1H),7.25(ddd,J=12.0,6.3,2.4Hz,2H),7.17(d,J=2.2Hz,1H),3.92(d,J=4.8Hz,6H),3.07-2.91(m,2H),1.71(d,J=7.7Hz,2H),1.16(dd,J=8.4,2.0Hz,2H),0.98(t,J=7.4Hz,2H),0.86(dd,J=5.3,1.8Hz,2H)。MS(ESI)262.1(M+H)。
步骤B.实施例311
根据针对实施例276的合成(步骤B和C)所描述的方法,通过使中间体276A与中间体311A反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.81(s,2H),7.63(s,1H),7.45(s,1H),7.34(br d,J=11.6Hz,1H),4.22(s,2H),3.76(s,2H),2.59-2.50(m,1H),2.37-2.22(m,1H),1.63-1.50(m,6H),1.44-1.31(m,6H),1.22-1.11(m,4H),1.10-1.03(m,2H),0.89-0.81(m,2H)。FXR EC50(nM)=9。MS(ESI)653(M+H)。
实施例312
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-8-氟-4-(氧杂环丁-3-基氧基)喹啉-2-甲酸
步骤A.中间体312A.8-氟-6-羟基-4-(氧杂环丁-3-基氧基)喹啉-2-甲酸甲酯的制备
根据针对中间体303D的合成(步骤C和D)所描述的方法,使用中间体303B和3-碘氧杂环丁烷作为起始物质来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ11.25-10.33(m,1H),7.31(d,J=1.9Hz,1H),7.26(dd,J=12.1,2.5Hz,1H),7.12(s,1H),5.68(t,J=5.1Hz,1H),5.06(t,J=6.7Hz,2H),4.68(dd,J=7.7,4.7Hz,2H),3.92(s,3H)。MS(ESI)294.1(M+H)。
步骤B.实施例312
根据针对实施例276的合成(步骤B和C)所描述的方法,通过使中间体276A与中间体312A反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.82(s,2H),7.37(br d,J=11.9Hz,1H),7.30(br s,1H),7.13(s,1H),5.68-5.60(m,1H),5.04(br t,J=6.6Hz,2H),4.82-4.68(m,2H),4.23(s,2H),3.74(s,2H),2.59-2.50(m,1H),2.37-2.22(m,1H),1.63-1.50(m,6H),1.44-1.31(m,6H),1.22-1.11(m,4H),1.10-1.03(m,2H)。FXR EC50(nM)=47。MS(ESI)685(M+H)。
实施例313
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-乙氧基-7-氟喹啉-2-甲酸
步骤A.中间体313A.4-乙氧基-7-氟-6-羟基-喹啉-2-甲酸甲酯的制备
根据针对中间体303D的合成(步骤C和D)所描述的方法,使用4-氨基-2-氟苯酚和碘乙烷作为起始物质来制备标题化合物:1H NMR(500MHz,氯仿-d)δ7.98-7.88(m,1H),7.75(d,J=9.6Hz,1H),7.51(s,1H),4.54(q,J=7.0Hz,2H),4.35(q,J=7.0Hz,2H),1.64-1.55(m,3H),1.48(t,J=7.0Hz,3H)。MS(ESI)280.1(M+H)。
步骤B.实施例313
根据针对实施例276的合成(步骤B和C)所描述的方法,通过使中间体276A与中间体313A反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.80(s,2H),7.80(br d,J=12.2Hz,1H),7.52-7.37(m,2H),4.34(q,J=6.7Hz,2H),4.21(s,2H),3.75(s,2H),2.34-2.24(m,1H),1.60-1.51(m,6H),1.46(br t,J=6.9Hz,3H),1.39-1.31(m,6H),1.20-1.11(m,2H),1.09-1.02(m,2H)。FXR EC50(nM)=48。MS(ESI)657(M+H)。
实施例314
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-(环丙基甲氧基)-7-氟喹啉-2-甲酸
步骤A.中间体314A.4-(环丙基甲氧基)-7-氟-6-羟基-喹啉-2-甲酸甲酯的制备
根据针对中间体303D的合成(步骤C和D)所描述的方法,使用4-氨基-2-氟苯酚和(溴甲基)环丙烷作为起始物质来制备标题化合物:1H NMR(500MHz,氯仿-d)δ7.98-7.87(m,1H),7.80(d,J=9.4Hz,1H),7.48(s,1H),4.53(q,J=7.0Hz,2H),4.12(d,J=6.9Hz,2H),1.47(t,J=7.0Hz,3H),1.44-1.35(m,1H),0.78-0.68(m,2H),0.52-0.42(m,2H)。MS(ESI)306.1(M+H)。
步骤B.实施例314
根据针对实施例276的合成(步骤B和C)所描述的方法,通过使中间体276A与中间体314A反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.81(s,2H),7.85(d,J=11.9Hz,1H),7.53-7.47(m,2H),4.22(s,2H),4.19(br d,J=7.0Hz,2H),3.79(s,2H),2.34-2.25(m,1H),1.62-1.52(m,6H),1.41-1.32(m,7H),1.19-1.12(m,2H),1.10-1.04(m,2H),0.67-0.60(m,2H),0.46-0.40(m,2H)。FXR EC50(nM)=67。MS(ESI)683(M+H)。
实施例321
3-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-5-甲氧基苯甲酸
步骤A.中间体321A.3-羟基-5-甲氧基苯甲酸叔丁酯的制备
向3-羟基-5-甲氧基苯甲酸(80mg,0.48mmol)于THF(3mL)和叔丁醇(0.30mL,3.1mmol)中的溶液中逐滴添加(E)-N,N'-二异丙基氨基甲酸叔丁酯(190mg,0.95mmol)。在环境温度搅拌反应物3h。浓缩反应混合物且用EtOAc稀释。有机层用H2O洗涤,经MgSO4干燥,过滤且浓缩。通过快速柱色谱(12g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至80%B;流速=12mL/min)纯化粗产物。将含有期望产物的级分合并、浓缩且在真空中干燥,得到呈透明液体状的标题化合物(40mg,0.18mmol,38%产率)。1H NMR(400MHz,氯仿-d)δ7.20(dd,J=2.3,1.4Hz,1H),7.10(dd,J=2.4,1.3Hz,1H),6.62(t,J=2.3Hz,1H),6.36(s,1H),3.80(s,3H),1.58(s,9H)。MS(ESI)225.0(M+H)。
步骤B.实施例321
步骤1:将中间体276A(18mg,0.043mmol)、中间体321A(11mg,0.047mmol)、Ph3P(17mg,0.064mmol)和(E)-二氮烯-1,2-二甲酸二异丙酯(0.013mL,0.064mmol)溶解于THF(0.5mL)中。在密封小瓶中于100℃搅拌混合物。1h后,使反应物冷却至rt,用DCM稀释,且通过快速柱色谱(12g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=12mL/min)纯化,得到呈透明液体状的叔丁酯(15mg,0.024mmol,56%产率)。
步骤2:将上文步骤1的叔丁酯(15mg,0.024mmol)溶解于1,4-二噁烷(1mL)和1MHCl(水溶液)(0.24mL,0.24mmol)中。在100℃搅拌反应物。1h后,使反应混合物冷却并浓缩。通过制备型HPLC(柱:XBridge C18,30×200mm,5μm颗粒;流动相A:5:95的乙腈:水/10mM乙酸铵;流动相B:95:5的乙腈:水/10mM乙酸铵;梯度:26-66%B经20分钟,接着在100%B下保持2分钟;流速:45mL/min)纯化粗物质。将含有期望产物的级分合并、浓缩且在真空中干燥,得到标题化合物(2.5mg,20%产率)。1H NMR(500MHz,DMSO-d6)δ8.82(s,2H),7.00(br d,J=17.1Hz,2H),6.56(s,1H),4.22(s,2H),3.74(s,2H),3.53(br d,J=11.3Hz,3H),2.41-2.20(m,1H),1.60-1.44(m,6H),1.40-1.28(m,6H),1.21-1.13(m,2H),1.11-1.01(m,2H)。FXREC50(nM)=7。MS(ESI)573.2(M+H)。
实施例324
4-环丙基-6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)喹啉-2-甲酸
步骤A.中间体324A.6-(苯甲基氧基)-4-氯喹啉-2-甲酸乙酯的制备
向6-(苯甲基氧基)-4-氧代-1,4-二氢喹啉-2-甲酸乙酯(100mg,0.31mmol)于DCM(5mL)中的经搅拌溶液中添加草酰氯(0.62mL,1.2mmol)和DMF(1滴)。在55℃搅拌反应物1小时。浓缩反应混合物且用EtOAc稀释。有机层用饱和NaHCO3(水溶液)洗涤,经MgSO4干燥,过滤且浓缩。通过快速柱色谱(12g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至70%B;流速=12mL/min)纯化粗产物。将含有期望产物的级分合并、浓缩且在真空中干燥,得到呈浅黄色固体状的标题化合物(93mg,0.27mmol,88%产率)。1H NMR(500MHz,氯仿-d)δ8.29-8.20(m,2H),7.61-7.49(m,4H),7.48-7.41(m,2H),7.41-7.35(m,1H),5.25(s,2H),4.56(q,J=7.2Hz,2H),1.50(t,J=7.2Hz,3H)。MS(ESI)342.0(M+H)。
步骤B.中间体324B.6-(苯甲基氧基)-4-环丙基喹啉-2-甲酸乙酯的制备
向中间体324A(45mg,0.13mmol)于1,4-二噁烷(1mL)中的经搅拌溶液中添加环丙基硼酸(28mg,0.33mmol)和K2CO3(64mg,0.46mmol)。用N2使混合物脱气5min,添加Pd(dppf)Cl2·CH2Cl2加合物(9.6mg,0.013mmol),且在100℃搅拌反应物。3h后,使反应混合物冷却,浓缩且用EtOAc稀释。有机层用H2O洗涤,经MgSO4干燥,过滤且浓缩。通过快速柱色谱(24g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至50%B;流速=24mL/min)纯化粗产物。将含有期望产物的级分合并、浓缩且在真空中干燥,得到呈透明液体状的标题化合物(20mg,0.058mmol,44%产率)。1H NMR(500MHz,氯仿-d)δ8.25(d,J=9.4Hz,1H),7.85(s,1H),7.68(d,J=2.8Hz,1H),7.57-7.50(m,3H),7.45(t,J=7.4Hz,2H),7.42-7.35(m,1H),5.28(s,2H),4.56(q,J=7.2Hz,2H),2.39-2.27(m,1H),1.50(t,J=7.2Hz,3H),1.25-1.14(m,2H),0.96-0.86(m,2H)。MS(ESI)348.0(M+H)。
步骤C.中间体324C.4-环丙基-6-羟基喹啉-2-甲酸乙酯的制备
用N2使中间体324B(63mg,0.18mmol)于EtOAc(3mL)中的经搅拌溶液脱气。向该混合物中添加钯/碳(29mg,0.0027mmol)(10重量%负载,基质活性碳载体)。在H2(1个大气压,气球)下搅拌反应物4h。观察到环丙基与正丙基产物的混合物。过滤且浓缩反应混合物。通过快速柱色谱(12g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=12mL/min)纯化粗产物。将含有期望产物的级分合并、浓缩且在真空中干燥,得到呈白色固体状的标题化合物(25mg,0.097mmol,54%产率)。1H NMR(500MHz,氯仿-d)δ8.88-8.42(m,1H),8.11(d,J=9.1Hz,1H),7.82(s,1H),7.70(d,J=2.5Hz,1H),7.38(dd,J=9.2,2.6Hz,1H),4.50(q,J=7.0Hz,2H),2.46-2.21(m,1H),1.41(t,J=7.2Hz,3H),1.20-1.09(m,2H),0.97-0.82(m,2H)。MS(ESI)258.2(M+H)。
步骤D.实施例324
根据针对实施例276的合成(步骤B和C)所描述的方法,通过使中间体276A与中间体324C反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.79(s,2H),8.05(br d,J=7.4Hz,1H),7.62(br d,J=10.3Hz,2H),7.47(br d,J=8.7Hz,1H),4.23(s,2H),3.78(s,2H),2.36-2.20(m,1H),1.59(br d,J=7.7Hz,6H),1.39(br s,6H),1.29-1.12(m,5H),1.08(br s,2H),0.85(br d,J=3.6Hz,2H)。FXR EC50(nM)=22。MS(ESI)634.2(M+H)。
实施例327
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-羟基喹啉-2-甲酸
步骤A.中间体327A.4-乙酰氧基-6-(苯甲基氧基)喹啉-2-甲酸乙酯的制备
向6-(苯甲基氧基)-4-氧代-1,4-二氢喹啉-2-甲酸乙酯(80mg,0.25mmol)于乙腈(3mL)中的经搅拌溶液中添加休尼格氏碱(0.086mL,0.50mmol)和乙酰氯(0.021mL,0.30mmol)。在rt搅拌反应物3h。浓缩反应混合物且用EtOAc稀释。有机层用饱和NaHCO3(水溶液)洗涤,经MgSO4干燥,过滤且浓缩。通过快速柱色谱(12g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至70%B;流速=12mL/min)纯化粗产物。将含有期望产物的级分合并、浓缩且在真空中干燥,得到呈浅黄色固体状的标题化合物(90mg,0.27mmol,100%产率)。1H NMR(400MHz,氯仿-d)δ8.24(d,J=9.2Hz,1H),8.02(s,1H),7.59-7.34(m,6H),7.22(d,J=2.9Hz,1H),5.21(s,2H),4.54(q,J=7.1Hz,2H),2.47(s,3H),1.47(t,J=7.0Hz,3H).MS(ESI)366.1(M+H)。
步骤B.中间体327B.4-乙酰氧基-6-羟基喹啉-2-甲酸乙酯的制备
根据针对中间体324C的合成所描述的方法,使用中间体327A作为起始物质来制备标题化合物:(54mg,0.196mmol,90%产率)。1H NMR(400MHz,氯仿-d)δ9.69(br d,J=2.4Hz,1H),8.04(d,J=9.2Hz,1H),8.00(s,1H),7.42(dd,J=9.2,2.6Hz,1H),7.28(d,J=2.6Hz,1H),4.46(q,J=7.1Hz,2H),2.38(s,3H),1.35(t,J=7.2Hz,3H)。MS(ESI)276.1(M+H)。
步骤C.实施例327
根据针对实施例276的合成(步骤B和C)所描述的方法,通过使中间体276A与中间体327B反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.82(s,2H),7.96(br d,J=9.0Hz,1H),7.49-7.33(m,3H),4.26(s,2H),3.24(br s,2H),2.34-2.26(m,1H),1.77-1.58(m,6H),1.53-1.39(m,6H),1.21-1.13(m,2H),1.10(br d,J=2.4Hz,2H)。FXR EC50(nM)=170。MS(ESI)610.3(M+H)。
实施例328
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-异丙氧基喹啉-2-甲酸
步骤A.中间体328A.6-(苯甲基氧基)-4-异丙氧基喹啉-2-甲酸乙酯的制备
向6-(苯甲基氧基)-4-氧代-1,4-二氢喹啉-2-甲酸乙酯(80mg,0.25mmol)于乙腈(3mL)中的经搅拌溶液中添加2-碘丙烷(126mg,0.74mmol)和K2CO3(103mg,0.74mmol)。在60℃搅拌反应物3h。浓缩反应混合物且用EtOAc稀释。有机层用饱和NaHCO3(水溶液)洗涤,经MgSO4干燥,过滤且浓缩。通过快速柱色谱(12g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至70%B;流速=12mL/min)纯化粗产物。将含有期望产物的级分合并、浓缩且在真空中干燥,得到呈浅黄色固体状的标题化合物(56mg,0.15mmol,62%产率)。1H NMR(400MHz,氯仿-d)δ8.13(d,J=9.2Hz,1H),7.56(d,J=2.9Hz,1H),7.54(s,1H),7.52-7.48(m,2H),7.47-7.39(m,3H),7.38-7.32(m,1H),5.21(s,2H),4.94(spt,J=6.1Hz,1H),4.54(q,J=7.0Hz,2H),1.56-1.45(m,9H)。MS(ESI)366.2(M+H)。
步骤B.中间体328B.6-羟基-4-异丙氧基喹啉-2-甲酸乙酯的制备
根据针对中间体324C的合成所描述的方法,使用中间体328A作为起始物质来制备标题化合物:1H NMR(400MHz,氯仿-d)δ8.68-8.19(m,1H),7.99(d,J=9.2Hz,1H),7.54(d,J=2.9Hz,1H),7.50(s,1H),7.31(dd,J=9.2,2.9Hz,1H),4.91(spt,J=6.0Hz,1H),4.47(q,J=7.2Hz,2H),1.46(d,J=6.2Hz,6H),1.38(t,J=7.2Hz,3H)。MS(ESI)276.2(M+H)。
步骤C.实施例328
根据针对实施例276的合成(步骤B和C)所描述的方法,通过使中间体276A与中间体328B反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.81(s,2H),8.00(d,J=9.3Hz,1H),7.50(s,1H),7.46(dd,J=9.2,2.7Hz,1H),7.38(d,J=2.5Hz,1H),5.14-4.98(m,1H),4.24(s,2H),3.72(s,2H),2.37-2.22(m,1H),1.69-1.54(m,6H),1.45(d,J=6.0Hz,6H),1.44-1.36(m,6H),1.22-1.13(m,2H),1.13-1.03(m,2H)。FXR EC50(nM)=15。MS(ESI)652.3(M+H)。
实施例329
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-(3-甲氧基氮杂环丁-1-基)喹啉-2-甲酸
步骤A.中间体329A.6-(苯甲基氧基)-4-(3-甲氧基氮杂环丁-1-基)喹啉-2-甲酸乙酯的制备
向中间体324A(40mg,0.12mmol)于DMF(1mL)中的经搅拌溶液中添加3-甲氧基氮杂环丁烷(100mg,1.2mmol)和休格尼氏碱(0.31mL,1.8mmol)。在100℃搅拌反应物30h。使反应混合物冷却,浓缩且用EtOAc稀释。有机层用饱和NaHCO3(水溶液)洗涤,经MgSO4干燥,过滤且浓缩。通过快速柱色谱(12g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=12mL/min)纯化粗产物。将含有期望产物的级分合并、浓缩且在真空中干燥,得到呈透明液体状的标题化合物(27mg,0.069mmol,59%产率)。1H NMR(500MHz,氯仿-d)δ8.13(d,J=9.1Hz,1H),7.52-7.46(m,2H),7.46-7.40(m,3H),7.40-7.33(m,1H),7.21(d,J=2.5Hz,1H),7.05(s,1H),5.21(s,2H),4.53(q,J=7.2Hz,2H),4.48-4.42(m,2H),4.41-4.31(m,1H),4.14(dd,J=8.8,3.9Hz,2H),3.38(s,3H),1.49(t,J=7.2Hz,3H)。MS(ESI)393.1(M+H)。
步骤B.中间体329B.6-羟基-4-(3-甲氧基氮杂环丁-1-基)喹啉-2-甲酸乙酯的制备
根据针对中间体324C的合成所描述的方法,使用中间体329A作为起始物质来制备标题化合物(16mg,0.053mmol,77%产率):1H NMR(400MHz,氯仿-d)δ7.87(d,J=9.0Hz,1H),7.29(d,J=2.6Hz,1H),7.23(dd,J=9.2,2.6Hz,1H),6.85(s,1H),4.44(dd,J=8.8,6.6Hz,2H),4.38(q,J=7.1Hz,2H),4.31-4.22(m,1H),4.18-4.05(m,2H),3.29(s,3H),1.29(t,J=7.2Hz,3H)。MS(ESI)303.1(M+H)。
步骤C.实施例329
根据针对实施例276的合成(步骤B和C)所描述的方法,通过使中间体276A与中间体329B反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.82(d,J=1.5Hz,2H),8.16(brd,J=9.3Hz,1H),7.59(br d,J=9.0Hz,1H),7.32(br s,1H),6.80(s,1H),4.46(br s,1H),4.23(s,2H),3.83-3.50(m,7H),3.41-3.28(m,2H),2.35-2.24(m,1H),1.54(br d,J=8.1Hz,6H),1.35(br s,6H),1.20-1.12(m,2H),1.08(br s,2H)。FXR EC50(nM)=1400。MS(ESI)679.3(M+H)。
实施例331
4-环丙氧基-6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)喹啉-2-甲酸
步骤A.中间体331A.6-(苯甲基氧基)-4-环丙氧基喹啉-2-甲酸乙酯的制备
用N2使Pd2dba3(6.7mg,7.3μmol)、Cs2CO3(48mg,0.15mmol)和2,2'-双(二苯基膦基)-1,1'-联萘(14mg,0.022mmol)于甲苯(1mL)中的混合物脱气5min。添加中间体324A(25mg,0.073mmol)和环丙醇(8.5mg,0.15mmol),且在100℃搅拌反应物16h。使反应混合物冷却,过滤且浓缩。通过制备型HPLC(Phenomenex Luna AXIA5m C18 30×100mm柱;在220nm检测;流速=40mL/min;连续梯度:0%B至100%B经12min+在100%B下保持3min,其中A=90:10:0.1的H2O:MeOH:TFA,且B=90:10:0.1的MeOH:H2O:TFA)纯化粗物质,得到呈白色固体状的标题化合物(12mg,0.033mmol,45%产率)。1H NMR(500MHz,氯仿-d)δ8.41(br d,J=9.1Hz,1H),8.02(s,1H),7.65(br dd,J=8.9,2.1Hz,1H),7.53(d,J=2.5Hz,1H),7.52-7.48(m,2H),7.45(t,J=7.3Hz,2H),7.43-7.38(m,1H),5.24(s,2H),4.59(q,J=7.0Hz,2H),4.22(tt,J=5.9,2.9Hz,1H),1.51(t,J=7.0Hz,3H),1.18-1.00(m,4H)。MS(ESI)364.1(M+H)。
步骤B.中间体331B.4-环丙氧基-6-羟基喹啉-2-甲酸乙酯的制备
根据针对中间体324C的合成所描述的方法,使用中间体331A作为起始物质来制备标题化合物:1H NMR(500MHz,氯仿-d)δ8.06(d,J=9.1Hz,1H),7.89(s,1H),7.46(d,J=2.8Hz,1H),7.35(dd,J=9.1,2.8Hz,1H),4.52(q,J=7.2Hz,2H),4.06(tt,J=5.9,3.0Hz,1H),1.43(t,J=7.0Hz,3H),1.05-0.85(m,4H)。MS(ESI)274.1(M+H)。
步骤C.实施例331
根据针对实施例276的合成(步骤B和C)所描述的方法,通过使中间体276A与中间体331B反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.75(s,2H),8.05(br d,J=8.2Hz,1H),7.82(s,1H),7.45(br d,J=7.2Hz,1H),7.28(br s,1H),4.21(s,2H),3.83-3.72(m,1H),3.60(s,2H),2.25(br s,1H),1.54(br d,J=7.7Hz,6H),1.36(br d,J=6.9Hz,6H),1.15(br d,J=5.7Hz,2H),1.05(br s,2H),0.96(br d,J=5.6Hz,2H),0.86(brs,2H)。FXR EC50(nM)=23。MS(ESI)650.2(M+H)。
实施例332
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-(甲基磺酰基)喹啉-2-甲酸
步骤A.中间体332A.6-(苯甲基氧基)-4-(甲基硫基)喹啉-2-甲酸甲酯的制备
步骤1:向中间体324A(35mg,0.10mmol)于MeOH(1mL)中的经搅拌溶液中添加甲硫醇钠(14mg,0.21mmol)。在60℃搅拌反应物16h。添加另外量的甲硫醇钠(70mg,1.1mmol),且在60℃搅拌反应物2天。使反应混合物冷却,浓缩且用EtOAc稀释。有机层用1M HCl(水溶液)洗涤,经MgSO4干燥,过滤且浓缩,得到呈黄色固体状的酸。MS(ESI)326.1(M+H)。
步骤2:向溶解于DMF(1mL)中的上文步骤1的产物中添加K2CO3(38mg,0.28mmol)和碘甲烷(0.14mL,0.28mmol)。在rt搅拌混合物14h。将反应混合物分配于盐水与EtOAc之间。分离有机层,用盐水洗涤,经无水MgSO4干燥,过滤且浓缩,得到呈黄色固体状的标题化合物(44mg,0.13mmol,100%产率)。1H NMR(500MHz,氯仿-d)δ8.19(d,J=9.4Hz,1H),7.94(s,1H),7.55-7.48(m,3H),7.47-7.42(m,3H),7.41-7.35(m,1H),5.24(s,2H),4.09(s,3H),2.71(s,3H)。MS(ESI)340.1(M+H)。
步骤B.中间体332B.6-(苯甲基氧基)-4-(甲基磺酰基)喹啉-2-甲酸甲酯的制备
向中间体332A(42mg,0.12mmol)于DCM(5mL)中的经搅拌溶液中添加mCPBA(140mg,0.62mmol)。在rt搅拌反应物4h。浓缩反应混合物且用EtOAc稀释。有机层用饱和NaHCO3(水溶液)洗涤,经MgSO4干燥,过滤且浓缩。通过快速柱色谱(12g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=12mL/min)纯化粗产物。将含有期望产物的级分合并、浓缩且在真空中干燥,得到呈白色固体状的标题化合物(35mg,0.094mmol,76%产率)。1H NMR(400MHz,氯仿-d)δ8.76(s,1H),8.35(d,J=9.5Hz,1H),8.03(d,J=2.9Hz,1H),7.64(dd,J=9.4,2.8Hz,1H),7.55-7.47(m,2H),7.46-7.38(m,2H),7.38-7.31(m,1H),5.34(s,2H),4.09(s,3H),2.97(s,3H)。MS(ESI)372.1(M+H)。
步骤C.中间体332C.6-羟基-4-(甲基磺酰基)喹啉-2-甲酸甲酯的制备
根据针对中间体324C的合成所描述的方法,使用中间体332A作为起始物质来制备标题化合物:(12mg,0.043mmol,45%产率)。1H NMR(400MHz,氯仿-d)δ8.75(s,1H),8.32(d,J=9.2Hz,1H),7.90(d,J=2.4Hz,1H),7.60-7.49(m,1H),7.28(d,J=0.9Hz,1H),4.09(s,3H),3.24(s,3H)。MS(ESI)282.0(M+H)。
步骤D.实施例332
根据针对实施例276的合成(步骤B和C)所描述的方法,通过使中间体276A与中间体332C反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.83(s,2H),8.53(s,1H),8.23(br d,J=8.5Hz,1H),7.79(br s,1H),7.60(br d,J=7.6Hz,1H),4.24(s,2H),3.77(s,2H),3.42(s,3H),2.39-2.22(m,1H),1.58(br d,J=8.2Hz,6H),1.37(br s,6H),1.21-1.13(m,2H),1.09(br d,J=2.7Hz,2H)。FXR EC50(nM)=830。MS(ESI)672.1(M+H)。
实施例334
5-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-3-异丙氧基吡啶-2-甲酸
步骤A.中间体334A.5-氟-3-异丙氧基吡啶-2-甲腈的制备
向异丙醇钠(82mg,1.0mmol)于2-丙醇(2mL)中的经搅拌溶液中添加含3,5-二氟吡啶-2-甲腈(140mg,1.0mmol)的2-丙醇(2mL)。在rt搅拌反应物1h。添加另外量的异丙醇钠(30mg),且反应在20min后完成。浓缩反应混合物且用EtOAc稀释。有机层用H2O洗涤,经MgSO4干燥,过滤且浓缩。通过快速柱色谱(40g硅胶滤筒;A=己烷,B=EtOAc;20min梯度;0%B至100%B;流速=40mL/min)纯化粗产物。将含有期望产物的级分合并、浓缩且在真空中干燥,得到呈透明液体状的标题化合物(60mg,0.33mmol,33%产率)。1H NMR(500MHz,氯仿-d)δ8.15(d,J=2.2Hz,1H),7.09(dd,J=9.6,2.2Hz,1H),4.65(dt,J=12.1,6.1Hz,1H),1.47(d,J=6.1Hz,6H)。MS(ESI)180.3(M+H)。
步骤B.中间体334B.5-(叔丁氧基)-3-异丙氧基吡啶-2-甲腈的制备
在0℃向中间体334A(62mg,0.34mmol)于THF(1mL)中的经搅拌溶液中添加叔丁醇钠(0.38mL,0.38mmol)(1M于THF中)。使混合物升温至rt且搅拌2h。浓缩反应混合物且用EtOAc稀释。有机层用H2O洗涤,经MgSO4干燥,过滤且浓缩。通过快速柱色谱(12g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=12mL/min)纯化粗产物。将含有期望产物的级分合并、浓缩且在真空中干燥,得到呈透明液体状的标题化合物(70mg,0.30mmol,87%产率)。1H NMR(400MHz,氯仿-d)δ7.98(d,J=2.2Hz,1H),6.87(d,J=1.8Hz,1H),4.65-4.52(m,1H),1.45(s,9H),1.42(d,J=6.2Hz,6H)。MS(ESI)235.2(M+H)。
步骤C.中间体334C.5-羟基-3-异丙氧基吡啶-2-甲腈的制备
向中间体334B(70mg,0.30mmol)于DCM(6mL)中的经搅拌溶液中添加TFA(0.23mL,3.0mmol)。搅拌反应物2h。浓缩反应混合物且用EtOAc稀释。有机层用H2O洗涤,经MgSO4干燥,过滤且浓缩。通过快速柱色谱(12g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=12mL/min)纯化粗产物。将含有期望产物的级分合并、浓缩且在真空中干燥,得到呈透明液体状的标题化合物(40mg,0.22mmol,75%产率)。1H NMR(500MHz,氯仿-d)δ7.93(d,J=1.7Hz,1H),6.96(d,J=1.9Hz,1H),4.68(spt,J=6.1Hz,1H),1.44(d,J=6.1Hz,6H)。MS(ESI)179.2(M+H)。
步骤D.实施例334
根据针对中间体276B和实施例278的合成(步骤C)所描述的组合方法,通过使中间体276A与中间体334C反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.80(s,2H),7.83(br s,1H),7.07(br s,1H),4.81-4.61(m,1H),4.23(s,2H),3.69(br s,2H),2.35-2.23(m,1H),1.53(br d,J=8.1Hz,6H),1.43-1.34(m,6H),1.27(br d,J=6.0Hz,6H),1.19-1.12(m,2H),1.08(br d,J=2.9Hz,2H)。FXR EC50(nM)=21。MS(ESI)602.2(M+H)。
实施例335
5-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-3-甲氧基吡啶-2-甲酸
步骤A.中间体335A.5-溴-3-甲氧基吡啶-2-甲腈的制备
在0℃向5-溴-3-硝基吡啶-2-甲腈(530mg,2.3mmol)于MeOH(5mL)中的经搅拌溶液中添加甲醇钠(0.58mL,2.5mmol)。使反应物升温至rt且搅拌1小时。浓缩反应混合物且用EtOAc稀释。有机层用H2O洗涤,经MgSO4干燥,过滤且浓缩。通过快速柱色谱(24g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至70%B;流速=24mL/min)纯化粗产物。将含有期望产物的级分合并、浓缩且在真空中干燥,得到呈浅黄色固体状的标题化合物(300mg,1.4mmol,61%产率)。1H NMR(500MHz,氯仿-d)δ8.38(d,J=1.7Hz,1H),7.55(d,J=1.7Hz,1H),4.01(s,3H)。MS(ESI)215.0(M+H)。
步骤B.中间体335B.5-羟基-3-甲氧基吡啶-2-甲腈的制备
向中间体335A(54mg,0.25mmol)于DMSO(0.5mL)中的经搅拌溶液中添加乙酰氧肟酸(57mg,0.76mmol)和K2CO3(180mg,1.3mmol)。在80℃搅拌反应物2h。使反应混合物冷却,浓缩且用EtOAc稀释。有机层用H2O洗涤,经MgSO4干燥,过滤且浓缩。通过快速柱色谱(24g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至70%B;流速=24mL/min)纯化粗产物。将含有期望产物的级分合并、浓缩且在真空中干燥,得到呈白色固体状的标题化合物(40mg,0.27mmol,100%产率)。1H NMR(400MHz,氯仿-d)δ7.85(d,J=2.2Hz,1H),6.79(d,J=2.2Hz,1H),3.92(s,3H)。MS(ESI)151.2(M+H)。
步骤C.实施例335
根据针对中间体276B和实施例278的合成(步骤C)所描述的组合方法,通过使中间体276A与中间体335B反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.79(s,2H),7.75(br s,1H),7.56(br s,1H),4.22(br s,2H),3.78(br s,3H),3.42(br s,2H),2.28(br s,1H),1.51(br s,6H),1.37(br s,6H),1.15(br d,J=8.0Hz,2H),1.07(br s,2H)。FXR EC50(nM)=170。MS(ESI)574.2(M+H)。
