CN116888100A - High-activity HPK1 kinase inhibitor - Google Patents
High-activity HPK1 kinase inhibitor Download PDFInfo
- Publication number
- CN116888100A CN116888100A CN202280013620.1A CN202280013620A CN116888100A CN 116888100 A CN116888100 A CN 116888100A CN 202280013620 A CN202280013620 A CN 202280013620A CN 116888100 A CN116888100 A CN 116888100A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- compound
- pharmaceutically acceptable
- represents hydrogen
- stereoisomer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 230000000694 effects Effects 0.000 title abstract description 20
- 229940125962 HPK1 kinase inhibitor Drugs 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 171
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 31
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 28
- 201000010099 disease Diseases 0.000 claims abstract description 28
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 23
- 238000011282 treatment Methods 0.000 claims abstract description 14
- 230000001404 mediated effect Effects 0.000 claims abstract description 12
- 201000011510 cancer Diseases 0.000 claims abstract description 10
- 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 9
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 9
- 230000002265 prevention Effects 0.000 claims abstract description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 79
- 239000001257 hydrogen Substances 0.000 claims description 79
- 125000000217 alkyl group Chemical group 0.000 claims description 66
- 238000000034 method Methods 0.000 claims description 57
- 150000003839 salts Chemical class 0.000 claims description 52
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 48
- 125000004432 carbon atom Chemical group C* 0.000 claims description 39
- 229910052736 halogen Inorganic materials 0.000 claims description 36
- 150000002367 halogens Chemical class 0.000 claims description 36
- 229910052757 nitrogen Inorganic materials 0.000 claims description 33
- 230000000155 isotopic effect Effects 0.000 claims description 26
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 25
- 125000005843 halogen group Chemical group 0.000 claims description 22
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 20
- 125000001424 substituent group Chemical group 0.000 claims description 18
- 125000003118 aryl group Chemical group 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 17
- 125000000623 heterocyclic group Chemical group 0.000 claims description 17
- 229910052717 sulfur Inorganic materials 0.000 claims description 15
- 239000003937 drug carrier Substances 0.000 claims description 14
- 229910052760 oxygen Inorganic materials 0.000 claims description 14
- 229910052799 carbon Inorganic materials 0.000 claims description 13
- 125000005842 heteroatom Chemical group 0.000 claims description 13
- 125000003342 alkenyl group Chemical group 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 8
- 125000001188 haloalkyl group Chemical group 0.000 claims description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 2
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 2
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 2
- 229910052721 tungsten Inorganic materials 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 8
- 101001059991 Homo sapiens Mitogen-activated protein kinase kinase kinase kinase 1 Proteins 0.000 abstract description 12
- 102100028199 Mitogen-activated protein kinase kinase kinase kinase 1 Human genes 0.000 abstract description 12
- 230000002401 inhibitory effect Effects 0.000 abstract description 4
- 238000006243 chemical reaction Methods 0.000 description 119
- -1 small molecule compounds Chemical class 0.000 description 95
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 82
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 69
- 239000000243 solution Substances 0.000 description 62
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 60
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 53
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 38
- 239000000203 mixture Substances 0.000 description 38
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 34
- 238000005481 NMR spectroscopy Methods 0.000 description 32
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 30
- 239000007787 solid Substances 0.000 description 29
- 239000011541 reaction mixture Substances 0.000 description 25
- 239000000706 filtrate Substances 0.000 description 20
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 19
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 18
- 238000010898 silica gel chromatography Methods 0.000 description 18
- 238000006467 substitution reaction Methods 0.000 description 17
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
- 239000000543 intermediate Substances 0.000 description 16
- 125000004122 cyclic group Chemical group 0.000 description 15
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 14
- GIKMWFAAEIACRF-UHFFFAOYSA-N 2,4,5-trichloropyrimidine Chemical compound ClC1=NC=C(Cl)C(Cl)=N1 GIKMWFAAEIACRF-UHFFFAOYSA-N 0.000 description 13
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 13
- 101000767160 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) Intracellular protein transport protein USO1 Proteins 0.000 description 13
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 13
- 229910000024 caesium carbonate Inorganic materials 0.000 description 13
- 210000004027 cell Anatomy 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- 239000003208 petroleum Substances 0.000 description 13
- 125000006413 ring segment Chemical group 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000012071 phase Substances 0.000 description 11
- 230000002441 reversible effect Effects 0.000 description 11
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 241000124008 Mammalia Species 0.000 description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
- 239000012980 RPMI-1640 medium Substances 0.000 description 10
- 239000004480 active ingredient Substances 0.000 description 10
- 239000003153 chemical reaction reagent Substances 0.000 description 10
- 239000012043 crude product Substances 0.000 description 10
- WDVGNXKCFBOKDF-UHFFFAOYSA-N dicyclohexyl-[3,6-dimethoxy-2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane Chemical compound COC1=CC=C(OC)C(C=2C(=CC(=CC=2C(C)C)C(C)C)C(C)C)=C1P(C1CCCCC1)C1CCCCC1 WDVGNXKCFBOKDF-UHFFFAOYSA-N 0.000 description 10
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 241001465754 Metazoa Species 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 239000012453 solvate Substances 0.000 description 9
- 208000024891 symptom Diseases 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000012298 atmosphere Substances 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 210000000056 organ Anatomy 0.000 description 8
- 238000002953 preparative HPLC Methods 0.000 description 8
- 238000012746 preparative thin layer chromatography Methods 0.000 description 8
- 150000003254 radicals Chemical class 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 7
- 108010002350 Interleukin-2 Proteins 0.000 description 7
- 102000000588 Interleukin-2 Human genes 0.000 description 7
- 239000000872 buffer Substances 0.000 description 7
- 125000001072 heteroaryl group Chemical group 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 239000012388 BrettPhos 3rd generation precatalyst Substances 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000013543 active substance Substances 0.000 description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 6
- 229930195733 hydrocarbon Natural products 0.000 description 6
- 238000001990 intravenous administration Methods 0.000 description 6
- 229940124597 therapeutic agent Drugs 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 241000282412 Homo Species 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 125000003710 aryl alkyl group Chemical group 0.000 description 5
- 125000002619 bicyclic group Chemical group 0.000 description 5
- 238000007796 conventional method Methods 0.000 description 5
- 125000000392 cycloalkenyl group Chemical group 0.000 description 5
- 210000004443 dendritic cell Anatomy 0.000 description 5
- 239000003085 diluting agent Substances 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 230000006872 improvement Effects 0.000 description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 description 5
- 230000003287 optical effect Effects 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 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 4
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- 239000004215 Carbon black (E152) Substances 0.000 description 4
- 238000002965 ELISA Methods 0.000 description 4
- 101001002657 Homo sapiens Interleukin-2 Proteins 0.000 description 4
- 101001090688 Homo sapiens Lymphocyte cytosolic protein 2 Proteins 0.000 description 4
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 4
- 102100034709 Lymphocyte cytosolic protein 2 Human genes 0.000 description 4
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 4
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 4
- 210000001744 T-lymphocyte Anatomy 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 239000007900 aqueous suspension Substances 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- 125000001041 indolyl group Chemical group 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000002207 metabolite Substances 0.000 description 4
- 125000002950 monocyclic group Chemical group 0.000 description 4
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 229940002612 prodrug Drugs 0.000 description 4
- 239000000651 prodrug Substances 0.000 description 4
- 238000007920 subcutaneous administration Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 3
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- KCBAMQOKOLXLOX-BSZYMOERSA-N CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O Chemical compound CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O KCBAMQOKOLXLOX-BSZYMOERSA-N 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 description 3
- 101100446506 Mus musculus Fgf3 gene Proteins 0.000 description 3
- OHVIRCSJFFPEGC-XMMPIXPASA-N N-[3-[[4-[[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl]phenyl]methoxy]phenyl]benzamide Chemical compound OC[C@H]1CCCN1Cc1ccc(COc2cccc(NC(=O)c3ccccc3)c2)cc1 OHVIRCSJFFPEGC-XMMPIXPASA-N 0.000 description 3
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 3
- 206010035226 Plasma cell myeloma Diseases 0.000 description 3
- 230000006044 T cell activation Effects 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 3
- 208000026935 allergic disease Diseases 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 239000000427 antigen Substances 0.000 description 3
- 102000036639 antigens Human genes 0.000 description 3
- 108091007433 antigens Proteins 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 125000001691 aryl alkyl amino group Chemical group 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 229940126086 compound 21 Drugs 0.000 description 3
- 229940125833 compound 23 Drugs 0.000 description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- 125000004438 haloalkoxy group Chemical group 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 150000004677 hydrates Chemical class 0.000 description 3
- 230000001506 immunosuppresive effect Effects 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 238000007918 intramuscular administration Methods 0.000 description 3
- 230000007794 irritation Effects 0.000 description 3
- 208000032839 leukemia Diseases 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 230000004770 neurodegeneration Effects 0.000 description 3
- 208000015122 neurodegenerative disease Diseases 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- MWUXSHHQAYIFBG-UHFFFAOYSA-N nitrogen oxide Inorganic materials O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 125000003367 polycyclic group Chemical group 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 description 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 230000000638 stimulation Effects 0.000 description 3
- 125000004434 sulfur atom Chemical group 0.000 description 3
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 125000001544 thienyl group Chemical group 0.000 description 3
- 230000000699 topical effect Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- SLTBMTIRYMGWLX-XMMPIXPASA-N (2r)-2-[(4-chloroanilino)carbamoylamino]-3-(1h-indol-3-yl)-n-(2-phenylethyl)propanamide Chemical compound C1=CC(Cl)=CC=C1NNC(=O)N[C@@H](C(=O)NCCC=1C=CC=CC=1)CC1=CNC2=CC=CC=C12 SLTBMTIRYMGWLX-XMMPIXPASA-N 0.000 description 2
- VGNCBRNRHXEODV-XXVHXNRLSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-6-dodecoxy-4,7-dihydroxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@H](O)[C@H](C(O2)(C(O)=O)C(O)(C(O1)C(O)=O)C(O)=O)OCCCCCCCCCCCC)C1=CC=CC=C1 VGNCBRNRHXEODV-XXVHXNRLSA-N 0.000 description 2
- RNOAOAWBMHREKO-QFIPXVFZSA-N (7S)-2-(4-phenoxyphenyl)-7-(1-prop-2-enoylpiperidin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound C(C=C)(=O)N1CCC(CC1)[C@@H]1CCNC=2N1N=C(C=2C(=O)N)C1=CC=C(C=C1)OC1=CC=CC=C1 RNOAOAWBMHREKO-QFIPXVFZSA-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
- QARVELJVEBLWGK-UHFFFAOYSA-N 1-methyl-3,5-dinitropyridin-2-one Chemical compound CN1C=C([N+]([O-])=O)C=C([N+]([O-])=O)C1=O QARVELJVEBLWGK-UHFFFAOYSA-N 0.000 description 2
- 125000005955 1H-indazolyl group Chemical group 0.000 description 2
- IDRUEHMBFUJKAK-UHFFFAOYSA-N 2,4-dichloro-5-(trifluoromethyl)pyrimidine Chemical group FC(F)(F)C1=CN=C(Cl)N=C1Cl IDRUEHMBFUJKAK-UHFFFAOYSA-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
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- 238000003727 ADP Glo Kinase Assay Methods 0.000 description 2
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 2
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- 208000003174 Brain Neoplasms Diseases 0.000 description 2
- 201000009030 Carcinoma Diseases 0.000 description 2
- 241000282693 Cercopithecidae Species 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 208000006332 Choriocarcinoma Diseases 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- 238000012286 ELISA Assay Methods 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- 208000017604 Hodgkin disease Diseases 0.000 description 2
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 206010021245 Idiopathic thrombocytopenic purpura Diseases 0.000 description 2
- 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 2
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 2
- 206010025323 Lymphomas Diseases 0.000 description 2
- 208000034578 Multiple myelomas Diseases 0.000 description 2
- 101100348848 Mus musculus Notch4 gene Proteins 0.000 description 2
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 2
- 201000007224 Myeloproliferative neoplasm Diseases 0.000 description 2
- 150000001204 N-oxides Chemical class 0.000 description 2
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- 229920001213 Polysorbate 20 Polymers 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- 239000007868 Raney catalyst Substances 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 description 2
- 230000006052 T cell proliferation Effects 0.000 description 2
- KZVWEOXAPZXAFB-BQFCYCMXSA-N Temocaprilat Chemical compound C([C@H](N[C@H]1CS[C@@H](CN(C1=O)CC(=O)O)C=1SC=CC=1)C(O)=O)CC1=CC=CC=C1 KZVWEOXAPZXAFB-BQFCYCMXSA-N 0.000 description 2
- 208000031981 Thrombocytopenic Idiopathic Purpura Diseases 0.000 description 2
- 206010052779 Transplant rejections Diseases 0.000 description 2
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 description 2
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 230000001270 agonistic effect Effects 0.000 description 2
- 125000005236 alkanoylamino group Chemical group 0.000 description 2
- 125000004414 alkyl thio group Chemical group 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 125000003277 amino group Chemical class 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000001769 aryl amino group Chemical group 0.000 description 2
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 208000010668 atopic eczema Diseases 0.000 description 2
- 230000001363 autoimmune Effects 0.000 description 2
- 201000003710 autoimmune thrombocytopenic purpura Diseases 0.000 description 2
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 2
- 125000006580 bicyclic heterocycloalkyl group Chemical group 0.000 description 2
- 239000004305 biphenyl Substances 0.000 description 2
- 235000010290 biphenyl Nutrition 0.000 description 2
- 230000003915 cell function Effects 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 229940125961 compound 24 Drugs 0.000 description 2
- 229940125851 compound 27 Drugs 0.000 description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 2
- 125000006165 cyclic alkyl group Chemical group 0.000 description 2
- 230000002939 deleterious effect Effects 0.000 description 2
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical class CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 206010017758 gastric cancer Diseases 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000007972 injectable composition Substances 0.000 description 2
- 230000002601 intratumoral effect Effects 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 2
- 125000005647 linker group Chemical group 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000006578 monocyclic heterocycloalkyl group Chemical group 0.000 description 2
- 125000002757 morpholinyl group Chemical group 0.000 description 2
- LVBWRNKEBGYENR-UHFFFAOYSA-N n-cyclopropyl-4-[8-(oxan-4-ylmethylamino)-6-[(1,1,1-trifluoro-2-methylpropan-2-yl)amino]imidazo[1,2-b]pyridazin-3-yl]benzamide Chemical compound C12=NC=C(C=3C=CC(=CC=3)C(=O)NC3CC3)N2N=C(NC(C)(C)C(F)(F)F)C=C1NCC1CCOCC1 LVBWRNKEBGYENR-UHFFFAOYSA-N 0.000 description 2
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 2
- 150000002823 nitrates Chemical class 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical class CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- PFGVNLZDWRZPJW-OPAMFIHVSA-N otamixaban Chemical compound C([C@@H](C(=O)OC)[C@@H](C)NC(=O)C=1C=CC(=CC=1)C=1C=C[N+]([O-])=CC=1)C1=CC=CC(C(N)=N)=C1 PFGVNLZDWRZPJW-OPAMFIHVSA-N 0.000 description 2
- 125000000160 oxazolidinyl group Chemical group 0.000 description 2
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
- 125000004043 oxo group Chemical group O=* 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 201000002528 pancreatic cancer Diseases 0.000 description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000008055 phosphate buffer solution Substances 0.000 description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 2
- 125000004193 piperazinyl group Chemical group 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 230000002685 pulmonary effect Effects 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 125000003003 spiro group Chemical group 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 201000011549 stomach cancer Diseases 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- KAFZOLYKKCWUBI-HPMAGDRPSA-N (2s)-2-[[(2s)-2-[[(2s)-1-[(2s)-3-amino-2-[[(2s)-2-[[(2s)-2-(3-cyclohexylpropanoylamino)-4-methylpentanoyl]amino]-5-methylhexanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]butanediamide Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CCC(C)C)C(=O)N[C@@H](CN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(N)=O)C(N)=O)C(=O)CCC1CCCCC1 KAFZOLYKKCWUBI-HPMAGDRPSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- AEVBPXDFDKBGLT-YOUFYPILSA-N (2s,3s,4r,5r)-n-[2-[4-(diethoxyphosphorylmethyl)anilino]-2-oxoethyl]-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolane-2-carboxamide Chemical compound C1=CC(CP(=O)(OCC)OCC)=CC=C1NC(=O)CNC(=O)[C@@H]1[C@@H](O)[C@@H](O)[C@H](N2C(NC(=O)C=C2)=O)O1 AEVBPXDFDKBGLT-YOUFYPILSA-N 0.000 description 1
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-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
- UXKLQDCALAWFIU-VKNDCNMPSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-tetradecoxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@H](O)[C@H](C(O2)(C(O)=O)C(O)(C(O1)C(O)=O)C(O)=O)OCCCCCCCCCCCCCC)C1=CC=CC=C1 UXKLQDCALAWFIU-VKNDCNMPSA-N 0.000 description 1
- IGVKWAAPMVVTFX-BUHFOSPRSA-N (e)-octadec-5-en-7,9-diynoic acid Chemical compound CCCCCCCCC#CC#C\C=C\CCCC(O)=O IGVKWAAPMVVTFX-BUHFOSPRSA-N 0.000 description 1
- FIARMZDBEGVMLV-UHFFFAOYSA-N 1,1,2,2,2-pentafluoroethanolate Chemical group [O-]C(F)(F)C(F)(F)F FIARMZDBEGVMLV-UHFFFAOYSA-N 0.000 description 1
- 125000004605 1,2,3,4-tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000004607 1,2,3,4-tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000004502 1,2,3-oxadiazolyl group Chemical group 0.000 description 1
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 description 1
- 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 description 1
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 description 1
- 125000004506 1,2,5-oxadiazolyl group Chemical group 0.000 description 1
- 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 description 1
- 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 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
- 125000006432 1-methyl cyclopropyl group Chemical group [H]C([H])([H])C1(*)C([H])([H])C1([H])[H] 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- HUUPVABNAQUEJW-UHFFFAOYSA-N 1-methylpiperidin-4-one Chemical compound CN1CCC(=O)CC1 HUUPVABNAQUEJW-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 1
- 102000004899 14-3-3 Proteins Human genes 0.000 description 1
- GBBSAMQTQCPOBF-UHFFFAOYSA-N 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane Chemical compound CB1OB(C)OB(C)O1 GBBSAMQTQCPOBF-UHFFFAOYSA-N 0.000 description 1
- WHPFEQUEHBULBW-UHFFFAOYSA-N 2,4-dichloro-5-fluoropyrimidine Chemical compound FC1=CN=C(Cl)N=C1Cl WHPFEQUEHBULBW-UHFFFAOYSA-N 0.000 description 1
- DQXNTSXKIUZJJS-UHFFFAOYSA-N 2,4-dichloro-5-methylpyrimidine Chemical compound CC1=CN=C(Cl)N=C1Cl DQXNTSXKIUZJJS-UHFFFAOYSA-N 0.000 description 1
- BTTNYQZNBZNDOR-UHFFFAOYSA-N 2,4-dichloropyrimidine Chemical group ClC1=CC=NC(Cl)=N1 BTTNYQZNBZNDOR-UHFFFAOYSA-N 0.000 description 1
- KMHSUNDEGHRBNV-UHFFFAOYSA-N 2,4-dichloropyrimidine-5-carbonitrile Chemical group ClC1=NC=C(C#N)C(Cl)=N1 KMHSUNDEGHRBNV-UHFFFAOYSA-N 0.000 description 1
- ZKLPARSLTMPFCP-OAQYLSRUSA-N 2-[2-[4-[(R)-(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]ethoxy]acetic acid Chemical compound C1CN(CCOCC(=O)O)CCN1[C@@H](C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-OAQYLSRUSA-N 0.000 description 1
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 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
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- QHRUXDXIVIYFJJ-UHFFFAOYSA-N 3-(aminomethyl)-1h-pyridin-2-one Chemical group NCC1=CC=CNC1=O QHRUXDXIVIYFJJ-UHFFFAOYSA-N 0.000 description 1
- PCJPGNCABBDNJU-UHFFFAOYSA-N 3-(aminomethyl)-4,6-dimethyl-1h-pyridin-2-one Chemical compound CC1=CC(C)=C(CN)C(=O)N1 PCJPGNCABBDNJU-UHFFFAOYSA-N 0.000 description 1
- PMVLHRHRTOBBHS-UHFFFAOYSA-N 3-(hydroxymethyl)pyrrolidin-2-one Chemical compound OCC1CCNC1=O PMVLHRHRTOBBHS-UHFFFAOYSA-N 0.000 description 1
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 1
- DDRFLSCTQJTMAA-UHFFFAOYSA-N 3-bromo-4-methyl-1h-pyridin-2-one Chemical compound CC=1C=CNC(=O)C=1Br DDRFLSCTQJTMAA-UHFFFAOYSA-N 0.000 description 1
- KHBRMXVUQOVORD-UHFFFAOYSA-N 3-bromo-5-methyl-1h-pyridin-2-one Chemical compound CC1=CN=C(O)C(Br)=C1 KHBRMXVUQOVORD-UHFFFAOYSA-N 0.000 description 1
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N 3-cyclopentylpropionic acid Chemical class OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical class OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- OCYMJCILWYHKAU-UHFFFAOYSA-N 4,6-dimethyl-2-oxo-1h-pyridine-3-carbonitrile Chemical compound CC1=CC(C)=C(C#N)C(O)=N1 OCYMJCILWYHKAU-UHFFFAOYSA-N 0.000 description 1
- ATKAUYDNXOBHBV-UHFFFAOYSA-N 4-(aminomethyl)-1-methylpyridin-2-one Chemical group CN1C=CC(CN)=CC1=O ATKAUYDNXOBHBV-UHFFFAOYSA-N 0.000 description 1
- ZYOSFZHXYZSRMA-UHFFFAOYSA-N 4-(aminomethyl)-1h-pyridin-2-one Chemical compound NCC=1C=CNC(=O)C=1 ZYOSFZHXYZSRMA-UHFFFAOYSA-N 0.000 description 1
- BSSUPYKXVPAKLX-UHFFFAOYSA-N 4-(aminomethyl)piperidin-2-one Chemical group NCC1CCNC(=O)C1 BSSUPYKXVPAKLX-UHFFFAOYSA-N 0.000 description 1
- 125000005986 4-piperidonyl group Chemical group 0.000 description 1
- 125000002471 4H-quinolizinyl group Chemical group C=1(C=CCN2C=CC=CC12)* 0.000 description 1
- 125000004608 5,6,7,8-tetrahydroquinolinyl group Chemical group N1=C(C=CC=2CCCCC12)* 0.000 description 1
- BUGNNHLZTBPABI-UHFFFAOYSA-N 5,6-dimethyl-2-oxo-1h-pyridine-3-carbonitrile Chemical compound CC=1C=C(C#N)C(=O)NC=1C BUGNNHLZTBPABI-UHFFFAOYSA-N 0.000 description 1
- CSVYITCBZGOVBG-UHFFFAOYSA-N 5-(aminomethyl)-1h-pyridin-2-one Chemical compound NCC=1C=CC(=O)NC=1 CSVYITCBZGOVBG-UHFFFAOYSA-N 0.000 description 1
- GFOAHABINHRDKL-UHFFFAOYSA-N 5-(aminomethyl)pyrrolidin-2-one Chemical group NCC1CCC(=O)N1 GFOAHABINHRDKL-UHFFFAOYSA-N 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 208000009746 Adult T-Cell Leukemia-Lymphoma Diseases 0.000 description 1
- 206010001413 Adult T-cell lymphoma/leukaemia Diseases 0.000 description 1
- 206010052613 Allergic bronchitis Diseases 0.000 description 1
- 206010049153 Allergic sinusitis Diseases 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 206010003571 Astrocytoma Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 208000003950 B-cell lymphoma Diseases 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 206010005949 Bone cancer Diseases 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 208000011691 Burkitt lymphomas Diseases 0.000 description 1
- QUMCIHKVKQYNPA-RUZDIDTESA-N C1(CCCCC1)CN1[C@@H](C=2N(C=3C=NC(=NC1=3)NC1=C(C=C(C(=O)NC3CCN(CC3)C)C=C1)OC)C(=NN=2)C)CC Chemical compound C1(CCCCC1)CN1[C@@H](C=2N(C=3C=NC(=NC1=3)NC1=C(C=C(C(=O)NC3CCN(CC3)C)C=C1)OC)C(=NN=2)C)CC QUMCIHKVKQYNPA-RUZDIDTESA-N 0.000 description 1
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 1
- 101100177670 Caenorhabditis elegans hpk-1 gene Proteins 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 101710167800 Capsid assembly scaffolding protein Proteins 0.000 description 1
- OKTJSMMVPCPJKN-OUBTZVSYSA-N Carbon-13 Chemical compound [13C] OKTJSMMVPCPJKN-OUBTZVSYSA-N 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- ZKLPARSLTMPFCP-UHFFFAOYSA-N Cetirizine Chemical compound C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-UHFFFAOYSA-N 0.000 description 1
- 208000005243 Chondrosarcoma Diseases 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 229940126639 Compound 33 Drugs 0.000 description 1
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 1
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical class OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- 206010012434 Dermatitis allergic Diseases 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 108010008165 Etanercept Proteins 0.000 description 1
- 102000008016 Eukaryotic Initiation Factor-3 Human genes 0.000 description 1
- 108010089790 Eukaryotic Initiation Factor-3 Proteins 0.000 description 1
- 208000006168 Ewing Sarcoma Diseases 0.000 description 1
- 201000006107 Familial adenomatous polyposis Diseases 0.000 description 1
- 241000282324 Felis Species 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical class OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 241000282575 Gorilla Species 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 206010018634 Gouty Arthritis Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 208000008051 Hereditary Nonpolyposis Colorectal Neoplasms Diseases 0.000 description 1
- 208000017095 Hereditary nonpolyposis colon cancer Diseases 0.000 description 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 1
- 241001272567 Hominoidea Species 0.000 description 1
- 101000760079 Homo sapiens 14-3-3 protein epsilon Proteins 0.000 description 1
- 101000914484 Homo sapiens T-lymphocyte activation antigen CD80 Proteins 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 208000003456 Juvenile Arthritis Diseases 0.000 description 1
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 description 1
- ZCVMWBYGMWKGHF-UHFFFAOYSA-N Ketotifene Chemical compound C1CN(C)CCC1=C1C2=CC=CC=C2CC(=O)C2=C1C=CS2 ZCVMWBYGMWKGHF-UHFFFAOYSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 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
- 206010023825 Laryngeal cancer Diseases 0.000 description 1
- 206010062038 Lip neoplasm Diseases 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 201000005027 Lynch syndrome Diseases 0.000 description 1
- 239000007993 MOPS buffer Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical class [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 208000009018 Medullary thyroid cancer Diseases 0.000 description 1
- 208000000172 Medulloblastoma Diseases 0.000 description 1
- 208000001145 Metabolic Syndrome Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 101100317378 Mus musculus Wnt3 gene Proteins 0.000 description 1
- 101100268066 Mus musculus Zap70 gene Proteins 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 208000005927 Myosarcoma Diseases 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 206010033701 Papillary thyroid cancer Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 208000029082 Pelvic Inflammatory Disease Diseases 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 208000007452 Plasmacytoma Diseases 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 101710130420 Probable capsid assembly scaffolding protein Proteins 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical class CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 102000004245 Proteasome Endopeptidase Complex Human genes 0.000 description 1
- 108090000708 Proteasome Endopeptidase Complex Proteins 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- 201000000582 Retinoblastoma Diseases 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 208000004337 Salivary Gland Neoplasms Diseases 0.000 description 1
- 206010061934 Salivary gland cancer Diseases 0.000 description 1
- 101710204410 Scaffold protein Proteins 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 201000010208 Seminoma Diseases 0.000 description 1
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 1
- 208000021386 Sjogren Syndrome Diseases 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 208000007156 Spondylarthritis Diseases 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-AKLPVKDBSA-N Sulfur-35 Chemical compound [35S] NINIDFKCEFEMDL-AKLPVKDBSA-N 0.000 description 1
- 108091008874 T cell receptors Proteins 0.000 description 1
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 1
- 206010042971 T-cell lymphoma Diseases 0.000 description 1
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 102100027222 T-lymphocyte activation antigen CD80 Human genes 0.000 description 1
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 1
- 206010043276 Teratoma Diseases 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- 206010062129 Tongue neoplasm Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- WREOTYWODABZMH-DTZQCDIJSA-N [[(2r,3s,4r,5r)-3,4-dihydroxy-5-[2-oxo-4-(2-phenylethoxyamino)pyrimidin-1-yl]oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O[C@H]1N(C=C\1)C(=O)NC/1=N\OCCC1=CC=CC=C1 WREOTYWODABZMH-DTZQCDIJSA-N 0.000 description 1
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 150000001278 adipic acid derivatives Chemical class 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 150000008055 alkyl aryl sulfonates Chemical class 0.000 description 1
- 229940045714 alkyl sulfonate alkylating agent Drugs 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- AEMOLEFTQBMNLQ-BKBMJHBISA-N alpha-D-galacturonic acid Chemical class O[C@H]1O[C@H](C(O)=O)[C@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-BKBMJHBISA-N 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 125000005140 aralkylsulfonyl group Chemical group 0.000 description 1
- 125000005239 aroylamino group Chemical group 0.000 description 1
- 230000002917 arthritic effect Effects 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 125000004659 aryl alkyl thio group Chemical group 0.000 description 1
- 125000005160 aryl oxy alkyl group Chemical group 0.000 description 1
- 150000005840 aryl radicals Chemical class 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- 125000005110 aryl thio group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 150000001509 aspartic acid derivatives Chemical class 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 208000010928 autoimmune thyroid disease Diseases 0.000 description 1
- 125000002785 azepinyl group Chemical group 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical class OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 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
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
- 125000004935 benzoxazolinyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 229960002537 betamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone 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-DVTGEIKXSA-N 0.000 description 1
- 150000005347 biaryls Chemical group 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 150000001642 boronic acid derivatives Chemical class 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 208000003362 bronchogenic carcinoma Diseases 0.000 description 1
- 150000004652 butanoic acids Chemical class 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940046731 calcineurin inhibitors Drugs 0.000 description 1
- FATUQANACHZLRT-KMRXSBRUSA-L calcium glucoheptonate Chemical class [Ca+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O FATUQANACHZLRT-KMRXSBRUSA-L 0.000 description 1
- LSPHULWDVZXLIL-QUBYGPBYSA-N camphoric acid Chemical class CC1(C)[C@H](C(O)=O)CC[C@]1(C)C(O)=O LSPHULWDVZXLIL-QUBYGPBYSA-N 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 125000004623 carbolinyl group Chemical group 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 229960001803 cetirizine Drugs 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical class OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 1
- 208000029664 classic familial adenomatous polyposis Diseases 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229960004544 cortisone Drugs 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000001047 cyclobutenyl group Chemical group C1(=CCC1)* 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000298 cyclopropenyl group Chemical group [H]C1=C([H])C1([H])* 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- AUNNTHNQWVSPPP-UHFFFAOYSA-N cyclopropyloxyboronic acid Chemical compound OB(O)OC1CC1 AUNNTHNQWVSPPP-UHFFFAOYSA-N 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 125000004856 decahydroquinolinyl group Chemical group N1(CCCC2CCCCC12)* 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- 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 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 1
- 229960002986 dinoprostone Drugs 0.000 description 1
- 229960000520 diphenhydramine Drugs 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical class CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- MJJALKDDGIKVBE-UHFFFAOYSA-N ebastine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)CCCN1CCC(OC(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 MJJALKDDGIKVBE-UHFFFAOYSA-N 0.000 description 1
- 229960001971 ebastine Drugs 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 125000002587 enol group Chemical group 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229960000403 etanercept Drugs 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical class CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 229960003592 fexofenadine Drugs 0.000 description 1
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 125000003709 fluoroalkyl group Chemical group 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 201000003444 follicular lymphoma Diseases 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 125000003838 furazanyl group Chemical group 0.000 description 1
- 201000010175 gallbladder cancer Diseases 0.000 description 1
- 201000007487 gallbladder carcinoma Diseases 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 150000002315 glycerophosphates Chemical class 0.000 description 1
- KUCDOJMOTMEEOF-UHFFFAOYSA-N gtpl6345 Chemical compound C1=CC(OC)=CC=C1N1C(=O)C(SC=2C3=C4NCCOC4=CN=2)=C3N=C1 KUCDOJMOTMEEOF-UHFFFAOYSA-N 0.000 description 1
- FODONWGPMXPGNC-UHFFFAOYSA-N gtpl6346 Chemical compound C1=CC(Cl)=CC=C1N1C(=O)C(SC=2C3=C4NCCOC4=CN=2)=C3N=C1 FODONWGPMXPGNC-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 description 1
- 201000009277 hairy cell leukemia Diseases 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000004995 haloalkylthio group Chemical group 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 210000002443 helper t lymphocyte Anatomy 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 125000006343 heptafluoro propyl group Chemical group 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical class CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-M hexanoate Chemical class CCCCCC([O-])=O FUZZWVXGSFPDMH-UHFFFAOYSA-M 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical class I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical class OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 229960000930 hydroxyzine Drugs 0.000 description 1
- ZQDWXGKKHFNSQK-UHFFFAOYSA-N hydroxyzine Chemical compound C1CN(CCOCCO)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZQDWXGKKHFNSQK-UHFFFAOYSA-N 0.000 description 1
- 201000006866 hypopharynx cancer Diseases 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000004857 imidazopyridinyl group Chemical group N1C(=NC2=C1C=CC=N2)* 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000004926 indolenyl group Chemical group 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 229960000598 infliximab Drugs 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 208000002551 irritable bowel syndrome Diseases 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical class OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 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
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229960004958 ketotifen Drugs 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 150000003893 lactate salts Chemical class 0.000 description 1
- JYTUSYBCFIZPBE-AMTLMPIISA-N lactobionic acid Chemical class OC(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 206010023841 laryngeal neoplasm Diseases 0.000 description 1
- 229960000681 leflunomide Drugs 0.000 description 1
- VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 description 1
- 229960001508 levocetirizine Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 201000006721 lip cancer Diseases 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 206010024627 liposarcoma Diseases 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 229960003088 loratadine Drugs 0.000 description 1
- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 210000003563 lymphoid tissue Anatomy 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 150000004701 malic acid derivatives Chemical class 0.000 description 1
- 150000002690 malonic acid derivatives Chemical class 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 208000023356 medullary thyroid gland carcinoma Diseases 0.000 description 1
- 206010027191 meningioma Diseases 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 201000002077 muscle cancer Diseases 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- NFPUARSXIMWASK-GOEBONIOSA-N n-[(5r,7s)-2-(3-chlorophenyl)-1-oxa-3-azaspiro[4.5]dec-2-en-7-yl]acetamide Chemical compound C1[C@@H](NC(=O)C)CCC[C@@]11OC(C=2C=C(Cl)C=CC=2)=NC1 NFPUARSXIMWASK-GOEBONIOSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-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
- 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
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000006070 nanosuspension Substances 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical class C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 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
- 230000007935 neutral effect Effects 0.000 description 1
- 150000006636 nicotinic acid Chemical class 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 125000003518 norbornenyl group Chemical group C12(C=CC(CC1)C2)* 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical class CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 125000004095 oxindolyl group Chemical group N1(C(CC2=CC=CC=C12)=O)* 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 150000002942 palmitic acid derivatives Chemical class 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 210000000578 peripheral nerve Anatomy 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L persulfate group Chemical group S(=O)(=O)([O-])OOS(=O)(=O)[O-] JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 description 1
- 125000004625 phenanthrolinyl group Chemical group N1=C(C=CC2=CC=C3C=CC=NC3=C12)* 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000000865 phosphorylative effect Effects 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- KASDHRXLYQOAKZ-ZPSXYTITSA-N pimecrolimus Chemical compound C/C([C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@]2(O)O[C@@H]([C@H](C[C@H]2C)OC)[C@@H](OC)C[C@@H](C)C/C(C)=C/[C@H](C(C[C@H](O)[C@H]1C)=O)CC)=C\[C@@H]1CC[C@@H](Cl)[C@H](OC)C1 KASDHRXLYQOAKZ-ZPSXYTITSA-N 0.000 description 1
- 229960005330 pimecrolimus Drugs 0.000 description 1
- 125000004928 piperidonyl group Chemical group 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 125000004591 piperonyl group Chemical group C(C1=CC=2OCOC2C=C1)* 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical class CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000004237 preparative chromatography Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 230000006916 protein interaction Effects 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 201000003651 pulmonary sarcoidosis Diseases 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl 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
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 201000005404 rubella Diseases 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000008299 semisolid dosage form Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 239000000779 smoke Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- SUBJHSREKVAVAR-UHFFFAOYSA-N sodium;methanol;methanolate Chemical compound [Na+].OC.[O-]C SUBJHSREKVAVAR-UHFFFAOYSA-N 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 150000003413 spiro compounds Chemical class 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000010922 spray-dried dispersion Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229960001967 tacrolimus Drugs 0.000 description 1
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- ROUYFJUVMYHXFJ-UHFFFAOYSA-N tert-butyl 4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)CC1 ROUYFJUVMYHXFJ-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
- 201000003120 testicular cancer Diseases 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical group C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 125000004627 thianthrenyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3SC12)* 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 150000003567 thiocyanates Chemical class 0.000 description 1
- 125000005403 thiohaloalkoxy group Chemical group 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 208000030045 thyroid gland papillary carcinoma Diseases 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 201000006134 tongue cancer Diseases 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 229940046728 tumor necrosis factor alpha inhibitor Drugs 0.000 description 1
- 239000002452 tumor necrosis factor alpha inhibitor Substances 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical class CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical class CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- JQSHBVHOMNKWFT-DTORHVGOSA-N varenicline Chemical compound C12=CC3=NC=CN=C3C=C2[C@H]2C[C@@H]1CNC2 JQSHBVHOMNKWFT-DTORHVGOSA-N 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
Abstract
The invention provides a compound with a structure shown in a formula (I) and capable of inhibiting HPK1 kinase activity and a pharmaceutical composition containing the compound. The invention also provides the use of the compounds in the prevention and/or treatment of cancer, tumour, inflammatory diseases, autoimmune diseases or immune mediated diseases.
Description
The present application claims priority to chinese patent application 202110378424.1 entitled "a highly active HPK1 kinase inhibitor" filed on 4/8 of 2021 to the national intellectual property agency of china, the contents of which are incorporated herein by reference in their entirety.
The application relates to a heterocyclic compound, in particular to a high-activity HPK1 kinase inhibitor and application thereof.
HPK1 is one of the members of the MAP4K family, is mainly expressed in hematopoietic cells, and acts as an intracellular negative regulator of T cell proliferation and signaling. Antigen stimulation of T cells causes recruitment of cytoplasmic linker protein SLP-76 to the lipid membrane TCR complex, providing binding sites for signal transduction-related kinases to effect TCR-mediated signaling to induce T cell activation. During this process HPK1 is activated by phosphorylation of tyrosine kinases Lck and Zap70, involved in regulating T cell receptor protein interactions. HPK1 blocks TCR signaling by phosphorylating the Ser376 site of the linker protein SLP-76, allowing SLP-76 to bind to the scaffold protein 14-3-3 epsilon and be degraded by the proteasome, and this effect allows SLP-76 to bind less to signal transduction-related kinases, blocking T cell activation and proliferation. On the other hand, HPK1 is also involved in regulating the maturation and activation of Dendritic Cells (DCs), particularly in inhibiting the expression of proteins involved in the activation of helper T cells in DC cells, such as CD80, CD86 and MHC complexes, thereby affecting the effect of DCs in regulating T cell activation; and the presentation of tumor antigens by activated DCs and the cooperation of DCs and T cells are one of the most important links in the anti-tumor immune system. Furthermore, there are a large number of immunosuppressive molecules such as PGE2 and TGF- β in the tumor microenvironment, and these factor-mediated immunosuppression effects are also important in connection with HPK 1. In general, small molecule compounds that specifically target to inhibit HPK1 can improve T cell function, enhance DC cell function and simultaneously reverse tumor immunosuppressive microenvironment, exert an enhanced anti-tumor immune effect through multiple pathways, thereby achieving the effect of inhibiting tumor growth.
Accordingly, there remains a strong need in the art for potent inhibitors of HPK1 kinase activity in order to provide more effective options for anti-tumor.
Disclosure of Invention
The present invention unexpectedly provides a compound of formula (I) and pharmaceutically acceptable salts or stereoisomers thereof which inhibit HPK1 kinase activity. Thus, in a first aspect, the present invention provides a compound having the structure of formula (I):
wherein the method comprises the steps of
X represents N or CR 10 ;
R 1 Represents hydrogen, C 1 -C 6 Alkyl, halogenated C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, halo C 3 -C 6 Cycloalkyl, halogen, cyano or-C (O) NH 2 ;
R 2 Represents hydrogen, halogen, hydroxy, (C) 1 -C 6 ) Alkyl, (C) 2 -C 6 ) Alkenyl, - (C) 0 -C 6 Alkylene group) (C) 3 -C 8 ) Cycloalkyl, - (C) 0 -C 6 Alkylene) (4-8 membered) heterocycloalkyl, (C) 1 -C 6 ) Alkoxy, (C) 3 -C 8 ) Cycloalkyl (C) 0 -C 6 Alkylene) oxy, (4-8 membered) heterocycloalkyl (C 0 -C 6 Alkylene) oxy;
R 3 represents hydrogen or C 1 -C 6 Alkyl, C 3 -C 6 Alkenyl, C 3 -C 6 Cycloalkyl, hydroxy (C) 1 -C 6 Alkyl, halo C 1 -C 6 Alkyl, 4-8 membered heterocycloalkyl;
R 4 represents hydrogen or C 1 -C 6 An alkyl group; and said C 1 -C 6 The alkyl group may be optionally substituted with a substituent selected from the group consisting of: halogen, -OR a 、-SR a 、-P(O)R a R b 、-S(O) 2 R a 、-S(O)(NH)R a 、-S(O)R a 、-S(O) 2 NR a R b 、-C(O)NR a R b 、-C(O)OH、-OC(O)NR a R b 、-NR a C(O)R b 、-NR a S(O) 2 R b ;
R 5 And R is 5’ Each independently represents hydrogen, C 1 -C 6 Alkyl, (C) 2 -C 6 ) Alkenyl, halogen, halo C 1 -C 6 Alkyl or hydroxy (C) 1 -C 6 An alkyl group);
or R is 5 And R is R 5’ Together with the carbon atoms to which they are attached form a 3-6 membered ring, which ring may optionally contain 0, 1 or 2 heteroatoms selected from N, O, S;
R 6 and R is 6’ Each independently represents hydrogen, C 1 -C 6 Alkyl, (C) 2 -C 6 ) Alkenyl, halogen, halo C 1 -C 6 Alkyl, hydroxy (C) 1 -C 6 An alkyl group);
or R is 6 And R is R 6’ Together with the carbon atoms to which they are attached form a 3-6 membered ring, which ring may optionally contain 0, 1 or 2 heteroatoms selected from N, O, S;
p represents 1 or 2;
R 7 and R is 7’ Each independently represents hydrogen, C 1 -C 6 Alkyl, (C) 2 -C 6 ) Alkenyl, halogen, halo C 1 -C 6 Alkyl, hydroxy (C) 1 -C 6 An alkyl group);
or R is 7 And R is R 7’ Together with the carbon atoms to which they are attached form a 3-6 membered ring, which ring may optionally contain 0, 1 or 2 heteroatoms selected from N, O, S;
w represents
Wherein A represents
Represents that the ring contains a single bond or a double bond;
when the bond between A and A 'is a double bond, A' represents CR a Or N, B represents CR b ;
When the bond between A and A 'is a single bond, A' represents CHR a B represents CHR b Or is absent;
R 8 and R is 9 Each independently represents hydrogen or C 1 -C 6 An alkyl group; or R is 8 And R is R 9 Can be combined with W 1 And W is 2 Together forming a 3-6 membered ring;
W 1 represents C, W 2 Represents CH or N;
R M And R is N Each independently represents hydrogen or C 1 -C 6 An alkyl group;
R 10 represents hydrogen, halogen, (C) 1 -C 6 ) Alkyl, (C) 2 -C 6 ) Alkenyl, - (C) 0 -C 6 Alkylene group) (C) 3 -C 8 ) Cycloalkyl, - (C) 0 -C 6 Alkylene) 4-10 membered heterocycloalkyl, - (C) 0 -C 6 Alkylene group) (C) 6 -C 10 ) Aryl, - (C) 0 -C 6 Alkylene) a 5-to 10-membered heteroaryl,
alternatively, when X represents CR 10 When R is 10 Can be adjacent to R 2 Together forming a (5-10 membered) cycloalkyl or a 5-10 membered heterocycloalkyl;
for cycloalkyl, heterocycloalkyl, aryl, heteroaryl groups as defined above, they may be optionally substituted with 0, 1, 2 or 3 substituents selected from: (C) 1 -C 6 ) Alkyl, (C) 2 -C 6 ) Alkenyl, halo (C) 1 -C 6 ) Alkyl, halo (C) 1 -C 6 ) Alkoxy, - (C) 1 -C 6 Alkylene) -O- (C 1 -C 6 ) Alkyl, (C) 3 -C 8 ) Cycloalkyl, halo (C) 3 -C 8 ) Cycloalkyl, halogen, -CN, oxo, -NR a R b 、-OR a 、-SR a 、-(C 1 -C 6 Alkylene) hydroxy, -C (O) R a 、-N(R a )C(O)R a 、-NR a C(O)OR a 、-NR a SO 2 R a 、-C(O)OR a 、-C(O)N R a R b 、-S(O) 2 N R a R b 、-S(O)R a 、-S(O) 2 R a 、-P(O)R a R b ;
R a 、R b Each independently represents hydrogen, C 1 -C 6 Alkyl, hydroxy (C) 1 -C 6 Alkyl, halo C 1 -C 6 An alkyl group;
m and n represent 0, 1 or 2, respectively.
In one embodiment of the present invention, W represents
Wherein A represents
Represents that the ring contains a single bond or a double bond;
each o independently represents 0 or 1;
R 8 represents hydrogen or C 1 -C 6 An alkyl group;
R 9 each independently represents hydrogen or C 1 -C 6 An alkyl group;
or R is 8 With adjacent R 9 Together with the carbon atoms to which they are attached, form a 3-6 membered ring;
W 2 、R M 、R N As previously described.
In one embodiment of the present invention, W representsOr alternatively
Represents that the ring contains a single bond or a double bond;
each o independently represents 0 or 1;
R 8 represents hydrogen or C 1 -C 6 An alkyl group;
R 9 each independently represents hydrogen or C 1 -C 6 An alkyl group;
or R is 8 With adjacent R 9 Together with the carbon atoms to which they are attached, form a 3-6 membered ring;
W 2 、R M 、R N the method of claim 1.
In one embodiment of the invention, W is an aromatic heterocycle, preferably an aromatic lactam.
In one embodiment of the invention, W is a saturated heterocycle, preferably a saturated lactam.
In a preferred embodiment of the invention, wherein ring W represents Or alternatively
In a further preferred embodiment of the invention, ring W represents
In a further preferred embodiment of the present invention, the ring W represents W
In a preferred embodiment of the present invention, wherein R 1 Represents hydrogen, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, cyano or-C (O) NH 2 The method comprises the steps of carrying out a first treatment on the surface of the More preferably, R 1 Represents hydrogen, halogen, C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group.
In a preferred embodiment of the present invention, wherein R 2 Represents hydroxy, (C) 1 -C 6 ) Alkyl, - (C) 0 -C 6 Alkylene group) (C) 3 -C 8 ) Cycloalkyl, - (C) 0 -C 6 Alkylene) (4-8 membered) heterocycloalkyl, (C) 1 -C 6 ) An alkoxy group; more preferably, R 2 Represent C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or C 3 -C 6 Cycloalkyl groups.
In a preferred embodiment of the present invention, wherein R 3 Represents hydrogen or C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, halo C 1 -C 6 An alkyl group; more preferably, R 3 Represents hydrogen or C 1 -C 6 An alkyl group.
In a preferred embodiment of the present invention, wherein R 4 Represents hydrogen or C 1 -C 6 An alkyl group; and said C 1 -C 6 The alkyl group may be optionally substituted with a substituent selected from the group consisting of: halogen, -OR a 、-SR a 、-P(O)R a R b 、-S(O) 2 R a 、-S(O)(NH)R a 、-S(O)R a 、-S(O) 2 NR a R b 、-C(O)NR a R b -C (O) OH; more preferably, R 4 Represents hydrogen or C 1 -C 6 An alkyl group.
In a preferred embodiment of the present invention, wherein R 5 、R 5’ Each independently represents hydrogen, halogen, C 1 -C 6 Alkyl or halo C 1 -C 6 An alkyl group.
In a preferred embodiment of the present invention, wherein R 6 、R 6’ Each independently represents hydrogen, halogen, C 1 -C 6 Alkyl or halo C 1 -C 6 An alkyl group.
In a preferred embodiment of the present invention, wherein R 7 、R 7’ Each independently represents hydrogen, halogen, C 1 -C 6 Alkyl, halogenated C 1 -C 6 Alkyl or hydroxy (C) 1 -C 6 Alkyl).
In a preferred embodiment of the present invention, wherein R 8 Represents hydrogen or C 1 -C 6 An alkyl group.
In a preferred embodiment of the present invention, wherein R 9 Represents hydrogen or C 1 -C 6 An alkyl group.
In a preferred embodiment of the present invention, wherein R 10 Represents hydrogen, halogen, (C) 1 -C 6 ) Alkyl, - (C) 0 -C 6 Alkylene group) (C) 3 -C 8 ) Cycloalkyl, - (C) 0 -C 6 Alkylene) 4-10 membered heterocycloalkyl; more preferably, R 10 Represents hydrogen, halogen or (C) 1 -C 6 ) An alkyl group.
In a preferred embodiment of the present invention, wherein R M Represents hydrogen or C 1 -C 6 An alkyl group.
In a preferred embodiment of the present invention, wherein R a 、R b Each independently represents hydrogen, C 1 -C 6 Alkyl or halo C 1 -C 6 An alkyl group.
Preferably, the compounds of the present invention have the following structure:
in addition, the invention also provides a pharmaceutical composition which comprises the compound and a pharmaceutically acceptable carrier.
In addition, the invention also provides application of the compound or the pharmaceutical composition in preparing medicines for preventing and/or treating cancers, tumors, inflammatory diseases, autoimmune diseases or immune mediated diseases.
In addition, the invention also provides the use of the compound of the invention for preventing and/or treating cancer, tumor, inflammatory diseases, autoimmune diseases or immune-mediated diseases.
It is particularly noted that, in this context, references to "compounds" of a particular structural formula are also generally intended to encompass stereoisomers, diastereomers, enantiomers, racemic mixtures, and isotopic derivatives thereof.
It is well known to those skilled in the art that salts, solvates, hydrates of a compound are alternative forms of a compound, all of which can be converted to the compound under certain conditions, and therefore, it is of particular note herein that when referring to a compound, generally also pharmaceutically acceptable salts thereof, and further solvates and hydrates thereof, are included.
Similarly, when a compound is referred to herein, prodrugs, metabolites, and nitrogen oxides thereof are also generally included.
Pharmaceutically acceptable salts according to the invention may be formed using, for example, the following mineral or organic acids: by "pharmaceutically acceptable salt" is meant a salt which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like commensurate with a reasonable benefit/risk ratio. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by reacting the free base or free acid with a suitable reagent alone, as outlined below. For example, the free base functionality may be reacted with a suitable acid. Furthermore, when the compounds of the present invention bear an acidic moiety, suitable pharmaceutically acceptable salts thereof may include metal salts, such as alkali metal salts (e.g., sodium or potassium salts); and alkaline earth metal salts (such as calcium or magnesium salts). Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups with inorganic acids (e.g., hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric) or organic acids (e.g., acetic, oxalic, maleic, tartaric, citric, succinic or malonic) or by using other methods in the art such as ion exchange. Other pharmaceutically acceptable salts include adipic acid salts, sodium alginate, ascorbate, aspartic acid salts, benzenesulfonate salts, benzoate salts, bisulfate salts, borate salts, butyric acid salts, camphoric acid salts, citric acid salts, cyclopentanepropionate salts, digluconate salts, dodecylsulfate salts, ethanesulfonate salts, formate salts, fumaric acid salts, glucoheptonate salts, glycerophosphate salts, gluconate salts, southern sulfate salts, heptanoate salts, caproate salts, hydroiodic acid salts, 2-hydroxy-ethanesulfonate salts, lactobionate salts, lactate salts, laurate salts, lauryl sulfate salts, malate salts, maleate salts, malonate salts, methanesulfonate salts, 2-naphthalenesulfonate salts, nicotinate salts, nitrate salts, oleate salts, oxalate salts, palmitate salts, pamoate salts, pectate salts, persulfates, 3-phenylpropionate salts, phosphate salts, bitter salts, pivalate salts, propionate salts, stearate salts, succinate salts, sulfate salts, tartrate salts, thiocyanate salts, p-toluenesulfonate salts, undecanoate salts, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include non-toxic ammonium salts, quaternary ammonium salts, and ammonium cations formed with counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, as appropriate.
The pharmaceutically acceptable salts of the invention may be prepared by conventional methods, for example by dissolving the compounds of the invention in a water miscible organic solvent (e.g. acetone, methanol, ethanol and acetonitrile), adding thereto an excess of an organic or inorganic acid aqueous solution to precipitate the salt from the resulting mixture, removing the solvent and the remaining free acid therefrom, and then isolating the precipitated salt.
The precursor or metabolite of the present invention may be a precursor or metabolite well known in the art, as long as the precursor or metabolite is convertible by in vivo metabolism to form the target compound. For example, "prodrugs" refer to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like commensurate with a reasonable benefit/risk ratio, and are effective for their intended use. The term "prodrug" refers to a compound that is rapidly transformed in vivo to produce the parent compound of the formula described above, for example by metabolism in vivo, or N-demethylation of a compound of the invention.
"solvate" as used herein means a physical association of a compound of the invention with one or more solvent molecules (whether organic or inorganic). The physical association includes hydrogen bonding. In some cases, for example when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be able to be isolated. The solvent molecules in the solvate may be present in a regular arrangement and/or in a disordered arrangement. The solvate may comprise a stoichiometric or non-stoichiometric solvent molecule. "solvate" encompasses both solution phases and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolamides. Solvation methods are well known in the art.
The term "stereoisomers" as used herein is divided into conformational isomerism and configurational isomerism, which may be also divided into cis-trans isomerism and optical isomerism (i.e. optical isomerism), and conformational isomerism refers to a stereoisomerism phenomenon that an organic molecule with a certain configuration makes each atom or group of molecules generate different arrangement modes in space due to rotation or twisting of carbon and carbon single bonds, and commonly includes structures of alkane and cycloalkane compounds, such as chair-type conformations and boat-type conformations, which occur in cyclohexane structures. "stereoisomers" means that when a compound of the invention contains one or more asymmetric centers, it is useful as racemate and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The compounds of the invention have asymmetric centers, each of which produces two optical isomers, and the scope of the invention includes all possible optical isomers and diastereomeric mixtures and pure or partially pure compounds. The compounds described herein may exist in tautomeric forms having different points of attachment of hydrogen through displacement of one or more double bonds. For example, the ketone and its enol form are keto-enol tautomers. Each tautomer and mixtures thereof are included in the compounds of the present invention. All enantiomers, diastereomers, racemates, meso, cis-trans isomers, tautomers, geometric isomers, epimers, mixtures thereof and the like of the compounds of formula (I) are included within the scope of the present invention.
The term "isotopically-labeled" as used herein refers to molecules wherein the compound is isotopically labeled. Isotopes commonly used as isotopic labels are: the hydrogen isotope is selected from the group consisting of, 2 h and 3 h is formed; carbon isotopes: 11 C、 13 c and C 14 C, performing operation; chlorine isotopes: 35 cl and Cl 37 Cl; fluorine isotopes: 18 f, performing the process; iodine isotopes: 123 i and 125 i, a step of I; nitrogen isotopes: 13 n and 15 n; oxygen isotopes: 15 O、 17 o and 18 isotopes of O and sulfur 35 S, S. These isotopically-labeled compounds can be used to study the distribution of a pharmaceutical molecule in a tissue. In particular deuterium 3 H and carbon 13 C, because they are easily labeled and conveniently detected, the application is wider. Certain heavy isotopes, such as heavy hydrogen @, for example 2 H) The substitution can enhance the metabolic stability and prolong the half-life period, thereby achieving the aim of reducing the dosage and providing curative effect advantages. Isotopically-labeled compounds are generally synthesized starting from a starting material that has been labeled, using known synthetic techniques as if it were a non-isotopically-labeled compound.
The invention also provides the use of the compounds of the invention in the manufacture of a medicament for the prophylaxis and/or treatment of cancer, tumour, inflammatory disease, autoimmune disease or immune mediated disease.
Furthermore, the present invention provides a pharmaceutical composition for preventing and/or treating cancer, tumor, inflammatory disease, autoimmune disease, neurodegenerative disease, attention-related disease or immune-mediated disease, comprising the compound of the present invention as an active ingredient.
Furthermore, the present invention provides a method for preventing and/or treating cancer, tumor, inflammatory disease, autoimmune disease, neurodegenerative disease, attention-related disease or immune-mediated disease comprising administering to a mammal in need thereof a compound of the present invention.
Representative examples of inflammatory, autoimmune and immune-mediated diseases may include but are not limited to, arthritis, rheumatoid arthritis, spinal arthritis, gouty arthritis, osteoarthritis, juvenile arthritis, other arthritic conditions, lupus, systemic Lupus Erythematosus (SLE), skin-related diseases, psoriasis, eczema, dermatitis, allergic dermatitis, pain, lung disease, pulmonary inflammation, adult Respiratory Distress Syndrome (ARDS), pulmonary sarcoidosis, chronic pulmonary inflammatory diseases, chronic Obstructive Pulmonary Disease (COPD), cardiovascular diseases, atherosclerosis, myocardial infarction, congestive heart failure, myocardial ischemia reperfusion injury, inflammatory bowel disease, crohn's disease, ulcerative colitis, irritable bowel syndrome, asthma, sjogren's syndrome, autoimmune thyroid disease urticaria (rubella), multiple sclerosis, scleroderma, organ transplant rejection, xenograft, idiopathic Thrombocytopenic Purpura (ITP), parkinson's disease, alzheimer's disease, diabetes-related diseases, inflammation, pelvic inflammatory disease, allergic rhinitis, allergic bronchitis, allergic sinusitis, leukemia, lymphoma, B-cell lymphoma, T-cell lymphoma, myeloma, acute Lymphoblastic Leukemia (ALL), chronic Lymphoblastic Leukemia (CLL), acute Myelogenous Leukemia (AML), chronic Myelogenous Leukemia (CML), hairy cell leukemia, hodgkin's disease, non-hodgkin's lymphoma, multiple myeloma, myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), diffuse large B-cell lymphoma and follicular lymphoma.
Representative examples of cancers or tumors may include but are not limited to, skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, pancreatic cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, neuroblastoma, rectal cancer, colon cancer, familial adenomatous polyposis, hereditary non-polyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharynx cancer, tongue cancer, salivary gland cancer, stomach cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, urinary carcinoma, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral nerve ectodermal tumors hodgkin's lymphoma, non-hodgkin's lymphoma, burkitt's lymphoma, acute Lymphoblastic Leukemia (ALL), chronic Lymphocytic Leukemia (CLL), acute Myelogenous Leukemia (AML), chronic Myelogenous Leukemia (CML), adult T-cell leukemia lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gall bladder carcinoma, bronchogenic carcinoma, small cell lung carcinoma, non-small cell lung carcinoma, multiple myeloma, basal cell carcinoma, teratoma, retinoblastoma, choriocarcinoma, seminoma, rhabdomyosarcoma, craniopharyngeal pipe carcinoma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, ewing's sarcoma, or plasmacytoma.
Representative examples of therapeutic agents for the treatment of inflammatory, autoimmune, and immune-mediated diseases may include, but are not limited to, steroidal drugs (e.g., prednisone, hydroprednisone, methyl hydroprednisone, cortisone, hydroxy cortisone, betamethasone, dexamethasone, etc.), methotrexate, leflunomide, anti-tnfα agents (e.g., etanercept, infliximab, ada Li Shan resistance, etc.), calcineurin inhibitors (e.g., tacrolimus, pimecrolimus, etc.), and antihistamines (e.g., diphenhydramine, hydroxyzine, loratadine, ebastine, ketotifen, cetirizine, levocetirizine, fexofenadine, etc.), and at least one therapeutic agent selected therefrom may be included in the pharmaceutical compositions of the present invention.
The compound of the present invention or a pharmaceutically acceptable salt thereof may be administered orally or parenterally as an active ingredient in an effective amount ranging from 0.1 to 2,000mg/kg body weight/day, preferably 1 to 1,000mg/kg body weight/day in the case of mammals including humans (body weight of about 70 kg), and administered in divided doses, single or 4 times daily, or with/without following a predetermined time. The dosage of the active ingredient may be adjusted according to a number of relevant factors, such as the condition of the subject to be treated, the type and severity of the disease, the rate of administration and the opinion of the physician. In some cases, amounts less than the above dosages may be suitable. An amount greater than the above dosage may be used if it does not cause deleterious side effects and may be administered in divided doses per day.
In addition, the present invention provides a method for preventing and/or treating a tumor, cancer, viral infection, organ transplant rejection, neurodegenerative disease, attention-related disease or autoimmune disease, comprising administering to a mammal in need thereof a compound of the present invention or a pharmaceutical composition of the present invention.
The pharmaceutical compositions of the present invention may be formulated according to any of the conventional methods into dosage forms for oral administration or parenteral administration (including intramuscular, intravenous and subcutaneous routes, intratumoral injection), such as tablets, granules, powders, capsules, syrups, emulsions, microemulsions, solutions or suspensions.
Other features of the present invention will become apparent in the course of describing exemplary embodiments of the invention, which are presented to illustrate the invention and are not intended to be limiting thereof, the following examples being prepared, isolated and characterized using the methods disclosed herein.
The compounds of the present invention may be prepared in a variety of ways known to those skilled in the art of organic synthesis, and may be synthesized using the methods described below as well as synthetic methods known in the art of organic synthetic chemistry or by variations thereof as will be appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reaction is carried out in a solvent or solvent mixture suitable for the kit materials used and for the transformation to be effected. Those skilled in the art of organic synthesis will understand that the functionalities present on the molecule are consistent with the proposed transformations. This sometimes requires judgment to change the order or starting materials of the synthesis steps to obtain the desired compounds of the invention.
Terminology
The terms used in the present application, including the specification and claims, are defined as follows, unless otherwise indicated. It must be noted that, in the specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Conventional methods of mass spectrometry, nuclear magnetism, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are used, if not otherwise indicated. In the present application, the use of "or" and "means" and/or "unless otherwise indicated.
In the description and claims, a given formula or name shall encompass all stereoisomers and optical isomers and racemates in which the isomers exist. Unless otherwise indicated, all chiral (enantiomers and diastereomers) and racemic forms are within the scope of the present application. Many geometric isomers of c=c double bonds, c=n double bonds, ring systems, etc. may also be present in the compounds, and all such stable isomers are contemplated within the present application. The present application describes cis-and trans- (or E-and Z-) geometric isomers of the compounds of the present application, and which may be separated into mixtures of isomers or separate isomeric forms. The compounds of the application may be isolated in optically active or racemic forms. All processes for preparing the compounds of the application and intermediates prepared therein are considered part of the present application. When preparing the enantiomeric or diastereomeric products, they can be separated by conventional methods, for example by chromatography or fractional crystallization. Depending on the process conditions, the end products of the application are obtained in free (neutral) or salt form. Both the free form and the salt of these end products are within the scope of the application. If desired, one form of the compound may be converted to another form. The free base or acid may be converted to a salt; the salt may be converted to the free compound or another salt; mixtures of the isomeric compounds of the application may be separated into the individual isomers. The compounds of the application, free forms and salts thereof, may exist in various tautomeric forms in which hydrogen atoms are transposed to other parts of the molecule and thereby the chemical bonds between the atoms of the molecule are rearranged. It is to be understood that all tautomeric forms that may exist are included within the application.
Unless otherwise defined, the definition of substituents of the invention are each independent of, and not interrelated with, each other, e.g. for R in a substituent a (or R) a ') which are independent of each other in the definition of the different substituents. Specifically, for R a (or R) a ' when a definition is selected in a substituent, it does not mean that R a (or R) a ') have the same definition in all other substituents. More specifically, for example (by way of non-exhaustive list) for NR a R a In' when R a (or R) a Where the definition of') is selected from hydrogen, it is not meant to be in-C (O) -NR a R a In' R a (or R) a ') is necessarily hydrogen.
Unless otherwise defined, when a substituent is noted as "optionally substituted", the substituent is selected from, for example, substituents such as alkyl, cycloalkyl, aryl, heterocyclyl, halogen, hydroxy, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amino groups (wherein 2 amino substituents are selected from alkyl, aryl or arylalkyl), alkanoylamino, aroylamino, aralkylamino, substituted alkanoylamino, substituted arylamino, substituted aralkylamino, thio, alkylthio, arylthio, arylalkylthio, arylthiocarbonyl, arylalkylthiocarbonyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, sulfonylamino, e.g., -SO 2 NH 2 Substituted sulfonylamino, nitro, cyano, carboxyl, carbamoylFor example-CONH 2 Substituted carbamoyl such as-CONH alkyl, -CONH aryl, -CONH arylalkyl or where there are two substituents on the nitrogen selected from alkyl, aryl or arylalkyl, alkoxycarbonyl, aryl, substituted aryl, guanidino, heterocyclyl such as indolyl, imidazolyl, furanyl, thienyl, thiazolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, homopiperazinyl and the like and substituted heterocyclyl.
The term "alkyl" or "alkylene" as used herein is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms. For example, "C 1 -C 6 Alkyl "means an alkyl group having 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl).
The term "alkenyl" denotes a straight or branched hydrocarbon radical containing one or more double bonds and typically having a length of 2 to 20 carbon atoms. For example, "C2-C6 alkenyl" contains two to six carbon atoms. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like.
The term "alkynyl" denotes a straight or branched hydrocarbon radical containing one or more triple bonds and typically ranging in length from 2 to 20 carbon atoms. For example, "C 2 -C 6 Alkynyl "contains two to six carbon atoms. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, and the like.
The term "alkoxy" or "alkyloxy" refers to an-O-alkyl group. "C 1 -C 6 Alkoxy "(or alkyloxy) is intended to include C 1 、C 2 、C 3 、C 4 、C 5 、C 6 An alkoxy group. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and t-butoxy. Similarly, "alkylthio" or "thioalkanesOxy "represents a sulfur-bridged alkyl group as defined above having the indicated number of carbon atoms; such as methyl-S-and ethyl-S-.
The term "carbonyl" refers to an organofunctional group (c=o) formed by the double bond connection of two atoms of carbon and oxygen.
The term "aryl", alone or as part of a larger moiety such as "aralkyl", "aralkoxy" or "aryloxyalkyl", refers to a monocyclic, bicyclic or tricyclic ring system having a total of 5 to 12 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. In certain embodiments of the present invention, "aryl" refers to an aromatic ring system including, but not limited to, phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetrahydronaphthyl. The term "aralkyl" or "arylalkyl" refers to an alkyl residue attached to an aryl ring. Non-limiting examples include benzyl, phenethyl, and the like. The fused aryl group may be attached to another group at a suitable position on the cycloalkyl ring or aromatic ring. Examples dashed lines drawn from the ring system indicate that the bond may be attached to any suitable ring atom.
The term "cycloalkyl" refers to a monocyclic or bicyclic cyclic alkyl group, preferably having 3 to 8 ring members. Monocyclic cyclic alkyl means C 3 -C 8 Including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl. Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl". Bicyclic cyclic alkyl groups include bridged, spiro, or fused cyclic cycloalkyl groups.
The term "cycloalkenyl" refers to a monocyclic or bicyclic cyclic alkenyl, preferably having 3 to 8 ring members. Monocyclic cyclic alkenyl means C 3 -C 8 Cyclic alkenyl groups of (c) including, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and norbornenyl. Branched cycloalkenyl groups such as 1-methylcyclopropenyl and 2-methylcyclopropenyl are included in the definition of "cycloalkenyl". Bicyclic cycloalkenyl groups include bridged, spiro, or fused cyclic alkenyl groups.
"halo" or "halogen" includes fluoro, chloro, bromo and iodo. "haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms and substituted with 1 or more halogens, preferably 1, 2 or 3 halogens. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examples of haloalkyl groups also include "fluoroalkyl groups" intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms (preferably 1 to 6 carbon atoms) and substituted with 1 or more fluorine atoms.
"haloalkoxy" or "haloalkyloxy" means an oxygen-bridged haloalkyl as defined above having the indicated number of carbon atoms, preferably 1 to 6 carbon atoms. For example, "halo C 1 -C 6 Alkoxy "is intended to include C 1 、C 2 、C 3 、C 4 、C 5 、C 6 Haloalkoxy groups. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, 2-trifluoroethoxy, and pentafluoroethoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" means a thio-bridged haloalkyl as defined above having the indicated number of carbon atoms (preferably 1 to 6 carbon atoms); such as trifluoromethyl-S-and pentafluoroethyl-S-.
In the present disclosure, C is used when referring to some substituents x1 -C x2 This means that the number of carbon atoms in the substituent group may be x1 to x 2. For example, C 0 -C 8 Represents that the radical contains 0, 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C 1 -C 8 Representing that the radicals contain 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C 2 -C 8 Representing that the radicals contain 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C 3 -C 8 Representing that the radicals contain 3, 4, 5, 6, 7 or 8 carbon atoms, C 4 -C 8 Indicating that the radicals containHaving 4, 5, 6, 7 or 8 carbon atoms, C 0 -C 6 Represents that the radical contains 0, 1, 2, 3, 4, 5 or 6 carbon atoms, C 1 -C 6 Representing that the radicals contain 1, 2, 3, 4, 5 or 6 carbon atoms, C 2 -C 6 Representing that the radicals contain 2, 3, 4, 5 or 6 carbon atoms, C 3 -C 6 Meaning that the group contains 3, 4, 5 or 6 carbon atoms.
In the present disclosure, the expression "x1-x2 membered ring" is used when referring to a cyclic group (e.g., aryl, heteroaryl, cycloalkyl, and heterocycloalkyl), which means that the number of ring atoms of the group can be x1 to x 2. For example, the 3-12 membered cyclic group may be a 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 membered ring, the number of ring atoms of which may be 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; the 3-6 membered ring represents that the cyclic group may be a 3, 4, 5 or 6 membered ring, and the number of ring atoms may be 3, 4, 5 or 6; the 3-8 membered ring represents that the cyclic group may be a 3, 4, 5, 6, 7 or 8 membered ring, and the number of ring atoms may be 3, 4, 5, 6, 7 or 8; the 3-9 membered ring represents that the cyclic group may be a 3, 4, 5, 6, 7, 8 or 9 membered ring, and the number of ring atoms may be 3, 4, 5, 6, 7, 8 or 9; the 4-7 membered ring represents that the cyclic group may be a 4, 5, 6 or 7 membered ring, and the number of ring atoms may be 4, 5, 6 or 7; the 5-8 membered ring represents that the cyclic group may be a 5, 6, 7 or 8 membered ring, and the number of ring atoms may be 5, 6, 7 or 8; the 5-12 membered ring represents that the cyclic group may be a 5, 6, 7, 8, 9, 10, 11 or 12 membered ring, and the number of ring atoms may be 5, 6, 7, 8, 9, 10, 11 or 12; the 6-12 membered ring means that the cyclic group may be a 6, 7, 8, 9, 10, 11 or 12 membered ring, and the number of ring atoms may be 6, 7, 8, 9, 10, 11 or 12. The ring atom may be a carbon atom or a heteroatom, for example a heteroatom selected from N, O and S. When the ring is a heterocyclic ring, the heterocyclic ring may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more ring heteroatoms, for example heteroatoms selected from N, O and S.
In the present disclosure, the one or more halogens may each be independently selected from fluorine, chlorine, bromine, and iodine.
The term "heteroaryl" means a stable 3-, 4-, 5-, 6-, or 7-membered aromatic monocyclic or aromatic bicyclic or 7-, 8-, 9-, 10-, 11-, 12-membered aromatic polycyclic heterocycle which is fully unsaturated, partially unsaturated and which contains carbon atoms and 1,2,3 or 4 heteroatoms independently selected from N, O and S; and includes any of the following polycyclic groups wherein any of the heterocycles defined above is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The nitrogen atom is substituted or unsubstituted (i.e., N or NR, where R is H or another substituent if defined). The heterocycle may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. If the resulting compound is stable, the heterocyclyl groups described herein may be substituted on a carbon or nitrogen atom. The nitrogen in the heterocycle may optionally be quaternized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocycle is no greater than 1. When the term "heterocycle" is used, it is intended to include heteroaryl. Examples of aryl radicals include, but are not limited to, acridinyl, azetidinyl, azepinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothienyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazole, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4 aH-carbazolyl, carbolinyl, chromanyl, chromen, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro [2,3-b ] tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazopyridinyl, indolyl (indolenyl), indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinyl (atinoyl), isobenzofuranyl, isochromanyl isoindazolyl, isoindolinyl, isoindolyl, isoquinolyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolyl, oxadiazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl, oxazolidinyl, naphthyridinyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidinonyl, 2H-pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2, 5-thiadiazinyl, 1,2, 3-thiadiazinyl, 1,2, 4-thiadiazinyl, 1,2, 5-thiadiazinyl, 1,3, 4-thiadiazinyl, thianthrenyl, thiazolyl, thienyl, thiazolopyridinyl thienothiazolyl, thienooxazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,2, 5-triazolyl, 1,3, 4-triazolyl and xanthenyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl, isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl, 1,2,3, 4-tetrahydroquinolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 5,6,7, 8-tetrahydro-quinolinyl, 2, 3-dihydro-benzofuranyl, chromanyl, 1,2,3, 4-tetrahydro-quinoxalinyl and 1,2,3, 4-tetrahydro-quinazolinyl. The term "heteroaryl" may also include biaryl structures formed from "aryl" and monocyclic "heteroaryl" as defined above, such as, but not limited to "-phenyl bipyridyl-", "-phenyl bipyrimidinyl", "-pyridinyl biphenyl", "-pyridinyl bipyrimidinyl-", "-pyrimidinyl biphenyl-"; wherein the invention also includes fused and spiro compounds containing, for example, the above-described heterocycles.
The term "heterocycloalkyl" as used herein refers to a monocyclic heterocycloalkyl system, or a bicyclic heterocycloalkyl system, and also includes spiroheterocycles or bridged heterocycloalkyl groups. A monocyclic heterocycloalkyl group refers to a 3-8 membered, and contains at least one saturated or unsaturated, but not aromatic, cyclic alkyl system selected from O, N, S, P. Bicyclic heterocycloalkyl system refers to a heterocycloalkyl fused to a phenyl, or a cycloalkyl, or a cycloalkenyl, or a heterocycloalkyl, or a heteroaryl.
The term "bridged cycloalkyl" as used herein refers to polycyclic compounds sharing two or more carbon atoms. Can be classified into bicyclic bridged ring hydrocarbons and polycyclic bridged ring hydrocarbons. The former is composed of two alicyclic rings sharing more than two carbon atoms; the latter is a bridged cyclic hydrocarbon consisting of three or more rings.
The term "spirocycloalkyl" as used herein refers to a polycyclic hydrocarbon having a single ring of carbon atoms in common with each other (referred to as spiro atoms).
The term "bridged cyclohexyl" as used herein refers to a polycyclic compound having a common use of two or more carbon atoms, at least one of the rings containing a member selected from the group consisting of O, N, S atoms. Can be divided into two-ring bridged heterocyclic rings and multiple-ring bridged heterocyclic rings.
The term "heterospirocyclic" as used herein refers to a polycyclic hydrocarbon having a single ring with at least one atom selected from O, N, S which shares a single carbon atom (referred to as the spiro atom).
The term "substituted" as used herein means that at least one hydrogen atom is replaced with a non-hydrogen group, provided that the normal valence is maintained and that the substitution results in a stable compound. As used herein, a ring double bond is a double bond formed between two adjacent ring atoms (e.g., c= C, C =n or n=n).
In the case where nitrogen atoms (e.g., amines) are present on the compounds of the present invention, these nitrogen atoms may be converted to N-oxides by treatment with an oxidizing agent (e.g., mCPBA and/or hydrogen peroxide) to obtain other compounds of the present invention. Thus, the nitrogen atoms shown and claimed are considered to both encompass the nitrogen shown and its N-oxides to obtain the derivatives of the invention.
When any variable occurs more than one time in any composition or formula of a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-3R, then the group may optionally be substituted with up to three R groups, and R is independently selected at each occurrence from the definition of R. Furthermore, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
The term "patient" as used herein refers to an organism treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murine, simian/monkey, equine, bovine, porcine, canine, feline, etc.) and most preferably refer to humans.
The term "effective amount" as used herein means the amount of a drug or pharmaceutical agent (i.e., a compound of the present invention) that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means an amount of: such amounts result in improved treatment, cure, prevention, or alleviation of a disease, disorder, or side effect, or a reduction in the rate of progression of a disease or disorder, as compared to a corresponding subject not receiving such amounts. An effective amount may be administered in one or more administrations, or dosages and is not intended to be limited to a particular formulation or route of administration. The term also includes within its scope an effective amount to enhance normal physiological function.
The term "treatment" as used herein includes any effect that results in an improvement in a condition, disease, disorder, etc., such as a reduction, decrease, modulation, improvement or elimination, or improvement of symptoms thereof.
The term "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and/or dosage forms which are: it is suitable for use in contact with human and animal tissue without undue toxicity, irritation, allergic response, and/or other problems or complications commensurate with a reasonable benefit/risk ratio, within the scope of sound medical judgment.
The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutical substance, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc, magnesium stearate, calcium or zinc stearate, or stearic acid), or solvent encapsulating material, which involves carrying or transporting the subject compound from one organ or body part to another organ or body part. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the patient.
The term "pharmaceutical composition" means a composition comprising a compound of the invention and at least one other pharmaceutically acceptable carrier. "pharmaceutically acceptable carrier" refers to a medium commonly accepted in the art for delivery of biologically active agents to animals, particularly mammals, and includes (i.e., adjuvants, excipients or vehicles such as diluents, preservatives, fillers, flow control agents, disintegrants, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, antibacterial agents, antifungal agents, lubricants, and dispersing agents, depending upon the mode of administration and the nature of the dosage form.
Specific pharmaceutical and medical terminology
The term "acceptable" as used herein, means that a prescription component or active ingredient does not unduly adversely affect the health of the general therapeutic objective.
The term "cancer", as used herein, refers to an abnormal growth of cells that is not controllable and is capable of metastasis (transmission) under certain conditions. Cancers of this type include, but are not limited to, solid tumors (e.g., bladder, intestine, brain, chest, uterus, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas, or other endocrinologic organ (e.g., thyroid), prostate, skin (melanoma), or hematological tumors (e.g., non-leukemia).
The term "co-administration" or similar terms, as used herein, refers to administration of several selected therapeutic agents to a patient, administered at the same or different times, in the same or different modes of administration.
The term "enhance" or "potentiating," as used herein, means that the intended result can be increased or prolonged in either potency or duration. Thus, in enhancing the therapeutic effect of a drug, the term "enhancing" refers to the ability of a drug to increase or prolong the potency or duration of the drug in the system. As used herein, "potentiating value" refers to the ability of an additional therapeutic agent to be maximally enhanced in an ideal system.
The term "immunological disorder" refers to a disease or condition that produces an adverse or detrimental response to an endogenous or exogenous antigen. As a result, the cells are often dysfunctional, or thus destroyed and dysfunctional, or destroy organs or tissues that may develop immune symptoms.
The term "kit" is synonymous with "product package".
The term "subject" or "patient" includes mammals and non-mammals. Mammals include, but are not limited to, mammals: humans, non-human primates such as gorillas, apes, and monkeys; agricultural animals such as cattle, horses, goats, sheep, pigs; domestic animals such as rabbits and dogs; laboratory animals include rodents such as rats, mice, guinea pigs, and the like. Non-mammalian animals include, but are not limited to, birds, fish, and the like. In a preferred embodiment, the mammal selected is a human.
The terms "treat," "course of treatment," or "therapy" as used herein include alleviation, inhibition, or amelioration of symptoms or conditions of a disease; inhibit the occurrence of complications; improving or preventing underlying metabolic syndrome; inhibiting the occurrence of a disease or condition, such as controlling the progression of a disease or condition; alleviating a disease or symptom; causing the disease or symptom to subside; alleviating complications caused by diseases or symptoms, or preventing and/or treating signs caused by diseases or symptoms.
As used herein, a compound or pharmaceutical composition, upon administration, may result in an improvement in a disease, symptom, or condition, particularly an improvement in severity, delay of onset, slow progression, or decrease in duration. Whether stationary or temporary, continuous or intermittent, may be due to or associated with administration.
Route of administration
Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transdermal, vaginal, auditory canal, nasal, and topical. Further, by way of example only, parenteral administration includes intramuscular, subcutaneous, intravenous, intramedullary, ventricular, intraperitoneal, intralymphatic, and intranasal.
In one aspect, the administration of the compounds described herein is topical rather than systemic. In certain embodiments, the depot is administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in another specific embodiment, the drug is administered by a targeted drug delivery system. For example, liposomes encapsulated by organ-specific antibodies. In this particular embodiment, the liposomes are selectively targeted to a specific organ and absorbed.
Pharmaceutical composition and dosage
The invention also provides pharmaceutical compositions comprising a therapeutically effective amount of one or more compounds of the invention, and optionally one or more other therapeutic agents described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents. The compounds of the invention may be administered by any suitable means for any of the above uses, for example, orally, such as tablets, pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups and emulsions; sublingual delivery; is taken orally; parenteral, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.g., in the form of sterile injectable aqueous or nonaqueous solutions or suspensions); transnasally, including administration to the nasal membrane, such as by inhalation spray; topical, such as in the form of a cream or ointment; or rectally, such as in the form of suppositories; or intratumoral injection. They may be administered alone, but are typically administered using a drug carrier selected based on the chosen route of administration and standard pharmaceutical practice.
Pharmaceutical carriers are formulated according to a number of factors within the purview of one skilled in the art. These factors include, but are not limited to: the type and nature of the active agent formulated; a subject to whom the active agent-containing composition is to be administered; the intended route of administration of the composition; and targeted therapeutic indications. Pharmaceutically acceptable carriers include aqueous and nonaqueous liquid media and various solid and semi-solid dosage forms.
The carrier may include a number of different ingredients and additives in addition to the active agent, which other ingredients are included in the formulation for a variety of reasons known to those skilled in the art, such as stabilizing the active agent, binder, etc. For a description of suitable pharmaceutical carriers and the factors involved in carrier selection, see a number of readily available sources, for example, allen l.v. jr.et al remington: the Science and Practice of Pharmacy (2 Volumes), 22nd Edition (2012), pharmaceutical Press.
Of course, the dosage regimen of the compounds of the invention will vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health condition, medical condition and weight of the recipient; the nature and extent of the symptoms; the type of concurrent treatment; treatment frequency; the route of administration, the renal and hepatic function of the patient, and the desired effect. According to general guidelines, when used for the indicated effects, the daily oral dosage of each active ingredient should be from about 0.001 mg/day to about 10-5000 mg/day, preferably from about 0.01 mg/day to about 1000 mg/day, and most preferably from about 0.1 mg/day to about 250 mg/day. During constant infusion, the most preferred dosage for intravenous administration should be about 0.01 mg/kg/min to about 10 mg/kg/min. The compounds of the present invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses of two, three or four times daily.
The compounds are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration (e.g., oral tablets, capsules, elixirs and syrups) and consistent with conventional pharmaceutical practices.
Dosage forms suitable for administration (pharmaceutical compositions) may contain from about 1 mg to about 2000 mg of active ingredient per dosage unit. In these pharmaceutical compositions, the active ingredient will typically be present in an amount of about 0.1 to 95% by weight, based on the total weight of the composition.
Typical capsules for oral administration contain at least one compound of the invention (250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture was passed through a 60 mesh screen and packaged into size 1 gelatin capsules.
Typical injectable formulations can be prepared as follows: at least one compound of the invention (250 mg) is placed in a bottle in a sterile manner, lyophilized in a sterile manner and sealed. For use, the vial contents were mixed with 2mL of physiological saline to produce an injectable formulation.
The scope of the present invention includes pharmaceutical compositions (alone or in combination with a pharmaceutical carrier) comprising a therapeutically effective amount of at least one compound of the present invention as an active ingredient. Optionally, the compounds of the present invention may be used alone, in combination with other compounds of the present invention, or in combination with one or more other therapeutic agents (e.g., anticancer agents or other pharmaceutically active substances).
Regardless of the route of administration selected, the compounds of the invention (which may be used in a suitable hydrated form) and/or the pharmaceutical compositions of the invention are formulated into pharmaceutical dosage forms by conventional methods known to those skilled in the art.
The actual dosage level of the active ingredient in the pharmaceutical compositions of the present invention may be varied to achieve amounts of the active ingredient that are effective to achieve the desired therapeutic response, composition and mode of administration for a particular patient, but which are non-toxic to the patient.
The selected dosage level will depend on a variety of factors including the activity of the particular compound of the invention or an ester, salt or amide thereof employed; a route of administration; administration time; the rate of excretion of the particular compound being used; the rate and extent of absorption; duration of treatment; other drugs, compounds and/or substances used in combination with the particular compound used; the age, sex, weight, condition, general health and previous medical history of the patient being treated.
A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, to achieve a desired therapeutic effect, a physician or veterinarian may begin the relative amounts of the compound of the invention used in the pharmaceutical composition at a level less than that required and step up the dosage until the desired effect is achieved. In general, a suitable daily dose of a compound of the invention will be the amount of the compound at the lowest dose effective to produce a therapeutic effect. Such effective dosages will generally depend on the factors described above. Generally, oral, intravenous, intraventricular and subcutaneous dosages of the compounds of the invention for patients range from about 0.01 to about 50mg/kg body weight/day. If desired, an effective daily dose of the active compound may be administered separately at appropriate intervals throughout the day in two, three, four, five, six or more sub-doses, optionally in unit dosage form. In certain aspects of the invention, the administration is once daily.
Although the compounds of the present invention may be administered alone, it is preferable to administer the compounds in the form of a pharmaceutical formulation (composition). Kit/product package
For use in the treatment of the above indications, the kit/product package is also described herein. These kits may consist of a conveyor, a pack or a container box which may be divided into multiple compartments to hold one or more containers, such as vials, tubes and the like, each of which contains a separate one of the components of the method. Suitable containers include bottles, vials, syringes, test tubes, and the like. The container is made of acceptable glass or plastic materials.
For example, the container may contain one or more compounds described herein, either in the form of pharmaceutical compositions or as a mixture with other ingredients described herein. The container may have a sterile outlet (e.g., the container may be an iv bag or vial, and the vial stopper may be pierced by a hypodermic needle). Such kits may carry a compound, and instructions, tags, or instructions for use as described herein.
A typical kit may include one or more containers, each containing one or more materials (e.g., reagents, or concentrated mother liquor, and/or equipment) to accommodate commercial popularization and use of the compound by the user. Such materials include, but are not limited to, buffers, diluents, filters, needles, syringes, conveyors, bags, containers, bottles and/or tubes with a content list and/or instructions for use, and with instructions for packaging. The complete set of instructions is included.
The label may be displayed on or closely associated with the container. The appearance of a label on a container means that the label letters, numbers or other features are affixed, molded, engraved on the container; the label may also be present in a container box or shipping box containing a variety of containers, such as in a product insert. A label may be used to indicate a particular therapeutic use of the contents. The label may also indicate instructions for use of the content, such as described in the methods above.
All of the features described in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so described, may be present in any combination, unless certain features or steps are mutually exclusive in the same combination.
The above-mentioned features of the invention, or of the embodiments, may be combined in any desired manner. All of the features disclosed in this specification may be combined with any combination of the features disclosed in this specification, and the various features disclosed in this specification may be substituted for any alternative feature serving the same, equivalent or similar purpose. Thus, unless expressly stated otherwise, the disclosed features are merely general examples of equivalent or similar features.
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental procedures, which do not address the specific conditions in the examples below, are generally carried out under conventional conditions or under conditions recommended by the manufacturer. All percentages, ratios, proportions, or parts are by weight unless otherwise indicated.
The units in weight volume percent are well known to those skilled in the art and refer, for example, to the weight of solute in 100 milliliters of solution. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred methods and materials described herein are presented for illustrative purposes only.
Examples
Universal procedure
When the preparation route is not included, the raw materials and reagents used in the present invention are known products, and can be synthesized according to the methods known in the art, or can be obtained by purchasing commercial products. The commercial reagents used were all used without further purification.
Room temperature refers to 20-30 ℃.
Unless otherwise specified in the reaction examples, the reactions were all carried out under nitrogen atmosphere. The nitrogen atmosphere is defined as the reaction flask being attached to a balloon of about 1L of nitrogen.
The hydrogenation reaction is usually vacuumized, filled with hydrogen and repeatedly operated for 3 times. The hydrogen atmosphere is defined as the reaction flask being connected to a balloon of hydrogen gas of about 1L.
Microwave reaction is usedInitiator + microwave reactor.
The structure of the compounds of the present invention is determined by Nuclear Magnetic Resonance (NMR) and Mass Spectrometry (MS). NMR shift (. Delta.) of 10 -6 Units of (ppm) are given. NMR was determined using (Bruker Assetnd TM 500) nuclear magnetic resonance apparatus, the measuring solvent is deuterated dimethyl sulfoxide (DMSO-d 6), deuterated chloroform (CDCl) 3 ) Deuterated methanol (CD) 3 OD), internal standard is Tetramethylsilane (TMS). The following abbreviations are used for multiplicity of NMR signals: s=singlet, brs=broad, d=doublet, t=triplet, m=multiplet. Coupling constants are listed as J values, measured in Hz.
LC-MS was determined using a Thermo liquid chromatography apparatus (UltiMate 3000+MSQ PLUS). HPLC was determined using a Thermo high pressure liquid chromatograph (UltiMate 3000). Reverse phase preparative chromatography a Thermo (UltiMate 3000) reverse phase preparative chromatograph was used. Quick column chromatography using Ai Jieer (FS-9200T) automatic column passing machine, silica gel pre-packed column using SantaiAnd (5) preassembling the column. The specification of the thin layer chromatography separation and purification product adopted by the smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate is 0.4 mm-0.5 mm.
The synthesis method of some intermediates in the invention is as follows:
intermediate 1
Intermediate 1 was prepared by the following steps:
the first step: 1-methyl-3, 5-dinitropyridin-2-one Int-1a (1.0 g,5.02 mmol) was dissolved in methanol (50 mL) and methanolic ammonia solution (7 mol/L,8.61mL,60.27 mmol) and 1-methylpiperidin-4-one Int-1b (625 mg,5.52 mmol) were added sequentially. The reaction mixture was heated to 50 ℃ and stirred for 5 hours. After cooling to room temperature, the reaction mixture was allowed to stand for 48 hours, concentrated under reduced pressure, and the residue was added to ethyl acetate (50 mL) and filtered. The filtrate was concentrated under reduced pressure to give Int-1c (1.0 g) as a red solid, which was used directly in the next reaction. ESI-MS (m/z): 194.4[ M+H ] ] + ; 1 H NMR(500MHz,DMSO-d 6 )δ9.14(d,J=2.5Hz,1H),8.36(d,J=2.5Hz,1H),3.64(s,2H),3.02(t,J=6.0Hz,2H),2.74(t,J=6.0Hz,2H),2.39(s,3H)。
And a second step of: the compound Int-1C (1.0 g) obtained in the previous step was dissolved in methanol (30 mL), 10% Pd-C (400 mg) was added thereto, and the mixture was reacted at room temperature under a hydrogen atmosphere for 6 hours. Palladium on carbon was removed by filtration, and the filtrate was concentrated to give Int-1d (800 mg, yield 94.70%) as a yellow solid. ESI-MS (m/z): 164.2[ M+H ]] + 。
And a third step of: compound Int-1d (100 mg,0.61 mmol) was dissolved in acetic acid (3 mL), N-bromosuccinimide (109 mg,0.61 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate until no bubbles were generated, the aqueous phase was extracted with methanol/dichloromethane (1/20, 50 mL. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by filtration to give compound Int-1e (38 mg, yield 25%). ESI-MS (m/z): 242.3[ M+H ]] + ; 1 H NMR(500MHz,DMSO-d 6 )δ6.77(s,1H),5.25(s,2H),3.37(s,2H),2.69(t,J=6.0Hz,2H),2.60(t,J=6.0Hz,2H),2.32(s,3H)。
Fourth step: compound Int-1e (37 mg,0.15 mmol) was dissolved in methanol (1 mL), and cuprous iodide (3 mg,0.015 mmol), 1, 10-phenanthroline (3 mg,0.03 mmol) and cesium carbonate (99 mg,0.30 mmol) were added. The reaction mixture was heated to 100 ℃ with microwaves after nitrogen substitution and stirred for 2 hours. The reaction was cooled to room temperature, the reaction mixture was concentrated, and the residue was purified by preparative thin layer chromatography (methanol/dichloromethane/triethylamine=1/10/0.1) to give Int-1 (20 mg, yield 67%) as a yellow solid. ESI-MS (m/z): 194.5[ M+H ] ] + ; 1 H NMR(500MHz,DMSO-d 6 )δ6.54(s,1H),4.68(s,2H),3.80(s,3H),3.30(s,2H),2.64(t,J=5.6Hz,2H),2.59(t,J=5.7Hz,2H),2.31(s,3H)。
Intermediate 2
Intermediate 2 was prepared by the following steps:
the first step: compound Int-1e (230 mg,0.94 mmol) was dissolved in ethanol (2 mL) and cuprous iodide (18 mg,0.095 mmol), 1, 10-phenanthroline (34 mg,0.18 mmol) and cesium carbonate (612 mg,1.90 mmol) were added. The reaction mixture was heated to 100 ℃ with microwaves after nitrogen substitution and stirred for 5 hours. The reaction was cooled to room temperature, filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (methanol/dichloromethane/triethylamine=1/50/0.1) to give Int-2 (113 mg, yield 57%) as a yellow solid. ESI-MS (m/z): 208.5[ M+H ]] + 。
Intermediate 3
Intermediate 3 was prepared by the following steps:
the first step: compound Int-1e (100 mg,0.41 mmol) and trimethylcyclotriboroxane (148 mg,1.19 mmol) were dissolved in dioxane (1.5 mL) and water (0.15 mL), potassium carbonate (171 mg,1.24 mmol), pd (dppf) Cl were added 2 (30 mg,0.041 mmol). After nitrogen was replaced by the reaction system, the reaction system was heated to 140℃with microwaves and stirred for 1 hour. The reaction was cooled to room temperature, the reaction mixture was filtered through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (methanol/dichloromethane=1/20) to give Int-3 (50 mg, yield 68%) as a yellow solid. ESI-MS (m/z): 178.6[ M+H ]] + 。
Intermediate 4
Intermediate 4 was prepared by the following steps:
The first step: compound Int-1e (350 mg,1.45 mmol) and potassium vinyltrifluoroborate (387 mg,2.89 mmol) were dissolved in 1, 4-dioxane (1.5 mL) and water (0.15 mL), and potassium carbonate (399 mg,2.89 mmol) and Pd (dppf) Cl were added 2 (105 mg,0.14 mmol). After nitrogen was replaced by the reaction system, the reaction system was heated to 120℃with a microwave reactor and stirred for 1 hour. After the reaction was cooled to room temperature, it was filtered through celite, the filtrate was concentrated, and the residue was separated by column chromatography (methanol/dichloromethane=1/20) to give Int-4a as a yellow solid (136 mg, yield 49%). ESI-MS (m/z): 190.7[ M+H ]] + ; 1 H NMR(500MHz,CDCl 3 )δ6.85(dd,J=17.2,11.0Hz,1H),6.66(s,1H),6.16(dd,J=17.3,1.9Hz,1H),5.49(dd,J=11.0,1.9Hz,1H),3.67-3.63(m,2H),3.55(s,2H),3.00(t,J=6.1Hz,2H),2.80(t,J=6.1Hz,2H),2.49(s,3H)。
And a second step of: compound Int-4a (60 mg,0.31 mmol) was dissolved in methanol (5 mL), 10% palladium on carbon (20 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. The reaction solution was filtered through celite, and the filtrate was concentrated to give intermediate 4 (37 mg, yield 61%). ESI-MS (m/z): 192.7[ M+H ]] + 。
Intermediate 5
Intermediate 5 was prepared by the following steps:
the first step: compound Int-1e (100 mg,0.41 mmol) was dissolved in a mixed solvent of toluene (3 mL) and water (0.3 mL), and cyclopropylboric acid (42 mg,0.49 mmol), potassium phosphate (306 mg,1.45 mmol), tricyclohexylphosphine (23 mg,0.082 mmol) and palladium acetate (9 mg,0.041 mmol) were added. The reaction system was heated to 100℃after nitrogen substitution and stirred for 18 hours. After the reaction was cooled to room temperature, the reaction solution was filtered through celite, the filtrate was concentrated, and the residue was separated by column chromatography (methanol/dichloromethane=1/20) to give Int-5 (61 mg, yield 72%) as a yellow solid. ESI-MS (m/z): 204.2[ M+H ] ] + 。
Intermediate 6
Intermediate 6 was prepared by the following steps:
the first step: N-Boc-4-piperidone Int-6a (4.4 g,22.1 mmol) and 1-methyl-3, 5-dinitro-2-pyridone Int-1a (4.0 g,20.1 mmol) were dissolved in methanol (150 mL) and methanolic ammonia solution (7N, 34.4mL,240.8 mmol) was added. Stirring at 60℃for 6 hours under nitrogen. The reaction solution was cooled to room temperature and stirred for 2 days. LCMS monitored the end of the reaction, the reaction was concentrated, ethyl acetate (150 mL) was added, stirred for half an hour, filtered, and the filtrate was concentrated to give Int-6b (5.1 g, 91% yield) as a yellow solid. ESI-MS (m/z): 280.1[ M+H ]] + 。
And a second step of: compound Int-6b (5.0 g,17.9 mmol) was dissolved in methanol (50 mL) and 10% palladium on carbon (500 mg) was added. The mixture was stirred at room temperature under a hydrogen atmosphere (hydrogen balloon) for 16 hours. After the completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated to give Int-6c (3.7 g, yield 84%) as a pale yellow solid. ESI-MS (m/z): 250.2[ M+H ]] + 。
And a third step of: compound Int-6c (3.7 g,14.8 mmol) was dissolved in DMF (20 mL) and N-bromosuccinimide (2.78 g,15.6 mmol) and acetic acid (370 mg) were added. The reaction mixture was stirred at room temperature for 2 hours and LCMS monitored the reaction to end. Water (100 mL) was added, the aqueous phase (150 mL. 3) was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by filtration, and the residue was separated by silica gel column chromatography to give Int-6d (3.6 g, 74% yield) as a yellow solid. ESI-MS (m/z): 328.2[ M+H ] ] + 。
Fourth step: compound Int-6d (500 mg,1.53 mmol) was dissolved in methanol (5 mL) and sodium methoxide methanol solution (5N, 0.33mL,1.65 mmol) was added. The reaction mixture was heated to 100 ℃ with microwaves and stirred for 3 hours. The reaction was cooled to room temperature, the reaction solution was concentrated, and the residue was separated by silica gel column chromatography to give Int-6 (330 mg, yield 77%) as a yellow solid. ESI-MS (m/z): 280.2[ M+H ]] + 。
Example 1
3- (((5-chloro-2- ((2-methoxy-6-methyl-5, 6,7, 8-tetrahydro-1, 6-naphthyridin-3-yl) amino) pyrimidin-4-yl) amino) methyl) -1-methylpyridin-2 (1H) -one
Compound 1 was prepared by the following steps:
the first step: 2,4, 5-Trichloropyrimidine 1a (57 mg,0.31 mmol) and 3- (aminomethyl) -1-methyl-1, 2-dihydropyridin-2-one hydrochloride 1b (50 mg,0.28 mmol) were dissolved in isopropanol (2 mL) and N, N-diisopropylethylamine (85 mg,0.65mmol,0.11 mL) was added. The reaction mixture was stirred at room temperature for 18 hours. The reaction solution was filtered, and the solid was washed with isopropyl alcohol and dried to give white solid 1c (62 mg, yield 75%). ESI-MS (m/z): 285.2[ M+H ]] + 。
And a second step of: compound 1c (62 mg,0.21 mmol) and Int-1 (42 mg,0.21 mmol) were dissolved in 1, 4-dioxane (5 mL), brettPhos Pd G3 (19 mg,0.021 mmol), brettPhos (23 mg,0.043 mmol) and cesium carbonate (141 mg,0.43 mmol) were added, and the reaction system was heated to 100℃with nitrogen substitution and stirred for 18 hours. After the reaction solution was cooled to room temperature, the reaction solution was filtered through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (methanol/dichloromethane=1/30) to give a crude product, which was separated by reverse phase preparative HPLC to give white solid 1 (25 mg, yield 26%). ESI-MS (m/z): 442.3[ M+H ] ] + ; 1 H NMR(500MHz,DMSO-d6)δ8.00(s,1H),7.86(s,1H),7.69-7.61(m,2H),7.56(s,1H),7.08(d,J=6.8Hz,1H),6.19(t,J=6.8Hz,1H),4.37(d,J=5.9Hz,2H),3.86(s,3H),3.50(s,3H),3.12(s,2H),2.70(t,J=6.0Hz,2H),2.60(t,J=5.9Hz,2H),2.33(s,3H)。
Example 2
3- (((5-chloro-2- ((2-ethoxy-6-methyl-5, 6,7, 8-tetrahydro-1, 6-naphthyridin-3-yl) amino) pyrimidin-4-yl) amino) methyl) -1-methylpyridin-2 (1H) -one
Substitution of Int-2 for Int-1 in the second step of example 1, in a similar manner and reaction procedure, gives compound 2.ESI-MS (m/z): 456.1[ M+H ]] + ; 1 HNMR(500MHz,DMSO-d6)δ8.00(s,1H), 7.87(s,1H),7.69(t,J=5.9Hz,1H),7.64(dd,J=6.7,2.0Hz,1H),7.48(s,1H),7.12-7.06(m,1H),6.18(t,J=6.8Hz,1H),4.38(d,J=5.9Hz,2H),4.30(q,J=7.0Hz,2H),3.50(s,3H),3.09(s,2H),2.67(d,J=5.9Hz,2H),2.59(d,J=5.7Hz,2H),2.32(s,3H),1.32(t,J=7.0Hz,3H)。
Example 3
3- (((2- ((2-ethoxy-6-methyl-5, 6,7, 8-tetrahydro-1, 6-naphthyridin-3-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) -1-methylpyridin-2 (1H) -one
Compound 3 can be obtained by a similar method and reaction procedure, substituting 2, 4-dichloro-5-trifluoromethylpyrimidine for 2,4, 5-trichloropyrimidine 1a in the first step of example 1, and then substituting Int-2 for Int-1 in the second step of example 1. ESI-MS (m/z): 490.2[ M+H ]] + ; 1 H NMR(500MHz,DMSO-d6)δ8.23(s,1H),7.95(s,1H),7.76(s,1H),7.64(dd,J=6.7,2.0Hz,1H),7.59(br s,1H),7.02(d,J=7.0Hz,1H),6.19(t,J=6.8Hz,1H),4.40(d,J=5.6Hz,2H),4.30(q,J=7.0Hz,2H),3.50(s,3H),3.10(br s,2H),2.69(t,J=5.9Hz,2H),2.59(t,J=5.9Hz,2H),2.33(s,3H),1.31(t,J=7.0Hz,3H)。
Example 4
5- (((5-chloro-2- ((2-methoxy-6-methyl-5, 6,7, 8-tetrahydro-1, 6-naphthyridin-3-yl) amino) pyrimidin-4-yl) amino) methyl) pyridin-2 (1H) -one
Compound 4 can be obtained by a similar method and reaction steps using 5- (aminomethyl) -1, 2-dihydropyridin-2-one instead of 3- (aminomethyl) -1-methyl-1, 2-dihydropyridin-2-one hydrochloride 1b in the first step of example 1. ESI-MS (m/z): 428.2[ M+H ]] + ; 1 H NMR(500MHz,DMSO-d6)δ7.99(s,1H),7.96(s,1H),7.74(s,1H),7.68(t,J=5.9Hz,1H),7.40(dd,J=9.4,2.6Hz,1H),7.20(br s,1H),6.27(d,J=9.4Hz,1H),4.29(d,J=5.6Hz,2H),3.88(s,3H),3.34-3.30(m,2H),2.74(t,J=5.8Hz,2H),2.63(t,J=5.9Hz,2H),2.33(s,3H)。
Example 5
3- (((5-chloro-2- ((2, 6-dimethyl-5, 6,7, 8-tetrahydro-1, 6-naphthyridin-3-yl) amino) pyrimidin-4-yl) amino) methyl) -1-methylpyridin-2 (1H) -one
Substitution of Int-3 for Int-1 in the second step of example 1, in a similar manner and reaction procedure, gives compound 5.ESI-MS (m/z): 426.2[ M+H ]] + ; 1 H NMR(500MHz,DMSO-d6)δ8.36(s,1H),7.91(s,1H),7.63(dd,J=6.8,2.0Hz,1H),7.50-7.40(m,2H),7.08-6.96(m,1H),6.18(t,J=6.8Hz,1H),4.29(d,J=5.9Hz,2H),3.47(s,3H),3.19(s,2H),2.76(t,J=6.0Hz,2H),2.62(t,J=6.0Hz,2H),2.31(s,3H),2.30(s,3H)。
Example 6
3- (((5-chloro-2- ((2-methoxy-6-methyl-5, 6,7, 8-tetrahydro-1, 6-naphthyridin-3-yl) amino) pyrimidin-4-yl) amino) methyl) -1,4, 6-trimethylpyridin-2 (1H) -one
Compound 6 was prepared by the following steps:
the first step: to a suspension of sodium hydride (202 mg,5.06mmol, 60% strength) in DMF (5 mL) was added a solution of compound 6a (500 mg,3.37 mmol) in DMF (5 mL) under an ice bath at 0deg.C and nitrogen atmosphere. After stirring for 30 minutes, methyl iodide (428 mg,5.06mmol,0.31 mL) was added and the mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with ethyl acetate, and washed with water and then with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated by filtration, and the residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give 6b (230 mg, yield 42%) as a yellow solid. ESI-MS (m/z): 163.1[ M+H ]] + 。
And a second step of: compound 6b (230 mg,1.42 mmol) was dissolved in methanol (5 mL) and Raney Ni (0.5 mL, aqueous suspension) and aqueous ammonia (0.5 mL) were added. The mixture was stirred at room temperature under an atmosphere of hydrogen (hydrogen balloon) for 16 hours. The reaction solution was filtered through celite, and the cake was washed with methanol, and the filtrate was concentrated to give compound 6c (200 mg) which was directly used in the next reaction. ESI-MS (m/z): 167.1[ M+H ] ] + 。
And a third step of: compound 6c (135 mg) was dissolved in isopropanol (2 mL), N-diisopropylethylamine (159 mg,1.23mmol,0.21 mL) and 2,4, 5-trichloropyrimidine 1a (150 mg,0.81 mmol) were added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated, and the residue was separated by silica gel column chromatography (dichloromethane/methanol=10/1) to give 6d (130 mg) as a white solid. ESI-MS (m/z): 313.2[ M+H ]] + 。
Fourth step: compound 6d (71 mg,0.22 mmol) and Int-1 (40 mg,0.20 mmol) were dissolved in 1, 4-dioxane (4 mL), cesium carbonate (202 mg,0.62 mmol), brettPhos (22 mg, 0.041 mmol) and BrettPhos Pd G3 (18 mg, 0.020mmol) were added. The reaction system was heated to 100℃after nitrogen substitution and stirred for 16 hours. After the reaction solution was cooled to room temperature, the reaction solution was concentrated, and the residue was purified by preparative thin layer chromatography (dichloroMethane/methanol=10/1) to give a crude product, which was separated by reverse phase preparative HPLC to give compound 6 (10 mg, yield 10%). ESI-MS (m/z): 470.2[ M+H ]] + ; 1 H NMR(500MHz,DMSO-d6)δ8.07(s,1H),7.94(s,1H),7.69(s,1H),7.07(br s,1H),6.05(s,1H),4.44(d,J=5.5Hz,2H),3.88(s,3H),3.46-3.40(m,5H),2.75(br s,2H),2.65(t,J=5.5Hz,2H),2.34(s,3H),2.30(s,3H),2.12(s,3H)。
Example 7
3- (((5-chloro-2- ((2-methoxy-6-methyl-5, 6,7, 8-tetrahydro-1, 6-naphthyridin-3-yl) amino) pyrimidin-4-yl) amino) methyl) -4, 6-dimethylpyridin-2 (1H) -one
Compound 7 can be obtained by a similar method and reaction steps using 3- (aminomethyl) -4, 6-dimethyl-1, 2-dihydropyridin-2-one instead of 3- (aminomethyl) -1-methyl-1, 2-dihydropyridin-2-one hydrochloride 1b in the first step of example 1. ESI-MS (m/z): 456.0[ M+H ] ] + ; 1 HNMR(500MHz,DMSO-d6)δ11.59(br s,1H),8.09(s,1H),7.94(s,1H),7.69(s,1H),7.20(br s,1H),5.89(s,1H),4.42(br s,2H),3.89(s,3H),3.42(s,2H),2.75(br s,2H),2.65(br s,2H),2.34(s,3H),2.12(s,6H)。
Example 8
4- (((5-chloro-2- ((2-methoxy-6-methyl-5, 6,7, 8-tetrahydro-1, 6-naphthyridin-3-yl) amino) pyrimidin-4-yl) amino) methyl) pyridin-2 (1H) -one
Compound 8 was obtained by a similar procedure and reaction steps using 4- (aminomethyl) -1, 2-dihydropyridin-2-one instead of 3- (aminomethyl) -1-methyl-1, 2-dihydropyridin-2-one hydrochloride 1b in the first step of example 1. ESI-MS (m/z): 428.1[ M+H ]] + ; 1 H NMR(500MHz,DMSO-d6)δ8.01(s,1H),7.90(s,1H),7.83(t,J=6.1Hz,1H),7.62(s,1H),7.31(d,J=6.7Hz,1H),6.11(dd,J=6.8,1.7Hz,1H),6.08(s,1H),4.41(d,J=5.8Hz,2H),3.86(s,3H),3.22(s,2H),2.71(t,J=5.9Hz,2H),2.61(t,J=5.9Hz,2H),2.33(s,3H)。
Example 9
3- (((5-chloro-2- ((2-methoxy-6-methyl-5, 6,7, 8-tetrahydro-1, 6-naphthyridin-3-yl) amino) pyrimidin-4-yl) amino) methyl) -1-ethylpyridin-2 (1H) -one
Compound 9 was prepared by the following steps:
the first step: compound 9a (700 mg,5.83 mmol) was dissolved in DMF (10 mL), cesium carbonate (2.28 g,6.99 mmol) was added, and then ethyl iodide (1.36 g,8.74mmol,0.70 mL) was added dropwise and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give 9b (730 mg, yield 84%) as a white solid. ESI-MS (m/z): 149.4[ M+H ]] + ; 1 HNMR(500MHz,Chloroform-d)δ7.80(dd,J=7.0,2.0Hz,1H),7.57(dd,J=7.0,2.0Hz,1H),6.28(t,J=7.0Hz,1H),4.05(q,J=7.0Hz,2H),1.40(t,J=7.0Hz,3H)。
And a second step of: compound 9b (100 mg,0.67 mmol) was dissolved in methanol (5 mL) and Raney Ni (0.3 mL, aqueous suspension) and aqueous ammonia (1 mL) were added. The mixture was stirred overnight at room temperature under a hydrogen atmosphere (hydrogen balloon). The reaction solution was filtered through celite, and the cake was washed with methanol, and the filtrate was concentrated to give compound 9c (100 mg) which was directly used for the next reaction.
And a third step of: compound 9c(100 mg) was dissolved in isopropyl alcohol (5 mL), N-diisopropylethylamine (169 mg,1.31mmol,0.23 mL) and 2,4, 5-trichloropyrimidine 1a (180 mg,0.98 mmol) were added, and the reaction mixture was stirred at room temperature overnight. The reaction solution was filtered, and the cake was washed with isopropyl alcohol and dried to give 9d (100 mg) of a white solid. ESI-MS (m/z): 299.2[ M+H ]] + 。
Fourth step: compound 9d (50 mg,0.16 mmol) and Int-1 (32 mg,0.16 mmol) were dissolved in 1, 4-dioxane (5 mL), cesium carbonate (108 mg,0.33 mmol), brettPhos (9 mg,0.016 mmol) and BrettPhos Pd G3 (15 mg,0.016 mmol) were added. The reaction system was heated to 100 ℃ after nitrogen substitution and stirred overnight. After the reaction solution was cooled to room temperature, the reaction solution was concentrated, and the residue was purified by preparative thin layer chromatography (dichloromethane/methanol=10/1) to give a crude product, which was separated by reverse phase preparative HPLC to give compound 9 (8 mg, yield 11%). ESI-MS (m/z): 456.1[ M+H ]] + ; 1 H NMR(500MHz,DMSO-d6)δ8.00(s,1H),7.91(s,1H),7.66-7.62(m,2H),7.56(s,1H),7.08(dd,J=7.0,2.0Hz,1H),6.20(t,J=7.0Hz,1H),4.39(d,J=6.0Hz,2H),3.98(q,J=7.0Hz,2H),3.85(s,3H),3.18(s,2H),2.70(t,J=6.0Hz,2H),2.60(t,J=6.0Hz,2H),2.32(s,3H),1.25(t,J=7.0Hz,3H)。
Example 10
3- (((5-chloro-2- ((2-methoxy-6-methyl-5, 6,7, 8-tetrahydro-1, 6-naphthyridin-3-yl) amino) pyrimidin-4-yl) amino) methyl) -1,5, 6-trimethylpyridin-2 (1H) -one
Compound 10 was obtained by a similar procedure and reaction steps using 2-hydroxy-3-cyano-5, 6-dimethylpyridine in place of 3-cyano-2-hydroxy-4, 6-dimethylpyridine in the first step of example 9. ESI-MS (m/z): 470.1[ M+H ] ] + ; 1 HNMR(500MHz,DMSO-d6)δ7.98(s,1H),7.93(s,1H),7.58(t,J=6.0Hz,1H),7.56(s,1H),6.94(s,1H),4.36(d,J=6.0Hz,2H),3.86(s,3H),3.52(s,3H),3.19(s,2H),2.71(t,J=6.0Hz,2H),2.60(t,J=6.0Hz,2H),2.33(s,3H),2.27(s,3H),1.99(s,3H)。
Example 11
3- (((5-chloro-2- ((2-methoxy-6-methyl-5, 6,7, 8-tetrahydro-1, 6-naphthyridin-3-yl) amino) pyrimidin-4-yl) amino) methyl) pyridin-2 (1H) -one
Compound 11 can be obtained by a similar method and reaction procedure substituting 3- (aminomethyl) -pyridin-2 (1H) -one for 3- (aminomethyl) -1-methyl-1, 2-dihydropyridin-2-one hydrochloride 1b in the first step of example 1.ESI-MS (m/z): 428.3[ M+H ]] + ; 1 H NMR(500MHz,DMSO-d6)δ11.68(br s,1H),8.00(s,1H),7.90(s,1H),7.65-7.62(m,1H),7.56(s,1H),7.33-7.28(m,1H),7.13-7.09(m,1H),6.15(t,J=6.6Hz,1H),4.35(d,J=5.9Hz,2H),3.86(s,3H),3.17(s,2H),2.69(d,J=5.9Hz,2H),2.60(d,J=5.7Hz,2H),2.33(s,3H)。
Example 12
3- (((5-chloro-2- ((2-cyclopropyl-6-methyl-5, 6,7, 8-tetrahydro-1, 6-naphthyridin-3-yl) amino) pyrimidin-4-yl) amino) methyl) -1-methylpyridin-2 (1H) -one
Substitution of Int-5 for Int-1 in the second step of example 1, followed by a similar procedure and reaction procedure, provided compound 12.ESI-MS (m/z): 452.2[ M+H ]] + ; 1 H NMR(500MHz,DMSO-d6)δ8.55(s,1H),7.90(s,1H),7.62(dd,J=6.7,2.0Hz,1H),7.36(t,J=6.0Hz,1H),7.34(s,1H),6.97(d,J=6.9Hz,1H),6.15(t,J=6.8Hz,1H),4.29(d,J=6.0Hz,2H),3.46(s,3H),3.20(s,2H),2.71(t,J=6.0Hz,2H),2.61(t,J=6.0Hz,2H),2.31(s,3H),2.23-2.12(m,1H),0.85-.075(m,4H)。
Example 13
3- (((5-chloro-2- ((2-ethyl-6-methyl-5, 6,7, 8-tetrahydro-1, 6-naphthyridin-3-yl) amino) pyrimidin-4-yl) amino) methyl) -1-methylpyridin-2 (1H) -one
Substitution of Int-4 for Int-1 in the second step of example 1, in a similar manner and reaction procedure, compound 13 was obtained. ESI-MS (m/z): 440.2[ M+H ]] + ; 1 HNMR(500MHz,DMSO-d6)δ8.36(s,1H),7.89(s,1H),7.62(dd,J=6.8,2.0Hz,1H),7.37(d,J=6.0Hz,1H),7.36(s,1H),6.98(d,J=6.9Hz,1H),6.16(t,J=6.8Hz,1H),4.27(d,J=6.0Hz,2H),3.46(s,3H),3.22(s,2H),2.78(t,J=6.0Hz,2H),2.69-2.61(m,4H),2.32(s,3H),1.07(t,J=7.5Hz,3H)。
Example 14
3- (((5-chloro-2- ((2-methoxy-6-methyl-5, 6,7, 8-tetrahydro-1, 6-naphthyridin-3-yl) amino) pyrimidin-4-yl) amino) methyl) -1-methylpyrrolidin-2-one
Compound 14 can be obtained by a similar method and reaction steps substituting 3- (aminomethyl) -1-methyl-1, 2-dihydropyridin-2-one hydrochloride 1b in the first step of example 1 with 3- (aminomethyl) -1-methylpyrrolidin-2-one. ESI-MS (m/z): 432.3[ M+H ]] + ; 1 H NMR(500MHz,DMSO-d6)δ8.13(s,1H),7.96(s,1H),7.61(s,1H),7.38-7.33(m,1H),3.88(s,3H),3.65-3.58(m,1H),3.50-3.40(m,3H),3.27-3.24(m,2H),2.79-2.73(m,6H),2.66-2.62(m,2H),2.34(s,3H),2.08-2.02(m,1H),1.78-1.72(m,1H)。
Example 15
5- (((5-chloro-2- ((2-methoxy-6-methyl-5, 6,7, 8-tetrahydro-1, 6-naphthyridin-3-yl) amino) pyrimidin-4-yl) amino) methyl) pyrrolidin-2-one
Compound 15 was obtained by a similar procedure and reaction steps substituting 5-aminomethyl-2-pyrrolidone for 3- (aminomethyl) -1-methyl-1, 2-dihydropyridin-2-one hydrochloride 1b in the first step of example 1. ESI-MS (m/z): 418.4[ M+H ]] + ; 1 HNMR(500MHz,DMSO-d6)δ8.10(s,1H),7.95(s,1H),7.75(br s,1H),7.67(s,1H),7.27(t,J=5.9Hz,1H),3.89(s,3H),3.82-3.77(m,1H),3.53-3.47(m,1H),3.41(s,2H),3.36-3.30(m,1H),2.75(t,J=5.9Hz,2H),2.64(t,J=6.3Hz,2H),2.34(s,3H),2.13-2.03(m,3H),1.78-1.71(m,1H)。
Example 16
3- (((2- ((2-methoxy-6-methyl-5, 6,7, 8-tetrahydro-1, 6-naphthyridin-3-yl) amino) -5-methylpyrimidin-4-yl) amino) methyl) -1-methylpyridin-2 (1H) -one
Compound 16 was obtained by a similar procedure and reaction steps using 2, 4-dichloro-5-methylpyrimidine instead of 2,4, 5-trichloropyrimidine 1a in the first step of example 1. ESI-MS (m/z): 422.3[ M+H ]] + ; 1 HNMR(500MHz,DMSO-d6)δ8.19(s,1H),7.74(s,1H),7.63(dd,J=6.8,1.9Hz,1H),7.35(br s,1H),7.31(br s,1H),7.15(d,J=6.8Hz,1H),6.19(t,J=6.8Hz,1H),4.41(d,J=5.9Hz,2H),3.96-3.85(m,5H),3.52(s,3H),3.30-3.22(m,2H),2.91(br s,2H),2.74(br s,2H),2.49(s,3H),2.02(s,3H)。
Example 17
3- (((5-fluoro-2- ((2-methoxy-6-methyl-5, 6,7, 8-tetrahydro-1, 6-naphthyridin-3-yl) amino) pyrimidin-4-yl) amino) methyl) -1-methylpyridin-2 (1H) -one
Compound 17 can be obtained by a similar method and reaction procedure using 2, 4-dichloro-5-fluoropyrimidine instead of 2,4, 5-trichloropyrimidine 1a in the first step of example 1. ESI-MS (m/z): 426.3[ M+H ]] + ; 1 H NMR(500MHz,DMSO-d6)δ8.03(s,1H),8.00-7.91(m,2H),7.64(dd,J=6.7,2.0Hz,1H),7.43(s,1H),7.19(dd,J=7.0,1.8Hz,1H),6.19(t,J=6.8Hz,1H),4.37(d,J=5.9Hz,2H),3.87(s,3H),3.50(s,3H),3.47(br s,2H),2.88(br s,2H),2.79(t,J=5.8Hz,2H),2.49(s,3H)。
Example 18
