WO2020020377A1 - 用作fgfr4抑制剂的稠环衍生物 - Google Patents
用作fgfr4抑制剂的稠环衍生物 Download PDFInfo
- Publication number
- WO2020020377A1 WO2020020377A1 PCT/CN2019/098076 CN2019098076W WO2020020377A1 WO 2020020377 A1 WO2020020377 A1 WO 2020020377A1 CN 2019098076 W CN2019098076 W CN 2019098076W WO 2020020377 A1 WO2020020377 A1 WO 2020020377A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- membered
- alkyl
- substituted
- ring
- methyl
- Prior art date
Links
- 229940125408 FGFR4 inhibitor Drugs 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 247
- 150000003839 salts Chemical class 0.000 claims abstract description 77
- 102100027844 Fibroblast growth factor receptor 4 Human genes 0.000 claims abstract description 38
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 34
- 201000010099 disease Diseases 0.000 claims abstract description 33
- 230000000694 effects Effects 0.000 claims abstract description 27
- 230000001404 mediated effect Effects 0.000 claims abstract description 20
- 239000003814 drug Substances 0.000 claims abstract description 15
- 101000917134 Homo sapiens Fibroblast growth factor receptor 4 Proteins 0.000 claims abstract 10
- 125000000217 alkyl group Chemical group 0.000 claims description 331
- 125000001424 substituent group Chemical group 0.000 claims description 292
- 125000003545 alkoxy group Chemical group 0.000 claims description 236
- 125000000623 heterocyclic group Chemical group 0.000 claims description 203
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 184
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 137
- 125000001072 heteroaryl group Chemical group 0.000 claims description 133
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 118
- -1 methoxy, ethoxy, propyl Oxy Chemical class 0.000 claims description 105
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 93
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 91
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 91
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 82
- 125000004122 cyclic group Chemical group 0.000 claims description 78
- 125000003118 aryl group Chemical group 0.000 claims description 74
- 229910052760 oxygen Inorganic materials 0.000 claims description 63
- 229910052739 hydrogen Inorganic materials 0.000 claims description 62
- 229910052805 deuterium Inorganic materials 0.000 claims description 61
- 125000005842 heteroatom Chemical group 0.000 claims description 61
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 claims description 54
- 125000003342 alkenyl group Chemical group 0.000 claims description 49
- 125000005843 halogen group Chemical group 0.000 claims description 44
- 125000000304 alkynyl group Chemical group 0.000 claims description 43
- 206010028980 Neoplasm Diseases 0.000 claims description 42
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 42
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 41
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 41
- 229910052717 sulfur Inorganic materials 0.000 claims description 41
- 229910052799 carbon Inorganic materials 0.000 claims description 38
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 36
- 239000008194 pharmaceutical composition Substances 0.000 claims description 35
- 125000002837 carbocyclic group Chemical group 0.000 claims description 32
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 32
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- 229910052736 halogen Inorganic materials 0.000 claims description 26
- 150000001721 carbon Chemical group 0.000 claims description 25
- 150000002367 halogens Chemical class 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 25
- 125000005110 aryl thio group Chemical group 0.000 claims description 24
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 24
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 24
- 125000004104 aryloxy group Chemical group 0.000 claims description 22
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 22
- 125000005368 heteroarylthio group Chemical group 0.000 claims description 22
- 125000005844 heterocyclyloxy group Chemical group 0.000 claims description 22
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 22
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 21
- 125000004429 atom Chemical group 0.000 claims description 20
- 125000004468 heterocyclylthio group Chemical group 0.000 claims description 20
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 20
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 19
- 201000007270 liver cancer Diseases 0.000 claims description 18
- 208000014018 liver neoplasm Diseases 0.000 claims description 18
- 125000004432 carbon atom Chemical group C* 0.000 claims description 17
- 125000001963 4 membered heterocyclic group Chemical group 0.000 claims description 15
- 201000011510 cancer Diseases 0.000 claims description 15
- 125000004008 6 membered carbocyclic group Chemical group 0.000 claims description 14
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 125000004011 3 membered carbocyclic group Chemical group 0.000 claims description 12
- 125000001845 4 membered carbocyclic group Chemical group 0.000 claims description 12
- 125000001054 5 membered carbocyclic group Chemical group 0.000 claims description 12
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 12
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 12
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 10
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 10
- 125000001627 3 membered heterocyclic group Chemical group 0.000 claims description 10
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 10
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
- 238000011282 treatment Methods 0.000 claims description 9
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 8
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 8
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 8
- 201000005202 lung cancer Diseases 0.000 claims description 8
- 208000020816 lung neoplasm Diseases 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- 206010006187 Breast cancer Diseases 0.000 claims description 7
- 208000026310 Breast neoplasm Diseases 0.000 claims description 7
- 206010009944 Colon cancer Diseases 0.000 claims description 7
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 7
- 206010060862 Prostate cancer Diseases 0.000 claims description 7
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 125000004470 heterocyclooxy group Chemical group 0.000 claims description 7
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical group C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 6
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 claims description 6
- 206010027476 Metastases Diseases 0.000 claims description 6
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 6
- 206010033128 Ovarian cancer Diseases 0.000 claims description 6
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 6
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 201000004101 esophageal cancer Diseases 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 206010017758 gastric cancer Diseases 0.000 claims description 6
- 201000010536 head and neck cancer Diseases 0.000 claims description 6
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 6
- 230000009401 metastasis Effects 0.000 claims description 6
- 125000002757 morpholinyl group Chemical group 0.000 claims description 6
- 125000004193 piperazinyl group Chemical group 0.000 claims description 6
- 201000011549 stomach cancer Diseases 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 6
- 125000003341 7 membered heterocyclic group Chemical group 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 claims description 4
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 claims description 4
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical group C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 4
- WYNCHZVNFNFDNH-UHFFFAOYSA-N Oxazolidine Chemical compound C1COCN1 WYNCHZVNFNFDNH-UHFFFAOYSA-N 0.000 claims description 4
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- IWELDVXSEVIIGI-UHFFFAOYSA-N piperazin-2-one Chemical compound O=C1CNCCN1 IWELDVXSEVIIGI-UHFFFAOYSA-N 0.000 claims description 4
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 claims description 4
- 125000003386 piperidinyl group Chemical group 0.000 claims description 4
- 125000004149 thio group Chemical group *S* 0.000 claims description 4
- 125000005330 8 membered heterocyclic group Chemical group 0.000 claims description 3
- 125000002393 azetidinyl group Chemical group 0.000 claims description 3
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 3
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 3
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 2
- 125000001960 7 membered carbocyclic group Chemical group 0.000 claims description 2
- 125000003627 8 membered carbocyclic group Chemical group 0.000 claims description 2
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 2
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 2
- 150000004885 piperazines Chemical group 0.000 claims description 2
- 201000009410 rhabdomyosarcoma Diseases 0.000 claims 3
- 230000002265 prevention Effects 0.000 claims 2
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 11
- 208000035475 disorder Diseases 0.000 abstract 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 51
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 34
- 239000000203 mixture Substances 0.000 description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 30
- 101710182387 Fibroblast growth factor receptor 4 Proteins 0.000 description 29
- 230000002829 reductive effect Effects 0.000 description 29
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 27
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 27
- 238000002360 preparation method Methods 0.000 description 25
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 23
- 210000004027 cell Anatomy 0.000 description 23
- 239000000543 intermediate Substances 0.000 description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 22
- 239000012071 phase Substances 0.000 description 22
- 239000000243 solution Substances 0.000 description 21
- 239000012074 organic phase Substances 0.000 description 19
- 229920006395 saturated elastomer Polymers 0.000 description 19
- 235000019439 ethyl acetate Nutrition 0.000 description 17
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 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 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 235000019253 formic acid Nutrition 0.000 description 14
- 239000011734 sodium Substances 0.000 description 14
- 239000004480 active ingredient Substances 0.000 description 13
- 238000010898 silica gel chromatography Methods 0.000 description 13
- 239000011780 sodium chloride Substances 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 239000008280 blood Substances 0.000 description 11
- 210000004369 blood Anatomy 0.000 description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 10
- 238000010828 elution Methods 0.000 description 10
- 238000002474 experimental method Methods 0.000 description 10
- 238000002347 injection Methods 0.000 description 10
- 239000007924 injection Substances 0.000 description 10
- 238000005070 sampling Methods 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 229940125904 compound 1 Drugs 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- VUEGYUOUAAVYAS-JGGQBBKZSA-N (6ar,9s,10ar)-9-(dimethylsulfamoylamino)-7-methyl-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline Chemical compound C1=CC([C@H]2C[C@@H](CN(C)[C@@H]2C2)NS(=O)(=O)N(C)C)=C3C2=CNC3=C1 VUEGYUOUAAVYAS-JGGQBBKZSA-N 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 8
- 125000003367 polycyclic group Chemical group 0.000 description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- 229940125810 compound 20 Drugs 0.000 description 7
- 229940125898 compound 5 Drugs 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 6
- 108091008794 FGF receptors Proteins 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 229940126142 compound 16 Drugs 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 231100000252 nontoxic Toxicity 0.000 description 6
- 230000003000 nontoxic effect Effects 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- 125000006413 ring segment Chemical group 0.000 description 6
- 102000044168 Fibroblast Growth Factor Receptor Human genes 0.000 description 5
- 102100031734 Fibroblast growth factor 19 Human genes 0.000 description 5
- 101000846394 Homo sapiens Fibroblast growth factor 19 Proteins 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 238000004113 cell culture Methods 0.000 description 5
- 238000013375 chromatographic separation Methods 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 125000002950 monocyclic group Chemical group 0.000 description 5
- 239000000651 prodrug Substances 0.000 description 5
- 229940002612 prodrug Drugs 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 5
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 125000001589 carboacyl group Chemical group 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 239000006285 cell suspension Substances 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 239000012091 fetal bovine serum Substances 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- 238000004949 mass spectrometry Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 239000012453 solvate Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000001308 synthesis method Methods 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- 229960001722 verapamil Drugs 0.000 description 4
- 239000011701 zinc Substances 0.000 description 4
- IEQAICDLOKRSRL-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-dodecoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO IEQAICDLOKRSRL-UHFFFAOYSA-N 0.000 description 3
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- JQUCWIWWWKZNCS-LESHARBVSA-N C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F Chemical compound C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F JQUCWIWWWKZNCS-LESHARBVSA-N 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 239000007995 HEPES buffer Substances 0.000 description 3
- 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 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 208000005678 Rhabdomyoma Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 3
- ZEEBGORNQSEQBE-UHFFFAOYSA-N [2-(3-phenylphenoxy)-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound C1(=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F)C1=CC=CC=C1 ZEEBGORNQSEQBE-UHFFFAOYSA-N 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 125000002619 bicyclic group Chemical group 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000007853 buffer solution Substances 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 229910002091 carbon monoxide Inorganic materials 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 235000015165 citric acid Nutrition 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 3
- 229960003957 dexamethasone Drugs 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- GWNFQAKCJYEJEW-UHFFFAOYSA-N ethyl 3-[8-[[4-methyl-5-[(3-methyl-4-oxophthalazin-1-yl)methyl]-1,2,4-triazol-3-yl]sulfanyl]octanoylamino]benzoate Chemical compound CCOC(=O)C1=CC(NC(=O)CCCCCCCSC2=NN=C(CC3=NN(C)C(=O)C4=CC=CC=C34)N2C)=CC=C1 GWNFQAKCJYEJEW-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 229910052749 magnesium Inorganic materials 0.000 description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 3
- 239000011976 maleic acid Substances 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 239000011975 tartaric acid Substances 0.000 description 3
- 235000002906 tartaric acid Nutrition 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 2
- ZXGNLASDUYGVFG-SCSAIBSYSA-N (2r)-1-methylsulfanylpropan-2-amine Chemical compound CSC[C@@H](C)N ZXGNLASDUYGVFG-SCSAIBSYSA-N 0.000 description 2
- OOKAZRDERJMRCJ-KOUAFAAESA-N (3r)-7-[(1s,2s,4ar,6s,8s)-2,6-dimethyl-8-[(2s)-2-methylbutanoyl]oxy-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl]-3-hydroxy-5-oxoheptanoic acid Chemical compound C1=C[C@H](C)[C@H](CCC(=O)C[C@@H](O)CC(O)=O)C2[C@@H](OC(=O)[C@@H](C)CC)C[C@@H](C)C[C@@H]21 OOKAZRDERJMRCJ-KOUAFAAESA-N 0.000 description 2
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 2
- 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 2
- KKHFRAFPESRGGD-UHFFFAOYSA-N 1,3-dimethyl-7-[3-(n-methylanilino)propyl]purine-2,6-dione Chemical compound C1=NC=2N(C)C(=O)N(C)C(=O)C=2N1CCCN(C)C1=CC=CC=C1 KKHFRAFPESRGGD-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- 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 2
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- GDUANFXPOZTYKS-UHFFFAOYSA-N 6-bromo-8-[(2,6-difluoro-4-methoxybenzoyl)amino]-4-oxochromene-2-carboxylic acid Chemical compound FC1=CC(OC)=CC(F)=C1C(=O)NC1=CC(Br)=CC2=C1OC(C(O)=O)=CC2=O GDUANFXPOZTYKS-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-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
- 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 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- PKMUHQIDVVOXHQ-HXUWFJFHSA-N C[C@H](C1=CC(C2=CC=C(CNC3CCCC3)S2)=CC=C1)NC(C1=C(C)C=CC(NC2CNC2)=C1)=O Chemical compound C[C@H](C1=CC(C2=CC=C(CNC3CCCC3)S2)=CC=C1)NC(C1=C(C)C=CC(NC2CNC2)=C1)=O PKMUHQIDVVOXHQ-HXUWFJFHSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- 206010013082 Discomfort Diseases 0.000 description 2
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 239000007821 HATU Substances 0.000 description 2
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 238000011789 NOD SCID mouse Methods 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 102000004278 Receptor Protein-Tyrosine Kinases Human genes 0.000 description 2
- 108090000873 Receptor Protein-Tyrosine Kinases Proteins 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 2
- 102000004142 Trypsin Human genes 0.000 description 2
- 108090000631 Trypsin Proteins 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 125000000129 anionic group Chemical group 0.000 description 2
- 230000010100 anticoagulation Effects 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 125000002091 cationic group Chemical group 0.000 description 2
- 239000006143 cell culture medium Substances 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 238000004296 chiral HPLC Methods 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
- 229940125851 compound 27 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940126179 compound 72 Drugs 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 235000008504 concentrate Nutrition 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- BJXYHBKEQFQVES-NWDGAFQWSA-N enpatoran Chemical compound N[C@H]1CN(C[C@H](C1)C(F)(F)F)C1=C2C=CC=NC2=C(C=C1)C#N BJXYHBKEQFQVES-NWDGAFQWSA-N 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 235000011087 fumaric acid Nutrition 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- 229960002442 glucosamine Drugs 0.000 description 2
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 229960002897 heparin Drugs 0.000 description 2
- 229920000669 heparin Polymers 0.000 description 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000001630 malic acid Substances 0.000 description 2
- 235000011090 malic acid Nutrition 0.000 description 2
- 229960002510 mandelic acid Drugs 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- YGBMCLDVRUGXOV-UHFFFAOYSA-N n-[6-[6-chloro-5-[(4-fluorophenyl)sulfonylamino]pyridin-3-yl]-1,3-benzothiazol-2-yl]acetamide Chemical compound C1=C2SC(NC(=O)C)=NC2=CC=C1C(C=1)=CN=C(Cl)C=1NS(=O)(=O)C1=CC=C(F)C=C1 YGBMCLDVRUGXOV-UHFFFAOYSA-N 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 230000002285 radioactive effect Effects 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 125000003003 spiro group Chemical group 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- YAPQBXQYLJRXSA-UHFFFAOYSA-N theobromine Chemical compound CN1C(=O)NC(=O)C2=C1N=CN2C YAPQBXQYLJRXSA-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 239000012588 trypsin Substances 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 238000002255 vaccination Methods 0.000 description 2
- 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 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
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- STPKWKPURVSAJF-LJEWAXOPSA-N (4r,5r)-5-[4-[[4-(1-aza-4-azoniabicyclo[2.2.2]octan-4-ylmethyl)phenyl]methoxy]phenyl]-3,3-dibutyl-7-(dimethylamino)-1,1-dioxo-4,5-dihydro-2h-1$l^{6}-benzothiepin-4-ol Chemical compound O[C@H]1C(CCCC)(CCCC)CS(=O)(=O)C2=CC=C(N(C)C)C=C2[C@H]1C(C=C1)=CC=C1OCC(C=C1)=CC=C1C[N+]1(CC2)CCN2CC1 STPKWKPURVSAJF-LJEWAXOPSA-N 0.000 description 1
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- YZCAFAKJYGDMSY-UHFFFAOYSA-N 1-amino-2-methylpropane-2-thiol;hydrochloride Chemical compound Cl.CC(C)(S)CN YZCAFAKJYGDMSY-UHFFFAOYSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
- IHPYMWDTONKSCO-UHFFFAOYSA-N 2,2'-piperazine-1,4-diylbisethanesulfonic acid Chemical compound OS(=O)(=O)CCN1CCN(CCS(O)(=O)=O)CC1 IHPYMWDTONKSCO-UHFFFAOYSA-N 0.000 description 1
- CVFNMMJJZBWXQP-UHFFFAOYSA-N 2,2-dimethoxyethyl acetate Chemical compound COC(OC)COC(C)=O CVFNMMJJZBWXQP-UHFFFAOYSA-N 0.000 description 1
- VEPOHXYIFQMVHW-XOZOLZJESA-N 2,3-dihydroxybutanedioic acid (2S,3S)-3,4-dimethyl-2-phenylmorpholine Chemical compound OC(C(O)C(O)=O)C(O)=O.C[C@H]1[C@@H](OCCN1C)c1ccccc1 VEPOHXYIFQMVHW-XOZOLZJESA-N 0.000 description 1
- NXMFJCRMSDRXLD-UHFFFAOYSA-N 2-aminopyridine-3-carbaldehyde Chemical compound NC1=NC=CC=C1C=O NXMFJCRMSDRXLD-UHFFFAOYSA-N 0.000 description 1
- RGHQKFQZGLKBCF-UHFFFAOYSA-N 2-bromoethyl acetate Chemical compound CC(=O)OCCBr RGHQKFQZGLKBCF-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- 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
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- CESUXLKAADQNTB-ZETCQYMHSA-N 2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@@](N)=O CESUXLKAADQNTB-ZETCQYMHSA-N 0.000 description 1
- CAHZAJIZZBIDFJ-UHFFFAOYSA-N 2-methylsulfanylethylazanium;chloride Chemical compound Cl.CSCCN CAHZAJIZZBIDFJ-UHFFFAOYSA-N 0.000 description 1
- WBBPRCNXBQTYLF-UHFFFAOYSA-N 2-methylthioethanol Chemical compound CSCCO WBBPRCNXBQTYLF-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- HRADVHZVMOMEPU-UHFFFAOYSA-N 3-iodopyrrolidine-2,5-dione Chemical compound IC1CC(=O)NC1=O HRADVHZVMOMEPU-UHFFFAOYSA-N 0.000 description 1
- APRZHQXAAWPYHS-UHFFFAOYSA-N 4-[5-[3-(carboxymethoxy)phenyl]-3-(4,5-dimethyl-1,3-thiazol-2-yl)tetrazol-3-ium-2-yl]benzenesulfonate Chemical compound S1C(C)=C(C)N=C1[N+]1=NC(C=2C=C(OCC(O)=O)C=CC=2)=NN1C1=CC=C(S([O-])(=O)=O)C=C1 APRZHQXAAWPYHS-UHFFFAOYSA-N 0.000 description 1
- DQAZPZIYEOGZAF-UHFFFAOYSA-N 4-ethyl-n-[4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl]piperazine-1-carboxamide Chemical compound C1CN(CC)CCN1C(=O)NC(C(=CC1=NC=N2)OC)=CC1=C2NC1=CC=CC(C#C)=C1 DQAZPZIYEOGZAF-UHFFFAOYSA-N 0.000 description 1
- WCCFLOQQACDOAX-UHFFFAOYSA-N 4-fluoropyridin-2-amine Chemical compound NC1=CC(F)=CC=N1 WCCFLOQQACDOAX-UHFFFAOYSA-N 0.000 description 1
- FQHJBVUTSWQWSN-UHFFFAOYSA-N 4-methyl-1,3,2-dioxathietane 2,2-dioxide Chemical compound CC1OS(=O)(=O)O1 FQHJBVUTSWQWSN-UHFFFAOYSA-N 0.000 description 1
- KVIZTDNKHOCNAM-UHFFFAOYSA-N 4-methylpiperazin-2-one Chemical compound CN1CCNC(=O)C1 KVIZTDNKHOCNAM-UHFFFAOYSA-N 0.000 description 1
- XFJBGINZIMNZBW-CRAIPNDOSA-N 5-chloro-2-[4-[(1r,2s)-2-[2-(5-methylsulfonylpyridin-2-yl)oxyethyl]cyclopropyl]piperidin-1-yl]pyrimidine Chemical compound N1=CC(S(=O)(=O)C)=CC=C1OCC[C@H]1[C@@H](C2CCN(CC2)C=2N=CC(Cl)=CN=2)C1 XFJBGINZIMNZBW-CRAIPNDOSA-N 0.000 description 1
- ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 241000143437 Aciculosporium take Species 0.000 description 1
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 230000007730 Akt signaling Effects 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 1
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 1
- SSPSXXVPGUTLPO-UHFFFAOYSA-N CC1=C(SC(=N1)N2N=C(NN2S(=O)(=O)C3=CC=CC=C3)C4=CC(=CC=C4)OCC(=O)O)C Chemical compound CC1=C(SC(=N1)N2N=C(NN2S(=O)(=O)C3=CC=CC=C3)C4=CC(=CC=C4)OCC(=O)O)C SSPSXXVPGUTLPO-UHFFFAOYSA-N 0.000 description 1
- WQYAJFWNJROGBX-UHFFFAOYSA-N CCC(CCCCN1Cc(cc2CCC3)c(C(OC)OC)nc2N3C(Nc(cc2F)ncc2[IH]N)=O)CC1=O Chemical compound CCC(CCCCN1Cc(cc2CCC3)c(C(OC)OC)nc2N3C(Nc(cc2F)ncc2[IH]N)=O)CC1=O WQYAJFWNJROGBX-UHFFFAOYSA-N 0.000 description 1
- 0 CCSCCNC1=CC(C)=C*C=C1* Chemical compound CCSCCNC1=CC(C)=C*C=C1* 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- UNXHWFMMPAWVPI-QWWZWVQMSA-N D-threitol Chemical compound OC[C@@H](O)[C@H](O)CO UNXHWFMMPAWVPI-QWWZWVQMSA-N 0.000 description 1
- 238000001712 DNA sequencing Methods 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical group [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- 239000004097 EU approved flavor enhancer Substances 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 1
- 102100021066 Fibroblast growth factor receptor substrate 2 Human genes 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- DSLZVSRJTYRBFB-UHFFFAOYSA-N Galactaric acid Natural products OC(=O)C(O)C(O)C(O)C(O)C(O)=O DSLZVSRJTYRBFB-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 102100033067 Growth factor receptor-bound protein 2 Human genes 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000818410 Homo sapiens Fibroblast growth factor receptor substrate 2 Proteins 0.000 description 1
- 101000871017 Homo sapiens Growth factor receptor-bound protein 2 Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 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
- 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
- 229930182821 L-proline Natural products 0.000 description 1
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 239000012448 Lithium borohydride Substances 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
- 241000124008 Mammalia Species 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 101100288142 Mus musculus Klkb1 gene Proteins 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 1
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 1
- 150000001204 N-oxides Chemical class 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 102000014384 Type C Phospholipases Human genes 0.000 description 1
- 108010079194 Type C Phospholipases Proteins 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- IOSLINNLJFQMFF-XMMPIXPASA-N [(2R)-1-[[4-[[3-[(4-fluorophenyl)methylsulfanyl]phenoxy]methyl]phenyl]methyl]pyrrolidin-2-yl]methanol Chemical compound FC1=CC=C(CSC=2C=C(OCC3=CC=C(CN4[C@H](CCC4)CO)C=C3)C=CC=2)C=C1 IOSLINNLJFQMFF-XMMPIXPASA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000013011 aqueous formulation Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229960003121 arginine Drugs 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 125000005334 azaindolyl group Chemical group N1N=C(C2=CC=CC=C12)* 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000005874 benzothiadiazolyl group Chemical group 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
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
- 229960003237 betaine Drugs 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000003560 cancer drug Substances 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- VDANGULDQQJODZ-UHFFFAOYSA-N chloroprocaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1Cl VDANGULDQQJODZ-UHFFFAOYSA-N 0.000 description 1
- 229960002023 chloroprocaine Drugs 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125900 compound 59 Drugs 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- ZHGASCUQXLPSDT-UHFFFAOYSA-N cyclohexanesulfonic acid Chemical compound OS(=O)(=O)C1CCCCC1 ZHGASCUQXLPSDT-UHFFFAOYSA-N 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 125000003438 dodecyl 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])C([H])([H])C([H])([H])* 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 238000010410 dusting Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 238000006345 epimerization reaction Methods 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- OCLXJTCGWSSVOE-UHFFFAOYSA-N ethanol etoh Chemical compound CCO.CCO OCLXJTCGWSSVOE-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 1
- 102000052178 fibroblast growth factor receptor activity proteins Human genes 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000019264 food flavour enhancer Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- DSLZVSRJTYRBFB-DUHBMQHGSA-N galactaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O DSLZVSRJTYRBFB-DUHBMQHGSA-N 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 239000010440 gypsum Substances 0.000 description 1
- 229910052602 gypsum Inorganic materials 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 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
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 229940045996 isethionic acid Drugs 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 229960000448 lactic acid Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 108010082117 matrigel Proteins 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- BCVXHSPFUWZLGQ-UHFFFAOYSA-N mecn acetonitrile Chemical compound CC#N.CC#N BCVXHSPFUWZLGQ-UHFFFAOYSA-N 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- IQJMLPYZYITYPJ-UHFFFAOYSA-N methyl sulfate piperazin-1-ium Chemical compound S(=O)(=O)(OC)[O-].[NH2+]1CCNCC1 IQJMLPYZYITYPJ-UHFFFAOYSA-N 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000007932 molded tablet Substances 0.000 description 1
- ACTNHJDHMQSOGL-UHFFFAOYSA-N n',n'-dibenzylethane-1,2-diamine Chemical compound C=1C=CC=CC=1CN(CCN)CC1=CC=CC=C1 ACTNHJDHMQSOGL-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-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
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 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
- 239000002547 new drug Substances 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- AVPKHOTUOHDTLW-UHFFFAOYSA-N oxane-4-carboxylic acid Chemical compound OC(=O)C1CCOCC1 AVPKHOTUOHDTLW-UHFFFAOYSA-N 0.000 description 1
- SFJGCXYXEFWEBK-UHFFFAOYSA-N oxazepine Chemical compound O1C=CC=CC=N1 SFJGCXYXEFWEBK-UHFFFAOYSA-N 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 229940055726 pantothenic acid Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 125000005575 polycyclic aromatic hydrocarbon group Chemical group 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000002335 preservative 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
- 230000008569 process Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
- 229960002429 proline Drugs 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 230000006920 protein precipitation Effects 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 229960003787 sorafenib Drugs 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- XTQHKBHJIVJGKJ-UHFFFAOYSA-N sulfur monoxide Chemical class S=O XTQHKBHJIVJGKJ-UHFFFAOYSA-N 0.000 description 1
- 229910052815 sulfur oxide Inorganic materials 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000009492 tablet coating Methods 0.000 description 1
- 239000002700 tablet coating Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- JJXOIFHXNBFRNV-UHFFFAOYSA-N tert-butyl (2-methylpropan-2-yl)oxycarbonyl carbonate Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C.CC(C)(C)OC(=O)OC(=O)OC(C)(C)C JJXOIFHXNBFRNV-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- GKWGBMHXVRSFRT-UHFFFAOYSA-N tert-butyl n-[2-(methylamino)ethyl]carbamate Chemical compound CNCCNC(=O)OC(C)(C)C GKWGBMHXVRSFRT-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- PHCBRBWANGJMHS-UHFFFAOYSA-J tetrasodium;disulfate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O PHCBRBWANGJMHS-UHFFFAOYSA-J 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- GBNRIMMKLMTDLW-UHFFFAOYSA-N thiolan-3-amine Chemical compound NC1CCSC1 GBNRIMMKLMTDLW-UHFFFAOYSA-N 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- ZCAGUOCUDGWENZ-UHFFFAOYSA-N thiomorpholinyl sulfoxide group Chemical group N1(CCSCC1)S(=O)N1CCSCC1 ZCAGUOCUDGWENZ-UHFFFAOYSA-N 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000013271 transdermal drug delivery Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- KQBSGRWMSNFIPG-UHFFFAOYSA-N trioxane Chemical compound C1COOOC1 KQBSGRWMSNFIPG-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 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
- 239000007762 w/o emulsion Substances 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- 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
- A61K31/495—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
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/541—Non-condensed thiazines containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Definitions
- the present invention provides a fused ring derivative compound, its use for inhibiting FGFR4, and a method for treating diseases using the compound.
