TWI596095B - Dihydropyridazine-3,5-dione derivatives - Google Patents

Info

Publication number

TWI596095B

TWI596095B TW103109058A TW103109058A TWI596095B TW I596095 B TWI596095 B TW I596095B TW 103109058 A TW103109058 A TW 103109058A TW 103109058 A TW103109058 A TW 103109058A TW I596095 B TWI596095 B TW I596095B

Authority

TW

Taiwan

Prior art keywords

group

methyl

trifluoromethyl

phenyl

substituted

Prior art date

2013-03-13

Links

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• -1 2,3-difluorophenyl Chemical group 0.000 claims description 419
• 150000001875 compounds Chemical class 0.000 claims description 259
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 258
• 150000003839 salts Chemical class 0.000 claims description 204
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 144
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 106
• 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 65
• 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 41
• 239000002253 acid Substances 0.000 claims description 22
• 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 22
• 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 19
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 14
• DMYLUKNFEYWGCH-UHFFFAOYSA-N pyridazine-3-carboxamide Chemical compound NC(=O)C1=CC=CN=N1 DMYLUKNFEYWGCH-UHFFFAOYSA-N 0.000 claims description 11
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 10
• 150000001412 amines Chemical class 0.000 claims description 10
• VZXTWGWHSMCWGA-UHFFFAOYSA-N 1,3,5-triazine-2,4-diamine Chemical compound NC1=NC=NC(N)=N1 VZXTWGWHSMCWGA-UHFFFAOYSA-N 0.000 claims description 8
• 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims description 8
• SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 6
• JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 claims description 6
• IHWDSEPNZDYMNF-UHFFFAOYSA-N 1H-indol-2-amine Chemical compound C1=CC=C2NC(N)=CC2=C1 IHWDSEPNZDYMNF-UHFFFAOYSA-N 0.000 claims description 5
• CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 claims description 5
• 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 5
• MNWFXJYAOYHMED-UHFFFAOYSA-N hexane carboxylic acid Natural products CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 claims description 5
• 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 5
• KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 4
• 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 claims description 4
• CFEBSMASIVKGFD-SSEXGKCCSA-N (3S)-3-tert-butyl-1-[[2,3-difluoro-4-(2-morpholin-4-ylethoxy)phenyl]methyl]-4-hydroxy-2-methyl-6-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-3H-pyridazine-5-carboxamide Chemical compound C(C)(C)(C)[C@@H]1N(N(C(C(=C1O)C(=O)NC1=C(C=C(C=C1)C(F)(F)F)C1=NC=NC(=C1)C(F)(F)F)=O)CC1=C(C(=C(C=C1)OCCN1CCOCC1)F)F)C CFEBSMASIVKGFD-SSEXGKCCSA-N 0.000 claims description 3
• VKYFVFIPASNPNM-WJOKGBTCSA-N (3S)-3-tert-butyl-N-[4-chloro-2-[6-(trifluoromethyl)pyridin-3-yl]phenyl]-1-[[2,3-difluoro-4-(2-morpholin-4-ylethoxy)phenyl]methyl]-4-hydroxy-2-methyl-6-oxo-3H-pyridazine-5-carboxamide Chemical compound C(C)(C)(C)[C@@H]1N(N(C(C(=C1O)C(=O)NC1=C(C=C(C=C1)Cl)C=1C=NC(=CC1)C(F)(F)F)=O)CC1=C(C(=C(C=C1)OCCN1CCOCC1)F)F)C VKYFVFIPASNPNM-WJOKGBTCSA-N 0.000 claims description 3
• 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
• 125000004567 azetidin-3-yl group Chemical group N1CC(C1)* 0.000 claims description 3
• YVAYNHLUKAJQGP-UHFFFAOYSA-N hex-5-ynoic acid Chemical compound OC(=O)CCCC#[C] YVAYNHLUKAJQGP-UHFFFAOYSA-N 0.000 claims description 3
• PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 3
• RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 3
• 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims description 3
• 229960005137 succinic acid Drugs 0.000 claims description 3
