OA11444A - Bicyclic heteroaromatic compound as protein tyrosine kinase inhibitors. - Google Patents

Info

Publication number

OA11444A

OA11444A OA1200000202A OA1200000202A OA11444A OA 11444 A OA11444 A OA 11444A OA 1200000202 A OA1200000202 A OA 1200000202A OA 1200000202 A OA1200000202 A OA 1200000202A OA 11444 A OA11444 A OA 11444A

Authority

OA

OAPI

Prior art keywords

methyl

methanesulphonyl

phenyl

amine

quinazolinamine

Prior art date

1998-01-12

Links

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• -1 Bicyclic heteroaromatic compound Chemical class 0.000 title claims abstract description 193
• 239000005483 tyrosine kinase inhibitor Substances 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims abstract description 188
• 238000000034 method Methods 0.000 claims abstract description 158
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 71
• YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 52
• 125000005843 halogen group Chemical group 0.000 claims abstract description 41
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 30
• 150000003839 salts Chemical class 0.000 claims abstract description 27
• FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims abstract description 25
• 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 24
• 238000011282 treatment Methods 0.000 claims abstract description 24
• 239000001257 hydrogen Substances 0.000 claims abstract description 19
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 17
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 15
• 230000008569 process Effects 0.000 claims abstract description 15
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 13
• 201000011510 cancer Diseases 0.000 claims abstract description 6
• 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims abstract description 5
• 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims abstract description 3
• 238000002560 therapeutic procedure Methods 0.000 claims abstract description 3
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract 2
• 238000006243 chemical reaction Methods 0.000 claims description 67
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 61
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 50
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 49
• 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 38
• 102000004022 Protein-Tyrosine Kinases Human genes 0.000 claims description 23
• 108090000412 Protein-Tyrosine Kinases Proteins 0.000 claims description 23
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 23
• 125000006284 3-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(F)=C1[H])C([H])([H])* 0.000 claims description 20
• 125000003545 alkoxy group Chemical group 0.000 claims description 20
• 125000000217 alkyl group Chemical group 0.000 claims description 19
• 239000003153 chemical reaction reagent Substances 0.000 claims description 18
• 230000000694 effects Effects 0.000 claims description 18
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 15
• 150000002240 furans Chemical class 0.000 claims description 12
• 125000001424 substituent group Chemical group 0.000 claims description 10
• 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 9
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 7
• 230000001404 mediated effect Effects 0.000 claims description 7
• 125000005955 1H-indazolyl group Chemical group 0.000 claims description 6
• 125000003282 alkyl amino group Chemical group 0.000 claims description 6
• 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 6
• 125000006279 3-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(Br)=C1[H])C([H])([H])* 0.000 claims description 5
• 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 5
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
• 125000004414 alkyl thio group Chemical group 0.000 claims description 4
• 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 4
• 229910052736 halogen Inorganic materials 0.000 claims description 4
• 150000002367 halogens Chemical class 0.000 claims description 4
• 150000003840 hydrochlorides Chemical class 0.000 claims description 4
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
• 125000005236 alkanoylamino group Chemical group 0.000 claims description 3
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 3
• 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 3
• 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 3
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 3
• 125000001041 indolyl group Chemical group 0.000 claims description 3
• BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 claims description 3
• NNWNJRWNKDIGML-UHFFFAOYSA-N n-[1-[(3-fluorophenyl)methyl]indazol-5-yl]-6-[2-[(2-methylsulfonylethylamino)methyl]-1,3-thiazol-4-yl]quinazolin-4-amine Chemical compound S1C(CNCCS(=O)(=O)C)=NC(C=2C=C3C(NC=4C=C5C=NN(CC=6C=C(F)C=CC=6)C5=CC=4)=NC=NC3=CC=2)=C1 NNWNJRWNKDIGML-UHFFFAOYSA-N 0.000 claims description 3
• YVUAXTVZWVNAGQ-UHFFFAOYSA-N n-[7-methoxy-2-[2-[5-[(2-methylsulfonylethylamino)methyl]furan-2-yl]phenyl]quinazolin-4-yl]benzenesulfonamide Chemical compound N=1C(C=2C(=CC=CC=2)C=2OC(CNCCS(C)(=O)=O)=CC=2)=NC2=CC(OC)=CC=C2C=1NS(=O)(=O)C1=CC=CC=C1 YVUAXTVZWVNAGQ-UHFFFAOYSA-N 0.000 claims description 3
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
• 239000003085 diluting agent Substances 0.000 claims description 2
• 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 claims description 2
• RRONZTYLARBRBH-UHFFFAOYSA-N n-(3-fluoro-4-phenylmethoxyphenyl)-6-[2-[(2-methylsulfonylethylamino)methyl]-1,3-thiazol-4-yl]quinazolin-4-amine Chemical compound S1C(CNCCS(=O)(=O)C)=NC(C=2C=C3C(NC=4C=C(F)C(OCC=5C=CC=CC=5)=CC=4)=NC=NC3=CC=2)=C1 RRONZTYLARBRBH-UHFFFAOYSA-N 0.000 claims description 2
• DNHCEIAFWBGYFK-UHFFFAOYSA-N n-[3-fluoro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[2-[(2-methylsulfonylethylamino)methyl]-1,3-thiazol-4-yl]quinazolin-4-amine Chemical compound S1C(CNCCS(=O)(=O)C)=NC(C=2C=C3C(NC=4C=C(F)C(OCC=5C=C(F)C=CC=5)=CC=4)=NC=NC3=CC=2)=C1 DNHCEIAFWBGYFK-UHFFFAOYSA-N 0.000 claims description 2
• UXXAYIVASCFMEV-UHFFFAOYSA-N n-[4-(benzenesulfonyl)phenyl]-6-[5-[(2-methylsulfonylethylamino)methyl]furan-2-yl]pyrido[3,4-d]pyrimidin-4-amine Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C(N=CC1=NC=N2)=CC1=C2NC1=CC=C(S(=O)(=O)C=2C=CC=CC=2)C=C1 UXXAYIVASCFMEV-UHFFFAOYSA-N 0.000 claims description 2
• 125000004076 pyridyl group Chemical group 0.000 claims description 2
• SGPGESCZOCHFCL-UHFFFAOYSA-N Tilisolol hydrochloride Chemical compound [Cl-].C1=CC=C2C(=O)N(C)C=C(OCC(O)C[NH2+]C(C)(C)C)C2=C1 SGPGESCZOCHFCL-UHFFFAOYSA-N 0.000 claims 3
• OYRRZWATULMEPF-UHFFFAOYSA-N pyrimidin-4-amine Chemical compound NC1=CC=NC=N1 OYRRZWATULMEPF-UHFFFAOYSA-N 0.000 claims 2
• 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims 1
• UJYWZVPEMTYMBL-UHFFFAOYSA-N 6-[4-[(2-methylsulfonylethylamino)methyl]furan-2-yl]-n-(4-phenylmethoxyphenyl)quinazolin-4-amine Chemical compound CS(=O)(=O)CCNCC1=COC(C=2C=C3C(NC=4C=CC(OCC=5C=CC=CC=5)=CC=4)=NC=NC3=CC=2)=C1 UJYWZVPEMTYMBL-UHFFFAOYSA-N 0.000 claims 1
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 1
• 239000002552 dosage form Substances 0.000 claims 1
• MNHCZHFLNIOWQH-UHFFFAOYSA-N n-[3-fluoro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[5-[(2-methylsulfonylethylamino)methyl]furan-2-yl]quinazolin-4-amine Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(F)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 MNHCZHFLNIOWQH-UHFFFAOYSA-N 0.000 claims 1
• RZEMPBRXCDBLDH-UHFFFAOYSA-N n-[4-[(3-fluorophenyl)methoxy]phenyl]-6-[5-[(2-methylsulfonylethylamino)methyl]furan-2-yl]quinazolin-4-amine Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=CC(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 RZEMPBRXCDBLDH-UHFFFAOYSA-N 0.000 claims 1
• 125000001309 chloro group Chemical group Cl* 0.000 abstract description 9
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 abstract description 3
• 125000001246 bromo group Chemical group Br* 0.000 abstract description 3
• 239000012453 solvate Substances 0.000 abstract 1
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 116
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 94
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 90
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 88
• 239000007787 solid Substances 0.000 description 80
• 239000000203 mixture Substances 0.000 description 69
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 55
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 47
• 239000000243 solution Substances 0.000 description 41
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 40
• 150000001412 amines Chemical class 0.000 description 39
• 238000005160 1H NMR spectroscopy Methods 0.000 description 38
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 35
• 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 34
• 239000000047 product Substances 0.000 description 34
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 31
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 31
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 30
• 235000019439 ethyl acetate Nutrition 0.000 description 30
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 29
• 229940093499 ethyl acetate Drugs 0.000 description 28
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 27
• 239000002904 solvent Substances 0.000 description 27
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 25
• 229910052757 nitrogen Inorganic materials 0.000 description 24
• 238000005481 NMR spectroscopy Methods 0.000 description 23
• 210000004027 cell Anatomy 0.000 description 23
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 22
• PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 20
• SDNXQWUJWNTDCC-UHFFFAOYSA-N 2-methylsulfonylethanamine Chemical compound CS(=O)(=O)CCN SDNXQWUJWNTDCC-UHFFFAOYSA-N 0.000 description 19
• 125000004122 cyclic group Chemical group 0.000 description 19
• 238000001914 filtration Methods 0.000 description 19
• 238000000746 purification Methods 0.000 description 18
• 238000010992 reflux Methods 0.000 description 18
• CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 18
• 239000011541 reaction mixture Substances 0.000 description 16
• 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 15
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 15
• BDAIUOPDSRAOKI-UHFFFAOYSA-N 4-chloro-6-iodoquinazoline Chemical compound C1=C(I)C=C2C(Cl)=NC=NC2=C1 BDAIUOPDSRAOKI-UHFFFAOYSA-N 0.000 description 14
• 101710100968 Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 14
• 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 14
• 239000003921 oil Substances 0.000 description 14
• MIQQFNUHWRYYFY-UHFFFAOYSA-N tributyl-[5-(1,3-dioxolan-2-yl)furan-2-yl]stannane Chemical compound O1C([Sn](CCCC)(CCCC)CCCC)=CC=C1C1OCCO1 MIQQFNUHWRYYFY-UHFFFAOYSA-N 0.000 description 14
• 239000000543 intermediate Substances 0.000 description 13
• AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 12
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
• PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 11
• 239000000725 suspension Substances 0.000 description 11
• OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 10
• 239000002585 base Substances 0.000 description 10
• 229910052799 carbon Inorganic materials 0.000 description 10
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
• 125000004546 quinazolin-4-yl group Chemical group N1=CN=C(C2=CC=CC=C12)* 0.000 description 10
• 229910000029 sodium carbonate Inorganic materials 0.000 description 10
• 239000002253 acid Substances 0.000 description 9
• 238000004587 chromatography analysis Methods 0.000 description 9
• 229960004132 diethyl ether Drugs 0.000 description 9
• 208000035475 disorder Diseases 0.000 description 9
• 238000009472 formulation Methods 0.000 description 9
• 150000002431 hydrogen Chemical class 0.000 description 9
• 239000002244 precipitate Substances 0.000 description 9
• 125000004549 quinolin-4-yl group Chemical group N1=CC=C(C2=CC=CC=C12)* 0.000 description 9
• 239000000377 silicon dioxide Substances 0.000 description 9
• 238000003756 stirring Methods 0.000 description 9
• 239000000758 substrate Substances 0.000 description 9
• 229910052727 yttrium Inorganic materials 0.000 description 9
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
• 229960000583 acetic acid Drugs 0.000 description 8
• 150000001721 carbon Chemical group 0.000 description 8
• 238000004440 column chromatography Methods 0.000 description 8
• 239000012044 organic layer Substances 0.000 description 8
• 239000012074 organic phase Substances 0.000 description 8
• WARKYKQCOXTIAO-UHFFFAOYSA-N tributyl(2-ethoxyethenyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)\C=C/OCC WARKYKQCOXTIAO-UHFFFAOYSA-N 0.000 description 8
• 101100268066 Mus musculus Zap70 gene Proteins 0.000 description 7
• 210000000481 breast Anatomy 0.000 description 7
• YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 description 7
• 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 7
• 238000001665 trituration Methods 0.000 description 7
• 229910052720 vanadium Inorganic materials 0.000 description 7
• GPWNWKWQOLEVEQ-UHFFFAOYSA-N 2,4-diaminopyrimidine-5-carbaldehyde Chemical compound NC1=NC=C(C=O)C(N)=N1 GPWNWKWQOLEVEQ-UHFFFAOYSA-N 0.000 description 6
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
• 108060006698 EGF receptor Proteins 0.000 description 6
• FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 6
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
• 230000001594 aberrant effect Effects 0.000 description 6
• 235000011054 acetic acid Nutrition 0.000 description 6
• 125000004175 fluorobenzyl group Chemical group 0.000 description 6
• 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 6
• 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 6
• 230000005764 inhibitory process Effects 0.000 description 6
• 239000000741 silica gel Substances 0.000 description 6
• 229910002027 silica gel Inorganic materials 0.000 description 6
• 229960001866 silicon dioxide Drugs 0.000 description 6
• 238000003786 synthesis reaction Methods 0.000 description 6
• HWIIAAVGRHKSOJ-UHFFFAOYSA-N 2-chloro-6,7-dimethoxyquinazolin-4-amine Chemical compound ClC1=NC(N)=C2C=C(OC)C(OC)=CC2=N1 HWIIAAVGRHKSOJ-UHFFFAOYSA-N 0.000 description 5
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 5
• VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 5
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
• 201000004681 Psoriasis Diseases 0.000 description 5
• 238000003556 assay Methods 0.000 description 5
• 125000002619 bicyclic group Chemical group 0.000 description 5
• 201000010099 disease Diseases 0.000 description 5
• 239000000706 filtrate Substances 0.000 description 5
• 238000004128 high performance liquid chromatography Methods 0.000 description 5
• 239000010410 layer Substances 0.000 description 5
• 239000007788 liquid Substances 0.000 description 5
• 230000026731 phosphorylation Effects 0.000 description 5
• 238000006366 phosphorylation reaction Methods 0.000 description 5
• 229910000027 potassium carbonate Inorganic materials 0.000 description 5
• 239000000843 powder Substances 0.000 description 5
• 108090000765 processed proteins & peptides Proteins 0.000 description 5
• 102000004169 proteins and genes Human genes 0.000 description 5
• 108090000623 proteins and genes Proteins 0.000 description 5
• 239000012321 sodium triacetoxyborohydride Substances 0.000 description 5
• 239000012258 stirred mixture Substances 0.000 description 5
• BQUSMTPKYUILPD-UHFFFAOYSA-N 1-benzylindazol-5-amine Chemical compound N1=CC2=CC(N)=CC=C2N1CC1=CC=CC=C1 BQUSMTPKYUILPD-UHFFFAOYSA-N 0.000 description 4
• BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical group C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 4
• NRKYWOKHZRQRJR-UHFFFAOYSA-N 2,2,2-trifluoroacetamide Chemical compound NC(=O)C(F)(F)F NRKYWOKHZRQRJR-UHFFFAOYSA-N 0.000 description 4
• CYWGSFFHHMQKET-UHFFFAOYSA-N 2-methylsulfanylethanamine Chemical compound CSCCN CYWGSFFHHMQKET-UHFFFAOYSA-N 0.000 description 4
• FIIDVVUUWRJXLF-UHFFFAOYSA-N 4-phenylmethoxyaniline Chemical compound C1=CC(N)=CC=C1OCC1=CC=CC=C1 FIIDVVUUWRJXLF-UHFFFAOYSA-N 0.000 description 4
• KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 4
• DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
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