TWI719949B - 稠合五環咪唑衍生物 - Google Patents

Info

Publication number

TWI719949B

TWI719949B TW104132631A TW104132631A TWI719949B TW I719949 B TWI719949 B TW I719949B TW 104132631 A TW104132631 A TW 104132631A TW 104132631 A TW104132631 A TW 104132631A TW I719949 B TWI719949 B TW I719949B

Authority

TW

Taiwan

Prior art keywords

alkyl

formula

group

methyl

compound

Prior art date

2014-10-03

Links

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• 150000002460 imidazoles Chemical class 0.000 title abstract description 6
• 229940079865 intestinal antiinfectives imidazole derivative Drugs 0.000 title abstract description 5
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 24
• 208000035475 disorder Diseases 0.000 claims abstract description 18
• 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 14
• 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 10
• 208000012902 Nervous system disease Diseases 0.000 claims abstract description 10
• 208000025966 Neurological disease Diseases 0.000 claims abstract description 10
• 208000030159 metabolic disease Diseases 0.000 claims abstract description 10
• 208000015122 neurodegenerative disease Diseases 0.000 claims abstract description 10
• 230000000926 neurological effect Effects 0.000 claims abstract description 10
• 208000002193 Pain Diseases 0.000 claims abstract description 9
• 208000027866 inflammatory disease Diseases 0.000 claims abstract description 9
• 230000003040 nociceptive effect Effects 0.000 claims abstract description 9
• 230000002265 prevention Effects 0.000 claims abstract description 8
• -1 as appropriate Chemical group 0.000 claims description 481
• 150000001875 compounds Chemical class 0.000 claims description 355
• 125000000217 alkyl group Chemical group 0.000 claims description 219
• 229910052739 hydrogen Inorganic materials 0.000 claims description 190
• 239000001257 hydrogen Substances 0.000 claims description 189
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 127
• 125000001424 substituent group Chemical group 0.000 claims description 100
• 229910052736 halogen Inorganic materials 0.000 claims description 81
• 150000002367 halogens Chemical group 0.000 claims description 81
• PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 69
• 125000001072 heteroaryl group Chemical group 0.000 claims description 66
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 61
• 150000002431 hydrogen Chemical class 0.000 claims description 59
• 150000003839 salts Chemical class 0.000 claims description 59
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 55
• 125000003118 aryl group Chemical group 0.000 claims description 42
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 41
• 108060008682 Tumor Necrosis Factor Proteins 0.000 claims description 34
• 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 claims description 34
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 33
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 32
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 25
• 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 20
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 18
• 229910019142 PO4 Inorganic materials 0.000 claims description 18
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 18
• 239000010452 phosphate Substances 0.000 claims description 18
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 15
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 15
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 14
• NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 14
• 150000001204 N-oxides Chemical class 0.000 claims description 13
• 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 13
• 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 13
• 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 12
• 230000002757 inflammatory effect Effects 0.000 claims description 11
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
• 125000003545 alkoxy group Chemical group 0.000 claims description 9
• 230000000711 cancerogenic effect Effects 0.000 claims description 9
• 231100000315 carcinogenic Toxicity 0.000 claims description 9
• 208000030533 eye disease Diseases 0.000 claims description 9
• 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 8
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
• 125000005215 cycloalkylheteroaryl group Chemical group 0.000 claims description 8
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
• 229910052760 oxygen Inorganic materials 0.000 claims description 8
• 239000001301 oxygen Substances 0.000 claims description 8
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 8
• QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 7
• 125000004366 heterocycloalkenyl group Chemical group 0.000 claims description 7
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 7
• 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 6
• 150000001412 amines Chemical class 0.000 claims description 6
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
• 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 6
• 238000004519 manufacturing process Methods 0.000 claims description 6
• 239000007983 Tris buffer Substances 0.000 claims description 5
• 150000001335 aliphatic alkanes Chemical group 0.000 claims description 5
• 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 5
• 239000003814 drug Substances 0.000 claims description 5
• 238000006467 substitution reaction Methods 0.000 claims description 5
• 125000006323 alkenyl amino group Chemical group 0.000 claims description 4
• 229910052805 deuterium Inorganic materials 0.000 claims description 4
• 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
• 239000003937 drug carrier Substances 0.000 claims description 4
• 239000008194 pharmaceutical composition Substances 0.000 claims description 4
• 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 3
• YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 3
• 125000004567 azetidin-3-yl group Chemical group N1CC(C1)* 0.000 claims description 2
• 150000004677 hydrates Chemical class 0.000 claims 5
• 125000004122 cyclic group Chemical group 0.000 claims 1
• 230000006806 disease prevention Effects 0.000 claims 1
• 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 1
• 230000001363 autoimmune Effects 0.000 abstract description 8
• 230000000694 effects Effects 0.000 abstract description 6
• 101000611183 Homo sapiens Tumor necrosis factor Proteins 0.000 abstract description 4
• 102000057041 human TNF Human genes 0.000 abstract description 4
• 230000008901 benefit Effects 0.000 abstract description 2
• RYFZCJDZUMKKFN-UHFFFAOYSA-N 2,9,12-triazapentacyclo[9.8.1.02,10.03,8.014,19]icosa-3,5,7,9,14,16,18-heptaen-13-one Chemical class C1=CC=CC=2C(NC3C=4N(C(C=21)C3)C1=C(N=4)C=CC=C1)=O RYFZCJDZUMKKFN-UHFFFAOYSA-N 0.000 abstract 1
• 208000022873 Ocular disease Diseases 0.000 abstract 1
• 230000000771 oncological effect Effects 0.000 abstract 1
• 230000003389 potentiating effect Effects 0.000 abstract 1
• 239000000543 intermediate Substances 0.000 description 316
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 211
• 238000000034 method Methods 0.000 description 161
• 239000002904 solvent Substances 0.000 description 123
• HKJFNKDFMOCHDQ-UHFFFAOYSA-N 13H-benzimidazolo[2,1-c][1,4]benzodiazepine Chemical compound C1=CC=CC=2N=CC=3N(CC=21)C1=C(N=3)C=CC=C1 HKJFNKDFMOCHDQ-UHFFFAOYSA-N 0.000 description 114
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 108
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 95
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 95
• 235000019439 ethyl acetate Nutrition 0.000 description 94
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 86
• 238000006243 chemical reaction Methods 0.000 description 83
• 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 77
• 239000000203 mixture Substances 0.000 description 72
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 69
• 239000011541 reaction mixture Substances 0.000 description 69
• 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 63
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 61
• 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 59
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 53
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 52
• 239000002585 base Substances 0.000 description 49
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 48
• 239000000243 solution Substances 0.000 description 46
• 239000007787 solid Substances 0.000 description 45
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 42
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 42
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 42
• 238000005481 NMR spectroscopy Methods 0.000 description 39
• SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 37
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 37
• 229940049706 benzodiazepine Drugs 0.000 description 37
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 36
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 35
• 239000012044 organic layer Substances 0.000 description 35
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 34
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 29
• 239000000460 chlorine Substances 0.000 description 29
• 238000004458 analytical method Methods 0.000 description 28
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 27
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 27
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 27
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 27
• 229910052794 bromium Inorganic materials 0.000 description 27
• OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 26
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 26
• 235000019253 formic acid Nutrition 0.000 description 26
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 25
• 229910004298 SiO 2 Inorganic materials 0.000 description 25
• 229910052801 chlorine Inorganic materials 0.000 description 25
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 24
• 238000004587 chromatography analysis Methods 0.000 description 24
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 24
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 23
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 23
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 22
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 22
• 229910052731 fluorine Inorganic materials 0.000 description 22
• 239000011737 fluorine Substances 0.000 description 22
• 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 21
• 229910052757 nitrogen Inorganic materials 0.000 description 21
• 239000003643 water by type Substances 0.000 description 21
• 239000012267 brine Substances 0.000 description 20
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 20
• 239000002253 acid Substances 0.000 description 19
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 19
• 238000002360 preparation method Methods 0.000 description 19
• 239000003054 catalyst Substances 0.000 description 18
• 239000010410 layer Substances 0.000 description 18
• 229910052938 sodium sulfate Inorganic materials 0.000 description 18
• 235000011152 sodium sulphate Nutrition 0.000 description 18
• 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 description 16
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 16
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 16
• 125000004432 carbon atom Chemical group C* 0.000 description 16
• 239000007924 injection Substances 0.000 description 16
• 238000002347 injection Methods 0.000 description 16
• 239000003921 oil Substances 0.000 description 16
• 235000019198 oils Nutrition 0.000 description 16
• 229910052723 transition metal Inorganic materials 0.000 description 16
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
• 239000003480 eluent Substances 0.000 description 15
• 238000000746 purification Methods 0.000 description 15
• 150000003624 transition metals Chemical class 0.000 description 15
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 14
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 13
• 125000003277 amino group Chemical group 0.000 description 13
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 13
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 13
• 230000002829 reductive effect Effects 0.000 description 13
• 229920006395 saturated elastomer Polymers 0.000 description 13
• 238000003756 stirring Methods 0.000 description 13
• 125000003107 substituted aryl group Chemical group 0.000 description 13
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 13
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
• 239000013058 crude material Substances 0.000 description 12
• 239000000706 filtrate Substances 0.000 description 12
• 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 12
• 229910000027 potassium carbonate Inorganic materials 0.000 description 12
• 239000011734 sodium Substances 0.000 description 12
• 210000004027 cell Anatomy 0.000 description 11
• 239000012043 crude product Substances 0.000 description 11
• 239000012071 phase Substances 0.000 description 11
• 239000000725 suspension Substances 0.000 description 11
• 230000002378 acidificating effect Effects 0.000 description 10
• 125000005605 benzo group Chemical group 0.000 description 10
• FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 10
• 229910000024 caesium carbonate Inorganic materials 0.000 description 10
• 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 10
• 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 10
• 239000012074 organic phase Substances 0.000 description 10
• RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 10
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 9
• IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 9
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 9
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 9
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
• NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 9
• 238000001514 detection method Methods 0.000 description 9
• 238000004090 dissolution Methods 0.000 description 9
• 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 9
• 125000000714 pyrimidinyl group Chemical group 0.000 description 9
• 239000012312 sodium hydride Substances 0.000 description 9
• 229910000104 sodium hydride Inorganic materials 0.000 description 9
• 238000004809 thin layer chromatography Methods 0.000 description 9
• HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 8
• 230000006870 function Effects 0.000 description 8
• MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 8
• JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 8
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 7
• 229910021529 ammonia Inorganic materials 0.000 description 7
• NDTSRXAMMQDVSW-UHFFFAOYSA-N benzthiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(S(N2)(=O)=O)=C1N=C2CSCC1=CC=CC=C1 NDTSRXAMMQDVSW-UHFFFAOYSA-N 0.000 description 7
• 229960001541 benzthiazide Drugs 0.000 description 7
• 229910052799 carbon Inorganic materials 0.000 description 7
• 229910002091 carbon monoxide Inorganic materials 0.000 description 7
• 239000003795 chemical substances by application Substances 0.000 description 7
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 7
• 239000000047 product Substances 0.000 description 7
• 125000006239 protecting group Chemical group 0.000 description 7
• 125000004076 pyridyl group Chemical group 0.000 description 7
• 230000002441 reversible effect Effects 0.000 description 7
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 6
• LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 6
• OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 6
• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 6
• WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
• WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical group CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
• ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 6
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 6
• 239000004480 active ingredient Substances 0.000 description 6
• 229910052783 alkali metal Inorganic materials 0.000 description 6
• 229910052784 alkaline earth metal Inorganic materials 0.000 description 6
• 125000004744 butyloxycarbonyl group Chemical group 0.000 description 6
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