• HTLRVHVJGODTHE-SSEXGKCCSA-N (3S)-3-tert-butyl-N-[4-chloro-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-1-[[2,3-difluoro-4-(2-morpholin-4-ylethoxy)phenyl]methyl]-4-hydroxy-2-methyl-6-oxo-3H-pyridazine-5-carboxamide Chemical compound C(C)(C)(C)[C@@H]1N(N(C(C(=C1O)C(=O)NC1=C(C=C(C=C1)Cl)C1=NC=NC(=C1)C(F)(F)F)=O)CC1=C(C(=C(C=C1)OCCN1CCOCC1)F)F)C HTLRVHVJGODTHE-SSEXGKCCSA-N 0.000 claims description 2
• XEMMEFHPILYXGE-AREMUKBSSA-N (4aR)-1-[(2,3-difluorophenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide Chemical compound FC1=C(C=CC=C1F)CN1N2[C@@](C(=C(C1=O)C(=O)NC1=C(C=C(C=C1)C(F)(F)F)C1=NC=NC(=C1)C(F)(F)F)O)(CCC2)C XEMMEFHPILYXGE-AREMUKBSSA-N 0.000 claims description 2
• GDLHQHRXMXMTIQ-JGCGQSQUSA-N (4aR)-1-[[2,3-difluoro-4-(morpholin-4-ylmethyl)phenyl]methyl]-4-hydroxy-4a-methyl-2-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyridin-3-yl]phenyl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide Chemical compound C[C@]12CCCN1N(CC1=CC=C(CN3CCOCC3)C(F)=C1F)C(=O)C(C(=O)NC1=C(C=C(C=C1)C(F)(F)F)C1=CN=C(C=C1)C(F)(F)F)=C2O GDLHQHRXMXMTIQ-JGCGQSQUSA-N 0.000 claims description 2
• SCSALJRMSJVVSA-GSTQUKTASA-N (4aR)-1-[[4-[4-[(2R)-2,3-dihydroxypropoxy]butoxy]-2,3-difluorophenyl]methyl]-4-hydroxy-4a-methyl-2-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide Chemical compound C[C@]12CCCN1N(CC1=CC=C(OCCCCOC[C@H](O)CO)C(F)=C1F)C(=O)C(C(=O)NC1=CC=C(C=C1C1=CC(=NC=N1)C(F)(F)F)C(F)(F)F)=C2O SCSALJRMSJVVSA-GSTQUKTASA-N 0.000 claims description 2
• 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 2
• 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 claims description 2
• 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 2
• FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims 2
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims 2
• KDYFGRWQOYBRFD-CQDYUVAPSA-N butanedioic acid Chemical compound O[13C](=O)CC[13C](O)=O KDYFGRWQOYBRFD-CQDYUVAPSA-N 0.000 claims 2
• NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims 2
• MTICOJZCSDQJGF-JGCGQSQUSA-N (3S)-3-tert-butyl-N-[2-(6-cyano-5-methylpyrimidin-4-yl)-4-(trifluoromethyl)phenyl]-1-[[2,3-difluoro-4-(2-morpholin-4-ylethoxy)phenyl]methyl]-4-hydroxy-2-methyl-6-oxo-3H-pyridazine-5-carboxamide Chemical compound C(C)(C)(C)[C@@H]1N(N(C(C(=C1O)C(=O)NC1=C(C=C(C=C1)C(F)(F)F)C1=NC=NC(=C1C)C#N)=O)CC1=C(C(=C(C=C1)OCCN1CCOCC1)F)F)C MTICOJZCSDQJGF-JGCGQSQUSA-N 0.000 claims 1
• PRACBPDDYXNYIK-DHYKOVJISA-N (4aR)-1-[[4-[3-[(2R)-2,3-dihydroxypropoxy]propoxy]-2,3-difluorophenyl]methyl]-4-hydroxy-4a-methyl-2-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyridin-3-yl]phenyl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide Chemical compound C[C@]12CCCN1N(CC1=CC=C(OCCCOC[C@H](O)CO)C(F)=C1F)C(=O)C(C(=O)NC1=CC=C(C=C1C1=CC=C(N=C1)C(F)(F)F)C(F)(F)F)=C2O PRACBPDDYXNYIK-DHYKOVJISA-N 0.000 claims 1
• POQJGRMVYIGSDZ-JOCHJYFZSA-N (4aR)-N-(4-bromo-3,5-difluorophenyl)-1-[(3-chloro-2-fluorophenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide Chemical compound BrC1=C(C=C(C=C1F)NC(=O)C1=C([C@@]2(N(N(C1=O)CC1=C(C(=CC=C1)Cl)F)CCC2)C)O)F POQJGRMVYIGSDZ-JOCHJYFZSA-N 0.000 claims 1
• GAWZCDMZIYPLMG-UUWRZZSWSA-N (4aR)-N-[2-(2-cyanopyridin-4-yl)-4-(trifluoromethyl)phenyl]-1-[[2,3-difluoro-4-(2-morpholin-4-ylethoxy)phenyl]methyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide Chemical compound C(#N)C1=NC=CC(=C1)C1=C(C=CC(=C1)C(F)(F)F)NC(=O)C1=C([C@@]2(N(N(C1=O)CC1=C(C(=C(C=C1)OCCN1CCOCC1)F)F)CCC2)C)O GAWZCDMZIYPLMG-UUWRZZSWSA-N 0.000 claims 1
• RCPCOSFPOFMGFC-JGCGQSQUSA-N C(C)(C)(C)[C@@H]1N(N(C(C(=C1O)C(=O)NC1=C(C=C(C=C1)Cl)C=1C=NC(=CC1)S(=O)(=O)C)=O)CC1=C(C(=C(C=C1)OCCN1CCOCC1)F)F)C Chemical compound C(C)(C)(C)[C@@H]1N(N(C(C(=C1O)C(=O)NC1=C(C=C(C=C1)Cl)C=1C=NC(=CC1)S(=O)(=O)C)=O)CC1=C(C(=C(C=C1)OCCN1CCOCC1)F)F)C RCPCOSFPOFMGFC-JGCGQSQUSA-N 0.000 claims 1
• 229920000180 alkyd Polymers 0.000 claims 1
• 125000001207 fluorophenyl group Chemical group 0.000 claims 1
• 125000003545 alkoxy group Chemical group 0.000 description 572
• 125000005843 halogen group Chemical group 0.000 description 302
• 125000000217 alkyl group Chemical group 0.000 description 296
• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 224
• 125000000592 heterocycloalkyl group Chemical group 0.000 description 166
• 239000012453 solvate Substances 0.000 description 148
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 126
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 125
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 124
• 125000001424 substituent group Chemical group 0.000 description 112
• 238000000034 method Methods 0.000 description 111
• 125000004435 hydrogen atom Chemical group [H]* 0.000 description 98
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 84
• 125000003118 aryl group Chemical group 0.000 description 83
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 70
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 65
• 238000006243 chemical reaction Methods 0.000 description 65
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 64
• 125000004093 cyano group Chemical group *C#N 0.000 description 62
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 61
• 229910052757 nitrogen Inorganic materials 0.000 description 59
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 57
• 125000004076 pyridyl group Chemical group 0.000 description 54
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 52
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
• 235000019439 ethyl acetate Nutrition 0.000 description 49
• 239000002904 solvent Substances 0.000 description 48
• 125000001313 C5-C10 heteroaryl group Chemical group 0.000 description 46
• 125000000304 alkynyl group Chemical group 0.000 description 45
• 125000004043 oxo group Chemical group O=* 0.000 description 44
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 43
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 43
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 43
• 125000000623 heterocyclic group Chemical group 0.000 description 43
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 42
• 125000004432 carbon atom Chemical group C* 0.000 description 42
• 239000011541 reaction mixture Substances 0.000 description 42
• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 description 41
• 239000000243 solution Substances 0.000 description 41
• 125000002757 morpholinyl group Chemical group 0.000 description 40
• 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 38
• 125000000714 pyrimidinyl group Chemical group 0.000 description 36
• 125000004649 C2-C8 alkynyl group Chemical group 0.000 description 35
• NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 35
• 125000001072 heteroaryl group Chemical group 0.000 description 34
• 125000004433 nitrogen atom Chemical group N* 0.000 description 34
• 125000005842 heteroatom Chemical group 0.000 description 32
• 239000012044 organic layer Substances 0.000 description 32
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 30
• OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 29
• 150000001335 aliphatic alkanes Chemical class 0.000 description 29
• 125000004429 atom Chemical group 0.000 description 28
• 230000002829 reductive effect Effects 0.000 description 27
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
• 239000012043 crude product Substances 0.000 description 26
• 239000000203 mixture Substances 0.000 description 26
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 26
• 239000002585 base Substances 0.000 description 25
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 25
• 229910052698 phosphorus Inorganic materials 0.000 description 25
• OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 24
• 239000011574 phosphorus Substances 0.000 description 24
• 229910052717 sulfur Inorganic materials 0.000 description 24
• 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 23
• 125000003277 amino group Chemical group 0.000 description 23
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 22
• 125000002837 carbocyclic group Chemical group 0.000 description 22
• 229910052760 oxygen Inorganic materials 0.000 description 22
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
• KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 21
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
• 201000005991 hyperphosphatemia Diseases 0.000 description 21
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
• 230000035484 reaction time Effects 0.000 description 21
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 21
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
• 125000003566 oxetanyl group Chemical group 0.000 description 20
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 19
• 238000004587 chromatography analysis Methods 0.000 description 19
• 238000002425 crystallisation Methods 0.000 description 19
• 230000008025 crystallization Effects 0.000 description 19
• 125000000168 pyrrolyl group Chemical group 0.000 description 19
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 18
• 229910052799 carbon Inorganic materials 0.000 description 18
• 238000004128 high performance liquid chromatography Methods 0.000 description 18
• 125000006413 ring segment Chemical group 0.000 description 18
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 17
• 208000020832 chronic kidney disease Diseases 0.000 description 17
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 17
• 230000014759 maintenance of location Effects 0.000 description 17
• 125000004430 oxygen atom Chemical group O* 0.000 description 17
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 17
• 125000006584 (C3-C10) heterocycloalkyl group Chemical group 0.000 description 16
• 239000012299 nitrogen atmosphere Substances 0.000 description 16
• 125000003386 piperidinyl group Chemical group 0.000 description 16
• 238000003756 stirring Methods 0.000 description 16
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
• 125000004414 alkyl thio group Chemical group 0.000 description 15
• 208000022831 chronic renal failure syndrome Diseases 0.000 description 15
• 239000003814 drug Substances 0.000 description 15
• 239000003112 inhibitor Substances 0.000 description 15
• 230000008569 process Effects 0.000 description 15
• 229920006395 saturated elastomer Polymers 0.000 description 15
• 125000006582 (C5-C6) heterocycloalkyl group Chemical group 0.000 description 14
• FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 14
• 239000012267 brine Substances 0.000 description 14
• 125000000753 cycloalkyl group Chemical group 0.000 description 14
• 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 14
• 229910052701 rubidium Inorganic materials 0.000 description 14
• 229910052938 sodium sulfate Inorganic materials 0.000 description 14
• 235000011152 sodium sulphate Nutrition 0.000 description 14
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 13
• YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 13
• 150000001721 carbon Chemical group 0.000 description 13
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 13
• VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 13
• 125000004193 piperazinyl group Chemical group 0.000 description 13
• 229910000027 potassium carbonate Inorganic materials 0.000 description 13
• 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 12
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
• SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 12
• FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 12
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