SG177691A1 - Sphingosine-1-phosphate receptor agonists - Google Patents

Info

Publication number

SG177691A1

SG177691A1 SG2012003430A SG2012003430A SG177691A1 SG 177691 A1 SG177691 A1 SG 177691A1 SG 2012003430 A SG2012003430 A SG 2012003430A SG 2012003430 A SG2012003430 A SG 2012003430A SG 177691 A1 SG177691 A1 SG 177691A1

Authority

SG

Singapore

Prior art keywords

phenyl

oxadiazol

trifluoromethyl

ethyl

hydroxy

Prior art date

2009-08-07

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• 102000011011 Sphingosine 1-phosphate receptors Human genes 0.000 title description 10
• 108050001083 Sphingosine 1-phosphate receptors Proteins 0.000 title description 10
• 239000000018 receptor agonist Substances 0.000 title description 3
• 229940044601 receptor agonist Drugs 0.000 title description 3
• 150000001875 compounds Chemical class 0.000 claims abstract description 265
• 150000003839 salts Chemical class 0.000 claims abstract description 123
• 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 33
• 229910052760 oxygen Inorganic materials 0.000 claims abstract description 27
• 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 18
• 125000002950 monocyclic group Chemical group 0.000 claims abstract description 17
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 12
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 127
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 79
• -1 Cy.shaloalkyl Chemical group 0.000 claims description 75
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 71
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 60
• 125000000217 alkyl group Chemical group 0.000 claims description 46
• 239000002253 acid Substances 0.000 claims description 45
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 44
• 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 claims description 42
• 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 40
• 125000004122 cyclic group Chemical group 0.000 claims description 36
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 34
• 229910052799 carbon Inorganic materials 0.000 claims description 27
• 125000005842 heteroatom Chemical group 0.000 claims description 25
• 229910052757 nitrogen Inorganic materials 0.000 claims description 24
• 125000001424 substituent group Chemical group 0.000 claims description 24
• 238000011282 treatment Methods 0.000 claims description 23
• 125000005843 halogen group Chemical group 0.000 claims description 22
• 125000003545 alkoxy group Chemical group 0.000 claims description 17
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 17
• 125000001544 thienyl group Chemical group 0.000 claims description 17
• 239000003814 drug Substances 0.000 claims description 16
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 15
• 125000004076 pyridyl group Chemical group 0.000 claims description 14
• 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 13
• 125000004438 haloalkoxy group Chemical group 0.000 claims description 13
• 125000001188 haloalkyl group Chemical group 0.000 claims description 13
• 125000003118 aryl group Chemical group 0.000 claims description 12
• 229910052731 fluorine Inorganic materials 0.000 claims description 12
• WPGIIIKQVNEYLG-UHFFFAOYSA-N 1-[2-hydroxy-2-[4-[5-(5-phenyl-4-propyl-1,2-oxazol-3-yl)-1,2,4-oxadiazol-3-yl]phenyl]ethyl]azetidine-3-carboxylic acid Chemical compound CCCC=1C(C=2ON=C(N=2)C=2C=CC(=CC=2)C(O)CN2CC(C2)C(O)=O)=NOC=1C1=CC=CC=C1 WPGIIIKQVNEYLG-UHFFFAOYSA-N 0.000 claims description 11
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 11
• 125000004432 carbon atom Chemical group C* 0.000 claims description 11
• 229910052801 chlorine Inorganic materials 0.000 claims description 11
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 11
• 125000002883 imidazolyl group Chemical group 0.000 claims description 10
• 125000001786 isothiazolyl group Chemical group 0.000 claims description 10
• KEQLVIFRZVZQOA-RBUKOAKNSA-N (3s)-1-[(2s)-2-hydroxy-2-[4-[5-[3-phenyl-4-(trifluoromethyl)-1,2-oxazol-5-yl]-1,2,4-oxadiazol-3-yl]phenyl]ethyl]piperidine-3-carboxylic acid Chemical compound C([C@@H](O)C=1C=CC(=CC=1)C=1N=C(ON=1)C1=C(C(=NO1)C=1C=CC=CC=1)C(F)(F)F)N1CCC[C@H](C(O)=O)C1 KEQLVIFRZVZQOA-RBUKOAKNSA-N 0.000 claims description 9
• ZXVMCGJQAUKOBZ-UHFFFAOYSA-N 1-[2-hydroxy-2-[4-[5-(5-phenyl-4-propyl-1,2-oxazol-3-yl)-1,2,4-oxadiazol-3-yl]phenyl]ethyl]piperidine-2-carboxylic acid Chemical compound CCCC=1C(C=2ON=C(N=2)C=2C=CC(=CC=2)C(O)CN2C(CCCC2)C(O)=O)=NOC=1C1=CC=CC=C1 ZXVMCGJQAUKOBZ-UHFFFAOYSA-N 0.000 claims description 9
• PGFMWCFCZOEQFY-UHFFFAOYSA-N 4-[2-hydroxy-2-[4-[5-[3-phenyl-4-(trifluoromethyl)-1,2-oxazol-5-yl]-1,2,4-oxadiazol-3-yl]phenyl]ethyl]morpholine-2-carboxylic acid Chemical compound C=1C=C(C=2N=C(ON=2)C2=C(C(=NO2)C=2C=CC=CC=2)C(F)(F)F)C=CC=1C(O)CN1CCOC(C(O)=O)C1 PGFMWCFCZOEQFY-UHFFFAOYSA-N 0.000 claims description 9
• CWDWFSXUQODZGW-UHFFFAOYSA-N 5-thiazolyl Chemical group [C]1=CN=CS1 CWDWFSXUQODZGW-UHFFFAOYSA-N 0.000 claims description 9
• 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 9
• SXEARXGUIYUIFF-FKHAVUOCSA-N (3r)-1-[2-hydroxy-2-[4-[5-(5-phenyl-4-propyl-1,2-oxazol-3-yl)-1,2,4-oxadiazol-3-yl]phenyl]ethyl]piperidine-3-carboxylic acid Chemical compound CCCC=1C(C=2ON=C(N=2)C=2C=CC(=CC=2)C(O)CN2C[C@@H](CCC2)C(O)=O)=NOC=1C1=CC=CC=C1 SXEARXGUIYUIFF-FKHAVUOCSA-N 0.000 claims description 8
• RCJRFCCXCZJHQL-UCFFOFKASA-N (3s)-1-[2-hydroxy-2-[4-[5-[3-phenyl-4-(trifluoromethyl)-1,2-oxazol-5-yl]-1,2,4-oxadiazol-3-yl]-3-(trifluoromethyl)phenyl]ethyl]piperidine-3-carboxylic acid Chemical compound C=1C=C(C=2N=C(ON=2)C2=C(C(=NO2)C=2C=CC=CC=2)C(F)(F)F)C(C(F)(F)F)=CC=1C(O)CN1CCC[C@H](C(O)=O)C1 RCJRFCCXCZJHQL-UCFFOFKASA-N 0.000 claims description 8
• LTIXIGNBOHGXDX-BHWOMJMDSA-N (3s)-1-[2-hydroxy-2-[4-[5-[5-(2-methylpropyl)-4-(trifluoromethyl)-1,2-oxazol-3-yl]-1,2,4-oxadiazol-3-yl]phenyl]ethyl]piperidine-3-carboxylic acid Chemical compound FC(F)(F)C1=C(CC(C)C)ON=C1C1=NC(C=2C=CC(=CC=2)C(O)CN2C[C@H](CCC2)C(O)=O)=NO1 LTIXIGNBOHGXDX-BHWOMJMDSA-N 0.000 claims description 8
• 229910052794 bromium Inorganic materials 0.000 claims description 8
• 239000003937 drug carrier Substances 0.000 claims description 8
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
• QFMFMLVBWMLNIV-UHFFFAOYSA-N 1-[2-hydroxy-2-[4-[5-(5-phenyl-4-propyl-1,2-oxazol-3-yl)-1,2,4-oxadiazol-3-yl]phenyl]ethyl]piperidin-3-ol Chemical compound CCCC=1C(C=2ON=C(N=2)C=2C=CC(=CC=2)C(O)CN2CC(O)CCC2)=NOC=1C1=CC=CC=C1 QFMFMLVBWMLNIV-UHFFFAOYSA-N 0.000 claims description 7
• SXEARXGUIYUIFF-UHFFFAOYSA-N 1-[2-hydroxy-2-[4-[5-(5-phenyl-4-propyl-1,2-oxazol-3-yl)-1,2,4-oxadiazol-3-yl]phenyl]ethyl]piperidine-3-carboxylic acid Chemical compound CCCC=1C(C=2ON=C(N=2)C=2C=CC(=CC=2)C(O)CN2CC(CCC2)C(O)=O)=NOC=1C1=CC=CC=C1 SXEARXGUIYUIFF-UHFFFAOYSA-N 0.000 claims description 7
• IYMYJRSILZWGPD-UHFFFAOYSA-N 2-[4-[2-hydroxy-2-[4-[5-[3-phenyl-4-(trifluoromethyl)-1,2-oxazol-5-yl]-1,2,4-oxadiazol-3-yl]phenyl]ethyl]morpholin-3-yl]acetic acid Chemical compound C=1C=C(C=2N=C(ON=2)C2=C(C(=NO2)C=2C=CC=CC=2)C(F)(F)F)C=CC=1C(O)CN1CCOCC1CC(O)=O IYMYJRSILZWGPD-UHFFFAOYSA-N 0.000 claims description 7
• ZMUBLNWRVTYIDY-UHFFFAOYSA-N 3-fluoro-1-[2-hydroxy-2-[4-[5-[3-phenyl-4-(trifluoromethyl)-1,2-oxazol-5-yl]-1,2,4-oxadiazol-3-yl]phenyl]ethyl]piperidine-3-carboxylic acid Chemical compound C=1C=C(C=2N=C(ON=2)C2=C(C(=NO2)C=2C=CC=CC=2)C(F)(F)F)C=CC=1C(O)CN1CCCC(F)(C(O)=O)C1 ZMUBLNWRVTYIDY-UHFFFAOYSA-N 0.000 claims description 7
• WPAXHVDZIROVIQ-UHFFFAOYSA-N 4-[2-hydroxy-2-[4-[5-(5-phenyl-4-propyl-1,2-oxazol-3-yl)-1,2,4-oxadiazol-3-yl]phenyl]ethyl]piperazine-2-carboxylic acid Chemical compound CCCC=1C(C=2ON=C(N=2)C=2C=CC(=CC=2)C(O)CN2CC(NCC2)C(O)=O)=NOC=1C1=CC=CC=C1 WPAXHVDZIROVIQ-UHFFFAOYSA-N 0.000 claims description 7
• SNDOUFIGQKTFES-ATNAJCNCSA-N (3s)-1-[2-hydroxy-2-[4-[5-[3-pyridin-2-yl-4-(trifluoromethyl)-1,2-oxazol-5-yl]-1,2,4-oxadiazol-3-yl]phenyl]ethyl]piperidine-3-carboxylic acid Chemical compound C=1C=C(C=2N=C(ON=2)C2=C(C(=NO2)C=2N=CC=CC=2)C(F)(F)F)C=CC=1C(O)CN1CCC[C@H](C(O)=O)C1 SNDOUFIGQKTFES-ATNAJCNCSA-N 0.000 claims description 6
• DWPIIZNSHBHXIM-UHFFFAOYSA-N 1-[2-hydroxy-2-[4-[5-[3-phenyl-4-(trifluoromethyl)-1,2-oxazol-5-yl]-1,2,4-oxadiazol-3-yl]phenyl]ethyl]-6-methylpiperidine-2-carboxylic acid Chemical compound CC1CCCC(C(O)=O)N1CC(O)C1=CC=C(C=2N=C(ON=2)C2=C(C(=NO2)C=2C=CC=CC=2)C(F)(F)F)C=C1 DWPIIZNSHBHXIM-UHFFFAOYSA-N 0.000 claims description 6
• CXNANLOOTYJTIE-UHFFFAOYSA-N 4-[2-hydroxy-2-[4-[5-(5-phenyl-4-propyl-1,2-oxazol-3-yl)-1,2,4-oxadiazol-3-yl]phenyl]ethyl]morpholine-2-carboxylic acid Chemical compound CCCC=1C(C=2ON=C(N=2)C=2C=CC(=CC=2)C(O)CN2CC(OCC2)C(O)=O)=NOC=1C1=CC=CC=C1 CXNANLOOTYJTIE-UHFFFAOYSA-N 0.000 claims description 6
• VEYWMSKEPZXKDS-MRTLOADZSA-N (2r)-1-[2-hydroxy-2-[4-[5-[3-phenyl-4-(trifluoromethyl)-1,2-oxazol-5-yl]-1,2,4-oxadiazol-3-yl]phenyl]ethyl]piperidine-2-carboxylic acid Chemical compound C=1C=C(C=2N=C(ON=2)C2=C(C(=NO2)C=2C=CC=CC=2)C(F)(F)F)C=CC=1C(O)CN1CCCC[C@@H]1C(O)=O VEYWMSKEPZXKDS-MRTLOADZSA-N 0.000 claims description 5
• 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 claims description 5
• PYANEAOOIPMWGW-UHFFFAOYSA-N 2-[3-(hydroxymethyl)piperidin-1-yl]-1-[4-[5-[3-phenyl-4-(trifluoromethyl)-1,2-oxazol-5-yl]-1,2,4-oxadiazol-3-yl]phenyl]ethanol Chemical compound C1C(CO)CCCN1CC(O)C1=CC=C(C=2N=C(ON=2)C2=C(C(=NO2)C=2C=CC=CC=2)C(F)(F)F)C=C1 PYANEAOOIPMWGW-UHFFFAOYSA-N 0.000 claims description 5
• KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical group [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 claims description 5
• ZDFKJCZJWMALGB-UHFFFAOYSA-N 5-hydroxy-1-[2-hydroxy-2-[4-[5-[3-phenyl-4-(trifluoromethyl)-1,2-oxazol-5-yl]-1,2,4-oxadiazol-3-yl]phenyl]ethyl]piperidine-3-carboxylic acid Chemical compound C=1C=C(C=2N=C(ON=2)C2=C(C(=NO2)C=2C=CC=CC=2)C(F)(F)F)C=CC=1C(O)CN1CC(O)CC(C(O)=O)C1 ZDFKJCZJWMALGB-UHFFFAOYSA-N 0.000 claims description 5
• DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical class CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 claims description 5
• SJYFMUOMOHKHBR-GHTZIAJQSA-N (3s)-1-[(2s)-2-[4-[5-[1-cyclohexyl-5-(trifluoromethyl)pyrazol-4-yl]-1,2,4-oxadiazol-3-yl]phenyl]-2-hydroxyethyl]piperidine-3-carboxylic acid Chemical compound C([C@@H](O)C=1C=CC(=CC=1)C=1N=C(ON=1)C1=C(N(C2CCCCC2)N=C1)C(F)(F)F)N1CCC[C@H](C(O)=O)C1 SJYFMUOMOHKHBR-GHTZIAJQSA-N 0.000 claims description 4
• RHYCULYFTJPPMK-SIKLNZKXSA-N (3s)-1-[(2s)-2-hydroxy-2-[4-[5-[1-(3-methylphenyl)-5-(trifluoromethyl)pyrazol-4-yl]-1,2,4-oxadiazol-3-yl]phenyl]ethyl]piperidine-3-carboxylic acid Chemical compound CC1=CC=CC(N2C(=C(C=3ON=C(N=3)C=3C=CC(=CC=3)[C@H](O)CN3C[C@H](CCC3)C(O)=O)C=N2)C(F)(F)F)=C1 RHYCULYFTJPPMK-SIKLNZKXSA-N 0.000 claims description 4
• YECQGGUYVNGSQW-GHTZIAJQSA-N (3s)-1-[(2s)-2-hydroxy-2-[4-[5-[1-phenyl-5-(trifluoromethyl)pyrazol-4-yl]-1,2,4-oxadiazol-3-yl]phenyl]ethyl]piperidine-3-carboxylic acid Chemical compound C([C@@H](O)C=1C=CC(=CC=1)C=1N=C(ON=1)C1=C(N(N=C1)C=1C=CC=CC=1)C(F)(F)F)N1CCC[C@H](C(O)=O)C1 YECQGGUYVNGSQW-GHTZIAJQSA-N 0.000 claims description 4
• AHULNQGXTUEURY-LBOXEOMUSA-N (3s)-1-[2-[4-[5-[3-(2-chlorophenyl)-1h-pyrazol-5-yl]-1,2,4-oxadiazol-3-yl]phenyl]-2-hydroxyethyl]piperidine-3-carboxylic acid Chemical compound C=1C=C(C=2N=C(ON=2)C=2NN=C(C=2)C=2C(=CC=CC=2)Cl)C=CC=1C(O)CN1CCC[C@H](C(O)=O)C1 AHULNQGXTUEURY-LBOXEOMUSA-N 0.000 claims description 4
• IXUPWWKYGWRAAD-HXBUSHRASA-N (3s)-1-[2-[4-[5-[3-(4-chlorophenyl)-1h-pyrazol-5-yl]-1,2,4-oxadiazol-3-yl]phenyl]-2-hydroxyethyl]piperidine-3-carboxylic acid Chemical compound C=1C=C(C=2N=C(ON=2)C=2NN=C(C=2)C=2C=CC(Cl)=CC=2)C=CC=1C(O)CN1CCC[C@H](C(O)=O)C1 IXUPWWKYGWRAAD-HXBUSHRASA-N 0.000 claims description 4
• MEHLDAAHMPABRE-BWDMCYIDSA-N (3s)-1-[2-hydroxy-2-[4-[5-(1-phenyl-5-propylpyrazol-4-yl)-1,2,4-oxadiazol-3-yl]phenyl]ethyl]piperidine-3-carboxylic acid Chemical compound CCCC1=C(C=2ON=C(N=2)C=2C=CC(=CC=2)C(O)CN2C[C@H](CCC2)C(O)=O)C=NN1C1=CC=CC=C1 MEHLDAAHMPABRE-BWDMCYIDSA-N 0.000 claims description 4
• RCAXPPQJUXLEDW-YDNXMHBPSA-N (3s)-1-[2-hydroxy-2-[4-[5-(1-phenylpyrazol-4-yl)-1,2,4-oxadiazol-3-yl]phenyl]ethyl]piperidine-3-carboxylic acid Chemical compound C=1C=C(C=2N=C(ON=2)C2=CN(N=C2)C=2C=CC=CC=2)C=CC=1C(O)CN1CCC[C@H](C(O)=O)C1 RCAXPPQJUXLEDW-YDNXMHBPSA-N 0.000 claims description 4
• XWNYRQCNTYBSGA-AJZOCDQUSA-N (3s)-1-[2-hydroxy-2-[4-[5-(2-methyl-5-phenylpyrazol-3-yl)-1,2,4-oxadiazol-3-yl]phenyl]ethyl]piperidine-3-carboxylic acid Chemical compound CN1N=C(C=2C=CC=CC=2)C=C1C(ON=1)=NC=1C(C=C1)=CC=C1C(O)CN1CCC[C@H](C(O)=O)C1 XWNYRQCNTYBSGA-AJZOCDQUSA-N 0.000 claims description 4
• JJQRUMAWHZZQBX-AJZOCDQUSA-N (3s)-1-[2-hydroxy-2-[4-[5-(5-methyl-1-phenylpyrazol-3-yl)-1,2,4-oxadiazol-3-yl]phenyl]ethyl]piperidine-3-carboxylic acid Chemical compound CC1=CC(C=2ON=C(N=2)C=2C=CC(=CC=2)C(O)CN2C[C@H](CCC2)C(O)=O)=NN1C1=CC=CC=C1 JJQRUMAWHZZQBX-AJZOCDQUSA-N 0.000 claims description 4
• MOFNVCHJYHWJMD-LROBGIAVSA-N (3s)-1-[2-hydroxy-2-[4-[5-(5-pyridin-2-ylthiophen-2-yl)-1,2,4-oxadiazol-3-yl]phenyl]ethyl]piperidine-3-carboxylic acid Chemical compound C=1C=C(C=2N=C(ON=2)C=2SC(=CC=2)C=2N=CC=CC=2)C=CC=1C(O)CN1CCC[C@H](C(O)=O)C1 MOFNVCHJYHWJMD-LROBGIAVSA-N 0.000 claims description 4
• FTIRVEBTARAWRH-UHFFFAOYSA-N 1-[2-hydroxy-2-[4-[5-(5-phenyl-4-propyl-1,2-oxazol-3-yl)-1,2,4-oxadiazol-3-yl]phenyl]ethyl]pyrrolidine-3-carboxylic acid Chemical compound CCCC=1C(C=2ON=C(N=2)C=2C=CC(=CC=2)C(O)CN2CC(CC2)C(O)=O)=NOC=1C1=CC=CC=C1 FTIRVEBTARAWRH-UHFFFAOYSA-N 0.000 claims description 4
• JMKXTJZWBTVYGQ-UHFFFAOYSA-N 1-[2-hydroxy-2-[4-[5-[3-phenyl-4-(trifluoromethyl)-1,2-oxazol-5-yl]-1,2,4-oxadiazol-3-yl]phenyl]ethyl]-3-methylpiperidine-3-carboxylic acid Chemical compound C1C(C)(C(O)=O)CCCN1CC(O)C1=CC=C(C=2N=C(ON=2)C2=C(C(=NO2)C=2C=CC=CC=2)C(F)(F)F)C=C1 JMKXTJZWBTVYGQ-UHFFFAOYSA-N 0.000 claims description 4
• NPGPDNHISZFRSA-OPAMFIHVSA-N 2-[(3r)-1-[(2s)-2-[4-[5-[1-(4-chlorophenyl)-5-(trifluoromethyl)pyrazol-4-yl]-1,2,4-oxadiazol-3-yl]phenyl]-2-hydroxyethyl]piperidin-3-yl]acetic acid Chemical compound C([C@@H](O)C=1C=CC(=CC=1)C=1N=C(ON=1)C1=C(N(N=C1)C=1C=CC(Cl)=CC=1)C(F)(F)F)N1CCC[C@H](CC(O)=O)C1 NPGPDNHISZFRSA-OPAMFIHVSA-N 0.000 claims description 4
• WLSLSTGNQRRUSK-JLTOFOAXSA-N 2-[(3r)-1-[(2s)-2-[4-[5-[1-[5-chloro-3-(trifluoromethyl)pyridin-2-yl]-5-(trifluoromethyl)pyrazol-4-yl]-1,2,4-oxadiazol-3-yl]phenyl]-2-hydroxyethyl]piperidin-3-yl]acetic acid Chemical compound C([C@@H](O)C=1C=CC(=CC=1)C=1N=C(ON=1)C1=C(N(N=C1)C=1C(=CC(Cl)=CN=1)C(F)(F)F)C(F)(F)F)N1CCC[C@H](CC(O)=O)C1 WLSLSTGNQRRUSK-JLTOFOAXSA-N 0.000 claims description 4
• RMOQISUDDHAYIY-WZONZLPQSA-N 2-[(3r)-1-[(2s)-2-hydroxy-2-[4-[5-[1-(2-methylphenyl)-5-(trifluoromethyl)pyrazol-4-yl]-1,2,4-oxadiazol-3-yl]phenyl]ethyl]piperidin-3-yl]acetic acid Chemical compound CC1=CC=CC=C1N1C(C(F)(F)F)=C(C=2ON=C(N=2)C=2C=CC(=CC=2)[C@H](O)CN2C[C@@H](CC(O)=O)CCC2)C=N1 RMOQISUDDHAYIY-WZONZLPQSA-N 0.000 claims description 4
• PXZNTMIDRVHIKC-UZUQRXQVSA-N 2-[(3r)-1-[(2s)-2-hydroxy-2-[4-[5-[1-(4-methoxyphenyl)-5-(trifluoromethyl)pyrazol-4-yl]-1,2,4-oxadiazol-3-yl]phenyl]ethyl]piperidin-3-yl]acetic acid Chemical compound C1=CC(OC)=CC=C1N1C(C(F)(F)F)=C(C=2ON=C(N=2)C=2C=CC(=CC=2)[C@H](O)CN2C[C@@H](CC(O)=O)CCC2)C=N1 PXZNTMIDRVHIKC-UZUQRXQVSA-N 0.000 claims description 4
• BFBKHGAZEBRFGK-WZONZLPQSA-N 2-[(3r)-1-[(2s)-2-hydroxy-2-[4-[5-[1-(4-methylphenyl)-5-(trifluoromethyl)pyrazol-4-yl]-1,2,4-oxadiazol-3-yl]phenyl]ethyl]piperidin-3-yl]acetic acid Chemical compound C1=CC(C)=CC=C1N1C(C(F)(F)F)=C(C=2ON=C(N=2)C=2C=CC(=CC=2)[C@H](O)CN2C[C@@H](CC(O)=O)CCC2)C=N1 BFBKHGAZEBRFGK-WZONZLPQSA-N 0.000 claims description 4
• ZTVXCSBZECDKMU-KBMIEXCESA-N 2-[(3r)-1-[(2s)-2-hydroxy-2-[4-[5-[1-(4-propan-2-ylphenyl)-5-(trifluoromethyl)pyrazol-4-yl]-1,2,4-oxadiazol-3-yl]phenyl]ethyl]piperidin-3-yl]acetic acid Chemical compound C1=CC(C(C)C)=CC=C1N1C(C(F)(F)F)=C(C=2ON=C(N=2)C=2C=CC(=CC=2)[C@H](O)CN2C[C@@H](CC(O)=O)CCC2)C=N1 ZTVXCSBZECDKMU-KBMIEXCESA-N 0.000 claims description 4
• 208000037976 chronic inflammation Diseases 0.000 claims description 4
• 208000037893 chronic inflammatory disorder Diseases 0.000 claims description 4
• 238000004519 manufacturing process Methods 0.000 claims description 4
• 238000002560 therapeutic procedure Methods 0.000 claims description 4
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• 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 claims description 3
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• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
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• RKPKRPQAUKWECJ-RBUKOAKNSA-N (3s)-1-[(2s)-2-hydroxy-2-[4-[5-[3-phenyl-4-(trifluoromethyl)-1,2-thiazol-5-yl]-1,2,4-oxadiazol-3-yl]phenyl]ethyl]piperidine-3-carboxylic acid Chemical compound C([C@@H](O)C=1C=CC(=CC=1)C=1N=C(ON=1)C1=C(C(=NS1)C=1C=CC=CC=1)C(F)(F)F)N1CCC[C@H](C(O)=O)C1 RKPKRPQAUKWECJ-RBUKOAKNSA-N 0.000 claims description 2
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• QOZKDPPGKUWYLO-IVZQSRNASA-N 2-[(3r)-1-[(2s)-2-[4-[5-[1-(3,4-dichlorophenyl)-5-(trifluoromethyl)pyrazol-4-yl]-1,2,4-oxadiazol-3-yl]phenyl]-2-hydroxyethyl]piperidin-3-yl]acetic acid Chemical compound C([C@@H](O)C=1C=CC(=CC=1)C=1N=C(ON=1)C1=C(N(N=C1)C=1C=C(Cl)C(Cl)=CC=1)C(F)(F)F)N1CCC[C@H](CC(O)=O)C1 QOZKDPPGKUWYLO-IVZQSRNASA-N 0.000 claims description 2
• HFSLAGPHKHVGJM-JLTOFOAXSA-N 2-[(3r)-1-[(2s)-2-[4-[5-[1-(3,5-dichloropyridin-2-yl)-5-(trifluoromethyl)pyrazol-4-yl]-1,2,4-oxadiazol-3-yl]phenyl]-2-hydroxyethyl]piperidin-3-yl]acetic acid Chemical compound C([C@@H](O)C=1C=CC(=CC=1)C=1N=C(ON=1)C1=C(N(N=C1)C=1C(=CC(Cl)=CN=1)Cl)C(F)(F)F)N1CCC[C@H](CC(O)=O)C1 HFSLAGPHKHVGJM-JLTOFOAXSA-N 0.000 claims description 2
• SBEXUXKNKORBJB-OPAMFIHVSA-N 2-[(3r)-1-[(2s)-2-[4-[5-[1-(3-chlorophenyl)-5-(trifluoromethyl)pyrazol-4-yl]-1,2,4-oxadiazol-3-yl]phenyl]-2-hydroxyethyl]piperidin-3-yl]acetic acid Chemical compound C([C@@H](O)C=1C=CC(=CC=1)C=1N=C(ON=1)C1=C(N(N=C1)C=1C=C(Cl)C=CC=1)C(F)(F)F)N1CCC[C@H](CC(O)=O)C1 SBEXUXKNKORBJB-OPAMFIHVSA-N 0.000 claims description 2
• UGFHPDPAZZCZHB-FOIQADDNSA-N 2-[(3r)-1-[(2s)-2-[4-[5-[1-(3-chloropyridin-2-yl)-5-(trifluoromethyl)pyrazol-4-yl]-1,2,4-oxadiazol-3-yl]phenyl]-2-hydroxyethyl]piperidin-3-yl]acetic acid Chemical compound C([C@@H](O)C=1C=CC(=CC=1)C=1N=C(ON=1)C1=C(N(N=C1)C=1C(=CC=CN=1)Cl)C(F)(F)F)N1CCC[C@H](CC(O)=O)C1 UGFHPDPAZZCZHB-FOIQADDNSA-N 0.000 claims description 2
• BPGFDHAVIDTFAD-UZUQRXQVSA-N 2-[(3r)-1-[(2s)-2-[4-[5-[1-(4-chloro-2-methylphenyl)-5-(trifluoromethyl)pyrazol-4-yl]-1,2,4-oxadiazol-3-yl]phenyl]-2-hydroxyethyl]piperidin-3-yl]acetic acid Chemical compound CC1=CC(Cl)=CC=C1N1C(C(F)(F)F)=C(C=2ON=C(N=2)C=2C=CC(=CC=2)[C@H](O)CN2C[C@@H](CC(O)=O)CCC2)C=N1 BPGFDHAVIDTFAD-UZUQRXQVSA-N 0.000 claims description 2
• DUFGKRTXLOFQEZ-OPAMFIHVSA-N 2-[(3r)-1-[(2s)-2-[4-[5-[1-(4-fluorophenyl)-5-(trifluoromethyl)pyrazol-4-yl]-1,2,4-oxadiazol-3-yl]phenyl]-2-hydroxyethyl]piperidin-3-yl]acetic acid Chemical compound C([C@@H](O)C=1C=CC(=CC=1)C=1N=C(ON=1)C1=C(N(N=C1)C=1C=CC(F)=CC=1)C(F)(F)F)N1CCC[C@H](CC(O)=O)C1 DUFGKRTXLOFQEZ-OPAMFIHVSA-N 0.000 claims description 2
• KXPZQOHYAFETOE-OPAMFIHVSA-N 2-[(3r)-1-[(2s)-2-[4-[5-[1-(5-ethoxy-3-fluoropyridin-2-yl)-5-(trifluoromethyl)pyrazol-4-yl]-1,2,4-oxadiazol-3-yl]phenyl]-2-hydroxyethyl]piperidin-3-yl]acetic acid Chemical compound FC1=CC(OCC)=CN=C1N1C(C(F)(F)F)=C(C=2ON=C(N=2)C=2C=CC(=CC=2)[C@H](O)CN2C[C@@H](CC(O)=O)CCC2)C=N1 KXPZQOHYAFETOE-OPAMFIHVSA-N 0.000 claims description 2
• GMIJHEPKYKBSCR-FOIQADDNSA-N 2-[(3r)-1-[(2s)-2-[4-[5-[1-(5-fluoropyridin-2-yl)-5-(trifluoromethyl)pyrazol-4-yl]-1,2,4-oxadiazol-3-yl]phenyl]-2-hydroxyethyl]piperidin-3-yl]acetic acid Chemical compound C([C@@H](O)C=1C=CC(=CC=1)C=1N=C(ON=1)C1=C(N(N=C1)C=1N=CC(F)=CC=1)C(F)(F)F)N1CCC[C@H](CC(O)=O)C1 GMIJHEPKYKBSCR-FOIQADDNSA-N 0.000 claims description 2
• OBYCSDNPWIRQRB-DNVCBOLYSA-N 2-[(3r)-1-[(2s)-2-[4-[5-[1-(6-chloropyridin-2-yl)-5-(trifluoromethyl)pyrazol-4-yl]-1,2,4-oxadiazol-3-yl]phenyl]-2-hydroxyethyl]piperidin-3-yl]acetic acid Chemical compound C([C@@H](O)C=1C=CC(=CC=1)C=1N=C(ON=1)C1=C(N(N=C1)C=1N=C(Cl)C=CC=1)C(F)(F)F)N1CCC[C@H](CC(O)=O)C1 OBYCSDNPWIRQRB-DNVCBOLYSA-N 0.000 claims description 2
• XZCCIKSOORLLDT-OXQOHEQNSA-N 2-[(3r)-1-[(2s)-2-[4-[5-[5-cyclohexyl-4-(trifluoromethyl)-1,2-oxazol-3-yl]-1,2,4-oxadiazol-3-yl]phenyl]-2-hydroxyethyl]piperidin-3-yl]acetic acid Chemical compound C([C@@H](O)C=1C=CC(=CC=1)C=1N=C(ON=1)C=1C(=C(C2CCCCC2)ON=1)C(F)(F)F)N1CCC[C@H](CC(O)=O)C1 XZCCIKSOORLLDT-OXQOHEQNSA-N 0.000 claims description 2
• JDPHPEUIQJNULE-CRAIPNDOSA-N 2-[(3r)-1-[(2s)-2-hydroxy-2-[4-[5-[5-(2-methylpropyl)-4-(trifluoromethyl)-1,2-oxazol-3-yl]-1,2,4-oxadiazol-3-yl]phenyl]ethyl]piperidin-3-yl]acetic acid Chemical compound FC(F)(F)C1=C(CC(C)C)ON=C1C1=NC(C=2C=CC(=CC=2)[C@H](O)CN2C[C@@H](CC(O)=O)CCC2)=NO1 JDPHPEUIQJNULE-CRAIPNDOSA-N 0.000 claims description 2
• XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 2
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• 235000019260 propionic acid Nutrition 0.000 claims description 2
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• RYZYNQIRCSGPMZ-QFBILLFUSA-N (3s)-1-[(2s)-2-[4-[5-[1-(5-chloropyridin-2-yl)-5-(trifluoromethyl)pyrazol-4-yl]-1,2,4-oxadiazol-3-yl]phenyl]-2-hydroxyethyl]piperidine-3-carboxylic acid Chemical compound C([C@@H](O)C=1C=CC(=CC=1)C=1N=C(ON=1)C1=C(N(N=C1)C=1N=CC(Cl)=CC=1)C(F)(F)F)N1CCC[C@H](C(O)=O)C1 RYZYNQIRCSGPMZ-QFBILLFUSA-N 0.000 claims 2
• NBAJVVQKVFSPLV-YDNXMHBPSA-N (3s)-1-[2-[4-[5-(5-ethyl-1-pyridin-2-ylpyrazol-4-yl)-1,2,4-oxadiazol-3-yl]phenyl]-2-hydroxyethyl]piperidine-3-carboxylic acid Chemical compound CCC1=C(C=2ON=C(N=2)C=2C=CC(=CC=2)C(O)CN2C[C@H](CCC2)C(O)=O)C=NN1C1=CC=CC=N1 NBAJVVQKVFSPLV-YDNXMHBPSA-N 0.000 claims 2
• ZAPDJMUOBGZNEG-YMXDCFFPSA-N (3s)-1-[2-[4-[5-[5-(4-chlorophenyl)-1,2-oxazol-3-yl]-1,2,4-oxadiazol-3-yl]phenyl]-2-hydroxyethyl]piperidine-3-carboxylic acid Chemical compound C=1C=C(C=2N=C(ON=2)C2=NOC(=C2)C=2C=CC(Cl)=CC=2)C=CC=1C(O)CN1CCC[C@H](C(O)=O)C1 ZAPDJMUOBGZNEG-YMXDCFFPSA-N 0.000 claims 2
• JDQQWZLAVFZPBI-OYKVQYDMSA-N (3s)-1-[2-hydroxy-2-[4-[5-[5-phenyl-4-(trifluoromethyl)-1,2-oxazol-3-yl]-1,2,4-oxadiazol-3-yl]phenyl]ethyl]piperidine-3-carboxylic acid Chemical compound C=1C=C(C=2N=C(ON=2)C=2C(=C(ON=2)C=2C=CC=CC=2)C(F)(F)F)C=CC=1C(O)CN1CCC[C@H](C(O)=O)C1 JDQQWZLAVFZPBI-OYKVQYDMSA-N 0.000 claims 2
• QUVDAYCPTOVHAD-FOIQADDNSA-N 2-[(3r)-1-[(2s)-2-[4-[5-[5-(3-chlorophenyl)-4-(trifluoromethyl)-1,2-oxazol-3-yl]-1,2,4-oxadiazol-3-yl]phenyl]-2-hydroxyethyl]piperidin-3-yl]acetic acid Chemical compound C([C@@H](O)C=1C=CC(=CC=1)C=1N=C(ON=1)C=1C(=C(ON=1)C=1C=C(Cl)C=CC=1)C(F)(F)F)N1CCC[C@H](CC(O)=O)C1 QUVDAYCPTOVHAD-FOIQADDNSA-N 0.000 claims 2
• YNXRXFSUFSBGFK-UHFFFAOYSA-N 2-[1-[2-hydroxy-2-[4-[5-(5-phenyl-4-propyl-1,2-oxazol-3-yl)-1,2,4-oxadiazol-3-yl]phenyl]ethyl]piperidin-3-yl]acetic acid Chemical compound CCCC=1C(C=2ON=C(N=2)C=2C=CC(=CC=2)C(O)CN2CC(CC(O)=O)CCC2)=NOC=1C1=CC=CC=C1 YNXRXFSUFSBGFK-UHFFFAOYSA-N 0.000 claims 2
• IADUEWIQBXOCDZ-UHFFFAOYSA-N azetidine-2-carboxylic acid Chemical compound OC(=O)C1CCN1 IADUEWIQBXOCDZ-UHFFFAOYSA-N 0.000 claims 2
• BVOCPVIXARZNQN-UHFFFAOYSA-N nipecotamide Chemical compound NC(=O)C1CCCNC1 BVOCPVIXARZNQN-UHFFFAOYSA-N 0.000 claims 2
• VTZFMIRYVNPKSO-QFBILLFUSA-N (3s)-1-[(2s)-2-[4-[5-[1-(5-fluoropyridin-2-yl)-5-(trifluoromethyl)pyrazol-4-yl]-1,2,4-oxadiazol-3-yl]phenyl]-2-hydroxyethyl]piperidine-3-carboxylic acid Chemical compound C([C@@H](O)C=1C=CC(=CC=1)C=1N=C(ON=1)C1=C(N(N=C1)C=1N=CC(F)=CC=1)C(F)(F)F)N1CCC[C@H](C(O)=O)C1 VTZFMIRYVNPKSO-QFBILLFUSA-N 0.000 claims 1
• RMUTVQJKINESCA-QFBILLFUSA-N (3s)-1-[(2s)-2-hydroxy-2-[4-[5-[5-(trifluoromethyl)-1-[5-(trifluoromethyl)pyridin-2-yl]pyrazol-4-yl]-1,2,4-oxadiazol-3-yl]phenyl]ethyl]piperidine-3-carboxylic acid Chemical compound C([C@@H](O)C=1C=CC(=CC=1)C=1N=C(ON=1)C1=C(N(N=C1)C=1N=CC(=CC=1)C(F)(F)F)C(F)(F)F)N1CCC[C@H](C(O)=O)C1 RMUTVQJKINESCA-QFBILLFUSA-N 0.000 claims 1
• KXIJRCWBWLZKGL-IVZQSRNASA-N 2-[(3r)-1-[(2s)-2-[4-[5-[1-(2,4-dichlorophenyl)-5-(trifluoromethyl)pyrazol-4-yl]-1,2,4-oxadiazol-3-yl]phenyl]-2-hydroxyethyl]piperidin-3-yl]acetic acid Chemical compound C([C@@H](O)C=1C=CC(=CC=1)C=1N=C(ON=1)C1=C(N(N=C1)C=1C(=CC(Cl)=CC=1)Cl)C(F)(F)F)N1CCC[C@H](CC(O)=O)C1 KXIJRCWBWLZKGL-IVZQSRNASA-N 0.000 claims 1
• GCMFJDSBOLNEPE-UZUQRXQVSA-N 2-[(3r)-1-[(2s)-2-[4-[5-[1-(4-chloro-3-methylphenyl)-5-(trifluoromethyl)pyrazol-4-yl]-1,2,4-oxadiazol-3-yl]phenyl]-2-hydroxyethyl]piperidin-3-yl]acetic acid Chemical compound C1=C(Cl)C(C)=CC(N2C(=C(C=3ON=C(N=3)C=3C=CC(=CC=3)[C@H](O)CN3C[C@@H](CC(O)=O)CCC3)C=N2)C(F)(F)F)=C1 GCMFJDSBOLNEPE-UZUQRXQVSA-N 0.000 claims 1
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