- Fibroblast growth factor receptor belongs to the family of receptor protein tyrosine kinases. Through receptor binding to ligands, it can activate many signaling pathways including Ras-MAPK, AKT-PI3K, and phospholipase C. These pathways Growth, proliferation, and survival all play important roles.
- FGFR4 is a tyrosine kinase receptor in the human body encoded by the gene FGFR4 and is highly conserved in evolution. It needs to bind to its specific ligand FGF19 to function.
- FGFR4 activation and FGF19 overexpression have important effects on the occurrence and development of liver cancer, and inhibition of FGFR4 can effectively reduce the incidence of liver cancer.
- FGFR4 ligand FGF19 and coreceptor KLB are highly expressed in tumors of about one-third of liver cancer patients.
- changes in FGFR4-FGF19 signal axis are also related to the occurrence of colorectal cancer, breast cancer, pancreatic cancer, prostate cancer, lung cancer, and thyroid cancer.
- fibroblast growth factor receptor 4 (FGFR4) inhibitors have great potential for treating liver cancer, and have better specificity and effectiveness than similar drugs.
- Liver cancer is the most common malignant tumor and fatal disease after lung cancer, and China has the largest number of liver cancer patients in the world.
- Sorafenib can only increase the average survival time of patients by 3 months, and because it is a multi-target tyrosine kinase inhibitor, it has strong toxic side effects. Therefore, the development of more effective liver cancer drugs has become an urgent need worldwide, and FGFR4 inhibitors provide a possibility for breakthroughs in this regard.
- FGFR4 inhibitors are a popular research direction in the field of global liver cancer treatment research and a market direction that the world's biopharmaceutical companies are vying for, but due to the limitations of experimental methods, research cycles and other factors, there is currently no FGFR4 inhibitor drug. Go to market. China, as the country with the highest incidence of liver cancer and the largest number of liver cancer patients in the world, a breakthrough in this direction will have strong clinical application significance. At present, no similar drugs have entered clinical research in China, and they are all in the early stage of clinical research internationally. Therefore, breakthroughs in this direction will also greatly enhance the international competitiveness of China's new drug research and development.
- the present invention relates to fused ring compounds for use as FGFR4 inhibitors for the treatment of diseases mediated by FGFR4.
- the present invention first provides a compound represented by Formula I or a pharmaceutically acceptable salt thereof:
- R 1 is independently at each occurrence
- X is independently selected at each occurrence from the absence, O, -NR X1 -or -CR X1 R X2- ; and p is 0, 1, 2 or 3;
- R X1 and R X2 are independently selected at each occurrence from H; D; -F; -Cl; -Br; -I; -C 1-6 alkyl; substituted with 1, 2 or 3 substituents C 1-6 alkyl; C 1-6 alkoxy or substituted with 1,2 or 3 substituents of C 1-6 alkoxy; each of the substituents at each occurrence is independently optionally Selected from D, halogen, -OH, -CN, -NH 2 , -NO 2 , -COOH, -C 1-3 alkyl, or -C 1-3 alkoxy;
- Y is independently selected at each occurrence from O or S;
- R 2 and R 3 are independently selected at each occurrence from H; D; -F; -Cl; -Br; -I; -OH; -SH; -CN; -NH 2 ; -NO 2 ; -N 3 ; -C 1-6 alkyl; 1, 2, or 3 -D, -F, -Cl, -Br, -I, -OH, -CN, -NH 2 , -NO 2 , -COOH,- -C 1-6 alkyl substituted by C 1-3 alkyl or C 1-3 alkoxy; C 1-6 alkoxy; substituted by 1, 2 or 3 -D, -F, -Cl, -Br , -I, -OH, -CN, -NH 2 , -NO 2 , -COOH, -C 1-3 alkyl or C 1-3 alkoxy substituted C 1-6 alkoxy; substituted or unsubstituted C 3-8 cycloalky
- G is independently selected at each occurrence from -CR G1 R G2- , -NR G1- , -S-, -SO-, -SO 2 -or O; m is 0, 1, 2, 3 or 4;
- Each R G1 and R G2 are independently at each occurrence selected from H; D; -C 1-6 alkyl; 2 or 3 substituents of -C 1-6 alkyl; -C 1-6 alkoxy; -C 1-6 alkoxy substituted with 1, 2 or 3 substituents; each of said substituents is independently optionally selected from D, halogen, -OH, -CN, -NH 2 , -NO 2 , -COOH, -C 1-3 alkyl or C 1-3 alkoxy;
- Q is independently selected at each occurrence from -CR 4 R 4 '-(CR 4 R 4 ') q -or -NR 4- (CR 4 R 4 ') q- , and q is selected from 0, 1, 2, 3 or 4;
- R 4 and R 4 ′ are independently selected at each occurrence from H; D; -F; -Cl; -Br; -I; -OH; -C 1-6 alkyl; substituted C 1-6 alkyl; -C 1-6 alkoxy; 2 or 3 substituents of C 1-6 alkoxy; -C 3-8 cycloalkyl; is 1 C 3-8 cycloalkyl substituted with 2, 3 or 2 substituents; 3-8 membered heterocyclic group; 3-8 membered heterocyclic group substituted with 1, 2 or 3 substituents; each of said substituents At each occurrence is independently optionally selected from D, halogen, -OH, -CN, -NH 2 , -NO 2 , -COOH, -C 1-3 alkyl, or C 1-3 alkoxy; or
- R 4 and R 4 ′ together with the carbon atoms to which they are connected form a C 3-8 carbocyclic ring, a 3-8 membered heterocyclic ring or a -5-10 membered heteroaromatic ring, each ring system can be independent at each occurrence Optionally substituted with one or more substituents, or unsubstituted;
- R 5 and R 5 ' are independently selected at each occurrence from H; D; -F; -Cl; -Br; -I; -OH; -C 1-6 alkyl; substituted with -C 1-6 alkyl; -C 1-6 alkoxy; 2 or 3 substituents of -C 1-6 alkoxy; -C 3-8 cycloalkyl; C 3-8 cycloalkyl substituted with 1, 2 or 3 substituents; 3-8 membered heterocyclic group; 3-8 membered heterocyclic group substituted with 1, 2 or 3 substituents; each of said The substituents are each independently optionally selected from D, halogen, -OH, -CN, -NH 2 , -NO 2 , -COOH, -C 1-3 alkyl, or C 1-3 alkoxy Base; or
- R 5 and R 5 ′ form a C 3-8 carbocyclic ring, a 3-8 membered heterocyclic ring, a 5-10 membered heteroaromatic ring with the carbon atom to which they are commonly connected, each heterocyclic group and each heteroaromatic group
- Each radical independently optionally contains 1 or 2 heteroatoms selected from N, O or S, and each of said ring systems can independently be optionally Multiple substituents substituted or unsubstituted; or
- R 4 and R 5 together with the atoms to which they are connected form a 5-10 membered aromatic ring, a -C 3-10 carbocyclic ring, and a 4-10 membered heterocyclic ring.
- Optionally contains 1 or 2 heteroatoms selected from N, O or S, each of said ring systems being independently optionally substituted with one or more substituents on each occurrence ;
- W is independently selected at each occurrence from- (CR w1 R w2 ) n -S-,-(CR w1 R w2 ) n -SO- or-(CR w1 R w2 ) n -SO 2- , n is selected From 0, 1, 2, 3 or 4;
- R w1 and R w2 are each independently selected from H; D; -F; -Cl; -Br; -OH; methyl; ethyl; propyl; isopropyl; -C 1-3 alkyl substituted with 1 substituent; methoxy; ethoxy; propoxy; isopropoxy; -C 1-3 alkoxy substituted with 1, 2 or 3 substituents; Cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; -C 3-6 cycloalkyl substituted with 1, 2 or 3 substituents; 3-membered heterocyclyl; 4-membered heterocyclyl; 5-membered heterocyclic A cyclic group; a 6-membered heterocyclic group or a 3-6-membered heterocyclic group substituted with 1, 2 or 3 substituents; each of said substituents is independently optionally selected from D,- F, -Cl, -Br, -I, -
- R 6 at each occurrence is independently selected from H; D; -F; -Cl; -Br; -I; -C 1-3 alkyl; -C 1 substituted with 1 , 2 or 3 substituents -3 alkyl; -C 1-3 alkoxy; 2 or 3 substituents of -C 1-3 alkoxy; -C 1-3 alkyl group -COO-C 1-3, -C 3-6 cycloalkyl, or two or three substituents -C 3-6 cycloalkyl; each of said substituents are independently selected from optionally D, halo, -OH, - CN, -NH 2 , -NO 2 , -COOH, -C 1-3 alkyl or C 1-3 alkoxy; or
- Q and R 6 together with the carbon atom and W to which they are respectively connected form a 4-6 membered heterocyclic ring, said heterocyclic ring is optionally optionally substituted with one or more substituents, and said heterocyclic ring is independently optionally containing 1, 2 or 3 heteroatoms selected from N, O or S, each of said substituents optionally selected from group D is independently, halo, -OH, -CN, -NH 2, -NO 2 , -COOH, -C 1-3 alkyl, or -C 1-3 alkoxy; or
- R 4 and R 6 form a 5-8 membered monocyclic heterocyclic group, a 5-10 membered spirocyclic heterocyclic group, a 5-10 membered condensed ring heterocyclic group, a 5-10 membered bridged heterocyclic ring together with the atoms to which they are connected
- Each R 9 is independently selected at each occurrence from H, D, -C 1-3 alkyl, -C 1-3 alkyl C 1-3 alkoxy, -C 2-4 alkenyl, -C 3-6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclic group, halogenated C 1-3 alkyl, phenyl, p-methylphenyl, amino, -NH-C 1-3 alkane Group, -N (C 1-3 alkyl) 2 or C 1-3 alkylamide group;
- Each R 10 is independently selected at each occurrence from H, D, -C 1-3 alkyl, -C 1-3 alkyl C 1-3 alkoxy, -C 3-6 cycloalkyl, -C 5-10 aryl, halo C 1-3 alkyl or hydroxy substituted C 1-3 alkyl;
- Each R 11 is independently selected at each occurrence from H, D, -C 1-3 alkyl, -C 1-3 alkoxy, -C 3-6 cycloalkyl, -C 3-6 ring Alkoxy, halo C 1-3 alkyl, halo C 1-3 alkoxy, hydroxy substituted C 1-3 alkyl or hydroxy substituted C 1-3 alkoxy;
- R 12 and R 13 are independently selected at each occurrence from H, D, -C 1-3 alkyl, -C 1-3 alkyl C 1-3 alkoxy, -C 1-3 alkoxy C 1-3 alkyl, -C 3-6 cycloalkyl, C 1-3 alkyl, -C 2-4 alkenyl, -C 2-4 alkynyl, -C 3-6 cycloalkyl, substituted Or unsubstituted C 5-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl or C 1-3 alkanoyl;
- t is independently selected at each occurrence from 0, 1, or 2.
- R 1 is independently at each occurrence
- X is independently selected at each occurrence from the absence, O, -NR X1 -or -CR X1 R X2- ; and p is 0, 1 or 2;
- R X1 and R X2 are independently selected at each occurrence from H; D; -F; -Cl; -Br; -I; -C 1-3 alkyl; substituted with 1, 2 or 3 substituents C 1-3 alkyl; a C 1-3 alkoxy group or substituted with 1,2 or 3 substituents of a C 1-3 alkoxy group; each of said substituents are independently selected from optionally D, - F, -Cl, -Br, -I, -OH, -CN, -NH 2 , -NO 2 , -COOH, -C 1-3 alkyl or C 1-3 alkoxy;
- Y is independently selected at each occurrence from O or S;
- R 7 at each occurrence is independently selected from H, D, -C 1-3 alkyl, -C 1-3 alkoxy, -C 3-5 cycloalkyl, or 3-8 membered heterocyclyl
- the heterocyclic group independently optionally comprises 1, 2 or 3 heteroatoms selected from N, O or S
- each R 9 is independently optionally selected from H, D, -C 1-3 alkyl, -C 1-3 alkyl C 1-3 alkoxy, -C 2 -4 alkenyl, -C 3-6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclic group, halogenated C 1-3 alkyl, phenyl, p-methylphenyl, amino, -NH -C 1-3 alkyl, -N (C 1-3 alkyl) 2 or C 1-3 alkylamide;
- each R 10 is independently optionally selected from H, D, -C 1-3 alkyl, -C 1-3 alkyl C 1-3 alkoxy, -C 3 -6 cycloalkyl, -C 5-10 aryl, halogenated C 1-3 alkyl or hydroxy substituted C 1-3 alkyl;
- each R 11 is independently optionally selected from the group consisting of H, D, -C 1-3 alkyl, -C 1-3 alkoxy, -C 3-6 cycloalkane Radical, -C 3-6 cycloalkoxy, halo C 1-3 alkyl, halo C 1-3 alkoxy, hydroxy substituted C 1-3 alkyl, or hydroxy substituted C 1-3 alkoxy;
- R 12 and R 13 are each independently selected from H, D, -C 1-3 alkyl, -C 1-3 alkyl C 1-3 alkoxy, -C 1-3 Alkoxy C 1-3 alkyl, -C 3-6 cycloalkyl C 1-3 alkyl, -C 2-4 alkenyl, -C 2-4 alkynyl, -C 3-6 cycloalkane Group, substituted or unsubstituted C 5-10 aryl group, substituted or unsubstituted 5-10 membered heteroaryl group or -C 1-3 alkanoyl group;
- t 0, 1, or 2.
- R 1 is independently at each occurrence
- X is independently selected at each occurrence from the absence, O, -NR X1 -or -CR X1 R X2- ; and p is 0 or 1;
- R X1 and R X2 are each independently selected from H; D; -F; -Cl; -Br; -I; methyl; ethyl; propyl; isopropyl; C 1-3 alkyl substituted with 1 substituent; methoxy; ethoxy; propoxy; isopropoxy or C 1-3 alkoxy substituted with 1, 2 or 3 substituents; said each optionally substituted group independently selected from D, -F, -Cl, -Br, -I, -OH, -CN, -NH 2, -NO 2, -COOH, methyl, ethyl, propyl , Isopropyl, methoxy, ethoxy, propoxy, or isopropoxy;
- Y is independently O at each occurrence
- R 8 is independently selected at each occurrence from H, D, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C 2- 4 -alkenyl, -C 2-4 alkynyl, -C (O) R 11 , -methyl-C (O) R 11 , -ethyl-C (O) R 11 , -propyl-C ( O) R 11 , -isopropyl-C (O) R 11 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 7-membered heterocyclyl, 8-membered heterocyclyl, and the heterocyclyl independently optionally contains 1 or 2 heteroatoms selected from N, O, or S, and R 8 independently
- R 7 and R 8 form a 5-membered monocyclic heterocyclic group, a 6-membered monocyclic heterocyclic group, a 7-membered monocyclic heterocyclic group, a 5-membered spirocyclic heterocyclic group, 6 7-membered spirocyclic heterocyclyl, 7-membered spirocyclic heterocyclyl, 8-membered spirocyclic heterocyclyl, 9-membered spirocyclic heterocyclyl, 10-membered spirocyclic heterocyclyl, 5-membered fused ring heterocyclyl, 6-membered fused Cycloheterocyclyl, 7-membered fused ring heterocyclyl, 8-membered fused ring heterocyclyl, 9-membered fused ring heterocyclyl, 10-membered fused ring heterocyclyl, 5-membered bridged heterocyclic ring, 6-membered bridged heterocyclic ring A
- each R 9 is independently optionally selected from H, D, methyl, ethyl, propyl, isopropyl, -C 1-3 alkyl C 1-3 alkoxy , -C 2-4 alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted or unsubstituted 3-6 membered heterocyclyl, halogenated C 1-3 alkyl, phenyl , P-methylphenyl, amino, -NH-C 1-3 alkyl, -N (C 1-3 alkyl) 2 or C 1-3 alkylamide;
- each R 10 is independently optionally selected from H, D, methyl, ethyl, propyl, isopropyl, -C 1-3 alkyl, C 1-3 alkoxy -C 3-6 cycloalkyl, -C 5-10 aryl, halogenated C 1-3 alkyl or hydroxy substituted C 1-3 alkyl;
- each R 11 is independently optionally selected from the group consisting of H, D, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, and propoxy , Isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -C 3-6 cycloalkoxy, halo C 1-3 alkyl, halo C 1-3 alkoxy, Hydroxy substituted C 1-3 alkyl or hydroxy substituted C 1-3 alkoxy;
- R 12 and R 13 are each independently selected from H, D, methyl, ethyl, propyl, isopropyl, -C 1-3 alkyl C 1-3 alkoxy, -C 1-3 alkoxy C 1-3 alkyl, -C 3-6 cycloalkyl C 1-3 alkyl, -C 2-4 alkenyl, -C 2-4 alkynyl, cyclopropyl Group, cyclobutyl, cyclopentyl, cyclohexyl, substituted or unsubstituted C 5-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl or -C 1-3 alkanoyl;
- t 0, 1, or 2.
- R 1 is independently at each occurrence
- X is independently selected at each occurrence from -CH 2- , -CHD-, -CD 2- , -CH (CH 3 )-, -C (CH 3 ) 2- , -CHF-, -CHBr- or -CH (OH)-; and p is 0 or 1;
- Y is independently O at each occurrence
- R 8 is independently selected at each occurrence from H, D, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C 2- 4 -alkenyl, -C 2-4 alkynyl, -C (O) H, -methyl-C (O) H, -ethyl-C (O) H, -propyl-C (O) H , -Isopropyl-C (O) H, -C (O) -methyl, -methyl-C (O) -methyl, -ethyl-C (O) -methyl, -propyl-C (O) -methyl, -isopropyl-C (O) -methyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclic A
- R 1 is selected from:
- R 1 is selected from:
- R 2 and R 3 are each independently selected from H; D; -F; -Cl; -Br; -I; -OH; -SH; -CN; -NH 2 ; -NO 2 ;- N 3 ; -C 1-3 alkyl; 1, 2, or 3 -D, -F, -Cl, -Br, -I, -OH, -CN, -NH 2 , -NO 2 , -COOH, -C 1-3 alkyl or C 1-3 alkoxy substituted -C 1-3 alkyl; -C 1-3 alkoxy; substituted by 1, 2 or 3 -D, -F, -Cl, -Br, -I, -OH, -CN, -NH 2 , -NO 2 , -COOH, -C 1-3 alkyl or C 1-3 alkoxy substituted C 1-3 alkoxy; substituted or Unsubstituted C 3-6 cycloal
- each R 9 is independently optionally selected from H, D, -C 1-3 alkyl, -C 1-3 alkyl C 1-3 alkoxy, -C 2 -4 alkenyl, -C 3-6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclic group, halogenated C 1-3 alkyl, phenyl, p-methylphenyl, amino, -NH -C 1-3 alkyl, -N (C 1-3 alkyl) 2 or C 1-3 alkylamide;
- each R 10 is independently optionally selected from H, D, -C 1-3 alkyl, -C 1-3 alkyl C 1-3 alkoxy, -C 3 -6 cycloalkyl, -C 5-8 aryl, halogenated C 1-3 alkyl or hydroxy substituted C 1-3 alkyl;
- each R 11 is independently optionally selected from the group consisting of H, D, -C 1-3 alkyl, -C 1-3 alkoxy, -C 3-6 cycloalkane Radical, -C 3-6 cycloalkoxy, halo C 1-3 alkyl, halo C 1-3 alkoxy, hydroxy substituted C 1-3 alkyl, or hydroxy substituted C 1-3 alkoxy;
- each of R 12 and R 13 is each independently optionally selected from H, D, -C 1-3 alkyl, -C 1-3 alkyl C 1-3 alkoxy, -C 1-3 alkoxy C 1-3 alkyl, -C 3-6 cycloalkyl C 1-3 alkyl, -C 2-4 alkenyl, -C 2-4 alkynyl, -C 3-6 cycloalkyl, substituted or unsubstituted C 5-8 aryl, substituted or unsubstituted 5-8 membered heteroaryl or C 1-3 alkanoyl;
- t 0, 1, or 2.
- R 2 and R 3 are each independently selected from H; D; -F; -Cl; -Br; -I; -OH; -SH; -CN; -NO 2 ; -N 3 ; A Ethyl; propyl; isopropyl; 1, 2, or 3 -D, -F, -Cl, -Br, -I, -OH, -CN, -NH 2 , -NO 2 , -COOH , -C 1-3 alkyl or a C 1-3 alkoxy-substituted -C 1-3 alkyl; methoxy; ethoxy; propoxy; isopropoxy; 1, 2 or 3 -D, -F, -Cl, -Br, -I, -OH, -CN, -NH 2 , -NO 2 , -COOH, -C 1-3 alkyl or C 1-3 alkoxy substituted C 1-3 alkoxy; substituted
- each R 9 is independently optionally selected from H, D, methyl, ethyl, propyl, isopropyl, -C 1-3 alkyl, C 1-3 alkoxy , -C 2-4 alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted or unsubstituted 3-6 membered heterocyclyl, halogenated C 1-3 alkyl, phenyl , P-methylphenyl, amino, -NH-C 1-3 alkyl, -N (C 1-3 alkyl) 2 or C 1-3 alkylamide;
- each R 10 is independently optionally selected from H, D, methyl, ethyl, propyl, isopropyl, -C 1-3 alkyl, C 1-3 alkoxy Cyclopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -C 5-8 aryl, halo C 1-3 alkyl or hydroxy substituted C 1-3 alkyl;
- each R 11 is independently optionally selected from the group consisting of H, D, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, and propoxy , Isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -C 3-6 cycloalkoxy, halo C 1-3 alkyl, halo C 1-3 alkoxy, Hydroxy substituted C 1-3 alkyl or hydroxy substituted C 1-3 alkoxy;
- each of R 12 and R 13 is each independently optionally selected from H, D, methyl, ethyl, propyl, isopropyl, -C 1-3 alkyl C 1- 3 alkoxy, -C 1-3 alkoxy C 1-3 alkyl, -C 3-6 cycloalkyl C 1-3 alkyl, -C 2-4 alkenyl, -C 2-4 chain Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted or unsubstituted C 5-8 aryl, substituted or unsubstituted 5-8 membered heteroaryl or C 1-3 alkanoyl;
- t 0 or 1.
- R 2 and R 3 are each independently selected from H; D; -F; -Cl; -Br; -I; -OH; -SH; -CN; -NO 2 ; -N 3 ; A Ethyl; propyl; isopropyl; 1, 2, or 3 -D, -F, -Cl, -Br, -I, -OH, -CN, -NH 2 , -NO 2 , -COOH , -C 1-3 alkyl or a C 1-3 alkoxy-substituted -C 1-3 alkyl; methoxy; ethoxy; propoxy; isopropoxy; 1, 2 or 3 -D, -F, -Cl, -Br, -I, -OH, -CN, -NH 2 , -NO 2 , -COOH, -C 1-3 alkyl or C 1-3 alkoxy substituted C 1-3 alkoxy; substituted
- R 2 and R 3 are each independently selected from H, D, -F, -Cl, -Br, -I, -OH, -SH, -CN, -NO 2 , -N 3 , a Group, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy.
- R 2 and R 3 are each independently selected from H, D, -F, or methyl.
- G is independently selected at each occurrence from -CR G1 R G2- , -NR G1- , -S-, -SO-, -SO 2- , or O; m is 0, 1, 2, 3 or 4;
- Each R G1 and R G2 are independently selected from H; D; -C 1-3 alkyl; 2 or 3 substituents of -C 1-3 alkyl; -C 1-3 alkoxy -C 1-3 alkoxy substituted with 1, 2 or 3 substituents; each of said substituents is independently optionally selected from D, halogen, -OH, -CN, -NH 2 ,- NO 2 , -COOH, -C 1-3 alkyl or C 1-3 alkoxy.
- G is independently selected at each occurrence from -CR G1 R G2- , -NR G1- , -S-, -SO-, -SO 2- , or O; m is 0, 1, 2 or 3;
- Each R G1 and R G2 are independently selected from H; D; -C 1-3 alkyl; 2 or 3 substituents of -C 1-3 alkyl; -C 1-3 alkoxy Or -C 1-3 alkoxy substituted with 1, 2 or 3 substituents; each of said substituents is independently optionally selected from D, -F, -Cl, -Br, -I, -OH, -CN, -NH 2 , -NO 2 , -COOH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy.
- G is independently selected at each occurrence from -CR G1 R G2- , -NR G1- , -S-, -SO-, -SO 2- , or O; m is 0, 1, 2 or 3;
- Each R G1 and R G2 is independently selected from H; D; methyl; ethyl; propyl; isopropyl; -C 1-3 alkyl substituted with 1, 2 or 3 substituents; methoxy Ethoxy; propoxy; isopropoxy; or -C 1-3 alkoxy substituted with 1, 2 or 3 substituents; each of said substituents is independently optionally selected from D , -F, -Cl, -Br, -I, -OH, -CN, -NH 2 , -NO 2 , -COOH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy , Propoxy, or isopropoxy.
- G is independently selected at each occurrence from -CH 2- , -CHD-, -CD 2- , -NH-, -S-, -SO-, -SO 2- , or O; m is 0, 1, or 2.
- G is independently selected at each occurrence from -CH 2- , -CHD-, -CD 2- , -NH-, -S-, -SO-, -SO 2- , or O; m is 0 or 1.
- G is independently selected at each occurrence from -NH- or O; m is 0 or 1.
- G is independently selected at each occurrence from -NH- or O; m is 1.
- G is independently selected at each occurrence from -NH-; m is 0 or 1.
- G is independently selected at each occurrence from -NH-; m is 1.
- m is 0.
- Q is independently selected at each occurrence from -CR 4 R 4 ′-(CR 4 R 4 ′) q- ;
- R 4 and R 4 ' are independently selected from H; D; -F; -Cl; -Br; -I; -OH; -C 1-6 alkyl; C substituted with 1, 2 or 3 substituents C1-6 alkyl; -C 1-6 alkoxy; 2 or 3 substituents of C 1-6 alkoxy; -C 3-8 cycloalkyl; by 1, 2 or 3 C 3-8 cycloalkyl substituted with a substituent; a 3-8 membered heterocyclic group; a 3-8 membered heterocyclic group substituted with 1, 2 or 3 substituents; each of said substituents is independently optionally Selected from D, halogen, -OH, -CN, -NH 2 , -NO 2 , -COOH, -C 1-3 alkyl, or C 1-3 alkoxy; or
- R 4 and R 4 ′ together with the carbon atom to which they are connected form a -C 3-8 carbocyclic ring, a -3-8-membered heterocyclic ring or a -5-10-membered heteroaromatic ring, each ring system can be independently selected Is substituted or unsubstituted with one or more substituents.
- Q is -NR 4- (CR 4 R 4 ') q- ;
- R 4 and R 4 ' are independently selected from H; D; -F; -Cl; -Br; -I; -OH; -C 1-6 alkyl; C substituted with 1, 2 or 3 substituents C1-6 alkyl; -C 1-6 alkoxy; 2 or 3 substituents of C 1-6 alkoxy; -C 3-8 cycloalkyl; by 1, 2 or 3 C 3-8 cycloalkyl substituted with a substituent; a 3-8 membered heterocyclic group; a 3-8 membered heterocyclic group substituted with 1, 2 or 3 substituents; each of said substituents is independently optionally Selected from D, halogen, -OH, -CN, -NH 2 , -NO 2 , -COOH, -C 1-3 alkyl, or C 1-3 alkoxy; or
- R 4 and R 4 ′ together with the carbon atom to which they are connected form a C 3-8 carbocyclic ring, a 3-8 membered heterocyclic ring or a -5-10 membered heteroaromatic ring, each ring system can be optionally optionally One or more substituents are substituted or unsubstituted.
- Q is -CR 4 R 4 '-(CR 4 R 4 ') q -or -NR 4- (CR 4 R 4 ') q- , and q is selected from 0, 1, 2, 3 Or 4;
- R 4 and R 4 ′ are each independently selected from H; D; -F; -Cl; -Br; -I; -OH; -C 1-3 alkyl; C substituted with 1, 2 or 3 substituents 1-3 alkyl; -C 1-3 alkoxy; a group 1, 2 or 3 substituents of a C 1-3 alkoxy; -C 3-6 cycloalkyl; by 1, 2 or 3 C 3-6 cycloalkyl substituted with a substituent; a 3-6 membered heterocyclic group; a 3-6 membered heterocyclic group substituted with 1, 2 or 3 substituents; each of said substituents is independently optionally Selected from D, halogen, -OH, -CN, -NH 2 , -NO 2 , -COOH, -C 1-3 alkyl, or C 1-3 alkoxy; or
- R 4 and R 4 ′ together with the carbon atom to which they are attached form a -C 3-6 carbocyclic ring, a 3-6 membered heterocyclic ring, or a 5-8 membered heteroaromatic ring, each ring system can be optionally optionally independently One or more substituents are substituted or unsubstituted.
- Q is -CR 4 R 4 ′-(CR 4 R 4 ′) q- ;
- R 4 and R 4 ′ are each independently selected from H; D; -F; -Cl; -Br; -I; -OH; -C 1-3 alkyl; C substituted with 1, 2 or 3 substituents 1-3 alkyl; -C 1-3 alkoxy; a group 1, 2 or 3 substituents of a C 1-3 alkoxy; -C 3-6 cycloalkyl; by 1, 2 or 3 C 3-6 cycloalkyl substituted with a substituent; a 3-6 membered heterocyclic group; a 3-6 membered heterocyclic group substituted with 1, 2 or 3 substituents; each of said substituents is independently optionally Selected from D, halogen, -OH, -CN, -NH 2 , -NO 2 , -COOH, -C 1-3 alkyl, or C 1-3 alkoxy; or
- R 4 and R 4 ′ together with the carbon atom to which they are attached form a -C 3-6 carbocyclic ring, a 3-6 membered heterocyclic ring, or a 5-8 membered heteroaromatic ring, each ring system can be optionally optionally independently One or more substituents are substituted or unsubstituted.
- Q is -NR 4- (CR 4 R 4 ') q- ;
- R 4 and R 4 ′ are each independently selected from H; D; -F; -Cl; -Br; -I; -OH; -C 1-3 alkyl; C substituted with 1, 2 or 3 substituents 1-3 alkyl; -C 1-3 alkoxy; a group 1, 2 or 3 substituents of a C 1-3 alkoxy; -C 3-6 cycloalkyl; by 1, 2 or 3 C 3-6 cycloalkyl substituted with a substituent; a 3-6 membered heterocyclic group; a 3-6 membered heterocyclic group substituted with 1, 2 or 3 substituents; each of said substituents is independently optionally Selected from D, halogen, -OH, -CN, -NH 2 , -NO 2 , -COOH, -C 1-3 alkyl, or C 1-3 alkoxy; or
- R 4 and R 4 ′ together with the carbon atom to which they are attached form a -C 3-6 carbocyclic ring, a 3-6 membered heterocyclic ring, or a 5-8 membered heteroaromatic ring, each ring system can be optionally optionally independently One or more substituents are substituted or unsubstituted.
- Q is -CR 4 R 4 '-(CR 4 R 4 ') q -or -NR 4- (CR 4 R 4 ') q- , and q is selected from 0, 1, 2, 3 Or 4;
- R 4 and R 4 ′ are each independently selected from H; D; -F; -Cl; -Br; -I; -OH; -C 1-3 alkyl; C substituted with 1, 2 or 3 substituents 1-3 alkyl; -C 1-3 alkoxy; a group 1, 2 or 3 substituents of a C 1-3 alkoxy; -C 3-6 cycloalkyl; by 1, 2 or 3 C 3-6 cycloalkyl substituted with a substituent; a 3-6 membered heterocyclic group; or a 3-6 membered heterocyclic group substituted with 1, 2 or 3 substituents; each of said substituents is independently optional Selected from D, -F, -Cl, -Br, -I, -OH, -CN, -NH 2 , -NO 2 , -COOH, methyl, ethyl, propyl, isopropyl, methoxy , Ethoxy, propoxy, or isoprop
- R 4 and R 4 ′ together with the carbon atom to which they are attached form a -C 3-6 carbocyclic ring, a 3-6 membered heterocyclic ring or a 5-8 membered heteroaromatic ring, each of said heterocyclic rings and each heteroaromatic ring
- the rings each independently optionally contain 1 or 2 heteroatoms selected from N, O, or S, and each ring system can be independently optionally substituted with one or more substituents.
- Q is -CR 4 R 4 ′-(CR 4 R 4 ′) q- ;
- R 4 and R 4 ′ are each independently selected from H; D; -F; -Cl; -Br; -I; -OH; -C 1-3 alkyl; C substituted with 1, 2 or 3 substituents 1-3 alkyl; -C 1-3 alkoxy; a group 1, 2 or 3 substituents of a C 1-3 alkoxy; -C 3-6 cycloalkyl; by 1, 2 or 3 C 3-6 cycloalkyl substituted with a substituent; a 3-6 membered heterocyclic group; or a 3-6 membered heterocyclic group substituted with 1, 2 or 3 substituents; each of said substituents is independently optional Selected from D, -F, -Cl, -Br, -I, -OH, -CN, -NH 2 , -NO 2 , -COOH, methyl, ethyl, propyl, isopropyl, methoxy , Ethoxy, propoxy, or isoprop
- R 4 and R 4 ′ together with the carbon atoms to which they are attached form a -C 3-6 carbocyclic ring, a 3-6-membered heterocyclic ring, or a -5-8-membered heteroaromatic ring, each of said heterocyclic rings and each Heteroaryl rings each independently optionally contain 1 or 2 heteroatoms selected from N, O, or S, and each ring system can be independently optionally substituted with one or more substituents.
- Q is -NR 4- (CR 4 R 4 ') q- ;
- R 4 and R 4 ′ are each independently selected from H; D; -F; -Cl; -Br; -I; -OH; -C 1-3 alkyl; C substituted with 1, 2 or 3 substituents 1-3 alkyl; -C 1-3 alkoxy; a group 1, 2 or 3 substituents of a C 1-3 alkoxy; -C 3-6 cycloalkyl; by 1, 2 or 3 C 3-6 cycloalkyl substituted with a substituent; a 3-6 membered heterocyclic group; or a 3-6 membered heterocyclic group substituted with 1, 2 or 3 substituents; each of said substituents is independently optional Selected from D, -F, -Cl, -Br, -I, -OH, -CN, -NH 2 , -NO 2 , -COOH, methyl, ethyl, propyl, isopropyl, methoxy , Ethoxy, propoxy, or isoprop
- R 4 and R 4 ′ together with the carbon atoms to which they are attached form a -C 3-6 carbocyclic ring, a 3-6 membered heterocyclic ring or a 5-8 membered heteroaromatic ring
- the rings each independently optionally contain 1 or 2 heteroatoms selected from N, O, or S, and each ring system can be independently optionally substituted with one or more substituents.
- Q is -CR 4 R 4 '-(CR 4 R 4 ') q -or -NR 4- (CR 4 R 4 ') q- , and q is selected from 0, 1, 2, 3 Or 4;
- R 4 and R 4 ′ are independently selected from H; D; -F; -Cl; -Br; -I; -OH; methyl; ethyl; propyl; isopropyl; -C 1-3 alkyl substituted with a substituent; methoxy; ethoxy; propoxy; isopropoxy; or -C 1-3 alkoxy substituted with 1, 2 or 3 substituents; Cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; C 3-6 cycloalkyl substituted with 1, 2 or 3 substituents; 3-6 membered heterocyclic group; or substituted with 1, 2 or 3 3-6 membered heterocyclic group substituted by substituents; each of said substituents is independently optionally selected from D, -F, -Cl, -Br, -I, -OH, -CN, -NH 2 ,- NO 2 , -COOH, methyl, ethy
- R 4 and R 4 ′ together with the carbon atom to which they are connected form a 3-membered carbocyclic ring; 4-membered carbocyclic ring; 5-membered carbocyclic ring; 6-membered carbocyclic ring; 6-membered heterocyclic ring; 5-membered heteroaromatic ring; 6-membered heteroaromatic ring; 7-membered heteroaromatic ring; 8-membered heteroaromatic ring; each of said heterocyclic rings and each heteroaromatic ring optionally contain 1 independently Or 2 heteroatoms selected from N, O, or S, and each of the carbocyclic rings, each heterocyclic ring, and each heteroaryl ring described are independently optionally substituted with 1, 2 or 3 substituents or Do not replace.
- Q is -CR 4 R 4 ′-(CR 4 R 4 ′) q- ;
- R 4 and R 4 ′ are independently selected from H; D; -F; -Cl; -Br; -I; -OH; methyl; ethyl; propyl; isopropyl; -C 1-3 alkyl substituted with a substituent; methoxy; ethoxy; propoxy; isopropoxy; or -C 1-3 alkoxy substituted with 1, 2 or 3 substituents; Cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; C 3-6 cycloalkyl substituted with 1, 2 or 3 substituents; 3-6 membered heterocyclic group; or substituted with 1, 2 or 3 3-6 membered heterocyclic group substituted by substituents; each of said substituents is independently optionally selected from D, -F, -Cl, -Br, -I, -OH, -CN, -NH 2 ,- NO 2 , -COOH, methyl, ethy
- R 4 and R 4 ′ together with the carbon atoms to which they are connected form a 3-membered carbocyclic ring; a 4-membered carbocyclic ring; a 5-membered carbocyclic ring; a 6-membered carbocyclic ring; a 3-membered heterocyclic ring; a 4-membered heterocyclic ring; a 5-membered heterocyclic ring; 6-membered heterocyclic ring; 5-membered heteroaromatic ring; 6-membered heteroaromatic ring; 7-membered heteroaromatic ring; 8-membered heteroaromatic ring; each of said heterocyclic rings and each heteroaromatic ring optionally contain 1 independently Or 2 heteroatoms selected from N, O, or S, and each of the carbocyclic rings, each heterocyclic ring, and each heteroaryl ring described are independently optionally substituted with 1, 2 or 3 substituents or Do not replace.
- Q is -NR 4- (CR 4 R 4 ') q- ;
- R 4 and R 4 ′ are each independently selected from H; D; -F; -Cl; -Br; -I; -OH; methyl; ethyl; propyl; isopropyl; -C 1-3 alkyl substituted with a substituent; methoxy; ethoxy; propoxy; isopropoxy; or -C 1-3 alkoxy substituted with 1, 2 or 3 substituents; Cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; C 3-6 cycloalkyl substituted with 1, 2 or 3 substituents; 3-6 membered heterocyclic group; or substituted with 1, 2 or 3 3-6 membered heterocyclic group substituted by substituents; each of said substituents is independently optionally selected from D, -F, -Cl, -Br, -I, -OH, -CN, -NH 2 ,- NO 2 , -COOH, methyl, eth
- R 4 and R 4 ′ together with the carbon atoms to which they are connected form a 3-membered carbocyclic ring; a 4-membered carbocyclic ring; a 5-membered carbocyclic ring; a 6-membered carbocyclic ring; a 3-membered heterocyclic ring; a 4-membered heterocyclic ring; a 5-membered heterocyclic ring; 6-membered heterocyclic ring; 5-membered heteroaromatic ring; 6-membered heteroaromatic ring; 7-membered heteroaromatic ring; 8-membered heteroaromatic ring; each of said heterocyclic rings and each heteroaromatic ring optionally contain 1 independently Or 2 heteroatoms selected from N, O, or S, and each of the carbocyclic rings, each heterocyclic ring, and each heteroaryl ring described are independently optionally substituted with 1, 2 or 3 substituents or Do not replace.
- R 5 and R 5 ′ are each independently selected from H; D; -F; -Cl; -Br; -I; -OH; -C 1-3 alkyl; substituents of -C 1-3 alkyl; -C 1-3 alkoxy; 2 or 3 substituents of -C 1-3 alkoxy; -C 3-6 cycloalkyl, ; C 3-6 cycloalkyl substituted with 1, 2 or 3 substituents; 3-6 membered heterocyclic group; 3-6 membered heterocyclic group substituted with 1, 2 or 3 substituents; said each Each substituent is independently optionally selected from D, halogen, -OH, -CN, -NH 2 , -NO 2 , -COOH, -C 1-3 alkyl, or C 1-3 alkoxy; or
- R 5 and R 5 ′ form a C 3-6 carbocyclic ring, a 3-6 membered heterocyclic ring, and a 5-8 membered heteroaromatic ring with the carbon atom to which they are commonly connected, each heterocyclic ring and each heteroaromatic ring described
- R 4 and R 5 together with the atoms to which they are respectively connected form a 5-10 membered aromatic ring, a -C 3-8 carbocyclic ring, and a 4-8 membered heterocyclic ring, each of said heterocyclic groups optionally optionally comprises 1 or 2 heteroatoms selected from N, O or S, each of said ring systems can be independently optionally substituted with one or more substituents.
- R 5 and R 5 ′ are each independently selected from H; D; -F; -Cl; -Br; -I; -OH; methyl; ethyl; propyl; isopropyl; -C 1-3 alkyl substituted with 1, 2 or 3 substituents; methoxy; ethoxy; propoxy; isopropoxy; -C 1- substituted with 1, 2 or 3 substituents 3 alkoxy; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; -C 3-6 cycloalkyl substituted with 1, 2 or 3 substituents; 3 membered heterocyclic group; 4 membered heterocyclic Cyclic group; 5-membered heterocyclic group; 6-membered heterocyclic group; 3-6 membered heterocyclic group substituted with 1, 2 or 3 substituents; each of said heterocyclic groups optionally independently contains 1 Or 2 heteroatoms selected from N, O, or S; each of
- R 5 and R 5 ′ form a 3-membered carbocyclic ring, 4-membered carbocyclic ring, 5-membered carbocyclic ring, 6-membered carbocyclic ring, 3-membered heterocyclic ring, 4-membered heterocyclic ring, 5-membered heterocyclic ring, 6 A heterocyclic ring, a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, a 7-membered heteroaromatic ring, or an 8-membered heteroaromatic ring. 2 heteroatoms selected from N, O or S, and each of said ring systems is independently optionally substituted with 1, 2 or 3 substituents; or
- R 4 and R 5 together with the atoms to which they are connected form a 5-membered aromatic ring, a 6-membered aromatic ring, a 7-membered aromatic ring, an 8-membered aromatic ring, a 9-membered aromatic ring, a 10-membered aromatic ring, a 4-membered carbon ring, and a 5-membered ring Carbocycle, 6-membered carbocyclic ring, 7-membered carbocyclic ring, 8-membered carbocyclic ring, 4-membered heterocyclic ring, 5-membered heterocyclic ring, 6-membered heterocyclic ring, 7-membered heterocyclic ring or 8-membered heterocyclic ring, each of said heterocyclic rings
- R 5 and R 5 ′ are each independently selected from H; D; -F; -Cl; -Br; -I; -OH; methyl; ethyl; propyl; isopropyl; -C 1-3 alkyl substituted with 1, 2 or 3 substituents; methoxy; ethoxy; propoxy; isopropoxy; -C 1- substituted with 1, 2 or 3 substituents 3 alkoxy; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; -C 3-6 cycloalkyl substituted with 1, 2 or 3 substituents; 3 membered heterocyclic group; 4 membered heterocyclic Cyclic group; 5-membered heterocyclic group; 6-membered heterocyclic group; 3-6 membered heterocyclic group substituted with 1, 2 or 3 substituents; each of said heterocyclic groups optionally independently contains 1 Or 2 heteroatoms selected from N, O, or S; each of
- R 4 and R 5 together with the atoms to which they are attached form benzene, naphthalene, 3-membered carbocyclic ring, 4-membered carbocyclic ring, 5-membered carbocyclic ring, 6-membered carbocyclic ring, piperidine, piperazine, oxopiperazine, oxo Piperidine, tetrahydrofuran, tetrahydroimidazole, tetrahydrothiazole, tetrahydrooxazole, tetrahydropyran, tetrahydropyrrole or azapentyl ring, each of said ring systems is optionally optionally 1, 2, or 3 D, -F, -Cl, -Br, -I, -OH, -NH 2 , -CN, -COOH, -NO 2 , methyl, ethyl, propyl, isopropyl, methoxy, Ethoxy, prop
- R 6 is independently selected at each occurrence from H; D; -F; -Cl; -Br; -I; methyl; ethyl; propyl; isopropyl; -C 1-3 alkyl substituted with 2 or 3 substituents; methoxy; ethoxy; propoxy; isopropoxy; C 1-3 alkoxy substituted with 1, 2 or 3 substituents -Methyl-COO-methyl; -ethyl-COO-ethyl; -propyl-COO-propyl; -isopropyl-COO-isopropyl; cyclopropyl; cyclobutyl; cyclopentyl Cyclohexyl; -C 3-6 carbocyclyl substituted with 1, 2 or 3 substituents; each of said substituents is independently optionally selected from D, -F, -Cl, -Br,- I, -OH, -NH 2 , -
- Q and R 6 together with the carbon atom and W to which they are respectively connected form a 4-membered heterocyclic ring, a 5-membered heterocyclic ring, a 6-membered heterocyclic ring, or a 7-membered heterocyclic ring, which heterocyclic ring is optionally optionally substituted by one or more Group is substituted or unsubstituted, the heterocyclic ring optionally optionally contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the substituents is optionally optionally selected from D,- F, -Cl, -Br, -I, -OH, -CN, -NH 2 , -NO 2 , -COOH, -C 1-3 alkyl or C 1-3 alkoxy; or R 4 and R 6 Forms a 5-membered monocyclic heterocyclic group, a 6-membered monocyclic heterocyclic group, a 7-membered monocyclic heterocyclic group, an 8-membere
- the compound is selected from:
- the compound is selected from:
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising at least one compound of Formula I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising at least one compound of the general formula represented by Formula I of the present invention or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
- the present invention also provides a compound of the general formula represented by Structural Formula I or a pharmaceutically acceptable salt thereof, or the use of the pharmaceutical composition in the preparation of a medicament.
- the medicament is used to treat, prevent or prevent a disease or condition mediated by FGFR4 activity.
- the disease or condition mediated by FGFR4 activity is cancer and / or cancer metastasis.
- the disease mediated by FGFR4 activity is selected from one or more of the following diseases: liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostate cancer, ovarian cancer, lung cancer, breast cancer, colorectal cancer, Rhabdomyomas and their combinations.
- the present invention also provides a method for treating, preventing or preventing a disease or condition mediated by FGFR4 activity, which comprises administering to a patient an effective dose of a compound represented by Formula I or a pharmaceutically acceptable salt thereof. , Or the pharmaceutical composition.
- the disease or condition mediated by FGFR4 activity is cancer and / or cancer metastasis.
- the disease mediated by FGFR4 activity is selected from one or more of the following diseases: liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostate cancer, ovarian cancer, lung cancer, breast cancer, colorectal cancer, Rhabdomyomas and their combinations.
- the present invention provides a compound represented by Formula I or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition for treating, preventing or preventing a disease or condition mediated by FGFR4 activity.
- the disease or condition mediated by FGFR4 activity is cancer and / or cancer metastasis.
- the disease mediated by FGFR4 activity is selected from one or more of the following diseases: liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostate cancer, ovarian cancer, lung cancer, breast cancer, colorectal cancer, Rhabdomyomas and their combinations.
- halogen means fluorine, chlorine, bromine or iodine.
- Preferred halogen radicals are fluorine, chlorine and bromine.
- haloC 1-6 alkyl halo C 2-6 alkenyl
- halo C 2-6 alkynyl halo C 1-6 alkoxy
- fluorinated C 1-6 alkyl, fluorinated C 2-6 alkenyl, fluorinated C 2-6 alkynyl, and fluorinated C 1-6 alkoxy especially fluorinated C 1 -3 alkyl, such as -CF 3 , -CHF 2 , -CH 2 F, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 ; fluorinated C 1-3 alkoxy, such as- OCF 3 , -OCHF 2 , -OCH 2 F, -OCH 2 CH 2 F, -OCH 2 CHF 2 or -OCH 2 CF 3 ; especially -CF 3 , -OCF 3 and -OCHF 2 .
- alkyl includes a saturated monovalent hydrocarbon group having a linear, branched, or cyclic moiety.
- alkyl includes methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, 3- (2 -Methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and cyclohexyl.
- a C 1-8 alkyl group is defined in the present invention as a group having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms arranged in a straight or branched chain.
- the alkylene group refers to a difunctional group obtained by removing a hydrogen atom from an alkyl group as defined above.
- methylene i.e. -CH 2-
- ethylene i.e. -CH 2 -CH 2 -or -CH (CH 3 )-
- propylene i.e. -CH 2 -CH 2 -CH 2- , -CH (-CH 2 -CH 3 )-or -CH 2 -CH (CH 3 )-).
- alkoxy refers to a straight-chain or branched-chain alkoxy group containing a specific number of carbon atoms.
- C 1-6 alkoxy means a straight or branched chain alkoxy group containing at least 1 and up to 6 carbon atoms, including, but not limited to, methoxy, ethoxy, propoxy, Prop-2-oxy, butoxy, but-2-oxy, 2-methylprop-1-oxy, 2-methylprop-2-oxy, pentoxy, hexyloxy, cyclopentyl Oxy or methylcyclopropoxy and the like.
- alkenyl refers to an alkyl group, as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond
- C 2-8 alkenyl refers to a group containing 2-8 A linear or branched alkenyl group of one carbon.
- alkynyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond
- C 2-8 alkynyl means containing 2-8 Carbon straight or branched chain alkynyl.
- ethynyl 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl and the like.
- aryl refers to a monocyclic or polycyclic aromatic hydrocarbon by itself or as part of another substituent. Phenyl and naphthyl are preferred aryl. The most preferred aryl is phenyl.
- heterocyclic ring refers to an unsubstituted and substituted monocyclic or polycyclic non-aromatic containing one or more heteroatoms, and some are not Saturated or fully saturated ring systems.
- Preferred heteroatoms include N, O, and S, including N-oxides, sulfur oxides, and dioxides.
- the ring is three to eight members and is fully saturated or has one or more degrees of unsaturation. This definition includes multiple degrees of substitution, preferably one, two or three degrees of substitution.
- heterocyclyls include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, azacycloheptyl, tetrahydrofuran Base, dioxolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, oxadioxane An azole, oxazepine, pyridazinyl, indolyl, pyrimidinyl, pyrazinyl, isothiazolyl, diazanaphthyl, or midazinyl.
- Heterocyclyl includes, but is not limited to, monocyclic heterocyclyl and / or polycyclic heterocyclyl.
- Monocyclic heterocyclyls include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, pyranyl, piperazinyl, morpholinyl, thiomorpholinyl, or homopiperazinyl, etc., preferably pyrrolidinyl, tetrahydrofuran Or pyranyl.
- Polycyclic heterocyclyls include, but are not limited to, spiro, fused and bridged heterocyclyls.
- a "spiroheterocyclyl” refers to a polycyclic heterocyclic atom that shares one atom (a spiro atom) between single rings, where one or more ring atoms are selected from nitrogen, oxygen, and S (O) r (where r is an integer 0 , 1, 2), and the remaining ring atoms are carbon. These can contain one or more double bonds, but none of the rings have a completely conjugated ⁇ -electron system.
- Spirocycloalkyl is divided into monospiroheterocyclyl, bispiroheterocyclyl or polyspiroheterocyclyl based on the number of spiro atoms shared between the rings.
- Spirocycloalkyl includes but is not limited to:
- fused heterocyclyl refers to a polycyclic heterocyclic group where each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more double bonds, but none of them
- the ring has a completely conjugated ⁇ -electron system, in which one or more ring atoms are selected from nitrogen, oxygen, heteroatoms of S (O) r (where r is an integer of 0, 1, 2), and the remaining ring atoms are carbon. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl.
- the fused heterocyclyl includes but is not limited to:
- Bridged heterocyclyl refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected. These may contain one or more double bonds, but none of the rings have a completely conjugated pi electron system.
- One or more ring atoms are selected from the group consisting of nitrogen, oxygen, and S (O) r (where r is an integer of 0, 1, 2), and the remaining ring atoms are carbon. It can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl according to the number of constituent rings.
- the bridged cycloalkyl includes but is not limited to:
- heteroaryl refers to an aromatic ring system containing carbon and at least one heteroatom.
- Heteroaryl groups can be monocyclic or polycyclic, substituted or unsubstituted.
- a monocyclic heteroaryl group may have 1 to 4 heteroatoms in the ring, and a polycyclic heteroaryl group may contain 1 to 10 heteroatoms.
- Polycyclic heteroaryl rings may contain fused spiro or bridged rings, for example, a ring heteroaryl is a polycyclic heteroaryl.
- a bicyclic heteroaryl ring may contain 8 to 12 member atoms.
- a monocyclic heteroaryl ring may contain 5 to 8 member atoms (carbon number and heteroatoms).
- heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridyl Azinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl gland Purinyl, quinolinyl or isoquinolinyl.
- cycloalkyl refers to a substituted or unsubstituted monocyclic, bicyclic or polycyclic non-aromatic saturated or partially unsubstituted hydrocarbon group, which An alkylene linker is optionally included through which a cycloalkyl group can be attached.
- exemplary "cycloalkyl” groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
- oxo refers to the formation of oxygen with the carbon atoms to which it is attached
- R- or S-isomer When a compound described herein is specifically designated as the R- or S-isomer by its chemical name, it should be understood that the main configuration is the R-isomer or the S-isomer, respectively.
- R- or S-designated isomers may be substantially free (less than 5%, less than 1%, or undetectable as determined by chiral HPLC) of each Another isomer at the chiral center.
- the R- or S-isomers can be prepared by the methods exemplified in this application, for example by using a chiral auxiliary such as R- or S-tert-butylsulfinamide during the synthesis.
- R- or S-isomers include, but are not limited to, chiral HPLC purification of a mixture of stereoisomers (e.g., a racemic mixture).
- chiral HPLC purification of a mixture of stereoisomers e.g., a racemic mixture.
- General methods for separating stereoisomers, such as enantiomers and / or diastereomers, using HPLC are known in the art.
- the compounds described herein may exist in isotopically labeled or enriched forms that contain one or more atoms having an atomic mass or mass number different from the most abundant atomic mass or mass number in nature.
- the isotope can be a radioactive or non-radioactive isotope.
- Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine, and iodine include, but are not limited to, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 32 P, 35 S, 18 F, 36 C1 and 125 I.
- Compounds containing other isotopes of these and / or other atoms are within the scope of the invention.
- one or more hydrogen atoms of any of the compounds described herein can be replaced with deuterium to provide the corresponding labeled or enriched compound.
- the term "subject” refers to an animal, preferably a mammal, most preferably a human, who has been the subject of a treatment, observation, or experiment.
- ring system (may also be referred to as “ring system”) as used herein includes, but is not limited to, carbocycles, heterocycles, heteroaryl rings, etc., and may also include only heterocycles and / or Heteroaryl rings, and specifically include which rings are determined as the context requires.
- composition in the present invention is intended to include a product containing a specific amount of a specific component, and also includes any product obtained directly or indirectly from a specific amount of a specific component. Therefore, a pharmaceutical composition containing the compound in the present invention as an active ingredient and a method for preparing the same are also the contents of the present invention. Moreover, the crystalline forms of some compounds may exist in polymorphic forms, and these are also included in the present invention. In addition, some compounds form solvates with water (such as hydrates) or common organic solvents, and these solvates are also included in the present invention.
- the compounds provided by the present invention may also exist in the form of pharmaceutically acceptable salts.
- the salt of the compound provided by the present invention refers to a non-toxic "pharmaceutically acceptable salt".
- Pharmaceutically acceptable salt forms include pharmaceutically acceptable acid / anionic or base / cationic salts.
- Pharmaceutically acceptable acid / anionic salts generally exist in the form of a basic nitrogen that is protonated with an inorganic or organic acid.
- Typical organic or inorganic acids include hydrochloric acid, hydrofluoric acid, hydroiodic acid, perchloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, lactic acid, succinic acid, maleic acid, fumaric acid, and malic acid , Tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, isethionic acid, benzenesulfonic acid, oxalic acid, acetic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfonic acid, water Salicylic acid, saccharinic acid or trifluoroacetic acid.
- Pharmaceutically acceptable base / cationic salts including, but not limited to, aluminum, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, lithium, magnesium, potassium, sodium Salt and
- Prodrugs of the compounds of the invention are included within the scope of the invention.
- the prodrug refers to a functional derivative that is easily converted into the desired compound in vivo. Therefore, the term "administration" in the method of treatment provided by the present invention includes administering a compound disclosed in the present invention, or, although not explicitly disclosed, it can be converted into the compound disclosed in the present invention after administration to a subject.
- Various diseases Conventional methods for selecting and preparing suitable prodrug derivatives have been described in books such as Design of Prodrugs (ed. H. Bundgaard, Elsevier, 1985).
- any substituent or variable at a particular position is independent of the definition of the substituent or variable at other positions in the molecule. It should be understood that the substituents and substituted forms on the compounds of the present invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and can be easily synthesized by techniques known in the art and those methods proposed herein.
- the compounds according to the invention may contain one or more asymmetric centers and may result in diastereomers and optical isomers.
- the invention includes all possible diastereomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and their pharmaceutically acceptable salts.
- the above formula (I) does not precisely define the stereo structure of a certain position of the compound.
- the present invention includes all stereoisomers of the compound represented by formula (I) and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers and specific stereoisomers isolated are also included in the present invention. During the synthesis of such compounds, or during the use of racemization or epimerization methods known to those of ordinary skill in the art, the product obtained may be a mixture of stereoisomers.
- the present invention includes any possible tautomer and a pharmaceutically acceptable salt thereof, and mixtures thereof.
- the present invention includes any possible solvate and polymorph.
- the type of the solvate-forming solvent is not particularly limited as long as the solvent is pharmacologically acceptable.
- water, ethanol, propanol, acetone and the like can be used.
- pharmaceutically acceptable salt refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid.
- pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases.
- Salts derived from inorganic bases include salts such as aluminum, ammonium, calcium, copper (high and low prices), ferric, ferrous, lithium, magnesium, manganese (high and low prices), potassium, sodium, zinc and the like. Particularly preferred are the salts of ammonium, calcium, magnesium, potassium and sodium.
- Non-toxic organic bases capable of deriving into pharmaceutically acceptable salts include primary, secondary, and tertiary amines, as well as cyclic amines and amines containing substituents, such as naturally occurring and synthetic amines containing substituents.
- non-toxic organic bases capable of forming salts include ion exchange resins and arginine, betaine, caffeine, choline, N ', N'-dibenzylethylenediamine, diethylamine, 2 -Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorphamine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, halamine, isopropylamine , Lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
- the compound provided by the present invention is a base
- its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids.
- acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionate , Lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, acetic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid.
- citric acid Preferably, citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid. More preferably, formic acid and hydrochloric acid. Since the compound represented by formula (I) will be used as a medicament, it is preferable to use a substantially pure form, for example, at least 60% purity, more suitably at least 75% purity, especially at least 98% purity (% is a weight ratio ).
- the pharmaceutical composition provided by the present invention comprises, as an active ingredient, a compound represented by formula (I) (or a pharmaceutically acceptable salt thereof), a pharmaceutically acceptable excipient, and other optional therapeutic components or Excipients.
- a compound represented by formula (I) or a pharmaceutically acceptable salt thereof
- a pharmaceutically acceptable excipient or other optional therapeutic components or Excipients.
- the pharmaceutical compositions of the present invention include those suitable for oral, rectal, topical and Pharmaceutical composition for parenteral (including subcutaneous, intramuscular, intravenous) administration.
- the pharmaceutical composition of the present invention can be conveniently prepared in the form of unit dosage forms known in the art and any preparation method known in the pharmaceutical field.
- the compound represented by formula (I), or a prodrug, or a metabolite, or a pharmaceutically acceptable salt of the present invention can be mixed with a drug carrier to form a drug combination as an active ingredient.
- a drug carrier can take a variety of forms depending on the mode of administration desired, for example, oral or injection (including intravenous). Therefore, the pharmaceutical composition of the present invention may be in the form of a separate unit suitable for oral administration, such as a capsule, cachet, or tablet containing a predetermined dose of the active ingredient.
- the pharmaceutical composition of the present invention may be in the form of a powder, granule, solution, aqueous suspension, non-aqueous liquid, oil-in-water emulsion, or water-in-oil emulsion.
- the compound represented by formula (I) or a pharmaceutically acceptable salt thereof may also be administered by a controlled release manner and / or a delivery device.
- the pharmaceutical composition of the present invention can be prepared by any pharmaceutical method. Generally, this method includes the step of associating the active ingredient with a carrier that makes up one or more of the necessary ingredients.
- the pharmaceutical composition is prepared by uniformly and intimately mixing an active ingredient with a liquid carrier or a finely divided solid carrier or a mixture of the two. The product can then be conveniently prepared to the desired appearance.
- the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier and a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
- a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and a compound having a therapeutic activity in combination with one or more other compounds are also included in the pharmaceutical composition of the present invention.
- the pharmaceutical carrier used in the present invention may be, for example, a solid carrier, a liquid carrier, or a gas carrier.
- Solid carriers include lactose, gypsum powder, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, and stearic acid.
- Liquid carriers including syrup, peanut oil, olive oil, and water.
- Gas carriers including carbon dioxide and nitrogen.
- any convenient pharmaceutical medium can be used.
- water, ethylene glycol, oils, alcohols, flavor enhancers, preservatives, colorants and the like can be used for oral liquid preparations such as suspensions, elixirs and solutions; and carriers such as starches, sugars, Microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like can be used for oral solid preparations such as powders, capsules and tablets.
- oral solid preparations such as powders, capsules and tablets.
- tablets and capsules are preferred for oral formulations.
- the tablet coating may use standard aqueous or non-aqueous formulation techniques.
- Tablets containing a compound or pharmaceutical composition of the invention can be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.
- the active ingredients are mixed in a free-flowing form, such as a powder or granules, with lubricants, inert diluents, surfactants or dispersants, and compressed tablets can be made by compression in a suitable machine.
- a powdered compound or pharmaceutical composition is wetted with an inert liquid diluent, and then molded in a suitable machine to form a molded tablet.
- each tablet contains about 0.05 mg to 5 g of active ingredient
- each cachet or capsule contains about 0.05 mg to 5 g of active ingredient.
- a dosage form intended for oral administration in humans contains from about 0.5 mg to about 5 g of active ingredient, compounded with a suitable and conveniently metered auxiliary material that accounts for about 5% to 95% of the total pharmaceutical composition.
- Unit dosage forms generally contain from about 1 mg to about 2 g of active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.
- the pharmaceutical composition suitable for parenteral administration provided by the present invention can be prepared by adding the active ingredient to water to prepare an aqueous solution or suspension.
- a suitable surfactant such as hydroxypropyl cellulose may be included.
- Dispersion systems can also be prepared in glycerol, liquid polyethylene glycols, and their mixtures in oils. Further, a preservative may be included in the pharmaceutical composition of the present invention to prevent the growth of harmful microorganisms.
- the invention provides pharmaceutical compositions suitable for injection, including sterile aqueous solutions or dispersions.
- the above-mentioned pharmaceutical composition can be prepared in the form of a sterile powder that can be used for instant preparation of a sterile injection solution or dispersion.
- the final injection form must be sterile and, for easy injection, it must be easy to flow.
- the pharmaceutical composition must be stable during preparation and storage. Therefore, preservation against contamination by microorganisms such as bacteria and fungi is preferred.
- the carrier can be a solvent or dispersion medium, for example, water, ethanol, polyol (such as glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.
- the pharmaceutical composition provided by the present invention may be in a form suitable for topical application, for example, an aerosol, an emulsion, an ointment, a lotion, a dusting powder, or other similar dosage forms. Further, the pharmaceutical composition provided by the present invention may be in a form suitable for use in a transdermal drug delivery device.
- These preparations can be prepared by a conventional processing method using the compound represented by formula (I) of the present invention, or a pharmaceutically acceptable salt thereof.
- an emulsion or ointment is prepared by adding a hydrophilic material and water to about 5 to 10% by weight of the above-mentioned compound to obtain an emulsion or ointment having a desired consistency.
- the pharmaceutical composition provided by the present invention can be made into a form suitable for rectal administration with a solid as a carrier.
- a preferred dosage form is that the mixture forms a unit dose suppository.
- Suitable excipients include cocoa butter and other materials commonly used in the art. Suppositories can be conveniently prepared by first mixing the pharmaceutical composition with softened or melted excipients, and then cooling and moulding.
- the above pharmaceutical preparations may also include, as appropriate, one or more additional excipient components such as diluents, buffers, flavoring agents, binders, surfactants, Thickeners, lubricants, preservatives (including antioxidants), etc.
- additional excipient components such as diluents, buffers, flavoring agents, binders, surfactants, Thickeners, lubricants, preservatives (including antioxidants), etc.
- other adjuvants may include penetration enhancers that regulate the isotonic pressure of the drug and blood.
- a pharmaceutical composition containing the compound represented by formula (I), or a pharmaceutically acceptable salt thereof may also be prepared in the form of a powder or a concentrated solution.
- the dosage level of the drug is about 0.01 mg / kg body weight to 150 mg / kg body weight per day, or 0.5 mg to 7 g per patient per day.
- inflammation, cancer, psoriasis, allergies / asthma, diseases and discomforts of the immune system, diseases and discomforts of the central nervous system (CNS) effective dosages of drugs for treatment from 0.01 mg / kg to 50 mg / kg body weight per day, 0.5mg to 3.5g per patient per day.
- the specific dose level for any particular patient will depend on a number of factors, including age, weight, general health, gender, diet, timing of administration, route of administration, excretion rate, status of combination medications and acceptance The severity of the specific disease being treated.
- Dimethoxyethyl acetate (147.59 g, 1.00 mol) was dissolved in EtOAc (150.23 g, 1.71 mol), Na (33.42 g, 1.45 mol) was added at 60 ° C, and the mixture was stirred at reflux overnight. It was cooled to room temperature, diluted with EtOAc (500 mL), concentrated under reduced pressure, and subjected to silica gel column chromatography to obtain compound A1-1 (135.47 g, 0.71 mol).
- the method for preparing compound E1-1 is the same as the method for synthesizing D1-1 in the preparation of intermediate D1.
- the method for preparing compound F1-1 is the same as the method for synthesizing D1-1 in the preparation of intermediate D1.
- the method for preparing compound F1 refers to the synthetic steps of E1-3 in preparing intermediate E1.
- This experiment employed a method of changing the mobility (mobility shift assay) test compound inhibition of FGFR4 kinase activity, and inhibition rate of the compound obtained FGFR4 kinase activity or on the half maximal inhibitory concentration IC 50.
- the test compound is configured as a concentration gradient in 100% DMSO, and a buffer solution (pH of the buffer solution is 7.5, which contains 50 mM HEPES (N- (2-hydroxyethyl) piperazine-N'-2 sulfonic acid) ), 0.00015% (ml / ml) Brij-35 (dodecyl polyethylene glycol ether) and the balance of water) were diluted to 10% DMSO, and added to a 384-well plate.
- a buffer solution pH of the buffer solution is 7.5, which contains 50 mM HEPES (N- (2-hydroxyethyl) piperazine-N'-2 sulfonic acid)
- 0.00015% ml / ml
- Brij-35 diodecyl polyethylene glycol ether
- FGFR4 enzyme (Invitrogen, Cat. No. PR4380A, Lot. No. 1856505A) buffer (the buffer pH is 7.5, which contains 50mM HEPES, 0.00015% (ml / ml) Brij-35, 2mM DTT (disulfide Threitol) and the balance of water) were diluted to the optimal concentration (final concentration 12.5 nM). Transfer 10 ⁇ l to a 384-well plate and incubate with the test compound for 10-15 minutes;
- the reference compound in the present invention has the following structure:
- the MTS method was used to test the inhibitory effect of the compound on the proliferation of hepatocellular carcinoma cells Hep3B (high expression of FGFR4 and FGF19), and the IC 50 of the inhibitory concentration of the compound on Hep3B was obtained.
- Hep3B cell line was purchased from ATCC, and its complete medium was MEM + 10% FBS + 1% PS.
- MEM cell culture medium, fetal bovine serum, trypsin were purchased from Gibco, cell culture bottles were purchased from Greiner, disposable cell counting plates, and trypan blue solution were purchased from Bio-Rad.
- the microplate reader measures the chemiluminescence signal value of each plate at a wavelength of 492nm;
- SD rats (Vitalone) are used to perform compound pharmacokinetic experiments on compounds.
- Mode of administration single intragastric administration and intravenous injection;
- Oral administration before administration, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 24h;
- Intravenous injection before administration, 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 24h;
- Mobile phase B 95% acetonitrile and 5% water (0.1% FA);
- Injection volume 5 ⁇ L.
- Mobile phase B 95% acetonitrile and 5% water (0.1% FA);
- Injection volume 3 ⁇ L.
- Mobile phase B 95% acetonitrile and 5% water (0.1% FA);
- Injection volume 10 ⁇ L.
- Mobile phase B 95% acetonitrile and 5% water (0.1% FA);
- Injection volume 2 ⁇ L.
- Q1, Q3, DP, EP, CE, and CXP in the table respectively represent Q1: parent ion; Q3: product ion; DP: declustered voltage; EP: inlet voltage; CE: collision energy; CXP: collision chamber outlet voltage.
- p.o. refers to oral administration.
- Example D NOD-SCID mouse PK / PD
- This experiment is an in vivo pharmacodynamic experiment. Blood and tumor are taken at different time points to administer intragastric administration to detect the blood concentration and the drug concentration in the tumor.
- Blood sample sampling time points Compound 4, reference compound sampling points were before administration, 1h, 2h, 4h, and 6h, and each sampling point was 3 mice.
- Tumor sample sampling time points Compound 4, reference compound sampling points were 4h, 6h each sampling point was 3 mice.
- Tumor sample collection 200-300mg of each tumor tissue was taken to indicate the tumor weight. After quick freezing in liquid nitrogen, it was tested in a refrigerator at -80 °C.
- the chromatographic separation conditions and mass spectrometry analysis conditions are as follows:
- Mobile phase B 95% acetonitrile and 5% water (0.1% FA);
- Injection volume 2 ⁇ L.
- Q1, Q3, DP, EP, CE, and CXP in the table respectively represent Q1: parent ion; Q3: product ion; DP: declustered voltage; EP: inlet voltage; CE: collision energy; CXP: collision chamber outlet voltage.
- p.o. refers to oral administration.
- Example E In vivo efficacy
- Hep3B cell line was purchased from ATCC, MEM cell culture medium, fetal bovine serum, trypsin was purchased from Gibco, cell culture bottles were purchased from Greiner, disposable cell counting plates and trypan blue solution were purchased from Bio-Rad. Disposable sterile syringes were purchased from Changzhou Jinlong Medical Plastic Equipment Co., Ltd. Ophthalmic surgical scissors and ophthalmic surgical tweezers were purchased from Shanghai Medical Instrument (Group) Co., Ltd. Surgical Instrument Factory. Viton Lihua.
- tumor volume (mm 3 ) length (mm) ⁇ width (mm) ⁇ width (mm) / 2
- the tumor grows to an average volume of 100-150 mm 3 , it is randomly divided into two groups for administration according to tumor size and mouse weight. Each group has 9 animals, one of which is the control group and the rest are the administration group.
- the method of administration is gavage.
- the control group is administered with 10% DMSO + 90% ddH 2 O.
- the dosages of the administration group are compound 4: 15/30 / 60mg / kg, which are administered once a day.
- Compound 4 15 mg / kg, twice daily, reference compound: 60 mg / kg, once daily.
- the solvent of compound 4 is: 10% DMSO + 90% ddH 2 O, and the solvent of the reference compound is: 100% ddH 2 O. Tumors were measured and weighed twice a week after the start of administration.
- TGI (Tumor growth inhibition)% (1-tumor weight of experimental group / tumor weight of control group) ⁇ 100%.
- the compound 4 of the present invention has an excellent tumor suppressing effect, and the effect of 60 mg / kg QD of the reference compound can be achieved by administering 15 mg / kg BID. The same effect is achieved, but the dosage is reduced by half, which results in less toxic and side effects and higher safety.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (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)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
Description
DCM | 二氯甲烷 |
EtOAc | 乙酸乙酯 |
EtOH | 乙醇 |
THF | 四氢呋喃 |
DMF | N,N-二甲基甲酰胺 |
CH 3CN | 乙腈 |
TFA | 三氟乙酸 |
MnO 2 | 二氧化锰 |
DPPF | 1,1'-双(二苯基膦)二茂铁 |
DIEA/DIPEA | N,N-二异丙基乙胺 |
Pd 2(dba) 3 | 三(二亚苄基丙酮)二钯 |
Zn(CN) 2 | 氰化锌 |
NIS | 碘代琥珀酰亚胺 |
Na | 钠 |
Na 2SO 4 | 硫酸钠 |
NaCl | 氯化钠 |
HATU | 2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯 |
Boc 2O | 二碳酸二叔丁酯 |
化合物 | Hep3B(IC 50μM) | 化合物 | Hep3B(IC 50μM) |
化合物1 | 0.023 | 化合物64 | 0.018 |
化合物2 | 0.028 | 化合物68 | 0.026 |
化合物4 | 0.014 | 化合物69 | 0.067 |
化合物6 | 0.049 | 化合物71 | 0.049 |
化合物7 | 0.011 | 化合物72 | 0.282 |
化合物8 | 0.008 | 化合物73 | 0.039 |
化合物9 | 0.009 | 化合物74 | 0.060 |
化合物11 | 0.035 | 化合物75 | 0.028 |
化合物16 | 0.029 | 化合物76 | 0.006 |
化合物20 | 0.021 | 化合物82 | 0.020 |
化合物27 | 0.282 | 化合物83 | 0.068 |
化合物56 | 0.013 | 参照化合物 | 0.024 |
化合物62 | 0.054 |
时间(Time) | 流动相A(%) | 流动相B(%) |
0.00 | 95.0 | 5.00 |
0.20 | 95.0 | 5.00 |
1.00 | 0.00 | 100 |
2.20 | 0.00 | 100 |
2.21 | 95.0 | 5.00 |
4.00 | 95.0 | 5.00 |
时间(Time) | 流动相A(%) | 流动相B(%) |
0.00 | 95.0 | 5.00 |
0.15 | 95.0 | 5.00 |
1.50 | 0.00 | 100 |
2.50 | 0.00 | 100 |
2.60 | 95.0 | 5.00 |
3.80 | 95.0 | 5.00 |
时间(Time) | 流动相A(%) | 流动相B(%) |
0.00 | 95.0 | 5.00 |
0.15 | 95.0 | 5.00 |
1.50 | 0.00 | 100 |
2.50 | 0.00 | 100 |
2.60 | 95.0 | 5.00 |
3.80 | 95.0 | 5.00 |
时间(Time) | 流动相A(%) | 流动相B(%) |
0.00 | 95.0 | 5.00 |
0.30 | 95.0 | 5.00 |
1.80 | 5.00 | 95.0 |
2.50 | 5.00 | 95.0 |
2.51 | 95.0 | 5.00 |
3.00 | 95.0 | 5.00 |
化合物 | Q1 | Q3 | DP | EP | CE | CXP |
化合物1 | 523.252 | 175.100 | 96 | 10 | 35 | 16 |
化合物7 | 508.287 | 175.100 | 96 | 10 | 35 | 16 |
化合物16 | 538.278 | 175.000 | 111 | 10 | 37 | 12 |
Verapamil | 455.216 | 165.100 | 91 | 10 | 37 | 12 |
化合物 | Q1 | Q3 | DP | EP | CE | CXP |
化合物4 | 537.083 | 175.100 | 76 | 10 | 37 | 14 |
化合物5 | 535.095 | 174.900 | 71 | 10 | 39 | 12 |
化合物20 | 549.071 | 175.100 | 71 | 10 | 37 | 12 |
化合物56 | 546.026 | 175.100 | 36 | 10 | 35 | 12 |
化合物71 | 537.078 | 175.000 | 146 | 10 | 37 | 14 |
Verapamil | 455.216 | 165.100 | 91 | 10 | 37 | 12 |
化合物 | Q1 | Q3 | DP | EP | CE | CXP |
参照化合物 | 507.252 | 175.100 | 56 | 10 | 25 | 14 |
Dexamethasone | 393.171 | 373.000 | 96 | 10 | 13 | 10 |
时间(Time) | 流动相A(%) | 流动相B(%) |
0.00 | 95.0 | 5.00 |
0.30 | 95.0 | 5.00 |
1.80 | 5.00 | 95.0 |
2.50 | 5.00 | 95.0 |
2.51 | 95.0 | 5.00 |
3.00 | 95.0 | 5.00 |
化合物 | Q1 | Q3 | DP | EP | CE | CXP |
参照化合物 | 507.252 | 175.100 | 56 | 10 | 25 | 14 |
Dexamethasone | 393.171 | 373.000 | 96 | 10 | 13 | 10 |
化合物 | Q1 | Q3 | DP | EP | CE | CXP |
化合物4 | 537.083 | 175.100 | 76 | 10 | 37 | 14 |
Verapamil | 455.216 | 165.100 | 91 | 10 | 37 | 12 |
组别 | TGI% |
化合物4 15mg/kg BID | 96.7 |
参照化合物60mg/kg QD | 97.7 |
Claims (50)
- 结构式I所示的化合物或其药学上可接受的盐:其中:X在每次出现时均独立地选自不存在、O、-NR X1-或-CR X1R X2-;且p是0、1、2或3;R X1和R X2在每次出现时均独立地选自H;D;-F;-Cl;-Br;-I;-C 1-6烷基;被1、2或3个取代基取代的C 1-6烷基;C 1-6烷氧基或被1、2或3个取代基取代的C 1-6烷氧基;所述每个取代基在每次出现时独立地任选地选自D、卤素、-OH、-CN、-NH 2、-NO 2、-COOH、-C 1-3烷基或C 1-3烷氧基;Y在每次出现时均独立地选自O或S;R 7在每次出现时均独立地选自H、D、-C 1-6烷基、-C 1-6烷氧基、-C 3-8环烷基或3-8元杂环基,R 7在每次出现时均独立地任选地被一个或多个选自D、-F、-Cl、-Br、-I、-OH、氧代、=O、-SH、-CN、-NO 2、-N 3、-C 1-3烷基、-C 1-3烷氧基、-C 2-4链烯基、-C 2-4链炔基、卤代C 1-3烷基、-C 3-6环烷基、3-6元杂环基、3-6元杂环基氧基、3-6元杂环基硫基、C 5-8芳基、C 5-8芳基氧基、C 5-8芳基硫基、5-8元杂芳环、5-8元杂芳基氧基、5-8元杂芳基硫基、-S(O) tR 9、-C 1-3烷基-S(O) tR 9、-O-R 10、-C 1-3烷基-O-R 10、-C(O)OR 10、-C 1-3烷基-C(O)OR 10、-C(O)R 11、-C 1-3烷基-C(O)R 11、-O-C(O)R 11、-C 1-3烷基-O-C(O)R 11、-NR 12R 13、-C 1-3烷基-NR 12R 13、-C(O)NR 12R 13、-C 1-3烷基-C(O)NR 12R 13、-N(R 12)-C(O)R 11或-N(R 12)-C(O)OR 10的取代基取代或不取代;R 8在每次出现时均独立地选自H、D、-C 1-6烷基、-C 1-6烷氧基、-C 2-6链烯基、-C 2-6链炔基、-C(O)R 11、-C 1-6烷基-C(O)R 11、-C 3-6环烷基、3-8元杂环基,R 8在每次出现时均独立 地任选地被一个或者多个选自D、-F、-Cl、-Br、-I、-OH、氧代、=O、-SH、-CN、-NO 2、-N 3、-C 1-3烷基、-C 2-4链烯基、-C 2-4链炔基、卤代C 1-3烷基、-C 3-6环烷基、3-6元杂环基、3-6元杂环基氧基、3-6元杂环基硫基、C 5-8芳基、C 5-8芳基氧基、C 5-8芳基硫基、5-8元杂芳环、5-8元杂芳基氧基、5-8元杂芳基硫基、-S(O) tR 9、-C 1-3烷基-S(O) tR 9、-O-R 10、-C 1-3烷基-O-R 10、-C(O)OR 10、-C 1-3烷基-C(O)OR 10、-C(O)R 11、-C 1-3烷基-C(O)R 11、-O-C(O)R 11、-C 1-3烷基-O-C(O)R 11、-NR 12R 13、-C 1-3烷基-NR 12R 13、-C(O)NR 12R 13、-C 1-3烷基-C(O)NR 12R 13、-N(R 12)-C(O)R 11或-N(R 12)-C(O)OR 10的取代基取代或不取代;或R 7和R 8与它们分别连接的碳原子和氮原子一起形成5-10元单环杂环基、5-12元螺环杂环基、5-12元稠环杂环基或5-12元桥环杂环基,所述每个环系在每次出现时均独立地任选地被一个或者多个选自D、-F、-Cl、-Br、-I、-OH、氧代、=O、-SH、-CN、-NO 2、-N 3、-C 1-3烷基、-C 1-3烷氧基、-C 2-4链烯基、-C 2-4链炔基、卤代C 1-3烷基、-C 3-6环烷基、取代或未取代的3-6元杂环基、3-6元杂环基氧基、3-6元杂环基硫基、C 5-8芳基、C 5-8芳基氧基、C 5-8芳基硫基、5-8元杂芳环、5-8元杂芳基氧基、5-8元杂芳基硫基、-S(O) tR 9、-C 1-3烷基-S(O) tR 9、-O-R 10、-C 1-3烷基-O-R 10、-C(O)OR 10、-C 1-3烷基-C(O)OR 10、-C(O)R 11、-C 1-3烷基-C(O)R 11、-O-C(O)R 11、-C 1-3烷基-O-C(O)R 11、-NR 12R 13、-C 1-3烷基-NR 12R 13、-C(O)NR 12R 13、-C 1-3烷基-C(O)NR 12R 13、-N(R 12)-C(O)R 11或-N(R 12)-C(O)OR 10的取代基取代或不取代;R 2和R 3在每次出现时均独立地选自H;D;-F;-Cl;-Br;-I;-OH;-SH;-CN;-NH 2;-NO 2;-N 3;-C 1-6烷基;被1、2或3个-D、-F、-Cl、-Br、-I、-OH、-CN、-NH 2、-NO 2、-COOH、-C 1-3烷基或C 1-3烷氧基取代的-C 1-6烷基;C 1-6烷氧基;被1、2或3个-D、-F、-Cl、-Br、-I、-OH、-CN、-NH 2、-NO 2、-COOH、-C 1-3烷基或C 1-3烷氧基取代的C 1-6烷氧基;取代或未取代的C 3-8环烷基;取代或未取代的3-8元杂环基;取代或未取代的3-8元杂环氧基;取代或未取代的3-8元杂环硫基;-S(O) tR 9;-C 1-6烷基-S(O) tR 9;-O-R 10;-C 1-6烷基-O-R 10;-C(O)OR 10;-C 1-6烷基-C(O)OR 10;-C(O)R 11;-C 1-6烷基-C(O)R 11;-O-C(O)R 11;-C 1-6烷基-O-C(O)R 11;-NR 12R 13;-C 1-6烷基-NR 12R 13;-C(O)NR 12R 13;-C 1-6烷基-C(O)NR 12R 13;-N(R 12)-C(O)R 11或-N(R 12)-C(O)OR 10;G在每次出现时均独立地选自-CR G1R G2-、-NR G1-、-S-、-SO-、-SO 2-或O;m是0、1、2、3或4;每个R G1和R G2在每次出现时均独立地选自H;D;-C 1-6烷基;被1、2或3个取代基取代的-C 1-6烷基;-C 1-6烷氧基;被1、2或3个取代基取代的-C 1-6烷氧基;所述每个取代基独立地任选地选自D、卤素、-OH、-CN、-NH 2、-NO 2、-COOH、-C 1-3烷基或C 1-3烷氧基;Q在每次出现时均独立地选自-CR 4R 4’-(CR 4R 4’) q-或-NR 4-(CR 4R 4’) q-,且q选自0、1、2、3或4;R 4和R 4’在每次出现时均独立地选自H;D;-F;-Cl;-Br;-I;-OH;-C 1-6烷基;被1、2或3个取代基取代的C 1-6烷基;-C 1-6烷氧基;被1、2或3个取代基取代的C 1-6烷氧基;-C 3-8环烷基;被1、2或3个取代基取代的C 3-8环烷基;3-8元杂环基;被1、2或3个取代基取代的3-8元杂环基;所述每个取代基在每次出现时均独立地任选地选自D、卤素、-OH、-CN、-NH 2、-NO 2、-COOH、-C 1-3烷基或C 1-3烷氧基;或R 4和R 4’与它们共同连接的碳原子一起形成C 3-8碳环、3-8元杂环或-5-10元杂芳环,每个环系在每次出现时均可独立地任选地被一个或多个取代基取代或不取代;R 5和R 5’在每次出现时均独立地选自H;D;-F;-Cl;-Br;-I;-OH;-C 1-6烷基;被1、2或3个取代基取代的-C 1-6烷基;-C 1-6烷氧基;被1、2或3个取代基取代的-C 1-6烷氧基;-C 3-8环烷基;被1、2或3个取代基取代的C 3-8环烷基;3-8元杂环基;被1、2或3个取代基取代的3-8元杂环基;所述每个取代基在每次出现时均独立地任选地选自D、卤素、-OH、-CN、-NH 2、-NO 2、-COOH、-C 1-3烷基或C 1-3烷氧基;或R 5和R 5’与它们共同连接的碳原子形成-C 3-8碳环、3-8元杂环、5-10元杂芳环,所述的每个杂环基和每个杂芳基在每次出现时均独立地任选地包含1或2个选自N、O或S的杂原子,所述的每个环系在每次出现时均可独立地任选地被一个或多个取代基取代或不取代;或R 4和R 5与它们分别连接的原子一起形成5-10元芳环、-C 3-10碳环、4-10元杂环,所述的每个杂环基在每次出现时均独立地任选地包含1或2个选自N、O或S的杂原子,所述的每个环系在每次出现时均可独立地任选地被一个或多个取代基取代或不取代;W在每次出现时均独立地选自-(CR w1R w2) n-S-、-(CR w1R w2) n-SO-或-(CR w1R w2) n-SO 2-,n选自0、1、2、3或4;R w1和R w2在每次出现时均独立地选自H;D;-F;-Cl;-Br;-OH;甲基;乙基;丙基;异丙基;被1、2或3个取代基取代的-C 1-3烷基;甲氧基;乙氧基;丙氧基;异丙氧基;被1、2或3个取代基取代的-C 1-3烷氧基;环丙基;环丁基;环戊基;环己基;被1、2或3个取代基取代的-C 3-6环烷基;3元杂环基;4元杂环基;5元杂环基;6元杂环基或被1、2或3个取代基取代的3-6元杂环基;所述每个取代基在每次出现时均独立地任选地选自D、-F、-Cl、-Br、-I、-OH、-CN、-NH 2、-NO 2、-COOH、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基;R 6在每次出现时均独立地选自H;D;-F;-Cl;-Br;-I;-C 1-3烷基;被1、2或3个 取代基取代的-C 1-3烷基;-C 1-3烷氧基;被1、2或3个取代基取代的-C 1-3烷氧;-C 1-3烷基-COO-C 1-3烷基、-C 3-6环烷基或被1、2或3个取代基取代的-C 3-6环烷基;所述每个取代基独立地任选地选自D、卤素、-OH、-CN、-NH 2、-NO 2、-COOH、-C 1-3烷基或C 1-3烷氧基;或Q和R 6与它们分别连接的碳原子和W一起形成4-6元杂环,所述杂环独立地任选地被一个或多个取代基取代或不取代,所述的杂环独立地任选地包含1、2或3个选自N、O或S的杂原子,所述每个取代基独立地任选地选自D、卤素、-OH、-CN、-NH 2、-NO 2、-COOH、-C 1-3烷基或-C 1-3烷氧基;或R 4和R 6与它们分别相连的原子一起形成5-8元单环杂环基、5-10元螺环杂环基、5-10元稠环杂环基、5-10元桥环杂环基或5-10元杂芳环,所述每个环系均独立地任选地包含1、2或3个选自N、O或S的杂原子,所述每个环系均独立地任选地被1个、2个或3个D、-F、-Cl、-Br、-I、-OH、-NH 2、-CN、-COOH、氧代基、=O、-C 1-3烷基或-C 1-3烷氧基取代或不取代;或R 5和R 6与它们分别连接的碳原子和W一起形成4-6元杂环或5-8元杂芳环,所述每个环系均独立地任选地包含1、2或3个选自N、O或S的杂原子,所述每个环系均独立地任选地被1个、2个或3个D、-F、-Cl、-Br、-I、-OH、-NH 2、-CN、-COOH、氧代基、=O、-C 1-3烷基、-C 1-3烷氧基取代或不取代;每个R 9在每次出现时均独立地选自H、D、-C 1-3烷基、-C 1-3烷基C 1-3烷氧基、-C 2-4链烯基、-C 3-6环烷基、取代或未取代的3-6元杂环基、卤代C 1-3烷基、苯基、对甲基苯基、氨基、-NH-C 1-3烷基、-N(C 1-3烷基) 2或C 1-3烷酰胺基;每个R 10在每次出现时均独立地选自H、D、-C 1-3烷基、-C 1-3烷基C 1-3烷氧基、-C 3-6环烷基、-C 5-10芳基、卤代C 1-3烷基或羟基取代C 1-3烷基;每个R 11在每次出现时均独立地选自H、D、-C 1-3烷基、-C 1-3烷氧基、-C 3-6环烷基、-C 3-6环烷氧基、卤代C 1-3烷基、卤代C 1-3烷氧基、羟基取代C 1-3烷基或羟基取代C 1-3烷氧基;R 12和R 13在每次出现时均独立地选自H、D、-C 1-3烷基、-C 1-3烷基C 1-3烷氧基、-C 1-3烷氧基C 1-3烷基、-C 3-6环烷基C 1-3烷基、-C 2-4链烯基、-C 2-4链炔基、-C 3-6环烷基、取代或未取代的C 5-10芳基、取代或未取代的5-10元杂芳基或C 1-3烷酰基;t在每次出现时均独立地选自0、1或2。
- 根据权利要求1所述的化合物或其药学上可接受的盐,其中:X在每次出现时均独立地选自不存在、O、-NR X1-或-CR X1R X2-;且p是0、1或2;R X1和R X2在每次出现时均独立地选自H;D;-F;-Cl;-Br;-I;-C 1-3烷基;被1、2或3个取代基取代的C 1-3烷基;C 1-3烷氧基或被1、2或3个取代基取代的C 1-3烷氧基;所述每个取代基独立地任选地选自D、-F、-Cl、-Br、-I、-OH、-CN、-NH 2、-NO 2、-COOH、-C 1-3烷基或C 1-3烷氧基;Y在每次出现时均独立地选自O或S;R 7在每次出现时均独立地选自H、D、-C 1-3烷基、-C 1-3烷氧基、-C 3-5环烷基或3-8元杂环基,且所述的杂环基独立地任选地包含1、2或3个选自N、O或S的杂原子,R 7在每次出现时均独立地任选地被一个或多个选自D、-F、-Cl、-Br、-I、-OH、氧代、=O、-SH、-CN、-NO 2、-N 3、-C 1-3烷基、-C 1-3烷氧基、-C 2-4链烯基、-C 2-4链炔基、卤代C 1-3烷基、C 3-6环烷基、3-6元杂环基、3-6元杂环基氧基、3-6元杂环基硫基、C 5-8芳基、C 5-8芳基氧基、C 5-8芳基硫基、5-8元杂芳环、5-8元杂芳基氧基、5-8元杂芳基硫基、-S(O) tR 9、-C 1-3烷基-S(O) tR 9、-O-R 10、-C 1-3烷基-O-R 10、-C(O)OR 10、-C 1-3烷基-C(O)OR 10、-C(O)R 11、-C 1-3烷基-C(O)R 11、-O-C(O)R 11、-C 1-3烷基-O-C(O)R 11、-NR 12R 13、-C 1-3烷基-NR 12R 13、-C(O)NR 12R 13、-C 1-3烷基-C(O)NR 12R 13、-N(R 12)-C(O)R 11或-N(R 12)-C(O)OR 10的取代基取代或不取代;R 8在每次出现时均独立地选自H、D、-C 1-3烷基、-C 1-3烷氧基、-C 2-4链烯基、-C 2-4链炔基、-C(O)R 11、-C 1-3烷基-C(O)R 11、-C 3-6环烷基、3-8元杂环基,R 8独立地任选地被一个或者多个选自D、-F、-Cl、-Br、-I、-OH、氧代、=O、-SH、-CN、-NO 2、-N 3、-C 1-3烷基、-C 2-4链烯基、-C 2-4链炔基、卤代C 1-3烷基、-C 3-6环烷基、3-6元杂环基、3-6元杂环基氧基、3-6元杂环基硫基、C 5-8芳基、C 5-8芳基氧基、C 5-8芳基硫基、5-8元杂芳环、5-8元杂芳基氧基、5-8元杂芳基硫基、-S(O) tR 9、-C 1-3烷基-S(O) tR 9、-O-R 10、-C 1-3烷基-O-R 10、-C(O)OR 10、-C 1-3烷基-C(O)OR 10、-C(O)R 11、-C 1-3烷基-C(O)R 11、-O-C(O)R 11、-C 1-3烷基-O-C(O)R 11、-NR 12R 13、-C 1-3烷基-NR 12R 13、-C(O)NR 12R 13、-C 1-3烷基-C(O)NR 12R 13、-N(R 12)-C(O)R 11或-N(R 12)-C(O)OR 10的取代基取代或不取代;或R 7和R 8与它们分别连接的碳原子和氮原子一起形成5-7元单环杂环基、5-10元螺环杂环基、5-10元稠环杂环基或5-10元桥环杂环基,所述的每个环系均独立地任选地包含1、2或3个选自N、O或S的杂原子,所述每个环系均独立地任选地被一个或者多个选自D、-F、-Cl、-Br、-I、-OH、氧代、=O、-SH、-CN、-NO 2、-N 3、-C 1-3烷基、-C 1-3烷氧基、-C 2-4 链烯基、-C 2-4链炔基、卤代C 1-3烷基、-C 3-6环烷基、取代或未取代的3-6元杂环基、3-6元杂环基氧基、3-6元杂环基硫基、C 5-8芳基、C 5-8芳基氧基、C 5-8芳基硫基、5-8元杂芳环、5-8元杂芳基氧基、5-8元杂芳基硫基、-S(O) tR 9、-C 1-3烷基-S(O) tR 9、-O-R 10、-C 1-3烷基-O-R 10、-C(O)OR 10、-C 1-3烷基-C(O)OR 10、-C(O)R 11、-C 1-3烷基-C(O)R 11、-O-C(O)R 11、-C 1-3烷基-O-C(O)R 11、-NR 12R 13、-C 1-3烷基-NR 12R 13、-C(O)NR 12R 13、-C 1-3烷基-C(O)NR 12R 13、-N(R 12)-C(O)R 11或-N(R 12)-C(O)OR 10的取代基取代或不取代;在R 7和R 8中,每个R 9均独立地任选地选自H、D、-C 1-3烷基、-C 1-3烷基C 1-3烷氧基、-C 2-4链烯基、-C 3-6环烷基、取代或未取代的3-6元杂环基、卤代C 1-3烷基、苯基、对甲基苯基、氨基、-NH-C 1-3烷基、-N(C 1-3烷基) 2或C 1-3烷酰胺基;在R 7和R 8中,每个R 10均独立地任选地选自H、D、-C 1-3烷基、-C 1-3烷基C 1-3烷氧基、-C 3-6环烷基、-C 5-10芳基、卤代C 1-3烷基或羟基取代C 1-3烷基;在R 7和R 8中,每个R 11均独立地任选地选自选自H、D、-C 1-3烷基、-C 1-3烷氧基、-C 3-6环烷基、-C 3-6环烷氧基、卤代C 1-3烷基、卤代C 1-3烷氧基、羟基取代C 1-3烷基或羟基取代C 1-3烷氧基;在R 7和R 8中,R 12和R 13各自独立地选自H、D、-C 1-3烷基、-C 1-3烷基C 1-3烷氧基、-C 1-3烷氧基C 1-3烷基、-C 3-6环烷基C 1-3烷基、-C 2-4链烯基、-C 2-4链炔基、-C 3-6环烷基、取代或未取代的C 5-10芳基、取代或未取代的5-10元杂芳基或-C 1-3烷酰基;t为0、1或2。
- 根据权利要求1或2所述的化合物或其药学上可接受的盐,其中:X在每次出现时均独立地选自不存在、O、-NR X1-或-CR X1R X2-;且p是0或1;R X1和R X2在每次出现时均独立地选自H;D;-F;-Cl;-Br;-I;甲基;乙基;丙基;异丙基;被1、2或3个取代基取代的C 1-3烷基;甲氧基;乙氧基;丙氧基;异丙氧基或被1、2或3个取代基取代的C 1-3烷氧基;所述每个取代基独立地任选地选自D、-F、-Cl、-Br、-I、-OH、-CN、-NH 2、-NO 2、-COOH、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基;Y在每次出现时均独立地为O;R 7在每次出现时均独立地选自H、D、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、环丙基、环丁基、环戊基、环己基、3元杂环基、4元杂环基、5元杂 环基、6元杂环基、7元杂环基、8元杂环基,且所述每个杂环基均独立地任选地包含1或2个选自N、O或S的杂原子,R 7在每次出现时均独立地任选地被一个或多个选自D、-F、-Cl、-Br、-I、-OH、氧代、=O、-SH、-CN、-NO 2、-N 3、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、-C 2-4链烯基、-C 2-4链炔基、卤代C 1-3烷基、C 3-6环烷基、3-6元杂环基、3-6元杂环基氧基、3-6元杂环基硫基、C 5-8芳基、C 5-8芳基氧基、C 5-8芳基硫基、5-8元杂芳环、5-8元杂芳基氧基、5-8元杂芳基硫基、-S(O) tR 9、-甲基-S(O) tR 9、-乙基-S(O) tR 9、-丙基-S(O) tR 9、异丙基-S(O) tR 9、-O-R 10、-甲基-O-R 10、-乙基-O-R 10、-丙基-O-R 10、-异丙基-O-R 10、-C(O)OR 10、-甲基-C(O)OR 10、-乙基-C(O)OR 10、-丙基-C(O)OR 10、-异丙基-C(O)OR 10、-C(O)R 11、-甲基-C(O)R 11、-乙基-C(O)R 11、-丙基-C(O)R 11、-异丙基-C(O)R 11、-O-C(O)R 11、-甲基-O-C(O)R 11、-乙基-O-C(O)R 11、-丙基-O-C(O)R 11、-异丙基-O-C(O)R 11、-NR 12R 13、-甲基-NR 12R 13、-乙基-NR 12R 13、-丙基-NR 12R 13、-异丙基-NR 12R 13、-C(O)NR 12R 13、-甲基-C(O)NR 12R 13、-乙基-C(O)NR 12R 13、-丙基-C(O)NR 12R 13、-异丙基-C(O)NR 12R 13、-N(R 12)-C(O)R 11或-N(R 12)-C(O)OR 10的取代基取代或不取代;R 8在每次出现时均独立地选自H、D、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、-C 2-4链烯基、-C 2-4链炔基、-C(O)R 11、-甲基-C(O)R 11、-乙基-C(O)R 11、-丙基-C(O)R 11、-异丙基-C(O)R 11、环丙基、环丁基、环戊基、环己基、3元杂环基、4元杂环基、5元杂环基、6元杂环基、7元杂环基、8元杂环基,且所述杂环基独立地任选地包含1或2个选自N、O或S的杂原子,R 8独立地任选地被一个或者多个选自D、-F、-Cl、-Br、-I、-OH、氧代、=O、-SH、-CN、-NO 2、-N 3、甲基、乙基、丙基、异丙基、C 2-4链烯基、C 2-4链炔基、卤代C 1-3烷基、C 3-6环烷基、3-6元杂环基、3-6元杂环基氧基、3-6元杂环基硫基、C 5-8芳基、C 5-8芳基氧基、C 5-8芳基硫基、5-8元杂芳环、5-8元杂芳基氧基、5-8元杂芳基硫基、-S(O) tR 9、-甲基-S(O) tR 9、-乙基-S(O) tR 9、-丙基-S(O) tR 9、-异丙基-S(O) tR 9、-O-R 10、-甲基-O-R 10、-乙基-O-R 10、-丙基-O-R 10、-异丙基-O-R 10、-C(O)OR 10、-甲基-C(O)OR 10、-乙基-C(O)OR 10、-丙基-C(O)OR 10、-异丙基-C(O)OR 10、-C(O)R 11、-甲基-C(O)R 11、-乙基-C(O)R 11、-丙基-C(O)R 11、-异丙基-C(O)R 11、-O-C(O)R 11、-甲基-O-C(O)R 11、-乙基-O-C(O)R 11、-丙基-O-C(O)R 11、-异丙基-O-C(O)R 11、-NR 12R 13、-甲基-NR 12R 13、-乙基-NR 12R 13、-丙基-NR 12R 13、-异丙基-NR 12R 13、-C(O)NR 12R 13、-甲基-C(O)NR 12R 13、-乙基-C(O)NR 12R 13、-丙基-C(O)NR 12R 13、-异丙基-C(O)NR 12R 13、-N(R 12)-C(O)R 11或-N(R 12)-C(O)OR 10的取代基取代或不取代;或R 7和R 8与它们分别连接的碳原子和氮原子一起形成5元单环杂环基、6元单环杂环基、7元单环杂环基、5元螺环杂环基、6元螺环杂环基、7元螺环杂环基、8元螺环杂环基、9 元螺环杂环基、10元螺环杂环基、5元稠环杂环基、6元稠环杂环基、7元稠环杂环基、8元稠环杂环基、9元稠环杂环基、10元稠环杂环基、5元桥环杂环基、6元桥环杂环基、7元桥环杂环基、8元桥环杂环基、9元桥环杂环基或10元桥环杂环基,所述的每个环系均独立地任选地包含1、2或3个选自N、O或S的杂原子,所述每个环系均独立地任选地被一个或者多个选自D、-F、-Cl、-Br、-I、-OH、氧代、=O、-SH、-CN、-NO 2、-N 3、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、C 2-4链烯基、C 2-4链炔基、卤代C 1-3烷基、环丙基、环丁基、环戊基、环己基、取代或未取代的3-6元杂环基、3-6元杂环基氧基、3-6元杂环基硫基、C 5-8芳基、C 5-8芳基氧基、C 5-8芳基硫基、5-8元杂芳环、5-8元杂芳基氧基、5-8元杂芳基硫基、-S(O) tR 9、-甲基-S(O) tR 9、-乙基-S(O) tR 9、-丙基-S(O) tR 9、-异丙基-S(O) tR 9、-O-R 10、-甲基-O-R 10、-乙基-O-R 10、-丙基-O-R 10、-异丙基-O-R 10、-C(O)OR 10、-甲基-C(O)OR 10、-乙基-C(O)OR 10、-丙基-C(O)OR 10、-异丙基-C(O)OR 10、-C(O)R 11、-甲基-C(O)R 11、-乙基-C(O)R 11、-丙基-C(O)R 11、-异丙基-C(O)R 11、-O-C(O)R 11、-甲基-O-C(O)R 11、-乙基-O-C(O)R 11、-丙基-O-C(O)R 11、-异丙基-O-C(O)R 11、-NR 12R 13、-甲基-NR 12R 13、-乙基-NR 12R 13、-丙基-NR 12R 13、-异丙基-NR 12R 13、-C(O)NR 12R 13、-甲基-C(O)NR 12R 13、-乙基-C(O)NR 12R 13、-丙基-C(O)NR 12R 13、-异丙基-C(O)NR 12R 13、-N(R 12)-C(O)R 11或-N(R 12)-C(O)OR 10的取代基取代或不取代;在R 7和R 8中,每个R 9均独立地任选地选自H、D、甲基、乙基、丙基、异丙基、-C 1-3烷基C 1-3烷氧基、-C 2-4链烯基、环丙基、环丁基、环戊基、环己基、取代或未取代的3-6元杂环基、卤代C 1-3烷基、苯基、对甲基苯基、氨基、-NH-C 1-3烷基、-N(C 1-3烷基) 2或C 1-3烷酰胺基;在R 7和R 8中,每个R 10均独立地任选地选自H、D、甲基、乙基、丙基、异丙基、-C 1-3烷基C 1-3烷氧基、-C 3-6环烷基、-C 5-10芳基、卤代C 1-3烷基或羟基取代C 1-3烷基;在R 7和R 8中,每个R 11均独立地任选地选自选自H、D、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、环丙基、环丁基、环戊基、环己基、-C 3-6环烷氧基、卤代C 1-3烷基、卤代C 1-3烷氧基、羟基取代C 1-3烷基或羟基取代C 1-3烷氧基;在R 7和R 8中,R 12和R 13各自独立地选自H、D、甲基、乙基、丙基、异丙基、-C 1-3烷基C 1-3烷氧基、-C 1-3烷氧基C 1-3烷基、-C 3-6环烷基C 1-3烷基、-C 2-4链烯基、-C 2-4链炔基、环丙基、环丁基、环戊基、环己基、取代或未取代的C 5-10芳基、取代或未取代的5-10元杂芳基或-C 1-3烷酰基;t为0、1或2。
- 根据权利要求1-3中任一项所述的化合物或其药学上可接受的盐,其中:X在每次出现时均独立地选自-CH 2-、-CHD-、-CD 2-、-CH(CH 3)-、-C(CH 3) 2-、-CHF-、-CHBr-或-CH(OH)-;且p是0或1;Y在每次出现时均独立地为O;R 7在每次出现时均独立地选自H、D、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、环丙基、环丁基、环戊基、环己基、二氧戊环基、氮杂环丁烷基、哌啶基、哌嗪基、氧代哌嗪基、氧代哌啶基、四氢呋喃基、四氢咪唑基、四氢噻唑基、四氢噁唑基、四氢吡喃基、吗啉基、硫代吗啉基或恶二唑,R 7在每次出现时均独立地任选地被一个或多个选自D、-F、-Cl、-Br、-I、-OH、氧代、=O、-SH、-CN、-NO 2、-N 3、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、-C 2-4链烯基、-C 2-4链炔基、卤代C 1-3烷基、C 3-6环烷基、3-6元杂环基、3-6元杂环基氧基、3-6元杂环基硫基、C 5-8芳基、C 5-8芳基氧基、C 5-8芳基硫基、5-8元杂芳环、5-8元杂芳基氧基、5-8元杂芳基硫基、-S(O)H、-S(O)CH 3、-甲基-S(O)H、-甲基-S(O)CH 3、-乙基-S(O)H、-乙基-S(O)CH 3、-丙基-S(O)H、-丙基-S(O)CH 3、-异丙基-S(O)H、-异丙基-S(O)CH 3、-甲基-OH、-甲基-OCH 3、-乙基-OH、-乙基-OCH 3、-丙基-OH、-丙基-OCH 3、-异丙基-OH、-异丙基-OCH 3、-C(O)OH、-C(O)OCH 3、-甲基-C(O)OH、-甲基-C(O)OCH 3、-乙基-C(O)OH、-乙基-C(O)OCH 3、-丙基-C(O)OH、-丙基-C(O)OCH 3、-异丙基-C(O)OH、-异丙基-C(O)OCH 3、-C(O)H、-C(O)CH 3、-甲基-C(O)H、-甲基-C(O)CH 3、-乙基-C(O)H、-乙基-C(O)CH 3、-丙基-C(O)H、-丙基-C(O)CH 3、-异丙基-C(O)H、-异丙基-C(O)CH 3、-O-C(O)H、-O-C(O)CH 3、-甲基-O-C(O)H、-甲基-O-C(O)CH 3、-乙基-O-C(O)H、-乙基-O-C(O)CH 3、-丙基-O-C(O)H、-丙基-O-C(O)CH 3、-异丙基-O-C(O)H、-异丙基-O-C(O)CH 3、-NH 2、-N(CH 3) 2、-甲基-NH 2、-甲基-N(CH 3) 2、-乙基-NH 2、-乙基-N(CH 3) 2、-丙基-NH 2、-丙基-N(CH 3) 2、-异丙基-NH 2、-异丙基-N(CH 3) 2、-C(O)NH 2、-C(O)N(CH 3) 2、-甲基-C(O)NH 2、-甲基-C(O)N(CH 3) 2、-乙基-C(O)NH 2、-乙基-C(O)N(CH 3) 2、-丙基-C(O)NH 2、-丙基-C(O)N(CH 3) 2、-异丙基-C(O)NH 2、-异丙基-C(O)N(CH 3) 2、-NH-C(O)H或-NH-C(O)OH的取代基取代或不取代;R 8在每次出现时均独立地选自H、D、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、-C 2-4链烯基、-C 2-4链炔基、-C(O)H、-甲基-C(O)H、-乙基-C(O)H、-丙基-C(O)H、-异丙基-C(O)H、-C(O)-甲基、-甲基-C(O)-甲基、-乙基-C(O)-甲基、-丙基-C(O)-甲基、-异丙基-C(O)-甲基、环丙基、环丁基、环戊基、环己基、3元杂环基、4元杂环基、 5元杂环基、6元杂环基、7元杂环基、8元杂环基,且所述杂环基独立地任选地包含1或2个选自N、O或S的杂原子,R 8独立地任选地被一个或者多个选自D、-F、-Cl、-Br、-I、-OH、氧代、=O、-SH、-CN、-NO 2、-N 3、甲基、乙基、丙基、异丙基、C 2-4链烯基、C 2-4链炔基、卤代C 1-3烷基、C 3-6环烷基、3-6元杂环基、3-6元杂环基氧基、3-6元杂环基硫基、C 5-8芳基、C 5-8芳基氧基、C 5-8芳基硫基、5-8元杂芳环、5-8元杂芳基氧基、5-8元杂芳基硫基、-S(O)H、-S(O)CH 3、-甲基-S(O)H、-甲基-S(O)CH 3、-乙基-S(O)H、-乙基-S(O)CH 3、-丙基-S(O)H、-丙基-S(O)CH 3、-异丙基-S(O)H、-异丙基-S(O)CH 3、-甲基-OH、-甲基-OCH 3、-乙基-OH、-乙基-OCH 3、-丙基-OH、-丙基-OCH 3、-异丙基-OH、-异丙基-OCH 3、-C(O)OH、-C(O)OCH 3、-甲基-C(O)OH、-甲基-C(O)OCH 3、-乙基-C(O)OH、-乙基-C(O)OCH 3、-丙基-C(O)OH、-丙基-C(O)OCH 3、-异丙基-C(O)OH、-异丙基-C(O)OCH 3、-C(O)H、-C(O)CH 3、-甲基-C(O)H、-甲基-C(O)CH 3、-乙基-C(O)H、-乙基-C(O)CH 3、-丙基-C(O)H、-丙基-C(O)CH 3、-异丙基-C(O)H、-异丙基-C(O)CH 3、-O-C(O)H、-O-C(O)CH 3、-甲基-O-C(O)H、-甲基-O-C(O)CH 3、-乙基-O-C(O)H、-乙基-O-C(O)CH 3、-丙基-O-C(O)H、-丙基-O-C(O)CH 3、-异丙基-O-C(O)H、-异丙基-O-C(O)CH 3、-NH 2、-N(CH 3) 2、-甲基-NH 2、-甲基-N(CH 3) 2、-乙基-NH 2、-乙基-N(CH 3) 2、-丙基-NH 2、-丙基-N(CH 3) 2、-异丙基-NH 2、-异丙基-N(CH 3) 2、-C(O)NH 2、-C(O)N(CH 3) 2、-甲基-C(O)NH 2、-甲基-C(O)N(CH 3) 2、-乙基-C(O)NH 2、-乙基-C(O)N(CH 3) 2、-丙基-C(O)NH 2、-丙基-C(O)N(CH 3) 2、-异丙基-C(O)NH 2、-异丙基-C(O)N(CH 3) 2、-NH-C(O)H或-NH-C(O)OH的取代基取代或不取代;或R 7和R 8与它们分别连接的碳原子和氮原子一起形成二氧戊环、氮杂环丁烷、哌啶、哌嗪、氧代哌嗪、氧代哌啶、四氢呋喃、四氢咪唑、四氢噻唑、四氢噁唑、四氢吡喃、四氢吡咯、氮杂戊环、吗啉基、硫代吗啉基、7元氮氧杂环或7元氮氧螺环,所述每个环系均独立地任选地被一个或者多个选自D、-F;-Cl;-Br;-I;-OH;氧代;=O;-SH;-CN;-NO 2;-N 3;甲基;乙基;丙基;异丙基;甲氧基;乙氧基;丙氧基;异丙氧基;C 2-4链烯基;C 2-4链炔基;卤代C 1-3烷基;环丙基;环丁基;环戊基;环己基;哌嗪基;被1、2或3个F、Cl、Br、-OH、-CH 3取代的哌嗪基;3-6元杂环基氧基;3-6元杂环基硫基;C 5-8芳基;C 5-8芳基氧基;C 5-8芳基硫基;5-8元杂芳环;5-8元杂芳基氧基;5-8元杂芳基硫基;-S(O)H;-S(O)CH 3;-甲基-S(O)H;-甲基-S(O)CH 3;-乙基-S(O)H;-乙基-S(O)CH 3;-丙基-S(O)H;-丙基-S(O)CH 3;-异丙基-S(O)H;-异丙基-S(O)CH 3;-甲基-OH;-甲基-OCH 3;-乙基-OH;-乙基-OCH 3;-丙基-OH;-丙基-OCH 3;-异丙基-OH;-异丙基-OCH 3;-C(O)OH;-C(O)OCH 3;-甲基-C(O)OH;-甲基-C(O)OCH 3;-乙基-C(O)OH;-乙基-C(O)OCH 3;-丙基-C(O)OH;-丙基-C(O)OCH 3;-异丙基-C(O)OH;-异丙基-C(O)OCH 3;-C(O)H;-C(O)CH 3; -甲基-C(O)H;-甲基-C(O)CH 3;-乙基-C(O)H;-乙基-C(O)CH 3;-丙基-C(O)H;-丙基-C(O)CH 3;-异丙基-C(O)H;-异丙基-C(O)CH 3;-O-C(O)H;-O-C(O)CH 3;-甲基-O-C(O)H;-甲基-O-C(O)CH 3;-乙基-O-C(O)H;-乙基-O-C(O)CH 3;-丙基-O-C(O)H;-丙基-O-C(O)CH 3;-异丙基-O-C(O)H;-异丙基-O-C(O)CH 3;-NH 2;-N(CH 3) 2;-甲基-NH 2;-甲基-N(CH 3) 2;-乙基-NH 2;-乙基-N(CH 3) 2;-丙基-NH 2;-丙基-N(CH 3) 2;-异丙基-NH 2;-异丙基-N(CH 3) 2;-C(O)NH 2;-C(O)N(CH 3) 2;-甲基-C(O)NH 2;-甲基-C(O)N(CH 3) 2;-乙基-C(O)NH 2;-乙基-C(O)N(CH 3) 2;-丙基-C(O)NH 2;-丙基-C(O)N(CH 3) 2;-异丙基-C(O)NH 2;-异丙基-C(O)N(CH 3) 2;-NH-C(O)H或-NH-C(O)OH的取代基取代或不取代。
- 根据权利要求1-6中任一项所述的化合物或其药学上可接受的盐,其中:R 2和R 3各自独立地选自H;D;-F;-Cl;-Br;-I;-OH;-SH;-CN;-NH 2;-NO 2;-N 3;-C 1-3烷基;被1、2或3个-D、-F、-Cl、-Br、-I、-OH、-CN、-NH 2、-NO 2、-COOH、 -C 1-3烷基或C 1-3烷氧基取代的-C 1-3烷基;-C 1-3烷氧基;被1、2或3个-D、-F、-Cl、-Br、-I、-OH、-CN、-NH 2、-NO 2、-COOH、-C 1-3烷基或C 1-3烷氧基取代的C 1-3烷氧基;取代或未取代的C 3-6环烷基;取代或未取代的3-6元杂环基;取代或未取代的3-6元杂环氧基;取代或未取代的3-6元杂环硫基;-S(O) tR 9;-C 1-3烷基-S(O) tR 9;-O-R 10;-C 1-3烷基-O-R 10;-C(O)OR 10;-C 1-3烷基-C(O)OR 10;-C(O)R 11;-C 1-3烷基-C(O)R 11;-O-C(O)R 11;-C 1-3烷基-O-C(O)R 11;-NR 12R 13;-C 1-3烷基-NR 12R 13;-C(O)NR 12R 13;-C 1-3烷基-C(O)NR 12R 13;-N(R 12)-C(O)R 11或-N(R 12)-C(O)OR 10;在R 2和R 3中,每个R 9均独立地任选地选自H、D、-C 1-3烷基、-C 1-3烷基C 1-3烷氧基、-C 2-4链烯基、-C 3-6环烷基、取代或未取代的3-6元杂环基、卤代C 1-3烷基、苯基、对甲基苯基、氨基、-NH-C 1-3烷基、-N(C 1-3烷基) 2或C 1-3烷酰胺基;在R 2和R 3中,每个R 10均独立地任选地选自H、D、-C 1-3烷基、-C 1-3烷基C 1-3烷氧基、-C 3-6环烷基、-C 5-8芳基、卤代C 1-3烷基或羟基取代C 1-3烷基;在R 2和R 3中,每个R 11均独立地任选地选自选自H、D、-C 1-3烷基、-C 1-3烷氧基、-C 3-6环烷基、-C 3-6环烷氧基、卤代C 1-3烷基、卤代C 1-3烷氧基、羟基取代C 1-3烷基或羟基取代C 1-3烷氧基;在R 2和R 3中,每个R 12和R 13各自独立地任选地选自H、D、-C 1-3烷基、-C 1-3烷基C 1-3烷氧基、-C 1-3烷氧基C 1-3烷基、-C 3-6环烷基C 1-3烷基、-C 2-4链烯基、-C 2-4链炔基、-C 3-6环烷基、取代或未取代的C 5-8芳基、取代或未取代的5-8元杂芳基或C 1-3烷酰基;t为0、1或2。
- 根据权利要求1-7中任一项所述的化合物或其药学上可接受的盐,其中:R 2和R 3各自独立地选自H;D;-F;-Cl;-Br;-I;-OH;-SH;-CN;-NO 2;-N 3;甲基;乙基;丙基;异丙基;被1、2或3个-D、-F、-Cl、-Br、-I、-OH、-CN、-NH 2、-NO 2、-COOH、-C 1-3烷基或C 1-3烷氧基取代的-C 1-3烷基;甲氧基;乙氧基;丙氧基;异丙氧基;被1、2或3个-D、-F、-Cl、-Br、-I、-OH、-CN、-NH 2、-NO 2、-COOH、-C 1-3烷基或C 1-3烷氧基取代的C 1-3烷氧基;取代或未取代的C 3-6环烷基;取代或未取代的3-6元杂环基;取代或未取代的3-6元杂环氧基;取代或未取代的3-6元杂环硫基;-S(O) tR 9;-C 1-3烷基-S(O) tR 9;-O-R 10;-C 1-3烷基-O-R 10;-C(O)OR 10;-C 1-3烷基-C(O)OR 10;-C(O)R 11;-C 1-3烷基-C(O)R 11;-O-C(O)R 11;-C 1-3烷基-O-C(O)R 11;-NR 12R 13;-C 1-3烷基-NR 12R 13;-C(O)NR 12R 13;-C 1-3烷基-C(O)NR 12R 13;-N(R 12)-C(O)R 11或-N(R 12)-C(O)OR 10;在R 2和R 3中,每个R 9均独立地任选地选自H、D、甲基、乙基、丙基、异丙基、-C 1-3烷基C 1-3烷氧基、-C 2-4链烯基、环丙基、环丁基、环戊基、环己基、取代或未取代的3-6 元杂环基、卤代C 1-3烷基、苯基、对甲基苯基、氨基、-NH-C 1-3烷基、-N(C 1-3烷基) 2或C 1-3烷酰胺基;在R 2和R 3中,每个R 10均独立地任选地选自H、D、甲基、乙基、丙基、异丙基、-C 1-3烷基C 1-3烷氧基、环丙基、环丁基、环戊基、环己基、-C 5-8芳基、卤代C 1-3烷基或羟基取代C 1-3烷基;在R 2和R 3中,每个R 11均独立地任选地选自选自H、D、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、环丙基、环丁基、环戊基、环己基、-C 3-6环烷氧基、卤代C 1-3烷基、卤代C 1-3烷氧基、羟基取代C 1-3烷基或羟基取代C 1-3烷氧基;在R 2和R 3中,每个R 12和R 13各自独立地任选地选自H、D、甲基、乙基、丙基、异丙基、-C 1-3烷基C 1-3烷氧基、-C 1-3烷氧基C 1-3烷基、-C 3-6环烷基C 1-3烷基、-C 2-4链烯基、-C 2-4链炔基、环丙基、环丁基、环戊基、环己基、取代或未取代的C 5-8芳基、取代或未取代的5-8元杂芳基或C 1-3烷酰基;t为0或1。
- 根据权利要求1-8中任一项所述的化合物或其药学上可接受的盐,其中:R 2和R 3各自独立地选自H;D;-F;-Cl;-Br;-I;-OH;-SH;-CN;-NO 2;-N 3;甲基;乙基;丙基;异丙基;被1、2或3个-D、-F、-Cl、-Br、-I、-OH、-CN、-NH 2、-NO 2、-COOH、-C 1-3烷基或C 1-3烷氧基取代的-C 1-3烷基;甲氧基;乙氧基;丙氧基;异丙氧基;被1、2或3个-D、-F、-Cl、-Br、-I、-OH、-CN、-NH 2、-NO 2、-COOH、-C 1-3烷基或C 1-3烷氧基取代的C 1-3烷氧基;取代或未取代的C 3-6环烷基;取代或未取代的3-6元杂环基;取代或未取代的3-6元杂环氧基;取代或未取代的3-6元杂环硫基;-S(O)H;-S(O)CH 3;-甲基-S(O)H;-甲基-S(O)CH 3;-乙基-S(O)H;-乙基-S(O)CH 3;-丙基-S(O)H;-丙基-S(O)CH 3;-异丙基-S(O)H;-异丙基-S(O)CH 3;-甲基-OH;-甲基-OCH 3;-乙基-OH;-乙基-OCH 3;-丙基-OH;-丙基-OCH 3;-异丙基-OH;-异丙基-OCH 3;-C(O)OH;-C(O)OCH 3;-甲基-C(O)OH;-甲基-C(O)OCH 3;-乙基-C(O)OH;-乙基-C(O)OCH 3;-丙基-C(O)OH;-丙基-C(O)OCH 3;-异丙基-C(O)OH;-异丙基-C(O)OCH 3;-C(O)H;-C(O)CH 3;-甲基-C(O)H;-甲基-C(O)CH 3;-乙基-C(O)H;-乙基-C(O)CH 3;-丙基-C(O)H;-丙基-C(O)CH 3;-异丙基-C(O)H;-异丙基-C(O)CH 3;-O-C(O)H;-O-C(O)CH 3;-甲基-O-C(O)H;-甲基-O-C(O)CH 3;-乙基-O-C(O)H;-乙基-O-C(O)CH 3;-丙基-O-C(O)H;-丙基-O-C(O)CH 3;-异丙基-O-C(O)H;-异丙基-O-C(O)CH 3;-NH 2;-N(CH 3) 2;-甲基-NH 2;-甲基-N(CH 3) 2;-乙基-NH 2;-乙基-N(CH 3) 2;-丙基-NH 2;-丙基-N(CH 3) 2;-异丙基-NH 2;-异丙基-N(CH 3) 2;-C(O)NH 2;-C(O)N(CH 3) 2;-甲基-C(O)NH 2;-甲基-C(O)N(CH 3) 2;-乙基-C(O)NH 2;-乙基-C(O)N(CH 3) 2;-丙基-C(O)NH 2; -丙基-C(O)N(CH 3) 2;-异丙基-C(O)NH 2;-异丙基-C(O)N(CH 3) 2;-NH-C(O)H或-NH-C(O)OH。
- 根据权利要求1-9中任一项所述的化合物或其药学上可接受的盐,其中:R 2和R 3各自独立地选自H、D、-F、-Cl、-Br、-I、-OH、-SH、-CN、-NO 2、-N 3、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基。
- 根据权利要求1-10中任一项所述的化合物或其药学上可接受的盐,其中:R 2和R 3各自独立地选自H、D、-F或甲基。
- 根据权利要求1-11中任一项所述的化合物或其药学上可接受的盐,其中:G在每次出现时均独立地选自-CR G1R G2-、-NR G1-、-S-、-SO-、-SO 2-或O;m是0、1、2、3或4;每个R G1和R G2均独立地选自H;D;-C 1-3烷基;被1、2或3个取代基取代的-C 1-3烷基;-C 1-3烷氧基;被1、2或3个取代基取代的-C 1-3烷氧基;所述每个取代基独立地任选地选自D、卤素、-OH、-CN、-NH 2、-NO 2、-COOH、-C 1-3烷基或C 1-3烷氧基。
- 根据权利要求1-12中任一项所述的化合物或其药学上可接受的盐,其中:G在每次出现时均独立地选自-CR G1R G2-、-NR G1-、-S-、-SO-、-SO 2-或O;m是0、1、2或3;每个R G1和R G2均独立地选自H;D;-C 1-3烷基;被1、2或3个取代基取代的-C 1-3烷基;-C 1-3烷氧基;或被1、2或3个取代基取代的-C 1-3烷氧基;所述每个取代基独立地任选地选自D、-F、-Cl、-Br、-I、-OH、-CN、-NH 2、-NO 2、-COOH、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基。
- 根据权利要求1-13中任一项所述的化合物或其药学上可接受的盐,其中:G在每次出现时均独立地选自-CR G1R G2-、-NR G1-、-S-、-SO-、-SO 2-或O;m是0、1、2或3;每个R G1和R G2均独立地选自H;D;甲基;乙基;丙基;异丙基;被1、2或3个取代基取代的-C 1-3烷基;甲氧基;乙氧基;丙氧基;异丙氧基;或被1、2或3个取代基取代的-C 1-3烷氧基;所述每个取代基独立地任选地选自D、-F、-Cl、-Br、-I、-OH、-CN、-NH 2、-NO 2、-COOH、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基。
- 根据权利要求1-14中任一项所述的化合物或其药学上可接受的盐,其中:G在每次出现时均独立地选自-CH 2-、-CHD-、-CD 2-、-NH-、-S-、-SO-、-SO 2-或O;m是0、1或2。
- 根据权利要求1-15中任一项所述的化合物或其药学上可接受的盐,其中:G在每次出现时均独立地选自-CH 2-、-CHD-、-CD 2-、-NH-、-S-、-SO-、-SO 2-或O; m是0或1。
- 根据权利要求1-16中任一项所述的化合物或其药学上可接受的盐,其中:G在每次出现时均独立地选自-NH-或O;m是0或1。
- 根据权利要求1-17中任一项所述的化合物或其药学上可接受的盐,其中:G在每次出现时均独立地选自-NH-或O;m是1。
- 根据权利要求1-18中任一项所述的化合物或其药学上可接受的盐,其中:G在每次出现时均独立地选自-NH-;m是0或1。
- 根据权利要求1-19中任一项所述的化合物或其药学上可接受的盐,其中:G在每次出现时均独立地选自-NH-;m是1。
- 根据权利要求1-20中任一项所述的化合物或其药学上可接受的盐,其中:m是0。
- 根据权利要求1-21中任一项所述的化合物或其药学上可接受的盐,其中:Q在每次出现时均独立地选自-CR 4R 4’-(CR 4R 4’) q-;R 4和R 4’均独立地选自H;D;-F;-Cl;-Br;-I;-OH;-C 1-6烷基;被1、2或3个取代基取代的C 1-6烷基;-C 1-6烷氧基;被1、2或3个取代基取代的C 1-6烷氧基;-C 3-8环烷基;被1、2或3个取代基取代的C 3-8环烷基;3-8元杂环基;被1、2或3个取代基取代的3-8元杂环基;所述每个取代基独立地任选地选自D、卤素、-OH、-CN、-NH 2、-NO 2、-COOH、-C 1-3烷基或C 1-3烷氧基;或R 4和R 4’与它们共同连接的碳原子一起形成-C 3-8碳环、-3-8元杂环或-5-10元杂芳环,每个环系均可独立地任选地被一个或多个取代基取代或不取代。
- 根据权利要求1-22中任一项所述的化合物或其药学上可接受的盐,其中:Q为-NR 4-(CR 4R 4’) q-;R 4和R 4’均独立地选自H;D;-F;-Cl;-Br;-I;-OH;-C 1-6烷基;被1、2或3个取代基取代的C 1-6烷基;-C 1-6烷氧基;被1、2或3个取代基取代的C 1-6烷氧基;-C 3-8环烷基;被1、2或3个取代基取代的C 3-8环烷基;3-8元杂环基;被1、2或3个取代基取代的3-8元杂环基;所述每个取代基独立地任选地选自D、卤素、-OH、-CN、-NH 2、-NO 2、-COOH、-C 1-3烷基或C 1-3烷氧基;或R 4和R 4’与它们共同连接的碳原子一起形成C 3-8碳环、3-8元杂环或-5-10元杂芳环,每个环系均可独立地任选地被一个或多个取代基取代或不取代。
- 根据权利要求1-23中任一项所述的化合物或其药学上可接受的盐,其中:Q为-CR 4R 4’-(CR 4R 4’) q-或-NR 4-(CR 4R 4’) q-,且q选自0、1、2、3或4;R 4和R 4’均独立地选自H;D;-F;-Cl;-Br;-I;-OH;-C 1-3烷基;被1、2或3个取代基取代的C 1-3烷基;-C 1-3烷氧基;被1、2或3个取代基取代的C 1-3烷氧基;-C 3-6环烷基;被1、2或3个取代基取代的C 3-6环烷基;3-6元杂环基;被1、2或3个取代基取代的3-6元杂环基;所述每个取代基独立地任选地选自D、卤素、-OH、-CN、-NH 2、-NO 2、-COOH、-C 1-3烷基或C 1-3烷氧基;或R 4和R 4’与它们共同连接的碳原子一起形成-C 3-6碳环、3-6元杂环或5-8元杂芳环,每个环系均可独立地任选地被一个或多个取代基取代或不取代。
- 根据权利要求1-24中任一项所述的化合物或其药学上可接受的盐,其中:Q为-CR 4R 4’-(CR 4R 4’) q-;R 4和R 4’均独立地选自H;D;-F;-Cl;-Br;-I;-OH;-C 1-3烷基;被1、2或3个取代基取代的C 1-3烷基;-C 1-3烷氧基;被1、2或3个取代基取代的C 1-3烷氧基;-C 3-6环烷基;被1、2或3个取代基取代的C 3-6环烷基;3-6元杂环基;被1、2或3个取代基取代的3-6元杂环基;所述每个取代基独立地任选地选自D、卤素、-OH、-CN、-NH 2、-NO 2、-COOH、-C 1-3烷基或C 1-3烷氧基;或R 4和R 4’与它们共同连接的碳原子一起形成-C 3-6碳环、3-6元杂环或5-8元杂芳环,每个环系均可独立地任选地被一个或多个取代基取代或不取代。
- 根据权利要求1-25中任一项所述的化合物或其药学上可接受的盐,其中:Q为-NR 4-(CR 4R 4’) q-;R 4和R 4’均独立地选自H;D;-F;-Cl;-Br;-I;-OH;-C 1-3烷基;被1、2或3个取代基取代的C 1-3烷基;-C 1-3烷氧基;被1、2或3个取代基取代的C 1-3烷氧基;-C 3-6环烷基;被1、2或3个取代基取代的C 3-6环烷基;3-6元杂环基;被1、2或3个取代基取代的3-6元杂环基;所述每个取代基独立地任选地选自D、卤素、-OH、-CN、-NH 2、-NO 2、-COOH、-C 1-3烷基或C 1-3烷氧基;或R 4和R 4’与它们共同连接的碳原子一起形成-C 3-6碳环、3-6元杂环或5-8元杂芳环,每个环系均可独立地任选地被一个或多个取代基取代或不取代。
- 根据权利要求1-26中任一项所述的化合物或其药学上可接受的盐,其中:Q为-CR 4R 4’-(CR 4R 4’) q-或-NR 4-(CR 4R 4’) q-,且q选自0、1、2、3或4;R 4和R 4’均独立地选自H;D;-F;-Cl;-Br;-I;-OH;-C 1-3烷基;被1、2或3个取代基取代的C 1-3烷基;-C 1-3烷氧基;被1、2或3个取代基取代的C 1-3烷氧基;-C 3-6环烷基;被1、2或3个取代基取代的C 3-6环烷基;3-6元杂环基;或被1、2或3个取代基取代的3-6元杂环基;所述每个取代基独立地任选地选自D、-F、-Cl、-Br、-I、-OH、-CN、 -NH 2、-NO 2、-COOH、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基;或R 4和R 4’与它们共同连接的碳原子一起形成-C 3-6碳环、3-6元杂环或5-8元杂芳环,所述的每个杂环和每个杂芳环均独立地任选地包含1或2个选自N、O或S的杂原子,每个环系均可独立地任选地被一个或多个取代基取代或不取代。
- 根据权利要求1-27中任一项所述的化合物或其药学上可接受的盐,其中:Q为-CR 4R 4’-(CR 4R 4’) q-;R 4和R 4’均独立地选自H;D;-F;-Cl;-Br;-I;-OH;-C 1-3烷基;被1、2或3个取代基取代的C 1-3烷基;-C 1-3烷氧基;被1、2或3个取代基取代的C 1-3烷氧基;-C 3-6环烷基;被1、2或3个取代基取代的C 3-6环烷基;3-6元杂环基;或被1、2或3个取代基取代的3-6元杂环基;所述每个取代基独立地任选地选自D、-F、-Cl、-Br、-I、-OH、-CN、-NH 2、-NO 2、-COOH、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基;或R 4和R 4’与它们共同连接的碳原子一起形成-C 3-6碳环、-3-6元杂环或-5-8元杂芳环,所述的每个杂环和每个杂芳环均独立地任选地包含1或2个选自N、O或S的杂原子,每个环系均可独立地任选地被一个或多个取代基取代或不取代。
- 根据权利要求1-28中任一项所述的化合物或其药学上可接受的盐,其中:Q为-NR 4-(CR 4R 4’) q-;R 4和R 4’均独立地选自H;D;-F;-Cl;-Br;-I;-OH;-C 1-3烷基;被1、2或3个取代基取代的C 1-3烷基;-C 1-3烷氧基;被1、2或3个取代基取代的C 1-3烷氧基;-C 3-6环烷基;被1、2或3个取代基取代的C 3-6环烷基;3-6元杂环基;或被1、2或3个取代基取代的3-6元杂环基;所述每个取代基独立地任选地选自D、-F、-Cl、-Br、-I、-OH、-CN、-NH 2、-NO 2、-COOH、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基;或R 4和R 4’与它们共同连接的碳原子一起形成-C 3-6碳环、3-6元杂环或5-8元杂芳环,所述的每个杂环和每个杂芳环均独立地任选地包含1或2个选自N、O或S的杂原子,每个环系均可独立地任选地被一个或多个取代基取代或不取代。
- 根据权利要求1-29中任一项所述的化合物或其药学上可接受的盐,其中:Q为-CR 4R 4’-(CR 4R 4’) q-或-NR 4-(CR 4R 4’) q-,且q选自0、1、2、3或4;R 4和R 4’均独立地选自H;D;-F;-Cl;-Br;-I;-OH;甲基;乙基;丙基;异丙基;被1、2或3个取代基取代的-C 1-3烷基;甲氧基;乙氧基;丙氧基;异丙氧基;或被1、2 或3个取代基取代的-C 1-3烷氧基;环丙基;环丁基;环戊基;环己基;被1、2或3个取代基取代的C 3-6环烷基;3-6元杂环基;或被1、2或3个取代基取代的3-6元杂环基;所述每个取代基独立地任选地选自D、-F、-Cl、-Br、-I、-OH、-CN、-NH 2、-NO 2、-COOH、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基;或R 4和R 4’与它们共同连接的碳原子一起形成3元碳环;4元碳环;5元碳环;6元碳环;3元杂环;4元杂环;5元杂环;6元杂环;5元杂芳环;6元杂芳环;7元杂芳环;8元杂芳环;所述的每个杂环和每个杂芳环均独立地任选地包含1或2个选自N、O或S的杂原子,且所述的每个碳环、每个杂环和每个杂芳环均独立地任选地被1、2或3个取代基取代或不取代。
- 根据权利要求1-30中任一项所述的化合物或其药学上可接受的盐,其中:Q为-CR 4R 4’-(CR 4R 4’) q-;R 4和R 4’均独立地选自H;D;-F;-Cl;-Br;-I;-OH;甲基;乙基;丙基;异丙基;被1、2或3个取代基取代的-C 1-3烷基;甲氧基;乙氧基;丙氧基;异丙氧基;或被1、2或3个取代基取代的-C 1-3烷氧基;环丙基;环丁基;环戊基;环己基;被1、2或3个取代基取代的C 3-6环烷基;3-6元杂环基;或被1、2或3个取代基取代的3-6元杂环基;所述每个取代基独立地任选地选自D、-F、-Cl、-Br、-I、-OH、-CN、-NH 2、-NO 2、-COOH、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基或R 4和R 4’与它们共同连接的碳原子一起形成3元碳环;4元碳环;5元碳环;6元碳环;3元杂环;4元杂环;5元杂环;6元杂环;5元杂芳环;6元杂芳环;7元杂芳环;8元杂芳环;所述的每个杂环和每个杂芳环均独立地任选地包含1或2个选自N、O或S的杂原子,且所述的每个碳环、每个杂环和每个杂芳环均独立地任选地被1、2或3个取代基取代或不取代。
- 根据权利要求1-31中任一项所述的化合物或其药学上可接受的盐,其中:Q为-NR 4-(CR 4R 4’) q-;R 4和R 4’均独立地选自H;D;-F;-Cl;-Br;-I;-OH;甲基;乙基;丙基;异丙基;被1、2或3个取代基取代的-C 1-3烷基;甲氧基;乙氧基;丙氧基;异丙氧基;或被1、2或3个取代基取代的-C 1-3烷氧基;环丙基;环丁基;环戊基;环己基;被1、2或3个取代基取代的C 3-6环烷基;3-6元杂环基;或被1、2或3个取代基取代的3-6元杂环基;所述每个取代基独立地任选地选自D、-F、-Cl、-Br、-I、-OH、-CN、-NH 2、-NO 2、-COOH、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基;或R 4和R 4’与它们共同连接的碳原子一起形成3元碳环;4元碳环;5元碳环;6元碳环; 3元杂环;4元杂环;5元杂环;6元杂环;5元杂芳环;6元杂芳环;7元杂芳环;8元杂芳环;所述的每个杂环和每个杂芳环均独立地任选地包含1或2个选自N、O或S的杂原子,且所述的每个碳环、每个杂环和每个杂芳环均独立地任选地被1、2或3个取代基取代或不取代。
- 根据权利要求1-32中任一项所述的化合物或其药学上可接受的盐,其中:R 5和R 5’均独立地选自H;D;-F;-Cl;-Br;-I;-OH;-C 1-3烷基;被1、2或3个取代基取代的-C 1-3烷基;-C 1-3烷氧基;被1、2或3个取代基取代的-C 1-3烷氧基;-C 3-6环烷基;被1、2或3个取代基取代的C 3-6环烷基;3-6元杂环基;被1、2或3个取代基取代的3-6元杂环基;所述每个取代基独立地任选地选自D、卤素、-OH、-CN、-NH 2、-NO 2、-COOH、-C 1-3烷基或C 1-3烷氧基;或R 5和R 5’与它们共同连接的碳原子形成-C 3-6碳环、3-6元杂环、5-8元杂芳环,所述的每个杂环和每个杂芳环均独立地任选地包含1或2个选自N、O或S的杂原子,所述的每个环系均可独立地任选地被一个或多个取代基取代或不取代;或R 4和R 5与它们分别连接的原子一起形成5-10元芳环、-C 3-8碳环、4-8元杂环,所述的每个杂环基均独立地任选地包含1或2个选自N、O或S的杂原子,所述的每个环系均可独立地任选地被一个或多个取代基取代或不取代。
- 根据权利要求1-33中任一项所述的化合物或其药学上可接受的盐,其中:R 5和R 5’均独立地选自H;D;-F;-Cl;-Br;-I;-OH;甲基;乙基;丙基;异丙基;被1、2或3个取代基取代的-C 1-3烷基;甲氧基;乙氧基;丙氧基;异丙氧基;被1、2或3个取代基取代的-C 1-3烷氧基;环丙基;环丁基;环戊基;环己基;被1、2或3个取代基取代的的-C 3-6环烷基;3元杂环基;4元杂环基;5元杂环基;6元杂环基;被1、2或3个取代基取代的3-6元杂环基;所述的每个杂环基均独立地任选地包含1或2个选自N、O或S的杂原子;所述每个取代基独立地任选地选自D、-F、-Cl、-Br、-I、-OH、-CN、-NH 2、-NO 2、-COOH、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基或R 5和R 5’与它们共同连接的碳原子形成3元碳环、4元碳环、5元碳环、6元碳环、3元杂环、4元杂环、5元杂环、6元杂环、5元杂芳环、6元杂芳环、7元杂芳环或8元杂芳环,所述的每个杂环和每个杂芳环均独立地任选地包含1或2个选自N、O或S的杂原子,且所述的每个环系均独立地任选地被1、2或3个取代基取代或不取代;或R 4和R 5与它们分别连接的原子一起形成5元芳环、6元芳环、7元芳环、8元芳环、9元芳环、10元芳环、4元碳环、5元碳环、6元碳环、7元碳环、8元碳环、4元杂环、5 元杂环、6元杂环、7元杂环或8元杂环,所述的每个杂环基均独立地任选地包含1或2个选自N、O或S的杂原子,且所述的每个环系均独立地任选地被1、2或3个取代基取代或不取代。
- 根据权利要求1-34中任一项所述的化合物或其药学上可接受的盐,其中:R 5和R 5’均独立地选自H;D;-F;-Cl;-Br;-I;-OH;甲基;乙基;丙基;异丙基;被1、2或3个取代基取代的-C 1-3烷基;甲氧基;乙氧基;丙氧基;异丙氧基;被1、2或3个取代基取代的-C 1-3烷氧基;环丙基;环丁基;环戊基;环己基;被1、2或3个取代基取代的的-C 3-6环烷基;3元杂环基;4元杂环基;5元杂环基;6元杂环基;被1、2或3个取代基取代的3-6元杂环基;所述的每个杂环基均独立地任选地包含1或2个选自N、O或S的杂原子;所述每个取代基独立地任选地选自D、-F、-Cl、-Br、-I、-OH、-CN、-NH 2、-NO 2、-COOH、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基;或R 5和R 5’与它们共同连接的碳原子形成3元碳环、4元碳环、5元碳环、6元碳环、3元杂环、4元杂环、5元杂环、6元杂环、5元杂芳环、6元杂芳环、7元杂芳环、8元杂芳环;所述的每个杂环和每个杂芳环均独立地任选地包含1或2个选自N、O或S的杂原子,且所述的每个环系均独立地任选地被1、2或3个D、-F、-Cl、-Br、-I、-OH、氧代、=O、-NH 2、-CN、-COOH、-NO 2、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基取代或不取代;或R 4和R 5与它们分别连接的原子一起形成苯、萘、3元碳环、4元碳环、5元碳环、6元碳环、哌啶、哌嗪、氧代哌嗪、氧代哌啶、四氢呋喃、四氢咪唑、四氢噻唑、四氢噁唑、四氢吡喃、四氢吡咯或氮杂戊环,所述的每个环系均独立地任选地被1、2或3个D、-F、-Cl、-Br、-I、-OH、-NH 2、-CN、-COOH、-NO 2、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基取代或不取代。
- 根据权利要求1-35中任一项所述的化合物或其药学上可接受的盐,其中:R 6在每次出现时均独立地选自H;D;-F;-Cl;-Br;-I;甲基;乙基;丙基;异丙基;被1、2或3个取代基取代的-C 1-3烷基;甲氧基;乙氧基;丙氧基;异丙氧基;被1、2或3个取代基取代的C 1-3烷氧基;-甲基-COO-甲基;-乙基-COO-乙基;-丙基-COO-丙基;-异丙基-COO-异丙基;环丙基;环丁基;环戊基;环己基;被1、2或3个取代基取代的-C 3-6碳环基;所述每个取代基独立地任选地选自D、-F、-Cl、-Br、-I、-OH、-NH 2、-CN、-COOH、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基;或Q和R 6与它们分别连接的碳原子和W一起形成4元杂环、5元杂环、6元杂环或7元 杂环,所述杂环独立地任选地被一个或多个取代基取代或不取代,所述的杂环独立地任选地包含1、2或3个选自N、O或S的杂原子,所述每个取代基独立地任选地选自D、-F、-Cl、-Br、-I、-OH、-CN、-NH 2、-NO 2、-COOH、-C 1-3烷基或C 1-3烷氧基;或R 4和R 6与它们分别相连的原子一起形成5元单环杂环基、6元单环杂环基、7元单环杂环基、8元单环杂环基、5元杂螺环、6元杂螺环、7元杂螺环、8元杂螺环、9元杂螺环、10元杂螺环、5元稠环杂环基、6元稠环杂环基、7元稠环杂环基、8元稠环杂环基、9元稠环杂环基、10元稠环杂环基、5元桥环杂环基、6元桥环杂环基、7元桥环杂环基、8元桥环杂环基、9元桥环杂环基、10元桥环杂环基、5元杂芳环、6元杂芳环、7元杂芳环、8元杂芳环、9元杂芳环或10元杂芳环,所述每个环系均独立地任选地包含1、2或3个选自N、O或S的杂原子,所述每个环系均独立地任选地被1个、2个或3个D、-F、-Cl、-Br、-I、-OH、-NH 2、-CN、-COOH、氧代基、=O、-C 1-3烷基或-C 1-3烷氧基取代或不取代;或R 5和R 6与它们分别连接的碳原子和W一起形成4元杂环、5元杂环、6元杂环、5元杂芳环、6元杂芳环、7元杂芳环或8元杂芳环,所述每个环系均独立地任选地包含1、2或3个选自N、O或S的杂原子,所述每个环系均独立地任选地被1个、2个或3个D、-F、-Cl、-Br、-I、-OH、-NH 2、-CN、-COOH、氧代基、=O、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基取代或不取代。
- 一种药物组合物,其包括至少一种权利要求1-40中任一项所述的化合物或其药学上可接受的盐,和至少一种药学上可接受的辅料。
- 权利要求1-40中任一项所述的化合物或其药学上可接受的盐或权利要求40中所述的药物组合物在制备用于治疗、阻止或预防由FGFR4活性介导的疾病或病症的药物中的用途。
- 根据权利要求42所述的用途,其中:所述由FGFR4活性介导的疾病或病症是癌症和/或癌转移。
- 根据权利要求42或43所述的用途,其中:所述由FGFR4活性介导的疾病选自一种或多种下列疾病:肝癌、头颈癌、食道癌、胃癌、前列腺癌、卵巢癌、肺癌、乳腺癌、结肠直肠癌、横纹肌瘤及其组合。
- 一种治疗、阻止或预防由FGFR4活性介导的疾病或病症的方法,其包括向患者给药有效剂量的权利要求1-40中任一项所述的化合物或其药学上可接受的盐或权利要求41中所述的药物组合物。
- 根据权利要求45中所述的方法,其中:所述由FGFR4活性介导的疾病或病症是癌症和/或癌转移。
- 根据权利要求45或46中所述的方法,其中:所述由FGFR4活性介导的疾病选自一种或多种下列疾病:肝癌、头颈癌、食道癌、胃癌、前列腺癌、卵巢癌、肺癌、乳腺癌、结肠直肠癌、横纹肌瘤及其组合。
- 权利要求1-40中任一项所述的化合物或其药学上可接受的盐或权利要求41中所述的药物组合物用于治疗、阻止或预防由FGFR4活性介导的疾病或病症。
- 根据权利要求48中所述的化合物或其药学上可接受的盐或所述的药物组合物,其中:所述由FGFR4活性介导的疾病或病症是癌症和/或癌转移。
- 根据权利要求49中所述的化合物或其药学上可接受的盐或所述的药物组合物,其中:所述由FGFR4活性介导的疾病选自一种或多种下列疾病:肝癌、头颈癌、食道癌、胃癌、前列腺癌、卵巢癌、肺癌、乳腺癌、结肠直肠癌、横纹肌瘤及其组合。
Priority Applications (14)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA3107897A CA3107897C (en) | 2018-07-27 | 2019-07-29 | Fused ring derivative used as fgfr4 inhibitor |
JP2021504357A JP7129728B2 (ja) | 2018-07-27 | 2019-07-29 | Fgfr4阻害剤として使用される縮環誘導体 |
SG11202102015QA SG11202102015QA (en) | 2018-07-27 | 2019-07-29 | Fused ring derivative used as fgfr4 inhibitor |
US17/263,571 US20210163478A1 (en) | 2018-07-27 | 2019-07-29 | Fused ring derivative used as fgfr4 inhibitor |
EA202190398A EA202190398A1 (ru) | 2018-07-27 | 2019-07-29 | Конденсированное кольцевое производное, применяемое в качестве ингибитора fgfr4 |
AU2019311121A AU2019311121B2 (en) | 2018-07-27 | 2019-07-29 | Fused ring derivative used as FGFR4 inhibitor |
BR112021003949-0A BR112021003949A2 (pt) | 2018-07-27 | 2019-07-29 | derivado de anel fundido usado como inibidor de fgfr4 |
CN201980049925.6A CN112513037A (zh) | 2018-07-27 | 2019-07-29 | 用作fgfr4抑制剂的稠环衍生物 |
CN202110519510.XA CN113248497B (zh) | 2018-07-27 | 2019-07-29 | 用作fgfr4抑制剂的稠环衍生物 |
KR1020217006091A KR102559624B1 (ko) | 2018-07-27 | 2019-07-29 | Fgfr4 억제제로서 사용된 융합된 환 유도체 |
EP19839905.7A EP3831827A4 (en) | 2018-07-27 | 2019-07-29 | CONDENSED RING DERIVATIVE AS FGFR4 INHIBITOR |
PH12021550406A PH12021550406A1 (en) | 2018-07-27 | 2021-02-26 | Fused ring derivative used as fgfr4 inhibitor |
US17/315,481 US11136320B2 (en) | 2018-07-27 | 2021-05-10 | Fused ring derivative used as FGFR4 inhibitor |
US17/470,572 US20220119386A1 (en) | 2018-07-27 | 2021-09-09 | Fused ring derivative used as fgfr4 inhibitor |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2018097450 | 2018-07-27 | ||
CNPCT/CN2018/097450 | 2018-07-27 |
Related Child Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US17/263,571 A-371-Of-International US20210163478A1 (en) | 2018-07-27 | 2019-07-29 | Fused ring derivative used as fgfr4 inhibitor |
US17/315,481 Continuation US11136320B2 (en) | 2018-07-27 | 2021-05-10 | Fused ring derivative used as FGFR4 inhibitor |
US17/470,572 Continuation US20220119386A1 (en) | 2018-07-27 | 2021-09-09 | Fused ring derivative used as fgfr4 inhibitor |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2020020377A1 true WO2020020377A1 (zh) | 2020-01-30 |
Family
ID=69181335
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2019/098076 WO2020020377A1 (zh) | 2018-07-27 | 2019-07-29 | 用作fgfr4抑制剂的稠环衍生物 |
Country Status (13)
Country | Link |
---|---|
US (3) | US20210163478A1 (zh) |
EP (1) | EP3831827A4 (zh) |
JP (1) | JP7129728B2 (zh) |
KR (1) | KR102559624B1 (zh) |
CN (2) | CN113248497B (zh) |
AU (1) | AU2019311121B2 (zh) |
BR (1) | BR112021003949A2 (zh) |
CA (1) | CA3107897C (zh) |
EA (1) | EA202190398A1 (zh) |
PH (1) | PH12021550406A1 (zh) |
SG (1) | SG11202102015QA (zh) |
TW (1) | TWI723480B (zh) |
WO (1) | WO2020020377A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022089648A1 (en) * | 2020-11-02 | 2022-05-05 | Jacobio Pharmaceuticals Co., Ltd. | Crystalline forms of salts of fgfr4 inhibitor |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113072550B (zh) * | 2020-01-06 | 2023-08-08 | 周龙兴 | 一种高选择性成纤维细胞生长因子受体抑制剂和应用 |
CN116444485B (zh) * | 2023-03-30 | 2024-01-23 | 广西中医药大学 | 吡啶基取代不对称脲的非金属催化、免柱层析合成方法 |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105683188A (zh) * | 2013-10-25 | 2016-06-15 | 诺华股份有限公司 | 作为fgfr4抑制剂的稠环二环吡啶基衍生物 |
CN107304211A (zh) * | 2016-04-25 | 2017-10-31 | 成都融科博海科技有限公司 | 一种选择性fgfr4激酶抑制剂 |
WO2017198149A1 (zh) * | 2016-05-20 | 2017-11-23 | 江苏豪森药业集团有限公司 | Fgfr4抑制剂、其制备方法和应用 |
WO2017202390A1 (zh) * | 2016-05-27 | 2017-11-30 | 杭州英创医药科技有限公司 | 作为fgfr4抑制剂的杂环化合物 |
WO2018028664A1 (zh) * | 2016-08-12 | 2018-02-15 | 江苏豪森药业集团有限公司 | Fgfr4抑制剂及其制备方法和应用 |
CN108341815A (zh) * | 2017-01-25 | 2018-07-31 | 上海喆邺生物科技有限公司 | 一种抑制激酶化合物及其用途 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016054483A1 (en) * | 2014-10-03 | 2016-04-07 | Novartis Ag | Use of ring-fused bicyclic pyridyl derivatives as fgfr4 inhibitors |
CA3024532C (en) | 2016-05-20 | 2021-02-09 | Zhejiang Hisun Pharmaceutical Co., Ltd. | Pyrimidine derivative, method for preparing same and use thereof in medicine |
-
2019
- 2019-07-26 TW TW108126494A patent/TWI723480B/zh active
- 2019-07-29 AU AU2019311121A patent/AU2019311121B2/en active Active
- 2019-07-29 CN CN202110519510.XA patent/CN113248497B/zh active Active
- 2019-07-29 EP EP19839905.7A patent/EP3831827A4/en active Pending
- 2019-07-29 WO PCT/CN2019/098076 patent/WO2020020377A1/zh unknown
- 2019-07-29 EA EA202190398A patent/EA202190398A1/ru unknown
- 2019-07-29 JP JP2021504357A patent/JP7129728B2/ja active Active
- 2019-07-29 SG SG11202102015QA patent/SG11202102015QA/en unknown
- 2019-07-29 KR KR1020217006091A patent/KR102559624B1/ko active IP Right Grant
- 2019-07-29 CN CN201980049925.6A patent/CN112513037A/zh active Pending
- 2019-07-29 CA CA3107897A patent/CA3107897C/en active Active
- 2019-07-29 BR BR112021003949-0A patent/BR112021003949A2/pt not_active Application Discontinuation
- 2019-07-29 US US17/263,571 patent/US20210163478A1/en active Pending
-
2021
- 2021-02-26 PH PH12021550406A patent/PH12021550406A1/en unknown
- 2021-05-10 US US17/315,481 patent/US11136320B2/en active Active
- 2021-09-09 US US17/470,572 patent/US20220119386A1/en active Pending
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105683188A (zh) * | 2013-10-25 | 2016-06-15 | 诺华股份有限公司 | 作为fgfr4抑制剂的稠环二环吡啶基衍生物 |
CN107304211A (zh) * | 2016-04-25 | 2017-10-31 | 成都融科博海科技有限公司 | 一种选择性fgfr4激酶抑制剂 |
CN107304210A (zh) * | 2016-04-25 | 2017-10-31 | 成都融科博海科技有限公司 | 一种选择性fgfr4激酶抑制剂 |
WO2017198149A1 (zh) * | 2016-05-20 | 2017-11-23 | 江苏豪森药业集团有限公司 | Fgfr4抑制剂、其制备方法和应用 |
WO2017202390A1 (zh) * | 2016-05-27 | 2017-11-30 | 杭州英创医药科技有限公司 | 作为fgfr4抑制剂的杂环化合物 |
WO2018028664A1 (zh) * | 2016-08-12 | 2018-02-15 | 江苏豪森药业集团有限公司 | Fgfr4抑制剂及其制备方法和应用 |
CN108341815A (zh) * | 2017-01-25 | 2018-07-31 | 上海喆邺生物科技有限公司 | 一种抑制激酶化合物及其用途 |
Non-Patent Citations (2)
Title |
---|
"Design of Prodrugs", 1985, ELSEVIER |
See also references of EP3831827A4 |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022089648A1 (en) * | 2020-11-02 | 2022-05-05 | Jacobio Pharmaceuticals Co., Ltd. | Crystalline forms of salts of fgfr4 inhibitor |
Also Published As
Publication number | Publication date |
---|---|
AU2019311121A1 (en) | 2021-03-18 |
EP3831827A4 (en) | 2022-04-13 |
US20210163478A1 (en) | 2021-06-03 |
CA3107897C (en) | 2023-03-21 |
SG11202102015QA (en) | 2021-04-29 |
KR20210068008A (ko) | 2021-06-08 |
CN113248497A (zh) | 2021-08-13 |
US20210269442A1 (en) | 2021-09-02 |
PH12021550406A1 (en) | 2021-09-20 |
EP3831827A1 (en) | 2021-06-09 |
CA3107897A1 (en) | 2020-01-30 |
EA202190398A1 (ru) | 2021-04-26 |
JP2021532147A (ja) | 2021-11-25 |
AU2019311121B2 (en) | 2021-10-07 |
TWI723480B (zh) | 2021-04-01 |
CN112513037A (zh) | 2021-03-16 |
KR102559624B1 (ko) | 2023-07-24 |
CN113248497B (zh) | 2022-08-19 |
JP7129728B2 (ja) | 2022-09-02 |
BR112021003949A2 (pt) | 2021-05-25 |
TW202033520A (zh) | 2020-09-16 |
US11136320B2 (en) | 2021-10-05 |
US20220119386A1 (en) | 2022-04-21 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10968221B2 (en) | Substituted [1,2,4]triazolo[1,5-a]pyrazines as LSD1 inhibitors | |
US9758523B2 (en) | Triazolopyridines and triazolopyrazines as LSD1 inhibitors | |
US9809572B2 (en) | Deuterated diaminopyrimidine compounds and pharmaceutical compositions comprising such compounds | |
JP6948659B1 (ja) | ピリダジニルチアアゾールカルボキシアミド化合物 | |
WO2021231526A1 (en) | Fused pyrimidine compounds as kras inhibitors | |
US11905247B2 (en) | Compounds as neurokinin-1 receptor antagonists and uses thereof | |
JP2019518059A (ja) | PI3Kβ阻害剤としてのアザベンゾイミダゾール誘導体 | |
US20220259235A1 (en) | EGFR Inhibitor, Composition, and Preparation Method Therefor | |
WO2015158310A1 (zh) | 一种酪氨酸激酶抑制剂及其用途 | |
US11136320B2 (en) | Fused ring derivative used as FGFR4 inhibitor | |
TW200813064A (en) | Purinone derivatives as HM74A agonists | |
CN114057771A (zh) | 大环化合物及其制备方法和应用 | |
WO2020182159A1 (zh) | Jak激酶抑制剂及其制备方法和在医药领域的应用 | |
CN111989332B (zh) | 作为cdk抑制剂的大环化合物、其制备方法及其在医药上的应用 | |
WO2019057053A1 (zh) | 用作fgfr4抑制剂的稠环衍生物 | |
WO2015014283A1 (zh) | 蛋白酪氨酸激酶抑制剂及其应用 | |
WO2021233371A1 (zh) | 作为溴结构域蛋白质抑制剂的化合物和组合物 | |
CN112851583A (zh) | 新型苯并氮杂䓬类化合物、组合物及其用途 | |
WO2023244619A2 (en) | Flavonoid compounds and methods and materials for using flavonoid compounds to treat fibrotic conditions | |
JP2023501288A (ja) | 架橋環縮合ホルミルピリジン誘導体及びその応用 | |
TW202237101A (zh) | Ctla-4小分子降解劑及其應用 |
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: 19839905 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2021504357 Country of ref document: JP Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 3107897 Country of ref document: CA |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112021003949 Country of ref document: BR |
|
ENP | Entry into the national phase |
Ref document number: 2019839905 Country of ref document: EP Effective date: 20210301 |
|
ENP | Entry into the national phase |
Ref document number: 2019311121 Country of ref document: AU Date of ref document: 20190729 Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 112021003949 Country of ref document: BR Kind code of ref document: A2 Effective date: 20210302 |