RU2751341C2 - Соединения-ингибиторы egfr - Google Patents
Соединения-ингибиторы egfr Download PDFInfo
- Publication number
- RU2751341C2 RU2751341C2 RU2018138584A RU2018138584A RU2751341C2 RU 2751341 C2 RU2751341 C2 RU 2751341C2 RU 2018138584 A RU2018138584 A RU 2018138584A RU 2018138584 A RU2018138584 A RU 2018138584A RU 2751341 C2 RU2751341 C2 RU 2751341C2
- Authority
- RU
- Russia
- Prior art keywords
- cancer
- substituted
- bicyclo
- pharmaceutically acceptable
- mmol
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims description 274
- 229940121647 egfr inhibitor Drugs 0.000 title description 25
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 141
- 230000000694 effects Effects 0.000 claims abstract description 134
- 201000011510 cancer Diseases 0.000 claims abstract description 101
- -1 bicyclo[1.1.1]pentyl Chemical group 0.000 claims abstract description 90
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 69
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 53
- 238000000034 method Methods 0.000 claims abstract description 48
- 125000001424 substituent group Chemical group 0.000 claims abstract description 23
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 20
- 150000002367 halogens Chemical class 0.000 claims abstract description 20
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 17
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 claims abstract 9
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 claims abstract 9
- 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 claims abstract 9
- 125000000217 alkyl group Chemical group 0.000 claims description 150
- 150000003839 salts Chemical class 0.000 claims description 121
- 230000035772 mutation Effects 0.000 claims description 60
- 229910052739 hydrogen Inorganic materials 0.000 claims description 43
- 239000001257 hydrogen Substances 0.000 claims description 43
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 38
- 230000037430 deletion Effects 0.000 claims description 24
- 238000012217 deletion Methods 0.000 claims description 24
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 125000003545 alkoxy group Chemical group 0.000 claims description 13
- 238000003780 insertion Methods 0.000 claims description 12
- 230000037431 insertion Effects 0.000 claims description 12
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 10
- 208000029742 colonic neoplasm Diseases 0.000 claims description 10
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 10
- 208000020816 lung neoplasm Diseases 0.000 claims description 10
- 206010006187 Breast cancer Diseases 0.000 claims description 9
- 208000026310 Breast neoplasm Diseases 0.000 claims description 9
- 239000003085 diluting agent Substances 0.000 claims description 9
- 206010009944 Colon cancer Diseases 0.000 claims description 7
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 7
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 7
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 7
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 7
- 208000006265 Renal cell carcinoma Diseases 0.000 claims description 7
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- 201000010536 head and neck cancer Diseases 0.000 claims description 7
- 201000005202 lung cancer Diseases 0.000 claims description 7
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 7
- 230000010076 replication Effects 0.000 claims description 7
- 206010033128 Ovarian cancer Diseases 0.000 claims description 6
- 206010060862 Prostate cancer Diseases 0.000 claims description 6
- 206010038389 Renal cancer Diseases 0.000 claims description 6
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 6
- 201000002528 pancreatic cancer Diseases 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 201000010174 renal carcinoma Diseases 0.000 claims description 6
- 125000001153 fluoro group Chemical group F* 0.000 claims description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 3
- 125000001041 indolyl group Chemical group 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- 230000036210 malignancy Effects 0.000 claims 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 8
- 102000001301 EGF receptor Human genes 0.000 description 166
- 108060006698 EGF receptor Proteins 0.000 description 165
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 128
- 239000000203 mixture Substances 0.000 description 109
- 125000001072 heteroaryl group Chemical group 0.000 description 74
- 125000000623 heterocyclic group Chemical group 0.000 description 73
- 239000000243 solution Substances 0.000 description 72
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 53
- 235000019439 ethyl acetate Nutrition 0.000 description 52
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 48
- 125000003118 aryl group Chemical group 0.000 description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 47
- 239000011541 reaction mixture Substances 0.000 description 45
- 210000004027 cell Anatomy 0.000 description 36
- 125000000753 cycloalkyl group Chemical group 0.000 description 34
- 230000005764 inhibitory process Effects 0.000 description 34
- 239000011734 sodium Substances 0.000 description 28
- 239000012044 organic layer Substances 0.000 description 27
- 239000007787 solid Substances 0.000 description 27
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 25
- 125000004429 atom Chemical group 0.000 description 25
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 23
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 23
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 22
- 125000003342 alkenyl group Chemical group 0.000 description 22
- 229910004298 SiO 2 Inorganic materials 0.000 description 21
- 125000005842 heteroatom Chemical group 0.000 description 21
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 description 20
- 125000000304 alkynyl group Chemical group 0.000 description 20
- 125000000392 cycloalkenyl group Chemical group 0.000 description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 19
- 239000003814 drug Substances 0.000 description 19
- 230000002018 overexpression Effects 0.000 description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 239000012267 brine Substances 0.000 description 17
- 125000004432 carbon atom Chemical group C* 0.000 description 17
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 17
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 239000000460 chlorine Substances 0.000 description 15
- 238000004440 column chromatography Methods 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 230000004913 activation Effects 0.000 description 14
- 230000002829 reductive effect Effects 0.000 description 14
- 241000282414 Homo sapiens Species 0.000 description 13
- 238000004519 manufacturing process Methods 0.000 description 13
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 12
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 12
- 125000002947 alkylene group Chemical group 0.000 description 11
- 150000001412 amines Chemical class 0.000 description 11
- 229910052799 carbon Inorganic materials 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 11
- 238000004587 chromatography analysis Methods 0.000 description 11
- 239000003480 eluent Substances 0.000 description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 11
- 238000012054 celltiter-glo Methods 0.000 description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 10
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 10
- 201000010099 disease Diseases 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 8
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 8
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 8
- 150000003254 radicals Chemical class 0.000 description 8
- 125000003107 substituted aryl group Chemical group 0.000 description 8
- 239000000758 substrate Substances 0.000 description 8
- 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 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- 229960002584 gefitinib Drugs 0.000 description 7
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 7
- 230000000670 limiting effect Effects 0.000 description 7
- 229910052760 oxygen Inorganic materials 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 229910052717 sulfur Inorganic materials 0.000 description 7
- PKHHKVLPYTZNMG-UHFFFAOYSA-N 1-(1-bicyclo[1.1.1]pentanyl)indole Chemical compound C12(CC(C1)C2)N1C=CC2=CC=CC=C12 PKHHKVLPYTZNMG-UHFFFAOYSA-N 0.000 description 6
- 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 6
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 6
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 6
- 230000003213 activating effect Effects 0.000 description 6
- 125000002252 acyl group Chemical group 0.000 description 6
