WO2020038458A1 - Classe de composé de triazole cyclique fusionné, procédé de préparation et utilisation - Google Patents
Classe de composé de triazole cyclique fusionné, procédé de préparation et utilisation Download PDFInfo
- Publication number
- WO2020038458A1 WO2020038458A1 PCT/CN2019/102214 CN2019102214W WO2020038458A1 WO 2020038458 A1 WO2020038458 A1 WO 2020038458A1 CN 2019102214 W CN2019102214 W CN 2019102214W WO 2020038458 A1 WO2020038458 A1 WO 2020038458A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- hydrogen
- membered
- group
- halogen
- Prior art date
Links
- -1 triazole compound Chemical class 0.000 title claims abstract description 108
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 51
- 239000000651 prodrug Substances 0.000 claims abstract description 42
- 229940002612 prodrug Drugs 0.000 claims abstract description 42
- 239000012453 solvate Substances 0.000 claims abstract description 39
- 229910052739 hydrogen Inorganic materials 0.000 claims description 210
- 239000001257 hydrogen Substances 0.000 claims description 204
- 150000001875 compounds Chemical class 0.000 claims description 197
- 229910052736 halogen Inorganic materials 0.000 claims description 178
- 150000002367 halogens Chemical class 0.000 claims description 178
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 161
- 150000002431 hydrogen Chemical class 0.000 claims description 138
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 106
- 125000000217 alkyl group Chemical group 0.000 claims description 103
- 125000003118 aryl group Chemical group 0.000 claims description 89
- 125000001072 heteroaryl group Chemical group 0.000 claims description 71
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 63
- 125000005842 heteroatom Chemical group 0.000 claims description 56
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 52
- 125000003545 alkoxy group Chemical group 0.000 claims description 51
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 46
- 229910052760 oxygen Inorganic materials 0.000 claims description 43
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 39
- 206010028980 Neoplasm Diseases 0.000 claims description 37
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 36
- 125000002252 acyl group Chemical group 0.000 claims description 36
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 36
- 229910052717 sulfur Inorganic materials 0.000 claims description 36
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 34
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 30
- 229910052731 fluorine Inorganic materials 0.000 claims description 29
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 29
- 238000000034 method Methods 0.000 claims description 29
- 108091008794 FGF receptors Proteins 0.000 claims description 27
- 229910052757 nitrogen Inorganic materials 0.000 claims description 25
- 125000004122 cyclic group Chemical group 0.000 claims description 24
- 239000011737 fluorine Substances 0.000 claims description 23
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 22
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 22
- 125000001424 substituent group Chemical group 0.000 claims description 21
- 102100027844 Fibroblast growth factor receptor 4 Human genes 0.000 claims description 20
- 101000917134 Homo sapiens Fibroblast growth factor receptor 4 Proteins 0.000 claims description 20
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 20
- 150000003462 sulfoxides Chemical class 0.000 claims description 19
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 18
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 18
- 125000003277 amino group Chemical group 0.000 claims description 17
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims description 16
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 15
- 201000010099 disease Diseases 0.000 claims description 15
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 14
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 14
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 14
- ZEOWTGPWHLSLOG-UHFFFAOYSA-N Cc1ccc(cc1-c1ccc2c(n[nH]c2c1)-c1cnn(c1)C1CC1)C(=O)Nc1cccc(c1)C(F)(F)F Chemical compound Cc1ccc(cc1-c1ccc2c(n[nH]c2c1)-c1cnn(c1)C1CC1)C(=O)Nc1cccc(c1)C(F)(F)F ZEOWTGPWHLSLOG-UHFFFAOYSA-N 0.000 claims description 13
- 102100023593 Fibroblast growth factor receptor 1 Human genes 0.000 claims description 13
- 101710182386 Fibroblast growth factor receptor 1 Proteins 0.000 claims description 13
- 125000003342 alkenyl group Chemical group 0.000 claims description 13
- 125000000304 alkynyl group Chemical group 0.000 claims description 13
- 125000003282 alkyl amino group Chemical group 0.000 claims description 12
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 12
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 12
- 238000006467 substitution reaction Methods 0.000 claims description 11
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 10
- 239000000460 chlorine Substances 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 10
- 229910052805 deuterium Inorganic materials 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
- 229910052698 phosphorus Inorganic materials 0.000 claims description 10
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 10
- 150000003457 sulfones Chemical class 0.000 claims description 10
- PFXVKGGZWQQTSE-UHFFFAOYSA-N sulfuryl dicyanide Chemical compound N#CS(=O)(=O)C#N PFXVKGGZWQQTSE-UHFFFAOYSA-N 0.000 claims description 10
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 claims description 10
- 125000003003 spiro group Chemical group 0.000 claims description 9
- 238000011282 treatment Methods 0.000 claims description 9
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 201000007270 liver cancer Diseases 0.000 claims description 8
- 208000014018 liver neoplasm Diseases 0.000 claims description 8
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 7
- 206010004593 Bile duct cancer Diseases 0.000 claims description 7
- 208000026900 bile duct neoplasm Diseases 0.000 claims description 7
- 208000006990 cholangiocarcinoma Diseases 0.000 claims description 7
- 102000052178 fibroblast growth factor receptor activity proteins Human genes 0.000 claims description 7
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000003386 piperidinyl group Chemical group 0.000 claims description 6
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 6
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000004193 piperazinyl group Chemical group 0.000 claims description 5
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 5
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 claims description 4
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 4
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- 206010061306 Nasopharyngeal cancer Diseases 0.000 claims description 4
- 206010060862 Prostate cancer Diseases 0.000 claims description 4
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 4
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 4
- 206010041067 Small cell lung cancer Diseases 0.000 claims description 4
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 4
- 229940079593 drug Drugs 0.000 claims description 4
- 206010017758 gastric cancer Diseases 0.000 claims description 4
- 208000032839 leukemia Diseases 0.000 claims description 4
- 201000005249 lung adenocarcinoma Diseases 0.000 claims description 4
- 201000005243 lung squamous cell carcinoma Diseases 0.000 claims description 4
- 125000006578 monocyclic heterocycloalkyl group Chemical group 0.000 claims description 4
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 4
- 201000000849 skin cancer Diseases 0.000 claims description 4
- 208000000587 small cell lung carcinoma Diseases 0.000 claims description 4
- 201000011549 stomach cancer Diseases 0.000 claims description 4
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 3
- 206010025323 Lymphomas Diseases 0.000 claims description 3
- 208000001894 Nasopharyngeal Neoplasms Diseases 0.000 claims description 3
- 125000006580 bicyclic heterocycloalkyl group Chemical group 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 125000002757 morpholinyl group Chemical group 0.000 claims description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000006568 (C4-C7) heterocycloalkyl group Chemical group 0.000 claims description 2
- 206010009944 Colon cancer Diseases 0.000 claims description 2
- 201000003741 Gastrointestinal carcinoma Diseases 0.000 claims description 2
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical group C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- 208000029742 colonic neoplasm Diseases 0.000 claims description 2
- 201000002313 intestinal cancer Diseases 0.000 claims description 2
- 229940043355 kinase inhibitor Drugs 0.000 claims description 2
- 125000002971 oxazolyl group Chemical group 0.000 claims description 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 claims description 2
- GBXQPDCOMJJCMJ-UHFFFAOYSA-M trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;bromide Chemical compound [Br-].C[N+](C)(C)CCCCCC[N+](C)(C)C GBXQPDCOMJJCMJ-UHFFFAOYSA-M 0.000 claims description 2
- 125000005343 heterocyclic alkyl group Chemical group 0.000 claims 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 2
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims 1
- 150000001924 cycloalkanes Chemical class 0.000 claims 1
- 239000002831 pharmacologic agent Substances 0.000 claims 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 description 45
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- 239000000543 intermediate Substances 0.000 description 31
- 239000000243 solution Substances 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 26
- 230000002401 inhibitory effect Effects 0.000 description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 23
- 238000012360 testing method Methods 0.000 description 22
- 102000044168 Fibroblast Growth Factor Receptor Human genes 0.000 description 19
- 125000004432 carbon atom Chemical group C* 0.000 description 19
- 239000007787 solid Substances 0.000 description 19
- 230000002829 reductive effect Effects 0.000 description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 16
- 108091000080 Phosphotransferase Proteins 0.000 description 16
- 239000000203 mixture Substances 0.000 description 16
- 102000020233 phosphotransferase Human genes 0.000 description 16
- 239000002904 solvent Substances 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 14
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 14
- 230000000694 effects Effects 0.000 description 12
- 239000001301 oxygen Substances 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 10
- 230000005764 inhibitory process Effects 0.000 description 10
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 10
- 239000013642 negative control Substances 0.000 description 10
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 10
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 10
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 125000000623 heterocyclic group Chemical group 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 8
- 230000004663 cell proliferation Effects 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- 239000011593 sulfur Substances 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 239000003054 catalyst Substances 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 125000002619 bicyclic group Chemical group 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 239000003638 chemical reducing agent Substances 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 238000011161 development Methods 0.000 description 6
- 230000018109 developmental process Effects 0.000 description 6
- 230000002503 metabolic effect Effects 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 102100023600 Fibroblast growth factor receptor 2 Human genes 0.000 description 5
- 101710182389 Fibroblast growth factor receptor 2 Proteins 0.000 description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 208000035475 disorder Diseases 0.000 description 5
- 238000007429 general method Methods 0.000 description 5
- 125000001183 hydrocarbyl group Chemical group 0.000 description 5
- 150000007530 organic bases Chemical class 0.000 description 5
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 5
- 239000000523 sample Substances 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 229910052723 transition metal Inorganic materials 0.000 description 5
- 150000003624 transition metals Chemical class 0.000 description 5
- 210000004881 tumor cell Anatomy 0.000 description 5
- HPYNZHMRTTWQTB-UHFFFAOYSA-N 2,3-dimethylpyridine Chemical compound CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 4
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 241000699660 Mus musculus Species 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 125000003710 aryl alkyl group Chemical group 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 4
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 4
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 4
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 238000009833 condensation Methods 0.000 description 4
- 230000005494 condensation Effects 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 150000007529 inorganic bases Chemical class 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- 230000035772 mutation Effects 0.000 description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 235000011181 potassium carbonates Nutrition 0.000 description 4
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 4
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
- VSOSXKMEQPYESP-UHFFFAOYSA-N 1,6-naphthyridine Chemical compound C1=CN=CC2=CC=CN=C21 VSOSXKMEQPYESP-UHFFFAOYSA-N 0.000 description 3
- 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 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 102100027842 Fibroblast growth factor receptor 3 Human genes 0.000 description 3