实施例338
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-丙基喹啉-2-甲酸
步骤A.中间体338A.6-羟基-4-丙基喹啉-2-甲酸乙酯的制备
向中间体324B(85mg,0.25mmol)于乙醇(5mL)和水(1mL)中的经搅拌溶液中添加钯/碳(26mg,0.024mmol)(10重量%负载,基质活性碳载体)和甲酸铵(150mg,2.5mmol)。在55℃搅拌反应物1小时。使混合物冷却,经由硅藻土过滤且浓缩滤液。通过快速柱色谱(12g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;10%B至100%B;流速=12mL/min)纯化粗产物。将含有期望产物的级分合并、浓缩且在真空中干燥,得到呈白色固体状的标题化合物(55mg,0.21mmol,87%产率)。1H NMR(500MHz,氯仿-d)δ8.05(d,J=9.4Hz,1H),7.99(s,1H),7.44(d,J=2.8Hz,1H),7.39(dd,J=9.2,2.6Hz,1H),4.46(q,J=7.2Hz,2H),3.03-2.88(m,2H),1.74(sxt,J=7.5Hz,2H),1.36(t,J=7.2Hz,3H),0.97(t,J=7.3Hz,3H)。MS(ESI)260.1(M+H)。
步骤B.实施例338
根据针对实施例276的合成(步骤B和C)所描述的方法,通过使中间体276A与中间体338A反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.83(s,2H),8.04(br d,J=9.5Hz,1H),7.91(s,1H),7.46(br d,J=8.2Hz,1H),7.36(br s,1H),4.24(s,2H),3.76(brs,2H),3.07(br t,J=7.2Hz,2H),2.32(br s,1H),1.86-1.69(m,2H),1.58(br d,J=6.1Hz,6H),1.38(br s,6H),1.17(br d,J=7.6Hz,2H),1.09(br s,2H),0.98(br t,J=7.2Hz,3H)。FXR EC50(nM)=17。MS(ESI)636.3(M+H)。
实施例348
5-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-3-甲基吡啶-2-甲酸
步骤A.中间体348A.5-羟基-3-甲基吡啶-2-甲酸甲酯的制备
向5-溴-3-甲基吡啶-2-甲酸甲酯(70mg,0.30mmol)于DMSO(600μl)中的经搅拌溶液中添加乙酰氧肟酸(69mg,0.91mmol)和K2CO3(210mg,1.5mmol)。在80℃搅拌混合物5h。使反应混合物冷却,浓缩且用EtOAc稀释。有机层用H2O洗涤,经MgSO4干燥,过滤且浓缩。通过快速柱色谱(12g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至70%B;流速=12mL/min)纯化粗产物。将含有期望产物的级分合并、浓缩且在真空中干燥,得到呈白色固体状的标题化合物(17mg,0.10mmol,33%产率)。1H NMR(500MHz,丙酮)δ9.46(br s,1H),8.10(d,J=2.5Hz,1H),7.15(d,J=2.5Hz,1H),3.84(s,3H),2.50(s,3H)。MS(ESI)168.2(M+H)。
步骤B.实施例348
根据针对实施例276的合成(步骤B和C)所描述的方法,通过使中间体276A与中间体348A反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.79(s,2H),8.09(br s,1H),7.28(br s,1H),4.21(s,2H),3.72(br s,2H),2.48(s,3H),2.33-2.22(m,1H),1.49(br d,J=7.9Hz,6H),1.33(br d,J=7.0Hz,6H),1.20-1.12(m,2H),1.06(br d,J=2.7Hz,2H)。FXREC50(nM)=59。MS(ESI)558.1(M+H)。
实施例349
8-环丁氧基-2-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)喹啉-5-甲酸
步骤A.中间体349A.8-羟基喹啉-5-甲酸甲酯的制备
步骤1:向3-氨基-4-羟基苯甲酸(2.0g,13mmol)于6M HCl(水溶液)(10mL)中的经搅拌悬浮液中逐滴添加丙烯醛(1.1g,20mmol)。在100℃搅拌反应物2h。使反应物冷却至rt,添加浓NH4OH直至pH约为9,且过滤反应混合物以移除固体。滤液用冰AcOH酸化至pH 4至5,且通过真空过滤收集固体。将固体悬浮于1:1的丙酮/水(30mL)中,且通过真空过滤收集产物,得到呈浅棕色固体状的期望酸(1.5g)。
步骤2:将粗产物酸溶解于MeOH(15mL)和1mL浓H2SO4中。在80℃搅拌混合物24h。使反应混合物冷却,浓缩且用EtOAc稀释。有机层用1M NaOH(水溶液)洗涤,经MgSO4干燥,过滤且浓缩。通过快速柱色谱(40g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=40mL/min)纯化粗产物。将含有期望产物的级分合并、浓缩且在真空中干燥,得到呈白色固体状的标题化合物(290mg,1.4mmol,11%产率)。1H NMR(500MHz,氯仿-d)δ9.53(dd,J=8.7,1.5Hz,1H),8.84(dd,J=4.1,1.7Hz,1H),8.39(d,J=8.3Hz,1H),7.62(dd,J=8.7,4.3Hz,1H),7.19(d,J=8.3Hz,1H),4.00(s,3H)。MS(ESI)204.2(M+H)。
步骤B.中间体349B.8-环丁氧基喹啉-5-甲酸环丁酯的制备
/>
将中间体349A(84mg,0.41mmol)、溴环丁烷(84mg,0.62mmol)和Cs2CO3(400mg,1.2mmol)溶解于无水DMF(1mL)中,且在密封小瓶中于95℃搅拌。16h后,使反应混合物冷却,浓缩且用EtOAc稀释。有机层用1M HCl(水溶液)洗涤,经MgSO4干燥,过滤且浓缩。通过快速柱色谱(12g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至50%B;流速=12mL/min)纯化粗产物。将含有期望产物的级分合并、浓缩且在真空中干燥,得到呈透明液体状的标题化合物(103mg,0.40mmol,97%产率)。1H NMR(400MHz,氯仿-d)δ9.45(dd,J=8.8,1.8Hz,1H),8.97(dd,J=4.2,1.8Hz,1H),8.27(d,J=8.4Hz,1H),7.54(dd,J=8.7,4.1Hz,1H),6.88(d,J=8.4Hz,1H),4.93(quin,J=7.2Hz,1H),3.95(s,3H),2.67-2.55(m,2H),2.53-2.41(m,2H),2.01-1.86(m,1H),1.83-1.68(m,1H)。MS(ESI)258.2(M+H)。
步骤C.中间体349.2-氯-8-环丁氧基喹啉-5-甲酸甲酯的制备
步骤1:向中间体349B(103mg,0.40mmol)于DCM(3mL)中的经搅拌悬浮液中添加mCPBA(150mg,0.52mmol)。在rt搅拌反应物20h。混合物用DCM稀释。有机层用偏亚硫酸氢钠溶液(水溶液)、饱和NaHCO3(水溶液)洗涤,经MgSO4干燥,过滤且浓缩,得到呈黄色固体状的粗产物N-氧化物(130mg,0.48mmol,119%产率)(含有一些mCPBA)。MS(ESI)274.2(M+H)。
步骤2:在0℃向上文步骤1的产物(130mg,0.48mmol)于DCM(5mL)中的溶液中添加氧氯化磷(0.053mL,0.57mmol)和DMF(0.018mL,0.24mmol)。搅拌5min后,使反应物达至rt,且在70℃搅拌3h。使反应混合物冷却,浓缩且用EtOAc稀释。有机层用1M NaOH(水溶液)洗涤,经MgSO4干燥,过滤且浓缩。通过快速柱色谱(12g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=12mL/min)纯化粗产物。将含有期望产物的级分合并、浓缩且在真空中干燥,得到呈透明液体状的标题化合物(50mg,0.17mmol,36%产率)。1H NMR(400MHz,氯仿-d)δ9.45(d,J=9.0Hz,1H),8.28(d,J=8.6Hz,1H),7.53(d,J=9.0Hz,1H),6.92(d,J=8.6Hz,1H),4.93(quin,J=7.2Hz,1H),3.97(s,3H),2.70-2.56(m,2H),2.54-2.41(m,2H),2.04-1.89(m,1H),1.86-1.71(m,1H)。MS(ESI)292.1(M+H)。
步骤D.实施例349
根据针对实施例104的合成所描述的方法,通过使中间体276A与中间体349C反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ9.60(br d,J=9.3Hz,1H),8.80(s,2H),7.74(br d,J=7.9Hz,1H),6.89(d,J=8.2Hz,1H),6.86(d,J=9.3Hz,1H),4.90-4.81(m,1H),4.24(s,2H),4.06(s,2H),2.49-2.41(m,2H),2.34-2.26(m,1H),2.20-2.08(m,2H),1.90-1.77(m,1H),1.67(br d,J=10.4Hz,1H),1.61-1.53(m,6H),1.45-1.33(m,6H),1.20-1.13(m,2H),1.09(br d,J=2.8Hz,2H)。FXR EC50(nM)=130。MS(ESI)664.1(M+H)。
实施例350
2-((4-((3-(3-氯-5-甲氧基吡啶-4-基)-5-环丙基异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-甲氧基喹啉-6-甲酸
步骤A.中间体350A.4-甲氧基喹啉-6-甲酸甲酯的制备
向4-溴喹啉-6-甲酸甲酯(130mg,0.47mmol)于MeOH(3mL)中的经搅拌悬浮液中添加甲醇钠(0.22mL,0.94mmol)。在80℃搅拌反应物16h。使反应混合物冷却,浓缩且用MeOH(3mL)溶解。向该溶液中添加浓H2SO4(0.5mL),且在80℃搅拌混合物15h。使反应混合物冷却,浓缩且用EtOAc稀释。有机层用1M NaOH(水溶液)洗涤,经MgSO4干燥,过滤且浓缩。通过快速柱色谱(12g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=12mL/min)纯化粗产物。将含有期望产物的级分合并、浓缩且在真空中干燥,得到呈白色固体状的标题化合物(74mg,0.34mmol,73%产率)。1H NMR(500MHz,氯仿-d)δ8.97(d,J=1.7Hz,1H),8.84(d,J=5.2Hz,1H),8.29(dd,J=8.8,1.9Hz,1H),8.07(d,J=8.8Hz,1H),6.80(d,J=5.2Hz,1H),4.10(s,3H),4.00(s,3H)。MS(ESI)218.2(M+H)。
步骤B.中间体350B.2-氯-4-甲氧基喹啉-6-甲酸甲酯的制备
根据针对中间体349C的合成所描述的方法,适当时代入中间体350A来制备标题化合物:(47mg,0.19mmol,24%产率,白色固体)。1H NMR(400MHz,氯仿-d)δ8.89(d,J=2.0Hz,1H),8.31(dd,J=8.8,2.0Hz,1H),7.98(d,J=8.8Hz,1H),6.81(s,1H),4.12(s,3H),4.01(s,3H)。MS(ESI)252.1(M+H)。
步骤C.实施例350
根据针对实施例104的合成所描述的方法,通过使中间体276A与中间体350B反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.56(s,1H),8.51(s,1H),8.43(s,1H),8.12(br d,J=8.4Hz,1H),7.54(br d,J=8.5Hz,1H),6.37(s,1H),4.15(s,2H),4.02(s,3H),3.91(s,2H),3.40(s,3H),2.26(ddd,J=13.2,8.4,4.8Hz,1H),1.67-1.49(m,6H),1.47-1.33(m,6H),1.20-1.10(m,2H),1.07(br d,J=3.3Hz,2H)。FXR EC50(nM)=890。MS(ESI)620.4(M+H)。
实施例351
2-((4-((3-(3-氯-5-甲氧基吡啶-4-基)-5-环丙基异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-8-环丙基喹啉-6-甲酸
步骤A.中间体351A.8-溴喹啉-6-甲酸甲酯的制备
向喹啉-6-甲酸(350mg,2.0mmol)于TFA(1mL)和0.3mL浓H2SO4中的经搅拌悬浮液中添加NBS(530mg,3.0mmol)。在80℃搅拌反应物16h。使反应混合物冷却,且用EtOAc稀释。有机层用1M NaOH(水溶液)洗涤,经MgSO4干燥,过滤且浓缩。将残余物溶解于MeOH(5mL)和0.5mL浓H2SO4中。在80℃搅拌混合物3h。使反应混合物冷却,浓缩且用EtOAc稀释。有机层用1M NaOH(水溶液)洗涤,经MgSO4干燥,过滤且浓缩。通过快速柱色谱(24g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=24mL/min)纯化粗产物。将含有期望产物的级分合并、浓缩且在真空中干燥,得到呈白色固体状的标题化合物(170mg,0.64mmol,32%产率)。1H NMR(400MHz,氯仿-d)δ8.98(dd,J=4.3,1.7Hz,1H),8.48(d,J=2.0Hz,1H),8.39(d,J=1.8Hz,1H),8.12(dd,J=8.3,1.7Hz,1H),7.39(dd,J=8.1,4.2Hz,1H),3.86(s,3H)。MS(ESI)268.0(M+H)。
步骤B.中间体351B.8-环丙基喹啉-6-甲酸甲酯的制备
根据针对中间体324B的合成所描述的方法,适当时代入中间体351A来制备标题化合物:(45mg,0.35mmol,80%产率,透明液体)。1H NMR(400MHz,氯仿-d)δ9.07(dd,J=4.2,1.8Hz,1H),8.39(d,J=1.8Hz,1H),8.25(dd,J=8.4,1.8Hz,1H),7.78(d,J=2.0Hz,1H),7.49(dd,J=8.4,4.2Hz,1H),3.99(s,3H),3.21(tt,J=8.6,5.3Hz,1H),1.29-1.18(m,2H),1.01-0.90(m,2H)。MS(ESI)228.2(M+H)。
步骤C.中间体351C.2-氯-8-环丙基喹啉-6-甲酸甲酯的制备
根据针对中间体349C的合成所描述的方法,适当时代入中间体351B来制备标题化合物:(13mg,0.050mmol,30%产率,透明液体)。1H NMR(400MHz,氯仿-d)δ8.35(d,J=1.8Hz,1H),8.18(d,J=8.6Hz,1H),7.75(d,J=2.0Hz,1H),7.46(d,J=8.6Hz,1H),3.99(s,3H),3.19(tt,J=8.6,5.3Hz,1H),1.30-1.17(m,2H),1.00-0.88(m,2H)。MS(ESI)262.1(M+H)。
步骤D.实施例351
根据针对实施例104的合成所描述的方法,通过使中间体276A与中间体351C反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.52(s,1H),8.45(s,1H),8.31(br d,J=8.9Hz,1H),8.25(s,1H),7.61(s,1H),7.03(br d,J=8.9Hz,1H),4.14(br s,2H),4.12(brs,2H),3.90(s,3H),2.97(br s,1H),2.28(br s,1H),1.56(br d,J=6.4Hz,6H),1.38(brs,6H),1.20-1.00(m,6H),0.82(br d,J=3.4Hz,2H)。FXR EC50(nM)=23。MS(ESI)630.3(M+H)。
实施例352
3-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)喹啉-8-甲酸
步骤A.中间体352A.喹啉-8-甲酸甲酯的制备
向喹啉-8-甲酸(140mg,0.78mmol)于MeOH(4mL)中的经搅拌溶液中添加浓H2SO4(0.1mL)。在70℃搅拌反应物16h。使反应混合物冷却,浓缩且用EtOAc稀释。有机层用1M HCl(水溶液)洗涤,经MgSO4干燥,过滤且浓缩。通过快速柱色谱(12g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=12mL/min)纯化粗产物。将含有期望产物的级分合并、浓缩且在真空中干燥,得到呈浅黄色液体状的标题化合物(110mg,0.60mmol,77%产率)。1H NMR(500MHz,氯仿-d)δ9.07(dd,J=4.3,1.8Hz,1H),8.19(dd,J=8.3,1.7Hz,1H),8.05(dd,J=7.2,1.4Hz,1H),7.95(dd,J=8.1,1.2Hz,1H),7.65-7.53(m,1H),7.47(dd,J=8.3,4.1Hz,1H),4.07(s,3H)。MS(ESI)188.2(M+H)。
步骤B.中间体352B.3-羟基喹啉-8-甲酸甲酯的制备
向中间体352A(110mg,0.60mmol)于冰乙酸(1mL)中的经搅拌溶液中添加30%H2O2(0.12mL,1.2mmol)。在70℃搅拌反应物2h。使反应混合物冷却,浓缩且用EtOAc稀释。有机层用饱和NaHCO3(水溶液)洗涤,经MgSO4干燥,过滤且浓缩。通过快速柱色谱(12g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=12mL/min)纯化粗产物。将含有期望产物的级分合并、浓缩且在真空中干燥,得到呈黄色固体状的标题化合物(30mg,0.15mmol,24%产率)。1H NMR(500MHz,氯仿-d)δ8.73(d,J=2.5Hz,1H),7.93(dd,J=7.2,0.8Hz,1H),7.79-7.73(m,1H),7.55(d,J=2.5Hz,1H),7.48(t,J=7.7Hz,1H),4.01(s,3H)。MS(ESI)204.2(M+H)。
步骤C.实施例352
根据针对实施例276的合成(步骤B和C)所描述的方法,通过使中间体276A与中间体352B反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.84(s,3H),8.28(br d,J=5.8Hz,1H),8.18(br d,J=8.5Hz,1H),8.09(br s,1H),7.76(t,J=7.6Hz,1H),4.25(s,2H),3.80(s,2H),2.36-2.26(m,1H),1.69-1.53(m,6H),1.46-1.32(m,6H),1.22-1.13(m,2H),1.12-1.04(m,2H)。FXR EC50(nM)=55。MS(ESI)594.3(M+H)。
实施例354
4-((1-氯-3-羟基丙-2-基)氧基)-6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)喹啉-2-甲酸
向实施例361(20mg,0.029mmol)于1,4-二噁烷(1mL)中的经搅拌溶液中添加1MHCl(水溶液)(0.10mL,0.10mmol)。搅拌1h后,浓缩反应物。通过制备型HPLC(柱:XBridgeC18,200mm×19mm,5μm颗粒;流动相A:5:95的乙腈:水/10mM乙酸铵;流动相B:95:5的乙腈:水/10mM乙酸铵;梯度:在27%B下保持0分钟,27-67%B经20分钟,接着在100%B下保持4分钟;流速:20mL/min;柱温度:25℃;级分收集系由UV信号引发)纯化粗物质。将含有期望产物的级分合并、浓缩且在真空中干燥,得到标题化合物:(12mg,57%产率)。1H NMR(500MHz,DMSO-d6)δ8.82(s,2H),8.02(br d,J=9.2Hz,1H),7.52(s,1H),7.49-7.39(m,2H),4.42-4.34(m,1H),4.33-4.27(m,1H),4.27-4.23(m,1H),4.23(s,2H),3.90-3.81(m,1H),3.81-3.75(m,1H),3.72(br s,2H),2.35-2.25(m,1H),1.56(br d,J=7.3Hz,6H),1.36(br d,J=7.3Hz,6H),1.22-1.13(m,2H),1.11-1.04(m,2H)。FXR EC50(nM)=200。MS(ESI)702.1(M+H)。
实施例357
7-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-1-异丙氧基异喹啉-3-甲酸
/>
步骤A.中间体357A.(R)-7-羟基-3,4-二氢异喹啉-2,3(1H)-二甲酸2-(叔丁基)酯3-甲酯的制备
向(R)-2-(叔丁氧基羰基)-7-羟基-1,2,3,4-四氢异喹啉-3-甲酸(1.0g,3.4mmol)于DCM(10mL)中的经搅拌溶液中添加休尼格氏碱(1.2mL,6.8mmol)和碘甲烷(3.4mL,6.8mmol)。在65℃搅拌反应物48h。使反应混合物冷却,用饱和NH4Cl(水溶液)洗涤,经MgSO4干燥,过滤且浓缩,得到呈深棕色液体状的标题化合物(1.5g,4.9mmol,143%产率)。1H NMR(400MHz,氯仿-d)δ6.98-6.86(m,1H),6.69-6.49(m,2H),5.04(br dd,J=5.9,2.9Hz,1H),4.63-4.50(m,1H),4.37(br t,J=16.4Hz,1H),3.57(s,3H),3.18(qd,J=7.4,3.3Hz,1H),3.01(br d,J=4.8Hz,1H),1.39(s,9H)。MS(ESI)308.2(M+H)。
步骤B.中间体357B.(R)-7-(苯甲基氧基)-3,4-二氢异喹啉-2,3(1H)-二甲酸2-(叔丁基)酯3-甲酯的制备
向中间体357A(1.5g,4.9mmol)于DMF(15mL)中的经搅拌溶液中添加K2CO3(1.0g,7.3mmol)和苯甲基溴(0.76mL,6.3mmol)。在70℃搅拌反应物24h。反应混合物用EtOAc稀释,且用H2O洗涤,经MgSO4干燥,过滤且浓缩。通过快速柱色谱(80g硅胶滤筒;A=己烷,B=EtOAc;25min梯度;0%B至100%B;流速=60mL/min)纯化粗产物。将含有期望产物的级分合并、浓缩且在真空中干燥,得到呈浅黄色液体状的标题化合物(0.88g,2.2mmol,45%产率)。1HNMR(500MHz,氯仿-d)δ7.49-7.38(m,4H),7.38-7.32(m,1H),7.08(d,J=8.3Hz,1H),6.88-6.73(m,2H),5.21-5.11(m,1H),5.06(s,2H),4.76-4.63(m,1H),4.57-4.43(m,1H),3.67(s,3H),3.29-3.18(m,1H),3.16-3.07(m,1H),1.58(s,9H)。MS(ESI)398.2(M+H)。
步骤C.中间体357C.7-(苯甲基氧基)异喹啉-3-甲酸甲酯的制备
将中间体357B(880mg,2.2mmol)于0.4M HCl(水溶液)(5.5mL,22mmol)中的经搅拌溶液在rt搅拌1h。浓缩反应物且将其溶解于甲苯(5mL)中。向该混合物中添加DDQ(1.0g,4.4mmol),且在回流下搅拌反应物30min。使反应混合物冷却,用EtOAc稀释且用H2O洗涤。有机层经MgSO4干燥,过滤且浓缩。通过快速柱色谱(80g硅胶滤筒;A=己烷,B=EtOAc;25min梯度;0%B至100%B;流速=60mL/min)纯化粗产物。将含有期望产物的级分合并、浓缩且在真空中干燥,得到呈浅黄色固体状的标题化合物(230mg,0.78mmol,35%产率)。1H NMR(400MHz,氯仿-d)δ9.23(s,1H),8.55(s,1H),7.92(d,J=9.0Hz,1H),7.58-7.49(m,3H),7.47-7.37(m,4H),5.26(s,2H),4.06(s,3H)。MS(ESI)294.1(M+H)。
步骤D.中间体357D.7-(苯甲基氧基)-1-氯异喹啉-3-甲酸甲酯的制备
根据针对中间体349C的合成所描述的方法,适当时代入中间体357C来制备标题化合物:(74mg,0.23mmol,58%产率,白色固体)。1H NMR(400MHz,氯仿-d)δ8.48(s,1H),7.93(d,J=9.0Hz,1H),7.75(d,J=2.4Hz,1H),7.61-7.50(m,3H),7.49-7.36(m,3H),5.29(s,2H),4.05(s,3H)。MS(ESI)328.1(M+H)。
步骤E.中间体357E.7-(苯甲基氧基)-1-异丙氧基异喹啉-3-甲酸甲酯的制备
步骤1:向中间体357D(62mg,0.19mmol)于2-丙醇(1.9mL)中的经搅拌溶液中添加异丙醇钠(62mg,0.76mmol)。在90℃搅拌反应物3天。使反应混合物冷却,浓缩且用EtOAc稀释。有机层用1M HCl(水溶液)洗涤,经MgSO4干燥,过滤且浓缩,得到酸(110mg)。MS(ESI)338.2(M+H)。
步骤2:向上文步骤1的产物溶解于丙酮(5mL)中的溶液中添加K2CO3(53mg,0.38mmol)和碘甲烷(40mg,0.285mmol)。在60℃搅拌混合物。5h后,使反应物冷却,过滤且浓缩。通过快速柱色谱(12g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=12mL/min)纯化粗产物。将含有期望产物的级分合并、浓缩且在真空中干燥,得到呈浅黄色液体状的标题化合物(20mg,0.057mmol,30%产率)。1H NMR(500MHz,氯仿-d)δ8.10(s,1H),7.80(d,J=9.1Hz,1H),7.71(d,J=2.5Hz,1H),7.53(d,J=7.4Hz,2H),7.49-7.42(m,3H),7.42-7.35(m,1H),5.75(spt,J=6.2Hz,1H),5.25(s,2H),4.00(s,3H),1.50(d,J=6.3Hz,6H)。MS(ESI)352.2(M+H)。
步骤F.中间体357F.7-羟基-1-异丙氧基异喹啉-3-甲酸甲酯的制备
根据针对中间体324C的合成所描述的方法,适当时代入中间体357E来制备标题化合物:(12mg,0.046mmol,81%产率,白色固体)。1H NMR(500MHz,丙酮-d6)δ8.20(s,1H),7.99(d,J=8.8Hz,1H),7.90(br s,1H),7.67(d,J=1.9Hz,1H),7.48(dd,J=8.8,2.5Hz,1H),5.72(spt,J=6.2Hz,1H),4.03(s,3H),1.57(d,J=6.3Hz,6H)。MS(ESI)262.2(M+H)。
步骤G.实施例357
根据针对实施例276的合成(步骤B和C)所描述的方法,通过使中间体276A与中间体352B反应来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ8.82(s,2H),8.08(s,1H),7.98(d,J=8.9Hz,1H),7.43(br d,J=8.9Hz,1H),7.40(s,1H),5.63(quin,J=6.1Hz,1H),4.23(s,2H),3.90(s,2H),2.35-2.26(m,1H),1.63-1.51(m,6H),1.40(d,J=6.1Hz,6H),1.38-1.32(m,6H),1.20-1.12(m,2H),1.11-1.04(m,2H)。FXR EC50(nM)=13。MS(ESI)652.3(M+H)。
实施例362
2-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲基)-1,2,3,4-四氢异喹啉-7-甲酸
步骤A.中间体362A.2-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲基)-1,2,3,4-四氢异喹啉-7-甲酸甲酯的制备
向中间体121A(15mg,0.036mmol)于DCE(1mL)中的溶液中添加1,2,3,4-四氢异喹啉-7-甲酸甲酯、HCl(24mg,0.11mmol)、冰AcOH(2滴)和分子筛(100mg),接着添加三乙酰氧基硼氢化钠(45mg,0.21mmol)。在85℃搅拌反应物12h。使反应混合物冷却,过滤,浓缩且用EtOAc稀释。有机层用饱和NH4Cl(水溶液)洗涤,经MgSO4干燥,过滤且浓缩。通过快速柱色谱(12g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=12mL/min)纯化粗产物。将含有期望产物的级分合并、浓缩且在真空中干燥,得到呈白色固体状的标题化合物(15mg,0.025mmol,71%产率)。1H NMR(400MHz,氯仿-d)δ7.77(dd,J=7.9,1.5Hz,1H),7.65(d,J=1.1Hz,1H),7.39(d,J=1.5Hz,1H),7.37(s,1H),7.34-7.28(m,1H),7.14(d,J=7.9Hz,1H),4.15(s,2H),3.89(s,3H),3.65(s,2H),2.94-2.83(m,2H),2.78-2.66(m,2H),2.34(t,J=7.6Hz,1H),2.13-2.06(m,2H),1.54-1.36(m,12H),1.25-1.16(m,2H),1.13-1.03(m,2H)。MS(ESI)595.3(M+H)。
步骤B.实施例362
根据针对实施例104的合成(步骤C)所描述的方法,使用中间体362A作为起始物质来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ7.66(br d,J=7.6Hz,1H),7.62-7.48(m,4H),7.18(d,J=7.9Hz,1H),4.11(s,2H),3.55(s,2H),2.79(br d,J=4.9Hz,2H),2.70-2.60(m,2H),2.33-2.18(m,1H),2.09(s,2H),1.38(br d,J=8.5Hz,6H),1.32-1.21(m,6H),1.17-1.09(m,2H),1.07-0.98(m,2H)。FXR EC50(nM)=170。MS(ESI)581.3(M+H)。
根据本文中其他处所描述的方法,使用适当起始物质、试剂和条件来制备(表6中的)以下实施例。
表6
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
实施例384
8-氰基-2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)喹啉-5-甲酸
步骤A.中间体384A.8-溴喹啉-5-甲酸甲酯的制备
将3-氨基-4-溴苯甲酸(3.6g,17mmol)、甘油(2.4mL,33mmol)和3-硝基苯磺酸钠盐(11g,50mmol)于75%H2SO4(水溶液)(40mL)中的溶液在100℃搅拌2h,且在140℃搅拌1h。使反应混合物冷却至rt,且添加MeOH(40mL)。在60℃搅拌反应物。18h后,使混合物冷却至rt,且将其倒入冰水中,且用12M NH4OH(水溶液)使其呈碱性。添加EtOAc且过滤溶液。分离各层且用EtOAc(2×)萃取水层。用盐水洗涤合并的有机层,干燥(MgSO4),过滤且浓缩。通过快速柱色谱(120g硅胶滤筒;A=己烷,B=EtOAc;30min梯度;0%B至70%B;流速=80mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈白色固体状的标题化合物(3.8g,14mmol,85%产率)。1H NMR(500MHz,氯仿-d)δ9.48-9.35(m,1H),9.10(dd,J=3.9,1.7Hz,1H),8.17-8.05(m,2H),7.60(dd,J=8.8,4.1Hz,1H),4.02(s,3H)。MS(ESI)265.8,267.8(M+H)。
步骤B.中间体384B.8-溴-2-(4-(甲氧基羰基)双环[2.2.2]辛-1-基)喹啉-5-甲酸甲酯TFA的制备
在75℃向中间体384A(1.8g,6.6mmol)、硝酸银(0.84g,4.9mmol)和4-(甲氧基羰基)双环[2.2.2]辛烷-1-甲酸(2.1g,9.9mmol)于10%H2SO4(水溶液)(27mL)中的溶液中逐滴添加过氧硫酸铵(2.3g,9.9mmol)于水(30mL)中的溶液。在75℃搅拌反应混合物10min。将反应混合物倒至碎冰上,且用12M NH4OH(水溶液)使其呈碱性。用EtOAc(3×)萃取溶液,且用盐水洗涤经合并的有机层,干燥(MgSO4),过滤且浓缩。通过制备型HPLC(柱:PhenomenexLuna AXIA 5u C18 21.2×100mm;流动相B:90:10的MeOH:H2O/0.1%TFA;流动相A=10:90的MeOH:H2O/0.1%TFA;梯度:40-100%B经10分钟,接着在100%B下保持5分钟;流速:20mL/min)纯化粗产物,得到呈米色固体状的标题化合物(1.7g,3.9mmol,59%产率)。MS(ESI)432.0,434.0(M+H)。
步骤C.中间体384C.8-溴-2-(4-羧基双环[2.2.2]辛-1-基)喹啉-5-甲酸的制备
向中间体384B(0.78g,1.4mmol)于THF(14mL)和MeOH(14mL)中的溶液中添加1MNaOH(水溶液)(8.5mL,8.5mmol)。在70℃搅拌反应物3h。使混合物冷却,浓缩,且用1M HCl(水溶液)酸化。过滤析出物且在真空中干燥,得到呈灰白色固体状的标题化合物(0.34g,0.83mmol,59%产率)。1H NMR(500MHz,THF)δ7.59(d,J=9.1Hz,1H),6.30-6.25(m,1H),6.24-6.20(m,1H),5.82(d,J=9.1Hz,1H),0.30-0.21(m,6H),0.16-0.06(m,6H)。MS(ESI)403.9,405.9(M+H)。
步骤D.中间体384D.8-溴-2-(4-碘双环[2.2.2]辛-1-基)喹啉-5-甲酸甲酯的制备
在85℃搅拌中间体384C(0.34g,0.83mmol)、二乙酸碘苯(0.35g,1.1mmol)和碘(0.53g,2.1mmol)于氯苯(42ml)中的溶液,且用蓝色LED照射。2h后,使反应混合物冷却并浓缩。将粗物质溶解于DMF(9mL)中,接着添加K2CO3(0.35g,2.5mmol)和碘甲烷(0.10mL,1.7mmol)。搅拌18h后,反应混合物用EtOAc稀释,有机层用水(5×)、盐水洗涤,干燥(MgSO4),过滤且浓缩。通过快速柱色谱(40g硅胶滤筒;A=己烷,B=EtOAc;20min梯度;0%B至70%B;流速=80mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈白色粉末状的标题化合物(0.24g,0.48mmol,58%产率)。MS(ESI)499.9,501.9(M+H)。
步骤E.中间体384E.8-溴-2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)喹啉-5-甲酸甲酯的制备
向(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲醇(0.10g,0.36mmol)和中间体384D(0.12g,0.24mmol)于DCE(0.47mL)中的溶液中添加三氟甲烷磺酸银(0.12g,0.47mmol),接着添加2,6-二-叔丁基吡啶(0.21mL,0.95mmol)。在压力小瓶中将反应混合物加热至100℃后保持3h,且使其冷却至rt。通过反相快速柱色谱(24g C-18反相硅胶滤筒;A=水/0.1%TFA,B=MeOH/0.1%TFA;15min梯度;20%B至100%B;流速=24mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈无色玻璃状的标题化合物(0.061g,0.092mmol,39%产率)。1H NMR(500MHz,氯仿-d)δ9.23(d,J=9.1Hz,1H),8.64(br s,2H),8.04(s,2H),7.53(d,J=9.1Hz,1H),4.29(s,2H),3.99(s,3H),2.21-2.01(m,7H),1.68-1.52(m,6H),1.30-1.24(m,2H),1.19-1.09(m,2H)。MS(ESI)656.0,658.0(M+H)。