- 229960001686 afatinib Drugs 0.000 description 6
- ULXXDDBFHOBEHA-CWDCEQMOSA-N afatinib Chemical compound N1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-CWDCEQMOSA-N 0.000 description 6
- 125000003277 amino group Chemical group 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- 239000012298 atmosphere Substances 0.000 description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 125000004122 cyclic group Chemical group 0.000 description 6
- 229960001433 erlotinib Drugs 0.000 description 6
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 6
- 210000003494 hepatocyte Anatomy 0.000 description 6
- 238000000338 in vitro Methods 0.000 description 6
- 125000002950 monocyclic group Chemical group 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 239000001301 oxygen Substances 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- JYVLIDXNZAXMDK-UHFFFAOYSA-N pentan-2-ol Chemical compound CCCC(C)O JYVLIDXNZAXMDK-UHFFFAOYSA-N 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 6
- 230000004044 response Effects 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000011593 sulfur Substances 0.000 description 6
- 208000024891 symptom Diseases 0.000 description 6
- 230000001988 toxicity Effects 0.000 description 6
- 231100000419 toxicity Toxicity 0.000 description 6
- 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 5
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 5
- 101150039808 Egfr gene Proteins 0.000 description 5
- 208000010201 Exanthema Diseases 0.000 description 5
- 241000282412 Homo Species 0.000 description 5
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 108700021358 erbB-1 Genes Proteins 0.000 description 5
- 201000005884 exanthem Diseases 0.000 description 5
- 235000019253 formic acid Nutrition 0.000 description 5
- 230000004927 fusion Effects 0.000 description 5
- 125000001188 haloalkyl group Chemical group 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- HVOYZOQVDYHUPF-UHFFFAOYSA-N n,n',n'-trimethylethane-1,2-diamine Chemical compound CNCCN(C)C HVOYZOQVDYHUPF-UHFFFAOYSA-N 0.000 description 5
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 5
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 230000026731 phosphorylation Effects 0.000 description 5
- 238000006366 phosphorylation reaction Methods 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 206010037844 rash Diseases 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 239000000377 silicon dioxide Substances 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- KBRCUFIWCIJABR-UHFFFAOYSA-N 1-(1-bicyclo[1.1.1]pentanyl)-3H-indol-2-one Chemical compound C12(CC(C1)C2)N1C(CC2=CC=CC=C12)=O KBRCUFIWCIJABR-UHFFFAOYSA-N 0.000 description 4
- BTTNYQZNBZNDOR-UHFFFAOYSA-N 2,4-dichloropyrimidine Chemical compound ClC1=CC=NC(Cl)=N1 BTTNYQZNBZNDOR-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 108091000080 Phosphotransferase Proteins 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 239000002246 antineoplastic agent Substances 0.000 description 4
- 125000002619 bicyclic group Chemical group 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 4
- 229910052681 coesite Inorganic materials 0.000 description 4
- 229910052906 cristobalite Inorganic materials 0.000 description 4
- 229910052805 deuterium Inorganic materials 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 4
- 239000002207 metabolite Substances 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- SZTYQQYYIMVETL-UHFFFAOYSA-N 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=CC(C=2C3=CC=CC=C3N(C)C=2)=N1 SZTYQQYYIMVETL-UHFFFAOYSA-N 0.000 description 4
- DUYJMQONPNNFPI-UHFFFAOYSA-N osimertinib Chemical class COC1=CC(N(C)CCN(C)C)=C(NC(=O)C=C)C=C1NC1=NC=CC(C=2C3=CC=CC=C3N(C)C=2)=N1 DUYJMQONPNNFPI-UHFFFAOYSA-N 0.000 description 4
- 102000020233 phosphotransferase Human genes 0.000 description 4
- 230000036470 plasma concentration Effects 0.000 description 4
- 235000012239 silicon dioxide Nutrition 0.000 description 4
- 125000003003 spiro group Chemical group 0.000 description 4
- 229910052682 stishovite Inorganic materials 0.000 description 4
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 229910052905 tridymite Inorganic materials 0.000 description 4
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 description 3
- USXAHPNCIHMFJC-UHFFFAOYSA-N 1-(1-bicyclo[1.1.1]pentanyl)-2,3-dihydroindole Chemical compound C12(CC(C1)C2)N1CCC2=CC=CC=C12 USXAHPNCIHMFJC-UHFFFAOYSA-N 0.000 description 3
- RGCWGTLMHRICTR-UHFFFAOYSA-N 1-(3-fluoro-1-bicyclo[1.1.1]pentanyl)indole Chemical compound FC12CC(C1)(C2)N1C=CC2=CC=CC=C12 RGCWGTLMHRICTR-UHFFFAOYSA-N 0.000 description 3
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
- DWXSYDKEWORWBT-UHFFFAOYSA-N 2-(2-bromophenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC=C1Br DWXSYDKEWORWBT-UHFFFAOYSA-N 0.000 description 3
- JIADHFGJRYUOQA-UHFFFAOYSA-N 3-indol-1-ylbicyclo[1.1.1]pentane-1-carbonitrile Chemical compound N1(C=CC2=CC=CC=C12)C12CC(C1)(C2)C#N JIADHFGJRYUOQA-UHFFFAOYSA-N 0.000 description 3
- LXVAHLBCMNFWGW-UHFFFAOYSA-N 4-[1-(1-bicyclo[1.1.1]pentanyl)indol-3-yl]-N-(4-fluoro-2-methoxy-5-nitrophenyl)pyrimidin-2-amine Chemical compound C12(CC(C1)C2)N1C=C(C2=CC=CC=C12)C1=NC(=NC=C1)NC1=C(C=C(C(=C1)[N+](=O)[O-])F)OC LXVAHLBCMNFWGW-UHFFFAOYSA-N 0.000 description 3
- 241000283707 Capra Species 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- 206010012735 Diarrhoea Diseases 0.000 description 3
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 3
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 125000005631 S-sulfonamido group Chemical group 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000003973 alkyl amines Chemical class 0.000 description 3
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 210000000481 breast Anatomy 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 229910002091 carbon monoxide Inorganic materials 0.000 description 3
- 230000004663 cell proliferation Effects 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 210000001072 colon Anatomy 0.000 description 3
- 239000012230 colorless oil Substances 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 125000004438 haloalkoxy group Chemical group 0.000 description 3
- 210000003128 head Anatomy 0.000 description 3
- 150000002430 hydrocarbons Chemical group 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 239000002480 mineral oil Substances 0.000 description 3
- 235000010446 mineral oil Nutrition 0.000 description 3
- 210000003739 neck Anatomy 0.000 description 3
- 229960003278 osimertinib Drugs 0.000 description 3
- 238000004806 packaging method and process Methods 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 150000003413 spiro compounds Chemical class 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 3
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 230000004614 tumor growth Effects 0.000 description 3
- JIJGCIDINLEGCZ-UHFFFAOYSA-N (2-fluorophenyl)-(2-methylsulfanylpyrimidin-4-yl)methanone Chemical compound CSC1=NC=CC(C(=O)C=2C(=CC=CC=2)F)=N1 JIJGCIDINLEGCZ-UHFFFAOYSA-N 0.000 description 2
- OZHLCLCPMVQDTA-UHFFFAOYSA-N (3-indol-1-yl-1-bicyclo[1.1.1]pentanyl)methanol Chemical compound N1(C=CC2=CC=CC=C12)C12CC(C1)(C2)CO OZHLCLCPMVQDTA-UHFFFAOYSA-N 0.000 description 2
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 2
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- RJRPWRIMGIHHJX-UHFFFAOYSA-N 1-(1-bicyclo[1.1.1]pentanyl)-3-(2-chloropyrimidin-4-yl)indole Chemical compound C12(CC(C1)C2)N1C=C(C2=CC=CC=C12)C1=NC(=NC=C1)Cl RJRPWRIMGIHHJX-UHFFFAOYSA-N 0.000 description 2
- JNPGLFIFYOSIOD-UHFFFAOYSA-N 1-(1-bicyclo[1.1.1]pentanyl)-3-(2-methylsulfanylpyrimidin-4-yl)indazole Chemical compound C12(CC(C1)C2)N1N=C(C2=CC=CC=C12)C1=NC(=NC=C1)SC JNPGLFIFYOSIOD-UHFFFAOYSA-N 0.000 description 2
- KHXMLJWZZSNWTQ-UHFFFAOYSA-N 1-(1-bicyclo[1.1.1]pentanyl)-3-(2-methylsulfonylpyrimidin-4-yl)indazole Chemical compound C12(CC(C1)C2)N1N=C(C2=CC=CC=C12)C1=NC(=NC=C1)S(=O)(=O)C KHXMLJWZZSNWTQ-UHFFFAOYSA-N 0.000 description 2
- KUTLULOYGMGNBN-UHFFFAOYSA-N 1-N-[2-(dimethylamino)ethyl]-4-N-[4-[1-(3-fluoro-1-bicyclo[1.1.1]pentanyl)indol-3-yl]pyrimidin-2-yl]-5-methoxy-1-N-methylbenzene-1,2,4-triamine Chemical compound CN(CCN(C=1C(=CC(=C(C=1)OC)NC1=NC=CC(=N1)C1=CN(C2=CC=CC=C12)C12CC(C1)(C2)F)N)C)C KUTLULOYGMGNBN-UHFFFAOYSA-N 0.000 description 2
- FWTCVQRHBURCLM-UHFFFAOYSA-N 1-N-[3-(dimethylamino)-1-bicyclo[1.1.1]pentanyl]-5-methoxy-1-N-methyl-4-N-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,2,4-triamine Chemical compound CN(C12CC(C1)(C2)N(C=1C(=CC(=C(C=1)OC)NC1=NC=CC(=N1)C1=CN(C2=CC=CC=C12)C)N)C)C FWTCVQRHBURCLM-UHFFFAOYSA-N 0.000 description 2
- RJLPDQBSFZOUPC-UHFFFAOYSA-N 1-N-[3-[(dimethylamino)methyl]-1-bicyclo[1.1.1]pentanyl]-5-methoxy-1-N-methyl-4-N-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,2,4-triamine Chemical compound CN(C)CC12CC(C1)(C2)N(C=1C(=CC(=C(C=1)OC)NC1=NC=CC(=N1)C1=CN(C2=CC=CC=C12)C)N)C RJLPDQBSFZOUPC-UHFFFAOYSA-N 0.000 description 2
- CBMSDCBJHHXDLZ-UHFFFAOYSA-N 1-N-[4-[1-(1-bicyclo[1.1.1]pentanyl)indol-3-yl]pyrimidin-2-yl]-2-methoxy-4-N-methyl-4-N-[2-(methylamino)ethyl]-5-nitrobenzene-1,4-diamine Chemical compound C12(CC(C1)C2)N1C=C(C2=CC=CC=C12)C1=NC(=NC=C1)NC1=C(C=C(C(=C1)[N+](=O)[O-])N(CCNC)C)OC CBMSDCBJHHXDLZ-UHFFFAOYSA-N 0.000 description 2
- RNZXUYOEOVHPLI-UHFFFAOYSA-N 1-N-[4-[1-(1-bicyclo[1.1.1]pentanyl)indol-3-yl]pyrimidin-2-yl]-4-N-[2-(dimethylamino)ethyl]-2-methoxy-4-N-methyl-5-nitrobenzene-1,4-diamine Chemical compound C12(CC(C1)C2)N1C=C(C2=CC=CC=C12)C1=NC(=NC=C1)NC1=C(C=C(C(=C1)[N+](=O)[O-])N(C)CCN(C)C)OC RNZXUYOEOVHPLI-UHFFFAOYSA-N 0.000 description 2
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- BLRHMMGNCXNXJL-UHFFFAOYSA-N 1-methylindole Chemical compound C1=CC=C2N(C)C=CC2=C1 BLRHMMGNCXNXJL-UHFFFAOYSA-N 0.000 description 2
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 2
- UDSAJFSYJMHNFI-UHFFFAOYSA-N 2,6-diazaspiro[3.3]heptane Chemical compound C1NCC11CNC1 UDSAJFSYJMHNFI-UHFFFAOYSA-N 0.000 description 2
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 2
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 description 2
- HPJALMWOZYIZGE-UHFFFAOYSA-N 2-oxa-6-azaspiro[3.3]heptane Chemical compound C1NCC11COC1 HPJALMWOZYIZGE-UHFFFAOYSA-N 0.000 description 2
- SQWAJUVHGSDHMI-UHFFFAOYSA-N 3-(2-chloropyrimidin-4-yl)-1-(3-fluoro-1-bicyclo[1.1.1]pentanyl)indole Chemical compound ClC1=NC=CC(=N1)C1=CN(C2=CC=CC=C12)C12CC(C1)(C2)F SQWAJUVHGSDHMI-UHFFFAOYSA-N 0.000 description 2
- RXPVJFXCFXCISX-UHFFFAOYSA-N 3-(dimethylcarbamoyl)bicyclo[1.1.1]pentane-1-carboxylic acid Chemical compound CN(C(=O)C12CC(C1)(C2)C(=O)O)C RXPVJFXCFXCISX-UHFFFAOYSA-N 0.000 description 2
- OUCGHQDMLPRABY-UHFFFAOYSA-N 3-N-[5-methoxy-4-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]-2-nitrophenyl]-1-N,1-N,3-N-trimethylbicyclo[1.1.1]pentane-1,3-diamine Chemical compound COC=1C(=CC(=C(C=1)N(C12CC(C1)(C2)N(C)C)C)[N+](=O)[O-])NC1=NC=CC(=N1)C1=CN(C2=CC=CC=C12)C OUCGHQDMLPRABY-UHFFFAOYSA-N 0.000 description 2
- UGUFCCPFMJMQBI-UHFFFAOYSA-N 3-[(dimethylamino)methyl]-N-methylbicyclo[1.1.1]pentan-1-amine Chemical compound CN(C)CC12CC(C1)(C2)NC UGUFCCPFMJMQBI-UHFFFAOYSA-N 0.000 description 2
- KDVBGERBUKUTDM-UHFFFAOYSA-N 3-[3-(2-chloropyrimidin-4-yl)indol-1-yl]bicyclo[1.1.1]pentane-1-carbonitrile Chemical compound ClC1=NC=CC(=N1)C1=CN(C2=CC=CC=C12)C12CC(C1)(C2)C#N KDVBGERBUKUTDM-UHFFFAOYSA-N 0.000 description 2
- IOUGQMHMZBOOGZ-UHFFFAOYSA-N 3-[3-[2-(4-fluoro-2-methoxy-5-nitroanilino)pyrimidin-4-yl]indol-1-yl]bicyclo[1.1.1]pentane-1-carbonitrile Chemical compound FC1=CC(=C(C=C1[N+](=O)[O-])NC1=NC=CC(=N1)C1=CN(C2=CC=CC=C12)C12CC(C1)(C2)C#N)OC IOUGQMHMZBOOGZ-UHFFFAOYSA-N 0.000 description 2
- PHGLWHFOJKSZAZ-UHFFFAOYSA-N 3-[3-[2-[5-amino-4-[2-(dimethylamino)ethyl-methylamino]-2-methoxyanilino]pyrimidin-4-yl]indol-1-yl]bicyclo[1.1.1]pentane-1-carbonitrile hydrochloride Chemical compound Cl.COc1cc(N(C)CCN(C)C)c(N)cc1Nc1nccc(n1)-c1cn(c2ccccc12)C12CC(C1)(C2)C#N PHGLWHFOJKSZAZ-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- LQKLVOWNBKJRJE-UHFFFAOYSA-N 3-bicyclo[1.1.1]pentanylazanium;chloride Chemical compound Cl.C1C2CC1(N)C2 LQKLVOWNBKJRJE-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- CJLRFYZGBQKNOD-UHFFFAOYSA-N 4-N-[4-[1-(1-bicyclo[1.1.1]pentanyl)indazol-3-yl]pyrimidin-2-yl]-1-N-[2-(dimethylamino)ethyl]-5-methoxy-1-N-methylbenzene-1,2,4-triamine Chemical compound C12(CC(C1)C2)N1N=C(C2=CC=CC=C12)C1=NC(=NC=C1)NC=1C=C(C(=CC=1OC)N(C)CCN(C)C)N CJLRFYZGBQKNOD-UHFFFAOYSA-N 0.000 description 2
- QVVJMZZIKNHCHG-UHFFFAOYSA-N 4-[1-(1-bicyclo[1.1.1]pentanyl)indazol-3-yl]-N-(4-fluoro-2-methoxy-5-nitrophenyl)pyrimidin-2-amine Chemical compound C12(CC(C1)C2)N1N=C(C2=CC=CC=C12)C1=NC(=NC=C1)NC1=C(C=C(C(=C1)[N+](=O)[O-])F)OC QVVJMZZIKNHCHG-UHFFFAOYSA-N 0.000 description 2
- OBRSVSITGVWECN-UHFFFAOYSA-N 4-[1-(1-bicyclo[1.1.1]pentanyl)indol-3-yl]-2-chloropyrimidine-5-carbonitrile Chemical compound C12(CC(C1)C2)N1C=C(C2=CC=CC=C12)C1=NC(=NC=C1C#N)Cl OBRSVSITGVWECN-UHFFFAOYSA-N 0.000 description 2
- NUTUXAJJRRJCHY-UHFFFAOYSA-N 4-[1-(3-fluoro-1-bicyclo[1.1.1]pentanyl)indol-3-yl]-N-(4-fluoro-2-methoxy-5-nitrophenyl)pyrimidin-2-amine Chemical compound FC1=CC(=C(C=C1[N+](=O)[O-])NC1=NC=CC(=N1)C1=CN(C2=CC=CC=C12)C12CC(C1)(C2)F)OC NUTUXAJJRRJCHY-UHFFFAOYSA-N 0.000 description 2
- VRJHQPZVIGNGMX-UHFFFAOYSA-N 4-piperidinone Chemical compound O=C1CCNCC1 VRJHQPZVIGNGMX-UHFFFAOYSA-N 0.000 description 2
- OIVLITBTBDPEFK-UHFFFAOYSA-N 5,6-dihydrouracil Chemical compound O=C1CCNC(=O)N1 OIVLITBTBDPEFK-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 241000282693 Cercopithecidae Species 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- CCMVDLXAFBRYIZ-UHFFFAOYSA-N N-[2-[[3-(dimethylamino)-1-bicyclo[1.1.1]pentanyl]-methylamino]-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]prop-2-enamide Chemical compound CN(C12CC(C1)(C2)N(C1=C(C=C(C(=C1)OC)NC1=NC=CC(=N1)C1=CN(C2=CC=CC=C12)C)NC(C=C)=O)C)C CCMVDLXAFBRYIZ-UHFFFAOYSA-N 0.000 description 2
- MRSAAYOIKXJZCT-UHFFFAOYSA-N N-[2-[[3-[(dimethylamino)methyl]-1-bicyclo[1.1.1]pentanyl]-methylamino]-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]prop-2-enamide Chemical compound CN(C)CC12CC(C1)(C2)N(C1=C(C=C(C(=C1)OC)NC1=NC=CC(=N1)C1=CN(C2=CC=CC=C12)C)NC(C=C)=O)C MRSAAYOIKXJZCT-UHFFFAOYSA-N 0.000 description 2
- YSGVGJKVQMITHY-UHFFFAOYSA-N N-[5-[[4-[1-(1-bicyclo[1.1.1]pentanyl)indazol-3-yl]pyrimidin-2-yl]amino]-2-[2-(dimethylamino)ethyl-methylamino]-4-methoxyphenyl]prop-2-enamide Chemical compound C12(CC(C1)C2)N1N=C(C2=CC=CC=C12)C1=NC(=NC=C1)NC=1C(=CC(=C(C=1)NC(C=C)=O)N(C)CCN(C)C)OC YSGVGJKVQMITHY-UHFFFAOYSA-N 0.000 description 2
- SHEISMOPKLIQOC-UHFFFAOYSA-N N-[5-[[4-[1-(1-bicyclo[1.1.1]pentanyl)indol-3-yl]pyrimidin-2-yl]amino]-4-methoxy-2-[methyl-[2-(methylamino)ethyl]amino]phenyl]prop-2-enamide Chemical compound C12(CC(C1)C2)N1C=C(C2=CC=CC=C12)C1=NC(=NC=C1)NC=1C(=CC(=C(C=1)NC(C=C)=O)N(CCNC)C)OC SHEISMOPKLIQOC-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 2
- 239000004473 Threonine Substances 0.000 description 2
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 2
- 208000009956 adenocarcinoma Diseases 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- CUFNKYGDVFVPHO-UHFFFAOYSA-N azulene Chemical compound C1=CC=CC2=CC=CC2=C1 CUFNKYGDVFVPHO-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 2
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 125000002837 carbocyclic group Chemical group 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 230000006037 cell lysis Effects 0.000 description 2
- 238000001516 cell proliferation assay Methods 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000006911 enzymatic reaction Methods 0.000 description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 2
- 208000021045 exocrine pancreatic carcinoma Diseases 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011888 foil Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 150000002391 heterocyclic compounds Chemical class 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 238000004020 luminiscence type Methods 0.000 description 2
- 239000006166 lysate Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 229930182817 methionine Natural products 0.000 description 2
- MMFXETKZXGGNJW-UHFFFAOYSA-N methyl 3-(dimethylcarbamoyl)bicyclo[1.1.1]pentane-1-carboxylate Chemical compound CN(C(=O)C12CC(C1)(C2)C(=O)OC)C MMFXETKZXGGNJW-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
- XNLICIUVMPYHGG-UHFFFAOYSA-N pentan-2-one Chemical compound CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 230000002685 pulmonary effect Effects 0.000 description 2
- XVIAPHVAGFEFFN-UHFFFAOYSA-N pyrimidine-5-carbonitrile Chemical compound N#CC1=CN=CN=C1 XVIAPHVAGFEFFN-UHFFFAOYSA-N 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000004007 reversed phase HPLC Methods 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- 238000001262 western blot Methods 0.000 description 2
- HFVMEOPYDLEHBR-UHFFFAOYSA-N (2-fluorophenyl)-phenylmethanol Chemical compound C=1C=CC=C(F)C=1C(O)C1=CC=CC=C1 HFVMEOPYDLEHBR-UHFFFAOYSA-N 0.000 description 1
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- RCRVZCIUKQNOIS-UHFFFAOYSA-N 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane Chemical compound ClCC1(CCl)CC1(Br)Br RCRVZCIUKQNOIS-UHFFFAOYSA-N 0.000 description 1
- UGUHFDPGDQDVGX-UHFFFAOYSA-N 1,2,3-thiadiazole Chemical compound C1=CSN=N1 UGUHFDPGDQDVGX-UHFFFAOYSA-N 0.000 description 1
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 1
- BBVIDBNAYOIXOE-UHFFFAOYSA-N 1,2,4-oxadiazole Chemical compound C=1N=CON=1 BBVIDBNAYOIXOE-UHFFFAOYSA-N 0.000 description 1
- YGTAZGSLCXNBQL-UHFFFAOYSA-N 1,2,4-thiadiazole Chemical compound C=1N=CSN=1 YGTAZGSLCXNBQL-UHFFFAOYSA-N 0.000 description 1
- KTZQTRPPVKQPFO-UHFFFAOYSA-N 1,2-benzoxazole Chemical compound C1=CC=C2C=NOC2=C1 KTZQTRPPVKQPFO-UHFFFAOYSA-N 0.000 description 1
- LKLLNYWECKEQIB-UHFFFAOYSA-N 1,3,5-triazinane Chemical compound C1NCNCN1 LKLLNYWECKEQIB-UHFFFAOYSA-N 0.000 description 1
- BGJSXRVXTHVRSN-UHFFFAOYSA-N 1,3,5-trioxane Chemical compound C1OCOCO1 BGJSXRVXTHVRSN-UHFFFAOYSA-N 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- SILNNFMWIMZVEQ-UHFFFAOYSA-N 1,3-dihydrobenzimidazol-2-one Chemical compound C1=CC=C2NC(O)=NC2=C1 SILNNFMWIMZVEQ-UHFFFAOYSA-N 0.000 description 1
- ARSMIBSHEYKMJT-UHFFFAOYSA-M 1,3-dimethylimidazolium iodide Chemical compound [I-].CN1C=C[N+](C)=C1 ARSMIBSHEYKMJT-UHFFFAOYSA-M 0.000 description 1
- VDFVNEFVBPFDSB-UHFFFAOYSA-N 1,3-dioxane Chemical compound C1COCOC1 VDFVNEFVBPFDSB-UHFFFAOYSA-N 0.000 description 1
- IMLSAISZLJGWPP-UHFFFAOYSA-N 1,3-dithiolane Chemical compound C1CSCS1 IMLSAISZLJGWPP-UHFFFAOYSA-N 0.000 description 1
- IVJFXSLMUSQZMC-UHFFFAOYSA-N 1,3-dithiole Chemical compound C1SC=CS1 IVJFXSLMUSQZMC-UHFFFAOYSA-N 0.000 description 1
- QVFHFKPGBODJJB-UHFFFAOYSA-N 1,3-oxathiane Chemical compound C1COCSC1 QVFHFKPGBODJJB-UHFFFAOYSA-N 0.000 description 1
- WJJSZTJGFCFNKI-UHFFFAOYSA-N 1,3-oxathiolane Chemical compound C1CSCO1 WJJSZTJGFCFNKI-UHFFFAOYSA-N 0.000 description 1
- HNSDLXPSAYFUHK-UHFFFAOYSA-N 1,4-bis(2-ethylhexyl) sulfosuccinate Chemical compound CCCCC(CC)COC(=O)CC(S(O)(=O)=O)C(=O)OCC(CC)CCCC HNSDLXPSAYFUHK-UHFFFAOYSA-N 0.000 description 1
- CMERUCKCPIMRAF-UHFFFAOYSA-N 1,4-diazabicyclo[3.1.1]heptane Chemical compound C1N2CC1NCC2 CMERUCKCPIMRAF-UHFFFAOYSA-N 0.000 description 1
- JBYHSSAVUBIJMK-UHFFFAOYSA-N 1,4-oxathiane Chemical compound C1CSCCO1 JBYHSSAVUBIJMK-UHFFFAOYSA-N 0.000 description 1
- CPRVXMQHLPTWLY-UHFFFAOYSA-N 1,4-oxathiine Chemical compound O1C=CSC=C1 CPRVXMQHLPTWLY-UHFFFAOYSA-N 0.000 description 1
- MWBSDEVVJYEAEO-UHFFFAOYSA-N 1-(3-fluoro-1-bicyclo[1.1.1]pentanyl)-3H-indol-2-one Chemical compound FC12CC(C1)(C2)N1C(CC2=CC=CC=C12)=O MWBSDEVVJYEAEO-UHFFFAOYSA-N 0.000 description 1
- KCAJWZZEJKENGW-UHFFFAOYSA-N 1-N,3-N,3-N-trimethylbicyclo[1.1.1]pentane-1,3-diamine hydrochloride Chemical compound Cl.CNC12CC(C1)(C2)N(C)C KCAJWZZEJKENGW-UHFFFAOYSA-N 0.000 description 1
- RYXXUTKMDBIOGN-UHFFFAOYSA-N 1-N-[4-[1-(1-bicyclo[1.1.1]pentanyl)indazol-3-yl]pyrimidin-2-yl]-4-N-[2-(dimethylamino)ethyl]-2-methoxy-4-N-methyl-5-nitrobenzene-1,4-diamine Chemical compound C12(CC(C1)C2)N1N=C(C2=CC=CC=C12)C1=NC(=NC=C1)NC1=C(C=C(C(=C1)[N+](=O)[O-])N(C)CCN(C)C)OC RYXXUTKMDBIOGN-UHFFFAOYSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
- QXQAPNSHUJORMC-UHFFFAOYSA-N 1-chloro-4-propylbenzene Chemical compound CCCC1=CC=C(Cl)C=C1 QXQAPNSHUJORMC-UHFFFAOYSA-N 0.000 description 1
- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 1
- CUCJJMLDIUSNPU-UHFFFAOYSA-N 1-oxidopiperidin-1-ium Chemical compound [O-][NH+]1CCCCC1 CUCJJMLDIUSNPU-UHFFFAOYSA-N 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- KMHSUNDEGHRBNV-UHFFFAOYSA-N 2,4-dichloropyrimidine-5-carbonitrile Chemical compound ClC1=NC=C(C#N)C(Cl)=N1 KMHSUNDEGHRBNV-UHFFFAOYSA-N 0.000 description 1
- XQLZHIBLSSHZAL-UHFFFAOYSA-N 2,6-dioxaspiro[3.3]heptane Chemical compound C1OCC11COC1 XQLZHIBLSSHZAL-UHFFFAOYSA-N 0.000 description 1
- JECYNCQXXKQDJN-UHFFFAOYSA-N 2-(2-methylhexan-2-yloxymethyl)oxirane Chemical compound CCCCC(C)(C)OCC1CO1 JECYNCQXXKQDJN-UHFFFAOYSA-N 0.000 description 1
- IYBDXJOILDXAAR-UHFFFAOYSA-N 2-[5-amino-4-[2-(dimethylamino)ethyl-methylamino]-2-methoxyanilino]-4-[1-(1-bicyclo[1.1.1]pentanyl)indol-3-yl]pyrimidine-5-carbonitrile Chemical compound NC=1C(=CC(=C(C=1)NC1=NC=C(C(=N1)C1=CN(C2=CC=CC=C12)C12CC(C1)C2)C#N)OC)N(C)CCN(C)C IYBDXJOILDXAAR-UHFFFAOYSA-N 0.000 description 1
- OAEYLEXXDOAPBX-UHFFFAOYSA-N 2-[5-amino-4-[2-(dimethylamino)ethyl-methylamino]-2-methoxyanilino]-4-[1-(1-bicyclo[1.1.1]pentanyl)indol-3-yl]pyrimidine-5-carbonitrile hydrochloride Chemical compound Cl.COc1cc(N(C)CCN(C)C)c(N)cc1Nc1ncc(C#N)c(n1)-c1cn(c2ccccc12)C12CC(C1)C2 OAEYLEXXDOAPBX-UHFFFAOYSA-N 0.000 description 1
- QPEJAHMNOVMSOZ-UHFFFAOYSA-N 2-azaspiro[3.3]heptane Chemical compound C1CCC21CNC2 QPEJAHMNOVMSOZ-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- IKCLCGXPQILATA-UHFFFAOYSA-N 2-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Cl IKCLCGXPQILATA-UHFFFAOYSA-N 0.000 description 1
- ZWDVQMVZZYIAHO-UHFFFAOYSA-N 2-fluorobenzaldehyde Chemical compound FC1=CC=CC=C1C=O ZWDVQMVZZYIAHO-UHFFFAOYSA-N 0.000 description 1
- 125000006020 2-methyl-1-propenyl group Chemical group 0.000 description 1
- NJBCRXCAPCODGX-UHFFFAOYSA-N 2-methyl-n-(2-methylpropyl)propan-1-amine Chemical compound CC(C)CNCC(C)C NJBCRXCAPCODGX-UHFFFAOYSA-N 0.000 description 1
- DKHYBELEERFQEU-UHFFFAOYSA-N 2-oxabicyclo[1.1.1]pentane Chemical compound C1C2CC1O2 DKHYBELEERFQEU-UHFFFAOYSA-N 0.000 description 1
- KPGXRSRHYNQIFN-UHFFFAOYSA-N 2-oxoglutaric acid Chemical compound OC(=O)CCC(=O)C(O)=O KPGXRSRHYNQIFN-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- RVBUGGBMJDPOST-UHFFFAOYSA-N 2-thiobarbituric acid Chemical compound O=C1CC(=O)NC(=S)N1 RVBUGGBMJDPOST-UHFFFAOYSA-N 0.000 description 1
- BCHZICNRHXRCHY-UHFFFAOYSA-N 2h-oxazine Chemical compound N1OC=CC=C1 BCHZICNRHXRCHY-UHFFFAOYSA-N 0.000 description 1
- XTTPBWQGEBNYFT-UHFFFAOYSA-N 3-[(dimethylamino)methyl]-N-methylbicyclo[1.1.1]pentan-1-amine dihydrochloride Chemical compound Cl.Cl.CNC12CC(CN(C)C)(C1)C2 XTTPBWQGEBNYFT-UHFFFAOYSA-N 0.000 description 1
- AOVBJQHIYJMKOG-UHFFFAOYSA-N 3-[3-[2-[4-[2-(dimethylamino)ethyl-methylamino]-2-methoxy-5-nitroanilino]pyrimidin-4-yl]indol-1-yl]bicyclo[1.1.1]pentane-1-carbonitrile Chemical compound CN(CCN(C1=CC(=C(C=C1[N+](=O)[O-])NC1=NC=CC(=N1)C1=CN(C2=CC=CC=C12)C12CC(C1)(C2)C#N)OC)C)C AOVBJQHIYJMKOG-UHFFFAOYSA-N 0.000 description 1
- VYDXZSUSCGFJCQ-UHFFFAOYSA-N 3-bicyclo[1.1.1]pentanylhydrazine Chemical compound C1C2CC1(NN)C2 VYDXZSUSCGFJCQ-UHFFFAOYSA-N 0.000 description 1
- INUNLMUAPJVRME-UHFFFAOYSA-N 3-chloropropanoyl chloride Chemical compound ClCCC(Cl)=O INUNLMUAPJVRME-UHFFFAOYSA-N 0.000 description 1
- UJZHYIMESNWEQA-UHFFFAOYSA-N 3-methoxycarbonylbicyclo[1.1.1]pentane-1-carboxylic acid Chemical compound C1C2(C(O)=O)CC1(C(=O)OC)C2 UJZHYIMESNWEQA-UHFFFAOYSA-N 0.000 description 1
- WEQPBCSPRXFQQS-UHFFFAOYSA-N 4,5-dihydro-1,2-oxazole Chemical compound C1CC=NO1 WEQPBCSPRXFQQS-UHFFFAOYSA-N 0.000 description 1
- OGNKMHCOXKJSJF-UHFFFAOYSA-N 4-N-[3-[(dimethylamino)methyl]-1-bicyclo[1.1.1]pentanyl]-2-methoxy-4-N-methyl-1-N-[4-(1-methylindol-3-yl)pyrimidin-2-yl]-5-nitrobenzene-1,4-diamine Chemical compound CN(C)CC12CC(C1)(C2)N(C1=C(C=C(C(=C1)OC)NC1=NC=CC(=N1)C1=CN(C2=CC=CC=C12)C)[N+](=O)[O-])C OGNKMHCOXKJSJF-UHFFFAOYSA-N 0.000 description 1
- YUNNEOMGBTUUQB-UHFFFAOYSA-N 4-[1-(1-bicyclo[1.1.1]pentanyl)indol-3-yl]-2-(4-fluoro-2-methoxy-5-nitroanilino)pyrimidine-5-carbonitrile Chemical compound C12(CC(C1)C2)N1C=C(C2=CC=CC=C12)C1=NC(=NC=C1C#N)NC1=C(C=C(C(=C1)[N+](=O)[O-])F)OC YUNNEOMGBTUUQB-UHFFFAOYSA-N 0.000 description 1
- QHSSZQGOKNYRJM-UHFFFAOYSA-N 4-[1-(1-bicyclo[1.1.1]pentanyl)indol-3-yl]-2-[4-[2-(dimethylamino)ethyl-methylamino]-2-methoxy-5-nitroanilino]pyrimidine-5-carbonitrile Chemical compound C12(CC(C1)C2)N1C=C(C2=CC=CC=C12)C1=NC(=NC=C1C#N)NC1=C(C=C(C(=C1)[N+](=O)[O-])N(C)CCN(C)C)OC QHSSZQGOKNYRJM-UHFFFAOYSA-N 0.000 description 1
- DFOHHQRGDOQMKG-UHFFFAOYSA-N 4-chloro-2-methylsulfanylpyrimidine Chemical compound CSC1=NC=CC(Cl)=N1 DFOHHQRGDOQMKG-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- MRUWJENAYHTDQG-UHFFFAOYSA-N 4H-pyran Chemical compound C1C=COC=C1 MRUWJENAYHTDQG-UHFFFAOYSA-N 0.000 description 1
- UCZQXJKDCHCTAI-UHFFFAOYSA-N 4h-1,3-dioxine Chemical compound C1OCC=CO1 UCZQXJKDCHCTAI-UHFFFAOYSA-N 0.000 description 1
- PXRKCOCTEMYUEG-UHFFFAOYSA-N 5-aminoisoindole-1,3-dione Chemical compound NC1=CC=C2C(=O)NC(=O)C2=C1 PXRKCOCTEMYUEG-UHFFFAOYSA-N 0.000 description 1
- WYVFAIDIZFAWMI-UHFFFAOYSA-N 5-azabicyclo[2.1.1]hexane Chemical compound C1CC2CC1N2 WYVFAIDIZFAWMI-UHFFFAOYSA-N 0.000 description 1
- HEOQXHNKRXRCTO-UHFFFAOYSA-N 6,7,8,9-tetrahydro-5h-benzo[7]annulene Chemical compound C1CCCCC2=CC=CC=C21 HEOQXHNKRXRCTO-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- DENNCEQUAZKJGC-UHFFFAOYSA-N 6-azabicyclo[3.1.1]heptane Chemical compound C1CCC2CC1N2 DENNCEQUAZKJGC-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 239000012116 Alexa Fluor 680 Substances 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 125000000041 C6-C10 aryl group Chemical group 0.000 description 1
- 125000005915 C6-C14 aryl group Chemical group 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 238000003734 CellTiter-Glo Luminescent Cell Viability Assay Methods 0.000 description 1
- 206010048832 Colon adenoma Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 241000938605 Crocodylia Species 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 208000000059 Dyspnea Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000009024 Epidermal Growth Factor Human genes 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 108700024394 Exon Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 241000282418 Hominidae Species 0.000 description 1
- 101000851181 Homo sapiens Epidermal growth factor receptor Proteins 0.000 description 1
- 101000851176 Homo sapiens Pro-epidermal growth factor Proteins 0.000 description 1
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 101150018665 MAPK3 gene Proteins 0.000 description 1
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 241000237852 Mollusca Species 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- IIGARQBGWATQRL-UHFFFAOYSA-N N-[2-[2-(dimethylamino)ethyl-methylamino]-5-[[4-[1-(3-fluoro-1-bicyclo[1.1.1]pentanyl)indol-3-yl]pyrimidin-2-yl]amino]-4-methoxyphenyl]prop-2-enamide Chemical compound CN(CCN(C1=C(C=C(C(=C1)OC)NC1=NC=CC(=N1)C1=CN(C2=CC=CC=C12)C12CC(C1)(C2)F)NC(C=C)=O)C)C IIGARQBGWATQRL-UHFFFAOYSA-N 0.000 description 1
- GGFYRMFMLYKGRQ-UHFFFAOYSA-N N-[5-[[4-[1-(1-bicyclo[1.1.1]pentanyl)indol-3-yl]-5-cyanopyrimidin-2-yl]amino]-2-[2-(dimethylamino)ethyl-methylamino]-4-methoxyphenyl]prop-2-enamide Chemical compound C12(CC(C1)C2)N1C=C(C2=CC=CC=C12)C1=NC(=NC=C1C#N)NC=1C(=CC(=C(C=1)NC(C=C)=O)N(C)CCN(C)C)OC GGFYRMFMLYKGRQ-UHFFFAOYSA-N 0.000 description 1
- JONVCQKONXAVRO-UHFFFAOYSA-N N-[5-[[4-[1-(1-bicyclo[1.1.1]pentanyl)indol-3-yl]pyrimidin-2-yl]amino]-2-[2-(dimethylamino)ethyl-methylamino]-4-methoxyphenyl]prop-2-enamide Chemical compound C12(CC(C1)C2)N1C=C(C2=CC=CC=C12)C1=NC(=NC=C1)NC=1C(=CC(=C(C=1)NC(C=C)=O)N(C)CCN(C)C)OC JONVCQKONXAVRO-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- 206010053159 Organ failure Diseases 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 102100037601 P2X purinoceptor 4 Human genes 0.000 description 1
- 241000282579 Pan Species 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 101710098940 Pro-epidermal growth factor Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 108010085249 Purinergic P2 Receptors Proteins 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 description 1
- QYTDEUPAUMOIOP-UHFFFAOYSA-N TEMPO Chemical group CC1(C)CCCC(C)(C)N1[O] QYTDEUPAUMOIOP-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical compound [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 239000004809 Teflon Substances 0.000 description 1
- 229920006362 Teflon® Polymers 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
- 238000010811 Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry Methods 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 239000012491 analyte Substances 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 238000013475 authorization Methods 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- MKCBRYIXFFGIKN-UHFFFAOYSA-N bicyclo[1.1.1]pentane Chemical compound C1C2CC1C2 MKCBRYIXFFGIKN-UHFFFAOYSA-N 0.000 description 1
- AOUMEYPKBXRHIU-UHFFFAOYSA-N bicyclo[1.1.1]pentane-3-carbonitrile Chemical compound C1C2CC1(C#N)C2 AOUMEYPKBXRHIU-UHFFFAOYSA-N 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 238000010256 biochemical assay Methods 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 201000000053 blastoma Diseases 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 230000009702 cancer cell proliferation Effects 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- 150000005323 carbonate salts Chemical class 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000013553 cell monolayer Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 229910052729 chemical element Inorganic materials 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- VZWXIQHBIQLMPN-UHFFFAOYSA-N chromane Chemical compound C1=CC=C2CCCOC2=C1 VZWXIQHBIQLMPN-UHFFFAOYSA-N 0.000 description 1
- WCZVZNOTHYJIEI-UHFFFAOYSA-N cinnoline Chemical compound N1=NC=CC2=CC=CC=C21 WCZVZNOTHYJIEI-UHFFFAOYSA-N 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 229940124301 concurrent medication Drugs 0.000 description 1
- 230000006552 constitutive activation Effects 0.000 description 1
- 238000011340 continuous therapy Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 125000006009 dihaloalkoxy group Chemical group 0.000 description 1
- 125000004982 dihaloalkyl group Chemical group 0.000 description 1
- SNQXJPARXFUULZ-UHFFFAOYSA-N dioxolane Chemical compound C1COOC1 SNQXJPARXFUULZ-UHFFFAOYSA-N 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 201000008184 embryoma Diseases 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000008029 eradication Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000011536 extraction buffer Substances 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- JKFAIQOWCVVSKC-UHFFFAOYSA-N furazan Chemical compound C=1C=NON=1 JKFAIQOWCVVSKC-UHFFFAOYSA-N 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N glycerol 1-phosphate Chemical compound OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 125000006456 halo alkyl cycloalkyl group Chemical group 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 201000000459 head and neck squamous cell carcinoma Diseases 0.000 description 1
- 125000004404 heteroalkyl group Chemical group 0.000 description 1
- 125000004475 heteroaralkyl group Chemical group 0.000 description 1
- WMCFGPHWGVXGOY-UHFFFAOYSA-N hexanoic acid;hydrochloride Chemical compound Cl.CCCCCC(O)=O WMCFGPHWGVXGOY-UHFFFAOYSA-N 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- MHLPKAGDPWUOOT-UHFFFAOYSA-N housane Chemical compound C1CC2CC21 MHLPKAGDPWUOOT-UHFFFAOYSA-N 0.000 description 1
- 102000045108 human EGFR Human genes 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 description 1
- 229940091173 hydantoin Drugs 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000003331 infrared imaging Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000031146 intracellular signal transduction Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 238000005304 joining Methods 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- DBYQHFPBWKKZAT-UHFFFAOYSA-N lithium;benzene Chemical compound [Li+].C1=CC=[C-]C=C1 DBYQHFPBWKKZAT-UHFFFAOYSA-N 0.000 description 1
- 208000037841 lung tumor Diseases 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 1
- 208000026037 malignant tumor of neck Diseases 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 125000006682 monohaloalkyl group Chemical group 0.000 description 1
- 238000004264 monolayer culture Methods 0.000 description 1
- KVKFRMCSXWQSNT-UHFFFAOYSA-N n,n'-dimethylethane-1,2-diamine Chemical compound CNCCNC KVKFRMCSXWQSNT-UHFFFAOYSA-N 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001326 naphthylalkyl group Chemical group 0.000 description 1
- GVUGOAYIVIDWIO-UFWWTJHBSA-N nepidermin Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CS)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CS)NC(=O)[C@H](C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C(C)C)C(C)C)C1=CC=C(O)C=C1 GVUGOAYIVIDWIO-UFWWTJHBSA-N 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- UMRZSTCPUPJPOJ-KNVOCYPGSA-N norbornane Chemical compound C1C[C@H]2CC[C@@H]1C2 UMRZSTCPUPJPOJ-KNVOCYPGSA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 108091005981 phosphorylated proteins Proteins 0.000 description 1
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 1
- JTHRRMFZHSDGNJ-UHFFFAOYSA-N piperazine-2,3-dione Chemical compound O=C1NCCNC1=O JTHRRMFZHSDGNJ-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 239000000955 prescription drug Substances 0.000 description 1
- 239000000092 prognostic biomarker Substances 0.000 description 1
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 230000005588 protonation Effects 0.000 description 1
- 210000001187 pylorus Anatomy 0.000 description 1
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 1
- DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- MPHJCYMVCWTKDY-UHFFFAOYSA-N pyridine;quinoline Chemical compound C1=CC=NC=C1.C1=CC=NC=C1.N1=CC=CC2=CC=CC=C21 MPHJCYMVCWTKDY-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000009094 second-line therapy Methods 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 208000013220 shortness of breath Diseases 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- LBJQKYPPYSCCBH-UHFFFAOYSA-N spiro[3.3]heptane Chemical compound C1CCC21CCC2 LBJQKYPPYSCCBH-UHFFFAOYSA-N 0.000 description 1
- CTDQAGUNKPRERK-UHFFFAOYSA-N spirodecane Chemical compound C1CCCC21CCCCC2 CTDQAGUNKPRERK-UHFFFAOYSA-N 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000004952 trihaloalkoxy group Chemical group 0.000 description 1
- 125000004385 trihaloalkyl group Chemical group 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 231100000588 tumorigenic Toxicity 0.000 description 1
- 230000000381 tumorigenic effect Effects 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 230000036642 wellbeing Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C13/00—Cyclic hydrocarbons containing rings other than, or in addition to, six-membered aromatic rings
- C07C13/28—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof
- C07C13/32—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings
- C07C13/36—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings with a bicyclo ring system containing five carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C211/34—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton
- C07C211/38—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton containing condensed ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
- C07C2602/38—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing five carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201662342141P | 2016-05-26 | 2016-05-26 | |
| US62/342,141 | 2016-05-26 | ||
| PCT/US2017/034163 WO2017205459A1 (en) | 2016-05-26 | 2017-05-24 | Egfr inhibitor compounds |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| RU2018138584A3 RU2018138584A3 (OSRAM) | 2020-06-26 |
| RU2018138584A RU2018138584A (ru) | 2020-06-26 |
| RU2751341C2 true RU2751341C2 (ru) | 2021-07-13 |
Family
ID=60411884
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| RU2018138584A RU2751341C2 (ru) | 2016-05-26 | 2017-05-24 | Соединения-ингибиторы egfr |
Country Status (16)
| Country | Link |
|---|---|
| US (3) | US10513509B2 (OSRAM) |
| EP (1) | EP3464275B1 (OSRAM) |
| JP (1) | JP7030066B2 (OSRAM) |
| KR (2) | KR20220130249A (OSRAM) |
| CN (2) | CN109311858B (OSRAM) |
| AR (1) | AR110038A1 (OSRAM) |
| AU (2) | AU2017269335B2 (OSRAM) |
| CA (1) | CA3023176A1 (OSRAM) |
| ES (1) | ES2979136T3 (OSRAM) |
| IL (2) | IL263081B (OSRAM) |
| MX (2) | MX383920B (OSRAM) |
| RU (1) | RU2751341C2 (OSRAM) |
| SG (2) | SG11201809751XA (OSRAM) |
| TW (1) | TWI752033B (OSRAM) |
| WO (1) | WO2017205459A1 (OSRAM) |
| ZA (1) | ZA201807399B (OSRAM) |
Families Citing this family (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20220130249A (ko) | 2016-05-26 | 2022-09-26 | 리커리엄 아이피 홀딩스, 엘엘씨 | Egfr 억제제 화합물 |
| CN108864079B (zh) * | 2017-05-15 | 2021-04-09 | 深圳福沃药业有限公司 | 一种三嗪化合物及其药学上可接受的盐 |
| WO2019051038A1 (en) | 2017-09-11 | 2019-03-14 | Zeno Royalties & Milestones, LLC | CONTINUOUS FLOW PROCESSES FOR THE PRODUCTION OF BICYCLIC COMPOUNDS |
| CN112955137B (zh) | 2018-09-10 | 2025-05-13 | 米拉蒂治疗股份有限公司 | 组合疗法 |
| CN110041302B (zh) * | 2019-03-01 | 2021-11-30 | 南方医科大学 | 2-氨基-4-取代吡啶衍生物及其合成方法和应用 |
| KR20210142154A (ko) | 2019-03-21 | 2021-11-24 | 옹쎄오 | 암 치료를 위한 키나제 억제제와 조합된 dbait 분자 |
| CA3138648A1 (en) * | 2019-05-22 | 2020-11-26 | Shanghai Hansoh Biomedical Co., Ltd. | Indole derivative-containing inhibitor, preparation method therefor and application thereof |
| US20220229072A1 (en) | 2019-06-04 | 2022-07-21 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Use of cd9 as a biomarker and as a biotarget in glomerulonephritis or glomerulosclerosis |
| JP2023500906A (ja) | 2019-11-08 | 2023-01-11 | インサーム（インスティテュ ナシオナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシェ メディカル） | キナーゼ阻害剤に対する獲得抵抗性を有するがんの処置方法 |
| WO2021148581A1 (en) | 2020-01-22 | 2021-07-29 | Onxeo | Novel dbait molecule and its use |
| EP4169914A4 (en) * | 2020-06-23 | 2024-07-24 | Shenzhen Forward Pharmaceuticals Co., Ltd. | SALT OF A COMPOUND AND PHARMACEUTICAL COMPOSITION CONTAINING THE SALT |
| EP4330256A4 (en) * | 2021-04-30 | 2025-03-05 | Suzhou Puhe Biopharma Co., Ltd. | PYRIMIDINYLAMINOBENZOLES FOR THE TREATMENT OF LUNG CANCER |
| JP7689191B2 (ja) * | 2021-09-13 | 2025-06-05 | 富士フイルム株式会社 | ハロゲノビシクロ［１．１．１］ペンタンの製造方法 |
| IL319661A (en) * | 2022-09-19 | 2025-05-01 | Advenchen Pharmaceuticals Llc | A novel pyrimidine compound as kinase inhibitors with biological activities on EGFR mutations |
| WO2024094064A1 (en) * | 2022-11-02 | 2024-05-10 | Suzhou Puhe Biopharma Co., Ltd | Pyrimidinylaminobenzenes for treating lung cancer with distant metastasis |
| KR20250164828A (ko) | 2023-03-30 | 2025-11-25 | 레볼루션 메디슨즈, 인크. | Ras gtp 가수분해 유도를 위한 조성물 및 이의 용도 |
| AU2024265078A1 (en) | 2023-05-04 | 2025-12-11 | Revolution Medicines, Inc. | Combination therapy for a ras related disease or disorder |
| WO2025034702A1 (en) | 2023-08-07 | 2025-02-13 | Revolution Medicines, Inc. | Rmc-6291 for use in the treatment of ras protein-related disease or disorder |
| WO2025080946A2 (en) | 2023-10-12 | 2025-04-17 | Revolution Medicines, Inc. | Ras inhibitors |
| WO2025171296A1 (en) | 2024-02-09 | 2025-08-14 | Revolution Medicines, Inc. | Ras inhibitors |
| WO2025240847A1 (en) | 2024-05-17 | 2025-11-20 | Revolution Medicines, Inc. | Ras inhibitors |
| WO2025255438A1 (en) | 2024-06-07 | 2025-12-11 | Revolution Medicines, Inc. | Methods of treating a ras protein-related disease or disorder |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EA201391491A1 (ru) * | 2011-07-27 | 2014-08-29 | Астразенека Аб | Производные 2-(2,4,5-замещенного анилино)пиримидина в качестве модуляторов egfr, полезных для лечения рака |
| RU2536584C2 (ru) * | 2008-06-27 | 2014-12-27 | Авила Терапьютикс, Инк. | Гетероарильные соединения и их применение |
| WO2015127872A1 (zh) * | 2014-02-25 | 2015-09-03 | 上海海雁医药科技有限公司 | 2,4-二取代苯-1,5-二胺衍生物及其应用以及由其制备的药物组合物和药用组合物 |
| WO2015195228A1 (en) * | 2014-06-19 | 2015-12-23 | Ariad Pharmaceuticals, Inc. | Heteroaryl compounds for kinase inhibition |
Family Cites Families (141)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US1051350A (en) | 1910-02-02 | 1913-01-21 | Thomas Nogier | Apparatus for the sterilization of liquids. |
| DE4124942A1 (de) | 1991-07-27 | 1993-01-28 | Thomae Gmbh Dr K | 5-gliedrige heterocyclen, verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel |
| JPH08503971A (ja) | 1993-10-01 | 1996-04-30 | チバ−ガイギー アクチェンゲゼルシャフト | ピリミジンアミン誘導体及びその調製のための方法 |
| TW440563B (en) | 1996-05-23 | 2001-06-16 | Hoffmann La Roche | Aryl pyrimidine derivatives and a pharmaceutical composition thereof |
| ATE337312T1 (de) | 2001-07-03 | 2006-09-15 | Vertex Pharma | Isoxazolyl-pyrimidines als inhibitoren von src- und lck-protein-kinasen |
| US7396940B2 (en) | 2003-10-23 | 2008-07-08 | Hoffmann-La Roche Inc. | Combinatorial library of 3-aryl-1H-indole-2-carboxylic acid |
| EP1773807A2 (en) | 2004-06-14 | 2007-04-18 | Takeda San Diego, Inc. | Kinase inhibitors |
| CA2583428A1 (en) | 2004-09-03 | 2006-03-09 | Plexxikon, Inc. | Bicyclic heteroaryl pde4b inhibitors |
| WO2006050076A1 (en) | 2004-10-29 | 2006-05-11 | Janssen Pharmaceutica, N.V. | Pyrimidinyl substituted fused-pyrrolyl compounds useful in treating kinase disorders |
| GB0500492D0 (en) | 2005-01-11 | 2005-02-16 | Cyclacel Ltd | Compound |
| MX2007010745A (es) | 2005-03-04 | 2007-09-12 | Merck & Co Inc | Compuestos aromaticos fusionados con actividad anti-diabetica. |
| GB0520657D0 (en) | 2005-10-11 | 2005-11-16 | Ludwig Inst Cancer Res | Pharmaceutical compounds |
| EP2040546A4 (en) | 2006-06-22 | 2009-12-23 | Merck & Co Inc | tyrosine kinase inhibitor |
| US20080119457A1 (en) | 2006-08-24 | 2008-05-22 | Serenex, Inc. | Benzene, Pyridine, and Pyridazine Derivatives |
| CA2688187C (en) | 2007-05-07 | 2016-10-11 | Merck & Co., Inc. | Method of treament using fused aromatic compounds having anti-diabetic activity |
| JP2010031249A (ja) | 2008-06-23 | 2010-02-12 | Sumitomo Chemical Co Ltd | 組成物及び該組成物を用いてなる発光素子 |
| GB0815369D0 (en) | 2008-08-22 | 2008-10-01 | Summit Corp Plc | Compounds for treatment of duchenne muscular dystrophy |
| DE102008052943A1 (de) * | 2008-10-23 | 2010-04-29 | Merck Patent Gmbh | Azaindolderivate |
| CN101723936B (zh) | 2008-10-27 | 2014-01-15 | 上海睿星基因技术有限公司 | 激酶抑制剂及其在药学中的用途 |
| EP2464647B1 (en) | 2009-08-11 | 2016-09-21 | Bristol-Myers Squibb Company | Azaindazoles as btk kinase modulators and use thereof |
| US20110230476A1 (en) | 2009-09-09 | 2011-09-22 | Avila Therapeutics, Inc. | Pi3 kinase inhibitors and uses thereof |
| KR101116234B1 (ko) | 2009-10-29 | 2014-03-06 | (주)퓨쳐켐 | (3-플루오로-2-히드록시)프로필 작용기가 도입된 아릴 유도체 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 함유하는 퇴행성 뇌질환의 진단 또는 치료용 약학적 조성물 |
| UY33539A (es) | 2010-08-02 | 2012-02-29 | Astrazeneca Ab | Compuestos químicos alk |
| ES2552462T3 (es) | 2010-10-14 | 2015-11-30 | Jw Pharmaceutical Corporation | Nuevo compuesto de un mimético de giro inverso y un procedimiento de producción y uso del mismo |
| CN103476768B (zh) | 2011-03-16 | 2015-07-08 | 弗·哈夫曼-拉罗切有限公司 | 6,5-杂环炔丙醇化合物及其用途 |
| WO2012126181A1 (en) | 2011-03-24 | 2012-09-27 | Ying Luo | Use of kinase inhibitors in preventing and treating inflammatory disorder |
| JP6106685B2 (ja) | 2011-11-17 | 2017-04-05 | ダナ−ファーバー キャンサー インスティテュート， インコーポレイテッド | Ｃ−ｊｕｎ−ｎ−末端キナーゼ（ｊｎｋ）の阻害剤 |
| WO2013155223A1 (en) | 2012-04-10 | 2013-10-17 | The Regents Of The University Of California | Compositions and methods for treating cancer |
| CN103508961B (zh) | 2012-06-26 | 2015-07-22 | 中美冠科生物技术（太仓）有限公司 | 抗肿瘤药物 |
| US9738610B2 (en) | 2012-09-24 | 2017-08-22 | Whitehead Institute For Biomedical Research | Indazole derivatives and uses thereof |
| US10112927B2 (en) | 2012-10-18 | 2018-10-30 | Dana-Farber Cancer Institute, Inc. | Inhibitors of cyclin-dependent kinase 7 (CDK7) |
| SI2922872T1 (sl) | 2012-11-21 | 2019-01-31 | Janssen Biotech, Inc., | Bispecifična protitelesa EGFR/C-MET |
| US9695228B2 (en) | 2012-11-21 | 2017-07-04 | Janssen Biotech, Inc. | EGFR and c-Met fibronectin type III domain binding molecules |
| NZ712696A (en) | 2013-04-29 | 2016-07-29 | Chong Kun Dang Pharm Corp | Novel compounds for selective histone deacetylase inhibitors, and pharmaceutical composition comprising the same |
| US20180057603A1 (en) | 2013-08-09 | 2018-03-01 | The Trustees Of The University Of Pennsylvania | Combination of IFN-gamma with Anti-ERBB Antibody for the Treatment of Cancers |
| JP6524094B2 (ja) | 2013-08-30 | 2019-06-05 | ピーティーシー セラピューティクス， インコーポレイテッド | 置換ピリミジンＢｍｉ−１阻害剤 |
| EP3044593A4 (en) | 2013-09-09 | 2017-05-17 | Triact Therapeutics, Inc. | Cancer therapy |
| EP3052523B1 (en) | 2013-10-01 | 2021-03-10 | Medimmune Limited | Methods of treating and diagnosing alpha-v-beta-6 overexpressing cancer |
| GB201400034D0 (en) | 2014-01-02 | 2014-02-19 | Astrazeneca Ab | Pharmaceutical Compositions comprising AZD9291 |
| CN104761544B (zh) | 2014-01-03 | 2019-03-15 | 北京轩义医药科技有限公司 | Egfr酪氨酸激酶的临床重要突变体的选择性抑制剂 |
| WO2015112705A2 (en) | 2014-01-24 | 2015-07-30 | Clovis Oncology, Inc. | Therapeutic combinations for treating cancer |
| WO2015127234A1 (en) | 2014-02-20 | 2015-08-27 | Board Of Regents, The University Of Texas System | Use of ibrutinib to treat egfr mutant cancer |
| CN104876914B (zh) | 2014-02-28 | 2017-04-19 | 山东轩竹医药科技有限公司 | 嘧啶衍生物类间变性淋巴瘤激酶抑制剂 |
| TW201622744A (zh) | 2014-03-04 | 2016-07-01 | 美國禮來大藥廠 | 癌症之組合療法 |
| CN104892585B (zh) | 2014-03-06 | 2018-07-03 | 山东轩竹医药科技有限公司 | 嘧啶衍生物类间变性淋巴瘤激酶抑制剂 |
| AU2015242407B2 (en) | 2014-04-04 | 2017-11-09 | Astrazeneca Ab | Combination of EGFR inhibitor and MEK inhibitor for use in the treatment of NRAS mutated cancer |
| WO2015154038A1 (en) * | 2014-04-04 | 2015-10-08 | Syros Pharmaceuticals, Inc. | Inhibitors of cyclin-dependent kinase 7 (cdk7) |
| WO2015175965A1 (en) | 2014-05-15 | 2015-11-19 | The Research Foundation For Suny | Compositions targeting the interaction domain between p27kip1 and brk and methods of use thereof |
| CN106660993B (zh) | 2014-06-12 | 2020-09-11 | 上海复尚慧创医药研究有限公司 | 一类激酶抑制剂 |
| CN105254615B (zh) | 2014-07-11 | 2017-02-22 | 杭州华东医药集团新药研究院有限公司 | 苯胺嘧啶衍生物及其在制备抗恶性肿瘤药物中的用途 |
| HRP20200283T1 (hr) | 2014-07-11 | 2020-05-29 | Genmab A/S | Protutijela koja se vežu na axl |
| CN105315285B (zh) | 2014-07-25 | 2017-12-08 | 上海海雁医药科技有限公司 | 2,4‑二取代7H‑吡咯并[2,3‑d]嘧啶衍生物、其制法与医药上的用途 |
| WO2016024185A1 (en) | 2014-08-12 | 2016-02-18 | Pfizer Inc. | Pyrrolo[2,3-d]pyrimidine derivatives useful for inhibiting janus kinase |
| JP2017523231A (ja) | 2014-08-15 | 2017-08-17 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 癌治療用アファチニブ医薬キット |
| CN104140418B (zh) | 2014-08-15 | 2016-08-24 | 常州润诺生物科技有限公司 | 2-(2，4，5-取代苯胺)嘧啶衍生物及其用途 |
| CN106458969A (zh) | 2014-08-25 | 2017-02-22 | 四川海思科制药有限公司 | 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 |
| WO2016032003A1 (ja) | 2014-08-30 | 2016-03-03 | 国立大学法人金沢大学 | 肺癌患者用治療剤及び肺癌患者治療の有効性の予測検査方法 |
| US10526416B2 (en) | 2014-09-08 | 2020-01-07 | Yeda Research And Development Co. Ltd. | Anti-HER3 antibodies and uses of same |
| WO2016038610A1 (en) | 2014-09-08 | 2016-03-17 | Yeda Research And Development Co. Ltd. | Compositions and methods for treating cancer resistant to a tyrosine kinase inhibitor (tki) |
| US20170190788A1 (en) | 2014-09-11 | 2017-07-06 | Bulldog Pharmaceuticals, Inc. | Uses of anti-her3 antibodies for treating cancer |
| EP3198030B1 (en) | 2014-09-26 | 2020-11-04 | HI-STEM gGmbH Im Deutschen Krebsforschungszentrum DKFZ | Novel methods for sub-typing and treating cancer |
| CN105461695B (zh) | 2014-09-29 | 2018-03-27 | 齐鲁制药有限公司 | 嘧啶或三嗪衍生物及其制备方法和用途 |
| CN105237515B (zh) | 2014-10-10 | 2018-06-05 | 益方生物科技（上海）有限公司 | 氘代嘧啶类化合物、其制备方法、药物组合物和用途 |
| CN111171000B (zh) | 2014-10-11 | 2023-09-01 | 上海翰森生物医药科技有限公司 | Egfr抑制剂及其制备和应用 |
| KR102073854B1 (ko) * | 2014-10-13 | 2020-02-05 | 주식회사유한양행 | Egfr 돌연변이 키나아제 활성을 조절하기 위한 화합물 및 조성물 |
| US10308648B2 (en) | 2014-10-16 | 2019-06-04 | Syros Pharmaceuticals, Inc. | Inhibitors of cyclin-dependent kinase 7 (CDK7) |
| CN111170998B (zh) * | 2014-11-05 | 2023-04-11 | 益方生物科技(上海)股份有限公司 | 嘧啶或吡啶类化合物、其制备方法和医药用途 |
| US10507210B2 (en) | 2014-12-03 | 2019-12-17 | Auckland Uniservices Limited | Kinase inhibitor prodrug for the treatment of cancer |
| KR20170098865A (ko) | 2014-12-11 | 2017-08-30 | 베타 파마, 인크. | Egfr 조정제로서의 치환된 2-아닐리노피리미딘 유도체 |
| RS64139B1 (sr) | 2014-12-24 | 2023-05-31 | Principia Biopharma Inc | Kompozicije za ileo-jejunalnu isporuku leka |
| WO2016112272A1 (en) | 2015-01-09 | 2016-07-14 | Metastat, Inc. | Method of use for inhibitors of epidermal growth factor receptor variant iii |
| WO2016112302A1 (en) | 2015-01-09 | 2016-07-14 | Metastat, Inc. | Method of predicting sensitivity of tumor cell growth to combination therapy of fgfr inhibitor |
| SG11201705952SA (en) | 2015-02-04 | 2017-09-28 | Beyondbio Inc | Heterocyclic compound and pharmaceutical composition comprising same |
| CN104961731A (zh) | 2015-02-05 | 2015-10-07 | 苏州晶云药物科技有限公司 | 一种表皮生长因子受体抑制剂的磷酸盐、其晶型及制备方法 |
| CN112494653A (zh) | 2015-02-05 | 2021-03-16 | 特尔诺沃有限公司 | 用于治疗癌症的irs/stat3双重调节剂与抗癌剂的组合 |
| CN105985323A (zh) | 2015-02-15 | 2016-10-05 | 宁波文达医药科技有限公司 | 新型表皮生长因子受体抑制剂及其应用 |
| EP3265562A4 (en) | 2015-03-05 | 2018-12-19 | TrovaGene, Inc. | Early assessment of mechanism of action and efficacy of anti-cancer therapies using molecular markers in bodily fluids |
| CN106138020A (zh) | 2015-04-03 | 2016-11-23 | 中国人民解放军第三军医大学第三附属医院 | 双胍类药物在制备预防或减弱肺纤维化的药物中的应用 |
| CN106138061B (zh) | 2015-04-03 | 2019-06-04 | 中国人民解放军第三军医大学第三附属医院 | 预防或减弱肺纤维化的复合物及其制剂和用途 |
| WO2016164217A1 (en) | 2015-04-09 | 2016-10-13 | Clovis Oncology, Inc. | Therapeutic combinations for treating cancer |
| CN104844580B (zh) | 2015-04-17 | 2017-10-20 | 中国药科大学 | 嘧啶类化合物、其制备方法及医药用途 |
| CN107530434A (zh) | 2015-04-23 | 2018-01-02 | 免疫医疗有限公司 | 非小细胞肺癌egfr突变阳性的联合疗法 |
| CN104817541B (zh) | 2015-05-11 | 2017-06-16 | 苏州东南药业股份有限公司 | 一种抗肿瘤药物的合成方法 |
| EP3294299A1 (en) | 2015-05-15 | 2018-03-21 | Novartis AG | Methods for treating egfr mutant cancers |
| CN108135168B (zh) | 2015-05-21 | 2021-07-20 | 凯莫森特里克斯股份有限公司 | Ccr2调节剂 |
| WO2016191471A1 (en) | 2015-05-27 | 2016-12-01 | Metastat, Inc. | Method of use for inhibitors of epidermal growth factor receptor variants ii, iii and vi |
| TWI648056B (zh) | 2015-06-03 | 2019-01-21 | 友杏生技醫藥股份有限公司 | 治療非小細胞肺癌之醫藥組合物及其方法 |
| US20160355503A1 (en) | 2015-06-04 | 2016-12-08 | Cleave Biosciences, Inc. | NITROGEN HEXACYCLE COMPOUNDS AS INHIBITORS OF p97 COMPLEX |
| AU2016276963C1 (en) | 2015-06-12 | 2021-08-05 | Dana-Farber Cancer Institute, Inc. | Combination therapy of transcription inhibitors and kinase inhibitors |
| CN104910049B (zh) | 2015-06-16 | 2016-06-29 | 苏州明锐医药科技有限公司 | Azd9291中间体及其制备方法 |
| SMT202000359T1 (it) | 2015-07-10 | 2020-09-10 | Genmab As | Coniugati anticorpo-farmaco specifici per axl per il trattamento del cancro |
| US11788145B2 (en) | 2015-07-17 | 2023-10-17 | Pacylex Pharmaceuticals Inc. | Epigeneiic silencing of NMT2 |
| TW201716439A (zh) | 2015-07-20 | 2017-05-16 | 美國禮來大藥廠 | Ｈｅｒ３抗體 |
| EP3325469A4 (en) | 2015-07-20 | 2019-01-23 | Dana Farber Cancer Institute, Inc. | NOVEL PYRIMIDINS AS EGFR INHIBITORS AND METHOD FOR THE DISEASE TREATMENT THEREWITH |
| EP3120851A1 (en) | 2015-07-21 | 2017-01-25 | Pangaea Biotech S.L. | 4-amino-6-(2,6-dichlorophenyl)-8-methyl-2-(phenylamino)-pyrido[2,3-d]pyrimidin-7(8h)-one for treatment of solid cancers |
| EP3327014A4 (en) | 2015-07-24 | 2019-01-02 | Shanghai Haiyan Pharmaceutical Technology Co., Ltd. | Egfr inhibitor and pharmaceutically acceptable salt and polymorph thereof, and use thereof |
| CN105001208A (zh) | 2015-08-06 | 2015-10-28 | 南京雷科星生物技术有限公司 | 一种表皮生长因子受体egfr抑制剂及其制备方法与用途 |
| US10980765B2 (en) | 2015-08-14 | 2021-04-20 | Board Of Supervisors Of Louisiana State University | Isothiocyanatostilbenes as a novel method and product for treating cancer |
| CN105153122B (zh) | 2015-08-27 | 2018-07-20 | 上海圣考医药科技有限公司 | [(吲哚-3-基)嘧啶-2-基]氨基苯基丙-2-烯酰胺衍生物及盐、制备方法、应用 |
| CN106478605A (zh) | 2015-09-02 | 2017-03-08 | 上海页岩科技有限公司 | 嘧啶类化合物、其制备方法和医药用途 |
| CN105126125A (zh) | 2015-09-12 | 2015-12-09 | 复旦大学 | 一种氧化锌-钆-药物复合纳米粒子及其制备方法和应用 |
| PT3353168T (pt) | 2015-09-25 | 2023-09-20 | Dizal Jiangsu Pharmaceutical Co Ltd | Compostos e métodos para inibir jak |
| CA3001655C (en) | 2015-10-19 | 2023-08-01 | Sunshine Lake Pharma Co., Ltd. | A salt of egfr inhibitor, crystalline form and uses thereof |
| US20170115275A1 (en) | 2015-10-23 | 2017-04-27 | Arizona Board Of Regents On Behalf Of Arizona State University | Engineered substrates for high-throughput generation of 3d models of tumor dormancy, relapse and micrometastases for phenotype specific drug discovery and development |
| US10093668B2 (en) | 2015-10-28 | 2018-10-09 | Northwestern University | Substituted aromatic N-heterocyclic compounds as inhibitors of mitogen-activated protein kinase interacting kinase 1 (Mnk1) and 2 (Mnk2) |
| RU2018120330A (ru) | 2015-11-02 | 2019-12-04 | Йейл Юниверсити | Химерные соединения, осуществляющие нацеливание для протеолиза, и способы их получения и применения |
| CN106674202A (zh) | 2015-11-05 | 2017-05-17 | 惠州信立泰药业有限公司 | 化合物a的二甲磺酸盐及其晶型和含有该盐的药物组合物 |
| CN106699736A (zh) | 2015-11-17 | 2017-05-24 | 惠州信立泰药业有限公司 | 化合物A甲磺酸盐的晶型γ和含有该晶型的药物组合物 |
| CN105461729B (zh) | 2015-11-18 | 2017-12-05 | 乳源瑶族自治县大众药品贸易有限公司 | 一种egfr抑制剂的盐、晶型及其用途 |
| CN105294717B (zh) | 2015-11-18 | 2017-12-22 | 乳源瑶族自治县大众药品贸易有限公司 | 一种egfr抑制剂的盐、晶型及其用途 |
| RU2603960C1 (ru) | 2015-11-19 | 2016-12-10 | Закрытое акционерное общество "Р-Фарм" (ЗАО "Р-Фарм") | Дихлорацетат n1,n2-дизамещенного n4-[4-(1-метил-1н-индол-3-ил)-пиримидин-2-ил]-5-метоксибензол-1,2,4-триамина в качестве модулятора egfr для лечения рака |
| RU2606949C9 (ru) | 2015-11-19 | 2018-03-14 | ЗАО "Р-Фарм" | Замещенные N-{ 3-[4-(1-метил-1Н-индол-3-ил)пиримидин-2-иламино]-4-метоксифенил} -амиды в качестве модуляторов EGFR, предназначенные для лечения рака |
| CN105348267A (zh) | 2015-12-01 | 2016-02-24 | 中山奕安泰医药科技有限公司 | 合成azd9291中间体的方法 |
| CN108289895B (zh) | 2015-12-03 | 2021-07-20 | 浙江尖峰亦恩生物科技有限公司 | 噻吩并嘧啶衍生物及其用途 |
| EP3383877B1 (en) | 2015-12-03 | 2021-09-15 | Zhejiang Jianfeng-Yien Biotechnology Co., Ltd. | Heterocycle compounds and uses thereof |
| JP2018536682A (ja) | 2015-12-11 | 2018-12-13 | リジェネロン・ファーマシューティカルズ・インコーポレイテッドＲｅｇｅｎｅｒｏｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ， Ｉｎｃ． | Ｅｇｆｒ及び／またはｅｒｂｂ３遮断に耐性のある腫瘍の成長を低減または防止するための方法 |
| TWI623316B (zh) | 2015-12-22 | 2018-05-11 | Taiho Pharmaceutical Co Ltd | Antitumor effect enhancer derived from pyrrolopyrimidine compound |
| CN105601620A (zh) | 2015-12-25 | 2016-05-25 | 北京康立生医药技术开发有限公司 | 一种甲磺酸迈瑞替尼的制备方法 |
| WO2017117070A1 (en) | 2015-12-27 | 2017-07-06 | NeuForm Pharmaceuticals, Inc. | Deuterated compounds for treating cancer and related diseases and conditions, and compositions and methods thereof |
| CN106928150B (zh) | 2015-12-31 | 2020-07-31 | 恩瑞生物医药科技（上海）有限公司 | 丙烯酰胺苯胺衍生物及其药学上的应用 |
| WO2017120429A1 (en) | 2016-01-07 | 2017-07-13 | CS Pharmasciences, Inc. | Selective inhibitors of clinically important mutants of the egfr tyrosine kinase |
| US20170196835A1 (en) | 2016-01-08 | 2017-07-13 | Euclises Pharmaceuticals, Inc. | Combination of a chromene compound and a second active agent |
| EP3399966B1 (en) | 2016-01-08 | 2023-03-29 | The Regents of the University of California | Mesoporous silica nanoparticles with lipid bilayer coating for cargo delivery |
| CN105646454B (zh) | 2016-01-19 | 2018-05-08 | 浙江大学 | 含异羟肟酸片段的2-芳胺基嘧啶类衍生物及制备和应用 |
| TWI745345B (zh) | 2016-02-01 | 2021-11-11 | 瑞典商阿斯特捷利康公司 | 製備奧希替尼（osimertinib，azd9291）或其鹽及「azd9291苯胺」或其鹽的改良方法 |
| WO2017136342A1 (en) | 2016-02-02 | 2017-08-10 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Fulvestrant for inducing immune-mediated cytotoxic lysis of cancer cells |
| SG11201805375PA (en) | 2016-02-04 | 2018-07-30 | Stem Cell Theranostics Inc | Pharmaceutical compositions and methods for countering chemotherapy induced cardiotoxicity |
| HRP20220351T1 (hr) | 2016-02-04 | 2022-05-13 | Pharmaengine, Inc. | 3,5-disupstituirani pirazoli korisni kao inhibitori kinaze 1 kontrolne točke (chk1), i njihove pripreme i primjene |
| CN105777716B (zh) | 2016-02-25 | 2018-04-10 | 清华大学 | 一种用于靶向治疗癌症的egfr抑制剂及其制备方法与应用 |
| CN105585557B (zh) | 2016-02-25 | 2018-06-22 | 清华大学 | 用于靶向治疗癌症的egfr抑制剂及其制备方法与应用 |
| KR20220130249A (ko) * | 2016-05-26 | 2022-09-26 | 리커리엄 아이피 홀딩스, 엘엘씨 | Egfr 억제제 화합물 |
| CN105886648A (zh) | 2016-06-06 | 2016-08-24 | 武汉海吉力生物科技有限公司 | 用于检测egfr基因t790m突变的试剂盒 |
| CN106366022B (zh) | 2016-08-19 | 2018-03-13 | 上海工程技术大学 | 一种用于制备azd9291的中间体及其制备方法和应用 |
| CN106366072B (zh) | 2016-08-19 | 2018-12-07 | 上海工程技术大学 | 一种azd9291的制备方法 |
| CN106397407B (zh) | 2016-08-31 | 2018-09-04 | 浙江科聚化工有限公司 | 抗肿瘤药物azd9291衍生物的制备方法 |
| CN106432231B (zh) | 2016-09-09 | 2018-06-12 | 无锡佰翱得生物科学有限公司 | Azd9291的药用盐、及其晶型和制备方法 |
| CN106565522A (zh) | 2016-09-29 | 2017-04-19 | 福格森（武汉）生物科技股份有限公司 | 一种由氟代芳香化合物制备烷氧基芳香化合物的方法 |
| CN106496196B (zh) | 2016-10-20 | 2019-07-02 | 南京雷科星生物技术有限公司 | 一种喹唑啉、吡啶并嘧啶或则双并嘧啶衍生物表皮生长因子抑制剂及其制备方法与用途 |
| CN106543060B (zh) | 2016-10-31 | 2018-11-06 | 湖南欧亚药业有限公司 | 一种奥斯替尼甲磺酸盐的制备方法 |
| CN106668866A (zh) | 2017-02-13 | 2017-05-17 | 江苏省中医药研究院 | 一种抗非小细胞肺癌的药物组合物及其应用 |
| CN106883216B (zh) | 2017-04-06 | 2020-03-13 | 张家港威胜生物医药有限公司 | 一种奥希替尼的制备方法 |
-
2017
- 2017-05-24 KR KR1020227031434A patent/KR20220130249A/ko not_active Ceased
- 2017-05-24 RU RU2018138584A patent/RU2751341C2/ru active
- 2017-05-24 WO PCT/US2017/034163 patent/WO2017205459A1/en not_active Ceased
- 2017-05-24 MX MX2018013413A patent/MX383920B/es unknown
- 2017-05-24 ES ES17803481T patent/ES2979136T3/es active Active
- 2017-05-24 JP JP2018561695A patent/JP7030066B2/ja active Active
- 2017-05-24 US US15/603,789 patent/US10513509B2/en active Active
- 2017-05-24 SG SG11201809751XA patent/SG11201809751XA/en unknown
- 2017-05-24 CN CN201780032202.6A patent/CN109311858B/zh active Active
- 2017-05-24 SG SG10202102920QA patent/SG10202102920QA/en unknown
- 2017-05-24 CA CA3023176A patent/CA3023176A1/en active Pending
- 2017-05-24 AU AU2017269335A patent/AU2017269335B2/en active Active
- 2017-05-24 CN CN202011563825.6A patent/CN112624954A/zh active Pending
- 2017-05-24 KR KR1020187034187A patent/KR102444835B1/ko active Active
- 2017-05-24 EP EP17803481.5A patent/EP3464275B1/en active Active
- 2017-05-24 AR ARP170101409A patent/AR110038A1/es unknown
- 2017-05-25 TW TW106117475A patent/TWI752033B/zh active
-
2018
- 2018-11-01 MX MX2021007773A patent/MX2021007773A/es unknown
- 2018-11-05 ZA ZA2018/07399A patent/ZA201807399B/en unknown
- 2018-11-18 IL IL263081A patent/IL263081B/en active IP Right Grant
-
2019
- 2019-12-04 US US16/703,544 patent/US11098030B2/en active Active
-
2021
- 2021-03-16 IL IL281537A patent/IL281537A/en unknown
- 2021-08-17 US US17/445,280 patent/US12049460B2/en active Active
- 2021-09-29 AU AU2021240162A patent/AU2021240162A1/en not_active Abandoned
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2536584C2 (ru) * | 2008-06-27 | 2014-12-27 | Авила Терапьютикс, Инк. | Гетероарильные соединения и их применение |
| EA201391491A1 (ru) * | 2011-07-27 | 2014-08-29 | Астразенека Аб | Производные 2-(2,4,5-замещенного анилино)пиримидина в качестве модуляторов egfr, полезных для лечения рака |
| WO2015127872A1 (zh) * | 2014-02-25 | 2015-09-03 | 上海海雁医药科技有限公司 | 2,4-二取代苯-1,5-二胺衍生物及其应用以及由其制备的药物组合物和药用组合物 |
| WO2015195228A1 (en) * | 2014-06-19 | 2015-12-23 | Ariad Pharmaceuticals, Inc. | Heteroaryl compounds for kinase inhibition |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2751341C2 (ru) | Соединения-ингибиторы egfr | |
| CA2958095C (en) | 2-(2,4,5-substituted aniline) pyrimidine derivative, pharmaceutical composition and use thereof | |
| EP2637502B1 (en) | Mutant-selective egfr inhibitors and uses thereof | |
| BR112012011287A2 (pt) | compostos inibidores de cinase, sua formulação farmacêutica e seus usos | |
| EA024109B1 (ru) | Ингибиторы протеинкиназ | |
| TW201706272A (zh) | 雙環化合物 | |
| WO2014093230A2 (en) | Compositions and methods for the production of pyrimidine and pyridine compounds with btk inhibitory activity | |
| WO2020261144A1 (en) | 5-(thiophen-2-yl)-1h-tetrazole derivatives as bckdk inhibitors useful for treating various diseases | |
| TW202328128A (zh) | Ｃｄｋ７抑制劑及治療癌症之方法 | |
| HK40003936A (en) | Egfr inhibitor compounds | |
| NZ747854B2 (en) | Egfr inhibitor compounds | |
| BR112018074232B1 (pt) | Acrilamida n-(3- ((4-(1-(biciclo[1.1.1]pentan-2-il)-1h-indol-3-il)pirimidin-2- il) amino)fenil) substituída e compostos de acrilamida n-(3-((4- (1-(biciclo[1.1.1] pentan-2-il)-1h-indazol-3-il)pirimidin-2- il)amino)fenil) substituída como inibidores de egfr para tratamento de câncer |