- 101710182396 Fibroblast growth factor receptor 3 Proteins 0.000 description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 3
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 229910052744 lithium Inorganic materials 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- 238000011580 nude mouse model Methods 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 235000019345 sodium thiosulphate Nutrition 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 2
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 2
- ATPXGQVBSCIPET-UHFFFAOYSA-N 1-methyl-4-nitropyrazol-3-amine Chemical compound CN1C=C([N+]([O-])=O)C(N)=N1 ATPXGQVBSCIPET-UHFFFAOYSA-N 0.000 description 2
- GNZVDWNVKZQTAV-UHFFFAOYSA-N 2,4-dichloro-1,5-dimethoxy-3-methylbenzene Chemical compound COC1=CC(OC)=C(Cl)C(C)=C1Cl GNZVDWNVKZQTAV-UHFFFAOYSA-N 0.000 description 2
- GXJWHTKHHNHFQH-UHFFFAOYSA-N 2-(2,6-dichloro-3,5-dimethoxyphenyl)-6-methylsulfanylpyridine Chemical compound ClC1=C(C(=C(C=C1OC)OC)Cl)C1=CC=CC(=N1)SC GXJWHTKHHNHFQH-UHFFFAOYSA-N 0.000 description 2
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 2
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 2
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 2
- ASSKVPFEZFQQNQ-UHFFFAOYSA-N 2-benzoxazolinone Chemical compound C1=CC=C2OC(O)=NC2=C1 ASSKVPFEZFQQNQ-UHFFFAOYSA-N 0.000 description 2
- RIZBLVRXRWHLFA-UHFFFAOYSA-N 3,5-dimethoxytoluene Chemical compound COC1=CC(C)=CC(OC)=C1 RIZBLVRXRWHLFA-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- DKBWCIIVNWOREJ-UHFFFAOYSA-N 4-(4-methylpiperazin-1-yl)-2-nitroaniline Chemical compound C1CN(C)CCN1C1=CC=C(N)C([N+]([O-])=O)=C1 DKBWCIIVNWOREJ-UHFFFAOYSA-N 0.000 description 2
- QZUZLFNBDSFDJY-UHFFFAOYSA-N 7-chloro-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1,6-naphthyridin-2-amine Chemical compound ClC1=NC=C2C=C(C(=NC2=C1)N)C1=C(C(=CC(=C1Cl)OC)OC)Cl QZUZLFNBDSFDJY-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 2
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 2
- 102100031734 Fibroblast growth factor 19 Human genes 0.000 description 2
- 239000007821 HATU Substances 0.000 description 2
- 101000846394 Homo sapiens Fibroblast growth factor 19 Proteins 0.000 description 2
- 101000916644 Homo sapiens Macrophage colony-stimulating factor 1 receptor Proteins 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 2
- 102100028198 Macrophage colony-stimulating factor 1 receptor Human genes 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- BERYCDVRHIAEKY-UHFFFAOYSA-N N-[4-(4-methylpiperazin-1-yl)-2-nitrophenyl]acetamide Chemical compound CN1CCN(CC1)C1=CC(=C(C=C1)NC(C)=O)[N+](=O)[O-] BERYCDVRHIAEKY-UHFFFAOYSA-N 0.000 description 2
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 2
- ACFIXJIJDZMPPO-NNYOXOHSSA-N NADPH Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](OP(O)(O)=O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 ACFIXJIJDZMPPO-NNYOXOHSSA-N 0.000 description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- 239000012317 TBTU Substances 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- 241000711955 Turkey rhinotracheitis virus Species 0.000 description 2
- 108091008605 VEGF receptors Proteins 0.000 description 2
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 2
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- DZBUGLKDJFMEHC-UHFFFAOYSA-N acridine Chemical compound C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 2
- 229960001948 caffeine Drugs 0.000 description 2
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 125000003636 chemical group Chemical group 0.000 description 2
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 2
- 229960001231 choline Drugs 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 229940125829 fibroblast growth factor receptor inhibitor Drugs 0.000 description 2
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 2
- QEWYKACRFQMRMB-UHFFFAOYSA-N fluoroacetic acid Chemical compound OC(=O)CF QEWYKACRFQMRMB-UHFFFAOYSA-N 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000013038 irreversible inhibitor Substances 0.000 description 2
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 2
- 125000000842 isoxazolyl group Chemical group 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 210000005229 liver cell Anatomy 0.000 description 2
- 210000001853 liver microsome Anatomy 0.000 description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- QAEVFGOUSCYAPU-UHFFFAOYSA-N n-[4-(4-methylpiperazin-1-yl)phenyl]acetamide Chemical compound C1CN(C)CCN1C1=CC=C(NC(C)=O)C=C1 QAEVFGOUSCYAPU-UHFFFAOYSA-N 0.000 description 2
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 2
- 150000002828 nitro derivatives Chemical class 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 230000002018 overexpression Effects 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- PBDBXAQKXCXZCJ-UHFFFAOYSA-L palladium(2+);2,2,2-trifluoroacetate Chemical compound [Pd+2].[O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F PBDBXAQKXCXZCJ-UHFFFAOYSA-L 0.000 description 2
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 description 2
- 201000002528 pancreatic cancer Diseases 0.000 description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 description 2
- CPJSUEIXXCENMM-UHFFFAOYSA-N phenacetin Chemical compound CCOC1=CC=C(NC(C)=O)C=C1 CPJSUEIXXCENMM-UHFFFAOYSA-N 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 235000011056 potassium acetate Nutrition 0.000 description 2
- 239000011698 potassium fluoride Substances 0.000 description 2
- 235000003270 potassium fluoride Nutrition 0.000 description 2
- 235000011118 potassium hydroxide Nutrition 0.000 description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 description 2
- 235000011009 potassium phosphates Nutrition 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 2
- LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 125000003107 substituted aryl group Chemical group 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- JSTLLXLGUZNADJ-UHFFFAOYSA-N tert-butyl N-(1-methyl-4-nitropyrazol-3-yl)carbamate Chemical compound CN1N=C(C(=C1)[N+](=O)[O-])NC(=O)OC(C)(C)C JSTLLXLGUZNADJ-UHFFFAOYSA-N 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- YAPQBXQYLJRXSA-UHFFFAOYSA-N theobromine Chemical compound CN1C(=O)NC(=O)C2=C1N=CN2C YAPQBXQYLJRXSA-UHFFFAOYSA-N 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 125000001425 triazolyl group Chemical group 0.000 description 2
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 2
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- BWHDROKFUHTORW-UHFFFAOYSA-N tritert-butylphosphane Chemical compound CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 2
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 1
- IGLYMJRIWWIQQE-QUOODJBBSA-N (1S,2R)-2-phenylcyclopropan-1-amine (1R,2S)-2-phenylcyclopropan-1-amine Chemical compound N[C@H]1C[C@@H]1C1=CC=CC=C1.N[C@@H]1C[C@H]1C1=CC=CC=C1 IGLYMJRIWWIQQE-QUOODJBBSA-N 0.000 description 1
- XMAYWYJOQHXEEK-OZXSUGGESA-N (2R,4S)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 description 1
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- FEOHYDSNGHIXOM-WLDMJGECSA-N (3R,4R,5S,6R)-3-amino-6-(hydroxymethyl)-2-methyloxane-2,4,5-triol Chemical compound CC1(O)[C@H](N)[C@@H](O)[C@H](O)[C@H](O1)CO FEOHYDSNGHIXOM-WLDMJGECSA-N 0.000 description 1
- METKIMKYRPQLGS-GFCCVEGCSA-N (R)-atenolol Chemical compound CC(C)NC[C@@H](O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-GFCCVEGCSA-N 0.000 description 1
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- BGNXWFHKYIWIEQ-UHFFFAOYSA-N 1,5-dichloro-2,4-dimethoxybenzene Chemical compound COC1=CC(OC)=C(Cl)C=C1Cl BGNXWFHKYIWIEQ-UHFFFAOYSA-N 0.000 description 1
- LUELEBJVRNPDAY-UHFFFAOYSA-N 1-(4-amino-3-nitrophenyl)-N,N-dimethylpiperidin-4-amine Chemical compound NC1=C(C=C(C=C1)N1CCC(CC1)N(C)C)[N+](=O)[O-] LUELEBJVRNPDAY-UHFFFAOYSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
- BMVXCPBXGZKUPN-UHFFFAOYSA-N 1-hexanamine Chemical compound CCCCCCN BMVXCPBXGZKUPN-UHFFFAOYSA-N 0.000 description 1
- OMMBYRSUPXNTEK-UHFFFAOYSA-N 1-methyl-4-nitro-1h-pyrazole-3-carboxylic acid Chemical compound CN1C=C([N+]([O-])=O)C(C(O)=O)=N1 OMMBYRSUPXNTEK-UHFFFAOYSA-N 0.000 description 1
- FRPZMMHWLSIFAZ-UHFFFAOYSA-N 10-undecenoic acid Chemical compound OC(=O)CCCCCCCCC=C FRPZMMHWLSIFAZ-UHFFFAOYSA-N 0.000 description 1
- 125000005938 2,3-dihydro-1H-isoindolyl group Chemical group 0.000 description 1
- AZUUAIVVBYHHDN-UHFFFAOYSA-N 2-(2,6-dichloro-3,5-dimethoxyphenyl)acetonitrile Chemical compound COC1=CC(OC)=C(Cl)C(CC#N)=C1Cl AZUUAIVVBYHHDN-UHFFFAOYSA-N 0.000 description 1
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- 229940013085 2-diethylaminoethanol Drugs 0.000 description 1
- OQHQOOLVQDEIGL-UHFFFAOYSA-N 2-methyl-2,7-diazaspiro[4.4]nonane Chemical compound C1N(C)CCC11CNCC1 OQHQOOLVQDEIGL-UHFFFAOYSA-N 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- NYJICBHILKIZMZ-UHFFFAOYSA-N 2-nitro-4-(4-propan-2-ylpiperazin-1-yl)aniline Chemical compound CC(C)N1CCN(CC1)c1ccc(N)c(c1)[N+]([O-])=O NYJICBHILKIZMZ-UHFFFAOYSA-N 0.000 description 1
- ATNSDMSONWVQDZ-UHFFFAOYSA-N 2-nitro-4-(4-pyrrolidin-1-ylpiperidin-1-yl)aniline Chemical compound [N+](=O)([O-])C1=C(N)C=CC(=C1)N1CCC(CC1)N1CCCC1 ATNSDMSONWVQDZ-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- TVJPTOKPOUDFGK-UHFFFAOYSA-N 3-(bromomethyl)-2,4-dichloro-1,5-dimethoxybenzene Chemical compound COc1cc(OC)c(Cl)c(CBr)c1Cl TVJPTOKPOUDFGK-UHFFFAOYSA-N 0.000 description 1
- 125000003469 3-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- AQAIHGAJWVUZLS-UHFFFAOYSA-N 4-(1-methylpiperidin-4-yl)-2-nitroaniline Chemical compound C1CN(C)CCC1C1=CC=C(N)C([N+]([O-])=O)=C1 AQAIHGAJWVUZLS-UHFFFAOYSA-N 0.000 description 1
- HTZZDIGHKJVORN-UHFFFAOYSA-N 4-(4-ethylpiperazin-1-yl)-2-nitroaniline Chemical compound CCN1CCN(CC1)c1ccc(N)c(c1)[N+]([O-])=O HTZZDIGHKJVORN-UHFFFAOYSA-N 0.000 description 1
- MOZNZNKHRXRLLF-UHFFFAOYSA-N 4-(4-methylpiperazin-1-yl)aniline Chemical compound C1CN(C)CCN1C1=CC=C(N)C=C1 MOZNZNKHRXRLLF-UHFFFAOYSA-N 0.000 description 1
- WQJKOGCPZOEIJY-UHFFFAOYSA-N 4-[(4-ethylpiperazin-1-yl)methyl]-2-nitroaniline Chemical compound C1CN(CC)CCN1CC1=CC=C(N)C([N+]([O-])=O)=C1 WQJKOGCPZOEIJY-UHFFFAOYSA-N 0.000 description 1
- CGMIFAMRODWNJB-UHFFFAOYSA-N 4-amino-6-chloropyridine-3-carbaldehyde Chemical compound NC1=CC(Cl)=NC=C1C=O CGMIFAMRODWNJB-UHFFFAOYSA-N 0.000 description 1
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 1
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 description 1
- ISLLQWJXOVDCJW-UHFFFAOYSA-N 6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-methylsulfanylpyrido[2,3-d]pyrimidin-7-amine Chemical compound COc1cc(OC)c(Cl)c(c1Cl)-c1cc2cnc(SC)nc2[nH]c1=N ISLLQWJXOVDCJW-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- LOIOZVDTIXFEGR-UHFFFAOYSA-N 7-(2,6-dichloro-3,5-dimethoxyphenyl)-12-methylsulfanyl-2,4,5,11,13-pentazatricyclo[7.4.0.02,6]trideca-1(13),3,5,7,9,11-hexaene Chemical compound N12C=NN=C1C(C=C1C2=NC(=N[CH]1)SC)=C1C(Cl)=C(OC)C=C(OC)[C]1Cl LOIOZVDTIXFEGR-UHFFFAOYSA-N 0.000 description 1
- FHFPEVZEAOIZOD-UHFFFAOYSA-N 7-chloro-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-methylsulfanylpyrido[2,3-d]pyrimidine Chemical compound S(C1=NC=C2C=C(C(=NC2=N1)Cl)C1=C(Cl)C(OC)=CC(OC)=C1Cl)C FHFPEVZEAOIZOD-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 230000035502 ADME Effects 0.000 description 1
- VRQMAABPASPXMW-HDICACEKSA-N AZD4547 Chemical compound COC1=CC(OC)=CC(CCC=2NN=C(NC(=O)C=3C=CC(=CC=3)N3C[C@@H](C)N[C@@H](C)C3)C=2)=C1 VRQMAABPASPXMW-HDICACEKSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- QADPYRIHXKWUSV-UHFFFAOYSA-N BGJ-398 Chemical compound C1CN(CC)CCN1C(C=C1)=CC=C1NC1=CC(N(C)C(=O)NC=2C(=C(OC)C=C(OC)C=2Cl)Cl)=NC=N1 QADPYRIHXKWUSV-UHFFFAOYSA-N 0.000 description 1
- KWIUHFFTVRNATP-UHFFFAOYSA-N Betaine Natural products C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 1
- 206010005949 Bone cancer Diseases 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 108091007914 CDKs Proteins 0.000 description 1
- FVAHHPPJYLVIIC-OLQVQODUSA-N C[C@H]1[C@@H](C)COC1 Chemical compound C[C@H]1[C@@H](C)COC1 FVAHHPPJYLVIIC-OLQVQODUSA-N 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- NSTUUHPBPDFGMR-UHFFFAOYSA-N Cc1cnccc1I Chemical compound Cc1cnccc1I NSTUUHPBPDFGMR-UHFFFAOYSA-N 0.000 description 1
- SHDMYGCRVXWTGR-UHFFFAOYSA-N Cc1n[nH]cc1I Chemical compound Cc1n[nH]cc1I SHDMYGCRVXWTGR-UHFFFAOYSA-N 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 102400000888 Cholecystokinin-8 Human genes 0.000 description 1
- 101800005151 Cholecystokinin-8 Proteins 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- 230000004544 DNA amplification Effects 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 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
- 241001125671 Eretmochelys imbricata Species 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 101150081124 FGFR gene Proteins 0.000 description 1
- 101150082429 FGFR4 gene Proteins 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 206010051066 Gastrointestinal stromal tumour Diseases 0.000 description 1
- 206010064571 Gene mutation Diseases 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- 101000692455 Homo sapiens Platelet-derived growth factor receptor beta Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- MKXZASYAUGDDCJ-SZMVWBNQSA-N LSM-2525 Chemical compound C1CCC[C@H]2[C@@]3([H])N(C)CC[C@]21C1=CC(OC)=CC=C1C3 MKXZASYAUGDDCJ-SZMVWBNQSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 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
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000003445 Mouth Neoplasms Diseases 0.000 description 1
- KWIUHFFTVRNATP-UHFFFAOYSA-O N,N,N-trimethylglycinium Chemical compound C[N+](C)(C)CC(O)=O KWIUHFFTVRNATP-UHFFFAOYSA-O 0.000 description 1
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 1
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 102100026547 Platelet-derived growth factor receptor beta Human genes 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 102100023347 Proto-oncogene tyrosine-protein kinase ROS Human genes 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- HJLSLZFTEKNLFI-UHFFFAOYSA-N Tinidazole Chemical compound CCS(=O)(=O)CCN1C(C)=NC=C1[N+]([O-])=O HJLSLZFTEKNLFI-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 102100025093 Zinc fingers and homeoboxes protein 2 Human genes 0.000 description 1
- NVSPJDGXKBDYIZ-UHFFFAOYSA-N [1,2,4]triazolo[4,3-a]pyrazine Chemical compound C1=NC=CN2C=NN=C21 NVSPJDGXKBDYIZ-UHFFFAOYSA-N 0.000 description 1
- AYSYSOQSKKDJJY-UHFFFAOYSA-N [1,2,4]triazolo[4,3-a]pyridine Chemical compound C1=CC=CN2C=NN=C21 AYSYSOQSKKDJJY-UHFFFAOYSA-N 0.000 description 1
- YRACHDVMKITFAZ-UHFFFAOYSA-N [1,2,4]triazolo[4,3-b]pyridazine Chemical compound C1=CC=NN2C=NN=C21 YRACHDVMKITFAZ-UHFFFAOYSA-N 0.000 description 1
- XUFCBCHWTOAVAA-UHFFFAOYSA-N [1,2,4]triazolo[4,3-c]pyrimidine Chemical compound C1=CN=CN2C=NN=C21 XUFCBCHWTOAVAA-UHFFFAOYSA-N 0.000 description 1
- FHZDBBFOUNSYSX-UHFFFAOYSA-N [6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-methylsulfanylpyrido[2,3-d]pyrimidin-7-yl]hydrazine Chemical compound N(N)C1=C(C=C2C(N=C(N=C2)SC)=N1)C1=C(Cl)C(OC)=CC(OC)=C1Cl FHZDBBFOUNSYSX-UHFFFAOYSA-N 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
- 238000010521 absorption reaction Methods 0.000 description 1
- LXNAVEXFUKBNMK-UHFFFAOYSA-N acetic acid;palladium Chemical compound [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical class OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 150000001335 aliphatic alkanes Chemical group 0.000 description 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229960003121 arginine Drugs 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 229960002274 atenolol Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 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
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- 229960003237 betaine Drugs 0.000 description 1
- 210000000941 bile Anatomy 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
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 125000004623 carbolinyl group Chemical group 0.000 description 1
- QNEFNFIKZWUAEQ-UHFFFAOYSA-N carbonic acid;potassium Chemical compound [K].OC(O)=O QNEFNFIKZWUAEQ-UHFFFAOYSA-N 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000004709 cell invasion Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 150000005829 chemical entities Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
- 229940114081 cinnamate Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 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
- 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 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
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 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
- 229960002887 deanol Drugs 0.000 description 1
- 125000004652 decahydroisoquinolinyl group Chemical group C1(NCCC2CCCCC12)* 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-M decanoate Chemical compound CCCCCCCCCC([O-])=O GHVNFZFCNZKVNT-UHFFFAOYSA-M 0.000 description 1
- 125000002704 decyl 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])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 229960001985 dextromethorphan Drugs 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- JXTHNDFMNIQAHM-UHFFFAOYSA-M dichloroacetate Chemical compound [O-]C(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-M 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 125000001070 dihydroindolyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000012972 dimethylethanolamine Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 230000002183 duodenal effect Effects 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 1
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 229940012017 ethylenediamine Drugs 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 229960002442 glucosamine Drugs 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 229940049906 glutamate Drugs 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 description 1
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 229960001008 heparin sodium Drugs 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004475 heteroaralkyl group Chemical group 0.000 description 1
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 229960002885 histidine Drugs 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- MBVAHHOKMIRXLP-UHFFFAOYSA-N imidazo[1,2-a]pyrazine Chemical compound C1=CN=CC2=NC=CN21 MBVAHHOKMIRXLP-UHFFFAOYSA-N 0.000 description 1
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 description 1
- VTVRXITWWZGKHV-UHFFFAOYSA-N imidazo[1,2-b]pyridazine Chemical compound N1=CC=CC2=NC=CN21 VTVRXITWWZGKHV-UHFFFAOYSA-N 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 125000005438 isoindazolyl group Chemical group 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 125000003965 isoxazolidinyl group Chemical group 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 229960004125 ketoconazole Drugs 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- 229940070765 laurate Drugs 0.000 description 1
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 229960003646 lysine Drugs 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 229960000906 mephenytoin Drugs 0.000 description 1
- GMHKMTDVRCWUDX-UHFFFAOYSA-N mephenytoin Chemical compound C=1C=CC=CC=1C1(CC)NC(=O)N(C)C1=O GMHKMTDVRCWUDX-UHFFFAOYSA-N 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 210000001589 microsome Anatomy 0.000 description 1
- DDLIGBOFAVUZHB-UHFFFAOYSA-N midazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NC=C2CN=C1C1=CC=CC=C1F DDLIGBOFAVUZHB-UHFFFAOYSA-N 0.000 description 1
- 229960003793 midazolam Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- TXEBNKKOLVBTFK-UHFFFAOYSA-N n-[2-[[6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl]amino]-3-methylphenyl]prop-2-enamide Chemical compound COC1=CC(OC)=C(Cl)C(C=2C=C3C=NC(NC=4C(=CC=CC=4C)NC(=O)C=C)=NC3=CC=2)=C1Cl TXEBNKKOLVBTFK-UHFFFAOYSA-N 0.000 description 1
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 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
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 201000011216 nasopharynx carcinoma Diseases 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 125000005060 octahydroindolyl group Chemical group N1(CCC2CCCCC12)* 0.000 description 1
- 125000005061 octahydroisoindolyl group Chemical group C1(NCC2CCCCC12)* 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 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
- 230000036961 partial effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229960003893 phenacetin Drugs 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 125000004437 phosphorous atom Chemical group 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- ZTRPYTHOEREHEN-UHFFFAOYSA-N piperazine pyridine Chemical compound N1CCNCC1.N1=CC=CC=C1.N1=CC=CC=C1 ZTRPYTHOEREHEN-UHFFFAOYSA-N 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 239000002952 polymeric resin Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- PHXJVRSECIGDHY-UHFFFAOYSA-N ponatinib Chemical compound C1CN(C)CCN1CC(C(=C1)C(F)(F)F)=CC=C1NC(=O)C1=CC=C(C)C(C#CC=2N3N=CC=CC3=NC=2)=C1 PHXJVRSECIGDHY-UHFFFAOYSA-N 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UDJFFSGCRRMVFH-UHFFFAOYSA-N pyrido[2,3-d]pyrimidine Chemical compound N1=CN=CC2=CC=CN=C21 UDJFFSGCRRMVFH-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 229940043131 pyroglutamate Drugs 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 229960001404 quinidine Drugs 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 1
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 201000006845 reticulosarcoma Diseases 0.000 description 1
- 208000029922 reticulum cell sarcoma Diseases 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000007447 staining method Methods 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229940114926 stearate Drugs 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229960005404 sulfamethoxazole Drugs 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 description 1
- 125000001174 sulfone group Chemical group 0.000 description 1
- 125000003375 sulfoxide group Chemical group 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- JLKIGFTWXXRPMT-UHFFFAOYSA-N sulphamethoxazole Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 JLKIGFTWXXRPMT-UHFFFAOYSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 239000012747 synergistic agent Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229920003002 synthetic resin Polymers 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- OWYHAYAJHNQBGG-UHFFFAOYSA-N tert-butyl 3-oxospiro[2h-indene-1,4'-piperidine]-1'-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC11C2=CC=CC=C2C(=O)C1 OWYHAYAJHNQBGG-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ZGNPLWZYVAFUNZ-UHFFFAOYSA-N tert-butylphosphane Chemical compound CC(C)(C)P ZGNPLWZYVAFUNZ-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 150000004685 tetrahydrates Chemical class 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 150000003573 thiols Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 229960005053 tinidazole Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 238000012384 transportation and delivery Methods 0.000 description 1
- 229960003741 tranylcypromine Drugs 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 229940075466 undecylenate Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- 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
- C07D471/12—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 three hetero rings
- C07D471/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/14—Ortho-condensed systems
Definitions
- the invention belongs to the field of medicinal chemistry, and particularly relates to a class of fused ring triazole compounds, a preparation method and uses thereof.
- Receptor tyrosine kinase activation or gene mutation plays a key role in tumor occurrence, development, invasion and metastasis, and drug resistance, so as to become an important target for the development of anti-tumor drugs.
- fibroblast growth factor receptor FGFR
- FGFR fibroblast growth factor receptor
- FGFRs are highly expressed and abnormally activated in many tumors, and are closely related to the poor prognosis of tumor patients. Therefore, FGFRs are recognized as an important target for antitumor, and the development of FGFR small molecule inhibitors has gradually received more and more attention.
- FGF19 is a ligand of FGFR4, which is responsible for regulating normal bile secretion and liver cell proliferation in the liver. Its overexpression or overactivation can promote liver cell proliferation and induce liver cancer formation. This has been confirmed in transgenic mice, and knocking out the FGFR4 gene can block the development of hepatocellular carcinoma.
- the technical problem to be solved by the present invention is to overcome the problems that the existing FGFR inhibitor compounds have a single structure, or have poor target selectivity, or low target inhibitory activity, or have poor pharmacological properties, or are prone to mutation and resistance. , And provides a class of fused ring triazole compounds, preparation method and application.
- the fused ring triazole compound of the present invention is a new type of specific irreversible inhibitor of FGFR kinase, has good target selectivity, and can be used to treat tumors.
- the present invention solves the above technical problems through the following technical solutions.
- the present invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polycrystal Type or prodrug,
- R 1 , R 2 , R 3 and R 4 are independently selected from hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino, acyl, or sulfonyl; preferably from hydrogen, halogen, alkane Radical, or alkoxy;
- R 5 is selected from hydrogen, halogen, cyano, alkyl, alkoxy, amino, or hydroxyl; preferably from hydrogen, halogen, or alkyl;
- Y is N and Z is CR 6 , or Y is CR 6 and Z is N;
- R 6 is selected from hydrogen, halogen, cyano, alkyl, alkoxy, alkenyl, alkynyl, acyl, sulfonyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or alkylene- NR 6-1 R 6-2 ; preferably from hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 heterocycloalkyl, or alkylene-NR 6-1 R 6-2 ; R 6- 1 and R 6-2 are independently hydrogen or C 1 -C 6 alkyl;
- M is selected from CR a or N;
- R a is selected from hydrogen, or halogen;
- Cy is selected from 3-8 membered cycloalkyl or heterocycloalkyl, 5-8 membered aryl or heteroaryl; preferably from 5-6 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
- R 7 is selected from hydrogen, halogen, cyano, hydroxy, amino, alkyl, alkenyl, alkynyl, acyl, sulfonyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; preferably from hydrogen, Halogen, C 1 -C 6 alkyl, 3-8 membered cycloalkyl, or 4-8 membered heterocycloalkyl; and one or more groups on R 7 may interact with one or more hydrogens on ring Cy Substitute to form the corresponding fused ring, parallel ring, spiro ring, or bridge ring ring system, the ring system has 0 to 3 heteroatoms including O, N, S; one or more of any of the above groups
- the hydrogen atom is optionally selected from the group consisting of deuterium, halogen, hydroxy, amino, cyano, sulfone, sulfoxide, C 1 -C 8 alkyl, C 1 -C
- n is selected from 0-4;
- R 8 , R 9 and R 10 are independently selected from hydrogen, halogen, cyano, nitro, alkyl, sulfone, sulfoxide, or alkylene-NR 8-1 R 8-2 ; any of the above One or more hydrogen atoms on the group are optionally selected from the group consisting of deuterium, halogen, hydroxyl, amino, cyano, sulfone, sulfoxide, C 1 -C 8 alkyl, C 1- C 8 alkoxy, C 1 -C 8 alkylamino, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, acyl, sulfonyl, 5-8 membered aryl or heteroaryl, 4 -8-membered cycloalkyl or heterocycloalkyl; R 8-1 and R 8-2 are independently hydrogen or C 1 -C 6 alkyl;
- the heteroaryl group includes 1-3 heteroatoms selected from the group: N, O, P, and S
- the heterocycloalkyl group includes 1-3 heteroatoms selected from the group: N , O, P, and S.
- the compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, or tautomer Conformers, solvates, polymorphs or prodrugs,
- R 1 , R 2 , R 3 and R 4 are independently selected from hydrogen, halogen, C 1 -C 6 alkyl, 3-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, C 1 -C 6 alkyl Oxy, amino, acyl, or sulfonyl; preferably from hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;
- R 5 is selected from hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, amino, or hydroxyl; preferably from hydrogen, halogen, or C 1 -C 6 alkyl;
- Y is N and Z is CR 6 , or Y is CR 6 and Z is N;
- R 6 is selected from hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, acyl, sulfonyl, C 6- C 10 aryl, 5-10 membered heteroaryl, 3-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, or C 1 -C 6 alkylene-NR 6-1 R 6-2 ; preferably from hydrogen, halo, C 1 -C 6 alkyl, 4-6 membered heterocycloalkyl, or a C 1 -C 6 alkylene group -NR 6-1 R 6-2; R 6- 1 and R 6 -2 is independently hydrogen or C 1 -C 6 alkyl;
- M is selected from CR a or N;
- R a is selected from hydrogen, or halogen;
- Cy is selected from 3-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, 5-8 membered aryl, or 5-8 membered heteroaryl; preferably from 5-6 membered cycloalkyl, 5-6 membered Heterocycloalkyl, 5-8 membered aryl, or 5-6 membered heteroaryl;
- R 7 is selected from hydrogen, halogen, cyano, hydroxyl, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, acyl, sulfonyl, C 6 -C 10 aromatic Radical, 5-10 membered heteroaryl, 3-8 membered cycloalkyl, or 4-11 membered heterocycloalkyl; preferably from hydrogen, halogen, C 1 -C 6 alkyl, 3-8 membered cycloalkyl, Or 4- to 8-membered heterocycloalkyl; and one or more groups on R 7 may be substituted with one or more hydrogens on the ring Cy to form the corresponding rings such as fused rings, fused rings, spiro rings, bridged rings, etc.
- the ring system has 0 to 3 heteroatoms including O, N, S; the C 1 -C 6 alkyl group is optionally substituted by 1-3 selected from hydroxyl, halogen, C 1 -C 6 alkyl Oxygen, -NR 7-2 R 7-3 , 4-8 membered heterocycloalkyl, or R 7-4 substituted 4-8 membered heterocycloalkyl; R 7-4 is C 1 -C 6 alkyl; R 7-2 and R 7-3 are independently selected from hydrogen or C 1 -C 6 alkyl; said C 6 -C 10 aryl, 5-10 membered heteroaryl, 3-8 membered cycloalkyl, 4-11 membered heterocycloalkyl or optionally independently substituted with 1-3 substituents selected from C 1 -C 6 alkyl, R 7-5 is a substituted C 1 -C 6 alkyl , -NR 7-6 R 7-7 , carbonyl, 3-8 membered cycloalkyl, or 4-8
- n is selected from 0, 1, 2, 3, or 4;
- R 8 , R 9 and R 10 are independently selected from hydrogen, halogen, cyano, nitro, C 1 -C 6 alkyl, sulfone, sulfoxide, or C 1 -C 6 alkylene-NR 8- 1 R 8-2 ; one or more hydrogen atoms on any of the above groups is optionally selected from the group consisting of deuterium, halogen, hydroxyl, amino, cyano, sulfone, sulfoxide , C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylamino, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, acyl, sulfonyl, 5- 8-membered aryl or heteroaryl, 4-8 membered cycloalkyl or heterocycloalkyl; R 8-1 and R 8-2 are independently hydrogen or C 1 -C 6 alkyl.
- the compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, or tautomer Conformers, solvates, polymorphs or prodrugs,
- R 1 , R 2 , R 3 and R 4 are independently selected from hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino, acyl, sulfonyl; preferably from hydrogen, halogen, alkyl , Alkoxy;
- R 5 is selected from hydrogen, halogen, cyano, alkyl, alkoxy, amino, hydroxyl, etc .; preferably, hydrogen, halogen, alkyl;
- Y, Z are each independently selected from N or CR 6 ;
- R 6 is independently selected from hydrogen, halogen, cyano, alkyl, alkoxy, alkenyl, alkynyl, acyl, sulfonyl, aryl, heteroaryl , Cycloalkyl, heterocycloalkyl, etc .; preferably from hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 heterocycloalkyl, etc .;
- M is independently selected from CR a or N;
- R a is independently selected from hydrogen, halogen;
- Cy is selected from 3-8 membered cycloalkyl or heterocycloalkyl, 5-8 membered aryl or heteroaryl, respectively; preferably from 5-6 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ;
- R 7 is selected from hydrogen, halogen, cyano, hydroxy, amino, alkyl, alkenyl, alkynyl, acyl, sulfonyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, etc .; preferably from hydrogen, Halogen, C 1 -C 6 alkyl, 3-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, etc .; and one or more groups on R 7 may be linked to one or more hydrogens on ring Cy Substitute to form the corresponding fused ring, parallel ring, spiro ring, bridge ring and other ring systems.
- the ring system may have 0 to 3 heteroatoms including O, N, S;
- n is independently selected from 0-4;
- R 8 , R 9 and R 10 are independently selected from hydrogen, halogen, cyano, nitro, alkyl, sulfone, sulfoxide, etc .; one or more hydrogen atoms on any of the above groups may be selected Substitution from the following groups: including but not limited to deuterium, halogen, hydroxy, amino, cyano, sulfone or sulfoxide, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1- C 8 alkylamino, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, acyl or sulfonyl, 5- to 8-membered aryl or heteroaryl, 4- to 8-membered cycloalkyl or heterocycloalkyl ; Wherein the heteroaryl group contains 1-3 heteroatoms selected from the group: N, O, P or S, and the heterocycloalkyl group contains 1-3 heteroatoms selected from the group: N, O
- the compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, or solvent thereof Compounds, polymorphs or prodrugs,
- M is independently selected from CH or N;
- R 1 and R 2 are independently selected from hydrogen and halogen, preferably from fluorine and chlorine;
- R 3 and R 4 are independently selected from halogen, alkoxy, alkyl, amino, cycloalkyl, or heterocycloalkyl, and more preferably From fluorine, methoxy;
- R 5 is selected from hydrogen, halogen, and alkyl; further preferably, hydrogen, fluorine, and methyl;
- Y, Z are each independently selected from N or CR 6 ;
- R 6 is independently selected from hydrogen, halogen, C1-C 6 alkyl, preferably from hydrogen;
- Cy is independently preferably a 4- to 6-membered cycloalkyl or heterocycloalkyl, a 5- to 6-membered aryl or heteroaryl; further preferably a tetrahydrofuran ring, a tetrahydropyran ring, a tetrahydropyrrole ring, piperidine Ring, benzene ring, pyridine ring, pyrazole ring, etc .;
- R 7 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, cyano, hydroxy, amino, 4- to 8-membered heterocycloalkyl, alkoxy, alkylamino, acyl or sulfonyl, and the like is more preferred. , Fluorine, cyano, amino, C 1 -C 6 alkyl or 4-7 membered heterocycloalkyl, etc .; more preferably hydrogen, fluorine, methyl, piperazinyl, morpholinyl, piperidinyl, Tetrahydropyrrolyl, etc .;
- n is independently selected from 0-4, preferably from 0-2.
- R 8 , R 9, and R 10 are independently selected from hydrogen, halogen, alkyl, and cyano; further preferably, they are selected from hydrogen, fluorine, methyl, and the like.
- the compound has the following general formulae (IA), (IB):
- each group is defined as described above.
- a method for preparing a compound of formula I characterized in that the method includes steps a-d:
- a compound of the general formula (I) is prepared by subjecting a compound of the general formula (D) to a condensation reaction with an acrylic acid or an acryloyl chloride compound in the presence of a base catalyst or a condensation reagent.
- LG represents a leaving group, such as halogen, sulfone group, sulfoxide group, sulfonate group, etc., and the definitions of other groups are as described above;
- the steps a), b), c), and d) are each performed in a solvent, and the solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, butanol, ethylene glycol, and ethyl acetate.
- the solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, butanol, ethylene glycol, and ethyl acetate.
- the transition metal catalyst is selected from the group consisting of tris (dibenzylideneacetone) dipalladium (Pd 2 (dba) 3 ), tetrakis (triphenylphosphine) palladium (Pd (PPh 3 ) 4 ), acetic acid Palladium, palladium chloride, dichlorobis (triphenylphosphine) palladium, palladium trifluoroacetate, palladium triphenylphosphine acetate, [1,1'-bis (diphenylphosphino) ferrocene] dichloride Palladium, bis (tri-o-phenylmethylphosphine) palladium dichloride, 1,2-bis (diphenylphosphino) ethane palladium dichloride, or a combination thereof; the catalyst ligand is selected from the group consisting of: Tri-tert-butylphosphine, tri-tert-butylphosphine t
- the condensation reagent is selected from the group consisting of DCC, DIC, CDI, EDCI, HOAt, HOBt, BOP, PyBOP, HATU, TBTU, etc., or a combination thereof.
- the inorganic base is selected from the group consisting of sodium hydride, potassium hydroxide, sodium acetate, potassium acetate, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, potassium carbonate, carbonic acid Potassium hydrogen, sodium carbonate, sodium bicarbonate, or a combination thereof;
- the organic base is selected from the group consisting of pyridine, triethylamine, N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] Undecyl-7-ene (DBU), lithium hexamethyldisilyl, sodium hexamethyldisilyl, dimethylpyridine, or a combination thereof.
- the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, formic acid, acetic acid, trifluoromethanesulfonic acid, or a combination thereof.
- R 1 , R 2 , R 3 and R 4 are independently selected from hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino, acyl, sulfonyl; preferably from hydrogen, halogen, alkyl , Alkoxy;
- R 5 is selected from hydrogen, halogen, cyano, alkyl, alkoxy, amino, hydroxyl, etc .; preferably, hydrogen, halogen, alkyl;
- Y is N and Z is CR 6 ;
- Y is CR 6 and Z is N;
- R 6 is independently selected from hydrogen, halogen, cyano, alkyl, alkoxy, alkenyl, alkynyl, acyl, sulfonyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl and the like; preferably from Hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 heterocycloalkyl, etc .;
- M is independently selected from CR a or N;
- R a is independently selected from hydrogen, halogen;
- Cy is selected from 3-8 membered cycloalkyl or heterocycloalkyl, 5-8 membered aryl or heteroaryl, respectively; preferably from 5-6 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ;
- R 7 is selected from hydrogen, halogen, cyano, hydroxy, amino, alkyl, alkenyl, alkynyl, acyl, sulfonyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, etc .; preferably from hydrogen, Halogen, C 1 -C 6 alkyl, 3-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, etc .; and one or more groups on R 7 may be linked to one or more hydrogens on ring Cy Substitute to form the corresponding fused ring, parallel ring, spiro ring, bridge ring and other ring systems.
- the ring system may have 0 to 3 heteroatoms including O, N, S;
- n is independently selected from 0-4;
- R 8 , R 9 and R 10 are independently selected from hydrogen, halogen, cyano, nitro, alkyl, sulfone, sulfoxide, etc .; one or more hydrogen atoms on any of the above groups may be selected Substitution from the following groups: including but not limited to deuterium, halogen, hydroxy, amino, cyano, sulfone or sulfoxide, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1- C 8 alkylamino, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, acyl or sulfonyl, 5- to 8-membered aryl or heteroaryl, 4- to 8-membered cycloalkyl or heterocycloalkyl .
- certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when R 1 and R 2 are independently When it is a halogen, the halogen is preferably fluorine or chlorine.
- certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when R 3 and R 4 are independently When it is halogen, the halogen is preferably fluorine.
- certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when R 3 and R 4 are independently When it is an alkoxy group, the alkoxy group is preferably a C 1 -C 6 alkoxy group, and more preferably a C 1 -C 4 alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy) , N-butoxy, isobutoxy, sec-butoxy, or tert-butoxy), and methoxy is more preferred.
- certain groups of the compound represented by the formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when R 6 is an alkyl group,
- the alkyl group is preferably a C 1 -C 6 alkyl group, and more preferably a C 1 -C 4 alkyl group (for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or Tert-butyl), more preferably methyl.
- certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when R 6 is -alkylene
- the alkylene group is preferably a C 1 -C 6 alkylene group, more preferably a C 1 -C 4 alkylene group, and still more preferably a methylene group.
- certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when R 6-2 and R 6 When -3 is independently C 1 -C 6 alkyl, the C 1 -C 6 alkyl is preferably C 1 -C 4 alkyl (for example, methyl, ethyl, propyl, isopropyl, n-butyl , Isobutyl, sec-butyl or tert-butyl), more preferably methyl.
- certain groups of the compound represented by the formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when Cy is 3-8 membered hetero
- the 3-8 membered heterocycloalkyl group is preferably a 5-6 membered "heteroatom selected from one or more of N, O, and S, and the number of heteroatoms is 1-3" Heterocycloalkyl, more preferably tetrahydrofuranyl (e.g. ), Tetrahydropyrrolyl (e.g. ), Tetrahydrothienyl (e.g. ), Or tetrahydropyranyl (e.g. ), More preferably tetrahydrofuranyl or tetrahydropyranyl.
- certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when Cy is 5-8 yuan aromatic As the radical, the 5- to 8-membered aryl group is preferably a phenyl group.
- certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when Cy is 5-8 membered hetero
- the 5- to 8-membered heteroaryl group is preferably a 5- to 6-membered heteroaryl group having "a heteroatom selected from one or more of N, O, and S, and the number of heteroatoms is 1-3" , More preferably pyrazolyl (e.g. ) Or pyridyl (e.g. ), More preferably pyrazolyl.
- certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when R 7 is alkyl,
- the alkyl group is preferably a C 1 -C 6 alkyl group, and more preferably a C 1 -C 4 alkyl group (for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or Tert-butyl), more preferably methyl, ethyl, n-propyl or isobutyl, and still more preferably methyl.
- certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when R 7 is heterocycloalkyl
- the heterocycloalkyl group is preferably a 4- to 11-membered heterocycloalkyl group, and more preferably 5 having a "heteroatom selected from one or more of N, O, or S, and the number of heteroatoms is 1-3.”
- the 5-7 membered monocyclic heterocycloalkyl group is preferably piperidinyl (e.g. ), Piperazinyl (e.g. ), Or homopiperazinyl (e.g. );
- the 8-9 membered bicyclic heterocycloalkyl group is preferred
- certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes):
- the C 1 -C 8 alkoxy group is preferably a C 1 -C 4 alkoxy group (for example, methoxy, ethoxy , Propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or t-butoxy), more preferably methoxy.
- certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes):
- said 4-8 membered heterocycloalkyl group is preferably "heteroatom selected from one or more of N, O or S
- certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes):
- the C 1 -C 8 alkyl is preferably C 1 -C 4 alkyl (eg methyl, ethyl, propyl , Isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), more preferably methyl, ethyl or isopropyl.
- certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes):
- the 4-8 membered cycloalkyl group is preferably "a heteroatom selected from one or more of N, O or S
- a 4- to 6-membered cycloalkyl group having 1 to 3 heteroatoms, more preferably a tetrahydropyrrolyl group is preferably "a heteroatom selected from one or more of N, O or S.
- certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): in R 7 , the substitutions described When one or more hydrogen atoms on the amino group, C 1 -C 8 alkyl group, 4-8 membered heterocycloalkyl group are optionally substituted by C 1 -C 6 alkyl group, C 1 -C 6 alkyl is preferably C 1 -C 4 alkyl (eg methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), more preferably methyl Or ethyl.
- C 1 -C 6 alkyl is preferably C 1 -C 4 alkyl (eg methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), more preferably methyl Or e
- certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): in R 7 , the substitutions described When one or more hydrogen atoms on the amino group, C 1 -C 8 alkyl group, 4-8 membered heterocycloalkyl group are optionally substituted by C 1 -C 6 alkoxy group, C 1 -C 6 alkoxy is preferably C 1 -C 4 alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy Or tert-butoxy), more preferably methoxy.
- certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): in R 7 , the substitutions described When one or more hydrogen atoms on the amino group, C 1 -C 8 alkyl group, 4-8 membered heterocycloalkyl group are optionally substituted by 5-10 membered heteroaryl group, or C 1 -C
- the 5-10 membered heteroaryl is preferably "a heteroatom selected from one or more of N, O or S, and the number of heteroatoms is 1- 3 "5-6 membered heteroaryl, more preferably pyrazolyl.
- certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): in R 7 , the substitutions described When the one or more hydrogen atoms on the amino group, C 1 -C 8 alkyl group, 4-8 membered heterocycloalkyl group are optionally substituted by C 1 -C 6 alkyl group, When the heteroaryl group is substituted, the C 1 -C 6 alkyl group is preferably a C 1 -C 4 alkyl group, and more preferably a methyl group.
- certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): in R 7 , the substitutions described When one or more hydrogen atoms on the amino group, C 1 -C 8 alkyl group, 4-8 membered heterocycloalkyl group are optionally substituted with 3-8 membered cycloalkyl group, the The 3-8 membered cycloalkyl group is preferably a 3-6 membered cycloalkyl group, and more preferably a cyclopropyl group.
- certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes):
- R 7 when R 7- 2.
- the C 1 -C 6 alkyl is preferably C 1 -C 4 alkyl (e.g. methyl, ethyl, propyl (Propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), more preferably methyl or ethyl.
- certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when R 7-5 is C 1
- the C 1 -C 6 alkoxy is preferably C 1 -C 4 alkoxy (for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy Group, isobutoxy, sec-butoxy or tert-butoxy), more preferably methoxy.
- certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when R 7-5 is 5- In the case of a 10-membered heteroaryl group or a 5- to 10-membered heteroaryl group substituted with R 7-5c , the 5- to 10-membered heteroaryl group is preferably "a heteroatom selected from one or more of N, O or S A 5-6 membered heteroaryl group having 1 to 3 heteroatoms, more preferably a pyrazolyl group.
- certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes):
- R 7-5 is 3-
- the 3-8-membered cycloalkyl group is preferably a 3-6-membered cycloalkyl group, and more preferably a cyclopropyl group.
- certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when R 7-6 , R 7 When -7 , R 7-5a and R 7-5b and R 7-5c are independently C 1 -C 6 alkyl, the C 1 -C 6 alkyl is preferably C 1 -C 4 alkyl (for example methyl , Ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), more preferably methyl.
- certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when R 8 is alkyl,
- the alkyl group is preferably a C 1 -C 6 alkyl group, and more preferably a C 1 -C 4 alkyl group (for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or Tert-butyl), more preferably methyl.
- certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes):
- the halogen is preferably fluorine.
- certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes):
- R 8 when the alkyl group is substituted with one or more halogens, the number of said halogens is preferably 1, 2 or 3, and more preferably 3.
- certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when R 9 and R 10 are independently When it is C 1 -C 6 alkylene-NR 8-1 R 8-2 , the C 1 -C 6 alkylene is preferably C 1 -C 4 alkylene, and more preferably methylene.
- certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when R 8-1 and R 8 When -2 is independently C 1 -C 6 alkyl, the C 1 -C 6 alkyl is preferably C 1 -C 4 alkyl (for example, methyl, ethyl, propyl, isopropyl, n-butyl , Isobutyl, sec-butyl or tert-butyl), more preferably methyl.
- R 1 and R 2 are independently selected From fluorine or chlorine.
- R 3 and R 4 are independently selected Self-fluorine or methoxy, preferably methoxy.
- certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): Y and Z are independently selected from N , -CH-, -C (CH 3 )-, or N or -CH- is preferred.
- certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): M is selected from CH or N.
- R 7 is selected from H, F, Me, CF 3 , H, F, Me,
- R 8 is selected from H, F, Cl, CN, Me or CF 3 , preferably H.
- R 9 and R 10 are independently selected From H, or H is preferred.
- R 1 , R 2 , R 3 and R 4 are independently selected from hydrogen, halogen, or alkoxy;
- R 5 is hydrogen
- Y is N and Z is CR 6 , or Y is CR 6 and Z is N;
- R 6 is selected from hydrogen, alkyl, or alkylene-NR 6-1 R 6-2 ;
- R 6-1 and R 6-2 are independently hydrogen or C 1 -C 6 alkyl;
- M is selected from CR a or N; R a is hydrogen;
- Cy is selected from 3-8 membered heterocycloalkyl, 5-8 membered aryl, or 5-8 membered heteroaryl;
- R 7 is selected from hydrogen, halogen, alkyl, or heterocycloalkyl; one or more hydrogen atoms on any of the above groups is optionally selected from the group consisting of halogen, hydroxy, amino, Cyano, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, carbonyl, 5-8 membered aryl or heteroaryl, 3-8 membered cycloalkyl or 4-8 membered heterocycloalkyl; In the substituent, one or more hydrogen atoms on the amino group, C 1 -C 8 alkyl group, and 4- to 8-membered heterocycloalkyl group are optionally substituted by hydroxyl group, cyano group, C 1 -C 6 Alkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted amino, 5-10 membered heteroaryl, C 1 -C 6 alkyl substituted 5-10 membered heteroaryl, or 3 -8-membered cycloalky
- n is selected from 0-4;
- R 8 , R 9 and R 10 are independently selected from hydrogen, halogen, cyano, alkyl, or alkylene-NR 8-1 R 8-2 ; one or more hydrogen atoms on any of the above groups Optionally substituted with halogen; R 8-1 and R 8-2 are independently hydrogen or C 1 -C 6 alkyl.
- R 1 , R 2 , R 3 and R 4 are independently selected from hydrogen, halogen, or C 1 -C 6 alkoxy;
- R 5 is hydrogen
- Y is N and Z is CR 6 , or Y is CR 6 and Z is N;
- R 6 is selected from hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 alkylene-NR 6-1 R 6-2 ;
- R 6-1 and R 6-2 are independently hydrogen or C 1- C 6 alkyl;
- M is selected from CR a or N; R a is hydrogen;
- Cy is selected from 3-8 membered heterocycloalkyl, 5-8 membered aryl, or 5-8 membered heteroaryl;
- R 7 is selected from hydrogen, halogen, C 1 -C 6 alkyl, or 4-11 membered heterocycloalkyl; said C 1 -C 6 alkyl is optionally selected from 1-3, selected from hydroxyl, halogen, C 1 -C 6 alkoxy, -NR 7-2 R 7-3 , 4-8 membered heterocycloalkyl, or R 7-4 substituted 4-8 membered heterocycloalkyl; R 7-4 is C 1 -C 6 alkyl or C 6 -C 10 aryl; R 7-2 and R 7-3 are independently selected from hydrogen or C 1 -C 6 alkyl; said heterocyclic ring Alkyl is optionally optionally substituted with 1-3 C 1 -C 6 alkyl, R 7-5 substituted C 1 -C 6 alkyl, -NR 7-6 R 7-7 , carbonyl, 3- 8-member ring group, or a 4-8 membered heterocycloalkyl substituents; wherein, R 7- 5 selected from hydroxy
- n is selected from 0-4;
- R 8 , R 9 and R 10 are independently selected from hydrogen, halogen, cyano, C 1 -C 6 alkyl, or C 1 -C 6 alkylene-NR 8-1 R 8-2 ; any of the above One or more hydrogen atoms on the group are optionally substituted with halogen; R 8-1 and R 8-2 are independently hydrogen or C 1 -C 6 alkyl.
- R 1 and R 2 are independently selected from halogen, or C 1 -C 6 alkoxy;
- R 3 and R 4 are independently selected from halogen, or C 1 -C 6 alkoxy
- R 5 is hydrogen
- Y is N, Z is CH, or Y is CH and Z is N;
- M is selected from CH or N;
- Cy is selected from 3-8 membered heterocycloalkyl, 5-8 membered aryl, or 5-8 membered heteroaryl;
- R 7 is selected from hydrogen, halogen, C 1 -C 6 alkyl, or 4-11 membered heterocycloalkyl; said 4-11 membered heterocycloalkyl is independently optionally selected from 1-3 C 1- C 6 alkyl, R 7-5 substituted C 1 -C 6 alkyl, -NR 7-6 R 7-7 , carbonyl, or a 4- to 8-membered heterocycloalkyl substituent; wherein, R 7-5 is a 3-8 membered cycloalkyl; R 7-6 and R 7-7 are independently C 1 -C 6 alkyl;
- n is selected from 0, 1 or 2;
- R 8 is selected from hydrogen, halogen, cyano, or C 1 -C 6 alkyl; said C 1 -C 6 alkyl is optionally substituted with 1-3 halogens;
- R 9 and R 10 are independently selected from hydrogen, or C 1 -C 6 alkylene-NR 8-1 R 8-2 ; R 8-1 and R 8-2 are independently C 1 -C 6 alkyl.
- R 1 and R 2 are independently halogen
- R 3 and R 4 are independently C 1 -C 6 alkoxy
- R 5 is hydrogen
- Y is N, Z is CH, or Y is CH and Z is N;
- M is selected from CH or N;
- Cy is selected from 3-8 membered heterocycloalkyl, 5-8 membered aryl, or 5-8 membered heteroaryl;
- R 7 is selected from hydrogen, halogen, C 1 -C 6 alkyl, or 4-11 membered heterocycloalkyl; said 4-11 membered heterocycloalkyl is independently optionally selected from 1-3 C 1- C 6 alkyl, R 7-5 substituted C 1 -C 6 alkyl, -NR 7-6 R 7-7 , carbonyl, or a 4- to 8-membered heterocycloalkyl substituent; wherein, R 7-5 is a 3-8 membered cycloalkyl; R 7-6 and R 7-7 are independently C 1 -C 6 alkyl;
- n is selected from 0, 1 or 2;
- R 8 is selected from hydrogen, halogen, cyano, or C 1 -C 6 alkyl; said C 1 -C 6 alkyl is optionally substituted with 1-3 halogens;
- R 9 and R 10 are hydrogen.
- R 1 and R 2 are independently halogen
- R 3 and R 4 are independently C 1 -C 6 alkoxy
- R 5 is hydrogen
- Y is N, Z is CH, or Y is CH and Z is N;
- M is selected from CH or N;
- Cy is selected from a 5-8 membered aryl group, or a 5-8 membered heteroaryl group;
- R 7 is selected from hydrogen, C 1 -C 6 alkyl, or 4-11 membered heterocycloalkyl; said 4-11 membered heterocycloalkyl is independently optionally selected from 1-3 selected from C 1- C 6 alkyl, R 7-5 substituted C 1 -C 6 alkyl, -NR 7-6 R 7-7 , carbonyl, or a 4- to 8-membered heterocycloalkyl substituent; wherein R 7 -5 is a 3-8 membered cycloalkyl group; R 7-6 and R 7-7 are independently C 1 -C 6 alkyl;
- n is selected from 0, 1 or 2;
- R 8 is selected from hydrogen, halogen, or C 1 -C 6 alkyl
- R 9 and R 10 are hydrogen.
- R 1 and R 2 are independently halogen
- R 3 and R 4 are independently C 1 -C 6 alkoxy
- R 5 is hydrogen
- Y is N, Z is CH, or Y is CH and Z is N;
- M is selected from CH or N;
- Cy is a 5-8 membered aryl group
- R 7 is selected from hydrogen, or a 4-11 membered heterocycloalkyl group; the 4-11 membered heterocycloalkyl group is independently optionally substituted with 1-3 C 1 -C 6 alkyl groups;
- n is selected from 0, 1 or 2;
- R 8 is hydrogen
- R 9 and R 10 are hydrogen.
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , Cy, M, and n are as defined above.
- the compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer Body, solvate, polymorph or prodrug, wherein the compound represented by formula (I) may be any one of the following compounds:
- the invention also provides a method for preparing a compound represented by formula (I), which comprises steps a-d:
- the reducing agent is a metal reducing agent hydrogen or sodium thiosulfate
- LG represents a leaving group conventionally used in such reactions in the art, such as halogen, sulfone, sulfoxide, sulfonate and the like, and the definitions of other groups are as described above.
- step a) the conditions and operations of step a) are the same as those in the literature.
- the steps a), b), c), and d) are each performed in a solvent, and each of the solvents is independently selected from water, methanol, ethanol, isopropanol, butanol, ethylene glycol, and ethyl acetate.
- the transition metal catalyst is selected from tris (dibenzylideneacetone) dipalladium (Pd 2 (dba) 3 ), tetrakis (triphenylphosphine) palladium (Pd (PPh 3 ) 4 ), palladium acetate, chlorine Palladium, dichlorobis (triphenylphosphine) palladium, palladium trifluoroacetate, palladium triphenylphosphine acetate, [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride, bis One or more of (tri-o-phenylmethylphosphine) palladium dichloride and 1,2-bis (diphenylphosphino) ethane palladium dichloride; the ligand of the transition metal catalyst is selected from tris One or more of tert-butylphosphine, tri-tert-butylphosphine tetrafluoroborate
- the condensation reagent is selected from one or more of DCC, DIC, CDI, EDCI, HOAt, HOBt, BOP, PyBOP, HATU and TBTU.
- the inorganic base is selected from the group consisting of sodium hydride, potassium hydroxide, sodium acetate, potassium acetate, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, potassium carbonate, potassium bicarbonate, One or more of sodium carbonate and sodium bicarbonate;
- the organic base is selected from the group consisting of pyridine, triethylamine, N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0 ]
- DBU undecyl-7-ene
- the acid is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, formic acid, acetic acid, and trifluoromethanesulfonic acid.
- the reducing agent is selected from one or more of iron powder, zinc powder, stannous chloride, sodium thiosulfate, sodium sulfite, and hydrogen.
- the invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer Body, solvate, polymorph or prodrug, and a pharmaceutically acceptable carrier.
- the compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or A prodrug may be a therapeutically effective amount.
- the pharmaceutical composition is preferably a pharmaceutical composition for treating tumors, which is composed of a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, Tautomers, solvates, polymorphs or prodrugs, and a pharmaceutically acceptable carrier.
- a pharmaceutical composition for treating tumors which is composed of a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, Tautomers, solvates, polymorphs or prodrugs, and a pharmaceutically acceptable carrier.
- the invention also provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, poly
- the medicament is preferably a medicament for preventing and / or treating tumors, or a medicament for diseases related to FGFR kinase.
- the tumors include, but are not limited to, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, gastric cancer, colon cancer, bile duct cancer, brain cancer, and leukemia.
- the FGFR kinase is preferably FGFR1 and / or FGFR4, and more preferably FGFR4.
- the invention also provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, poly Use of a crystalline form or a prodrug, or the above pharmaceutical composition in the preparation of an FGFR kinase inhibitor.
- the FGFR kinase is preferably FGFR1 and / or FGFR4, and more preferably FGFR4.
- the present invention also provides a method for preventing and / or treating a tumor, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or Enantiomers, diastereomers, tautomers, solvates, polymorphs or prodrugs, or pharmaceutical compositions described above.
- a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or Enantiomers, diastereomers, tautomers, solvates, polymorphs or prodrugs, or pharmaceutical compositions described above.
- the manufacturer's instructions for use of the kit can be used, or the reaction and purification can be performed in a manner known in the art or as described in the present invention.
- the techniques and methods described above can generally be implemented according to conventional methods well known in the art, based on descriptions in several summary and more specific references that are cited and discussed in this specification. In this specification, groups and their substituents can be selected by those skilled in the art to provide stable moieties and compounds.
- substituent When a substituent is described by a general chemical formula written from left to right, the substituent also includes a chemically equivalent substituent obtained when the structural formula is written from right to left.
- substituent -CH2O- is equivalent to -OCH2-.
- C1-6 alkyl refers to an alkyl group, as defined below, having a total of 1 to 6 carbon atoms.
- the total number of carbon atoms in the simplified symbol does not include carbons that may be present in the substituents of the group.
- halogen refers to fluorine, chlorine, bromine or iodine
- hydroxy refers to the -OH group
- hydroxyalkyl refers to an alkane group as defined below substituted with a hydroxyl group (-OH)
- nitro refers to -NO 2
- cyano refers to -CN
- amino refers to -NH 2
- substituted amino Means an amino group substituted with one or two alkyl, alkylcarbonyl, aralkyl, and heteroaralkyl groups as defined below, for example, monoalkylamino, dialkylamino, alkylamido, arane Amino, heteroaralkylamino
- carbboxy means -COOH.
- alkyl means only composed of carbon atoms and hydrogen atoms, and no unsaturated A straight or branched hydrocarbon chain group having a bond, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms and connected to the rest of the molecule through a single bond.
- alkyl examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2 , 2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl and decyl.
- alkenyl means composed of only carbon atoms and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10) (More preferably 2 to 6) carbon atoms and a straight or branched hydrocarbon chain group connected to the rest of the molecule through a single bond, such as, but not limited to, vinyl, propenyl, allyl, butane- 1-alkenyl, but-2-enyl, pent-1-enyl, pent-1,4-dienyl and the like.
- alkynyl means composed of only carbon and hydrogen atoms, containing at least one triple bond and optionally one or more double bonds, having, for example, A straight or branched hydrocarbon chain group of 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms connected to the rest of the molecule by a single bond, such as, but not limited to, ethynyl , Prop-1-ynyl, but-1-ynyl, pent-1-en-4-ynyl, and the like.
- cycloalkyl means a stable non-aromatic monocyclic or polycyclic hydrocarbon group composed of only carbon atoms and hydrogen atoms, which may include fused Ring system, bridged ring system or spiro ring system, having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms, and which are saturated or unsaturated and may pass through any suitable The carbon atom is connected to the rest of the molecule by a single bond. Unless specifically stated otherwise in this specification, carbon atoms in a cycloalkyl group may be optionally oxidized.
- cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H- Indenyl, 2,3-dihydroindenyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzene Acylcycloheptene-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctenyl , Fluorenyl, bicyclo [2.2.1] heptyl, 7,7-dimethyl-bicyclo [
- heterocyclyl also means “heterocycloalkyl”, which means from 2 to 14 carbon atoms and 1 to 6 selected from nitrogen and phosphorus A stable 3- to 20-membered non-aromatic cyclic group consisting of heteroatoms of oxygen, oxygen and sulfur.
- a heterocyclic group may be a monocyclic, bicyclic, tricyclic, or more cyclic ring system, which may include a fused ring system, a bridged ring system, or a spiro ring system; Nitrogen, carbon or sulfur atoms may be optionally oxidized; nitrogen atoms may be optionally quaternized; and heterocyclic groups may be partially or fully saturated. Heterocyclyl can be attached to the rest of the molecule via a carbon atom or a heteroatom and via a single bond.
- one or more rings may be an aryl or heteroaryl group as defined below, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom.
- the heterocyclic group is preferably a stable 4- to 11-membered non-aromatic monocyclic, bicyclic, bridged, or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur.
- the group is more preferably a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged, or spiro ring group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur.
- heterocyclic groups include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro [3.5] non Alk-7-yl, 2-oxa-6-aza-spiro [3.3] heptane-6-yl, 2,5-diaza-bicyclo [2.2.1] heptane-2-yl, aza Cyclobutyl, pyranyl, tetrahydropyranyl, thioranyl, tetrahydrofuranyl, oxazinyl, dioxocyclopentyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, Imidazolidinyl, quinazinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl,
- aryl means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms, preferably 6 to 10 carbon atoms.
- the aryl group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and may also be fused with a cycloalkyl or heterocyclic group as defined above, provided that the aryl group is via The atoms on the aromatic ring are connected to the rest of the molecule by a single bond.
- aryl examples include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthryl, fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4-benzoxazin-3 (4H) -one-7-yl and the like.
- arylalkyl refers to an alkyl group, as defined above, substituted with an aryl group, as defined above.
- heteroaryl means having 1 to 15 carbon atoms in the ring (preferably having 1 to 10 carbon atoms) and 1 to 6 selected from nitrogen A 5- to 16-membered conjugated ring system group of a heteroatom of oxygen, oxygen, sulfur, and phosphorus.
- a heteroaryl group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and may be fused with a cycloalkyl or heterocyclic group as defined above, provided that the The aryl group is connected to the rest of the molecule via a single bond via an atom on the aromatic ring.
- the nitrogen, oxygen, sulfur, and phosphorus atoms in the heteroaryl group can be optionally oxidized; the nitrogen atoms can be optionally quaternized.
- the heteroaryl group is preferably a stable 5- to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur, and more preferably 1 to 4 members.
- heteroaryl examples include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, Benzimidazolyl, benpyrazolyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indazinyl, isoindolyl, indazolyl, isoindazolyl , Purinyl, quinolinyl, isoquinolinyl, diazonaphthyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthroline, phenanthroline, acridine Base, phenazin
- heteroarylalkyl refers to an alkyl group, as defined above, substituted with a heteroaryl group, as defined above.
- optionally or “optionally” means that the event or condition described later may or may not occur, and the description includes both the occurrence or non-occurrence of the event or condition.
- optionally substituted aryl means that the aryl group is substituted or unsubstituted, and the description includes both a substituted aryl group and an unsubstituted aryl group.
- portion refers to a specific fragment or functional group in a molecule.
- a chemical moiety is generally considered to be a chemical entity that is embedded or attached to a molecule.
- a “stereoisomer” refers to a compound that is composed of the same atom and is bonded through the same bond, but has a different three-dimensional structure.
- the invention will cover various stereoisomers and mixtures thereof.
- the compound of the present invention contains an olefinic double bond, unless otherwise stated, the compound of the present invention is intended to include E- and Z-geometric isomers.
- Tautomers refers to isomers formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the invention will also be included within the scope of the invention.
- the compounds of the invention may contain one or more chiral carbon atoms, and may thus give rise to enantiomers, diastereomers and other stereoisomeric forms.
- Each chiral carbon atom can be defined as (R)-or (S)-based on stereochemistry.
- the invention is intended to include all possible isomers, as well as their racemates and optically pure forms.
- the compounds of the present invention can be prepared as racemates, diastereomers or enantiomers as raw materials or intermediates.
- Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.
- pharmaceutically acceptable salt includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
- “Pharmaceutically acceptable acid addition salt” refers to a salt formed with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects.
- Inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc .
- organic acid salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate , Trifluoroacetate, propionate, hexanoate, caprylate, caprate, undecylenate, glycolate, gluconate, lactate, sebacate, adipate Salt, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate , Cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, mesylate, benzenesul
- “Pharmaceutically acceptable base addition salt” refers to a salt formed with an inorganic or organic base capable of maintaining the biological effectiveness of the free acid without other side effects.
- Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
- Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts.
- Salts derived from organic bases include, but are not limited to, the following salts: primary, secondary, and tertiary amines, substituted amines, including natural substituted amines, cyclic amines, and basic ion exchange resins , Such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, bicyclic Hexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperazine Pyridine, N-ethylpiperidine, polyamine resin and the like.
- Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine
- Polymorph refers to different solid crystalline phases produced by certain compounds of the present invention due to the presence of two or more different molecular arrangements in the solid state. Certain compounds of the invention may exist in more than one crystalline form, and the invention is intended to include various crystalline forms and mixtures thereof.
- solvate refers to an aggregate comprising one or more molecules of a compound of the present invention and one or more solvent molecules.
- the solvent may be water, and the solvate in this case is a hydrate.
- the solvent may be an organic solvent.
- the compounds of the present invention may exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, and the like, as well as the corresponding solvated forms.
- the compounds of the present invention can form true solvates, but in some cases it is also possible to keep only the water or a mixture of water plus a portion of the solvent.
- the compounds of the present invention can be reacted in a solvent or precipitated or crystallized from the solvent. Solvates of the compounds of the invention are also included within the scope of the invention.
- the invention also includes prodrugs of the aforementioned compounds.
- prodrug means a compound that can be converted into a biologically active compound of the present invention under physiological conditions or by solvolysis. Accordingly, the term “prodrug” refers to a pharmaceutically acceptable metabolic precursor of a compound of the invention.
- the prodrug When administered to an individual in need, the prodrug may not be active, but is transformed in vivo into the active compound of the invention.
- Prodrugs are usually rapidly transformed in vivo to produce the parent compound of the invention, for example, by hydrolysis in blood.
- Prodrug compounds generally provide the advantages of solubility, histocompatibility, or sustained release in mammalian organisms.
- Prodrugs include known amino protecting groups and carboxy protecting groups.
- prodrug preparation methods can refer to Saulnier, M.G., et al., Bioorg. Med. Chem. Lett. 1994, 4, 1985-1990; Greenwald, R.B., et al., J. Med. Chem. 2000, 43, 475.
- pharmaceutical composition refers to a formulation of a compound of the present invention and a medium generally accepted in the art for delivering a biologically active compound to a mammal (eg, a human).
- the medium includes a pharmaceutically acceptable carrier.
- the purpose of the pharmaceutical composition is to promote the administration of the organism, which is beneficial to the absorption of the active ingredient and then exerts the biological activity.
- the term "pharmaceutically acceptable” refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention, and is relatively non-toxic, i.e., the substance can be administered to an individual without causing undesirable organisms. React or interact in an undesirable manner with any of the components contained in the composition.
- pharmaceutically acceptable carrier includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener approved by the relevant government authority as acceptable for human or livestock use. , Diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.
- tumor and abnormal cell proliferation-related diseases include, but are not limited to, leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, lung squamous cell carcinoma, Lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cancer, cervical cancer, ovarian cancer, bowel cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, kidney cancer, oral cancer, etc. disease.
- prevention include enabling a patient to reduce the likelihood of the occurrence or worsening of a disease or disorder.
- treatment and other similar synonyms as used herein include the following meanings:
- an "effective amount” for use in therapy is an amount of a composition comprising a compound disclosed herein that is required to provide a significant clinically alleviating effect on a condition.
- An effective amount suitable for any individual case can be determined using techniques such as a dose escalation test.
- the terms "taking,” “administering,” “administering,” and the like refer to a method capable of delivering a compound or composition to a desired site for a biological effect. These methods include, but are not limited to, the oral route, the duodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration and rectal administration.
- parenteral injection including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion
- topical administration topical administration and rectal administration.
- Those skilled in the art are familiar with the application techniques that can be used for the compounds and methods described herein, such as in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current. The ones discussed in Easton, Pa.
- the compounds and compositions discussed herein are administered orally.
- the terms “pharmaceutical combination”, “drug combination”, “combination”, “administration of other treatments”, “administration of other therapeutic agents”, etc. refer to a drug treatment obtained by mixing or combining more than one active ingredient, It includes fixed and non-fixed combinations of active ingredients.
- the term “fixed combination” refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient in the form of a single entity or a single dosage form.
- the term “unfixed combination” refers to the simultaneous, combined, or sequential administration of at least one compound described herein and at least one synergistic formulation to a patient in the form of separate entities. These also apply to cocktail therapies, for example the administration of three or more active ingredients.
- the intermediate compound functional group may need to be protected by a suitable protecting group.
- suitable protecting groups include trialkylsilyl or diarylalkylsilyl (e.g. tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , Tetrahydropyranyl, benzyl and the like.
- Suitable protecting groups for amino, fluorenyl and guanidino include tert-butoxycarbonyl, benzyloxycarbonyl and the like.
- Suitable thiol protecting groups include -C (O) -R "(where R” is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like.
- Suitable carboxy protecting groups include alkyl, aryl or aralkyl esters.
- Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is detailed in Greene, T.W. and P.G.M.Wuts, Protective Groups in Synthesis, (1999), 4th Ed., Wiley.
- the protective group may also be a polymer resin.
- the reagents and raw materials used in the present invention are all commercially available.
- the positive progress effect of the present invention lies in that the fused ring triazole compound of the present invention is a novel specific irreversible inhibitor of FGFR kinase, has good target selectivity, and can be used for treating tumors.
- the present inventors prepared a class of compounds having a novel structure represented by Formula I, and found that they have good FGFR kinase inhibitory activity, and the compounds are at extremely low concentrations (can be as low as ⁇ Under 10nmol / L), it has specific and irreversible inhibitory effect on FGFR kinase, and its inhibitory activity is quite excellent, so it can be used to treat related diseases such as tumors caused by FGFR kinase mutation or abnormal expression. Based on the above findings, the inventors have completed the present invention.
- Step 1 Add 1,3-dimethoxy-5-methylbenzene (30g, 0.20mol) and dichloromethane (900mL) to a dry round bottom flask (1L), and add the solution to the above solution under ice-cooling. Dichlorosulfone (52.5 g, 0.40 mol) was added dropwise. After the dropwise addition was completed, the mixture was stirred at room temperature overnight.
- Step 2 Dissolve 2,4-dichloro-1,5-dimethoxy-3-methylbenzene (31g, 0.14mol) in CCl 4 (600mL) and place in a dry round bottom flask (1000mL) At room temperature, azobisisobutylcyanide (3.0 g, 0.018 mol) and NBS (27.6 g, 0.154 mol) were sequentially added at room temperature. The reaction was carried out at 80 degrees for 3 hours. The reaction was quenched by adding NaHCO 3 aqueous solution, and then extracted with dichloromethane. The organic phase was dried, concentrated, and methyl tert-butyl ether was crystallized to obtain the compound 3-bromomethyl-2,4-dichloro-1. , 5-dimethoxybenzene (30 g, white solid).
- Step 3 Add the compound 3-bromomethyl-2,4-dichloro-1,5-dimethoxybenzene (30g, 0.1mol) and acetonitrile (500mL) to a dry 1000mL round bottom flask at room temperature. Trimethylsilyl cyanide (12 g, 0.34 mmol) and tetrabutylammonium fluoride (100 mL, 1 mol / L) were added. After stirring at room temperature for 1 h, TLC showed the reaction was over. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, and the organic phase was washed with water and saturated brine, dried and concentrated. The concentrate was slurried with ethyl acetate to obtain the compound (2,6-dichloro-3,5-dimethoxy-benzene). ) -Acetonitrile (20 g, white solid).
- Step 4 In a dry 250mL round bottom flask, add (2,6-dichloro-3,5-dimethoxy-phenyl) -acetonitrile (10.4g, 0.028mol) and DMF (100mL) at room temperature. Next, 4-amino-2-methylthio-pyrimidine-5-carbaldehyde (5 g, 0.02 mol) and potassium carbonate (12.25 g, 0.06 mol) were sequentially added, and the reaction was stirred overnight until the reaction was completed. The reaction solution was extracted with ethyl acetate, the organic phase was washed with distilled water and saturated brine, dried and filtered, and concentrated under reduced pressure.
- Step 1 Dissolve 4- (4-methyl-piperazin-1-yl) -aniline (5g) and triethylamine (5g) in dry ethyl acetate (20mL). Add acetic anhydride (5 mL). After the dropwise addition, the reaction was carried out at room temperature for 3 hours. A solid was precipitated in the reaction solution, filtered under reduced pressure, washed with ethyl acetate, and dried to obtain N- [4- (4-methyl-piperazin-1-yl) -phenyl] -acetamide as a solid (4 g).
- LC-MS: ESI [M + H] + 234.3.
- Step 3 Dissolve N- [4- (4-methyl-piperazin-1-yl) -2-nitro-phenyl] -acetamide (2.5g) in methanol (10mL), and add 4N hydrochloric acid The solution (10 mL) was heated at reflux for 1 hour. After the reaction, the reaction solution was diluted with water, and the pH was adjusted to 8-9 with ammonia water under ice-cooling, extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 4- (4-methyl- Piperazin-1-yl) -2-nitro-aniline.
- LC-MS: ESI [M + H] + 237.2.
- Step 1 6- (2,6-dichloro-3,5-dimethoxy-phenyl) -2-methylthio-pyrido [2,3-d] pyrimidin-7-ylamine ( 4g, 10mmol) was dissolved in methanol (300mL), N, N-dimethylformamide dimethyl acetal (2.4g, 20mmol) was added, the temperature was raised to 80 ° C, stirred overnight, concentrated under reduced pressure, ethyl acetate Purified and purified, filtered and dried to obtain compound N '-(6- (2,6-dichloro-3,5-dimethoxy-phenyl) -2- (methylthio) pyridine [2,3-d] pyrimidine -7-yl) -N, N-dimethylformimide (3.6 g, yellow solid) was used directly in the next reaction.
- LC-MS: ESI [M + H] + 452.1.
- N '-(6- (2,6-dichloro-3,5-dimethoxy-phenyl) -2- (methylthio) pyridine [2,3-d] pyrimidine-7 -Yl) -N, N-dimethylformimide (2.3g, 5mmol) was dissolved in methanol (50mL), and pyridine (0.8g, 10mmol) and hydroxylammonium hydrochloride (417mg, 6mmol) were sequentially added at room temperature. And stirred at room temperature overnight. The reaction was monitored by LCMS and the reaction was concentrated under reduced pressure.
- the third step 4- (2,6-dichloro-3,5-dimethoxy-phenyl) -8- (methylthio)-[1,2,4] triazol [1 ', 5 ': 1,6] pyridine
- pyrimidine 1.1g, 2.6mmol
- chloroform 100mL
- m-CPBA 1.6g, 7.8mmol
- the reaction solution was washed successively with a saturated sodium bicarbonate solution and water, extracted with dichloromethane, dried over anhydrous sodium sulfate, and filtered to obtain the compound 4- (2,6-dichloro-3,5-dimethoxy-phenyl).
- the third step 6- (2,6-dichloro-3,5-dimethoxyphenyl) -2- (methylthio)-[1,2,4] triazolo [4 ', 3 ': 1,6] pyrido [2,3-d] pyrimidine (1.1 g, 2.6 mmol) was dissolved in chloroform (100 mL), m-CPBA (1.6 g, 7.8 mmol) was added, and the reaction was performed at room temperature for 3 h.
- Step 1 Add triethylamine (2.5mL, 17.3mmol) to 1-methyl-4-nitro-1H-pyrazole-3-carboxylic acid (1.6g, 8.64mmol) and DMF under cooling in an ice bath. (15 mL) and tert-butanol (5 mL), DPPA (3.6 g, 12.97 mmol) was then added, and the reaction solution was heated to 80 ° C. and stirred for 4 h. After completion of the reaction, some solvents were removed under reduced pressure and diluted with ethyl acetate.
- the nitro compound (1 eq.) was dissolved in methanol, and a saturated sodium thiosulfate solution (2 eq.) And a sodium carbonate solution (2 eq.) Were added, followed by stirring at room temperature overnight. After completion of the reaction, ethyl acetate was added for extraction, and the mixture was washed with saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and recrystallized from ethyl acetate to obtain an amino intermediate.
- Test method (1) Prepare 1 ⁇ Kinase buffer. (2) Formulation of compound concentration gradient: the test compound test concentration is 10uM starting, 3 times diluted 10 concentrations, duplicate well test, 10 different concentrations of 100 times final concentration in 96-well plate. Compounds of each concentration were then further diluted with a 1 ⁇ Kinase buffer to a 5x final concentration intermediate dilution solution. (3) 5 ⁇ L of the prepared compound solution was added to the compound wells of the 384-well plate, and each concentration was tested in a single well; 5 ⁇ L of 5% DMSO was added to the negative control well and the positive control well. (4) A 2.5-fold final concentration of the kinase solution was prepared with 1 ⁇ Kinase buffer.
- Inhibition rate (%) (OD negative control well-OD administration well) / OD negative control well x 100%. Analysis of the results. The IC 50 value was obtained by a four-parameter regression method using the software provided with the microplate reader.
- the majority of embodiments of the present invention provides inhibitory activity IC 50 value is less than the FGFR4 100nM, most of the inhibitory activity of IC 50 of the embodiment is less than 20nM, the inhibitory activity of some embodiments even less than 1nM, show a more Strong enzyme inhibitory activity; and FGFR1 inhibitory activity is weak, the IC 50 of FGFR1 inhibitory activity of most of the compounds of the examples is greater than 20 nM, and some examples are even greater than 1000 nM, showing a higher selectivity of kinase subtypes.
- Table 1 The specific results are shown in Table 1.
- Table 1 FGFR kinase inhibitory activity of some example compounds
- Table 2 Comparison of kinase activity and selectivity of some example compounds and comparative compounds.
- Test Example 2 Effect of the Example of the Invention on FGFR-Mediated Tumor Cell Proliferation Ability
- Test method Hep3B cells (ATCC) in logarithmic growth phase were seeded into a 96-well culture plate at an appropriate density, 100 ⁇ L per well. After overnight culture, compounds of different concentrations were added for 72 hours, and a solvent control group was set. (Negative control). Incubate at 37 ° C under 5% CO2. 10 mM compound stock solution was added to the cells, and the effect of the compounds on cell proliferation was 72 hours after the compounds were applied to the cells. (Promega) method, add 30 ⁇ L of CTG reagent to each well, place in a 37 degree incubator for 2-4 hours, read with a full-wavelength microplate microplate reader, Envision, and measure the wavelength at 450 nm.
- inhibition rate (%) (OD negative control well-OD administration well) / OD negative control well x 100%.
- IC 50 value was obtained by Graphpad Prism 5 software with four-parameter regression.
- results Some of the examples 1 to 50 provided by the present invention have inhibitory activity on Hep3B cells.
- the IC 50 values are all less than 500 nM.
- the inhibitory activity IC 50 values of some compound compounds are even less than 100 nM.
- Cell proliferation inhibitory activity The specific results are shown in Table 3:
- Table 3 Inhibitory activity of some example compounds on Hep3B cell proliferation.
- Test Example 3 Tests of Example Compounds Not Different in Kinase Inhibition Activity
- the compounds of the present invention have different kinases such as EGFR, VEGFR, PDGFR, FGFR1-3, RET, MET, Src, Lyn, Syk, MEK, CDK, RAF, ROS, FGFR1, FGFR2, FGFR3, FGFR gated mutants V550L, CSF1R, etc. Inhibitory activity was also tested, and some of the compounds of Examples, such as Example 3, Example 7, Example 11, Example 35, Example 47, etc., showed good FGFR4 kinase selectivity (IC 50 ⁇ 5nM).
- VEGFR, FGFR3, CDK and other kinases (IC 50 > 500nM) are more than 100 times more selective; while for FGFR1, FGFR2, CSF1R, FGFR4 gated mutant kinases (20nM ⁇ IC 50 ⁇ 400nM) and other selectivity are 10-100 times; in contrast, some embodiments exhibits a higher FGFR1, FGFR2 inhibitory activity (IC 50 ⁇ 50nM), its FGFR4 kinase (IC 50> 1000 nM selectivity) is greater than 100 times, as described in Example 43.
- Test Example 4 Test of the compound of the Example for inhibiting the proliferation of different tumor cells
- SRB staining method or CCK8 method or CTG method to test a variety of tumor cells such as BaF3-FGFR4, BaF3-FGFR V550L, HuH-7, JHH-7, MDA-MB-453, DMS114, SNU-16, KG1, UM -UC-14, HCT116, NCI-H716, MCF-7, KATOIII, Colo-205, KMS11, H1581, RT-112, RT-4, OPM-2, NCI-H460, SNU-869, SNU878, CNE, NCI -H2122, NCI-H1299, A204, A427, A549, MG63, Kappars-299, SK-OV-3, U87MG, BT474, LNCAP, A498, KYSE140, HUCC-T1, PANC-1, etc., partial implementation Exemplary compounds such as Example 3, Example 4, Example 7, Example 11, Example 32, Example 34, etc., showed a strong inhibitory activity on the inhibition of the increase in value of different cells, showing
- Metabolic stability test 150 microliters of liver microsomes (final concentration 0.5mg / mL) were used for metabolic stability incubation.
- the system contains NADPH (final concentration 1mM), 1 ⁇ M test compound and positive control midazole.
- negative control atenolol the reaction was stopped with tinidazole-containing acetonitrile at 0min, 5min, 10min, and 30min, vortexed for 10min, centrifuged at 15000rmp for 10min, and 50 ⁇ L of the supernatant was injected in a 96-well plate.
- the compound's metabolic stability was calculated by measuring the relative decrease of the original drug.
- DI test Direct inhibition test: 100 ⁇ L of human liver microsomes (final concentration 0.2 mg / mL) were used for direct inhibition incubation. The system contained NADPH (final concentration 1 mM), 10 ⁇ M compound, and positive inhibitor cocktail.
- Example 3 Some example compounds such as Example 3, Example 4, Example 5, Example 32, etc. have high metabolic stability to microsomes, T 1/2 is greater than 30 min, has no direct inhibitory effect on major metabolic enzymes, and IC 50 is greater than 20uM, showing a good drugability.
- Test Example 6 Test of Pharmacokinetic Parameters of Compounds of Examples in Rats and Mice in Vivo
- test compounds Six male SPF-grade SD rats (Shanghai Xipuer-Bikai experimental animals) were divided into two groups, and the test compounds were configured into appropriate solutions or suspensions; one group was administered by intravenous injection (1 mg / kg dose), and the other was administered orally Administration (5 mg / kg dose). Blood was collected via jugular vein puncture, and each sample was collected at about 0.2 mL / time point. Heparin sodium was used for anticoagulation.
- the time points for blood collection were as follows: before administration and 5, 15, and 30 minutes after administration, 1, 2, 4, 6, 8, and 24h; After collecting blood samples, place them on ice, centrifuge the plasma (centrifugation conditions: 8000 rpm, 6 minutes, 2-8 ° C), and store the collected plasma at -80 ° C before analysis. Plasma samples were analyzed by LC-MS / MS.
- the pharmacokinetic calculation software WinNonlin5.2 non-compartment model was used to calculate the pharmacokinetic parameters AUC0-t, AUC0- ⁇ , MRT0- ⁇ , Cmax, Tmax, T1 of the test product. Parameters such as / 2 and Vd and their average and standard deviation.
- the bioavailability (F) will be calculated by the following formula.
- Example 3 Some example compounds such as Example 3, Example 4, Example 5, Example 32, etc. were administered by gavage with Cmax greater than 200 nM, AUC greater than 2000 hr * nM, and F% greater than 15%, showing good drug-making properties. .
- Test Example 7 Test of Inhibition of Hep3B Xenograft Tumor Growth in Nude Mice by Compounds of Examples
- the tumor tissue during the vigorous growth period was cut to about 1.5 mm 3 and inoculated subcutaneously in the right armpit of nude mice under sterile conditions.
- Subcutaneously transplanted tumors in nude mice were measured with vernier calipers. The diameter of the transplanted tumors was measured, and the animals were randomly divided into groups until the average tumor volume reached about 130 mm 3 .
- the compound of the example (configured with water for injection containing 1% Tween80 to a desired concentration for use) was orally administered daily at a given dose for three consecutive weeks, and the solvent control group was given the same amount of solvent.
- the diameter of the transplanted tumor was measured twice a week, and the weight of the mice was weighed.
- Example 3 Example 7 and the like were administered orally for 21 days at a dose of 40 mg / kg, with T / C less than 10%, and some experimental animals.
- the tumors in the group subsided.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
L'invention concerne une classe de composés de triazole cycliques fusionnés, un procédé de préparation et une utilisation. L'invention concerne particulièrement un composé de triazole cyclique fusionné tel que représenté par la formule (I), ou son sel pharmaceutiquement acceptable, ou son énantiomère, diastéréoisomère, tautomère, solvate, polymorphe ou promédicament, son procédé de préparation, et une utilisation pharmaceutique de celui-ci. (I)
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201810965291.6 | 2018-08-23 | ||
CN201810965291 | 2018-08-23 | ||
CN201811283207 | 2018-10-31 | ||
CN201811283207.9 | 2018-10-31 | ||
CN201811498192 | 2018-12-07 | ||
CN201811498192.8 | 2018-12-07 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2020038458A1 true WO2020038458A1 (fr) | 2020-02-27 |
Family
ID=69592873
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2019/102214 WO2020038458A1 (fr) | 2018-08-23 | 2019-08-23 | Classe de composé de triazole cyclique fusionné, procédé de préparation et utilisation |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN110857300B (fr) |
WO (1) | WO2020038458A1 (fr) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114907350A (zh) * | 2021-02-10 | 2022-08-16 | 上海凌达生物医药有限公司 | 一类含氮稠环类化合物、制备方法和用途 |
WO2024044713A1 (fr) * | 2022-08-25 | 2024-02-29 | Enliven Inc. | Composés de naphtyridine pour l'inhibition de kinases raf |
EP4130004A4 (fr) * | 2020-03-27 | 2024-04-10 | Betta Pharmaceuticals Co Ltd | Sel et formes cristallines d'inhibiteur de fgfr4 et leurs utilisations |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1646529A (zh) * | 2002-04-03 | 2005-07-27 | 霍夫曼-拉罗奇有限公司 | 咪唑并稠合化合物 |
CN105524048A (zh) * | 2014-08-19 | 2016-04-27 | 上海海和药物研究开发有限公司 | 作为fgfr激酶抑制剂的吲唑类化合物及其制备和应用 |
WO2018004258A1 (fr) * | 2016-06-28 | 2018-01-04 | 한미약품 주식회사 | Nouveau dérivé hétérocyclique et son utilisation |
CN109721600A (zh) * | 2017-10-30 | 2019-05-07 | 如东凌达生物医药科技有限公司 | 一类含氮稠环化合物及其制备方法和用途 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TWI741155B (zh) * | 2017-02-27 | 2021-10-01 | 大陸商貝達藥業股份有限公司 | Fgfr抑制劑及其應用 |
-
2019
- 2019-08-23 WO PCT/CN2019/102214 patent/WO2020038458A1/fr active Application Filing
- 2019-08-23 CN CN201910782471.5A patent/CN110857300B/zh active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1646529A (zh) * | 2002-04-03 | 2005-07-27 | 霍夫曼-拉罗奇有限公司 | 咪唑并稠合化合物 |
CN105524048A (zh) * | 2014-08-19 | 2016-04-27 | 上海海和药物研究开发有限公司 | 作为fgfr激酶抑制剂的吲唑类化合物及其制备和应用 |
WO2018004258A1 (fr) * | 2016-06-28 | 2018-01-04 | 한미약품 주식회사 | Nouveau dérivé hétérocyclique et son utilisation |
CN109721600A (zh) * | 2017-10-30 | 2019-05-07 | 如东凌达生物医药科技有限公司 | 一类含氮稠环化合物及其制备方法和用途 |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP4130004A4 (fr) * | 2020-03-27 | 2024-04-10 | Betta Pharmaceuticals Co Ltd | Sel et formes cristallines d'inhibiteur de fgfr4 et leurs utilisations |
CN114907350A (zh) * | 2021-02-10 | 2022-08-16 | 上海凌达生物医药有限公司 | 一类含氮稠环类化合物、制备方法和用途 |
CN114907350B (zh) * | 2021-02-10 | 2023-12-29 | 上海凌达生物医药有限公司 | 一类含氮稠环类化合物、制备方法和用途 |
WO2024044713A1 (fr) * | 2022-08-25 | 2024-02-29 | Enliven Inc. | Composés de naphtyridine pour l'inhibition de kinases raf |
Also Published As
Publication number | Publication date |
---|---|
CN110857300A (zh) | 2020-03-03 |
CN110857300B (zh) | 2021-11-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN111704611B (zh) | 一类芳基螺环类shp2抑制剂化合物、制备方法和用途 | |
CN111138412B (zh) | 一种螺芳环化合物及其应用 | |
CN112300194B (zh) | 一类稠环吡啶酮类化合物、制备方法和用途 | |
WO2020094104A1 (fr) | Composé inhibiteur de shp2 hétérocyclique fusionné contenant de l'azote, procédé de préparation et utilisation | |
CN109721600B (zh) | 一类含氮稠环化合物及其制备方法和用途 | |
CN109721599B (zh) | 一类氨基取代含氮稠环化合物及其制备方法和用途 | |
WO2020038458A1 (fr) | Classe de composé de triazole cyclique fusionné, procédé de préparation et utilisation | |
CN110950876B (zh) | 一类呋喃并内酰胺类化合物、制备方法和用途 | |
CN113527299B (zh) | 一类含氮稠环类化合物、制备方法和用途 | |
WO2021244659A1 (fr) | Composé cyclique spiro aromatique substitué par un isotope et son application | |
CN112745335A (zh) | 一种三并杂环化合物及其用途 | |
WO2020063976A1 (fr) | Composé d'alcool biaryl-benzylique hétérocyclique condensé, procédé de préparation et utilisation | |
TW201910331A (zh) | 成纖維細胞生長因子受體抑制劑、含有其的藥物製劑及其用途 | |
WO2022135590A1 (fr) | Composés pyrimido-hétérocycliques, et leur procédé de préparation et leur utilisation | |
CN115260187A (zh) | 吡啶酮化合物及其用途 | |
CN112300173B (zh) | 一类含氮多环类化合物、制备方法和用途 | |
WO2022105921A1 (fr) | Composé pyrimido-hétérocyclique, son procédé de préparation et son utilisation | |
WO2021083383A1 (fr) | Composé cyclique fusionné contenant de l'azote en tant que régulateur de sting, son procédé de préparation et son utilisation | |
WO2020187123A1 (fr) | Composé de pyrrole amidopyridone, son procédé de préparation et son utilisation | |
WO2023143147A1 (fr) | Composés de pyridazopyridone, composition pharmaceutique de ceux-ci et leur utilisation | |
WO2022052924A1 (fr) | Procédé de préparation de composés cycliques fusionnés contenant de l'azote et leur utilisation | |
CN115611888A (zh) | 吡啶并嘧啶酮类衍生物及其制备方法和用途 | |
WO2022037691A1 (fr) | Composé lactame à cyclique aromatique, son procédé de préparation et son utilisation | |
CN111763217B (zh) | 一类噻吩并氮杂环类化合物、制备方法和用途 | |
WO2023134374A1 (fr) | Composé pyrimido-hétérocyclique, procédé de préparation et utilisation |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 19851111 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 19851111 Country of ref document: EP Kind code of ref document: A1 |