4- (((5-chloro-2- ((2-methoxy-6-methyl-5, 6,7, 8-tetrahydro-1, 6-naphthyridin-3-yl) amino) pyrimidin-4-yl) amino) methyl) -1-methylpyridin-2 (1H) -one
Compound 33 was obtained by a similar procedure and reaction steps substituting 4- (aminomethyl) -1-methyl-1, 2-dihydropyridin-2-one for 3- (aminomethyl) -1-methyl-1, 2-dihydropyridin-2-one hydrochloride 1b in the first step of example 1. ESI-MS (m/z): 442.3[ M+H ]] + ; 1 H NMR(500MHz,DMSO-d6)δ8.01(s,1H),7.89(s,1H),7.84(t,J=5.5Hz,1H),7.66-7.60(m,2H),6.17-6.13(m,2H),4.41(d,J=5.9Hz,2H),3.85(s,3H),3.37(s,3H),3.21(br s,2H),2.71(t,J=5.3Hz,2H),2.61(t,J=5.7Hz,2H),2.33(s,3H)。
Example 19
3- (((5-chloro-2- ((2-methoxy-5, 6,7, 8-tetrahydro-1, 6-naphthyridin-3-yl) amino) pyrimidin-4-yl) amino) methyl) -1-methylpyridin-2 (1H) -one
Compound 19 was prepared by the following steps:
the first step: compound 1b (244 mg,0.85 mmol) and Int-7 (200 mg,0.71 mmol) were dissolved in 1, 4-dioxane (5 mL), cesium carbonate (700 mg,2.15 mmol), brettPhos (76 mg,0.14 mmol) and BrettPhos Pd G3 (64 mg,0.071 mmol) were added. The reaction system was heated to 120℃after nitrogen substitution and stirred for 16 hours. After the reaction solution was cooled to room temperature, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=20/1) to give a crude product (300 mg) of compound 19a, which was directly used for the next reaction. ESI-MS (m/z): 528.1[ M+H ] ] + 。
And a second step of: the crude 19a product (300 mg) obtained in the previous step was dissolved in acetonitrile (5 mL), and p-toluenesulfonic acid monohydrate (323 mg,1.70 mmol) was added. The reaction mixture was warmed to 70 ℃ and stirred for 2 hours. The reaction solution was concentrated to obtain a crude product (240 mg) of compound 19, 20mg of which was purified by reverse phase preparative HPLC to obtain compound 19 (1 mg). ESI-MS (m/z): 428.3[ M+H ]] + ; 1 H NMR(500MHz,DMSO-d6)δ8.00(s,1H),7.84(s,1H),7.69-7.60(m,2H),7.53(s,1H),7.09(d,J=6.9Hz,1H),6.18(t,J=6.8Hz,1H),4.37(d,J=5.9Hz,2H),3.85(s,3H),3.52(s,2H),3.49(s,3H),2.96(t,J=5.8Hz,2H),2.59(t,J=5.8Hz,2H)。
Example 20
2- ((2-methoxy-6-methyl-5, 6,7, 8-tetrahydro-1, 6-naphthyridin-3-yl) amino) -4- (((1-methyl-2-carbonyl-1, 2-dihydropyridin-3-yl) methyl) amino) pyrimidine-5-carbonitrile
Compound 20 was obtained by a similar procedure and reaction steps substituting 2, 4-dichloro-5-cyanopyrimidine for 2,4, 5-trichloropyrimidine 1a in the first step of example 1. ESI-MS (m/z): 433.2[ M+H ]] + ; 1 H NMR(500MHz,DMSO-d6)δ8.38(s,1H),8.24-8.19(m,1H),8.16(s,1H),7.71(s,1H),7.63-7.60(m,1H),6.98-6.94(m,1H),6.15-6.12(m,1H),4.16(d,J=6.1Hz,2H),3.85(s,3H),3.47(s,3H),3.14(br s,2H),2.73(d,J=6.1Hz,2H),2.63-2.60(m,2H),2.33(s,3H)。
Example 21
3- (((5-chloro-2- ((2-methoxy-6-methyl-5, 6,7, 8-tetrahydro-1, 6-naphthyridin-3-yl) amino) pyrimidin-4-yl) amino) methyl) -1, 5-dimethylpyridin-2 (1H) -one
Compound 21 was prepared by the following steps:
the first step: 3-bromo-2-hydroxy-5-methylpyridine 21a (200 mg,1.06 mmol) was dissolved in tetrahydrofuran (5 mL), naH (50 mg,1.28mmol, content 60%) was added at 0deg.C, and the reaction was stirred for 30 minutes. Methyl iodide (227 mg,1.60 mmol) was added dropwise to the reaction solution, and the reaction solution was stirred at 0℃for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/3) to give compound 21b (200 mg, yield 93%). ESI-MS (m/z): 202.5[ M+H ] ] + 。
And a second step of: compound 21b (180 mg,0.89 mmol) was dissolved in DMF (5 mL) and Pd (PPh) was added 3 ) 4 (103 mg,0.09 mmol) and Zn (CN) 2 (105 mg,0.89 mmol) and the reaction system was replaced with nitrogen, and then heated to 130℃with microwaves for 4 hours. After the reaction solution was cooled to room temperature, the reaction solution was filtered through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/4) to give 21c (122 mg, yield 92%) as a white solid. ESI-MS (m/z): 149.4[ M+H ]] + 。
And a third step of: compound 21c (120 mg,0.81 mmol) was dissolvedTo methanol (5 mL) and aqueous ammonia (0.5 mL) were added Raney Nickel (0.3 mL, aqueous suspension) and BOC anhydride (212 mg,0.97 mmol), and the mixture was stirred overnight at room temperature under a hydrogen atmosphere (hydrogen balloon). The reaction solution was filtered through celite, and the filtrate was concentrated. The residue was dissolved in 4N dioxane hydrochloride solution (5 mL), and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated to obtain a crude product of compound 21d, which was directly used for the next reaction. ESI-MS (m/z): 153.8[ M+H ]] + 。
Fourth step: the crude compound 21d obtained in the previous step and 2,4, 5-trichloropyrimidine 1a (169 mg,0.92 mmol) were dissolved in i-PrOH (5 mL), N-diisopropylethylamine (356 mg,2.76 mmol) was added, and the reaction was stirred at 90℃overnight. After the reaction solution was cooled to room temperature, the reaction solution was concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/4) to give 21e (98 mg, yield 36%) as a white solid. ESI-MS (m/z): 300.2[ M+H ] ] + 。
Fifth step: compound 21e (50 mg,0.17 mmol) and Int-1 (36 mg,0.18 mmol) were dissolved in 1, 4-dioxane (5 mL), and BrettPhos G3Pd (15 mg,17 umol), brettPhos (9 mg,17 umol) and cesium carbonate (109 mg,0.34 mmol) were added. The reaction system was heated to 100 ℃ after nitrogen substitution and stirred overnight. After the reaction solution was cooled to room temperature, the reaction solution was filtered through celite, and the filtrate was concentrated. The residue was purified by preparative thin layer chromatography (petroleum ether/ethyl acetate=1/1) to give crude product of compound 21, which was purified by reverse phase preparative HPLC to give compound 21 (6 mg, yield 8%). ESI-MS (m/z): 456.2[ M+H ]] + 。 1 H NMR(500MHz,DMSO-d 6 )δ7.99(s,1H),7.89(s,1H),7.62(t,J=6.0Hz,1H),7.57(s,1H),7.43(s,1H),6.97(s,1H),4.37(d,J=5.8Hz,2H),3.86(s,3H),3.45(s,3H),3.16(s,2H),2.70(t,J=5.7Hz,2H),2.60(t,J=5.9Hz,2H),2.33(s,3H),1.96(s,3H)。
Example 22
3- (((2- ((2-methoxy-6-methyl-5, 6,7, 8-tetrahydro-1, 6-naphthyridin-3-yl) amino) pyrimidin-4-yl) amino) methyl) -1-methylpyridin-2 (1H) -one
Compound 22 was obtained by a similar procedure and reaction steps, substituting 2, 4-dichloropyrimidine for 2,4, 5-trichloropyrimidine 1a in the first step of example 1. ESI-MS (m/z): 408.3[ M+H ]] + ; 1 HNMR(500MHz,DMSO-d6)δ8.08(br s,1H),7.83(d,J=5.8Hz,1H),7.68(br s,1H),7.63(dd,J=6.7,1.9Hz,1H),7.28(s,1H),7.19(br s,1H),6.19(t,J=6.8Hz,1H),6.10(br s,1H),4.30(br s,2H),3.88(s,3H),3.49(s,3H),3.19(br s,2H),2.70(t,J=6.6Hz,2H),2.62(t,J=5.7Hz,2H),2.33(s,3H)。
Example 23
3- (((5-chloro-2- ((2-methoxy-6-methyl-5, 6,7, 8-tetrahydro-1, 6-naphthyridin-3-yl) amino) pyrimidin-4-yl) amino) methyl) -1, 4-dimethylpyridin-2 (1H) -one
Compound 23 was prepared by the following steps:
the first step: 3-bromo-2-hydroxy-4-methylpyridine 23a (200 mg,1.06 mmol) was dissolved in tetrahydrofuran (5 mL), naH (50 mg,1.28mmol, content 60%) was added at 0deg.C, and the reaction was stirred for 30 minutes. Methyl iodide (227 mg,1.60 mmol) was added dropwise to the reaction solution, and the reaction solution was stirred at 0℃for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/3) to give 23b (210 mg, yield 98%) as a yellow oil. ESI-MS (m/z): 202.5[ M+H ] ] + 。
And a second step of: compound 23b (210 mg,1.04 mmol) was dissolved in DMF (5 mL) and addedPd (PPh) 3 ) 4 (120 mg,0.11 mmol) and Zn (CN) 2 (122 mg,1.04 mmol) and the reaction system replaced nitrogen and was then heated to 130℃with microwaves for 4 hours. After the reaction solution was cooled to room temperature, the reaction solution was filtered through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/4) to give 23c (143 mg, yield 92%) as a white solid. ESI-MS (m/z): 149.4[ M+H ]] + 。
And a third step of: compound 23c (143 mg,0.97 mmol) was dissolved in methanol (5 mL) and aqueous ammonia (0.5 mL), raney Nickel (0.3 mL, aqueous suspension) and BOC anhydride (255 mg,1.16 mmol) were added and the mixture was stirred overnight at room temperature under a hydrogen atmosphere (hydrogen balloon). The reaction solution was filtered through celite, and the filtrate was concentrated. The residue was dissolved in 4N dioxane hydrochloride solution (5 mL), and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated to give a crude product of compound 23d, which was directly used for the next reaction. ESI-MS (m/z): 153.5[ M+H ]] + 。
Fourth step: the crude compound 23d obtained in the previous step and 2,4, 5-trichloropyrimidine (176 mg,0.96 mmol) were dissolved in i-PrOH (5 mL), DIEA (372 mg,2.88 mmol) was added and the reaction stirred at 90℃overnight. After the reaction solution was cooled to room temperature, the reaction solution was concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/4) to give 23e (161 mg, yield 56%) as a white solid. ESI-MS (m/z): 300.2[ M+H ] ] + 。
Fifth step: compound 23e (50 mg,0.17 mmol) and Int-1 (32 mg,0.17 mmol) were dissolved in 1, 4-dioxane (5 mL), and BrettPhos G3Pd (15 mg,17 umol), brettPhos (9 mg,17 umol) and cesium carbonate (109 mg,0.34 mmol) were added. The reaction system was heated to 100 ℃ after nitrogen substitution and stirred overnight. After the reaction solution was cooled to room temperature, the reaction solution was filtered through celite, and the filtrate was concentrated. The residue was purified by preparative thin layer chromatography (petroleum ether/ethyl acetate=1/1) to give crude compound 23, which was purified by reverse phase preparative HPLC to give compound 23 (7 mg, yield 9%). ESI-MS (m/z): 456.1[ M+H ]] + ; 1 H NMR(500MHz,DMSO-d 6 )δ8.07(s,1H),7.95(s,1H),7.71(s,1H),7.56(d,J=6.9Hz,1H),7.14(t,J=5.4Hz,1H),6.12(d,J=7.0Hz,1H),4.47(d,J=5.4Hz,2H),3.88(s,3H),3.43(s,5H),2.76(t,J=5.8Hz,2H),2.65(t,J=5.9Hz, 2H),2.34(s,3H),2.16(s,3H)。
Example 24
3- (((5-chloro-2- ((2-methoxy-6-methyl-5, 6,7, 8-tetrahydro-1, 6-naphthyridin-3-yl) amino) pyrimidin-4-yl) amino) methyl) pyrrolidin-2-one
Compound 24 was prepared by the following steps:
the first step: compound 3- (hydroxymethyl) pyrrolidin-2-one 24a (258 mg,2.24 mmol), phthalimide (362 mg2.4,7 mmol) and triphenylphosphine (646 mg,2.47 mmol) were dissolved in THF (5 mL) and diisopropyl azodicarboxylate (498 mg,2.47mmol,0.48 mL) was slowly added dropwise at 0deg.C. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours, LCMS detected reaction complete. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography to give 24b (335 mg, yield 61%) as a white solid. ESI-MS (m/z): 245.5[ M+H ] ] + 。
And a second step of: compound 24b (335 mg,1.37 mmol) was dissolved in ethanol (5 mL), hydrazine hydrate ((171 mg,2.74mmol,0.17mL, content 80%) was added, the reaction mixture was stirred at 85℃for 2 hours and then cooled to room temperature, the reaction solution was filtered, and the filtrate was concentrated to give crude compound 24c (156 mg) which was used directly in the next reaction.
And a third step of: crude compound 24c (156 mg) obtained in the previous step and 2,4, 5-trichloropyrimidine 1a (501 mg,2.73 mmol) were dissolved in i-PrOH (5 mL), and DIPEA (529 mg,4.10 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give 24d (300 mg, yield 84%) as a white solid. ESI-MSm/z):261.2[M+H] + 。
Fourth step: compound 24d (54 mg,0.20 mmol) and Int-1 (40 mg,0.20 mmol) were dissolved in 1, 4-dioxane (4 mL), cesium carbonate (134 mg,0.41 mmol), brettPhos (22 mg,0.041 mmol) and BrettPhos Pd G3 (18 mg, 0.020mmol) were added. The reaction system was heated to 110℃after nitrogen substitution and stirred for 16 hours. After the reaction solution was cooled to room temperature, the reaction solution was concentrated, and the residue was purified by preparative thin layer chromatography to give a crude product, which was separated by reverse phase preparative HPLC to give compound 24 (17 mg, yield 20%). ESI-MS (m/z): 418.2[ M+H ] ] + ; 1 HNMR(500MHz,DMSO-d6)δ8.15(s,1H),7.96(s,1H),7.74(br s,1H),7.61(s,1H),7.35-7.31(m,1H),3.88(s,3H),3.65-3.59(m,1H),3.48-3.37(m,3H),3.21-3.11(m,2H),2.74(t,J=5.9Hz,2H),2.69-2.61(m,3H),2.34(s,3H),2.14-2.06(m,1H),1.85-1.76(m,1H)。
Example 25
4- (((5-chloro-2- ((2-methoxy-6-methyl-5, 6,7, 8-tetrahydro-1, 6-naphthyridin-3-yl) amino) pyrimidin-4-yl) amino) methyl) piperidin-2-one
Compound 25 was obtained by a similar procedure and reaction steps substituting 4- (aminomethyl) piperidin-2-one for 3- (aminomethyl) -1-methyl-1, 2-dihydropyridin-2-one hydrochloride 1b in the first step of example 1. ESI-MS (m/z): 432.2[ M+H ]] + ; 1 H NMR(500MHz,DMSO-d6)δ8.07(s,1H),7.94(s,1H),7.64(s,1H),7.43(s,1H),7.39(t,J=5.9Hz,1H),3.88(s,3H),3.41(s,2H),3.31-3.27(m,2H),3.21-3.14(m,1H),3.10-3.03(m,1H),2.75(t,J=5.9Hz,2H),2.64(t,J=5.9Hz,2H),2.34(s,3H),2.23-2.15(m,2H),1.94-1.83(m,1H),1.81-1.74(m,1H),1.36-1.27(m,1H)。
Example 26
3- (((2- ((2-methoxy-6-methyl-5, 6,7, 8-tetrahydro-1, 6-naphthyridin-3-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) -1-methylpyridin-2 (1H) -one
Compound 26 was obtained by a similar method and reaction procedure using 2, 4-dichloro-5-trifluoromethylpyrimidine instead of 2,4, 5-trichloropyrimidine 1a in the first step of example 1. ESI-MS (m/z): 476.2[ M+H ]] + ; 1 H NMR(500MHz,DMSO-d6)δ8.23(s,1H),8.06(s,1H),7.74(s,1H),7.64(d,J=6.5Hz,1H),7.57(br s,1H),7.01(d,J=6.8Hz,1H),6.19(t,J=6.8Hz,1H),4.39(d,J=5.2Hz,2H),3.84(s,3H),3.50(s,3H),3.12(s,2H),2.71(d,J=6.9Hz,2H),2.60(t,J=5.9Hz,2H),2.33(s,3H)。
Example 27
(R) -3- (1- ((5-chloro-2- ((2-methoxy-6-methyl-5, 6,7, 8-tetrahydro-1, 6-naphthyridin-3-yl) amino) pyrimidin-4-yl) amino) ethyl) -1-methylpyridin-2 (1H) -one
Compound 27 was prepared by the following steps:
the first step: compound 27a (500 mg,4.06 mmol) was dissolved in DMF (5 mL) and cesium carbonate (1.59 g,4.87 mmol) and methyl iodide (692 mg,4.87 mmol) were added at 0deg.C in ice and the reaction was warmed to room temperature and stirred for 16 hours. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (40 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=2/1) to give compound 27b (290 mg, yield 52%) as a white solid. 1 H NMR(500MHz,CDCl 3 )δ10.37(s,1H),8.04(dd,J=7.0.4.5Hz,1H),7.63(dd,J=6.5,2,0Hz,1H),6.32(t,J=7.0Hz,1H),3.64(s,3H)。
And a second step of: compound 27b (200 mg,1.46 mmol) was dissolved in DCE (5 mL), cesium carbonate (950 mg,2.92 mmol) and S-tert-butylsulfinamide (212 mg,1.75 mmol) were added and the mixture was stirred at 65℃for 16 h. After completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 27c (330 mg, yield 94%) as a pale yellow oil. ESI-MS (m/z): 241.4[ M+H ]] + ; 1 H NMR(500MHz,DMSO-d6)δ8.71(s,1H),8.15(dd,J=6.0.2.0Hz,1H),8.05(dd,J=6.5,2,5Hz,1H),6.41(t,J=7.0Hz,1H),3.52(s,3H),1.15(s,9H)。
And a third step of: compound 27c (35 mg,0.14 mmol) was dissolved in DCM (3 mL) and methyl magnesium bromide (1 mol/L in THF,0.29 mL) was added under nitrogen at-78deg.C and the mixture stirred at-78deg.C for 2 h. After completion of the reaction, the reaction was quenched by addition of saturated ammonium chloride solution (20 mL) and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 27d (30 mg, yield 80%) as a pale yellow oil. ESI-MS (m/z): 257.5[ M+H ]] + ; 1 H NMR (500 mhz, dmso-d 6) delta 7.61 (dd, j=7.0.2.0 hz, 1H), 7.46 (dd, j=6.5, 2,0hz, 1H), 6.25-6.20 (m, 1H), 5.68 (d, j=10.5 hz, 1H), 4.42-4.37 (m, 1H), 3.44 (s, 3H), 1.29 (d, j=6.5 hz, 3H), 1.10 (s, 9H). The steric configuration of the newly generated chiral center of compound 27d is assumed to be R-type.
Fourth step: compound 27d (30 mg,0.11 mmol) was dissolved in MeOH (2 mL) and dioxane hydrochloride solution (4 mol/L,0.12 mL) was added and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to give compound 27e (22 mg, yield 99%) as a white solid. ESI-MS (m/z): 153.1[ M+H ]] + 。
Fifth step: compound 27e (22 mg,0.11 mmol) was dissolved in isopropanol (2 mL) and 2,4, 5-trichloropyrimidine 1a (32 mg,0.17 mmol) and N, N-diisopropylethylamine (30 mg,0.23 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. To be reactedAfter completion, the reaction solution was concentrated, and the residue was purified by preparative thin layer chromatography (petroleum ether/ethyl acetate=1/1) to give compound 27f (31 mg, yield 88%) as a white solid. ESI-MS (m/z): 299.1[ M+H ]] + 。
Sixth step: compound Int-1 (20 mg,0.10 mmol) and compound 27f (31 mg,0.10 mmol) were dissolved in 1, 4-dioxane (3 mL), cesium carbonate (67 mg,0.20 mmol), brettPhos (11 mg, 0.020mmol) and BrettPhos Pd G3 (9 mg, 0.010mmol) were added. The reaction mixture was heated to 100 ℃ after nitrogen substitution and stirred for 18 hours. The reaction solution was filtered through celite, the filtrate was concentrated, and the residue was purified by preparative thin layer chromatography (dichloromethane/methanol=10/1) to give a crude product, which was separated by reverse phase preparative HPLC to give compound 27 (3 mg, yield 6%). ESI-MS (m/z): 299.1[ M+H ] ] + ; 1 H NMR(400MHz,DMSO-d6)δ8.00(s,1H),7.99(s,1H),7.67-7.63(m,1H),7.57(s,1H),7.53(d,J=8.4Hz,1H),7.37-7.33(m,1H),6.26-6.19(m,1H),5.35-5.26(m,1H),3.87(s,3H),3.49(s,3H),3.45-3.43(m,2H),2.77-2.71(m,2H),2.68-2.60(m,2H),2.37(s,3H),1.44(d,J=6.8Hz,3H)。
The following examples were prepared according to the synthetic routes and synthetic methods of intermediates described in the examples above.
Biological screening and results for HPK1 inhibitors
Test example 1: detection of the ability of Compounds to inhibit the Activity of HPK1 kinase (method 1)
The required reagents are as follows
Experimental procedure
The specific operation is as follows: preparing an enzymatic reaction system buffer (10mM MOPS,pH 7.2,5mM beta-glycol-phosphate, 10mM MgCl2,0.8mM EDTA,2mM EGTA,0.1mM DTT); the compounds tested (1 mM stock of compound in DMSO) were diluted with buffer to a maximum concentration of 60uM (containing 6% DMSO) and a gradient of 8 spots in total of 5-fold dilution of the compound with buffer containing 6% DMSO was prepared starting at a concentration of 60 uM; the HPK1 kinase was then diluted to 30nM using buffer. Mu.l of HPK1 kinase diluent was added to each well of Greiner 384 well microplates (cat# 784075), and 2. Mu.l of buffer was added to control wells; after brief centrifugation, 1. Mu.l of the diluted compound was added to the reaction wells and 1. Mu.l of buffer containing 6% DMSO was added to the control wells; after brief centrifugation, the mixture was placed in a constant temperature incubator (Shanghai-Heng scientific instruments Co., ltd., product number: LRH-150) at 25℃for 20min. 3. Mu.l of the reaction substrate (10. Mu.M MBP and 20. Mu.M ATP in distilled water) was added to each well, centrifuged briefly and incubated in a constant temperature incubator at 25℃for 60min, and the enzymatic activity was detected by ADP-Glo Kinase Assay Kit, with ADP-Glo Kinase Assay Kit all according to the instructions of the kit. Data are described using half inhibition concentration IC50 of the compound.
Numbering of compounds | IC50(nM) | Numbering of compounds | IC50(nM) |
1 | <0.1 | 2 | 88 |
3 | 45.73 | 5 | 18.52 |
6 | 2.6 | 7 | <0.1 |
8 | 5.43 | 9 | 16.12 |
10 | 98.54 | 11 | 4.98 |
13 | 82.59 | 14 | 18.99 |
16 | 34.42 | 17 | 82.82 |
19 | 8.52 | 21 | 94.75 |
23 | 0.16 | 24 | 0.71 |
25 | 33.99 | 26 | 1.35 |
27 | 1.92 | 28 | 18.35 |
29 | 19.43 | 30 | 29.78 |
31 | 11.80 | 32 | 0.85 |
33 | 13.56 | 34 | 43.51 |
35 | 42.28 | 36 | 3.44 |
37 | 8.03 | 38 | 12.82 |
39 | 19.01 | 40 | 2.06 |
42 | 81.06 | 43 | 4.26 |
44 | 0.48 | 45 | 29.40 |
46 | 44.97 | 47 | 20.97 |
48 | 17.94 | 49 | 5.78 |
50 | 9.67 | 51 | 14.61 |
52 | 9.00 | 53 | 2.69 |
Test example 2: detection of the agonistic Capacity of Jurkat cells to secrete the cytokine interleukin-2 (IL-2) (method 2)
The reagents and cells to be used are as follows
Experimental reagent:
reagent(s) | Branding | Goods number | Preservation conditions |
RPMI1640 | BI | 01-100-1ACS | 4℃ |
FBS | BI | 04-002-1A | -80℃ |
BSA | Amresco | 0332-1KG | 4℃ |
Phosphate buffer solution | BI | 02-024-1ACS | 4℃ |
Tween-20 | Solarbio | T8220 | RT |
Anti-human CD3 Antibody | invitrogen | 16-0037-85 | 4℃ |
Anti-human CD28 Antibody | invitrogen | 16-0289-85 | 4℃ |
Human IL-2 DuoSet ELISA | R&D | DY202 | 4℃ |
Experimental cells:
cells | Cell type | Branding |
Jurkat E6-1 | Human T lymphocyte leukemia cells | Cell bank of Chinese academy |
Experimental procedure
The specific operation is as follows: compound powder was dissolved in DMSO to 10mM, 2 μl of compound was added to 998 μl RPMI 1640 medium (10% fbs in each of the experiments) and vortexed to the highest concentration point. The compound solution was gradually diluted 3-fold with 0.2% dmso medium for a total of 8 concentration points. As a control, RPMI 1640 medium solution containing dmso at a concentration of 0.1% was used. 1X 105Jurkat E6-1 cells were added to each well of a Corning 96 well cell culture plate (cat# 3599), followed by an equal volume of compound dilution, control addition of RPMI 1640 medium containing 0.2% DMSO, and incubation in a 37℃cell incubator (Thermo Fisher Scientific, model: 3111) for 1h. Then adding Anti-human CD3 Anti-body and Anti-human CD28 Anti-body antibodies with the final concentration of 1 mug/ml, and placing the mixture in a cell culture incubator at 37 ℃ for incubation for 24 hours. IL-2 content in cell supernatants was detected using a Human IL-2 DuoSet ELISA KIT ELISA assay performed according to the instructions of the kit. Data are described as the highest fold ratio of the stimulation signal of the compound to the signal of 0.1% dmso.
Test example 3: detection of the agonistic Capacity of the Compounds to secrete the cytokine interleukin-2 (IL-2) by human PBMC cells (method 3)
The required reagents are as follows
Reagent(s) | Branding | Goods number | Preservation conditions |
RPMI1640 | BI | 01-100-1ACS | 4℃ |
FBS | BI | 04-002-1A | -80℃ |
BSA | Amresco | 0332-1KG | 4℃ |
Phosphate buffer solution | BI | 02-024-1ACS | 4℃ |
Tween-20 | Solarbio | T8220 | RT |
Anti-human CD3 Antibody | invitrogen | 16-0037-85 | 4℃ |
Anti-human CD28 Antibody | invitrogen | 16-0289-85 | 4℃ |
Human IL-2 DuoSet ELISA | R&D | DY202 | 4℃ |
Experimental cell source information:
experimental procedure
The specific operation is as follows: human PBMC were removed from liquid nitrogen according to standard procedures, thawed and resuscitated in a 37℃water bath, and cells were resuspended in RPMI 1640 medium (10% FBS in each case), washed twice by centrifugation; human PBMC cells were then resuspended in RPMI 1640 medium for use. The compound powder was dissolved to 10mM with DMSO, 2. Mu.l of the compound was added to 998. Mu.l of RPMI 1640 medium, and the mixture was vortexed to the highest concentration point. The compound solution was gradually diluted 3-fold with 0.2% dmso medium for a total of 8 concentration points. As a control, RPMI 1640 medium solution containing dmso at a concentration of 0.1% was used. 1X 105 human PBMC cells were added to each well of a Corning 96 well cell culture plate (cat# 3599), followed by an equal volume of compound dilution, control group addition of RPMI 1640 medium containing 0.2% DMSO, and incubation in a 37℃cell incubator (Thermo Fisher Scientific, model: 3111) for 1h. Then adding Anti-human CD3 Anti-body Antibody with the final concentration of 0.01 mug/ml and Anti-human CD28 Anti-body Antibody with the final concentration of 1 mug/ml, and placing the mixture in a cell incubator at 37 ℃ for incubation for 24 hours. IL-2 content in cell supernatants was detected using a Human IL-2 DuoSet ELISA KIT ELISA assay performed according to the instructions of the kit. Data are described as the highest fold ratio of the stimulation signal of the compound to the signal of 0.1% dmso.
The above results indicate that the compounds of the present invention can significantly increase IL-2.
Claims (27)
- A compound having the structure of formula (I) or a pharmaceutically acceptable salt, isotopic derivative or stereoisomer thereof:wherein the method comprises the steps ofX represents N or CR 10 ;R 1 Represents hydrogen, C 1 -C 6 Alkyl, halogenated C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, halo C 3 -C 6 Cycloalkyl, halogen, cyano or-C (O) NH 2 ;R 2 Represents hydrogen, halogen, hydroxy, (C) 1 -C 6 ) Alkyl, (C) 2 -C 6 ) Alkenyl, - (C) 0 -C 6 Alkylene group) (C) 3 -C 8 ) Cycloalkyl, - (C) 0 -C 6 Alkylene) (4-8 membered) heterocycloalkyl, (C) 1 -C 6 ) Alkoxy, (C) 3 -C 8 ) Cycloalkyl (C) 0 -C 6 Alkylene) oxy or (4-8 membered heterocycloalkyl) (C 0 -C 6 Alkylene) oxy;R 3 represents hydrogen or C 1 -C 6 Alkyl, C 3 -C 6 Alkenyl, C 3 -C 6 Cycloalkyl, hydroxy (C) 1 -C 6 Alkyl, halo C 1 -C 6 Alkyl, 4-8 membered heterocycloalkyl;R 4 represents hydrogen or C 1 -C 6 An alkyl group; and said C 1 -C 6 The alkyl group may be optionally substituted with a substituent selected from the group consisting of: halogen, -OR a 、-SR a 、-P(O)R a R b 、-S(O) 2 R a 、-S(O)(NH)R a 、-S(O)R a 、-S(O) 2 NR a R b 、-C(O)NR a R b 、-C(O)OH、-OC(O)NR a R b 、-NR a C(O)R b 、-NR a S(O) 2 R b ;R 5 And R is 5’ Each independently represents hydrogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, halogen, halo C 1 -C 6 Alkyl or hydroxy (C) 1 -C 6 An alkyl group);or R is 5 And R is R 5’ Together with the carbon atoms to which they are attached form a 3-6 membered ring, which ring may optionally contain 0, 1 or 2 heteroatoms selected from N, O, S;R 6 and R is 6’ Each independently represents hydrogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, halogen, halo C 1 -C 6 Alkyl or hydroxy (C) 1 -C 6 An alkyl group);or R is 6 And R is R 6’ Together with the carbon atoms to which they are attached form a 3-6 membered ring, which ring may optionally contain 0, 1 or 2 heteroatoms selected from N, O, S;p represents 1 or 2;R 7 and R is 7’ Each independently represents hydrogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, halogen, halo C 1 -C 6 Alkyl or hydroxy (C) 1 -C 6 An alkyl group);or R is 7 And R is R 7’ Together with the carbon atoms to which they are attached form a 3-6 membered ring, which ring may optionally contain 0, 1 or 2 heteroatoms selected from N, O, S;w representsWherein A representsRepresents that the ring contains a single bond or a double bond;when the bond between A and A 'is a double bond, A' represents CR a Or N, B represents CR b ;When the bond between A and A 'is a single bond, A' represents CHR a B represents CHR b Or is absent;R 8 and R is 9 Each independently represents hydrogen or C 1 -C 6 An alkyl group; or R is 8 And R is R 9 Can be combined with W 1 And W is 2 Together forming a 3-6 membered ring;W 1 represents C, W 2 Represents CH or N;R M and R is N Each independently represents hydrogen or C 1 -C 6 An alkyl group;R 10 represents hydrogen, halogen, (C) 1 -C 6 ) Alkyl, (C) 2 -C 6 ) Alkenyl, - (C) 0 -C 6 Alkylene group) (C) 3 -C 8 ) Cycloalkyl, - (C) 0 -C 6 Alkylene) 4-10 membered heterocycloalkyl, - (C) 0 -C 6 Alkylene group) (C) 6 -C 10 ) Aryl or- (C) 0 -C 6 Alkylene) a 5-to 10-membered heteroaryl,alternatively, when X represents CR 10 When R is 10 Can be adjacent to R 2 Together forming a 5-10 membered cycloalkyl or 5-10 membered heterocycloalkyl;wherein R is a 、R b Each independently represents hydrogen, C 1 -C 6 Alkyl, hydroxy (C) 1 -C 6 Alkyl) or halogenated C 1 -C 6 An alkyl group;m and n represent 0, 1 or 2, respectively.
- The compound of claim 1, or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof, wherein,w representsWherein A representsRepresents that the ring contains a single bond or a double bond;each o independently represents 0 or 1;R 8 represents hydrogen or C 1 -C 6 An alkyl group;R 9 each independently represents hydrogen or C 1 -C 6 An alkyl group;or R is 8 With adjacent R 9 Together with the carbon atoms to which they are attached, form a 3-6 membered ring;W 2 、R M 、R N the method of claim 1.
- The compound of claim 2, or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof, wherein,w representsOr alternativelyRepresents that the ring contains a single bond or a double bond;each o independently represents 0 or 1;R 8 represents hydrogen or C 1 -C 6 An alkyl group;R 9 each independently represents hydrogen or C 1 -C 6 An alkyl group;or R is 8 With adjacent R 9 Together with the carbon atoms to which they are attached, form a 3-6 membered ring;W 2 、R M 、R N the method of claim 1.
- A compound according to claim 3, or a pharmaceutically acceptable salt, isotopic derivative or stereoisomer thereof, wherein W is an aromatic heterocycle.
- A compound according to claim 3, or a pharmaceutically acceptable salt, isotopic derivative or stereoisomer thereof, wherein W is a saturated heterocycle.
- A compound according to claim 1, or a pharmaceutically acceptable salt, isotopic derivative or stereoisomer thereof, wherein ring W represents Or alternatively
- A compound according to claim 6, wherein ring W represents
- The compound according to claim 7, wherein ring W represents
- A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, isotopic derivative or stereoisomer thereof, wherein R 1 Represents hydrogen, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, cyano or-C (O) NH 2 。
- The compound of claim 9, or a pharmaceutically acceptable salt isotope derivative thereof, or a stereoisomer thereof, wherein R 1 Represents hydrogen, halogen, C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group.
- A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt isotopic derivative or stereoisomer thereof, wherein R 2 Represents hydroxy, (C) 1 -C 6 ) Alkyl, - (C) 0 -C 6 Alkylene group) (C) 3 -C 8 ) Cycloalkyl, - (C) 0 -C 6 Alkylene) (4-8 membered) heterocycloalkyl, (C) 1 -C 6 ) An alkoxy group.
- As claimed inThe compound of claim 11, or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof, wherein R 2 Represent C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or C 3 -C 6 Cycloalkyl groups.
- A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt isotopic derivative or stereoisomer thereof, wherein R 3 Represents hydrogen or C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, halo C 1 -C 6 An alkyl group;
- the compound of claim 13, or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof, wherein R 3 Represents hydrogen or C 1 -C 6 An alkyl group.
- A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt isotopic derivative or stereoisomer thereof, wherein R 4 Represents hydrogen or C 1 -C 6 An alkyl group; and said C 1 -C 6 The alkyl group may be optionally substituted with a substituent selected from the group consisting of: halogen, -OR a 、-SR a 、-P(O)R a R b 、-S(O) 2 R a 、-S(O)(NH)R a 、-S(O)R a 、-S(O) 2 NR a R b 、-C(O)NR a R b 、-C(O)OH。
- The compound of claim 15, or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof, wherein R 4 Represents hydrogen or C 1 -C 6 An alkyl group. 17. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt isotopic derivative or stereoisomer thereof, wherein R 5 、R 5’ Each independently represents hydrogen, halogen, C 1 -C 6 Alkyl or halo C 1 -C 6 An alkyl group.
- A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt isotopic derivative or stereoisomer thereof, wherein R 6 、R 6’ Each independently represents hydrogen, halogen, C 1 -C 6 Alkyl or halo C 1 -C 6 An alkyl group.
- A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt isotopic derivative or stereoisomer thereof, wherein R 7 、R 7’ Each independently represents hydrogen, halogen, C 1 -C 6 Alkyl, halogenated C 1 -C 6 Alkyl or hydroxy (C) 1 -C 6 Alkyl). 20. A compound according to any one of the preceding claims or a pharmaceutically acceptable salt isotopic derivative or stereoisomer thereof, wherein R 8 Represents hydrogen or C 1 -C 6 An alkyl group.
- A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt isotopic derivative or stereoisomer thereof, wherein R 9 Represents hydrogen or C 1 -C 6 An alkyl group.
- A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt isotopic derivative or stereoisomer thereof, wherein R 10 Represents hydrogen, halogen, (C) 1 -C 6 ) Alkyl, - (C) 0 -C 6 Alkylene group) (C) 3 -C 8 ) Cycloalkyl, - (C) 0 -C 6 Alkylene) 4-10 membered heterocycloalkyl.
- The compound of claim 22, or a pharmaceutically acceptable salt isotope derivative thereof, or a stereoisomer thereof, wherein R 10 Represents hydrogen, halogen or (C) 1 -C 6 ) An alkyl group.
- A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt isotopic derivative or stereoisomer thereof, wherein R M Represents hydrogen or C 1 -C 6 An alkyl group.
- A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt isotopic derivative or stereoisomer thereof, wherein R a 、R b Each independently represents hydrogen, C 1 -C 6 Alkyl or halo C 1 -C 6 An alkyl group.
- A compound having the structure:
- a pharmaceutical composition comprising a compound according to any one of the preceding claims or a pharmaceutically acceptable salt, isotopic derivative or stereoisomer thereof, and a pharmaceutically acceptable carrier.
- Use of a compound according to any one of claims 1 to 26 or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof or a pharmaceutical composition according to claim 27 for the manufacture of a medicament for the prevention and/or treatment of cancer, tumour, inflammatory disease, autoimmune disease or immune mediated disease.
- Use of a compound according to claims 1-26, or a pharmaceutically acceptable salt, isotopic derivative or stereoisomer thereof, for the prevention and/or treatment of cancer, tumor, inflammatory disease, autoimmune disease or immune mediated disease.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2021103784241 | 2021-04-08 | ||
CN202110378424 | 2021-04-08 | ||
PCT/CN2022/085446 WO2022214009A1 (en) | 2021-04-08 | 2022-04-07 | High-activity hpk1 kinase inhibitor |
Publications (1)
Publication Number | Publication Date |
---|---|
CN116888100A true CN116888100A (en) | 2023-10-13 |
Family
ID=83546012
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202280013620.1A Pending CN116888100A (en) | 2021-04-08 | 2022-04-07 | High-activity HPK1 kinase inhibitor |
Country Status (3)
Country | Link |
---|---|
CN (1) | CN116888100A (en) |
TW (1) | TW202304434A (en) |
WO (1) | WO2022214009A1 (en) |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ATE530530T1 (en) * | 2002-06-28 | 2011-11-15 | Astellas Pharma Inc | DIAMINOPYRIMIDINE CARBONIC ACID AMIDE DERIVATIVE |
CA2529611C (en) * | 2002-12-20 | 2009-12-15 | Pfizer Products Inc. | Pyrimidine derivatives for the treatment of abnormal cell growth |
MXPA06013165A (en) * | 2004-05-14 | 2007-02-13 | Pfizer Prod Inc | Pyrimidine derivatives for the treatment of abnormal cell growth. |
MX2019011511A (en) * | 2017-03-30 | 2019-11-18 | Hoffmann La Roche | Naphthyridines as inhibitors of hpk1. |
CN112243439A (en) * | 2018-06-13 | 2021-01-19 | 百济神州有限公司 | Pyrrolo [2,3-B ] pyridines or pyrrolo [2,3-B ] pyrazines as HPK1 inhibitors and uses thereof |
-
2022
- 2022-04-07 TW TW111113324A patent/TW202304434A/en unknown
- 2022-04-07 CN CN202280013620.1A patent/CN116888100A/en active Pending
- 2022-04-07 WO PCT/CN2022/085446 patent/WO2022214009A1/en active Application Filing
Also Published As
Publication number | Publication date |
---|---|
WO2022214009A1 (en) | 2022-10-13 |
TW202304434A (en) | 2023-02-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6653471B2 (en) | Heterocyclic compounds as ligands of the GABAA receptor | |
WO2018045956A1 (en) | Benzimidazole compound kinase inhibitor, preparation method therefor and application thereof | |
AU2017302182A1 (en) | Substituted thiazolo-pyridine compounds as MALT1 inhibitors | |
JP5824068B2 (en) | Novel triazolylphenylsulfonamides as serine / threonine kinase inhibitors | |
KR20130041068A (en) | Tetrahydro-pyrido-pyrimidine derivatives | |
JP6322275B2 (en) | N- (2-cyanoheterocyclyl) pyrazolopyridone as Janus kinase inhibitor | |
EP4074710A1 (en) | Pyrazolo[1,5-a]pyridine compound, preparation method therefor and use thereof | |
CN116348469A (en) | High-activity Wnt pathway inhibitor compound | |
CN116685585A (en) | High-activity HPK1 kinase inhibitor | |
JP2020537645A (en) | Amine-substituted heterocyclic compounds as EHMT2 inhibitors and their derivatives | |
CN116655602A (en) | PI3K alpha allosteric inhibitors | |
CN112313220B (en) | PD-L1 antagonist compounds | |
JP7349750B2 (en) | Aromatic heterocyclic compounds with kinase inhibitory activity | |
CN116964053A (en) | Wnt pathway inhibitor compound | |
BR112020026337A2 (en) | TRICYCLIC COMPOUNDS | |
TWI768781B (en) | TRANSFORMING GROWTH FACTOR-β RECEPTOR INHIBITOR | |
CN116888100A (en) | High-activity HPK1 kinase inhibitor | |
TW202222797A (en) | Pyrazolo[1,5-a]pyridine compound, preparation method therefor and use thereof | |
CA3151039A1 (en) | Substituted benzimidazole carboxamides and their use in the treatment of medical disorders | |
CN115066423A (en) | PD-L1 antagonist compounds | |
CN116848103A (en) | High activity HPK1 kinase inhibitors | |
CN116348117A (en) | HPK1 kinase inhibitor compounds | |
CN117903169A (en) | Pan-KRAS inhibitor compound | |
CN116848115A (en) | Wnt pathway inhibitor compounds | |
CN117396482A (en) | Wnt pathway inhibitor compound |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |