CA2477601C - 5-phenylthiazole derivatives and use as pi3 kinase inhibitors - Google Patents
5-phenylthiazole derivatives and use as pi3 kinase inhibitors Download PDFInfo
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- CA2477601C CA2477601C CA2477601A CA2477601A CA2477601C CA 2477601 C CA2477601 C CA 2477601C CA 2477601 A CA2477601 A CA 2477601A CA 2477601 A CA2477601 A CA 2477601A CA 2477601 C CA2477601 C CA 2477601C
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- Prior art keywords
- alkyl
- optionally substituted
- hydroxy
- ring
- nitrogen
- Prior art date
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- ZLLOWHFKKIOINR-UHFFFAOYSA-N 5-phenyl-1,3-thiazole Chemical class S1C=NC=C1C1=CC=CC=C1 ZLLOWHFKKIOINR-UHFFFAOYSA-N 0.000 title 1
- 239000002935 phosphatidylinositol 3 kinase inhibitor Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 262
- 238000000034 method Methods 0.000 claims abstract description 108
- 150000003839 salts Chemical group 0.000 claims abstract description 39
- 230000008569 process Effects 0.000 claims abstract description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 17
- 201000010099 disease Diseases 0.000 claims abstract description 11
- 102000003993 Phosphatidylinositol 3-kinases Human genes 0.000 claims abstract description 6
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 claims abstract description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- 108091007960 PI3Ks Proteins 0.000 claims abstract description 4
- 230000001404 mediated effect Effects 0.000 claims abstract description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 194
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 130
- 229910052757 nitrogen Inorganic materials 0.000 claims description 127
- -1 C1-C8-alkylamino Chemical group 0.000 claims description 109
- 229910052739 hydrogen Inorganic materials 0.000 claims description 106
- 239000001257 hydrogen Substances 0.000 claims description 106
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 97
- 229910052760 oxygen Inorganic materials 0.000 claims description 97
- 239000001301 oxygen Substances 0.000 claims description 97
- 125000005842 heteroatom Chemical group 0.000 claims description 96
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 88
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 85
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 81
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 72
- 239000005864 Sulphur Substances 0.000 claims description 72
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 62
- 229910052736 halogen Inorganic materials 0.000 claims description 59
- 150000002367 halogens Chemical group 0.000 claims description 59
- 150000002825 nitriles Chemical group 0.000 claims description 59
- 238000006243 chemical reaction Methods 0.000 claims description 50
- 238000002360 preparation method Methods 0.000 claims description 34
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 29
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 29
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 29
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 26
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 26
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 20
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 20
- 229910052794 bromium Inorganic materials 0.000 claims description 20
- 229910006074 SO2NH2 Inorganic materials 0.000 claims description 17
- 239000000460 chlorine Substances 0.000 claims description 16
- 239000011737 fluorine Substances 0.000 claims description 16
- 229910052731 fluorine Inorganic materials 0.000 claims description 16
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 15
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 15
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 15
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 14
- 229910052801 chlorine Inorganic materials 0.000 claims description 14
- 229910021529 ammonia Inorganic materials 0.000 claims description 12
- 125000005843 halogen group Chemical group 0.000 claims description 12
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 10
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 9
- 125000001963 4 membered heterocyclic group Chemical group 0.000 claims description 8
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 8
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 8
- 229910052783 alkali metal Inorganic materials 0.000 claims description 7
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 7
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 208000035475 disorder Diseases 0.000 claims description 6
- 230000002140 halogenating effect Effects 0.000 claims description 5
- 150000001340 alkali metals Chemical class 0.000 claims description 4
- 150000001350 alkyl halides Chemical class 0.000 claims description 4
- 206010012601 diabetes mellitus Diseases 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 4
- 229910052723 transition metal Inorganic materials 0.000 claims description 4
- 150000003624 transition metals Chemical class 0.000 claims description 4
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 230000002062 proliferating effect Effects 0.000 claims description 3
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical compound [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 claims description 3
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 2
- 208000011231 Crohn disease Diseases 0.000 claims description 2
- 206010028980 Neoplasm Diseases 0.000 claims description 2
- 208000008589 Obesity Diseases 0.000 claims description 2
- 201000004681 Psoriasis Diseases 0.000 claims description 2
- 206010040070 Septic Shock Diseases 0.000 claims description 2
- 208000006011 Stroke Diseases 0.000 claims description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 2
- 201000011510 cancer Diseases 0.000 claims description 2
- SYGWYBOJXOGMRU-UHFFFAOYSA-N chembl233051 Chemical compound C1=CC=C2C3=CC(C(N(CCN(C)C)C4=O)=O)=C5C4=CC=CC5=C3SC2=C1 SYGWYBOJXOGMRU-UHFFFAOYSA-N 0.000 claims description 2
- 235000020824 obesity Nutrition 0.000 claims description 2
- 201000008482 osteoarthritis Diseases 0.000 claims description 2
- 208000037803 restenosis Diseases 0.000 claims description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 2
- 230000036303 septic shock Effects 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- 238000002054 transplantation Methods 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 79
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 3
- 229910005948 SO2Cl Inorganic materials 0.000 claims 2
- ISCVJALAVAXARV-UHFFFAOYSA-N 2-(diethylamino)-n-(4-methyl-5-phenyl-1,3-thiazol-2-yl)acetamide Chemical compound S1C(NC(=O)CN(CC)CC)=NC(C)=C1C1=CC=CC=C1 ISCVJALAVAXARV-UHFFFAOYSA-N 0.000 claims 1
- ADUCIDRRGKFELT-UHFFFAOYSA-N 2-(dimethylamino)-n-(4-methyl-5-phenyl-1,3-thiazol-2-yl)acetamide Chemical compound S1C(NC(=O)CN(C)C)=NC(C)=C1C1=CC=CC=C1 ADUCIDRRGKFELT-UHFFFAOYSA-N 0.000 claims 1
- 201000001320 Atherosclerosis Diseases 0.000 claims 1
- 206010020751 Hypersensitivity Diseases 0.000 claims 1
- 208000025747 Rheumatic disease Diseases 0.000 claims 1
- 230000007815 allergy Effects 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- DNBSFXNLTUCKCZ-UHFFFAOYSA-N n-(4-methyl-5-phenyl-1,3-thiazol-2-yl)-2-piperidin-1-ylacetamide Chemical compound S1C(C=2C=CC=CC=2)=C(C)N=C1NC(=O)CN1CCCCC1 DNBSFXNLTUCKCZ-UHFFFAOYSA-N 0.000 claims 1
- 208000023504 respiratory system disease Diseases 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 94
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 87
- 239000000243 solution Substances 0.000 description 76
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 74
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 73
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 70
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 69
- 239000011541 reaction mixture Substances 0.000 description 66
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 63
- 239000000203 mixture Substances 0.000 description 61
- 239000002904 solvent Substances 0.000 description 51
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 41
- 239000007787 solid Substances 0.000 description 38
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 37
- 235000019341 magnesium sulphate Nutrition 0.000 description 37
- 235000019439 ethyl acetate Nutrition 0.000 description 31
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- CVFIJYWRPAZCAK-UHFFFAOYSA-N 5-(3-fluoro-4-methylsulfonylphenyl)-4-methyl-1,3-thiazol-2-amine Chemical compound N1=C(N)SC(C=2C=C(F)C(=CC=2)S(C)(=O)=O)=C1C CVFIJYWRPAZCAK-UHFFFAOYSA-N 0.000 description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
- 239000003795 chemical substances by application Substances 0.000 description 26
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 25
- 229940093499 ethyl acetate Drugs 0.000 description 25
- 239000000047 product Substances 0.000 description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 23
- 208000006673 asthma Diseases 0.000 description 22
- BNPONKLNSVKAJY-UHFFFAOYSA-N n-[5-(3-fluoro-4-methylsulfonylphenyl)-4-methyl-1,3-thiazol-2-yl]acetamide Chemical compound S1C(NC(=O)C)=NC(C)=C1C1=CC=C(S(C)(=O)=O)C(F)=C1 BNPONKLNSVKAJY-UHFFFAOYSA-N 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- 238000004587 chromatography analysis Methods 0.000 description 21
- 239000000377 silicon dioxide Substances 0.000 description 20
- 239000012267 brine Substances 0.000 description 19
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 19
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 150000002431 hydrogen Chemical group 0.000 description 18
- 239000012044 organic layer Substances 0.000 description 18
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 17
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 17
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 16
- 239000000284 extract Substances 0.000 description 16
- 238000003756 stirring Methods 0.000 description 16
- 150000001412 amines Chemical class 0.000 description 15
- OPPVMWMBVQKACT-UHFFFAOYSA-N ethyl 4-[[5-(3-fluoro-4-methylsulfonylphenyl)-4-methyl-1,3-thiazol-2-yl]carbamoylamino]butanoate Chemical compound S1C(NC(=O)NCCCC(=O)OCC)=NC(C)=C1C1=CC=C(S(C)(=O)=O)C(F)=C1 OPPVMWMBVQKACT-UHFFFAOYSA-N 0.000 description 15
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 13
- 239000004202 carbamide Substances 0.000 description 13
- 239000000463 material Substances 0.000 description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- 238000001914 filtration Methods 0.000 description 12
- 230000002757 inflammatory effect Effects 0.000 description 12
- 239000003960 organic solvent Substances 0.000 description 12
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 12
- ZVMIGNWPXSUFMG-UHFFFAOYSA-N 5-(4-chloro-3-methylsulfonylphenyl)-4-methyl-1,3-thiazol-2-amine Chemical compound N1=C(N)SC(C=2C=C(C(Cl)=CC=2)S(C)(=O)=O)=C1C ZVMIGNWPXSUFMG-UHFFFAOYSA-N 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 11
- WFWKNGZODAOLEO-UHFFFAOYSA-N 1-(4-Methoxyphenyl)-2-propanone Chemical compound COC1=CC=C(CC(C)=O)C=C1 WFWKNGZODAOLEO-UHFFFAOYSA-N 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- IPCRBOOJBPETMF-UHFFFAOYSA-N N-acetylthiourea Chemical compound CC(=O)NC(N)=S IPCRBOOJBPETMF-UHFFFAOYSA-N 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 10
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 10
- UOWSEQVPKQYSGA-UHFFFAOYSA-N 4-(2-acetamido-4-methyl-1,3-thiazol-5-yl)benzenesulfonyl chloride Chemical compound S1C(NC(=O)C)=NC(C)=C1C1=CC=C(S(Cl)(=O)=O)C=C1 UOWSEQVPKQYSGA-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000005557 antagonist Substances 0.000 description 9
- 229910052786 argon Inorganic materials 0.000 description 9
- WUDNUHPRLBTKOJ-UHFFFAOYSA-N ethyl isocyanate Chemical compound CCN=C=O WUDNUHPRLBTKOJ-UHFFFAOYSA-N 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 8
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 229960000583 acetic acid Drugs 0.000 description 8
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 8
- XBSGYVHOINMTIM-UHFFFAOYSA-N ethyl 3-isocyanatopropanoate Chemical compound CCOC(=O)CCN=C=O XBSGYVHOINMTIM-UHFFFAOYSA-N 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- ZASMRPOKAYRYIC-UHFFFAOYSA-N n-[4-methyl-5-(4-sulfamoylphenyl)-1,3-thiazol-2-yl]acetamide Chemical compound S1C(NC(=O)C)=NC(C)=C1C1=CC=C(S(N)(=O)=O)C=C1 ZASMRPOKAYRYIC-UHFFFAOYSA-N 0.000 description 8
- CBRAFMMINFVNBL-UHFFFAOYSA-N n-[5-(4-aminophenyl)-4-methyl-1,3-thiazol-2-yl]acetamide Chemical compound S1C(NC(=O)C)=NC(C)=C1C1=CC=C(N)C=C1 CBRAFMMINFVNBL-UHFFFAOYSA-N 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- 229910000029 sodium carbonate Inorganic materials 0.000 description 8
- 235000017550 sodium carbonate Nutrition 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
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- KOXKCSXWBTVCJG-UHFFFAOYSA-N n-[4-methyl-5-(3-nitrophenyl)-1,3-thiazol-2-yl]acetamide Chemical compound S1C(NC(=O)C)=NC(C)=C1C1=CC=CC([N+]([O-])=O)=C1 KOXKCSXWBTVCJG-UHFFFAOYSA-N 0.000 description 7
- SQWAXHGWLCYBIN-UHFFFAOYSA-N n-[5-(3-imidazol-1-yl-4-methylsulfonylphenyl)-4-methyl-1,3-thiazol-2-yl]acetamide Chemical compound S1C(NC(=O)C)=NC(C)=C1C1=CC=C(S(C)(=O)=O)C(N2C=NC=C2)=C1 SQWAXHGWLCYBIN-UHFFFAOYSA-N 0.000 description 7
- 239000002244 precipitate Substances 0.000 description 7
- AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 6
- MATCEQKDDNRWON-UHFFFAOYSA-N 1-bromo-1-(3-nitrophenyl)propan-2-one Chemical compound CC(=O)C(Br)C1=CC=CC([N+]([O-])=O)=C1 MATCEQKDDNRWON-UHFFFAOYSA-N 0.000 description 6
- RFVMFEVRMBBYJS-UHFFFAOYSA-N 2-(5-ethyl-1,3-oxazol-2-yl)ethanamine;hydrochloride Chemical compound Cl.CCC1=CN=C(CCN)O1 RFVMFEVRMBBYJS-UHFFFAOYSA-N 0.000 description 6
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/40—Unsubstituted amino or imino radicals
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- 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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