步骤F.中间体384F.8-氰基-2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)喹啉-5-甲酸甲酯的制备
用氮气(3×)吹扫含有甲基中间体384E(0.015g,0.023mmol)、Xantphos(2.6mg,4.6μmol)、Pd2(dba)3(4.2mg,4.6μmol)和氰化锌(5.4mg,0.046mmol)的压力小瓶,且添加无水DMF(0.23mL)。将反应小瓶加盖且在90℃搅拌混合物。18h后,使反应物冷却至rt,用EtOAc稀释且用水(3×)洗涤。用盐水洗涤有机层,干燥(MgSO4),过滤且浓缩。粗产物不经进一步纯化即使用。
步骤G.实施例384
根据针对实施例130的合成(步骤C)所描述的方法,适当时代入中间体384F来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ9.15(br d,J=9.2Hz,1H),8.84(s,2H),8.35(d,J=7.6Hz,1H),8.17(br d,J=7.3Hz,1H),7.81(br d,J=8.9Hz,1H),4.28(s,2H),2.37-2.27(m,1H),2.05-1.93(m,6H),1.55-1.42(m,6H),1.19-1.13(m,2H),1.13-1.06(m,2H)。FXREC50(nM)=820。MS(ESI)589.1(M+H)。
实施例385
8-环丙基-2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)喹啉-5-甲酸
步骤A.中间体385A.8-环丙基-2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)喹啉-5-甲酸甲酯的制备
/>
向压力小瓶中添加环丙基硼酸(2.9mg,0.034mmol)、中间体384E(0.015g,0.023mmol)、K3PO4(0.015g,0.068mmol)和Pd(Ph3P)4(1.3mg,1.1μmol)。用氮气(3×)吹扫小瓶,接着添加甲苯(0.28mL)和经脱气的水(0.028mL)。将反应小瓶加盖且在90℃搅拌混合物。18h后,将反应混合物用EtOAc稀释且用盐水洗涤。分离各层,且有机层经干燥(MgSO4)和浓缩。粗产物不经进一步纯化即使用。
步骤B.实施例385
根据针对实施例130的合成(步骤C)所描述的方法,适当时代入中间体385A来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ9.54-9.04(m,1H),8.86(br s,2H),8.25-7.86(m,1H),7.63(br s,1H),7.28(br s,1H),4.27(s,2H),3.48(br s,1H),2.33(br s,1H),1.99(br s,6H),1.48(br s,6H),1.17(br d,J=4.6Hz,4H),1.10(br d,J=2.7Hz,2H),0.91(brs,2H)。FXR EC50(nM)=13。MS(ESI)604.3(M+H)。
实施例391
2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-8-异丙氧基喹啉-5-甲酸
步骤A.中间体391A.2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-8-羟基喹啉-5-甲酸甲酯的制备
步骤1:向压力小瓶中添加中间体384E(0.056g,0.085mmol)、双(频哪醇合)二硼(0.043g,0.17mmol)、乙酸钾(0.033g,0.34mmol)和Pd(dppf)Cl2·CH2Cl2加合物(3.5mg,4.3μmol)。用氮气(3×)吹扫小瓶。添加DMF(0.6mL)并将小瓶加盖,且在95℃搅拌反应物。4h后,反应混合物用EtOAc稀释,用水、盐水洗涤,干燥(MgSO4),过滤且浓缩。粗产物硼酸酯产物不经进一步纯化即用于下一步骤。
步骤2:在0℃向上文步骤1的产物(0.060g,0.085mmol)于EtOAc(2mL)中的溶液中逐滴添加30%过氧化氢(水溶液)(0.087mL,0.85mmol)。使反应混合物缓慢升温至rt且搅拌。18h后,将反应混合物冷却至0℃,且用饱和亚硫酸钠溶液(水溶液)淬灭。用EtOAc(3×)萃取产物。合并有机层,用盐水洗涤,干燥(MgSO4),过滤且浓缩。通过快速柱色谱(12g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=12mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈无色玻璃状的标题化合物(0.032g,0.053mmol,63%产率)。1H NMR(500MHz,氯仿-d)δ9.37(d,J=9.1Hz,1H),8.64(s,2H),8.28(d,J=8.0Hz,1H),7.55(d,J=9.1Hz,1H),7.13(d,J=8.3Hz,1H),4.29(s,2H),3.95(s,3H),2.17-2.11(m,1H),2.11-2.05(m,6H),1.69-1.56(m,6H),1.29-1.25(m,2H),1.18-1.10(m,2H)。MS(ESI)594.1(M+H)。
步骤B.中间体391B.2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-8-异丙氧基喹啉-5-甲酸甲酯的制备
向中间体391A(0.016g,0.027mmol)于乙腈(0.27mL)中的溶液中添加K2CO3(0.011g,0.081mmol)和2-碘丙烷(8.1μL,0.081mmol)。在70℃搅拌反应混合物。18h后,将反应混合物过滤并浓缩,且不经进一步纯化即使用。MS(ESI)636.2(M+H)。
步骤C.实施例391
根据针对实施例130的合成(步骤C)所描述的方法,适当时代入中间体391B来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ9.26(br d,J=9.2Hz,1H),8.84(s,2H),8.16(br d,J=8.2Hz,1H),7.65(d,J=9.2Hz,1H),7.21(br d,J=8.2Hz,1H),4.93(dt,J=11.9,6.0Hz,1H),4.27(s,2H),2.36-2.28(m,1H),2.03-1.89(m,6H),1.54-1.42(m,6H),1.38(d,J=6.1Hz,6H),1.21-1.14(m,2H),1.12-1.06(m,2H)。FXR EC50(nM)=14。MS(ESI)622.2(M+H)。
实施例410
2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-8-吗啉代喹啉-5-甲酸
步骤A.中间体410A.2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-8-吗啉代喹啉-5-甲酸乙酯的制备
向压力小瓶中添加中间体384E(0.020g,0.030mmol)、碳酸铯(0.019g,0.060mmol)和第2代RuPhos预催化剂(1.2mg,1.5μmol)。用氮气(3×)吹扫小瓶,且添加1,4-二噁烷(0.30mL)和吗啉(0.013mL,0.15mmol)。在90℃搅拌反应混合物。18h后,将反应混合物冷却至rt,用EtOAc稀释,用水和盐水洗涤,干燥(MgSO4),过滤且浓缩。粗物质不经进一步纯化即使用。MS(ESI)677.4(M+H)。
步骤B.实施例410
根据针对实施例130的合成(步骤C)所描述的方法,适当时代入中间体410A来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ9.30(br d,J=9.2Hz,1H),8.83(s,2H),8.11(br d,J=8.2Hz,1H),7.62(br d,J=9.2Hz,1H),7.07(br d,J=7.9Hz,1H),4.27(s,2H),3.86(brs,4H),3.63-3.40(m,2H),2.56(s,2H),2.37-2.24(m,1H),2.02-1.87(m,6H),1.55-1.39(m,6H),1.21-1.14(m,2H),1.12-1.05(m,2H)。FXR EC50(nM)=36。MS(ESI)649.1(M+H)。
实施例418
2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-8-(2-羟基-2-甲基丙氧基)喹啉-5-甲酸
步骤A.中间体418A.2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-8-(2-羟基-2-甲基丙氧基)喹啉-5-甲酸乙酯的制备
向2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-8-羟基喹啉-5-甲酸乙酯(21mg,0.035mmol)和K2CO3(19mg,0.14mmol)于乙腈(0.5mL)和水(0.033mL)中的溶液中添加2,2-二甲基环氧乙烷(9.2μL,0.10mmol)。在120℃(微波)照射反应混合物35min。将反应混合物转移至压力小瓶中,且添加DMF(0.35mL),接着添加另外的2,2-二甲基环氧乙烷(9.2μL,0.10mmol)。在80℃(常规加热)搅拌反应混合物18h。添加另外的2,2-二甲基环氧乙烷(62μL,0.70mmol),且在80℃搅拌反应物。18h后,反应混合物用EtOAc稀释,用水、盐水洗涤,干燥(MgSO4),过滤且浓缩。粗产物不经进一步纯化即用于下一步骤。MS(ESI)680.4(M+H)。
步骤B.实施例418
根据针对实施例130的合成(步骤C)所描述的方法,适当时代入中间体418A来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ9.24(br d,J=9.0Hz,1H),8.80(br s,2H),8.18(d,J=8.3Hz,1H),7.65(d,J=9.1Hz,1H),7.18(d,J=8.3Hz,1H),4.27(s,2H),3.98(s,2H),2.34-2.23(m,1H),2.08-1.95(m,6H),1.59-1.42(m,6H),1.33(s,6H),1.21-1.14(m,2H),1.13-1.04(m,2H)。FXR EC50(nM)=120。MS(ESI)652.3(M+H)。
实施例423
2-(4-((5-环丙基-3-(二环丙基甲基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-7-(三氟甲基)喹啉-5-甲酸
步骤A.中间体423A.(E)-2,2-二环丙基乙醛肟的制备
向2,2-二环丙基乙醛(2.0g,16mmol)于吡啶(8mL)中的溶液中添加羟胺盐酸盐(1.7g,24mmol)。搅拌1h后,反应混合物用水稀释且用EtOAc萃取。将有机层用水、盐水洗涤,经Na2SO4干燥,过滤且浓缩。将产物在真空中干燥,得到呈无色油状物的标题化合物(1.7g,12mmol,76%产率)。1H NMR(400MHz,氯仿-d)δ7.43(dd,J=1.7,0.8Hz,1H),1.75(br s,1H),1.01-0.93(m,2H),0.32-0.11(m,4H),0.09-0.13(m,4H)。
步骤B.中间体423B.(Z)-2,2-二环丙基-N-羟基乙酰亚胺酰氯的制备
向中间体423A(1.7g,12mmol)于DMF(16mL)中的溶液中逐份添加NCS(2.0g,15mmol)。在40℃搅拌反应物。1.5h后,将混合物倒入至水中且用EtOAc(2×)萃取。将有机相合并,用盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过快速柱色谱(40g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=40mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈无色油状物的标题化合物(1.5g,8.9mmol,73%产率)。1H NMR(400MHz,氯仿-d)δ7.46(s,1H),0.93-0.80(m,2H),0.76-0.60(m,1H),0.43(dddd,J=9.1,8.0,5.8,4.5Hz,2H),0.33-0.22(m,2H),0.12(dt,J=5.6,4.7Hz,2H),0.05--0.06(m,2H)。
步骤C.中间体423C.5-环丙基-3-(二环丙基甲基)异噁唑-4-甲酸甲酯的制备
向含有3-环丙基-3-氧代丙酸甲酯(0.75g,5.3mmol)的25mL烧瓶中添加Et3N(1.4mL,10mmol)。在rt搅拌混合物30min,接着冷却至0℃。在5min的时间段内向该混合物中添加中间体423B于EtOH(3mL)中的溶液。使反应物升温至rt并搅拌。3h后,将混合物倒入至水中且用EtOAc(2×)萃取。将有机相合并,用盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过快速柱色谱(40g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=40mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈无色油状物的标题化合物(0.68g,2.6mmol,52%产率)。1H NMR(400MHz,氯仿-d)δ3.69(s,3H),2.66-2.57(m,1H),1.54(dd,J=2.6,2.0Hz,1H),1.15-1.11(m,2H),1.01-0.97(m,4H),0.44-0.34(m,2H),0.21(br dd,J=8.4,4.4Hz,2H),0.12(dd,J=9.5,4.6Hz,2H),-0.01(dd,J=9.6,4.3Hz,2H)。MS(ESI)262.1(M+H)。
步骤D.中间体423D.(5-环丙基-3-(二环丙基甲基)异噁唑-4-基)甲醇的制备
在-78℃向中间体423C(1.2g,4.6mmol)于DCM(50mL)中的溶液中添加DIBAL-H(13mL,13mmol)(于DCM中的1M溶液)。在该温度搅拌反应物1h。向该混合物中添加罗谢尔盐溶液(水溶液)(约100mL),且使混合物升温至rt并搅拌。4h后,分离有机层,用盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过快速柱色谱(40g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=20mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈白色固体状的标题化合物(0.82g,3.5mmol,76%产率)。1H NMR(500MHz,氯仿-d)δ4.62(d,J=5.5Hz,2H),2.11-2.06(m,1H),1.65(t,J=9.2Hz,1H),1.43(t,J=5.4Hz,1H),1.31-1.22(m,2H),1.18(dd,J=4.8,2.1Hz,2H),1.08(dd,J=8.3,2.5Hz,2H),0.68-0.61(m,2H),0.48-0.42(m,2H),0.34(dd,J=9.5,4.8Hz,2H),0.20(dd,J=9.5,4.8Hz,2H)。MS(ESI)234.0(M+H)。
步骤E.实施例423
根据针对实施例384的合成所描述的方法,适当时代入中间体423D和7-(三氟甲基)喹啉-5-甲酸甲酯来制备标题化合物:1H NMR(500MHz,DMSO-d6)δ9.18(br d,J=9.1Hz,1H),8.39(s,1H),8.23(s,1H),7.85(br d,J=9.1Hz,1H),4.22(s,2H),2.13-2.08(m,1H),2.04(br d,J=7.3Hz,6H),1.76(br s,6H),1.48-1.39(m,1H),1.13(br dd,J=8.2,4.4Hz,2H),1.02-0.96(m,2H),0.90(br d,J=2.6Hz,2H),0.53-0.41(m,2H),0.28-0.20(m,4H),0.02(br d,J=5.5Hz,2H)。FXR EC50(nM)=67。MS(ESI)581.4(M+H)。
实施例425
2-(4-((5-环丙基-3-(2,2-二氟-1-甲基环丙基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)喹啉-5-甲酸
步骤A.中间体425A.(2,2-二氟-1-甲基环丙基)甲醇的制备
在0℃向LAH(0.17g,4.5mmol)于THF(8mL)中的悬浮液中逐滴添加2,2-二氟-1-甲基环丙烷-1-甲酸(0.61g,4.5mmol)于THF(8mL)中的溶液。使反应物升温至rt并搅拌。4h后,用水(0.17mL),接着用15%NaOH(水溶液)(0.17mL)谨慎地淬灭反应物。搅拌15min后,添加固体MgSO4。搅拌另外15min后,过滤且浓缩反应物,得到呈无色油状物的标题化合物(0.53g,4.3mmol,97%产率)。1H NMR(400MHz,氯仿-d)δ3.72-3.68(m,1H),3.62-3.57(m,1H),1.91-1.82(m,1H),1.31(dd,J=2.9,1.5Hz,3H),1.24(ddd,J=13.8,7.6,4.1Hz,1H),1.07(ddd,J=12.1,7.8,4.1Hz,1H)。
步骤B.中间体425B.2,2-二氟-1-甲基环丙烷-1-甲醛的制备
向中间体425A(0.33g,2.7mmol)于DCM(10mL)中的溶液中添加PCC(0.64g,3.0mmol)。搅拌2h后,经由硅藻土过滤混合物,用DCM(10mL)洗涤滤饼,且所得滤液不经额外处理或表征即用于后续步骤。
步骤C.中间体425C.(E)-2,2-二氟-1-甲基环丙烷-1-甲醛肟的制备
向中间体425B(0.32g,2.7mmol)于DCM(20mL)中的溶液中添加吡啶(2.6mL,32mmol)。向该混合物中添加羟胺盐酸盐(0.28g,4.1mmol)。搅拌3.5h后,将反应物用水稀释且用DCM萃取。将有机层用盐水洗涤,经MgSO4干燥,过滤且浓缩,得到呈绿色半固体状的标题化合物(0.29g,2.1mmol,79%产率)。MS(ESI)136.0(M+H)。
步骤C.中间体425C.(Z)-2,2-二氟-N-羟基-1-甲基环丙烷-1-甲酰亚胺酰氯的制备
向中间体425B(0.29g,2.2mmol)于DMF(3mL)中的溶液中逐份添加NCS(0.32g,2.4mmol)。在40℃搅拌反应物。2.5h后,将混合物倒入至水中且用EtOAc(2×)萃取。将有机相合并,用盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过快速柱色谱(12g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=12mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈无色油状物的标题化合物(150mg,0.885mmol,41%产率)。MS(ESI)169.9(M+H)。
步骤D.中间体425D.5-环丙基-3-(2,2-二氟-1-甲基环丙基)异噁唑-4-甲酸甲酯的制备
向含有3-环丙基-3-氧代丙酸甲酯(140mg,0.97mmol)的小瓶中添加Et3N(250μL,1.8mmol)。在rt搅拌混合物。20min后,添加中间体425C(150mg,0.89mmol)于EtOH(0.5mL)中的溶液,此时澄清溶液变成悬浮液。搅拌1h后,用EtOAc稀释混合物。将有机层用水、盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过快速柱色谱(12g硅胶筒;A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=12mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈无色油的标题化合物(150mg,0.58mmol,66%产率)。1H NMR(400MHz,氯仿-d)δ3.97-3.85(m,3H),2.91-2.73(m,1H),1.96(ddd,J=13.0,8.2,4.3Hz,1H),1.53(d,J=1.5Hz,3H),1.50-1.42(m,1H),1.25-1.17(m,4H)。MS(ESI)258.1(M+H)。
步骤E.中间体425E.(5-环丙基-3-(2,2-二氟-1-甲基环丙基)异噁唑-4-基)甲醇的制备
在-78℃向中间体425D(150mg,0.58mmol)于DCM(6mL)中的溶液中添加DIBAL-H(1.6mL,1.6mmol)(于DCM中的1M溶液)。在此温度搅拌反应物1h。向该混合物中添加罗谢尔盐溶液(水溶液)(约5mL),且使混合物升温至rt并搅拌。2h后,分离有机层,用盐水洗,经Na2SO4干燥,过滤且浓缩。通过快速柱色谱(4g硅胶筒;A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=4mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈白色固体的标题化合物(90mg,0.39mmol,67%产率)。1H NMR(400MHz,氯仿-d)δ4.60(d,J=3.7Hz,2H),2.15-1.99(m,3H),1.56(dd,J=3.0,1.9Hz,3H),1.47(ddd,J=12.0,8.0,5.3Hz,1H),1.14(td,J=3.1,1.3Hz,2H),1.10-1.03(m,2H)。MS(ESI)230.1(M+H)。
步骤F.实施例425
根据实施例384的合成所述的方法,适当时代入中间体425E和喹啉-5-甲酸甲酯来制备标题化合物:(3.7mg,0.0070mmol,13%产率)。1H NMR(500MHz,DMSO-d6)δ9.20(br d,J=8.9Hz,1H),8.11(br t,J=7.5Hz,2H),7.80-7.58(m,2H),4.45-4.24(m,2H),2.23-2.05(m,7H),2.04-1.95(m,1H),1.88(br d,J=8.9Hz,6H),1.79-1.69(m,1H),1.52(br s,3H),1.09(br d,J=8.2Hz,2H),0.99(br d,J=7.0Hz,2H)。FXR EC50(nM)=3400。MS(ESI)509.3(M+H)。
实施例426
8-氯-2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-6-甲氧基喹啉-5-甲酸
步骤A.中间体426A.6-溴-8-氯喹啉-5-甲酸甲酯的制备
向6-溴-8-氯喹啉-5-甲酸(2.6g,9.0mmol)于DMF(18mL)中的溶液中添加K2CO3(3.7g,27mmol)和碘甲烷(6.7mL,14mmol)(于叔丁基甲醚中的2M溶液)。搅拌3h后,用水稀释混合物且用EtOAc萃取水相。将有机相用盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过快速柱色谱(12g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=12mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈棕色固体状的标题化合物(2.3g,7.5mmol,84%产率)。1H NMR(400MHz,氯仿-d)δ9.08(dd,J=4.2,1.5Hz,1H),8.16(dd,J=8.6,1.8Hz,1H),8.04(s,1H),7.56(dd,J=8.6,4.2Hz,1H),4.08(s,3H)。MS(ESI)301.9(M+H)。
步骤B.中间体426B.6-溴-8-氯-2-(4-(甲氧基羰基)双环[2.2.2]辛-1-基)喹啉-5-甲酸甲酯的制备
根据针对中间体384B的合成所描述的方法,适当时代入中间体426A来制备标题化合物:(0.79g,1.7mmol,39%产率)。1H NMR(400MHz,氯仿-d)δ8.06-7.99(m,1H),7.96(s,1H),7.55(d,J=8.8Hz,1H),4.05(s,3H),3.69(s,3H),2.11-2.04(m,6H),2.01-1.93(m,6H)。MS(ESI)468.1(M+H)。
步骤C.中间体426C.8-氯-2-(4-(甲氧基羰基)双环[2.2.2]辛-1-基)-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)喹啉-5-甲酸甲酯的制备
向圆底烧瓶中添加中间体426B(0.79g,1.7mmol)、双(频哪醇合)二硼(0.65g,2.5mmol)、乙酸钾(0.50g,5.1mmol)和Pd(dppf)Cl2·CH2Cl2加合物(0.062g,0.085mmol)。用氮气吹扫并冲洗容器。向该混合物中添加1,4-二噁烷(11mL),且在80℃搅拌反应混合物。16h后,使混合物冷却且用EtOAc稀释。将有机层用水、盐水洗涤,经Na2SO4干燥,过滤且浓缩。将产物在真空中干燥,得到呈棕色泡沫状的标题化合物(约1.2g,粗产物)。MS(ESI)514.3(M+H)。
步骤D.中间体426D.8-氯-6-羟基-2-(4-(甲氧基羰基)双环[2.2.2]辛-1-基)喹啉-5-甲酸甲酯的制备
在0℃向中间体426C(0.87g,1.7mmol)溶解于EtOAc(34mL)中的溶液中逐滴添加30%过氧化氢(水溶液)(1.7mL,17mmol)。使反应物升温至rt并搅拌。2h后,将混合物冷却至0℃且用饱和亚硫酸氢钠(水溶液)淬灭。用EtOAc(3×)萃取水相。将有机相合并,用盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过快速柱色谱(40g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=40mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈棕色油状物的标题化合物(0.68g,1.7mmol,100%产率)。1H NMR(400MHz,氯仿-d)δ9.03-8.91(m,1H),7.57-7.41(m,2H),4.09(s,3H),3.74-3.62(m,4H),2.08-2.03(m,6H),2.00-1.95(m,6H)。MS(ESI)404.1(M+H)。
步骤E.中间体426E.8-氯-6-甲氧基-2-(4-(甲氧基羰基)双环[2.2.2]辛-1-基)喹啉-5-甲酸甲酯的制备
向中间体426D(250mg,0.62mmol)和K2CO3(260mg,1.9mmol)于DMF(4mL)中的溶液中添加碘甲烷(460μL,0.93mmol)(于叔丁基甲醚中的2M溶液)。搅拌18h后,将反应混合物用EtOAc稀释。将有机层用水、盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过快速柱色谱(24g硅胶滤筒;A=DCM,B=MeOH;15min梯度;100%A;流速=24mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈白色固体状的标题化合物(200mg,0.48mmol,77%产率)。1HNMR(400MHz,氯仿-d)δ8.09(d,J=9.0Hz,1H),7.60(s,1H),7.51-7.44(m,1H),4.01(d,J=1.3Hz,3H),3.98-3.95(m,3H),3.69(d,J=1.3Hz,3H),2.10-2.02(m,6H),2.00-1.91(m,6H)。MS(ESI)418.2(M+H)。
步骤F.中间体426F.4-(8-氯-6-甲氧基-5-(甲氧基羰基)喹啉-2-基)双环[2.2.2]辛烷-1-甲酸的制备
向中间体426E(200mg,0.48mmol)溶解于THF(4mL)和MeOH(1mL)中的溶液中添加2MNaOH(水溶液)(2.4mL,4.8mmol)。搅拌18h后,浓缩挥发性溶剂。所得水相用1M HCl(水溶液)(pH约3)酸化且用EtOAc萃取。将有机相用盐水洗涤,经Na2SO4干燥,过滤且浓缩。将产物在真空中干燥,得到呈白色固体状的标题化合物(190mg,0.47mmol,98%产率)。1H NMR(400MHz,氯仿-d)δ8.09(d,J=9.0Hz,1H),7.61(s,1H),7.49(d,J=9.0Hz,1H),4.01(s,3H),3.98(s,3H),2.10-2.05(m,6H),2.04-1.97(m,7H)。MS(ESI)418.2(M+H)。MS(ESI)404.2(M+H)。
步骤G.中间体426G.8-氯-2-(4-碘双环[2.2.2]辛-1-基)-6-甲氧基喹啉-5-甲酸甲酯的制备
向中间体426F(190mg,0.47mmol)于氯苯(23mL)中的溶液中添加二乙酸碘苯(170mg,0.52mmol)和碘(360mg,1.4mmol)。在85℃搅拌反应物,且在蓝色LED下照射。3h后,使混合物冷却并浓缩。通过快速柱色谱(12g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=12mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈白色固体状的标题化合物(130mg,0.26mmol,55%产率)。1H NMR(400MHz,氯仿-d)δ8.08(d,J=9.0Hz,1H),7.60(s,1H),7.42(d,J=9.0Hz,1H),4.00(s,3H),3.97(s,3H),2.66-2.60(m,6H),2.21-2.15(m,6H)。MS(ESI)485.7(M+H)。
步骤H.实施例426
根据针对实施例4的合成(步骤E)所描述的方法,通过使中间体426G与(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲醇反应来制备标题化合物:(3.7mg,0.0070mmol,13%产率)。1H NMR(500MHz,DMSO-d6)δ8.80(s,2H),8.06(br d,J=8.8Hz,1H),7.77(s,1H),7.57(d,J=8.8Hz,1H),4.27(s,2H),3.91(s,3H),2.34-2.26(m,1H),1.97(br d,J=7.6Hz,6H),1.49(br d,J=6.9Hz,6H),1.20-1.13(m,2H),1.08(br s,2H)。FXR EC50(nM)=12。MS(ESI)628.3(M+H)。
实施例430
6-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙基)-4-(三氟甲基)喹啉-2-甲酸
步骤A.中间体430A.4-乙炔基双环[2.2.2]辛烷-1-甲酸甲酯的制备
向烘箱干燥的烧瓶中添加中间体159B(120mg,0.61mmol)和K2CO3(170mg,1.2mmol)。添加无水MeOH(2.4mL),且在N2下搅拌反应物。30min后,添加(1-重氮-2-氧代丙基)膦酸二甲酯(140mg,0.73mmol)。搅拌1h后,将混合物用醚稀释,用水、盐水洗涤,经MgSO4干燥,过滤且浓缩。通过快速柱色谱(12g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=12mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈白色固体状的标题化合物(75mg,0.39mmol,64%产率)。1H NMR(400MHz,氯仿-d)δ3.64(s,3H),2.09(s,1H),1.80(s,12H)。
步骤B.中间体430B.4-乙炔基双环[2.2.2]辛烷-1-甲酸甲酯的制备
根据针对中间体130B的合成所描述的方法,适当时代入中间体430A来制备标题化合物:(100mg,0.22mmol,91%产率,白色固体)。1H NMR(400MHz,氯仿-d)δ8.45(s,1H),8.30(d,J=8.8Hz,1H),8.14(s,1H),7.81(dd,J=8.9,1.7Hz,1H),4.58(q,J=7.1Hz,2H),3.67(s,3H),1.98-1.84(m,12H),1.50(t,J=7.2Hz,3H)。MS(ESI)460.6(M+H)。
步骤C.中间体430C.6-(2-(4-(甲氧基羰基)双环[2.2.2]辛-1-基)乙基)-4-(三氟甲基)喹啉-2-甲酸乙酯的制备
用N2吹扫并冲洗中间体430B(100mg,0.22mmol)于MeOH(7mL)中的溶液。向该混合物中添加钯/碳(23mg,0.022mmol)(10重量%负载,基质活性碳载体),且再次用N2吹扫并冲洗容器。在氢气(1个大气压,气球)下搅拌反应物。18h后,用1,4-二噁烷(2mL)稀释混合物,且添加DDQ(150mg,0.65mmol)。搅拌10min后,将反应物用EtOAc稀释。有机层用2N NaOH(水溶液)、盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过快速柱色谱(12g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=12mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈棕色油状物的标题化合物(30mg,0.065mmol,30%产率)。1H NMR(500MHz,氯仿-d)δ8.48-8.46(m,1H),8.37-8.29(m,1H),7.92(br s,1H),7.74(dd,J=8.8,1.4Hz,1H),4.61(d,J=7.2Hz,2H),3.68(s,3H),2.83-2.75(m,2H),1.94-1.89(m,2H),1.88-1.82(m,6H),1.58-1.52(m,9H)。MS(ESI)464.4(M+H)。
步骤D.中间体430D.6-(2-(4-碘双环[2.2.2]辛-1-基)乙基)-4-(三氟甲基)喹啉-2-甲酸甲酯的制备
根据针对中间体426G的合成(步骤F和G)所描述的方法,适当时代入中间体430C来制备标题化合物:(19mg,0.037mmol,53%产率)(含有杂质)。MS(ESI)518.2(M+H)。
步骤F.实施例430
根据针对实施例4的合成(步骤E)所描述的方法,通过使中间体430D与(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲醇反应来制备标题化合物:(2.4mg,0.0040mmol,29%产率)。1H NMR(500MHz,DMSO-d6)δ8.87-8.68(m,2H),8.40-8.07(m,2H),7.85-7.63(m,2H),4.33-4.09(m,2H),2.77-2.64(m,2H),2.34-2.21(m,1H),1.47-1.39(m,6H),1.37(brd,J=8.5Hz,2H),1.31(br d,J=7.0Hz,6H),1.18-1.12(m,2H),1.07(br d,J=2.7Hz,2H)。FXR EC50(nM)=24。MS(ESI)660.3(M+H)。
根据本文中其他处所描述的方法,使用适当起始物质、试剂和条件来制备(表7中的)以下实施例。
表7
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
实施例435
2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-5-(三氟甲基)苯并[d]噻唑-7-甲酰胺
在0℃向实施例434(20mg,0.031mmol)和DMF(1mL)的经搅拌溶液中添加BOP(17mg,0.038mmol)、氯化铵(17mg,0.31mmol)和Et3N(0.022mL,0.16mmol)。使反应物升温至rt并搅拌。12h后,浓缩溶剂,且经由制备型HPLC(柱:Waters XBridge C18,19×150mm,5μm颗粒;流动相A:10mM乙酸铵;流动相B:乙腈;梯度:10-40%B经20分钟,接着在100%B下保持5分钟;流速:15mL/min)纯化粗产物。将含有期望产物的级分合并、浓缩且在真空中干燥,得到标题化合物(4.2mg,6.6μmol,21%产率)。1H NMR(400MHz,DMSO-d6)δ8.85(s,2H),8.59(br.s.,1H),8.43(d,J=5.1Hz,2H),7.92(br.s.,1H),4.27(s,2H),2.37-2.32(m,1H),2.11-1.98(m,6H),1.63-1.46(m,6H),1.21-1.08(m,4H)。FXR EC50(nM)=460。MS(ESI)637(M+H)。
实施例436
(E)-3-(5-(4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-5-(三氟甲基)苯甲酸
步骤A.中间体436A.((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲基)膦酸二乙酯的制备
根据针对中间体194G的合成所描述的方法,适当时代入4-(溴甲基)-5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑来制备标题化合物:(800mg,2.0mmol,52%产率,白色固体)。1H NMR(400MHz,DMSO-d6)δ8.83(s,2H),3.88-3.83(m,4H),2.97(d,J=20.00Hz,2H),2.49(m,1H),1.16-1.12(m,2H),1.12-1.08(m,8H)。MS(ESI)405(M+H)。
步骤B.中间体436B.(E)-4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)双环[2.2.2]辛烷-1-甲酸甲酯的制备
根据针对中间体194H的合成所描述的方法,通过使中间体436A与中间体159B反应来制备标题化合物:(0.085g,0.19mmol,73%产率,白色固体)。1H NMR(400MHz,DMSO-d6)δ8.86(s,2H),5.99(d,J=16.8Hz,1H),5.24(d,J=16.8Hz,1H),3.54(s,3H),2.36-2.33(m,1H),1.68-1.64(m,6H),1.36-1.32(m,6H),1.26-1.14(m,4H)。MS(ESI)447(M+H)。
步骤C.中间体436C.(E)-4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)双环[2.2.2]辛烷-1-甲酸的制备
根据针对中间体159E的合成所描述的方法,适当时代入中间体436B来制备标题化合物:(0.06g,0.138mmol,88%产率,白色固体)。MS(ESI)433(M+H)。
步骤D.实施例436
根据针对实施例64的合成(步骤C)所描述的方法,通过使中间体436C与中间体264B反应来制备标题化合物:(10mg,0.016μmol,53%产率)。1H NMR(400MHz,DMSO-d6)δ8.89(s,2H),8.74(s,1H),8.32(d,J=8.1Hz,2H),6.08(d,J=16.6Hz,1H),5.32(d,J=16.6Hz,1H),2.45-2.37(m,1H),2.07-1.93(m,6H),1.59-1.42(m,6H),1.23-1.16(m,2H),1.15-1.06(m,2H)。FXR EC50(nM)=18。MS(ESI)645(M+H)。
实施例443
(E)-3-(5-(4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-5-(二氟甲氧基)苯甲酸甲酯
步骤A.中间体443A.3-溴-5-(二氟甲氧基)苯甲酸甲酯的制备
向3-溴-5-羟基苯甲酸甲酯(900mg,3.9mmol)(Park,K.等人WO 2014/112798)于DMF(18mL)中的经搅拌溶液中添加碳酸钾(540mg,3.9mmol),接着添加氯二氟乙酸甲酯(560mg,3.9mmol)。在80℃搅拌混合物。18h后,使反应物冷却,浓缩,用水稀释且用乙酸乙酯(2×30mL)萃取。合并有机层,用盐水洗涤,经MgSO4干燥且浓缩。通过快速柱色谱(40g硅胶滤筒;A=PE,B=EtOAc;20min梯度;0%B至50%B;流速=40mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈粘稠油状物的标题化合物(350mg,1.2mmol,30%产率)。MS(ESI)281(M+H)。
步骤B.中间体443B.3-氰基-5-(二氟甲氧基)苯甲酸甲酯的制备
向中间体443A(350mg,1.3mmol)于DMF(5mL)中的溶液中添加氰化铜(I)(170mg,1.9mmol)。在150℃搅拌混合物。12h后,将反应物冷却至rt,用EtOAc稀释且经由硅藻土过滤。滤液用盐水洗涤,经MgSO4干燥,过滤且浓缩。通过快速柱色谱(40g硅胶滤筒;A=PE,B=EtOAc;20min梯度;0%B至50%B;流速=40mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到标题化合物(140mg,0.62mmol,50%产率)。1H NMR(400MHz,DMSO-d6)δ8.22(t,J=1.5Hz,1H),8.09(dd,J=2.5,1.5Hz,1H),7.99-7.97(m,1H),7.64-7.26(m,1H),3.90(s,3H)。
步骤C.中间体443C.(Z)-3-(二氟甲氧基)-5-(N'-羟基甲脒基)苯甲酸甲酯的制备
根据针对中间体4C的合成所描述的方法,使用中间体443B作为起始物质来制备标题化合物:(60mg,0.21mmol,41%产率,白色固体)。MS(ESI)261(M+H)。
步骤D.实施例443
根据针对实施例64的合成(步骤C)所描述的方法,通过使中间体436C与中间体443C反应来制备标题化合物:(20mg,0.031mmol,41%产率)。1H NMR(400MHz,DMSO-d6)δ8.90(s,2H),8.37(t,J=1.3Hz,1H),7.92(s,1H),7.86(s,1H),7.45(t,J=73.2Hz,1H),6.08(d,J=16.4Hz,1H),5.31(d,J=16.6Hz,1H),2.47-2.37(m,1H),2.08-1.87(m,6H),1.61-1.41(m,6H),1.23-1.15(m,2H),1.15-1.03(m,2H)。FXR EC50(nM)=49。MS(ESI)643(M+H)。
实施例444
(E)-3-((4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)甲氧基)-5-(二氟甲氧基)苯甲酸
步骤A.中间体444A.(E)-(4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)甲醇的制备
在Ar下将中间体436B(65mg,0.15mmol)于DCM(8mL)中的溶液冷却至-78℃。向该混合物中逐滴添加DIBAL-H(0.36mL,0.36mmol)(于庚烷中的1M溶液)。在相同温度搅拌0.5h后,用饱和NH4Cl(水溶液)(20mL)淬灭反应混合物,且用DCM(2×20mL)萃取水层。合并的有机层用盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过快速柱色谱(12g硅胶滤筒;A=PE,B=EtOAc;15min梯度;0%B至50%B;流速=12mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到标题化合物(42mg,0.098mmol,68%产率)。1H NMR(400MHz,氯仿-d)δ8.6(s,2H),5.83(d,J=16.8Hz,1H),5.38(d,J=16.8Hz,1H),4.12(d,J=7.2Hz,2H),3.25(m,1H),2.36-2.33(m,1H),1.68-1.64(m,6H),1.36-1.32(m,6H),1.26-1.14(m,4H)。MS(ESI)419(M+H)。
步骤B.中间体444B.(E)-3-((4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)甲氧基)-5-(二氟甲氧基)苯甲酸甲酯的制备
向中间体444A于甲苯(1mL)中的经搅拌溶液中添加3-(二氟甲氧基)-5-羟基苯甲酸甲酯(13mg,0.057mmol)和氰基亚甲基三丁基磷烷(23mg,0.095mmol)。将反应混合物加热至100℃并搅拌。2h后,使反应混合物冷却,将其倒入冰水中,且用EtOAc(2×50mL)萃取水层。合并的有机层经MgSO4干燥,过滤且浓缩。通过快速柱色谱(12g硅胶滤筒;A=PE,B=EtOAc;15min梯度;0%B至50%B;流速=12mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到标题化合物(27mg,0.031mmol,64%产率)。MS(ESI)619(M+H)。
步骤C.实施例444
根据针对实施例151的合成(步骤C)所描述的方法,适当时代入中间体444B来制备标题化合物:(14mg,0.023mmol,72%产率)。1H NMR(400MHz,DMSO-d6)δ8.88(s,2H),7.39-7.24(m,2H),7.22(s,1H),6.89(s,1H),6.01(d,J=16.6Hz,1H),5.28(d,J=16.4Hz,1H),3.64(s,2H),2.41-2.34(m,1H),1.59-1.45(m,6H),1.42-1.32(m,6H),1.22-1.04(m,4H)。FXR EC50(nM)=16。MS(ESI)605(M+H)。
实施例446
(E)-5-(5-(4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-2-(二氟甲氧基)苯甲酸
步骤A.中间体446A.5-溴-2-(二氟甲氧基)苯甲酸甲酯的制备
根据针对中间体443A的合成所描述的方法,适当时代入5-溴-2-羟基苯甲酸甲酯来制备标题化合物:(1.0g,3.6mmol,55%产率)。1H NMR(400MHz,氯仿-d)δ8.02(d,J=2.5Hz,1H),7.66-7.61(m,1H),7.15(d,J=8.5Hz,1H),6.74-6.36(m,1H),3.93(s,3H)。
步骤B.中间体446B.5-氰基-2-(二氟甲氧基)苯甲酸甲酯的制备
根据针对中间体443B的合成所描述的方法,适当时代入中间体446A来制备标题化合物:(350mg,1.5mmol,67%产率)。1H NMR(400MHz,DMSO-d6)δ8.30(d,J=2.0Hz,1H),8.17(dd,J=8.5,2.0Hz,1H),7.54(d,J=8.5Hz,1H),7.4(t,J=73Hz,1H),3.87(s,3H)。MS(ESI)228(M+H)。
步骤C.中间体446C.(Z)-2-(二氟甲氧基)-5-(N'-羟基甲脒基)苯甲酸甲酯的制备
根据针对中间体4C的合成所描述的方法,适当时代入中间体446B来制备标题化合物:(120mg,0.44mmol,40%产率)。1H NMR(400MHz,DMSO-d6)δ9.78(d,J=1.0Hz,1H),8.16-8.15(m,1H),7.94-7.90(m,1H),7.40-7.02(m,2H),5.94(s,2H),3.85(s,3H)。MS(ESI)261(M+H)。
步骤D.实施例446
根据针对实施例64的合成(步骤C)所描述的方法,通过使中间体436C与中间体446C反应来制备标题化合物:(15mg,0.023mmol,30%产率)。1H NMR(400MHz,DMSO-d6)δ13.52(s,1H),8.89(s,2H),8.39(d,J=2.2Hz,1H),8.19(dd,J=8.7,2.3Hz,1H),7.49-7.46(m,1H),7.31(t,J=73.6Hz,1H),6.07(d,J=16.6Hz,1H),5.32(d,J=16.4Hz,1H),2.46-2.37(m,1H),2.07-1.86(m,6H),1.62-1.42(m,6H),1.22-1.05(m,4H)。FXR EC50(nM)=350。MS(ESI)643(M+H)。
实施例452
(E)-6-((4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)甲氧基)-4-(三氟甲基)喹啉-2-甲酸
步骤A.中间体452A.6-(5,5-二甲基-1,3,2-二氧硼己烷-2-基)-4-(三氟甲基)喹啉-2-甲酸乙酯的制备
向6-氯-4-(三氟甲基)喹啉-2-甲酸乙酯(350mg,1.2mmol)于1,4-二噁烷(14mL)中的经搅拌溶液中添加乙酸钾(510mg,5.2mmol)和5,5,5',5'-四甲基-2,2'-二(1,3,2-二氧硼己烷)(520mg,2.3mmol)。用Ar吹扫反应混合物持续5min。向该混合物中添加Pd(dppf)Cl2(42mg,0.058mmol),且在110℃搅拌反应物。4h后,浓缩反应混合物,用水稀释且用乙酸乙酯(2×20mL)萃取。合并的有机层经硫酸钠干燥,过滤且浓缩。通过快速柱色谱(80g硅胶滤筒;A=PE,B=EtOAc;20min梯度;0%B至70%B;流速=60mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到标题化合物(230mg,0.57mmol,50%产率,黄色粘稠油状物)。MS(ESI)382(M+H)。
步骤B.中间体452B.6-羟基-4-(三氟甲基)喹啉-2-甲酸乙酯的制备
向中间体452A(230mg,0.60mmol)于H2O(2mL)和THF(2mL)中的经搅拌溶液中添加四水合过硼酸钠(370mg,2.4mmol)。在45℃搅拌反应物。30min后,浓缩反应混合物,用(20mL)水稀释且用乙酸乙酯(2×20mL)萃取。合并的有机层经硫酸钠干燥,过滤且浓缩。通过快速柱色谱(24g硅胶滤筒;A=PE,B=EtOAc;15min梯度;0%B至60%B;流速=24mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈黄色固体状的标题化合物(130mg,0.43mmol,72%产率)。1H NMR(400MHz,DMSO-d6)δ8.24(s,1H),8.22(d,J=9.5Hz,1H),7.57(dd,J=9.5,2.5Hz,1H),7.36(br s,1H),4.44(q,J=7.0Hz,2H),1.45(t,J=7.0Hz,3H)。MS(ESI)286(M+H)。
步骤C.实施例452
根据针对实施例444的合成(步骤B和C)所描述的方法,适当时代入中间体452B来制备标题化合物:(4.0mg,6.0μmol,16%产率)。1H NMR(400MHz,DMSO-d6)δ8.89(s,2H),8.31(s,1H),8.21(d,J=9.3Hz,1H),7.64(dd,J=9.4,2.6Hz,1H),7.27(br.s.,1H),6.02(d,J=16.4Hz,1H),5.29(d,J=16.4Hz,1H),3.80(s,2H),2.42-2.34(m,1H),1.63-1.50(m,6H),1.47-1.32(m,6H),1.19(dt,J=8.3,3.1Hz,2H),1.14-1.03(m,2H)。FXR EC50(nM)=14。MS(ESI)658(M+H)。
实施例456
2-(4-(2-(5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)乙基)双环[2.2.2]辛-1-基)苯并[d]噻唑-7-甲酸
步骤A.中间体456A.4-(2-(5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)乙基)双环[2.2.2]辛烷-1-甲酸甲酯的制备
用氮气使中间体182B(140mg,0.30mmol)于乙醇(2mL)中的经搅拌溶液脱气。向该混合物中添加钯/碳(52mg,0.049mmol)(10重量%负载,基质活性碳载体)。在H2(1个大气压,气球)下搅拌反应物。2h后,用甲醇(10mL)稀释混合物并过滤。浓缩滤液且在真空中干燥,得到标题化合物(140mg,0.29mmol,96%产率)。MS(ESI)464(M+H)。
步骤B.中间体456B.4-(2-(5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)乙基)双环[2.2.2]辛烷-1-甲酸的制备
根据针对中间体159E的合成所描述的方法,适当时代入中间体456A来制备标题化合物:(110mg,0.25mmol,76%产率)。1H NMR(400MHz,DMSO-d6)δ12.00(br.s,1H),7.66-7.70(m,1H),7.54-7.58(m,3H),2.20-2.30(m,2H),2.10-2.20(m,1H),1.70-1.81(m,6H),1.17-1.25(m,6H),1.06-1.10(m,4H),0.97-1.04(m,2H)。MS(ESI)450(M+H)。
步骤C.实施例456
根据针对实施例182的合成(步骤D、E和F)所描述的方法,适当时代入中间体456B来制备标题化合物:(8.5mg,0.015mmol,9%产率)。1H NMR(400MHz,DMSO-d6)d 13.61(s,1H),8.16(d,J=7.8Hz,1H),8.02(d,J=7.3Hz,1H),7.75-7.64(m,1H),7.63-7.48(m,4H),2.35-2.27(m,2H),2.21-2.12(m,1H),2.01-1.82(m,6H),1.48-1.31(m,6H),1.19-1.06(m,4H),1.04-0.94(m,2H)。FXR EC50(nM)=22。MS(ESI)583(M+H)。
实施例464
3-((4-(((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛-1-基)甲氧基)-5-(三氟甲基)苯甲酸
步骤A.中间体464A.4-(((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛烷-1-甲酸甲酯的制备
根据针对中间体162A的合成所描述的方法,适当时代入4-(溴甲基)-5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑来制备呈白色固体状的标题化合物:(400mg,0.84mmol,56%产率)。1H NMR(400MHz,DMSO-d6)δ8.83(s,2H),4.28(s,2H),3.55(s,3H),2.90(s,2H),2.32(s,1H),1.70-1.64(m,4H),1.59-1.52(m,4H),1.37-1.31(m,4H),1.12-1.05(m,4H)。MS(ESI)465(M+H)。
步骤B.中间体464B.(4-(((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛-1-基)甲醇的制备
根据针对中间体444A的合成所描述的方法,适当时代入中间体464A来制备标题化合物:(100mg,0.21mmol,52%产率)。1H NMR(400MHz,DMSO-d6)δ8.82(s,2H),4.28(s,2H),4.24-4.21(m,1H),2.96(d,J=5.5Hz,2H),2.87(s,2H),1.54-1.51(m,1H),1.37-1.35(m,2H),1.17-1.2(m,10H),1.06-1.01(m,4H)。MS(ESI)437(M+H)。
步骤C.实施例464
根据针对实施例444的合成(步骤B和C)所描述的方法,通过使中间体464B与3-羟基-5-(三氟甲基)苯甲酸甲酯反应来制备标题化合物:(3.9mg,6.2μmol,13%产率)。1H NMR(400MHz,DMSO-d6)δ8.84(s,2H),7.72(s,1H),7.64(s,1H),7.34(s,1H),4.30(s,2H),3.68(s,2H),2.96(s,2H),2.35-2.28(m,1H),1.48-1.27(m,6H),1.26-0.98(m,10H)。FXR EC50(nM)=300。MS(ESI)625(M+H)。
实施例467
(E)-3-(5-(4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)-2-氧杂双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸
步骤A.中间体467A.3-(5-(4-甲酰基-2-氧杂双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸甲酯的制备
向中间体210D(110mg,0.32mmol)于DCM(3mL)中的经搅拌溶液中添加DMP(200mg,0.48mmol)。搅拌30min后,将反应混合物用DCM(15mL)稀释,且用10%NaHCO3(水溶液)(2×20mL)、盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过快速柱色谱(12g硅胶滤筒;A=PE,B=EtOAc;15min梯度;0%B至50%B;流速=12mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈无色固体状的标题化合物(90mg,0.26mmol,82%产率)。MS(ESI)343(M+H)。
步骤B.中间体467B.(E)-3-(5-(4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)-2-氧杂双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸甲酯的制备
根据针对中间体194H的合成所描述的方法,通过使中间体436A与中间体467A反应来制备标题化合物:(25mg,0.042mmol,48%产率,棕色固体)。1H NMR(400MHz,DMSO-d6)δ9.51(s,1H),8.53(t,J=1.5Hz,1H),8.28-8.26(m,1H),8.18-8.16(m,1H),7.76-7.73(m,1H),4.02(s,2H),3.91(s,3H),2.38-2.32(m,2H),2.25-2.18(m,2H),2.00-1.93(m,4H)。MS(ESI)593(M+H)。
步骤C.实施例467
根据针对实施例151的合成(步骤C)所描述的方法,适当时代入中间体467B来制备标题化合物:(5.0mg,8.6μmol,20%产率)。1H NMR(400MHz,DMSO-d6)δ8.90(s,2H),8.52(s,1H),8.10(d,J=7.6Hz,2H),7.61(t,J=7.7Hz,1H),6.18(d,J=16.6Hz,1H),5.29(d,J=16.6Hz,1H),3.71(s,2H),2.48-2.41(m,1H),2.32-2.24(m,2H),2.20-2.04(m,2H),1.82-1.59(m,4H),1.29-1.10(m,4H)。FXR EC50(nM)=260。MS(ESI)579(M+H)。
实施例468
(E)-3-((4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)-2-氧杂双环[2.2.2]辛-1-基)甲氧基)-5-(三氟甲基)苯甲酸
步骤A.中间体468A.4-甲基苯磺酸(1-(羟基甲基)-2-氧杂双环[2.2.2]辛-4-基)甲酯的制备
在0℃向中间体193D(6.0g,18mmol)于THF(15mL)中的经搅拌溶液中添加甲硼烷二甲基硫醚络合物(5.0mL,53mmol)。使反应混合物缓慢升温至rt且搅拌。2h后,使反应物冷却至0℃,用MeOH淬灭且在rt搅拌。2h后,浓缩溶剂。通过快速柱色谱(12g硅胶滤筒;A=PE,B=EtOAc;15min梯度;0%B至100%B;流速=12mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈白色固体状的标题化合物(3.7g,11mmol,60%产率)。1H NMR(400MHz,DMSO-d6)δ7.79(d,J=8.0Hz,2H),7.50(d,J=8.0Hz,2H),4.49(t,J=6.0Hz,1H),3.74(s,2H),3.48(s,2H),3.13(d,J=6.00Hz,2H),2.44(s,3H),1.40-1.63(m,8H)。MS(ESI)344(M+NH3)。
步骤B.中间体468B.3-((4-((甲苯磺酰基氧基)甲基)-2-氧杂双环[2.2.2]辛-1-基)甲氧基)-5-(三氟甲基)苯甲酸甲酯的制备
向中间体468A(200mg,0.61mmol)于THF(6mL)中的经搅拌溶液中添加3-羟基-5-(三氟甲基)苯甲酸甲酯(160mg,0.74mmol)、三苯膦(400mg,1.5mmol),接着添加偶氮二甲酸二异丙酯(0.30mL,1.5mmol)。在回流下搅拌1.5h后,使反应物冷却且用乙酸乙酯(20mL)稀释。有机相用水(20mL)、盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过快速柱色谱(40g硅胶滤筒;A=PE,B=EtOAc;15min梯度;0%B至70%B;流速=40mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈粉红色半固体状的标题化合物(400mg,0.55mmol,90%产率)。MS(ESI)546(M+NH3)。
步骤C.中间体468C.3-((4-(羟基甲基)-2-氧杂双环[2.2.2]辛-1-基)甲氧基)-5-(三氟甲基)苯甲酸甲酯的制备
/>
根据针对中间体194E的合成(步骤D和E)所描述的方法,适当时代入中间体468B来制备标题化合物:(70mg,0.19mmol,97%产率,白色固体)。1H NMR(400MHz,DMSO-d6)δ7.76(s,1H),7.72(s,1H),7.58(s,1H),4.49(s,1H),3.95(s,2H),3.90(s,3H),3.63(s,2H),3.12(d,J=4.80Hz,2H),1.86-1.89(m,2H),1.58-1.69(m,6H)。MS(ESI)392(M+NH3)。
步骤D.中间体468D.3-((4-甲酰基-2-氧杂双环[2.2.2]辛-1-基)甲氧基)-5-(三氟甲基)苯甲酸甲酯的制备
根据针对中间体194F的合成所描述的方法,适当时代入中间体468C来制备标题化合物:(60mg,0.16mmol,80%产率,棕色固体)。1H NMR(400MHz,DMSO-d6)δ9.47(s,1H),7.76(s,1H),7.73(s,1H),7.59(s,1H),4.00(s,2H),3.90(s,3H),3.84(s,2H),1.80-1.99(m,8H)。
步骤E.实施例468
根据针对实施例194的合成(步骤H和I)所描述的方法,通过使中间体468D与中间体436A反应来制备标题化合物:1H NMR(400MHz,甲醇-d4)δ8.75(s,2H),7.84(s,1H),7.75(s,1H),7.27(s,1H),6.10(d,J=16.6Hz,1H),5.33(d,J=16.6Hz,1H),3.89(s,2H),3.65(s,2H),2.34-2.26(m,1H),2.10-2.00(m,2H),1.84-1.75(m,2H),1.70(d,J=9.0Hz,4H),1.25-1.21(m,2H),1.20-1.14(m,2H)。FXR EC50(nM)=70。MS(ESI)609(M+H)。
实施例471
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)-2-氧杂双环[2.2.2]辛-1-基)甲氧基)-4-(二氟甲氧基)喹啉-2-甲酸
步骤A.中间体471A.4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)-2-氧杂双环[2.2.2]辛烷-1-甲酸的制备
根据针对中间体219C的合成所描述的方法,适当时代入4-(溴甲基)-5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑来制备呈无色固体状的标题化合物:(100mg,0.18mmol,56%产率)。MS(ESI)439(M+H)。
步骤B.中间体471B.(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)-2-氧杂双环[2.2.2]辛-1-基)甲醇的制备
根据针对中间体468A的合成所描述的方法,适当时代入中间体471A来制备标题化合物:(50mg,0.099mmol,44%产率,无色油状物)。MS(ESI)425(M+H)。
步骤C.实施例471
根据针对实施例444的合成(步骤B和C)所描述的方法,通过使中间体471B与中间体284B反应来制备标题化合物:(1.6mg,2.4μmol,4%产率)。1H NMR(400MHz,DMSO-d6)δ8.86(s,2H),8.08(d,J=9.60Hz,1H),7.77-7.97(m,2H),7.57(d,J=11.60Hz,1H),7.35(s,1H),4.31(s,2H),3.95(s,2H),2.34-2.35(m,1H),1.91-1.94(m,2H),1.69-1.77(m,4H),1.42-1.46(m,2H),1.09-1.18(m,4H)。FXR EC50(nM)=200。MS(ESI)662(M+H)。
实施例472
(E)-6-((1-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)-2-氧杂双环[2.2.2]辛-4-基)甲氧基)-4-(二氟甲氧基)喹啉-2-甲酸
步骤A.中间体472A.4-甲基苯磺酸(1-甲酰基-2-氧杂双环[2.2.2]辛-4-基)甲酯的制备
在-78℃向草酰氯(0.67mL,7.7mmol)于DCM(10mL)中的经搅拌溶液中添加含DMSO(0.54mL,7.7mmol)的DCM(5mL)。在该温度搅拌15min后,添加含中间体468A(1.0g,3.1mmol)的DCM(10mL),且在-78℃搅拌反应物。在该温度搅拌3h后,添加TEA(3.0mL,22mmol),且使反应物升温至rt并搅拌。2h后,将混合物用DCM(35mL)稀释,且用10%NaHCO3溶液(水溶液)(2×35mL)、盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过快速柱色谱(80g硅胶滤筒;A=PE,B=EtOAc;15min梯度;0%B至70%B;流速=60mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈白色固体状的标题化合物(800mg,2.5mmol,80%产率)。1H NMR(400MHz,DMSO-d6)δ9.48(s,1H),7.79(d,J=6.80Hz,2H),7.50(d,J=8.40Hz,2H),3.78(s,2H),3.62(s,2H),2.44(s,3H),1.67-1.79(m,4H),1.51-1.57(m,4H)。
步骤B.中间体472B.4-甲基苯磺酸(E)-(1-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)-2-氧杂双环[2.2.2]辛-4-基)甲酯的制备
根据针对中间体194H的合成所描述的方法,通过使中间体436A与中间体472A反应来制备呈棕色半固体状的标题化合物:(600mg,1.0mmol,48%产率)。1H NMR(400MHz,DMSO-d6)δ8.87(s,2H),7.85-7.70(m,J=8.3Hz,2H),7.55-7.38(m,J=8.1Hz,2H),6.18(d,J=16.4Hz,1H),5.32(d,J=16.4Hz,1H),3.72(s,2H),3.51(s,2H),2.43(s,3H),2.39-2.26(m,1H),1.65-1.35(m,8H),1.24-1.15(m,2H),1.14-1.01(m,2H)。MS(ESI)575(M+H)。
步骤C.中间体472C.(E)-(1-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)-2-氧杂双环[2.2.2]辛-4-基)甲醇的制备
根据针对中间体194E的合成(步骤D和E)所描述的方法,适当时代入中间体472D来制备标题化合物:(330mg,0.78mmol,72%产率,白色固体)。MS(ESI)421(M+H)。
步骤D.实施例472
根据针对实施例444的合成(步骤B和C)所描述的方法,通过使中间体472C与中间体284B反应来制备标题化合物:1H NMR(400MHz,DMSO-d6)δ8.90(s,2H),8.00(d,J=9.3Hz,1H),7.85-7.45(m,2H),77.43(dd,J=9.5,2.9Hz,1H),7.27(d,J=2.9Hz,1H),6.25(d,J=16.4Hz,1H),5.40(d,J=16.4Hz,1H),3.82(s,2H),3.79(s,2H),2.41-2.37(m,1H),1.76(d,J=5.4Hz,2H),1.67(br s,6H),1.33-1.17(m,2H),1.14-1.10(m,2H)。FXR EC50(nM)=290。MS(ESI)658(M+H)。
实施例478
(E)-3-(5-(4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)-2-氧杂双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-5-(三氟甲基)苯甲酸
/>
步骤A.中间体478A.乙酸(1-(羟基甲基)-2-氧杂双环[2.2.2]辛-4-基)甲酯的制备
根据针对中间体194D的合成所描述的方法,适当时代入中间体468A来制备标题化合物:(1.3g,6.1mmol,99%产率,棕色半固体)。1H NMR(400MHz,DMSO-d6)δ4.48(t,J=6.0Hz,1H),3.73(s,2H),3.58(s,2H),3.15(d,J=6.0Hz,2H),2.01(s,3H),1.66-1.46(m,8H)。
步骤B.中间体478B.乙酸(1-((甲苯磺酰基氧基)甲基)-2-氧杂双环[2.2.2]辛-4-基)甲酯的制备
在0℃向中间体478A(1.3g,6.1mmol)于吡啶(15mL)中的经搅拌溶液中添加对甲苯磺酰氯(1.4g,7.3mmol)。使反应物升温至rt并搅拌。18h后,将反应混合物用水(100mL)稀释且用乙酸乙酯(2×50mL)萃取。合并有机层,用1.5N HCl(水溶液)(3×50mL)、盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过快速柱色谱(80g硅胶滤筒;A=PE,B=EtOAc;15min梯度;0%B至70%B;流速=60mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈棕色固体状的标题化合物(1.5g,3.5mmol,58%产率)。1H NMR(400MHz,DMSO-d6)δ7.76(d,J=8.5Hz,2H),7.47(d,J=8.0Hz,2H),3.78(s,2H),3.71(s,2H),3.54(s,2H),2.42(s,3H),1.99(s,3H),1.68-1.43(m,8H)。MS(ESI)369(M+H)。
步骤C.中间体478C.4-甲基苯磺酸(4-(羟基甲基)-2-氧杂双环[2.2.2]辛-1-基)甲酯的制备
根据针对中间体194E的合成所描述的方法,适当时代入中间体478B来制备标题化合物:(1.2g,3.6mmol,67%产率,白色固体)。1H NMR(400MHz,DMSO-d6)δ7.80-7.75(m,2H),7.49(d,J=8.0Hz,2H),4.47(t,J=5.3Hz,1H),3.77(s,2H),3.53(s,2H),3.07(d,J=5.0Hz,2H),2.43(s,3H),1.68-1.59(m,2H),1.52-1.34(m,6H)。MS(ESI)327(M+H)。
步骤D.中间体478D.4-甲基苯磺酸(4-甲酰基-2-氧杂双环[2.2.2]辛-1-基)甲酯的制备
根据针对中间体472A的合成所描述的方法,适当时代入中间体478C来制备标题化合物:(60mg,0.19mmol,86%产率,白色固体)。1H NMR(400MHz,DMSO-d6)δ9.41(s,1H),7.80-7.77(m,2H),7.49(d,J=8.0Hz,2H),3.82(s,2H),3.74(s,2H),2.43(s,3H),1.78-1.70(m,5H),1.59-1.51(m,3H)。MS(ESI)325(M+H)。
步骤E.中间体478E.4-甲基苯磺酸(E)-(4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)-2-氧杂双环[2.2.2]辛-1-基)甲酯的制备
根据针对中间体194H的合成所描述的方法,通过使中间体478D与中间体436A反应来制备标题化合物:(70mg,0.12mmol,56%产率)。MS(ESI)575(M+H)。
步骤F.中间体478F.(E)-(4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)-2-氧杂双环[2.2.2]辛-1-基)甲醇的制备
根据针对中间体194E的合成(步骤D和E)所描述的方法,适当时代入中间体478E来制备标题化合物:(340mg,0.80mmol,67%产率)。1H NMR(400MHz,DMSO-d6)δ8.87(s,2H),6.05(d,J=16.6Hz,1H),5.17(d,J=16.6Hz,1H),4.46(t,J=6.0Hz,1H),3.44(s,2H),3.12(d,J=6.0Hz,2H),2.33-2.31(m,1H),1.63-1.58(m,2H),1.53-1.43(m,6H),1.19-1.14(m,2H),1.11-1.06(m,2H)。MS(ESI)421(M+H)。
步骤G.中间体478G.(E)-4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)-2-氧杂双环[2.2.2]辛烷-1-甲酸的制备
在0℃向中间体478F(150mg,0.36mmol)于DMF(3mL)中的经搅拌溶液中添加PDC(400mg,1.1mmol)。使反应物升温至40℃并搅拌。3h后,将混合物用水(50mL)稀释且用乙酸乙酯(5×30mL)萃取。将有机层合并,经Na2SO4干燥,过滤且浓缩。通过快速柱色谱(24g硅胶滤筒;A=PE,B=EtOAc;15min梯度;0%B至100%B;流速=24mL/min)纯化粗产物。将纯级分合并、浓缩且在真空中干燥,得到呈棕色固体状的标题化合物(60mg,0.087mmol,24%产率)。1H NMR(400MHz,DMSO-d6)δ12.42(bs,1H),8.88(s,2H),6.08(d,J=16.6Hz,1H),5.18(d,J=16.6Hz,1H),3.52(s,2H),2.43-2.38(m,1H),1.93-1.79(m,2H),1.56-1.52(m,6H),1.22-1.08(m,4H)。MS(ESI)435(M+H)。
步骤H.实施例478
根据针对实施例64的合成(步骤C)所描述的方法,通过使中间体478G与中间体235A反应来制备标题化合物:(5.2mg,7.9μmol,21%产率)。1H NMR(400MHz,DMSO-d6)δ8.90(s,2H),8.75(s,1H),8.44(s,1H),8.37(s,1H),6.19(d,J=16.6Hz,1H),5.28(d,J=16.6Hz,1H),3.72(s,2H),2.48-2.43(m,1H),2.29(br s,2H),2.18(d,J=11.5Hz,2H),1.80-1.64(m,4H),1.30-1.18(m,2H),1.16-1.10(m,2H)。FXR EC50(nM)=120。MS(ESI)647(M+H)。
根据本文中其他处所描述的方法,使用适当起始物质、试剂和条件来制备表8中的以下实施例。
表8
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
实施例515
6-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙基)喹啉-2-甲酸
步骤A.中间体515A.5-环丙基-3-(3,5-二氯吡啶-4-基)-4-(((4-乙烯基双环[2.2.2]辛-1-基)氧基)甲基)异噁唑的制备
向溴化甲基三苯基鏻(2.4g,6.7mmol)于甲苯(56mL)中的0℃悬浮液中添加KHMDS溶液(0.5N于THF中)(13mL,6.7mmol)。搅拌15min后,添加中间体519D(1.2g,2.8mmol)于甲苯(6mL)中的溶液。在0℃搅拌反应混合物1h。反应物用饱和NH4Cl水溶液淬灭且用EtOAc萃取。有机层用盐水洗涤,经无水硫酸钠干燥,过滤且浓缩。通过快速柱色谱(80g硅胶滤筒;A=己烷,B=EtOAc;30min梯度;0%B至100%B;流速=60mL/min)纯化粗产物,得到呈无色油状物的标题化合物(0.84g,2.0mmol,72%产率)。1H NMR(400MHz,氯仿-d)δ8.77-8.29(m,2H),5.66(dd,J=17.4,11.0Hz,1H),4.85-4.75(m,2H),4.20(s,2H),2.12-2.06(m,1H),1.55-1.50(m,6H),1.45-1.41(m,6H),1.24(dd,J=5.0,2.3Hz,2H),1.11(dd,J=8.3,2.8Hz,2H)。MS(ESI)419(M+H)。
步骤B.实施例515
向中间体515A(66mg,0.16mmol)于THF(530μL)中的0℃溶液中添加9-BBN溶液(0.5N于THF中)(76μL,0.38mmol)。添加后,搅拌反应混合物1.5h,且随后使其冷却至0℃。添加水(0.2mL)。在rt搅拌1h后,将一半反应混合物添加至6-溴喹啉-2-甲酸甲酯(HCl盐)(24mg,0.079mmol)、磷酸三钾(117mg,0.55mmol)、氯化锂(20mg,0.47mmol)和Pd(Ph3P)4(20mg,0.017mmol)于EtOH(1.0mL)中的溶液中。用N2吹扫反应混合物,且加热至80℃后保持过夜。反应物用饱和NH4Cl水溶液淬灭且用EtOAc萃取。有机层用水和盐水洗涤,经无水硫酸钠干燥且真空浓缩。通过制备型HPLC(柱:XBridge C18,19×200mm,5μm颗粒;流动相A:5:95的乙腈:水+0.1%三氟乙酸;流动相B:95:5的乙腈:水+0.1%三氟乙酸;梯度:57-82%B经20分钟,接着在100%B下保持2分钟;流速:20mL/min)纯化粗产物。将含有期望产物的级分合并、浓缩且在真空中干燥,得到标题化合物(3.2mg,0.005mmol,6.5%产率)。1H NMR(500MHz,DMSO-d6)δ8.86-8.70(m,2H),8.36(br d,J=8.4Hz,1H),8.03(br d,J=8.5Hz,2H),7.76(s,1H),7.64(br d,J=8.8Hz,1H),4.21(s,2H),2.74-2.61(m,2H),2.35-2.19(m,1H),1.53-1.41(m,8H),1.39-1.30(m,6H),1.15(br d,J=8.2Hz,2H),1.08(br d,J=3.3Hz,2H)。FXR EC50(nM)=87。MS(ESI)592(M+H)。
实施例516
(E)-2-(4-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)苯基)乙酸
向用N2吹扫的中间体515A(43mg,0.10mmol)、2-(4-溴苯基)乙酸乙酯(62mg,0.26mmol)和K2CO3(85mg,0.62mmol)于DMF(2.0mL)中的溶液中添加PdCl2(dppf)(6.6mg,9.2μmol)。在110℃搅拌反应混合物过夜。反应混合物用EtOAc稀释。有机层用水和盐水洗涤,经无水硫酸钠干燥且真空浓缩,得到深棕色油状物。向深棕色油状物中添加THF(1.0mL)、MeOH(0.5mL)和2N NaOH(0.5mL,1.0mmol)。搅拌反应混合物1h。浓缩反应混合物,将其再溶解于DMF中,用乙酸(0.05mL)酸化并过滤。通过制备型HPLC(柱:XBridge C18,19×200mm,5μm颗粒;流动相A:5:95的乙腈:水+0.1%三氟乙酸;流动相B:95:5的乙腈:水+0.1%三氟乙酸;梯度:57-82%B经20分钟,接着在100%B下保持2分钟;流速:20mL/min)纯化粗产物。将含有期望产物的级分合并、浓缩且在真空中干燥,得到标题化合物(4.1mg,0.007mmol,6.8%产率)。1H NMR(500MHz,DMSO-d6)δ8.94-8.45(m,2H),7.26(br d,J=7.9Hz,2H),7.20-7.08(m,2H),6.17(d,J=17.0Hz,1H),6.09(d,J=17.0Hz,1H),4.28-4.14(m,2H),3.64-3.42(m,2H),2.32-2.18(m,1H),1.65-1.46(m,6H),1.43-1.33(m,6H),1.19-1.11(m,2H),1.09-1.00(m,2H)。FXR EC50(nM)=173。MS(ESI)553(M+H)。
实施例517
(E)-7-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)-1-甲氧基异喹啉-3-甲酸
步骤A.中间体517A.(E)-1-氯-7-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)异喹啉-3-甲酸甲酯的制备
向用N2吹扫的中间体515A(170mg,0.40mmol)、7-溴-1-氯异喹啉-3-甲酸甲酯(130mg,0.42mmol)和K2CO3(220mg,1.6mmol)于DMF(4.0mL)中的溶液中添加PdCl2(dppf)(18mg,0.024mmol)。在100℃搅拌反应混合物过夜。反应混合物用EtOAc稀释。有机层用水和盐水洗涤,经无水硫酸钠干燥并浓缩。通过快速柱色谱(24g硅胶滤筒;A=己烷,B=EtOAc;15min梯度;0%B至100%B;流速=35mL/min)纯化粗产物,得到标题化合物(120mg,0.188mmol,46.9%产率)。1H NMR(400MHz,氯仿-d)δ8.69-8.57(m,2H),8.46(d,J=0.7Hz,1H),8.17(s,1H),7.96-7.75(m,2H),6.42(d,J=16.2Hz,1H),6.34(d,J=16.2Hz,1H),4.24(s,2H),4.03(s,3H),2.11-2.09(m,1H),1.73-1.68(m,6H),1.54-1.49(m,6H),1.27-1.24(m,2H),1.15-1.10(m,2H)。MS(ESI)638(M+H)。
步骤B.实施例517
向中间体517A(17mg,0.027mmol)于MeOH(0.30mL)和THF(0.30mL)中的溶液中添加25%甲醇钠于MeOH(0.030mL,0.13mmol)中的溶液。在rt搅拌反应混合物过夜。添加水(0.10mL),且搅拌反应混合物0.5h。浓缩反应混合物,将其再溶解于DMF中,用乙酸(0.05mL)酸化并过滤。通过制备型HPLC(柱:XBridge C18,19×200mm,5μm颗粒;流动相A:5:95的乙腈:水+0.1%三氟乙酸;流动相B:95:5的乙腈:水+0.1%三氟乙酸;梯度:57-82%B经20分钟,接着在100%B下保持2分钟;流速:20mL/min)纯化粗产物。将含有期望产物的级分合并、浓缩且在真空中干燥,得到标题化合物(5.1mg,0.008mmol,30%产率)。1H NMR(500MHz,DMSO-d6)δ8.82(s,2H),8.14(s,1H),8.06(s,1H),8.00(br d,J=8.5Hz,1H),7.91(br d,J=8.2Hz,1H),6.44(d,J=16.0Hz,1H),6.38(d,J=16.0Hz,1H),4.22(s,2H),4.11(s,3H),2.34-2.26(m,1H),1.65-1.56(m,6H),1.42-1.34(m,6H),1.19-1.12(m,2H),1.08(br d,J=2.4Hz,2H)。FXR EC50(nM)=42。MS(ESI)620(M+H)。
实施例518
(E)-7-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)-1-异丙氧基异喹啉-3-甲酸
/>
向含有i-PrOH(291μL)的小瓶中添加60%NaH(7.3mg,0.18mmol)。10min后,添加中间体517A(13mg,0.020mmol)。在rt搅拌过夜后,添加另外的60%NaH(7.3mg,0.18mmol)和THF(0.2mL)。将反应混合物加热至70℃后保持1h。反应物用饱和NH4Cl水溶液淬灭且用EtOAc萃取。有机层用水和盐水洗涤,经无水硫酸钠干燥且真空浓缩。通过制备型HPLC(柱:XBridge C18,19×200mm,5μm颗粒;流动相A:5:95的乙腈:水+0.1%三氟乙酸;流动相B:95:5的乙腈:水+0.1%三氟乙酸;梯度:57-82%B经20分钟,接着在100%B下保持2分钟;流速:20mL/min)纯化粗产物。将含有期望产物的级分合并、浓缩且在真空中干燥,得到标题化合物(3.4mg,0.005mmol,24%产率)。1H NMR(400MHz,DMSO-d6)δ8.84(s,2H),8.10(d,J=0.7Hz,1H),8.05-7.86(m,3H),6.55-6.27(m,2H),5.64(quin,J=6.2Hz,1H),4.24(s,2H),2.36-2.23(m,1H),1.69-1.53(m,6H),1.47-1.31(m,12H),1.16(dt,J=8.4,2.9Hz,2H),1.11-1.07(m,2H)。FXR EC50(nM)=62。MS(ESI)648(M+H)。
实施例519
7-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-1-(4-甲基哌嗪-1-基)异喹啉-3-甲酸
步骤A.中间体519A.3,5-二氯吡啶-4-甲醛肟的制备
在rt向3,5-二氯吡啶-4-甲醛(1.00g,5.68mmol)于吡啶(2.8mL)中的溶液中添加羟胺盐酸盐(0.592g,8.52mmol),产生轻度放热。10min后,在真空中移除多余吡啶。用1MK2HPO4水溶液使残余物碱化,且用EtOAc萃取。通过过滤收集所形成的白色固体。有机层用盐水洗涤,经Na2SO4干燥,过滤且浓缩。合并经过滤的固体与经浓缩的物质,得到E:Z比率为2.5:1的呈白色固体状的标题化合物(1.07g,5.60mmol,99%产率),其不经进一步纯化即使用。主要异构体:1H NMR(400MHz,DMSO-d6)δ12.33(s,1H),8.71(s,2H),8.28(s,1H)。次要异构体:1H NMR(400MHz,DMSO-d6)δ11.88(s,1H),8.69(s,2H),7.70(s,1H)。MS(ESI)190.9(M+H)。
步骤B.中间体519B.5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-甲酸乙酯的制备
向含有3-环丙基-3-氧代丙酸乙酯(161g,1030mmol)的500mL 3颈圆底烧瓶中添加TEA(470mL)。在rt搅拌反应混合物15min且接着冷却至5℃。经10min添加中间体519A(233g,1030mmol)于EtOH(470mL)中的溶液,使反应混合物升温至rt且搅拌15h。浓缩反应混合物且通过硅胶色谱来纯化。将经分离固体悬浮于正戊烷中,搅拌10min,过滤且用正戊烷洗涤,得到呈白色固体状的标题化合物(300g,917mmol,89%产率)。1H NMR(400MHz,氯仿-d)δ8.61(s,2H),4.15(q,J=7.1Hz,2H),2.94(tt,J=8.4,5.1Hz,1H),1.47-1.38(m,2H),1.34-1.26(m,2H),1.06(t,J=7.1Hz,3H)。MS(ESI)327.1(M+H)。
步骤C.中间体519C.(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲醇的制备
在-78℃经8min向519B(50.0g,153mmol)于无水CH2Cl2(2000mL)中的溶液中添加DIBAL-H于CH2Cl2(428mL,428mmol)中的1M溶液。5min后,用罗谢尔盐水溶液(450g于1L水中)缓慢淬灭反应物。在rt剧烈搅拌反应混合物过夜。分离各层且用CH2Cl2(2000L)萃取水层。用盐水(1000L)洗涤合并的有机层,干燥(Na2SO4)且浓缩。将粗物质溶解于CH2Cl2(100mL)中,且在搅拌的同时添加正戊烷(400mL)。搅拌混合物30min,且接着倾析溶液。用正戊烷(200mL)洗涤倾析出的固体。将物质在真空下干燥,得到呈白色固体状的标题化合物(41.0g,138mmol,90%产率)。1H NMR(500MHz,氯仿-d)δ8.64(s,2H),4.46(s,2H),2.19(tt,J=8.4,5.1Hz,1H),1.33-1.26(m,2H),1.22-1.14(m,2H)。MS(ESI)285.2(M+H)。
步骤D.中间体69A.4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛烷-1-甲酸甲酯的制备
向压力小瓶中添加中间体519C(2.57g,9.00mmol)、中间体4A(3.97g,13.5mmol)和三氟甲基甲苯(18mL)。搅拌反应混合物以确保材料充分混合。添加三氟甲烷磺酸银(3.47g,13.5mmol)。在搅拌的同时添加2,6-二-叔丁基吡啶(3.96mL,18.0mmol)。将反应混合物加盖,且加热至100℃后保持过夜。添加另外的中间体4A(2.0g),且将反应混合物加热至100℃后保持2h。反应混合物用EtOAc稀释且用1M HCl水溶液洗涤。用EtOAc(2×)萃取水层。合并的有机层用1M HCl水溶液(2×)和盐水洗涤,干燥(MgSO4),且经由硅藻土过滤。通过硅胶色谱纯化粗物质,得到呈无色玻璃状的标题化合物(1.87g,4.15mmol,46%产率)。1H NMR(500MHz,氯仿-d)δ8.61(s,2H),4.20(s,2H),3.62(s,3H),2.08(tt,J=8.5,5.0Hz,1H),1.88-1.77(m,6H),1.48-1.40(m,6H),1.27-1.21(m,2H),1.16-1.08(m,2H)。MS(ESI)451.4(M+H)。
步骤E.中间体276A.(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲醇的制备
在-78℃向中间体69A(1.10g,2.44mmol)于THF(24mL)中的经搅拌溶液中逐滴添加LAH于THF(1.03mL,2.07mmol)中的2M溶液。使反应混合物缓慢升温至0℃后保持30min。依序用水(0.08mL)、15%NaOH水溶液(0.08mL)和水(0.24mL)逐滴淬灭反应物。剧烈搅拌反应混合物1h。添加MgSO4,且过滤并浓缩混合物。通过硅胶色谱纯化粗产物,得到呈白色泡沫状的标题化合物(1.01g,2.39mmol,98%产率)。1H NMR(500MHz,氯仿-d)δ8.62(s,2H),4.23(s,2H),3.24(d,J=5.5Hz,2H),2.18-2.08(m,1H),1.53-1.40(m,12H),1.34-1.23(m,2H),1.20-1.09(m,2H)。MS(ESI)423.0(M+H)。
步骤F.中间体519D.4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛烷-1-甲醛的制备
在-78℃向草酰氯(0.019mL,0.21mmol)于CH2Cl2(1.1mL)中的溶液中逐滴添加DMSO(0.035mL,0.49mmol)于CH2Cl2(0.55mL)中的溶液,且搅拌反应混合物10min。接着,缓慢添加中间体276A(0.069g,0.16mmol)于CH2Cl2(1mL)中的溶液,用CH2Cl2(0.5)冲洗烧瓶,且搅拌反应混合物30min。添加TEA(0.11mL,0.82mmol),且使反应混合物升温至rt并搅拌30min。将反应混合物用CH2Cl2稀释,且用水、饱和NaHCO3水溶液和盐水洗涤,干燥(MgSO4)且浓缩,得到呈泡沫状的标题化合物(0.070g,0.16mmol,100%产率),其固化成灰白色固体。1H NMR(500MHz,氯仿-d)δ9.40(s,1H),8.60(s,2H),4.21(s,2H),2.07(tt,J=8.5,5.0Hz,1H),1.73-1.63(m,6H),1.51-1.43(m,6H),1.27-1.22(m,2H),1.15-1.09(m,2H)。MS(ESI)421.0(M+H)。
步骤G.中间体519E.5-环丙基-3-(3,5-二氯吡啶-4-基)-4-(((4-乙炔基双环[2.2.2]辛-1-基)氧基)甲基)异噁唑的制备
向中间体519D(1.80g,4.26mmol)和K2CO3(1.18g,8.52mmol)的混合物中添加无水MeOH(17mL),且在rt搅拌混合物30min。添加(1-重氮-2-氧代丙基)膦酸二甲酯(0.98g,5.1mmol),且在rt搅拌反应混合物过夜。将反应混合物用Et2O稀释,用1M K2HPO4水溶液洗涤,干燥(MgSO4)且浓缩。通过硅胶色谱纯化粗产物,得到呈无色玻璃状的标题化合物(1.40g,3.36mmol,79%产率),其固化成白色固体。1H NMR(500MHz,氯仿-d)δ8.60(s,2H),4.18(s,2H),2.10-2.03(m,2H),1.87-1.76(m,6H),1.48-1.38(m,6H),1.27-1.21(m,2H),1.15-1.09(m,2H)。MS(ESI)417.4(M+H)。
步骤H.中间体519F.5-溴-2-(二溴甲基)苯甲酸甲酯的制备
将5-溴-2-甲基苯甲酸甲酯(5.00g,21.8mmol)、NBS(3.88g,21.8mmol)和AIBN(0.179g,1.09mmol)的溶液加热至回流后保持6h,且随后在rt搅拌过夜。添加另外的AIBN(0.179g,1.091mmol)和NBS(3.88g,21.8mmol),且将反应混合物回流2天。添加另外的AIBN(0.179g,1.09mmol)和NBS(3.88g,21.8mmol),且将反应混合物回流过夜。过滤反应混合物,且用CH2Cl2稀释。将有机层用1M NaOH、Na2S2O3水溶液和盐水洗涤,干燥(MgSO4),且经由硅胶塞过滤,得到呈灰白色固体状的标题化合物(7.59g,19.6mmol,90%产率)。1H NMR(500MHz,氯仿-d)δ8.05(d,J=7.7Hz,1H),8.04(d,J=1.1Hz,1H),7.98(s,1H),7.75(dd,J=8.5,2.2Hz,1H),3.97(s,3H)。
步骤I.中间体519G.5-溴-2-甲酰基苯甲酸甲酯的制备
在避光烧瓶中,经20min向中间体519F(7.31g,18.9mmol)于i-PrOH(132mL)中的悬浮液中逐滴添加硝酸银(6.58g,38.7mmol)于水(13mL)中的溶液。将反应混合物加热至回流后保持1h。过滤且浓缩反应混合物以移除i-PrOH。用EtOAc(3×)萃取产物,且将合并的有机层用水和盐水洗涤,干燥(MgSO4)且浓缩。分离标题化合物(3.28g,13.5mmol,71%产率),且其不经进一步纯化即使用。1H NMR(500MHz,氯仿-d)δ10.59(s,1H),8.14(d,J=1.7Hz,1H),7.85-7.82(m,1H),7.82-7.78(m,1H),4.00(s,3H)。
步骤J.中间体519H.7-溴-1-氧代-1,2-二氢异喹啉-3-甲酸甲酯的制备
步骤1.将中间体519G(1.65g,6.79mmol)、苯甲酰甘氨酸(1.34g,7.47mmol)、乙酸钠(0.613g,7.47mmol)和乙酸酐(3.2mL,34mmol)的溶液加热至100℃后保持4h。使反应混合物冷却至rt。添加水以使产物析出物,过滤且用水洗涤。将物质在真空下干燥,得到呈暗黄色固体状的粗产物5-溴-2-((5-氧代-2-苯基噁唑-4(5H)-亚基)甲基)苯甲酸甲酯,其不经进一步纯化即用于后续步骤。
步骤2.向前一步骤的物质(2.62g,6.79mmol)于MeOH(41mL)中的溶液中添加KOH(0.762g,13.6mmol)。使反应混合物回流1h。浓缩反应混合物且将其分配于水/EtOAc之间。分离各层且用EtOAc(2×)萃取水层。将合并的有机层用水和盐水洗涤,干燥(MgSO4)且浓缩。向粗物质中添加1:1的CH3CN/水+0.1%TFA(200mL)。将混合物加热至75℃后保持1h。将反应混合物冷却至rt且随后冷却至0℃。过滤经析出的产物,用水洗涤,且在真空下干燥,得到呈米色固体状的标题化合物(1.83g,6.50mmol,53%产率)。1H NMR(500MHz,DMSO-d6)δ11.42(br s,1H),8.32(d,J=2.2Hz,1H),7.98(dd,J=8.5,2.2Hz,1H),7.89(d,J=8.5Hz,1H),7.46(s,1H),3.89(s,3H)。MS(ESI)282.0,284.0(M+H)。
步骤K.中间体519J.7-溴-1-氯异喹啉-3-甲酸甲酯的制备
向中间体519H(0.7140g,2.53mmol)于无水甲苯(7.7mL)中的溶液中添加DIPEA(0.044mL,0.25mmol)和POCl3(0.28mL,3.0mmol)。将反应混合物加热至回流后保持3.5h。浓缩反应混合物。将粗物质再溶解于CH2Cl2中,且经由硅胶塞过滤,用CH2Cl2洗涤且浓缩,得到呈白色固体状的标题化合物(0.750g,2.50mmol,99%产率)。1H NMR(500MHz,氯仿-d)δ8.62-8.58(m,1H),8.51(s,1H),7.97-7.92(m,1H),7.91-7.86(m,1H),4.06(s,3H)。MS(ESI)300.1,302.1(M+H)。
步骤L.中间体519K.7-溴-1-(4-甲基哌嗪-1-基)异喹啉-3-甲酸甲酯的制备
向中间体519J(0.750g,2.50mmol)于DMF(8.9mL)中的溶液中添加1-甲基哌嗪(0.83mL,7.5mmol),接着添加DIPEA(1.3mL,7.5mmol)。反应混合物在120℃微波处理20min。将反应混合物用EtOAc稀释,且用水(5×)和盐水洗涤,干燥(MgSO4)且浓缩,得到呈米色固体状的标题化合物(0.865g,2.38mmol,95%产率),其不经进一步纯化即使用。1H NMR(500MHz,氯仿-d)δ8.25(d,J=1.1Hz,1H),8.09(d,J=0.8Hz,1H),7.78-7.73(m,2H),4.00(s,3H),3.61-3.49(m,4H),2.72(br t,J=4.7Hz,4H),2.43(s,3H)。MS(ESI)364.2,366.2(M+H)。
步骤M.实施例519.
步骤1.用氮气和真空(3×)吹扫含有CuI(0.18mg,0.94μmol)和PdCl2(dppf)(0.68mg,0.94μmol)、中间体519K(0.015g,0.061mmol)和中间体519E(0.020g,0.047mmol)的压力小瓶。添加无水THF(0.37mL)和TEA(0.10mL),且在70℃搅拌反应混合物1.5h。过滤且浓缩反应混合物。
步骤2.将粗物质溶解于THF(0.39mL)中,且添加1M NaOH水溶液(0.28mL,0.28mmol)。在70℃搅拌反应混合物2h。浓缩反应混合物,用1M HCl水溶液酸化,且用EtOAc(3×)萃取产物。将合并的有机层干燥(MgSO4)且浓缩。通过RP制备型HPLC纯化粗物质,得到标题化合物(11mg,0.020mmol,43%产率)。1H NMR(500MHz,DMSO-d6)δ8.80(s,2H),8.09(s,1H),7.99(br d,J=8.5Hz,1H),7.91(s,1H),7.60(br d,J=8.2Hz,1H),4.19(s,2H),3.62-3.43(m,2H),3.36(br s,2H),2.65(br s,4H),2.32(s,3H),2.30-2.23(m,1H),1.88-1.79(m,6H),1.42-1.31(m,6H),1.18-1.11(m,2H),1.10-1.03(m,2H)。FXR EC50(nM)=28。小鼠体内(3mg/kg,6h情况下):Cypa7a1=-92%,Ffg15=+1.4x。MS(ESI)686.3(M+H)。
实施例520
3-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-6-氟咪唑并[1,2-a]吡啶-8-甲酸
步骤A.中间体520A.8-溴-6-氟咪唑并[1,2-a]吡啶HCl的制备
将含有3-溴-5-氟吡啶-2-胺(0.500g,2.62mmol)和50%氯乙醛水溶液(0.67mL,5.2mmol)的压力小瓶加热至80℃。浓缩反应混合物。将粗产物固体悬浮于CH2Cl2中,且倾析黄色溶液(3×)。分离呈淡棕色固体状的标题化合物(0.674g,2.62mmol,100%产率)。1HNMR(500MHz,DMSO-d6)δ9.15(dd,J=3.7,2.1Hz,1H),8.40-8.31(m,2H),8.09(s,1H)。MS(ESI)215.1(M+H)。
步骤B.中间体520B.6-氟咪唑并[1,2-a]吡啶-8-甲腈的制备
用氮气(3×)吹扫含有中间体520A(0.300g,1.40mmol)、Xantphos(0.040g,0.070mmol)、Pd2(dba)3(0.032g,0.035mmol)和氰化锌(0.328g,2.79mmol)的微波小瓶,且随后添加无水DMF(5mL)。反应混合物在120℃微波处理1h。自试管底部的固体倾析出溶液,用少量DMF(2×)冲洗该等固体。向合并的溶液中逐滴添加水(20mL)。形成棕色析出物。过滤析出物且用水洗涤。用EtOAc(3×)萃取水性滤液,且随后将合并的有机层用水(3×)和盐水洗涤,干燥(MgSO4)并浓缩。分离呈米色固体状的标题化合物(0.158g,0.983mmol,71%产率),其不经进一步纯化即使用。1H NMR(500MHz,氯仿-d)δ8.34(dd,J=3.4,2.3Hz,1H),7.87(d,J=1.1Hz,1H),7.77(d,J=1.4Hz,1H),7.59(dd,J=7.7,2.2Hz,1H)。MS(ESI)162.2(M+H)。
步骤C.中间体520C.6-氟-3-碘咪唑并[1,2-a]吡啶-8-甲腈的制备
在0℃向中间体520B(0.144g,0.892mmol)于CH3CN(3.6mL)中的溶液中一次性添加NIS。使反应混合物缓慢升温至rt且在rt搅拌过夜。在rt添加另外0.2当量的NIS。10min后,浓缩反应混合物。将物质悬浮于CH2Cl2中,且用1M NaOH(2×)、Na2S2O3水溶液和盐水洗涤,干燥(MgSO4)并浓缩,得到标题化合物(0.236g,0.822mmol,92%产率),其不经进一步纯化即使用。1H NMR(500MHz,氯仿-d)δ8.36(dd,J=3.6,2.2Hz,1H),7.92(s,1H),7.64(dd,J=7.4,2.2Hz,1H)。MS(ESI)288.1(M+H)。
步骤D.中间体520D.6-氟-3-碘咪唑并[1,2-a]吡啶-8-甲酸甲酯的制备
向中间体520C(0.100g,0.348mmol)于MeOH(3.5mL)中的溶液中添加浓H2SO4(0.50mL,9.4mmol)。使反应混合物回流2天。浓缩反应混合物。将溶液分配于EtOAc与1MNaOH之间。分离各层且用EtOAc(2×)萃取水层。用盐水洗涤合并的有机层,干燥(MgSO4)且浓缩。通过硅胶色谱纯化粗产物,得到呈黄褐色固体状的标题化合物(0.0635g,0.198mmol,57%产率)。1H NMR(500MHz,氯仿-d)δ8.30(dd,J=3.6,2.5Hz,1H),7.94(dd,J=8.4,2.3Hz,1H),7.87(s,1H),4.06(s,3H)。MS(ESI)321.0(M+H)。
步骤E.实施例520
根据针对实施例130的合成(步骤B和C)所描述的方法,由中间体520D和中间体519E制备标题化合物:(9.7mg,0.016mmol,28%产率)。1H NMR(500MHz,DMSO-d6)δ8.78(s,2H),8.67(br s,1H),7.99(br d,J=8.1Hz,1H),7.95(s,1H),4.21(s,2H),2.33-2.19(m,1H),2.00-1.82(m,6H),1.51-1.32(m,6H),1.19-1.11(m,2H),1.07(br d,J=2.3Hz,2H)。FXR EC50(nM)=4。MS(ESI)595.0(M+H)。
实施例521
7-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-1-甲氧基异喹啉-3-甲酸
步骤A.中间体521A.7-溴-1-甲氧基异喹啉-3-甲酸甲酯的制备
向含有中间体519J(0.100g,0.333mmol)的压力小瓶中添加含25%甲醇钠(0.38mL,1.7mmol)的MeOH。将反应混合物加热至70℃后保持2h。
使反应混合物冷却至rt且用水稀释。过滤析出物,用水洗涤,且在真空下干燥,得到呈白色固体状的标题化合物(0.0758g,0.256mmol,77%产率)。1H NMR(500MHz,氯仿-d)δ8.50-8.44(m,1H),8.13(s,1H),7.85-7.79(m,1H),7.78-7.72(m,1H),4.23(s,3H),4.01(s,3H)。MS(ESI)296.0,298.0(M+H)。
步骤B.实施例521.
根据针对实施例130的合成(步骤B和C)所描述的方法,由中间体521A和中间体519E制备标题化合物:(11.8mg,0.019mmol,58%产率)。1H NMR(500MHz,DMSO-d6)δ8.79(d,J=1.4Hz,2H),8.12(s,1H),8.09(s,1H),8.00(d,J=8.3Hz,1H),7.66(br d,J=8.4Hz,1H),4.20(s,2H),4.12(s,3H),2.32-2.21(m,1H),1.95-1.78(m,6H),1.49-1.36(m,6H),1.18-1.11(m,2H),1.08(br s,2H)。FXR EC50(nM)=40。MS(ESI)618.2(M+H)。
实施例522
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-4-甲氧基-N,N-二甲基喹啉-2-甲酰胺
向实施例375(0.012g,0.019mmol)和HATU(8.1mg,0.021mmol)于DMF(0.19ml)中的溶液中添加2M二甲胺于MeOH(0.015ml,0.029mmol)中的溶液,接着添加TEA(8.1μL,0.058mmol)。在rt搅拌反应混合物过夜。过滤反应混合物,用DMF稀释,且通过RP制备型HPLC纯化,得到标题化合物(10mg,0.016mmol,83%产率)。1H NMR(500MHz,DMSO-d6)δ8.80(s,2H),8.03(s,1H),7.87(d,J=8.5Hz,1H),7.63(br d,J=8.9Hz,1H),7.09(s,1H),4.19(s,2H),4.04(s,3H),3.03(s,3H),2.94(s,3H),2.33-2.22(m,1H),1.88-1.77(m,6H),1.45-1.31(m,6H),1.20-1.10(m,2H),1.06(br d,J=2.1Hz,2H)。FXR EC50(nM)=52。MS(ESI)645.2(M+H)。
实施例523
5-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-6-(3-氟氮杂环丁-1-基)吡啶-3-甲酸
步骤A.中间体523A.5-溴-6-(3-氟氮杂环丁-1-基)吡啶-3-甲酸甲酯的制备
向5-溴-6-氯吡啶-3-甲酸甲酯(0.130g,0.519mmol)于DMF(1.6mL)中的溶液中添加3-氟氮杂环丁烷、HCl(0.174g,1.56mmol),接着添加休尼格氏碱(0.54mL,3.1mmol)。反应混合物在120℃微波处理20min。用水稀释反应混合物,且形成深棕色析出物,过滤析出物且用水洗涤。将固体溶解于EtOAc/CH2Cl2中,且经由硅胶塞过滤,得到呈淡棕色固体状的标题化合物(0.135g,0.468mmol,90%产率)。1H NMR(500MHz,氯仿-d)δ8.70(d,J=1.9Hz,1H),8.21(d,J=1.9Hz,1H),5.46-5.25(m,1H),4.69(ddd,J=11.1,6.0,1.7Hz,1H),4.65(ddd,J=11.1,5.9,1.7Hz,1H),4.52-4.47(m,1H),4.47-4.42(m,1H),3.89(s,3H)。MS(ESI)289.0,291.0(M+H)。
步骤B.实施例523.
根据针对实施例130的合成(步骤B和C)所描述的方法,由中间体523A和中间体519E制备标题化合物:(18.8mg,0.031mmol,64%产率)。1H NMR(500MHz,DMSO-d6)δ8.81(s,2H),8.50(s,1H),7.76(d,J=1.5Hz,1H),5.55-5.28(m,1H),4.57(br dd,J=16.6,5.3Hz,2H),4.31-4.20(m,2H),4.19(s,2H),2.35-2.21(m,1H),1.87-1.73(m,6H),1.44-1.29(m,6H),1.14(br d,J=7.9Hz,2H),1.08(br d,J=2.7Hz,2H)。FXR EC50(nM)=24。MS(ESI)611.3(M+H)。
中间体
实施例524的中间体的制备.2-(5-乙基-3-羟基-1H-吡唑-1-基)乙酸叔丁酯
在丙酮/DMF(8mL/2mL,4:1)中合并5-乙基-1H-吡唑-3-醇(200mg,1.784mmol)与2-溴乙酸叔丁酯(0.237mL,1.605mmol)和K2CO3(247mg,1.784mmol)。在25℃搅拌反应混合物16小时。反应混合物中形成两种异构体。浓缩反应物,接着用EtOAc稀释,用盐水洗涤,经Na2SO4干燥,过滤且浓缩。通过柱色谱(24g硅胶滤筒,用0-100%EtOAc/己烷洗脱)纯化残余物,得到混合物形式的标题化合物,其经由制备型HPLC(柱:Phenomenex Luna Axia 5u 30×100(10min梯度);流动相A:5:95的乙腈:水+0.1%三氟乙酸;流动相B:95:5的乙腈:水+0.1%三氟乙酸;梯度:20-100%B经10分钟,接着在100%B下保持2分钟;流速:40mL/min)进一步纯化。将含有期望产物的级分合并、浓缩且在真空中干燥,得到呈无色油状物的标题化合物(78mg,0.345mmol,19.33%产率)。1H NMR(500MHz,氯仿-d)δ=5.48(s,1H),4.49(s,2H),2.47(q,J=7.4Hz,2H),1.46(s,9H),1.25(t,J=7.4Hz,3H)。MS(ESI)227.2(M+H)+。
实施例527的中间体的制备.6-(溴甲基)-4-(三氟甲基)吡啶-2-甲酸甲酯
将6-甲基-4-(三氟甲基)吡啶-2-甲酸甲酯(300mg,1.369mmol)、NBS(244mg,1.369mmol)和AIBN(22.48mg,0.137mmol)于CCl4(7ml)中的混合物在90℃搅拌过夜。在冷却至RT之后,过滤固体且用CCl4洗涤。将合并的有机层用饱和NaHCO3水溶液和盐水洗涤,经Na2SO4干燥,且在减压下浓缩。通过柱色谱(24g硅胶滤筒,用0-70%EtOAc/己烷洗脱)纯化残余物,得到呈灰白色泡沫状的标题化合物(16mg,0.054mmol,3.92%产率)。1H NMR(500MHz,氯仿-d)δ=8.27(s,1H),7.91(s,1H),4.70(s,2H),4.06(s,3H)。MS(ESI)298.0(M+H)+。
实施例528的中间体的制备.1-(环丙基甲基)-3-羟基-1H-吡唑-5-甲酸甲酯
步骤A.中间体528A.3-((叔丁基二甲基硅烷基)氧基)-1H-吡唑-5-甲酸甲酯的制备
向3-羟基-1H-吡唑-5-甲酸甲酯(620mg,4.36mmol)于乙腈(14mL)中的经搅拌悬浮液中添加TBDMS-Cl(986mg,6.54mmol)和咪唑(475mg,6.98mmol)。在RT搅拌反应混合物20min,且随后浓缩。残余物用H2O稀释且用EtOAc(2×)萃取。合并的有机层用盐水洗涤,干燥(Na2SO4),且在减压下浓缩。通过柱色谱(24g硅胶滤筒,用0-30%EtOAc/己烷洗脱)纯化残余物,得到呈白色固体状的3-((叔丁基二甲基硅烷基)氧基)-1H-吡唑-5-甲酸甲酯(980mg,3.82mmol,88%产率)。1H NMR(500MHz,氯仿-d)6.18(s,1H),3.92(s,3H),1.00(s,9H),0.29(s,6H)。MS(ESI)257.1(M+H)+。
步骤B.中间体528B.3-((叔丁基二甲基硅烷基)氧基)-1-(环丙基甲基)-1H-吡唑-5-甲酸甲酯的制备
将3-((叔丁基二甲基硅烷基)氧基)-1H-吡唑-5-甲酸甲酯(200mg,0.780mmol)、环丙基甲醇(113mg,1.560mmol)、Ph3P(368mg,1.404mmol)和(E)-二氮烯-1,2-二甲酸二异丙酯(276μl,1.404mmol)溶解于无水THF(3901μl)中,且在密封小瓶中在100℃加热16小时。在冷却至RT之后,通过柱色谱(24g,用0-60%EtOAc/己烷洗脱)直接纯化反应混合物,得到呈无色油状物的3-((叔丁基二甲基硅烷基)氧基)-1-(环丙基甲基)-1H-吡唑-5-甲酸甲酯(160mg,0.515mmol,66.1%产率)。1H NMR(500MHz,氯仿-d)δ6.14(s,1H),4.27(d,J=7.2Hz,2H),3.85(s,3H),1.36-1.25(m,1H),0.98(s,9H),0.53-0.45(m,2H),0.42-0.36(m,2H),0.26(s,6H)。MS(ESI)311.2(M+H)+。
步骤C.中间体528.1-(环丙基甲基)-3-羟基-1H-吡唑-5-甲酸甲酯
向3-((叔丁基二甲基硅烷基)氧基)-1-(环丙基甲基)-1H-吡唑-5-甲酸甲酯(160mg,0.515mmol)于THF(2mL)中的溶液中添加TBAF(0.773mL,0.773mmol)。在RT搅拌反应物16小时。将反应物用水稀释且用乙酸乙酯(2×)萃取。合并的有机层用盐水洗涤且经硫酸钠干燥。通过过滤移除干燥剂且在减压下浓缩滤液。通过柱色谱(24g硅胶滤筒,用0-70%EtOAc/己烷洗脱)纯化所得残余物,得到呈白色粉末状的标题化合物(69mg,0.352mmol,68.2%产率)。1H NMR(500MHz,氯仿-d)δ11.46(br s,1H),6.16(br s,1H),4.53-3.61(m,5H),1.49-1.16(m,1H),0.78-0.23(m,4H)。MS(ESI)197.1(M+H)+。
实施例529的中间体的制备.1-乙基-7-羟基异喹啉-3-甲酸甲酯
步骤A.中间体529A.1-乙基-7-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)异喹啉-3-甲酸甲酯的制备
用氮气使7-氯-1-乙基异喹啉-3-甲酸甲酯(160mg,0.641mmol)、4,4,4',4',5,5,5',5'-八甲基-2,2'-二(1,3,2-二氧硼戊烷)(212mg,0.833mmol)和乙酸钾(189mg,1.922mmol)于二噁烷(3.2mL)中的混合物鼓泡,同时搅拌2min。随后添加PdCl2(dppf)(94mg,0.128mmol),且在100℃搅拌反应物2小时。冷却至室温后,将反应物用水稀释且用乙酸乙酯(2×)萃取。将合并的有机层用盐水洗涤且经硫酸钠干燥。通过过滤移除干燥剂且在减压下浓缩滤液。通过柱色谱(12g硅胶滤筒,用0-100%EtOAc/己烷洗脱)纯化所得残余物,得到呈油状物的1-乙基-7-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)异喹啉-3-甲酸甲酯(219mg,0.645mmol,100%产率)。MS(ESI)342.2(M+H)+。
步骤B.中间体529.1-乙基-7-羟基异喹啉-3-甲酸甲酯的制备
向1-乙基-7-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)异喹啉-3-甲酸甲酯(219mg,0.645mmol)于THF(3mL)中的0℃溶液中添加NaOH(1.290mL,1.290mmol),接着添加H2O2(0.198mL,1.934mmol)。将反应物保持在0℃,且5分钟后,将反应物用EtOAc稀释且用Na2SO3水溶液淬灭,并且用水和盐水洗涤。合并的水层用EtOAc反萃取,且合并的有机物经Na2SO4干燥,过滤且浓缩至干燥。通过柱色谱(24g硅胶滤筒,用0-60%EtOAc/己烷洗脱)纯化残余物,得到呈白色固体状的1-乙基-7-羟基异喹啉-3-甲酸甲酯(72mg,0.311mmol,48.3%产率)。1H NMR(500MHz,氯仿-d)δ8.41(br s,1H),7.87(br s,1H),7.66-7.40(m,2H),4.00(br s,3H),3.21(br s,2H),1.28(br s,3H)。MS(ESI)232.1(M+H)+。
实施例530的中间体的制备.1-乙基-3-羟基-4-甲基-1H-吡唑-5-甲酸乙酯
步骤A.中间体530A.4-甲基-5-氧代-2,5-二氢-1H-吡唑-3-甲酸乙酯的制备
根据Organic Letters,16(23),6120-6123;2014中所描述的方法制备标题化合物。
步骤B.中间体530B.1-乙基-3-羟基-4-甲基-1H-吡唑-5-甲酸乙酯的制备
根据针对中间体528的合成所描述的方法,以中间体530A和乙醇作为起始物质来制备标题化合物。1H NMR(500MHz,氯仿-d)δ11.00(s,1H),4.40-4.00(m,4H),2.14(br s,3H),1.64-0.90(m,6H)。MS(ESI)199.1(M+H)+。
实施例531的中间体的制备.3-羟基-1-异丙基-4-甲基-1H-吡唑-5-甲酸乙酯
根据针对中间体528的合成所描述的方法,以中间体530A和异丙醇作为起始物质来制备标题化合物。1H NMR(500MHz,DMSO-d6)δ9.88(br s,1H),5.28-5.10(m,1H),4.27(q,J=6.3Hz,2H),1.99(br s,3H),1.45-1.1(m,9H)。MS(ESI)213.1(M+H)+。
实施例532的中间体的制备.1-(环丙基甲基)-3-羟基-4-甲基-1H-吡唑-5-甲酸乙酯
根据针对中间体528的合成所描述的方法,使用中间体530A和环丙基甲醇作为起始物质来制备标题化合物。1H(500MHz,氯仿-d)δ=11.44(brs,1H),4.37(q,J=6.9Hz,2H),4.23(br d,J=6.9Hz,2H),2.16(s,3H),1.40(br t,J=7.0Hz,3H),1.35-1.22(m,1H),0.55-0.46(m,2H),0.45-0.36(m,2H)。MS(ESI)225.0(M+H)+。
实施例533的中间体的制备.3-羟基-4-甲基-1-(氧杂环丁-3-基甲基)-1H-吡唑-5-甲酸乙酯
根据针对中间体528的合成所描述的方法,以中间体530A和氧杂环丁-3-基甲醇作为起始物质来制备标题化合物。1H(500MHz,氯仿-d)δ11.2(br s,1H),4.74(t,J=7.2Hz,2H),4.66(d,J=7.2Hz,2H),4.55(t,J=6.3Hz,2H),4.36(q,J=7.2Hz,2H),3.46(td,J=6.9,14.2Hz,1H),2.13(s,3H),1.40(t,J=7.2Hz,3H)。MS(ESI)241.1(M+H)+。
实施例534的中间体的制备.3-羟基-1,4-二甲基-1H-吡唑-5-甲酸乙酯
根据针对中间体528的合成所描述的方法,以中间体530A和甲醇作为起始物质来制备标题化合物。1H(500MHz,氯仿-d)δ11.3(br s,1H),4.37(q,J=6.9Hz,2H),3.98(s,3H),2.15(s,3H),1.40(br t,J=7.0Hz,3H)。MS(ESI)185.1(M+H)+。
实施例535的中间体的制备.1-(环丙基甲基)-4-氟-3-羟基-1H-吡唑-5-甲酸乙酯
在密封小瓶中,将3-((叔丁基二甲基硅烷基)氧基)-1-(环丙基甲基)-1H-吡唑-5-甲酸乙酯(中间体528B)(200mg,0.616mmol)和选择性氟试剂(Selectfluor)(262mg,0.740mmol)于乙腈(3mL)中的溶液在90℃加热30min。冷却后,将溶液与1M盐酸混合,且用乙酸乙酯萃取两次。将有机相用饱和氯化钠溶液洗涤,经Na2SO4干燥,过滤,且通过在真空中蒸发而浓缩。在硅胶上色谱纯化(24g硅胶滤筒,用0-100%EtOAc/己烷洗脱),得到呈白色固体状的标题化合物(71mg,0.311mmol,50.5%产率)。1H(500MHz,氯仿-d)δ9.50(br s,1H),4.50-4.30(m,2H),4.27(br d,J=6.9Hz,2H),1.46-1.35(m,3H),1.34-1.19(m,1H),0.57-0.48(m,2H),0.47-0.36(m,2H)。MS(ESI)229.1(M+H)+。
实施例536的中间体的制备.3-(1,1-二氟乙基)-5-羟基吡啶-2-甲酸甲酯
步骤A.中间体536A.1-(5-(苯甲基氧基)-2-氯吡啶-3-基)乙-1-酮的制备
根据Bioorganic&Medicinal Chemistry Letters,20(2),679-683;2010中所描述的方法制备标题化合物。
步骤B.中间体536B.3-乙酰基-5-(苯甲基氧基)吡啶-2-甲酸甲酯的制备
向1-(5-(苯甲基氧基)-2-氯吡啶-3-基)乙-1-酮(261mg,0.997mmol)于MeOH(12mL)中的溶液中添加[1,1'-双(二苯基膦基)二茂铁]二氯钯(II)(73.0mg,0.100mmol),接着添加Et3N(0.278mL,1.995mmol)。将反应物在一氧化碳氛围(40-50psi)下在85℃加热16小时。使反应混合物冷却至室温,经由硅藻土过滤且在减压下蒸发。通过柱色谱(24g硅胶滤筒,用0-100%EtOAc/己烷洗脱)纯化残余物,得到呈白色泡沫状的3-乙酰基-5-(苯甲基氧基)吡啶-2-甲酸甲酯(131mg,0.459mmol,46.0%产率)。1H NMR(500MHz,氯仿-d)δ8.53-8.40(m,1H),7.51-7.36(m,5H),7.19(d,J=2.8Hz,1H),5.19(s,2H),3.99(s,3H),2.55(s,3H)。MS(ESI)286.1(M+H)+。
步骤C.中间体536C.5-(苯甲基氧基)-3-(1,1-二氟乙基)吡啶-2-甲酸甲酯的制备
在N2下,将3-乙酰基-5-(苯甲基氧基)吡啶-2-甲酸甲酯(56mg,0.196mmol)和50%脱氧加氟物(Deoxofluor)于甲苯(1mL,2.71mmol)中的混合物在80℃加热2h。使混合物冷却至室温且用DCM稀释。有机层用饱和NaHCO3(水溶液)和盐水洗涤,干燥(MgSO4)且浓缩。通过硅胶色谱(用0-60%EtOAc/己烷洗脱)纯化残余物,得到呈白色泡沫状的5-(苯甲基氧基)-3-(1,1-二氟乙基)吡啶-2-甲酸甲酯(42mg,0.137mmol,69.6%产率)。MS(ESI)308.1(M+H)+。
步骤D.中间体536.
向5-(苯甲基氧基)-3-(1,1-二氟乙基)吡啶-2-甲酸甲酯(37mg,0.120mmol)于MeOH(3mL)中的经搅拌溶液中添加10%Pd-C(30mg,0.028mmol),接着添加2滴乙酸。将反应物在H2气球下放置16小时。过滤且浓缩反应混合物。通过柱色谱(用0-100%EtOAc/己烷洗脱)纯化粗产物,得到呈白色固体状的标题化合物(21mg,0.097mmol,80%产率)。1H NMR(500MHz,氯仿-d)δ9.30(br s,1H),8.22(d,J=2.8Hz,1H),7.44(d,J=2.5Hz,1H),3.92(s,3H),2.09(t,J=18.4Hz,3H);MS(ESI)218.0(M+H)+。
实施例539和实施例541的中间体的制备.1-环丙基-5-羟基-1H-吡唑-3-甲酸乙酯和1-环丙基-3-羟基-1H-吡唑-5-甲酸乙酯
向环丙基肼二盐酸盐(0.515g,3.55mmol)于THF(3.55mL)中的悬浮液中添加Et3N(1.089ml,7.81mmol),且在室温搅拌混合物30min。接着添加丁-2-炔二酸二乙酯(0.570ml,3.55mmol),且在80℃搅拌反应物16小时。在冷却至RT之后,滤出盐且浓缩滤液。通过柱色谱(用0-100%EtOAc/己烷洗脱)纯化粗产物,得到1-环丙基-5-羟基-1H-吡唑-3-甲酸乙酯(中间体539)(150mg,0.765mmol,21.53%产率)和1-环丙基-3-羟基-1H-吡唑-5-甲酸乙酯(中间体541)(85mg,0.433mmol,12.20%产率)。
中间体539:1H NMR(500MHz,氯仿-d)δ11.01(s,1H),),6.16(s,1H),4.35(d,J=7.2Hz,2H),3.90-3.80(m,1H),1.37(d,J=7.2Hz,3H),1.13-0.97(m,4H)。MS(ESI)197.0(M+H)+。
中间体541:1H NMR(500MHz,DMSO-d6)δ=11.44(s,1H),5.75(s,1H),4.20(q,J=7.1Hz,2H),3.52-3.40(m,1H),1.24(t,J=7.2Hz,3H),1.03-0.85(m,4H)。MS(ESI)197.0(M+H)+。
根据本文中其他处所描述的方法,使用适当起始物质、试剂和条件来制备表9中的以下实施例。
表9
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
生物学评价
在瞬时人类FXR/Gal4-萤光素酶报道物测定法中测试本发明的示例性化合物,且测定结果描述于上文实施例部分中。
使用Gal4-hFXR融合构建体报道物系统作为主要测定法以表征化合物活性。包括萤火虫萤光素酶报道物cDNA上游的Gal4启动子反应元件的5个拷贝的构建体在HEK293细胞中稳定表达。将该报道物细胞系在潮湿的5%CO2氛围中,在37℃维持于补充有1%青霉素-链霉素(P/S)溶液、500μg/ml的吉欧霉素(Zeocin)和经10%炭/聚葡萄糖处理的胎牛血清(cs-FBS)的杜贝克改良伊格尔培养基(Dulbecco's Modified Eagle's medium;DMEM;Gibco)中。构建另一质粒,其中pcDNA3.1载体中的人类巨细胞病毒启动子导引编码融合蛋白的cDNA的表达,该融合蛋白包含来自Gal4转录因子的DNA结合域,该转录因子与来自人类FXR的配体结合域融合。
在转染前一天,用胰蛋白酶自板剥离培养物中的报道物细胞且以足以在第二天上午实现约90%汇合的密度涂布于T75烧瓶中。通过以下步骤制备转染试剂:分别在1.87mLOpti-MEM(Thermo-Fisher)中稀释25μg pcDNA3.1-Gal4-FXR质粒和在1.87mL Opti-MEM中稀释40μL Lipofectamine 2000(Thermo-Fisher),且接着将经稀释的DNA溶液添加至经稀释的Lipofectamine 2000溶液中且在室温培育15-20分钟。在即将转移至细胞中的前,混合物用10mL包含DMEM、10%cs-FBS和1%P/S的溶液进一步稀释。自细胞抽吸维持培养基且添加最终转染混合物,随后细胞在潮湿的5%CO2氛围中,在37℃培育过夜。该方案可按比例放大,且经短暂转染的细胞可以测定法备用形式低温保藏。
对于化合物测试,用Echo声学分配器(Labcyte)将100nL化合物(于DMSO中的连续稀释物)分配至Corning/Costar透明底部384孔白色板的孔中。收集经转染的细胞,计数且稀释,使得10-25,000个细胞(25μL)涂布至384孔化合物测定板的各孔中。经化合物处理的细胞在潮湿的5%CO2氛围中,在37℃培育过夜。第二天上午,向板的各孔中添加25μLSteady-Glo(Promega),混合物在振荡下培育15分钟且用Envision(Perkin Elmer)板读取器量测荧光。来自仅用DMSO处理的细胞的背景计数减去所有未经处理的计数,且将校正值转化成用8μM GW-4064实现的对照响应的百分比。针对4参数对数激动剂-响应方程式拟合这些数据以计算EC50值。
体内测试实施例:急性小鼠PK/PD
自Taconic Labs(Hudson,NY)购得体重为25-28g的雄性C57BL6/NTac小鼠且保持Teklad Global 18%蛋白啮齿类动物饲料(Protein Rodent Diet)(HarlanLaboratories)。在1周环境适应之后,基于体重将小鼠分配至各组中。向小鼠给药单次口服剂量的媒介物或实验化合物。在来源于血液的血浆中评价全身性化合物暴露,该血液是在给药后1小时和在研究终止时(6h)经由颌下静脉收集。在研究终止时,处死动物且快速解剖。分割肝脏的内侧叶,其中一半经均质化且用于分析化合物暴露,且另一半保存于RNAlater(Thermo-Fisher Scientific)中。还解剖回肠且保藏于RNAlater中。RNAlater中的组织样品用MP Biomedicals的珠粒均质化。使用MagMax-96 Total RNA Isolation试剂盒(Thermo-Fisher Scientific)根据制造商方案提取RNA。用Nano-Drop 8000分光光度计(Thermo Fisher)测定RNA浓度。用Invitrogen的VILO cDNA合成试剂盒根据制造商方案进行逆转录。用Applied Biosystems的Taqman PCR主要混合物根据制造商方案进行实时PCR。所有引物皆购自Thermo-Fisher Scientific。所分析的小鼠基因包括肝脏中的Nr0b2(其编码小型杂二聚体搭配物,SHP)、Abcb11(其编码胆汁盐分泌泵,BSEP)、Cyp7a1和Cyp8b1以及回肠中的Fgf15、Fabp6(其编码回肠胆酸结合蛋白,I-BABP)、Slc51a(其编码有机溶质转运蛋白α亚基,OSTA)和Slc51b(其编码有机溶质转运蛋白β亚基,OSTB)。相对于媒介物对照,FGF15基因表达中的统计显著变化表示为增加倍数且CYP7A1表达中的统计显著变化表示为降低百分比。
表A.小鼠PD
本发明的其他特征在示例性实施方案的以上描述中应变得显而易见,提供所述示例性实施方案以用于说明本发明且不意欲对其进行限制。本发明可在不背离其精神或基本特质的情况下以其他特定形式来实施。本发明包含本文所提及的优选方面的所有组合。应理解,本发明的任何和所有实施方案可与任何其他实施方案结合以描述额外实施方案。还应理解,实施方案中的各个别要素为其自身的独立实施方案。此外,一个实施方案的任何要素意欲与任何实施方案的任何和所有其他要素组合以描述另一实施方案。
Claims (10)
1.一种化合物,其具有以下结构:
或其药学上可接受的盐;其中:
R1为-CH(CH3)2或环丙基;
E1、E2和E3一起形成选自以下的部分
B为
L1为共价键、-CH2-、-CH2CH2-、-CH=CH-、-C≡C-、-CH(OH)-、-CH(OH)CH2-、-CH2O-、-CH2OCH2-、-CH2NH-、-C(O)-、-C(O)NH-、-C(O)NHCH2-、-C(O)N(CH3)CH2-、-C(S)NH-、咪唑基、噁二唑基、噻二唑基、噻唑基或三唑基;
Z为1,5-二氮杂萘基、苯并[d]咪唑基、苯并[d]噁唑基、苯并[d]噻唑基、环丙基、环己基、咪唑并[1,2-a]吡啶基、咪唑并[1,2-b]哒嗪基、吲唑基、吲哚基、异喹啉基、萘基、噁二唑基、噁唑基、苯基、哌啶基、吡嗪基、吡唑并[1,5-a]吡啶基、吡唑并[3,4-b]吡啶基、吡唑基、吡啶基、哒嗪基、嘧啶基、吡咯并[2,3-b]吡啶基、喹唑啉基、喹啉基、四氢咪唑并[1,2-a]吡嗪基、四氢异喹啉基或噻唑基,各自经零至3个R10取代;
Rx为-CN、-CH2OH、-C(O)OH、-C(CH3)2C(O)CN、-C(CH3)2C(O)NH2、-C(CH3)2C(O)OH、-C(CH3)2CN、-C(O)N(CH3)2、-C(O)NH2、-C(O)NHS(O)2(环丙基)、-C(O)NHS(O)2(苯基)、-C(O)NHS(O)2CH3、-CH2(四唑基)、-CH2C(O)N(CH3)2、-CH2C(O)NH(CH3)、-CH2C(O)OH、-CH2CH2C(O)OH、-CH2OCH2C(O)OH、-C(O)OCH3、羧基环丙基、-OCH(CH3)C(O)OH、-OCH2C(O)OH、四唑基或羧基噻唑基;
各R10独立地为F、Cl、-OH、-CN、-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2、C1-3烷基、-CHF2、-CF3、-CF2CH3、-CH2OCH3、-OCH3、-OCH2CH3、-OCH(CH3)2、-OCHF2、-OCF3、-OCH2CHF2、-OCH2CF3、-OCH2C(CH3)2OH、-OCH2CH2OCH3、-OCH2CH2CH2OCH3、-OCH(CH2Cl)(CH2OH)、-OCH2CH(CH2Cl)(CH2OH)、-O(C3-5环烷基)、-N(CH3)2、-S(O)2CH3、-CH2(环丙基)、-CH2(氧杂环丁烷基)、-OCH2(环丙基)、-NH(环丙基)、-NH(苯基)、-O(氧杂环丁烷基)、-O(四氢呋喃基)、-O(四氢吡喃基)、-OCH2(环丙基)、-OCH2(环丁基)、-OCH2(氧杂环丁烷基)、-OCH2CH2(吡咯烷基)、环丙基、氮杂环丁烷基、(羟基甲基)氮杂环丁烷基、氟氮杂环丁烷基、(二甲基氨基)氮杂环丁烷基、甲氧基氮杂环丁烷基、羟基氮杂环丁烷基、吗啉基、哌嗪基、甲基哌嗪基、羟基哌啶基、吡咯烷基或羟基吡咯烷基;
L2为共价键或-CH(环丙基)-;
R2为环丙基、苯基、吡啶基或吡唑基,各自独立地经0至3个R16取代;且
各R16独立地为F、Cl、-CH3、-CF3、-OCH3或-OCF3。
2.根据权利要求1所述的化合物,其中:
R1为环丙基;
E1、E2和E3一起形成选自以下的部分
B为
L1为共价键、
Z为苯并[d]噻唑基、异喹啉基、苯基、吡唑基、吡啶基或喹啉基,各自经零至3个R10取代;
Rx为-C(O)OH、-C(O)NH2、-C(O)NHS(O)2CH3、-CH2C(O)OH或-C(O)OCH3;
各R10独立地为F、Cl、-CH3、-CH2CH3、-CF3、-OCH3、-OCH2CH3、-OCH(CH3)2、-OCHF2、-OCF3、-O(C3-5环烷基)或环丙基;
L2为共价键;
R2为苯基或吡啶基,各自独立地经0至3个R16取代;且
各R16独立地为F、Cl、-CH3、-CF3、-OCH3或-OCF3。
3.根据权利要求1至2中任一项所述的化合物,或其药学上可接受的盐;其中:
L2为共价键;且
Rx为-C(O)OH、-CH2C(O)OH、-C(O)OCH3、-C(O)NHS(O)2CH3或四唑基。
4.根据权利要求1所述的化合物,或其药学上可接受的盐;其中所述化合物选自:
5.根据权利要求1所述的化合物,或其药学上可接受的盐,所述化合物选自:
3-(5-(4-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸(1);
4-(5-(4-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸(2);
4-(5-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-N-(甲基磺酰基)苯甲酰胺(3);
5-(5-(4-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-2-甲氧基苯甲酸(4);
3-(5-(4-((4-环丙基-1-(2,6-二氯苯基)-1H-1,2,3-三唑-5-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸(5);
2-(4-((5-环丙基-3-(2-(三氟甲基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)苯并[d]噻唑-6-甲酸(6);
(E)-3-(2-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)苯甲酸(7);
(E)-4-(((4-(3-(1H-四唑-5-基)苯乙烯基)双环[2.2.2]辛-1-基)氧基)甲基)-5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑(8);
6-(5-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)吡啶-3-甲酸(9);
2-(5-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)吡啶-4-甲酸(10);
5-(5-(4-((5-环丙基-3-(2-(三氟甲基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)吡啶-3-甲酸(11);
5-(5-(4-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)吡啶-2-甲酸(12);
6-(5-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)吡啶-2-甲酸(13);
4-(5-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)吡啶-2-甲酸(14);
2-(4-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-4-氟苯并[d]噻唑-6-甲酸(15);
2-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-4-氟苯并[d]噻唑-6-甲酸(16);
2-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1H-苯并[d]咪唑-5-甲酸(17);
3-(5-(4-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,3,4噁二唑-2-基)苯甲酸(18);
3-(5-(4-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,3,4-噻二唑-2-基)苯甲酸(19);
3-(3-(4-((5-环丙基-3-(2-(三氟甲基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-5-基)苯甲酸(20);
4-(3-(4-((5-环丙基-3-(2-(三氟甲基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-5-基)苯甲酸(21);
4-(3-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-5-基)吡啶-2-甲酸(22);
6-(3-(4-((5-环丙基-3-(2-(三氟甲基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-5-基)吡啶-2-甲酸(23);
2-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)喹唑啉-6-甲酸(24);
3-(5-(4-((5-环丙基-3-(2-(三氟甲基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸(25);
4-(5-(4-((5-异丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸(26);
3-(5-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸(27);
4-(5-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸(28);
4-(5-(4-((5-环丙基-3-(2-(三氟甲基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸(29);
5-(5-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-2-甲氧基苯甲酸(30);
5-(5-(4-((5-环丙基-3-(2-(三氟甲基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-2-甲氧基苯甲酸(31);
4-(5-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-N-(苯磺酰基)苯甲酰胺(32);
4-(5-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸甲酯(33);
4-(5-(4-((5-环丙基-3-(2-(三氟甲基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸甲酯(34);
4-(5-(4-((5-异丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸甲酯(35);
3-(5-(4-((5-环丙基-3-(2-(三氟甲基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸甲酯(36);
4-(5-(4-((4-环丙基-1-(2,6-二氯苯基)-1H-1,2,3-三唑-5-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸(37);
2-(4-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)苯并[d]噻唑-6-甲酸(38);
2-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)苯并[d]噻唑-6-甲酸(39);
(E)-3-(2-(4-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)苯甲酸(40);
(E)-3-(2-(4-((5-环丙基-3-(2-(三氟甲基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)苯甲酸(41);
6-(5-(4-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)吡啶-3-甲酸(42);
5-(5-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)吡啶-3-甲酸(43);
5-(5-(4-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)吡啶-3-甲酸(44);
5-(5-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)吡啶-2-甲酸(45);
5-(5-(4-((5-环丙基-3-(2-(三氟甲基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)吡啶-2-甲酸(46);
6-(5-(4-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)吡啶-2-甲酸(47);
6-(5-(4-((5-环丙基-3-(2-(三氟甲基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)吡啶-2-甲酸(48);
4-(5-(4-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)吡啶-2-甲酸(49);
4-(5-(4-((5-环丙基-3-(2-(三氟甲基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)吡啶-2-甲酸(50);
2-(4-((5-环丙基-3-(2-(三氟甲基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-4-氟苯并[d]噻唑-6-甲酸(51);
3-(5-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,3,4噁二唑-2-基)苯甲酸(52);
3-(5-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,3,4-噻二唑-2-基)苯甲酸(53);
3-(3-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-5-基)苯甲酸(54);
3-(3-(4-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-5-基)苯甲酸(55);
4-(3-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-5-基)苯甲酸(56);
4-(3-(4-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-5-基)苯甲酸(57);
4-(3-(4-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-5-基)吡啶-2-甲酸(58);
4-(3-(4-((5-环丙基-3-(2-(三氟甲基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-5-基)吡啶-2-甲酸(59);
6-(3-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-5-基)吡啶-2-甲酸(60);
6-(3-(4-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-5-基)吡啶-2-甲酸(61);
2-(4-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)喹唑啉-6-甲酸(62);
5-(5-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-2-氟苯甲酸(64);
4-(((4-(6-(1H-四唑-5-基)苯并[d]噻唑-2-基)双环[2.2.2]辛-1-基)氧基)甲基)-5-环丙基-3-(2,6-二氯苯基)异噁唑(66);
3-(5-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-2,6-二氟苯甲酸(68);
5-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-2-甲氧基苯甲酸(69);
3-(3-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-5-基)-1-甲基-1H-吡唑-5-甲酸(70);
3-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-2-氟苯甲酸(71);
2-(5-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)乙酸(72);
(5-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)甲醇(73);
5-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-甲酰胺(74);
1-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲基)-1H-吡唑-4-甲酸(76);
3-((4-((5-环丙基-3-(2-三氟甲氧基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)苯甲酸(77);
3-((4-((5-环丙基-3-(2-三氟甲氧基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)吡啶-3-甲酸(78);
2-((4-((5-环丙基-3-(2-三氟甲氧基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-氟苯并[d]噻唑-6-甲酸(79);
顺-3-((4-((5-环丙基-3-(2-三氟甲氧基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)环己烷甲酸(80);
反-3-((4-((5-环丙基-3-(2-三氟甲氧基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)环己烷甲酸(81);
3-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)苯甲酸(82);
2-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-氟苯并[d]噻唑-6-甲酸(83);
6-((4-((5-环丙基-3-(2-三氟甲氧基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-甲基-1H-吲哚-3-甲酸(84);
3-((4-((5-环丙基-3-(2-三氟甲氧基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氨基)苯甲酸(85);
3-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)苯甲腈(88);
4-((4-((3-(2H-四唑-5-基)苯氧基)甲基)双环[2.2.2]辛-1-基氧基)甲基)-5-环丙基-3-(2,6-二氯苯基)异噁唑(89);
6-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-1-甲基-1H-吲哚-3-甲酸(90);
3-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)苯甲酸(91);
3-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-氟苯甲酸(92);
5-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-2-氟苯甲酸(93);
3-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-5-氟苯甲酸(94);
3-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-2-甲基苯甲酸(95);
3-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-2-氟苯甲酸(96);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-1-甲基-1H-吲哚-3-甲酸(97);
3-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-氟苯甲酸(98);
4-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)苯甲酸(99);
6-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-(三氟甲基)喹啉-2-甲酸(100);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-(三氟甲基)喹啉-2-甲酸(101);
3-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-5-氟苯甲酸(102);
3-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-5-(三氟甲基)苯甲酸(103);
2-(2-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)吡啶-4-基)乙酸(104);
6-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)喹啉-2-甲酸(105);
2-(3-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)苯基)乙酸(106);
6-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)吡啶-3-甲酸(107);
2-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)嘧啶-4-甲酸(108);
5-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)吡啶-3-甲酸(109);
6-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)吡啶-2-甲酸(110);
2-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)吡啶-4-甲酸(111);
6-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)吡嗪-2-甲酸(112);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)吡啶-2-甲酸(113);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)吡啶-3-甲酸(114);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)喹啉-2-甲酸(115);
2-(2-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)苯基)乙酸(116);
6-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)吡啶-2-甲酰胺(117);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-5-氟吡啶-3-甲酸(118);
6-((4-((3-(3-氯-5-甲氧基吡啶-4-基)-5-环丙基异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-甲基吡啶-3-甲酸(119);
6-((4-((3-(3-氯-5-甲氧基吡啶-4-基)-5-环丙基异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-3-甲基吡啶-2-甲酸(120);
3-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)(羟基)甲基)-4-氟苯甲酸(121);
2-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)(羟基)甲基)-4-氟苯并[d]噻唑-6-甲酸(122);
2-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)(羟基)甲基)-4-氟苯并[d]噻唑-6-甲酰胺(123);
2-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)(羟基)甲基)苯并[d]噻唑-6-甲酸(124);
4-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)(羟基)甲基)-3-氟苯甲酸(125);
6-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)(羟基)甲基)-2-萘甲酸(126);
3-(2-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-2-羟乙基)苯甲酸(127);
4-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)(羟基)甲基)喹啉-7-甲酸(128);
1-(3-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)(羟基)甲基)苯基)环丙烷-1-甲酸(129);
3-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)苯甲酸(130);
3-(4-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1H-1,2,3-三唑-1-基)苯甲酸(131);
2-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)吡啶-4-甲酸(132);
2-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-4-氟苯并[d]噻唑-6-甲酸(133);
2-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)喹啉-6-甲酸(134);
6-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1-甲基-1H-吡咯并[2,3-b]吡啶-3-甲酸(135);
6-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,5-二氮杂萘-2-甲酸(136);
2-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)吡啶-4-甲酸(137);
6-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)吡啶-3-甲酸(138);
2-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛烷-1-羰基)-1,2,3,4-四氢异喹啉-5-甲酸(139);
2-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛烷-1-羰基)-1,2,3,4-四氢异喹啉-6-甲酸(140);
4-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛烷-1-甲酰氨基)甲基)苯甲酸(141);
2-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛烷-1-甲酰氨基)甲基)苯甲酸(142);
3-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛烷-1-甲酰氨基)甲基)苯甲酸(143);
2-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)-N-甲基双环[2.2.2]辛烷-1-甲酰氨基)甲基)苯甲酸(144);
2-(1-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛烷-1-羰基)哌啶-4-基)乙酸(145);
2-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛烷-1-羰基)-1,2,3,4-四氢异喹啉-8-甲酸(146);
3-(5-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸(151);
4-(5-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸(152);
3-(5-(4-(((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸(153);
4-(5-(4-(((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸(154);
4-(5-(4-(((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸甲酯(155);
4-(5-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸甲酯(156);
3-(5-(4-(2-(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸甲酯(158);
(E)-3-(5-(4-(2-(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸(159);
(E)-4-(5-(4-(2-(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸(160);
4-(5-(4-(2-(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸甲酯(161);
2-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛-1-基)噻唑-4-甲酸(162);
(Z)-3-(5-(4-(2-(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸(163);
(Z)-4-(5-(4-(2-(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸(164);
3-氯-4-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛烷-1-甲酰氨基)苯甲酸甲酯(165);
3-(5-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)氨基)甲基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸(166);
4-(5-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)氨基)甲基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸(167);
2-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛-1-基)苯并[d]噻唑-6-甲酸(168);
3-氯-4-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛烷-1-硫代碳酰氨基)苯甲酸甲酯(169);
3-氯-4-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛烷-1-甲酰氨基)苯甲酸(170);
3-氯-4-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛烷-1-硫代碳酰氨基)苯甲酸(171);
2-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛-1-基)苯并[d]噻唑-7-甲酸(172);
2-氯-3-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛烷-1-甲酰氨基)苯甲酸(173);
4-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛-1-基)苯甲酸(174);
2-((4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛-1-基)甲氧基)噻唑-4-甲酸(176);
2-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛-1-基)噁唑-4-甲酸(177);
2-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛-1-基)苯并[d]噁唑-6-甲酸(178);
2-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛-1-基)-4-甲基噻唑-5-甲酸(179);
(E)-2-(4-(2-(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)苯并[d]噻唑-6-甲酸(180);
(Z)-2-(4-(2-(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)苯并[d]噻唑-6-甲酸(181);
(E)-2-(4-(2-(5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)苯并[d]噻唑-6-甲酸(182);
2-(4-(2-(5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)苯并[d]噻唑-7-甲酸(183);
2-(4-(2-(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)苯并[d]噻唑-7-甲酸(184);
2-氯-3-(4-(2-(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)乙烯基)双环[2.2.2]辛烷-1-甲酰氨基)苯甲酸(185);
2-(4-(2-(5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)苯并[d]噻唑-7-甲酸(186);
3-(4-(2-(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)乙烯基)双环[2.2.2]辛烷-1-甲酰氨基)苯甲酸甲酯(187);
3-(4-(2-(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)乙烯基)双环[2.2.2]辛烷-1-甲酰氨基)苯甲酸(188);
2-(4-(2-(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)苯并[d]噻唑-7-甲酸(189);
3-(4-(2-(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)乙烯基)双环[2.2.2]辛烷-1-甲酰氨基)苯甲酸(190);
2-((4-(2-(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)甲氧基)-4-氟苯并[d]噻唑-6-甲酸(191);
2-((4-(2-(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)甲氧基)苯并[d]噻唑-6-甲酸(192);
3-(5-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)-2-氧杂双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸(193);
(E)-4-(4-(2-(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)乙烯基)-2-氧杂双环[2.2.2]辛-1-基)苯甲酸(194);
3-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)-2-氧杂双环[2.2.2]辛-1-基)苯甲酸(195);
4-(5-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)-2-氧杂双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸(196);
(E)-3-(2-(4-(((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)甲基)-2-氧杂双环[2.2.2]辛-1-基)乙烯基)苯甲酸(197);
5-(5-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)-2-氧杂双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-2-氟苯甲酸(198);
3-(5-(4-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-2-氧杂双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸(199);
(E)-3-(2-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)-2-氧杂双环[2.2.2]辛-1-基)乙烯基)苯甲酸(200);
4-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)-2-氧杂双环[2.2.2]辛-1-基)苯甲酸(201);
5-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)-2-氧杂双环[2.2.2]辛-1-基)-2-氟苯甲酸(202);
4-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)氨基)甲基)-2-氧杂双环[2.2.2]辛-1-基)苯甲酸(203);
3-(4-(((5-环丙基-3-(2-三氟甲氧基苯基)异噁唑-4-基)甲氧基)甲基)-2-氧杂双环[2.2.2]辛-1-基)苯甲酸(204);
4-(4-(((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)甲基)-2-氧杂双环[2.2.2]辛-1-基)苯甲酸(205);
3-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)-2-氧杂双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸(206);
5-(4-(((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)甲基)-2-氧杂双环[2.2.2]辛-1-基)-2-氟苯甲酸(207);
4-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)氨基)甲基)-2-氧杂双环[2.2.2]辛-1-基)苯甲酰胺(208);
4-(5-(4-(((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)甲基)-2-氧杂双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸(209);
3-(5-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)-2-氧杂双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸(210);
4-(5-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)-2-氧杂双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸(211);
4-(5-(4-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-2-氧杂双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸(212);
3-(5-(4-(((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)甲基)-2-氧杂双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸(213);
2-(4-(((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)甲基)-2-氧杂双环[2.2.2]辛-1-基)噻唑-4-甲酸(214);
3-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)-2-氧杂双环[2.2.2]辛-1-基)-N-(甲基磺酰基)苯甲酰胺(215);
2-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)-2-氧杂双环[2.2.2]辛-1-基)噻唑-4-甲酸(216);
4-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)氨基)甲基)-2-氧杂双环[2.2.2]辛-1-基)苯甲酸甲酯(217);
4-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)-2-氧杂双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸(218);
3-(5-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)-2-氧杂双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-5-氟苯甲酸(219);
4-(((1-(3-(1H-四唑-5-基)苯基)-2-氧杂双环[2.2.2]辛-4-基)甲氧基)甲基)-5-环丙基-3-(2,6-二氯苯基)异噁唑(220);
3-(5-((1R,4R)-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.1]庚-1-基)-1,2,4-噁二唑-3-基)苯甲酸(221);
4-(5-((1R,4R)-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.1]庚-1-基)-1,2,4-噁二唑-3-基)苯甲酸(222);
3-(5-((1R,4R)-4-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)双环[2.2.1]庚-1-基)-1,2,4-噁二唑-3-基)苯甲酸(223);
4-(5-((1R,4R)-4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)双环[2.2.1]庚-1-基)-1,2,4-噁二唑-3-基)苯甲酸(224);
3-(5-((1R,4R)-4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)双环[2.2.1]庚-1-基)-1,2,4-噁二唑-3-基)苯甲酸(225);
4-(5-(4-(2-(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)乙烯基)双环[2.2.1]庚-1-基)-1,2,4-噁二唑-3-基)苯甲酸(226);
4-(5-(4-(2-(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)乙烯基)双环[2.2.1]庚-1-基)-1,2,4-噁二唑-3-基)苯甲酸(227);
4-(5-(4-(2-(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)乙烯基)双环[2.2.1]庚-1-基)-1,2,4-噁二唑-3-基)苯甲酸甲酯(228);
3-(4-(2-(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)乙烯基)双环[2.2.1]庚烷-1-甲酰氨基)苯甲酸甲酯(229);
3-(4-(2-(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)乙烯基)双环[2.2.1]庚烷-1-甲酰氨基)苯甲酸(230);
2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-4-氟苯并[d]噻唑-6-甲酸(231);
3-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸(232);
5-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-2-氟苯甲酸(233);
5-(3-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-5-基)-2-甲氧基苯甲酸(234);
3-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-5-(三氟甲基)苯甲酸(235);
5-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-2-甲氧基-N-(甲基磺酰基)苯甲酰胺(236);
3-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-2-甲氧基苯甲酸(237);
5-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-3-氟-2-甲氧基苯甲酸(238);
3-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-5-甲氧基苯甲酸(239);
5-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-2-甲氧基苯甲酰胺(240);
5-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-2-氟-3-甲氧基苯甲酸(241);
4-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-2-(1H-四唑-5-基)苯酚(242);
5-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-2,3-二甲氧基苯甲酸(243);
3-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-2-氟-5-甲氧基苯甲酸(244);
3-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-5-氟-2-甲氧基苯甲酸(245);
3-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-2,5-二甲氧基苯甲酸(246);
6-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)吡啶-2-甲酸(247);
3-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-2,6-二氟苯甲酸(248);
4-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)吡啶-2-甲酸(249);
3-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-2-氟-6-甲氧基苯甲酸(250);
3-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-5-异丙氧基苯甲酸(251);
5-(4-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)噁唑-2-基)-2-甲氧基苯甲酸(252);
6-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-3-甲氧基吡啶-2-甲酸(253);
5-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-2-(三氟甲基)苯甲酸(254);
5-(4-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)噻唑-2-基)-2-甲氧基苯甲酸(255);
5-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-2-异丙氧基苯甲酸(256);
4-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-6-甲氧基吡啶-2-甲酸(257);
4-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-6-异丙氧基吡啶-2-甲酸(258);
5-(4-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1H-咪唑-2-基)-2-甲氧基苯甲酸(259);
6-环丙氧基-4-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)吡啶-2-甲酸(260);
6-环丁氧基-4-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)吡啶-2-甲酸(261);
4-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-6-(二甲氨基)吡啶-2-甲酸(262);
4-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-6-(2,2,2-三氟乙氧基)吡啶-2-甲酸(263);
4-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-6-(三氟甲基)吡啶-2-甲酸(264);
5-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-3-甲氧基吡啶-2-甲酸(265);
2-(5-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)环丙烷-1-甲酸(266);
5-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-3-(2H-四唑-5-基)-1,2,4-噁二唑(267);
-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲基)-3-(二氟甲基)-1H-吡唑-4-甲酸(268);
1-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲基)-5-(二氟甲基)-1H-吡唑-4-甲酸(269);
2-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)环丙烷-1-甲酸(270);
1-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)环丙烷-1-甲酸(271);
2-(5-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲基)-1,2,4-噁二唑-3-基)环丙烷-1-甲酸(272);
5-(5-(4-((3-(4-氯-1-甲基-1H-吡唑-5-基)-5-环丙基异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-2-甲氧基苯甲酸(273);
14-(5-(4-((3-(4-氯-1-甲基-1H-吡唑-5-基)-5-环丙基异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-6-异丙氧基吡啶-2-甲酸(274);
4-(5-(4-((3-(4-氯-1-甲基-1H-吡唑-5-基)-5-环丙基异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-6-甲氧基吡啶-2-甲酸(275);
4-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-3-氟苯甲酸(276);
5-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-2-氟苯甲酸(277);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-5-(三氟甲基)吡啶-3-甲酰胺(278);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-5-(三氟甲基)吡啶-3-甲酸(279);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-(三氟甲基)吡啶-2-甲酸(280);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-甲氧基喹啉-2-甲酸(282);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-(三氟甲基)吡啶-3-甲酸(283);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-(二氟甲氧基)喹啉-2-甲酸(284);
5-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-3-(三氟甲基)吡啶-2-甲酸(285);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-N-(甲基磺酰基)-4-(三氟甲基)喹啉-2-甲酰胺(286);
7-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)异喹啉-3-甲酸(287);
6-((4-((5-环丙基-3-(2-(三氟甲基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-(三氟甲基)喹啉-2-甲酸(288);
6-((4-((5-环丙基-3-(2-(三氟甲基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-甲氧基喹啉-2-甲酸(289);
5-((4-((5-环丙基-3-(2-(三氟甲基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-2-氟苯甲酸(290);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-(三氟甲基)喹啉-2-甲酰胺(291);
4-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)异喹啉-1-甲酸(292);
5-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-3-(甲氧基甲基)吡啶-2-甲酸(293);
5-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-3-乙氧基吡啶-2-甲酸(294);
5-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-3-乙氧基吡啶-2-甲酰胺(295);
4-((4-((5-环丙基-3-(2-(三氟甲基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)异喹啉-1-甲酸(296);
5-((4-((5-环丙基-3-(2-(三氟甲基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-3-乙氧基吡啶-2-甲酸(297);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-1,5-二氮杂萘-2-甲酸(298);
5-((4-((5-环丙基-3-(2-(三氟甲基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-3-乙氧基吡啶-2-甲酰胺(299);
5-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-3-(2,2,2-三氟乙氧基)吡啶-2-甲酸(300);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-甲氧基吡啶-3-甲酸(301);
8-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)喹啉-5-甲酸(302);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-8-氟-4-甲氧基喹啉-2-甲酸(303);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-8-氟-4-异丙氧基喹啉-2-甲酸(304);
8-((4-((5-环丙基-3-(2-(三氟甲基)苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)喹啉-5-甲酸(305);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-乙氧基-8-氟喹啉-2-甲酸(306);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-8-氟-4-甲基喹啉-2-甲酸(307);
4-环丁氧基-6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-8-氟喹啉-2-甲酸(308);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-8-氟-4-丙基喹啉-2-甲酸(309);
2-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-8-甲氧基喹啉-6-甲酸(310);
4-环丙基-6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-8-氟喹啉-2-甲酸(311);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-8-氟-4-(氧杂环丁-3-基氧基)喹啉-2-甲酸(312);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-乙氧基-7-氟喹啉-2-甲酸(313);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-(环丙基甲氧基)-7-氟喹啉-2-甲酸(314);
3-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-1-甲基-1H-吡唑-5-甲酸(315);
3-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-1-乙基-1H-吡唑-5-甲酸(316);
2-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-(三氟甲基)噻唑-5-甲酸(317);
2-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-甲基噻唑-5-甲酸(318);
5-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)吡啶-2-甲酸(319);
4-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-3-(三氟甲基)苯甲酸(320);
3-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-5-甲氧基苯甲酸(321);
3-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-5-甲基苯甲酸(322);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-甲氧基吡啶-2-甲酸(323);
4-环丙基-6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)喹啉-2-甲酸(324);
-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-甲基喹啉-2-甲酸(325);
3-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-5-异丙氧基苯甲酸(326);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-羟基喹啉-2-甲酸(327);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-异丙氧基喹啉-2-甲酸(328);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-(3-甲氧基氮杂环丁-1-基)喹啉-2-甲酸(329);
66-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-(二甲氨基)喹啉-2-甲酸(330);
4-环丙氧基-6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)喹啉-2-甲酸(331);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-(甲基磺酰基)喹啉-2-甲酸(332);
5-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-3-甲基吡啶-2-甲酰胺(333);
5-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-3-异丙氧基吡啶-2-甲酸(334);
5-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-3-甲氧基吡啶-2-甲酸(335);
5-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-3-(2-甲氧基乙氧基)吡啶-2-甲酸(336);
5-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-3-(环丙基甲氧基)吡啶-2-甲酸(337);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-丙基喹啉-2-甲酸(338);
3-环丁氧基-5-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)吡啶-2-甲酸(339);
3-环丙氧基-5-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)吡啶-2-甲酸(340);
2-(4-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)苯氧基)丙酸(341);
2-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-8-甲氧基喹啉-5-甲酸(342);
2-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)喹啉-5-甲酸(343);
4-环丁氧基-6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)喹啉-2-甲酸(344);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-乙氧基喹啉-2-甲酸(345);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-(环丙基甲氧基)喹啉-2-甲酸(346);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-乙基喹啉-2-甲酸(347);
5-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-3-甲基吡啶-2-甲酸(348);
8-环丁氧基-2-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)喹啉-5-甲酸(349);
2-((4-((3-(3-氯-5-甲氧基吡啶-4-基)-5-环丙基异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-甲氧基喹啉-6-甲酸(350);
2-((4-((3-(3-氯-5-甲氧基吡啶-4-基)-5-环丙基异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-8-环丙基喹啉-6-甲酸(351);
3-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)喹啉-8-甲酸(352);
4-(环丁基甲氧基)-6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)喹啉-2-甲酸(353);
4-((1-氯-3-羟基丙-2-基)氧基)-6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)喹啉-2-甲酸(354);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-异丁氧基喹啉-2-甲酸(355);
4-(3-氯-2-(羟基甲基)丙氧基)-6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)喹啉-2-甲酸(356);
7-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-1-异丙氧基异喹啉-3-甲酸(357);
4-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-2-甲氧基苯甲酸(358);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-(氧杂环丁-3-基甲氧基)喹啉-2-甲酸(360);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-(氧杂环丁-3-基氧基)喹啉-2-甲酸(361);
2-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲基)-1,2,3,4-四氢异喹啉-7-甲酸(362);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-1-甲基-1H-吡咯并[2,3-b]吡啶-3-甲酸(363);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-4-(三氟甲基)喹啉-2-甲酸(364);
6-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1-甲基-1H-吡唑并[3,4-b]吡啶-3-甲酸(365);
3-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-5-(三氟甲基)苯甲酸(366);
5-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-2-甲氧基苯甲酸(367);
2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)喹啉-5-甲酸(368);
2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-8-氟喹啉-6-甲酸(369);
2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-8-(三氟甲基)喹啉-6-甲酸(370);
2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-8-甲氧基喹啉-5-甲酸(371);
4-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-8-(三氟甲基)喹啉-6-甲酸(372);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-4-(三氟甲基)吡啶-2-甲酸(373);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-4-(三氟甲基)吡啶-3-甲酸(374);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-4-甲氧基喹啉-2-甲酸(375);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-4-(二氟甲氧基)喹啉-2-甲酸(376);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-4-甲氧基吡啶-2-甲酸(377);
3-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-5-(三氟甲氧基)苯甲酸(378);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-5-氟吡啶-3-甲酸(379);
3-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-5-甲氧基苯甲酸(380);
3-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-2-甲氧基苯甲酸(381);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)喹啉-2-甲酸(382);
3-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-2-甲氧基苯甲酸(383);
8-氰基-2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)喹啉-5-甲酸(384);
8-环丙基-2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)喹啉-5-甲酸(385);
3-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-5-(甲氧基甲基)苯甲酸(386);
5-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-4-甲基吡啶-2-甲酸(387);
5-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-3-甲基吡啶-2-甲酸(388);
2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-8-甲基喹啉-5-甲酸(389);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-4-异丙氧基喹啉-2-甲酸(390);
2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-8-异丙氧基喹啉-5-甲酸(391);
2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-8-(环丙基甲氧基)喹啉-5-甲酸(392);
3-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)咪唑并[1,2-a]吡啶-7-甲酸(393);
7-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)咪唑并[1,2-a]吡啶-2-甲酸(394);
5-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)吡唑并[1,5-a]吡啶-3-甲酸(395);
5-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)吡唑并[1,5-a]吡啶-3-甲酸(396);
3-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)咪唑并[1,2-a]吡啶-8-甲酸(397);
2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-8-(三氟甲基)喹啉-5-甲酸(398);
3-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-1-甲基-1H-吲哚-6-甲酸(399);
3-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-5-异丙氧基苯甲酸(400);
5-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-1H-吲唑-7-甲酸(401);
4-环丁氧基-6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)喹啉-2-甲酸(402);
6-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1-乙基-1H-吡唑并[3,4-b]吡啶-3-甲酸(403);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)咪唑并[1,2-a]吡啶-8-甲酸(404);
8-环丁氧基-2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)喹啉-5-甲酸(405);
2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-8-(氧杂环丁-3-基氧基)喹啉-5-甲酸(406);
2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-8-羟基喹啉-5-甲酸(407);
8-(环戊氧基)-2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)喹啉-5-甲酸(408);
2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-8-(吡咯烷-1-基)喹啉-5-甲酸(409);
2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-8-吗啉代喹啉-5-甲酸(410);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-1H-吲唑-4-甲酸(411);
8-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)喹啉-5-甲酸(412);
2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-8-(4-甲基哌嗪-1-基)喹啉-5-甲酸(413);
2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-8-((四氢-2H-吡喃-4-基)氧基)喹啉-5-甲酸(414);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-1H-吲哚-4-甲酸(415);
4-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-1H-吲哚-6-甲酸(416);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-2-甲基吡啶-3-甲酸(417);
2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-8-(2-羟基-2-甲基丙氧基)喹啉-5-甲酸(418);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)哒嗪-3-甲酸(419);
2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-7-(三氟甲基)喹啉-5-甲酸(420);
6-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,5-二氮杂萘-2-甲酸(421);
2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-5-(三氟甲基)喹啉-7-甲酸(422);
2-(4-((5-环丙基-3-(二环丙基甲基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-7-(三氟甲基)喹啉-5-甲酸(423);
8-环丙基-2-(4-((5-环丙基-3-(二环丙基甲基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)喹啉-5-甲酸(424);
2-(4-((5-环丙基-3-(2,2-二氟-1-甲基环丙基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)喹啉-5-甲酸(425);
8-氯-2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-6-甲氧基喹啉-5-甲酸(426);
8-氯-2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-6-异丙氧基喹啉-5-甲酸(427);
2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-6-甲氧基喹啉-5-甲酸(428);
8-氯-6-环丁氧基-2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)喹啉-5-甲酸(429);
6-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙基)-4-(三氟甲基)喹啉-2-甲酸(430);
2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)苯并[d]噻唑-7-甲酸(432);
3-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛烷-1-甲酰氨基)-5-(三氟甲基)苯甲酸(433);
2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-5-(三氟甲基)苯并[d]噻唑-7-甲酸(434);
2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-5-(三氟甲基)苯并[d]噻唑-7-甲酰胺(435);
(E)-3-(5-(4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-5-(三氟甲基)苯甲酸(436);
(E)-5-(5-(4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-2-甲氧基苯甲酸(437);
(E)-5-(5-(4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-2-甲氧基-N-(甲基磺酰基)苯甲酰胺(438);
(E)-5-(5-(4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-N-(环丙磺酰基)-2-甲氧基苯甲酰胺(439);
(E)-3-(5-(4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-N-(甲基磺酰基)-5-(三氟甲基)苯甲酰胺(440);
(E)-3-(5-(4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-5-(三氟甲基)苯甲酰胺(441);
(E)-3-(5-(4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-5-氟苯甲酸(442);
(E)-3-(5-(4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-5-(二氟甲氧基)苯甲酸甲酯(443);
(E)-3-((4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)甲氧基)-5-(二氟甲氧基)苯甲酸(444);
(E)-3-(5-(4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-N-(甲基磺酰基)-5-(三氟甲基)苯甲酰胺(445);
(E)-5-(5-(4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-2-(二氟甲氧基)苯甲酸(446);
(E)-4-((4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)甲氧基)-8-氟-2-甲基喹啉-6-甲酸(447);
(E)-3-(5-(4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-2-甲氧基苯甲酸(448);
(E)-3-(5-(4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-N-(甲基磺酰基)-5-(三氟甲基)苯甲酰胺(449);
(E)-4-((4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)甲氧基)-3-甲氧基苯甲酸(450);
(E)-6-((4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)甲氧基)-4-(二氟甲氧基)喹啉-2-甲酸(451);
(E)-6-((4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)甲氧基)-4-(三氟甲基)喹啉-2-甲酸(452);
2-(4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)-2-氧杂双环[2.2.2]辛-1-基)苯并[d]噻唑-7-甲酸(454);
5-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)-2-氧杂双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-2-甲氧基苯甲酸(455);
2-(4-(2-(5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)乙基)双环[2.2.2]辛-1-基)苯并[d]噻唑-7-甲酸(456);
(E)-4-(4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)-2-氧杂双环[2.2.2]辛-1-基)苯甲酸(457);
3-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-5-氟苯甲酸(458);
3-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-4-甲氧基苯甲酸(459);
3-(5-(4-((5-环丙基-3-(3-氟吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸(460);
3-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-4-氟苯甲酸(461);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)咪唑并[1,2-b]哒嗪-3-甲腈(462);
2-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-5-氟苯并[d]噻唑-7-甲酸(463);
3-((4-(((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛-1-基)甲氧基)-5-(三氟甲基)苯甲酸(464);
2-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)噻唑-4-甲酸(465);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)咪唑并[1,2-b]哒嗪-3-甲酸(466);
(E)-3-(5-(4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)-2-氧杂双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸(467);
(E)-3-((4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)-2-氧杂双环[2.2.2]辛-1-基)甲氧基)-5-(三氟甲基)苯甲酸(468);
(E)-2-((4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)甲氧基)-5-氟苯并[d]噻唑-7-甲酸(469);
(E)-3-((4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)-2-氧杂双环[2.2.2]辛-1-基)甲氧基)-5-甲氧基苯甲酸(470);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)-2-氧杂双环[2.2.2]辛-1-基)甲氧基)-4-(二氟甲氧基)喹啉-2-甲酸(471);
(E)-6-((1-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)-2-氧杂双环[2.2.2]辛-4-基)甲氧基)-4-(二氟甲氧基)喹啉-2-甲酸(472);
(E)-3-((1-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)-2-氧杂双环[2.2.2]辛-4-基)甲氧基)-5-(三氟甲基)苯甲酸(473);
(E)-3-((1-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)-2-氧杂双环[2.2.2]辛-4-基)甲氧基)-5-甲氧基苯甲酸(474);
(E)-2-(4-(4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)-2-氧杂双环[2.2.2]辛-1-基)苯基)-2-甲基丙腈(475);
(E)-2-(4-(4-(2-(5-环丙基-3-(2-(三氟甲基)苯基)异噁唑-4-基)乙烯基)-2-氧杂双环[2.2.2]辛-1-基)苯基)-2-甲基丙腈(476);
(E)-2-(4-(4-(2-(5-环丙基-3-(2-(三氟甲基)苯基)异噁唑-4-基)乙烯基)-2-氧杂双环[2.2.2]辛-1-基)苯基)-2-甲基丙酸(477);
(E)-3-(5-(4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)-2-氧杂双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-5-(三氟甲基)苯甲酸(478);
(E)-3-(5-(4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)-2-氧杂双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-5-(二氟甲氧基)苯甲酸(479);
(E)-2-(4-(4-(2-(5-环丙基-3-(2-(三氟甲基)苯基)异噁唑-4-基)乙烯基)-2-氧杂双环[2.2.2]辛-1-基)苯基)-2-甲基丙酰胺(480);
(E)-2-(4-(4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)-2-氧杂双环[2.2.2]辛-1-基)苯基)-2-甲基丙酰胺(481);
(E)-2-(4-(4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)-2-氧杂双环[2.2.2]辛-1-基)苯基)-2-甲基丙酸(482);
(E)-2-(4-(4-(2-(3-(3-氯-5-甲氧基吡啶-4-基)-5-环丙基异噁唑-4-基)乙烯基)-2-氧杂双环[2.2.2]辛-1-基)苯基)-2-甲基丙酸(483);
3-((4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛-1-基)甲氧基)苯甲酸(484);
3-(5-(4-(((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-5-(三氟甲基)苯甲酸(485);
3-(5-(4-(((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-4-氟苯甲酸(486);
3-(5-(4-(((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)甲基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-4-甲氧基苯甲酸(487);
3-(4-(((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)甲基)-2-氧杂双环[2.2.2]辛-1-基)-5-(三氟甲基)苯甲腈(488);
3-(4-(((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)甲基)-2-氧杂双环[2.2.2]辛-1-基)-5-(三氟甲基)苯甲酰胺(489);
3-(4-(((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)甲基)-2-氧杂双环[2.2.2]辛-1-基)-5-(三氟甲基)苯甲酸(490);
(E)-3-(4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)-2-氧杂双环[2.2.2]辛-1-基)-5-(三氟甲基)苯甲酸(491);
(E)-5-(5-(4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)-2-氧杂双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-2-甲氧基苯甲酸(492);
(E)-3-((4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)甲氧基)-5-甲氧基苯甲酸(493);
(E)-3-(5-(1-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)-2-氧杂双环[2.2.2]辛-4-基)-1,2,4-噁二唑-3-基)-5-(三氟甲基)苯甲酸(494);
(E)-3-(5-(1-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)-2-氧杂双环[2.2.2]辛-4-基)-1,2,4-噁二唑-3-基)苯甲酸(495);
(E)-5-(5-(1-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)-2-氧杂双环[2.2.2]辛-4-基)-1,2,4-噁二唑-3-基)-2-甲氧基苯甲酸(496);
(E)-3-(5-(1-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)-2-氧杂双环[2.2.2]辛-4-基)-1,2,4-噁二唑-3-基)-5-(二氟甲氧基)苯甲酸(497);
(E)-6-((4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)-2-氧杂双环[2.2.2]辛-1-基)甲氧基)-4-(二氟甲氧基)喹啉-2-甲酸(498);
(E)-3-((4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)-2-氧杂双环[2.2.2]辛-1-基)甲氧基)-5-(二氟甲氧基)苯甲酸(499);
(E)-6-((4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)-2-氧杂双环[2.2.2]辛-1-基)甲氧基)-4-(三氟甲基)喹啉-2-甲酸(500);
(E)-6-((4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)-2-氧杂双环[2.2.2]辛-1-基)甲氧基)-4-异丙氧基喹啉-2-甲酸(501);
(Z)-2-(4-(2-(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)苯并[d]噻唑-7-甲酸(502);
(E)-2-(4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)苯并[d]噻唑-7-甲酸(503);
(E)-3-(5-(4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)苯甲酸(504);
(E)-2-(4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)苯并[d]噻唑-6-甲酸(505);
(E)-3-((4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)甲氧基)-5-(三氟甲基)苯甲酸(506);
(E)-2-(4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)-5-(三氟甲基)苯并[d]噻唑-7-甲酸(507);
(E)-6-((4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)甲氧基)-4-甲氧基喹啉-2-甲酸(508);
(E)-2-(4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)-4-甲基噻唑-5-甲酸(509);
(E)-2-(4-(2-(5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)乙烯基)双环[2.2.2]辛-1-基)噻唑-4-甲酸(510);
3-(4-(((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)甲基)-2-氧杂双环[2.2.2]辛-1-基)苯甲酸(511);
2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-6-氟苯并[d]噻唑-7-甲酸(512);
3-(5-(4-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)立方烷-1-基)-1,2,4-噁二唑-3-基)苯甲酸(513);
3-(5-(3-(((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)甲基)双环[1.1.1]戊-1-基)-1,2,4-噁二唑-3-基)苯甲酸(514);
6-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙基)喹啉-2-甲酸(515);
(E)-2-(4-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)苯基)乙酸(516);
(E)-7-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)-1-甲氧基异喹啉-3-甲酸(517);
(E)-7-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)-1-异丙氧基异喹啉-3-甲酸(518);
7-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-1-(4-甲基哌嗪-1-基)异喹啉-3-甲酸(519);
3-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-6-氟咪唑并[1,2-a]吡啶-8-甲酸(520);
7-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-1-甲氧基异喹啉-3-甲酸(521);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-4-甲氧基-N,N-二甲基喹啉-2-甲酰胺(522);
5-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-6-(3-氟氮杂环丁-1-基)吡啶-3-甲酸(523);
2-(3-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-5-乙基-1H-吡唑-1-基)乙酸(524);
3-(((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)甲基)苯甲酸(525);
5-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-1-甲基-1H-吡唑-3-甲酸(526);
6-(((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)甲基)-4-(三氟甲基)吡啶-2-甲酸(527);
3-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-1-(环丙基甲基)-1H-吡唑-5-甲酸(528);
7-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-1-乙基异喹啉-3-甲酸(529);
3-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-1-乙基-4-甲基-1H-吡唑-5-甲酸(530);
3-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-1-异丙基-4-甲基-1H-吡唑-5-甲酸(531);
3-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-1-(环丙基甲基)-4-甲基-1H-吡唑-5-甲酸(532);
3-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-4-甲基-1-(氧杂环丁-3-基甲基)-1H-吡唑-5-甲酸(533);
3-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-1,4-二甲基-1H-吡唑-5-甲酸(534);
3-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-1-(环丙基甲基)-4-氟-1H-吡唑-5-甲酸(535);
5-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-3-(1,1-二氟乙基)吡啶-2-甲酸(536);
5-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-1-乙基-1H-吡唑-3-甲酸(537);
2-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)咪唑并[1,2-a]吡啶-7-甲酸(538);
1-环丙基-3-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-1H-吡唑-5-甲酸(539);
5-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-1-乙基-4-氟-1H-吡唑-3-甲酸(540);
1-环丙基-5-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-1H-吡唑-3-甲酸(541);
5-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)吡嗪-2-甲酸(542);
2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-8-吗啉代喹啉-6-甲酸(543);
2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-8-(氧杂环丁-3-基氧基)喹啉-6-甲酸(544);
3-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-6-(三氟甲基)咪唑并[1,2-a]吡啶-8-甲酸(545);
3-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-6-乙基咪唑并[1,2-a]吡啶-8-甲酸(546);
7-氯-1-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)异喹啉-3-甲酸(547);
7-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-1-吗啉代异喹啉-3-甲酸(548);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-1-(3-甲氧基丙氧基)异喹啉-3-甲酸(549);
7-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-1-(苯基氨基)异喹啉-3-甲酸(550);
7-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-1-(环丙基氨基)异喹啉-3-甲酸(551);
7-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-1-(3-羟基氮杂环丁-1-基)异喹啉-3-甲酸(552);
7-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-1-(3-氟氮杂环丁-1-基)异喹啉-3-甲酸(553);
2-(4-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-3-氟苯氧基)乙酸(554);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-1-吗啉代异喹啉-3-甲酸(555);
2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-8-(3-甲氧基丙氧基)喹啉-6-甲酸(556);
7-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-1-(3-羟基吡咯烷-1-基)异喹啉-3-甲酸(557);
7-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-1-(4-羟基哌啶-1-基)异喹啉-3-甲酸(558);
1-(氮杂环丁-1-基)-7-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)异喹啉-3-甲酸(559);
2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-8-((四氢呋喃-3-基)氧基)喹啉-6-甲酸(560);
2-((4-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)吡啶-2-基)氧基)乙酸(561);
6-(氮杂环丁-1-基)-5-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)吡啶-3-甲酸(562);
5-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-6-甲氧基吡啶-3-甲酸(563);
3-(4-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)苯基)丙酸(564);
2-(4-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-3-(三氟甲基)苯基)乙酸(565);
2-((4-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)苯甲基)氧基)乙酸(566);
2-(4-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-2-氟苯基)乙酸(567);
5-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-6-(4-甲基哌嗪-1-基)吡啶-3-甲酸(568);
2-((6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)吡啶-3-基)甲氧基)乙酸(569);
6-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-1-(4-甲基哌嗪-1-基)异喹啉-3-甲酸(570);
2-((5-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)吡啶-2-基)甲氧基)乙酸(571);
7-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-1-(3-(二甲氨基)氮杂环丁-1-基)异喹啉-3-甲酸(572);
7-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-1-(哌嗪-1-基)异喹啉-3-甲酸(573);
7-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙炔基)-1-(2-(吡咯烷-1-基)乙氧基)异喹啉-3-甲酸(574);
7-((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲氧基)-1-乙氧基异喹啉-3-甲酸(575);
2-(3-(((4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲基)氨基)-1H-吡唑-1-基)乙酸(576);
2-(2-(((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲基)氨基)-4-甲基噻唑-5-基)乙酸(577);
7-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲基)-5,6,7,8-四氢咪唑并[1,2-a]吡嗪-2-甲酸(578);
7-((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲基)-5,6,7,8-四氢咪唑并[1,2-a]吡嗪-2-甲酸(579);
5-(((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲基)氨基)吡啶-3-甲酸(580);
3-(((4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)甲基)氨基)-1-甲基-1H-吡唑-5-甲酸(581);
4-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-6-甲氧基吡啶-2-甲酸(582);
6-环丙氧基-4-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)吡啶-2-甲酸(583);
3-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-2-甲氧基苯甲酸(584);
5-(5-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)-1,2,4-噁二唑-3-基)-2-甲氧基吡啶-3-甲酸(585);
6-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙基)-4-异丙氧基喹啉-2-甲酸(586);
(E)-2-(4-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)苯基)乙酸(587);
(E)-6-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)喹啉-2-甲酸(588);
(E)-4-(环戊氧基)-6-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)喹啉-2-甲酸(589);
(E)-6-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)-4-甲氧基喹唑啉-2-甲酸(590);
(E)-6-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)-4-异丙氧基喹啉-2-甲酸(591);
(E)-7-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)咪唑并[1,2-a]吡啶-3-甲酸(592);
(E)-6-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)咪唑并[1,2-a]吡啶-3-甲酸(593);
(E)-2-(4-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)-2-氟苯基)乙酸(594);
(E)-6-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)-1-甲基-1H-吲哚-2-甲酸(595);
(E)-2-(5-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)吡啶-2-基)乙酸(596);
(E)-4-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)-1-甲基-1H-吲哚-2-甲酸(597);
(E)-6-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)-4-乙氧基喹啉-2-甲酸(598);
(E)-1-氯-7-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)异喹啉-3-甲酸(599);
(E)-2-(3-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)苯基)乙酸(600);
(E)-7-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)-1-(3-甲氧基丙氧基)异喹啉-3-甲酸(601);
(E)-2-(4-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)-3-氟苯基)乙酸(602);
(E)-7-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)-1-吗啉代异喹啉-3-甲酸(603);
(E)-7-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)-1-乙氧基异喹啉-3-甲酸(604);
(E)-3-(5-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)-2-甲氧基苯基)丙酸(605);
(E)-3-(4-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)苯基)丙酸(606);
(E)-3-(4-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)-2-氟苯基)丙酸(607);
(E)-2-(4-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)-3-氟苯氧基)乙酸(608);
(E)-7-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)-1-(3-甲氧基氮杂环丁-1-基)异喹啉-3-甲酸(609);
(E)-7-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)-1-(3-羟基氮杂环丁-1-基)异喹啉-3-甲酸(610);
(E)-7-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)-1-(3-氟氮杂环丁-1-基)异喹啉-3-甲酸(611);
(E)-7-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)-1-(3-(羟基甲基)氮杂环丁-1-基)异喹啉-3-甲酸(612);
(E)-1-环丁氧基-7-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)异喹啉-3-甲酸(613);
(E)-1-环丙氧基-7-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)异喹啉-3-甲酸(614);
(E)-1-(环戊氧基)-7-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)异喹啉-3-甲酸(615);
(E)-2-((5-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)吡啶-2-基)氧基)乙酸(616);
(E)-2-((4-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)吡啶-2-基)氧基)乙酸(617);
(E)-2-(4-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)苯基)-N-甲基乙酰胺(618);
(E)-4-(((4-(4-((2H-四唑-5-基)甲基)苯乙烯基)双环[2.2.2]辛-1-基)氧基)甲基)-5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑(619);
(E)-2-(4-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)苯基)-N,N-二甲基乙酰胺(620);
(E)-2-(4-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)-3-(三氟甲基)苯基)乙酸(621);
(E)-2-((4-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)苯甲基)氧基)乙酸(622);
(E)-3-(3-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)苯基)丙酸(623);
(E)-3-(5-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)-2-(2,2-二氟乙氧基)苯基)丙酸(624);
(E)-4-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)苯甲酸(625);
(E)-4-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)吡啶-2-甲酸(626);
(E)-5-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)吡啶-3-甲酸(627);
(E)-2-(4-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)苯基)噻唑-4-甲酸(628);或
(E)-7-(2-(4-((5-环丙基-3-(3,5-二氯吡啶-4-基)异噁唑-4-基)甲氧基)双环[2.2.2]辛-1-基)乙烯基)-1-(4-甲基哌嗪-1-基)异喹啉-3-甲酸(629)。
6.一种药物组合物,其包含药学上可接受的载体和根据权利要求1至5中任一项所述的化合物或其药学上可接受的盐。
7.根据权利要求1至5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法尼酯X受体调节性疾病或病症的药物中的用途,所述法尼酯X受体调节性疾病或病症选自病理性纤维化、癌症、炎性病症、代谢或胆汁郁积性病症。
8.根据权利要求7的用途,其中所述病理性纤维化为肝纤维化、肾纤维化、胆纤维化或胰纤维化。
9.根据权利要求1至5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法尼酯X受体调节性疾病或病症的药物中的用途,所述法尼酯X受体调节性疾病或病症选自非酒精性脂肪变性肝炎、非酒精性脂肪肝病、慢性肾病、原发性硬化性胆管炎或原发性胆汁性肝硬化。
10.根据权利要求1至5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法尼酯X受体调节性疾病或病症的药物中的用途,所述法尼酯X受体调节性疾病或病症为特发性肺纤维化。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201762580075P | 2017-11-01 | 2017-11-01 | |
US62/580,075 | 2017-11-01 | ||
PCT/US2018/058315 WO2019089667A1 (en) | 2017-11-01 | 2018-10-31 | Bridged bicyclic compounds as farnesoid x receptor modulators |
Publications (2)
Publication Number | Publication Date |
---|---|
CN111295382A CN111295382A (zh) | 2020-06-16 |
CN111295382B true CN111295382B (zh) | 2024-02-02 |
Family
ID=64332182
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201880070852.4A Active CN111295382B (zh) | 2017-11-01 | 2018-10-31 | 作为法尼酯x受体调节剂的桥联双环化合物 |
Country Status (19)
Country | Link |
---|---|
US (1) | US10730863B2 (zh) |
EP (1) | EP3704113B1 (zh) |
JP (1) | JP7212693B2 (zh) |
KR (1) | KR20200081434A (zh) |
CN (1) | CN111295382B (zh) |
AR (1) | AR113820A1 (zh) |
AU (1) | AU2018360577A1 (zh) |
BR (1) | BR112020008457A2 (zh) |
CA (1) | CA3079833A1 (zh) |
CL (1) | CL2020001138A1 (zh) |
CO (1) | CO2020005459A2 (zh) |
EA (1) | EA202091063A1 (zh) |
ES (1) | ES2964964T3 (zh) |
IL (1) | IL274321A (zh) |
MX (1) | MX2020004405A (zh) |
PE (1) | PE20201170A1 (zh) |
SG (1) | SG11202003827YA (zh) |
TW (1) | TW201922722A (zh) |
WO (1) | WO2019089667A1 (zh) |
Families Citing this family (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110128432B (zh) | 2018-02-02 | 2021-03-02 | 广东东阳光药业有限公司 | 含氮三环化合物及其在药物中的应用 |
JP2022512588A (ja) | 2018-10-05 | 2022-02-07 | バーテックス ファーマシューティカルズ インコーポレイテッド | アルファ1アンチトリプシンのモジュレーター |
UY38696A (es) | 2019-05-14 | 2020-11-30 | Vertex Pharma | Moduladores de alfa-1 antitripsina |
MX2021014443A (es) | 2019-05-31 | 2022-01-06 | Ikena Oncology Inc | Inhibidores del dominio asociado mejorador de la transcripcion (tead) y usos de los mismos. |
KR20220034739A (ko) | 2019-05-31 | 2022-03-18 | 이케나 온콜로지, 인코포레이티드 | Tead 억제제 및 이의 용도 |
CN110922368B (zh) * | 2019-11-29 | 2022-08-16 | 扬州工业职业技术学院 | 一种氯代苯异噁唑氨基苯甲酸衍生物及其制备方法与应用 |
CN110804025B (zh) * | 2019-11-29 | 2022-02-08 | 扬州工业职业技术学院 | 一种卤代苯异噁唑衍生物及其制备方法与应用 |
AU2021207253A1 (en) | 2020-01-15 | 2022-06-09 | Centre National De La Recherche Scientifique | Use of FXR agonists for treating an infection by hepatitis D virus |
US20230159504A1 (en) * | 2020-04-03 | 2023-05-25 | Vertex Pharmaceuticals Incorporated | 7- or 8-hydroxy-isoquinoline and 7- or 8-hydroxy-quinoline derivatives as alpha-1-antitrypsin modulators for treating alpha-1-antitrypsin deficiency (aatd) |
WO2022120353A1 (en) * | 2020-12-02 | 2022-06-09 | Ikena Oncology, Inc. | Tead inhibitors and uses thereof |
WO2022152770A1 (en) | 2021-01-14 | 2022-07-21 | Enyo Pharma | Synergistic effect of a fxr agonist and ifn for the treatment of hbv infection |
WO2022229302A1 (en) | 2021-04-28 | 2022-11-03 | Enyo Pharma | Strong potentiation of tlr3 agonists effects using fxr agonists as a combined treatment |
WO2024061768A1 (en) | 2022-09-19 | 2024-03-28 | Basf Se | Azole pesticidal compounds |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101877966A (zh) * | 2007-07-02 | 2010-11-03 | 葛兰素史密丝克莱恩有限责任公司 | 类法尼醇x受体激动剂 |
CN103443099A (zh) * | 2010-12-20 | 2013-12-11 | Irm责任有限公司 | 调节fxr的组合物和方法 |
EP3034501A1 (en) * | 2014-12-17 | 2016-06-22 | Gilead Sciences, Inc. | Hydroxy containing FXR (NR1H4) modulating compounds |
CN106146483A (zh) * | 2015-04-23 | 2016-11-23 | 上海迪诺医药科技有限公司 | 杂环类法尼酯衍生物x受体调节剂 |
CN106946867A (zh) * | 2016-01-06 | 2017-07-14 | 广州市恒诺康医药科技有限公司 | Fxr受体调节剂及其制备方法和用途 |
Family Cites Families (49)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1993013101A1 (en) | 1991-12-27 | 1993-07-08 | Yoshitomi Pharmaceutical Industries, Ltd. | Pyridonecarboxylate compound, pharmaceutical use thereof, and spiro compound |
WO1998017276A1 (en) | 1996-10-25 | 1998-04-30 | Merck & Co., Inc. | Heteroaryl spiroethercycloalkyl tachykinin receptor antagonists |
EP1071655A1 (en) | 1998-04-17 | 2001-01-31 | Kenneth Curry | Cubane derivatives as metabotropic glutamate receptor antagonists and process for their preparation |
MEP42208A (en) | 1999-11-12 | 2011-02-10 | Biogen Idec Inc | Polycycloalkylpurines as adenosine receptor antagonists |
WO2001079261A1 (en) | 2000-04-14 | 2001-10-25 | Corvas International, Inc. | Tetrahydro-azepinone derivatives as thrombin inhibitors |
EP1270558B1 (en) | 2001-06-21 | 2007-04-25 | Cesare Casagrande | "Compound for the treatment of atherosclerotic-thrombotic pathological conditions" |
EP1581525A2 (en) | 2002-08-09 | 2005-10-05 | AstraZeneca AB | Compounds having an activity at metabotropic glutamate receptors |
US20060004087A1 (en) | 2004-07-01 | 2006-01-05 | Wyeth | Tetracyclic compounds as estrogen ligands |
WO2006006490A1 (ja) | 2004-07-08 | 2006-01-19 | Ono Pharmaceutical Co., Ltd. | スピロ化合物 |
MX2007012206A (es) | 2005-04-08 | 2007-12-05 | Ptc Therapeutics Inc | Composiciones de 1,2,4-oxadiazol activo por via oral para terapia de supresion de mutacion interruptora. |
EP1962838B1 (en) | 2005-12-19 | 2011-09-28 | GlaxoSmithKline LLC | Farnesoid x receptor agonists |
AU2007292993B2 (en) | 2006-09-07 | 2013-01-24 | Idorsia Pharmaceuticals Ltd | Pyridin-4-yl derivatives as immunomodulating agents |
CL2007003035A1 (es) | 2006-10-24 | 2008-05-16 | Smithkline Beechman Corp | Compuestos derivados de isoxazol sustituidos, agonistas de receptores farnesoid x; procedimiento de preparacion; composicion farmaceutica que lo comprende; y uso del compuesto en el tratamiento de la obesidad, diabetes mellitus, fibrosis en organos, |
US20100035918A1 (en) | 2007-01-30 | 2010-02-11 | Biogen Idec Ma Inc | Imidazolone Compounds and Methods of Making and Using the Same |
WO2009009059A1 (en) | 2007-07-09 | 2009-01-15 | Biogen Idec Ma Inc. | Spiro compounds as antagonists of tgf-beta |
TW200906823A (en) | 2007-07-16 | 2009-02-16 | Lilly Co Eli | Compounds and methods for modulating FXR |
CN101910151A (zh) | 2007-10-22 | 2010-12-08 | 先灵公司 | 双环杂环衍生物及其作为gpr119活性调节剂的用途 |
CA2741839A1 (en) | 2008-11-21 | 2010-05-27 | Pfizer Inc. | 1-oxa-8-azaspiro [4,5] decane-8-carboxamide compounds as faah inhibitors |
US8791142B2 (en) | 2009-03-03 | 2014-07-29 | Merck Serono S.A. | Oxazole pyridine derivatives useful as S1P1 receptor agonists |
KR101384829B1 (ko) | 2009-05-05 | 2014-04-15 | 에프. 호프만-라 로슈 아게 | 이속사졸-피라졸 유도체 |
US8440710B2 (en) | 2009-10-15 | 2013-05-14 | Hoffmann-La Roche Inc. | HSL inhibitors useful in the treatment of diabetes |
WO2012054510A1 (en) | 2010-10-19 | 2012-04-26 | Comentis, Inc. | Oxadiazole compounds which inhibit beta-secretase activity and methods of use thereof |
WO2012068450A1 (en) | 2010-11-19 | 2012-05-24 | Incyte Corporation | Cyclobutyl substituted pyrrolopyridine and pyrrolopyrimidine derivatives as jak inhibitors |
TWI548621B (zh) | 2011-04-22 | 2016-09-11 | 標誌製藥公司 | 經取代之二胺基甲醯胺及二胺基甲腈嘧啶、其組合物、及以該等治療之方法 |
EP2520566A1 (en) | 2011-05-06 | 2012-11-07 | Orion Corporation | New Pharmaceutical Compounds |
EP2545964A1 (en) | 2011-07-13 | 2013-01-16 | Phenex Pharmaceuticals AG | Novel FXR (NR1H4) binding and activity modulating compounds |
MA37756B1 (fr) | 2012-06-13 | 2018-09-28 | Hoffmann La Roche | Nouveaux composés diazaspirocycloalcane et azaspirocycloalcane |
JP6099753B2 (ja) | 2012-10-03 | 2017-03-22 | アドビナス セラピューティクス リミテッド | スピロ環化合物、その組成物及びその医薬応用 |
WO2014071247A1 (en) | 2012-11-02 | 2014-05-08 | Dana-Farber Cancer Institute, Inc. | Pyrrol-1 -yl benzoic acid derivates useful as myc inhibitors |
EP2774919A1 (en) | 2013-03-06 | 2014-09-10 | Pharmeste S.R.L. In Liquidazione | Novel sulfonamide TRPA1 receptor antagonists |
SG11201506800YA (en) | 2013-03-14 | 2015-09-29 | Bristol Myers Squibb Co | Bicyclo [2.2.2] acid gpr120 modulators |
TW201605859A (zh) | 2013-11-14 | 2016-02-16 | 必治妥美雅史谷比公司 | 作為酪蛋白激酶1δ/ε抑制劑之新穎經取代之吡唑并-哌 |
WO2015172747A1 (en) | 2014-05-16 | 2015-11-19 | Zhaoyin Wang | Spirocyclic molecules as mth1 inhibitors |
WO2016073545A1 (en) | 2014-11-06 | 2016-05-12 | Concert Pharmaceuticals, Inc. | Phenyloxadiazole benzoic acids |
EP3034499A1 (en) | 2014-12-17 | 2016-06-22 | Gilead Sciences, Inc. | Novel FXR (NR1H4) modulating compounds |
WO2016097933A1 (en) | 2014-12-18 | 2016-06-23 | Novartis Ag | Azabicyclooctane derivatives as fxr agonists for use in the treatment of liver and gastrointestinal diseases |
EA038045B1 (ru) | 2015-02-20 | 2021-06-28 | Инсайт Корпорейшн | Бициклические гетероциклы в качестве ингибиторов fgfr |
CN107021958A (zh) | 2016-02-01 | 2017-08-08 | 山东轩竹医药科技有限公司 | Fxr受体激动剂 |
CN108602811B (zh) | 2016-02-01 | 2021-11-16 | 轩竹生物科技有限公司 | Fxr受体激动剂 |
JP6941109B2 (ja) | 2016-02-22 | 2021-09-29 | ノバルティス アーゲー | Fxrアゴニストを使用するための方法 |
SI3419625T1 (sl) | 2016-02-22 | 2021-08-31 | Novartis Ag | Postopki za uporabo agonistov FXR |
WO2017189663A1 (en) | 2016-04-26 | 2017-11-02 | Enanta Pharmaceuticals, Inc. | Isoxazole derivatives as fxr agonists and methods of use thereof |
US10080741B2 (en) | 2016-04-26 | 2018-09-25 | Enanta Pharmaceuticals, Inc. | Isoxazole derivatives as FXR agonists and methods of use thereof |
US10080742B2 (en) | 2016-04-26 | 2018-09-25 | Enanta Pharmaceuticals, Inc. | Isoxazole derivatives as FXR agonists and methods of use thereof |
WO2017201155A1 (en) | 2016-05-18 | 2017-11-23 | Enanta Pharmaceuticals, Inc. | lSOXAZOLE DERIVATIVES AS FXR AGONISTS AND METHODS OF USE THEREOF |
AR108711A1 (es) | 2016-06-13 | 2018-09-19 | Gilead Sciences Inc | Compuestos moduladores de fxr (nr1h4) |
JP6678779B2 (ja) | 2016-06-13 | 2020-04-08 | ギリアード サイエンシーズ, インコーポレイテッド | Fxr(nr1h4)調節化合物 |
CN108430998B (zh) | 2016-09-28 | 2021-07-09 | 四川科伦博泰生物医药股份有限公司 | 氮杂双环衍生物及其制备方法和用途 |
CN106632294A (zh) | 2016-12-15 | 2017-05-10 | 宁波百纳西药业有限公司 | 一种螺环化合物及其药物用途 |
-
2018
- 2018-10-31 WO PCT/US2018/058315 patent/WO2019089667A1/en unknown
- 2018-10-31 KR KR1020207015270A patent/KR20200081434A/ko not_active Application Discontinuation
- 2018-10-31 AR ARP180103177A patent/AR113820A1/es unknown
- 2018-10-31 BR BR112020008457-3A patent/BR112020008457A2/pt not_active Application Discontinuation
- 2018-10-31 CN CN201880070852.4A patent/CN111295382B/zh active Active
- 2018-10-31 US US16/175,895 patent/US10730863B2/en active Active
- 2018-10-31 PE PE2020000719A patent/PE20201170A1/es unknown
- 2018-10-31 AU AU2018360577A patent/AU2018360577A1/en not_active Abandoned
- 2018-10-31 EA EA202091063A patent/EA202091063A1/ru unknown
- 2018-10-31 CA CA3079833A patent/CA3079833A1/en active Pending
- 2018-10-31 TW TW107138558A patent/TW201922722A/zh unknown
- 2018-10-31 MX MX2020004405A patent/MX2020004405A/es unknown
- 2018-10-31 EP EP18804187.5A patent/EP3704113B1/en active Active
- 2018-10-31 SG SG11202003827YA patent/SG11202003827YA/en unknown
- 2018-10-31 JP JP2020544333A patent/JP7212693B2/ja active Active
- 2018-10-31 ES ES18804187T patent/ES2964964T3/es active Active
-
2020
- 2020-04-28 IL IL274321A patent/IL274321A/en unknown
- 2020-04-29 CL CL2020001138A patent/CL2020001138A1/es unknown
- 2020-04-30 CO CONC2020/0005459A patent/CO2020005459A2/es unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101877966A (zh) * | 2007-07-02 | 2010-11-03 | 葛兰素史密丝克莱恩有限责任公司 | 类法尼醇x受体激动剂 |
CN103443099A (zh) * | 2010-12-20 | 2013-12-11 | Irm责任有限公司 | 调节fxr的组合物和方法 |
EP3034501A1 (en) * | 2014-12-17 | 2016-06-22 | Gilead Sciences, Inc. | Hydroxy containing FXR (NR1H4) modulating compounds |
CN106146483A (zh) * | 2015-04-23 | 2016-11-23 | 上海迪诺医药科技有限公司 | 杂环类法尼酯衍生物x受体调节剂 |
CN106946867A (zh) * | 2016-01-06 | 2017-07-14 | 广州市恒诺康医药科技有限公司 | Fxr受体调节剂及其制备方法和用途 |
Also Published As
Publication number | Publication date |
---|---|
US10730863B2 (en) | 2020-08-04 |
WO2019089667A1 (en) | 2019-05-09 |
SG11202003827YA (en) | 2020-05-28 |
IL274321A (en) | 2020-06-30 |
US20190127358A1 (en) | 2019-05-02 |
CN111295382A (zh) | 2020-06-16 |
CA3079833A1 (en) | 2019-05-09 |
PE20201170A1 (es) | 2020-10-28 |
ES2964964T3 (es) | 2024-04-10 |
EP3704113B1 (en) | 2023-10-11 |
KR20200081434A (ko) | 2020-07-07 |
JP7212693B2 (ja) | 2023-01-25 |
AU2018360577A1 (en) | 2020-06-18 |
TW201922722A (zh) | 2019-06-16 |
CO2020005459A2 (es) | 2020-05-15 |
AR113820A1 (es) | 2020-06-17 |
JP2021501220A (ja) | 2021-01-14 |
EA202091063A1 (ru) | 2020-09-18 |
BR112020008457A2 (pt) | 2020-10-20 |
MX2020004405A (es) | 2020-08-06 |
CL2020001138A1 (es) | 2020-08-21 |
EP3704113A1 (en) | 2020-09-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN111295382B (zh) | 作为法尼酯x受体调节剂的桥联双环化合物 | |
EP3704106B1 (en) | Alkene compounds as farnesoid x receptor modulators | |
CN111278817B (zh) | 作为法尼醇x受体调节剂的多环化合物 | |
CN111630051B (zh) | 作为法尼醇x受体调节剂的烯烃螺环化合物 | |
EP2976341A1 (en) | Acyclic cyanoethylpyrazolo pyridones as janus kinase inhibitors | |
CA3081424A1 (en) | Spirocyclic compounds as farnesoid x receptor modulators | |
JP2024514010A (ja) | カルボキシ-ベンズイミダゾールglp-1r調節化合物 | |
CN113727973A (zh) | 可用作类法尼醇x受体调节剂的取代酰胺化合物 | |
JP7465883B2 (ja) | ファルネソイドx受容体モジュレータとしての置換二環式化合物 | |
JP7449300B2 (ja) | ファルネソイドx受容体モジュレータとして有用な置換アミド化合物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |