CN113121575A - 一种(取代的苯基)(取代的嘧啶)胺基衍生物及其制备方法和药物用途 - Google Patents

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Publication number

CN113121575A

CN113121575A CN202110329149.4A CN202110329149A CN113121575A CN 113121575 A CN113121575 A CN 113121575A CN 202110329149 A CN202110329149 A CN 202110329149A CN 113121575 A CN113121575 A CN 113121575A

Authority

CN

China

Prior art keywords

alkyl

methyl

amino

pyrimidin

methoxy

Prior art date

2014-08-25

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

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• -1 (substituted phenyl) (substituted pyrimidine) amino derivative Chemical class 0.000 title claims abstract description 456
• 238000002360 preparation method Methods 0.000 title claims abstract description 7
• 150000001875 compounds Chemical class 0.000 claims abstract description 147
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 41
• 150000003839 salts Chemical class 0.000 claims abstract description 34
• 239000013078 crystal Substances 0.000 claims abstract description 25
• 230000003287 optical effect Effects 0.000 claims abstract description 23
• 239000003814 drug Substances 0.000 claims abstract description 9
• 125000000623 heterocyclic group Chemical group 0.000 claims description 284
• 229910052801 chlorine Inorganic materials 0.000 claims description 182
• 229910052731 fluorine Inorganic materials 0.000 claims description 181
• 229910052794 bromium Inorganic materials 0.000 claims description 148
• 229910052740 iodine Inorganic materials 0.000 claims description 138
• 229910052739 hydrogen Inorganic materials 0.000 claims description 124
• 125000005842 heteroatom Chemical group 0.000 claims description 107
• 125000001424 substituent group Chemical group 0.000 claims description 106
• 125000003545 alkoxy group Chemical group 0.000 claims description 95
• 125000000217 alkyl group Chemical group 0.000 claims description 92
• 150000003254 radicals Chemical class 0.000 claims description 92
• 229910052717 sulfur Inorganic materials 0.000 claims description 88
• 229910052760 oxygen Inorganic materials 0.000 claims description 76
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 67
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 56
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 50
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 32
• 125000002757 morpholinyl group Chemical group 0.000 claims description 32
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 31
• 201000011510 cancer Diseases 0.000 claims description 29
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 27
• 125000004193 piperazinyl group Chemical group 0.000 claims description 26
• 125000003386 piperidinyl group Chemical group 0.000 claims description 22
• 125000003554 tetrahydropyrrolyl group Chemical group 0.000 claims description 22
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 18
• 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 14
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 14
• 125000002837 carbocyclic group Chemical group 0.000 claims description 13
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 11
• 229910052799 carbon Inorganic materials 0.000 claims description 10
• 229910052736 halogen Inorganic materials 0.000 claims description 9
• 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 8
• 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 8
• 125000003277 amino group Chemical class 0.000 claims description 8
• 201000005202 lung cancer Diseases 0.000 claims description 8
• 208000020816 lung neoplasm Diseases 0.000 claims description 8
• 238000000034 method Methods 0.000 claims description 8
• 239000008194 pharmaceutical composition Substances 0.000 claims description 8
• 125000003342 alkenyl group Chemical group 0.000 claims description 7
• 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 7
• 229910052698 phosphorus Inorganic materials 0.000 claims description 7
• 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 7
• 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims description 6
• 206010005003 Bladder cancer Diseases 0.000 claims description 6
• 208000003174 Brain Neoplasms Diseases 0.000 claims description 6
• 206010006187 Breast cancer Diseases 0.000 claims description 6
• 208000026310 Breast neoplasm Diseases 0.000 claims description 6
• 206010008342 Cervix carcinoma Diseases 0.000 claims description 6
• 206010009944 Colon cancer Diseases 0.000 claims description 6
• 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 6
• 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 6
• 206010033128 Ovarian cancer Diseases 0.000 claims description 6
• 206010061535 Ovarian neoplasm Diseases 0.000 claims description 6
• 208000005718 Stomach Neoplasms Diseases 0.000 claims description 6
• 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 6
• 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 6
• 201000010881 cervical cancer Diseases 0.000 claims description 6
• 208000029742 colonic neoplasm Diseases 0.000 claims description 6
• 125000004122 cyclic group Chemical group 0.000 claims description 6
• 201000004101 esophageal cancer Diseases 0.000 claims description 6
• 206010017758 gastric cancer Diseases 0.000 claims description 6
• 201000010536 head and neck cancer Diseases 0.000 claims description 6
• 208000014829 head and neck neoplasm Diseases 0.000 claims description 6
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
• 201000011549 stomach cancer Diseases 0.000 claims description 6
• VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 6
• 201000005112 urinary bladder cancer Diseases 0.000 claims description 6
• 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 5
• VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 5
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 5
• 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 5
• WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 5
• 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 5
• 201000002528 pancreatic cancer Diseases 0.000 claims description 5
• 208000008443 pancreatic carcinoma Diseases 0.000 claims description 5
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 5
• 125000003341 7 membered heterocyclic group Chemical group 0.000 claims description 4
• QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 4
• DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 4
• 208000005017 glioblastoma Diseases 0.000 claims description 4
• 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 4
• 229920002554 vinyl polymer Polymers 0.000 claims description 4
• 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 3
• GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims description 3
• 229910019142 PO4 Inorganic materials 0.000 claims description 3
• QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 3
• 125000004429 atom Chemical group 0.000 claims description 3
• 229940077388 benzenesulfonate Drugs 0.000 claims description 3
• SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 claims description 3
• 239000003937 drug carrier Substances 0.000 claims description 3
• NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 3
• 239000010452 phosphate Substances 0.000 claims description 3
• ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 3
• 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 2
• 125000003566 oxetanyl group Chemical group 0.000 claims description 2
• 125000005843 halogen group Chemical group 0.000 claims 3
• 125000006661 (C4-C6) heterocyclic group Chemical group 0.000 claims 1
• 230000005496 eutectics Effects 0.000 abstract description 8
• 229940079593 drug Drugs 0.000 abstract description 6
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 390
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 223
• 238000006243 chemical reaction Methods 0.000 description 214
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 201
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 149
• 239000000460 chlorine Substances 0.000 description 136
• 239000007787 solid Substances 0.000 description 127
• 239000012074 organic phase Substances 0.000 description 107
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 98
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 98
• 238000004949 mass spectrometry Methods 0.000 description 98
• 239000000243 solution Substances 0.000 description 93
• 238000005160 1H NMR spectroscopy Methods 0.000 description 85
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 83
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 75
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 75
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 69
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical group CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 68
• 238000010898 silica gel chromatography Methods 0.000 description 57
• 125000003118 aryl group Chemical group 0.000 description 55
• 125000001072 heteroaryl group Chemical group 0.000 description 52
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 51
• 230000002829 reductive effect Effects 0.000 description 49
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 49
• 239000000203 mixture Substances 0.000 description 47
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 39
• 125000003003 spiro group Chemical group 0.000 description 37
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 36
• 239000011541 reaction mixture Substances 0.000 description 36
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 32
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 32
• 239000012065 filter cake Substances 0.000 description 31
• XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 31
• 239000003208 petroleum Substances 0.000 description 31
• 238000000605 extraction Methods 0.000 description 29
• 235000019441 ethanol Nutrition 0.000 description 28
• 229960004756 ethanol Drugs 0.000 description 27
• JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 27
• 235000019270 ammonium chloride Nutrition 0.000 description 25
• 229910052757 nitrogen Inorganic materials 0.000 description 25
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 24
• 238000004440 column chromatography Methods 0.000 description 23
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 22
• 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 22
• 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 22
• JYVLIDXNZAXMDK-UHFFFAOYSA-N pentan-2-ol Chemical compound CCCC(C)O JYVLIDXNZAXMDK-UHFFFAOYSA-N 0.000 description 22
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
• YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 21
• 239000000706 filtrate Substances 0.000 description 20
• HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 19
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 19
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 19
• 229940117913 acrylamide Drugs 0.000 description 19
• 229920006395 saturated elastomer Polymers 0.000 description 19
• 239000012312 sodium hydride Substances 0.000 description 19
• 229910000104 sodium hydride Inorganic materials 0.000 description 19
• 150000001299 aldehydes Chemical class 0.000 description 18
• 125000004432 carbon atom Chemical group C* 0.000 description 18
• 125000002462 isocyano group Chemical group *[N+]#[C-] 0.000 description 18
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 18
• 235000017557 sodium bicarbonate Nutrition 0.000 description 18
• HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 17
• 239000008346 aqueous phase Substances 0.000 description 17
• 125000001188 haloalkyl group Chemical group 0.000 description 17
• 125000002768 hydroxyalkyl group Chemical group 0.000 description 17
• 230000035772 mutation Effects 0.000 description 17
• 102200048955 rs121434569 Human genes 0.000 description 17
• 150000003573 thiols Chemical class 0.000 description 17
• FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 16
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
• HVOYZOQVDYHUPF-UHFFFAOYSA-N n,n',n'-trimethylethane-1,2-diamine Chemical compound CNCCN(C)C HVOYZOQVDYHUPF-UHFFFAOYSA-N 0.000 description 16
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 16
• 238000003756 stirring Methods 0.000 description 16
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 15
• FYSIGSQCZXQTIH-UHFFFAOYSA-N 4-fluoro-2-methoxy-5-nitroaniline Chemical compound COC1=CC(F)=C([N+]([O-])=O)C=C1N FYSIGSQCZXQTIH-UHFFFAOYSA-N 0.000 description 15
• 125000005110 aryl thio group Chemical group 0.000 description 15
• 239000010410 layer Substances 0.000 description 15
• LJXQPZWIHJMPQQ-UHFFFAOYSA-N pyrimidin-2-amine Chemical compound NC1=NC=CC=N1 LJXQPZWIHJMPQQ-UHFFFAOYSA-N 0.000 description 15
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 15
• SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 14
• NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 14
• 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 14
• 238000000926 separation method Methods 0.000 description 14
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 13
• 150000001733 carboxylic acid esters Chemical class 0.000 description 13
• 150000002148 esters Chemical class 0.000 description 13
• 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 13
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 13
• 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 13
• 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 13
• 125000003006 2-dimethylaminoethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 12
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
• 238000001816 cooling Methods 0.000 description 12
• UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 12
• 239000007788 liquid Substances 0.000 description 12
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
• MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 12
• YJGKIMCJZOZIOQ-UHFFFAOYSA-N 3-(2-chloropyrimidin-4-yl)-1h-indole Chemical compound ClC1=NC=CC(C=2C3=CC=CC=C3NC=2)=N1 YJGKIMCJZOZIOQ-UHFFFAOYSA-N 0.000 description 11
• 238000001035 drying Methods 0.000 description 11
• OLFHYKFISGHKLX-UHFFFAOYSA-N N-[2-[(1-aminocyclopropyl)methoxy]-5-[[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]amino]-4-methoxyphenyl]prop-2-enamide Chemical compound NC1(CC1)COC1=C(C=C(C(=C1)OC)NC1=NC=C(C(=N1)C1=CNC2=CC=CC=C12)Cl)NC(C=C)=O OLFHYKFISGHKLX-UHFFFAOYSA-N 0.000 description 10
• 230000000670 limiting effect Effects 0.000 description 10
• 238000010992 reflux Methods 0.000 description 10
• MBYZPCLOMQCIEV-UHFFFAOYSA-N 3-(2,5-dichloropyrimidin-4-yl)-1-methylindole Chemical compound C12=CC=CC=C2N(C)C=C1C1=NC(Cl)=NC=C1Cl MBYZPCLOMQCIEV-UHFFFAOYSA-N 0.000 description 9
• IWIIPOFGVHSGJK-UHFFFAOYSA-N ClC1=NC=C(C(=N1)C=1C=NN2C=1C=CC=C2)OC Chemical compound ClC1=NC=C(C(=N1)C=1C=NN2C=1C=CC=C2)OC IWIIPOFGVHSGJK-UHFFFAOYSA-N 0.000 description 9
• LSAXAUHMKAFARK-UHFFFAOYSA-N ClC=1C(=NC(=NC=1)NC=1C(=CC(=C(C=1)NC(C=C)=O)N(CCN1CCCC1)C)OC)C1=CNC2=CC=CC=C12 Chemical compound ClC=1C(=NC(=NC=1)NC=1C(=CC(=C(C=1)NC(C=C)=O)N(CCN1CCCC1)C)OC)C1=CNC2=CC=CC=C12 LSAXAUHMKAFARK-UHFFFAOYSA-N 0.000 description 9
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 9
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 9
• 229940121647 egfr inhibitor Drugs 0.000 description 9
• 238000001914 filtration Methods 0.000 description 9
• IIBWXYHPBMUNJP-UHFFFAOYSA-N 3-(2-chloropyrimidin-4-yl)-1-methylindole Chemical compound C12=CC=CC=C2N(C)C=C1C1=CC=NC(Cl)=N1 IIBWXYHPBMUNJP-UHFFFAOYSA-N 0.000 description 8
• NAIQFJQMXDXVRV-UHFFFAOYSA-N 5-chloro-n-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine Chemical compound COC1=CC(F)=C([N+]([O-])=O)C=C1NC1=NC=C(Cl)C(C=2C3=CC=CC=C3N(C)C=2)=N1 NAIQFJQMXDXVRV-UHFFFAOYSA-N 0.000 description 8
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
• 239000002585 base Substances 0.000 description 8
• SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 8
• 238000005303 weighing Methods 0.000 description 8
• BFBRQEGSKHTTKV-UHFFFAOYSA-N 1-(6-aminoindol-1-yl)ethanone Chemical compound C1=C(N)C=C2N(C(=O)C)C=CC2=C1 BFBRQEGSKHTTKV-UHFFFAOYSA-N 0.000 description 7
• KGDIMUBURADHIJ-UHFFFAOYSA-N 1-(6-nitroindol-1-yl)ethanone Chemical compound C1=C([N+]([O-])=O)C=C2N(C(=O)C)C=CC2=C1 KGDIMUBURADHIJ-UHFFFAOYSA-N 0.000 description 7
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