CA3129619A1 - Substituted amide compounds useful as farnesoid x receptor modulators - Google Patents
Substituted amide compounds useful as farnesoid x receptor modulators Download PDFInfo
- Publication number
- CA3129619A1 CA3129619A1 CA3129619A CA3129619A CA3129619A1 CA 3129619 A1 CA3129619 A1 CA 3129619A1 CA 3129619 A CA3129619 A CA 3129619A CA 3129619 A CA3129619 A CA 3129619A CA 3129619 A1 CA3129619 A1 CA 3129619A1
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- CA
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- Prior art keywords
- methyl
- phenyl
- alkyl
- octan
- 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.)
- Pending
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- -1 amide compounds Chemical class 0.000 title claims description 176
- 102100038495 Bile acid receptor Human genes 0.000 title abstract description 72
- 101000603876 Homo sapiens Bile acid receptor Proteins 0.000 title abstract description 72
- 150000001875 compounds Chemical class 0.000 claims abstract description 370
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 86
- 150000003839 salts Chemical class 0.000 claims abstract description 72
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 67
- 239000012453 solvate Substances 0.000 claims abstract description 57
- 208000035475 disorder Diseases 0.000 claims abstract description 42
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 30
- 206010016654 Fibrosis Diseases 0.000 claims abstract description 22
- 230000004761 fibrosis Effects 0.000 claims abstract description 21
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 20
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 17
- 201000011510 cancer Diseases 0.000 claims abstract description 12
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 12
- 230000001575 pathological effect Effects 0.000 claims abstract description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 216
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 133
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 claims description 78
- 125000000217 alkyl group Chemical group 0.000 claims description 63
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 57
- 229910052739 hydrogen Inorganic materials 0.000 claims description 45
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 43
- 239000001257 hydrogen Substances 0.000 claims description 43
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 34
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 29
- 125000003545 alkoxy group Chemical group 0.000 claims description 29
- 125000004043 oxo group Chemical group O=* 0.000 claims description 29
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 27
- 150000002431 hydrogen Chemical class 0.000 claims description 27
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 25
- 125000001072 heteroaryl group Chemical group 0.000 claims description 24
- 125000004122 cyclic group Chemical group 0.000 claims description 23
- 125000005843 halogen group Chemical group 0.000 claims description 23
- 229910052801 chlorine Inorganic materials 0.000 claims description 22
- 229910052731 fluorine Inorganic materials 0.000 claims description 22
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 22
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 20
- 125000003118 aryl group Chemical group 0.000 claims description 19
- 229910052799 carbon Inorganic materials 0.000 claims description 19
- 229910052757 nitrogen Inorganic materials 0.000 claims description 18
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 17
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims description 17
- 125000004432 carbon atom Chemical group C* 0.000 claims description 16
- 239000003937 drug carrier Substances 0.000 claims description 16
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 15
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 15
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 15
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 14
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 12
- BSTCSVVVYCMKAR-SFQUDFHCSA-N methyl (E)-3-[3-[cyclohexanecarbonyl-[[4-[4-(dimethylamino)phenyl]-1-bicyclo[2.2.2]octanyl]methyl]amino]phenyl]prop-2-enoate Chemical compound CN(C1=CC=C(C=C1)C12CCC(CC1)(CC2)CN(C(=O)C1CCCCC1)C=1C=C(C=CC=1)/C=C/C(=O)OC)C BSTCSVVVYCMKAR-SFQUDFHCSA-N 0.000 claims description 12
- LDHQCZJRKDOVOX-NSCUHMNNSA-M crotonate Chemical compound C\C=C\C([O-])=O LDHQCZJRKDOVOX-NSCUHMNNSA-M 0.000 claims description 11
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 11
- 125000001424 substituent group Chemical group 0.000 claims description 11
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 claims description 10
- 208000036971 interstitial lung disease 2 Diseases 0.000 claims description 10
- 208000033222 Biliary cirrhosis primary Diseases 0.000 claims description 9
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 9
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 9
- 208000012654 Primary biliary cholangitis Diseases 0.000 claims description 9
- 150000001602 bicycloalkyls Chemical group 0.000 claims description 9
- 125000004428 fluoroalkoxy group Chemical group 0.000 claims description 9
- 125000003709 fluoroalkyl group Chemical group 0.000 claims description 9
- PZGWYVQYEPHLTQ-LFIBNONCSA-N (E)-3-[3-[cyclohexanecarbonyl-[[4-[4-(dimethylamino)phenyl]-1-bicyclo[2.2.2]octanyl]methyl]amino]phenyl]prop-2-enoic acid Chemical compound CN(C1=CC=C(C=C1)C12CCC(CC1)(CC2)CN(C(=O)C1CCCCC1)C=1C=C(C=CC=1)/C=C/C(=O)O)C PZGWYVQYEPHLTQ-LFIBNONCSA-N 0.000 claims description 8
- 125000003342 alkenyl group Chemical group 0.000 claims description 8
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 8
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 8
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 claims description 7
- 125000000304 alkynyl group Chemical group 0.000 claims description 7
- 125000002619 bicyclic group Chemical group 0.000 claims description 7
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- ITGXBYHEMGZUGW-LFIBNONCSA-N methyl (E)-3-[3-[[4-[4-(azetidin-1-yl)phenyl]-1-bicyclo[2.2.2]octanyl]methyl-(cyclohexanecarbonyl)amino]phenyl]prop-2-enoate Chemical compound N1(CCC1)C1=CC=C(C=C1)C12CCC(CC1)(CC2)CN(C(=O)C1CCCCC1)C=1C=C(C=CC=1)/C=C/C(=O)OC ITGXBYHEMGZUGW-LFIBNONCSA-N 0.000 claims description 7
- CRUPKDGDYYWNRS-KPKJPENVSA-N methyl (E)-3-[3-[[4-[4-(dimethylamino)phenyl]-1-bicyclo[2.2.2]octanyl]methyl-(oxane-4-carbonyl)amino]phenyl]prop-2-enoate Chemical compound CN(C1=CC=C(C=C1)C12CCC(CC1)(CC2)CN(C(=O)C1CCOCC1)C=1C=C(C=CC=1)/C=C/C(=O)OC)C CRUPKDGDYYWNRS-KPKJPENVSA-N 0.000 claims description 7
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 7
- 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims description 6
- XYJIMLOUDYZGMG-FOCLMDBBSA-N methyl (E)-3-[3-[cyclohexanecarbonyl-[(4-phenyl-1-bicyclo[2.2.2]octanyl)methyl]amino]phenyl]prop-2-enoate Chemical compound C1(=CC=CC=C1)C12CCC(CC1)(CC2)CN(C(=O)C1CCCCC1)C=1C=C(C=CC=1)/C=C/C(=O)OC XYJIMLOUDYZGMG-FOCLMDBBSA-N 0.000 claims description 6
- SHVGKSDCHMKEGE-WNAAXNPUSA-N methyl (E)-3-[3-[cyclohexanecarbonyl-[[4-(4-cyclopropylphenyl)-1-bicyclo[2.2.2]octanyl]methyl]amino]phenyl]but-2-enoate Chemical compound C1(CC1)C1=CC=C(C=C1)C12CCC(CC1)(CC2)CN(C(=O)C1CCCCC1)C=1C=C(C=CC=1)/C(=C/C(=O)OC)/C SHVGKSDCHMKEGE-WNAAXNPUSA-N 0.000 claims description 6
- DYTARZZFGBZQPK-YYDJUVGSSA-N methyl (E)-3-[3-[cyclohexanecarbonyl-[[4-(4-methoxyphenyl)-1-bicyclo[2.2.2]octanyl]methyl]amino]phenyl]but-2-enoate Chemical compound COC1=CC=C(C=C1)C12CCC(CC1)(CC2)CN(C(=O)C1CCCCC1)C=1C=C(C=CC=1)/C(=C/C(=O)OC)/C DYTARZZFGBZQPK-YYDJUVGSSA-N 0.000 claims description 6
- CLSNSTQTEFIYRX-SFQUDFHCSA-N methyl (E)-3-[3-[cyclohexanecarbonyl-[[4-(4-pyrrolidin-1-ylphenyl)-1-bicyclo[2.2.2]octanyl]methyl]amino]phenyl]prop-2-enoate Chemical compound N1(CCCC1)C1=CC=C(C=C1)C12CCC(CC1)(CC2)CN(C(=O)C1CCCCC1)C=1C=C(C=CC=1)/C=C/C(=O)OC CLSNSTQTEFIYRX-SFQUDFHCSA-N 0.000 claims description 6
- PWVODGFPGSDADR-UHFFFAOYSA-N methyl 5-[cyclohexanecarbonyl-[[4-(4-morpholin-4-ylphenyl)-1-bicyclo[2.2.2]octanyl]methyl]amino]-3,4-dihydronaphthalene-2-carboxylate Chemical compound O1CCN(CC1)C1=CC=C(C=C1)C12CCC(CC1)(CC2)CN(C(=O)C1CCCCC1)C1=C2CCC(=CC2=CC=C1)C(=O)OC PWVODGFPGSDADR-UHFFFAOYSA-N 0.000 claims description 6
- 238000002560 therapeutic procedure Methods 0.000 claims description 6
- VVFDGIGPKHXRSX-UHFFFAOYSA-N 5-[cyclohexanecarbonyl-[[4-(4-methoxyphenyl)-1-bicyclo[2.2.2]octanyl]methyl]amino]-3,4-dihydronaphthalene-2-carboxylic acid Chemical compound COC1=CC=C(C=C1)C12CCC(CC1)(CC2)CN(C(=O)C1CCCCC1)C1=C2CCC(=CC2=CC=C1)C(=O)O VVFDGIGPKHXRSX-UHFFFAOYSA-N 0.000 claims description 5
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 5
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 5
- 208000033679 diabetic kidney disease Diseases 0.000 claims description 5
- KREDIGMOKHWQAG-LICLKQGHSA-N methyl (E)-3-[3-[cyclohexanecarbonyl-[[4-(4-cyclopropylphenyl)-1-bicyclo[2.2.2]octanyl]methyl]amino]phenyl]prop-2-enoate Chemical compound C1(CC1)C1=CC=C(C=C1)C12CCC(CC1)(CC2)CN(C(=O)C1CCCCC1)C=1C=C(C=CC=1)/C=C/C(=O)OC KREDIGMOKHWQAG-LICLKQGHSA-N 0.000 claims description 5
- KLWUYKGPJXDYJX-UHFFFAOYSA-N methyl 5-[[4-(4-cyclopropylphenyl)-1-bicyclo[2.2.2]octanyl]methyl-(2-methylpropanoyl)amino]-3,4-dihydronaphthalene-2-carboxylate Chemical compound C1(CC1)C1=CC=C(C=C1)C12CCC(CC1)(CC2)CN(C(C(C)C)=O)C1=C2CCC(=CC2=CC=C1)C(=O)OC KLWUYKGPJXDYJX-UHFFFAOYSA-N 0.000 claims description 5
- DJLSFFLAVNQIND-UHFFFAOYSA-N methyl 5-[cyclopropanecarbonyl-[[4-(4-cyclopropylphenyl)-1-bicyclo[2.2.2]octanyl]methyl]amino]-3,4-dihydronaphthalene-2-carboxylate Chemical compound COC(=O)C1=CC2=C(CC1)C(=CC=C2)N(CC34CCC(CC3)(CC4)C5=CC=C(C=C5)C6CC6)C(=O)C7CC7 DJLSFFLAVNQIND-UHFFFAOYSA-N 0.000 claims description 5
- 125000002757 morpholinyl group Chemical group 0.000 claims description 5
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 5
- 208000010157 sclerosing cholangitis Diseases 0.000 claims description 5
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 5
- 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims description 4
- 125000002393 azetidinyl group Chemical group 0.000 claims description 4
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 4
- 230000001587 cholestatic effect Effects 0.000 claims description 4
- 208000020832 chronic kidney disease Diseases 0.000 claims description 4
- 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 4
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 4
- TXGFQBKOECKEBC-LFIBNONCSA-N methyl (E)-3-[3-[cyclohexanecarbonyl-[[4-(4-methoxyphenyl)-1-bicyclo[2.2.2]octanyl]methyl]amino]phenyl]prop-2-enoate Chemical compound COC1=CC=C(C=C1)C12CCC(CC1)(CC2)CN(C(=O)C1CCCCC1)C=1C=C(C=CC=1)/C=C/C(=O)OC TXGFQBKOECKEBC-LFIBNONCSA-N 0.000 claims description 4
- BFVYIYPSVNHQQM-BSYVCWPDSA-N methyl (E)-3-[3-[cyclopropanecarbonyl-[[4-(4-cyclopropylphenyl)-1-bicyclo[2.2.2]octanyl]methyl]amino]phenyl]but-2-enoate Chemical compound C1(CC1)C1=CC=C(C=C1)C12CCC(CC1)(CC2)CN(C(=O)C1CC1)C=1C=C(C=CC=1)/C(=C/C(=O)OC)/C BFVYIYPSVNHQQM-BSYVCWPDSA-N 0.000 claims description 4
- ZIMNNYVYOMUIER-UHFFFAOYSA-N methyl 5-[cyclohexanecarbonyl-[[4-(4-cyclopropylphenyl)-1-bicyclo[2.2.2]octanyl]methyl]amino]-3,4-dihydronaphthalene-2-carboxylate Chemical compound C1(CC1)C1=CC=C(C=C1)C12CCC(CC1)(CC2)CN(C(=O)C1CCCCC1)C1=C2CCC(=CC2=CC=C1)C(=O)OC ZIMNNYVYOMUIER-UHFFFAOYSA-N 0.000 claims description 4
- 125000003386 piperidinyl group Chemical group 0.000 claims description 4
- 229920002554 vinyl polymer Polymers 0.000 claims description 4
- 206010004664 Biliary fibrosis Diseases 0.000 claims description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 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 claims description 3
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 230000002503 metabolic effect Effects 0.000 claims description 3
- KQJOCHSBQGSUNJ-VGOFMYFVSA-N methyl (E)-3-[3-[cyclopropanecarbonyl-[[4-(4-propan-2-ylphenyl)-1-bicyclo[2.2.2]octanyl]methyl]amino]phenyl]prop-2-enoate Chemical compound C(C)(C)C1=CC=C(C=C1)C12CCC(CC1)(CC2)CN(C(=O)C1CC1)C=1C=C(C=CC=1)/C=C/C(=O)OC KQJOCHSBQGSUNJ-VGOFMYFVSA-N 0.000 claims description 3
- SKKDSMAVQQYFDV-UHFFFAOYSA-N methyl 5-[cyclohexanecarbonyl-[[4-[4-(diethylamino)phenyl]-1-bicyclo[2.2.2]octanyl]methyl]amino]-3,4-dihydronaphthalene-2-carboxylate Chemical compound C(C)N(C1=CC=C(C=C1)C12CCC(CC1)(CC2)CN(C(=O)C1CCCCC1)C1=C2CCC(=CC2=CC=C1)C(=O)OC)CC SKKDSMAVQQYFDV-UHFFFAOYSA-N 0.000 claims description 3
- DZSFUOMJLJHNIV-UHFFFAOYSA-N methyl 5-[cyclohexanecarbonyl-[[4-[4-(dimethylamino)phenyl]-1-bicyclo[2.2.2]octanyl]methyl]amino]-3,4-dihydronaphthalene-2-carboxylate Chemical compound CN(C1=CC=C(C=C1)C12CCC(CC1)(CC2)CN(C(=O)C1CCCCC1)C1=C2CCC(=CC2=CC=C1)C(=O)OC)C DZSFUOMJLJHNIV-UHFFFAOYSA-N 0.000 claims description 3
- AWXXNEOTLRMFKW-UHFFFAOYSA-N bicyclo[1.1.1]pentane-3-carboxamide Chemical compound C1C2CC1(C(=O)N)C2 AWXXNEOTLRMFKW-UHFFFAOYSA-N 0.000 claims description 2
- 201000002793 renal fibrosis Diseases 0.000 claims description 2
- RHJVIGLEIFVHIJ-UHFFFAOYSA-N cyclohexanecarboxamide Chemical compound NC(=O)C1[CH]CCCC1 RHJVIGLEIFVHIJ-UHFFFAOYSA-N 0.000 claims 2
- 238000000034 method Methods 0.000 abstract description 167
- 201000010099 disease Diseases 0.000 abstract description 24
- 230000000694 effects Effects 0.000 abstract description 13
- 229910052760 oxygen Inorganic materials 0.000 abstract description 6
- 229910052717 sulfur Inorganic materials 0.000 abstract description 4
- 230000008482 dysregulation Effects 0.000 abstract description 3
- 125000006163 5-membered heteroaryl group Chemical group 0.000 abstract 1
- 208000001132 Osteoporosis Diseases 0.000 abstract 1
- 206010052779 Transplant rejections Diseases 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 608
- 238000003786 synthesis reaction Methods 0.000 description 165
- 230000015572 biosynthetic process Effects 0.000 description 162
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 151
- 239000011541 reaction mixture Substances 0.000 description 134
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 133
- 238000002360 preparation method Methods 0.000 description 120
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 104
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 98
- 230000002829 reductive effect Effects 0.000 description 87
- 239000000243 solution Substances 0.000 description 78
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 74
- 239000002585 base Substances 0.000 description 67
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 57
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 55
- 239000003814 drug Substances 0.000 description 53
- 239000007787 solid Substances 0.000 description 53
- 238000005859 coupling reaction Methods 0.000 description 51
- 239000003153 chemical reaction reagent Substances 0.000 description 49
- 238000011282 treatment Methods 0.000 description 49
- 229940048053 acrylate Drugs 0.000 description 48
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 46
- 238000006243 chemical reaction Methods 0.000 description 46
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 45
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 44
- 239000003880 polar aprotic solvent Substances 0.000 description 43
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 42
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 42
- 239000002253 acid Substances 0.000 description 42
- 150000001408 amides Chemical class 0.000 description 39
- 239000002904 solvent Substances 0.000 description 39
- 229910052938 sodium sulfate Inorganic materials 0.000 description 37
- 235000011152 sodium sulphate Nutrition 0.000 description 37
- 230000008878 coupling Effects 0.000 description 36
- 238000010168 coupling process Methods 0.000 description 36
- 229940124597 therapeutic agent Drugs 0.000 description 36
- 239000012044 organic layer Substances 0.000 description 34
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 34
- 239000013058 crude material Substances 0.000 description 33
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 31
- 238000010992 reflux Methods 0.000 description 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 29
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 29
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 28
- 230000009467 reduction Effects 0.000 description 28
- 238000006722 reduction reaction Methods 0.000 description 28
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 28
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 27
- 229910052751 metal Inorganic materials 0.000 description 27
- 239000002184 metal Substances 0.000 description 27
- 238000005481 NMR spectroscopy Methods 0.000 description 26
- 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 26
- 230000003647 oxidation Effects 0.000 description 26
- 238000007254 oxidation reaction Methods 0.000 description 26
- 238000003818 flash chromatography Methods 0.000 description 25
- 239000000741 silica gel Substances 0.000 description 25
- 229910002027 silica gel Inorganic materials 0.000 description 25
- 238000005160 1H NMR spectroscopy Methods 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 230000007062 hydrolysis Effects 0.000 description 24
- 238000006460 hydrolysis reaction Methods 0.000 description 24
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 23
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 23
- 239000000203 mixture Substances 0.000 description 21
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 21
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical class CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 18
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- 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
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Classifications
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- 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
- C07D413/12—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 linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
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- 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
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- A—HUMAN NECESSITIES
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- 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
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
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- 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
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pain & Pain Management (AREA)
- Gastroenterology & Hepatology (AREA)
- Rheumatology (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pyridine Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201962806042P | 2019-02-15 | 2019-02-15 | |
| US62/806,042 | 2019-02-15 | ||
| PCT/US2020/018217 WO2020168152A2 (en) | 2019-02-15 | 2020-02-14 | Substituted amide compounds useful as farnesoid x receptor modulators |
Publications (1)
| Publication Number | Publication Date |
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| CA3129619A1 true CA3129619A1 (en) | 2020-08-20 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA3129619A Pending CA3129619A1 (en) | 2019-02-15 | 2020-02-14 | Substituted amide compounds useful as farnesoid x receptor modulators |
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|---|---|
| US (1) | US12227496B2 (https=) |
| EP (1) | EP3924337A1 (https=) |
| JP (1) | JP7465883B2 (https=) |
| KR (1) | KR102905880B1 (https=) |
| CN (1) | CN113677666A (https=) |
| CA (1) | CA3129619A1 (https=) |
| IL (1) | IL285570A (https=) |
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| US20240360265A1 (en) | 2021-10-01 | 2024-10-31 | Lg Chem, Ltd. | Multiblock Copolymer, Resin Composition and Method for Preparing the Multiblock Copolymer |
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|---|---|---|---|---|
| WO1993013101A1 (fr) | 1991-12-27 | 1993-07-08 | Yoshitomi Pharmaceutical Industries, Ltd. | Compose de pyridonecarboxylate, son utilisation pharmaceutique et compose spiro |
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-
2020
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- 2020-02-14 US US17/431,006 patent/US12227496B2/en active Active
- 2020-02-14 KR KR1020217029609A patent/KR102905880B1/ko active Active
- 2020-02-14 CN CN202080028340.9A patent/CN113677666A/zh active Pending
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| US12227496B2 (en) | 2025-02-18 |
| KR102905880B1 (ko) | 2025-12-29 |
| US20220162201A1 (en) | 2022-05-26 |
| JP2022521895A (ja) | 2022-04-13 |
| US20230109670A9 (en) | 2023-04-06 |
| KR20210130757A (ko) | 2021-11-01 |
| IL285570A (en) | 2021-09-30 |
| CN113677666A (zh) | 2021-11-19 |
| JP7465883B2 (ja) | 2024-04-11 |
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