CN114539223A - Aryl-containing aza-heptacyclic compound and preparation method and application thereof - Google Patents
Aryl-containing aza-heptacyclic compound and preparation method and application thereof Download PDFInfo
- Publication number
- CN114539223A CN114539223A CN202210194719.8A CN202210194719A CN114539223A CN 114539223 A CN114539223 A CN 114539223A CN 202210194719 A CN202210194719 A CN 202210194719A CN 114539223 A CN114539223 A CN 114539223A
- Authority
- CN
- China
- Prior art keywords
- compound
- synthesis
- reaction
- radical
- amino
- 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.)
- Granted
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 86
- 125000003118 aryl group Chemical group 0.000 title claims abstract description 8
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- -1 polymorphs Substances 0.000 claims abstract description 36
- 229940002612 prodrug Drugs 0.000 claims abstract description 6
- 239000000651 prodrug Substances 0.000 claims abstract description 6
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- 239000012453 solvate Substances 0.000 claims abstract description 4
- 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 claims abstract 2
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 150000002431 hydrogen Chemical class 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 8
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 8
- 229910052805 deuterium Inorganic materials 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 239000002246 antineoplastic agent Substances 0.000 claims description 7
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 125000003368 amide group Chemical group 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 2
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 2
- 239000004593 Epoxy Substances 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 239000008176 lyophilized powder Substances 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 230000001225 therapeutic effect Effects 0.000 claims 1
- 239000003112 inhibitor Substances 0.000 abstract description 12
- YGUFCDOEKKVKJK-UHFFFAOYSA-N 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine Chemical compound NC1(CCN(CC1)C1=CN=C(C(=N1)N)C1=C(C(=CC=C1)Cl)Cl)C YGUFCDOEKKVKJK-UHFFFAOYSA-N 0.000 abstract description 8
- 230000000694 effects Effects 0.000 abstract description 7
- 238000011161 development Methods 0.000 abstract description 6
- 102000007607 Non-Receptor Type 11 Protein Tyrosine Phosphatase Human genes 0.000 abstract description 4
- 108010032107 Non-Receptor Type 11 Protein Tyrosine Phosphatase Proteins 0.000 abstract description 4
- 150000002611 lead compounds Chemical class 0.000 abstract description 2
- 238000012986 modification Methods 0.000 abstract 2
- 230000004048 modification Effects 0.000 abstract 2
- 230000008850 allosteric inhibition Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 90
- 238000006243 chemical reaction Methods 0.000 description 82
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 78
- 230000015572 biosynthetic process Effects 0.000 description 75
- 238000003786 synthesis reaction Methods 0.000 description 75
- 239000000243 solution Substances 0.000 description 43
- 238000005160 1H NMR spectroscopy Methods 0.000 description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 25
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 25
- 229910001868 water Inorganic materials 0.000 description 25
- 239000012074 organic phase Substances 0.000 description 23
- 238000004440 column chromatography Methods 0.000 description 20
- 239000007858 starting material Substances 0.000 description 20
- 238000000034 method Methods 0.000 description 19
- 102100033019 Tyrosine-protein phosphatase non-receptor type 11 Human genes 0.000 description 18
- 101710116241 Tyrosine-protein phosphatase non-receptor type 11 Proteins 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 18
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 18
- 238000012544 monitoring process Methods 0.000 description 17
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 14
- 239000000203 mixture Substances 0.000 description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- UJTAUNNBWGAQIB-UHFFFAOYSA-N 1h-azepin-4-amine Chemical compound NC1=CC=CNC=C1 UJTAUNNBWGAQIB-UHFFFAOYSA-N 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 238000001035 drying Methods 0.000 description 12
- 229940125904 compound 1 Drugs 0.000 description 11
- 238000001914 filtration Methods 0.000 description 11
- 238000005406 washing Methods 0.000 description 11
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 239000001963 growth medium Substances 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 5
- 230000018109 developmental process Effects 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 229940041181 antineoplastic drug Drugs 0.000 description 4
- NPHKCBFALXEZDP-UHFFFAOYSA-N azepin-1-amine Chemical compound NN1C=CC=CC=C1 NPHKCBFALXEZDP-UHFFFAOYSA-N 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 239000012894 fetal calf serum Substances 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 3
- 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 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 239000005909 Kieselgur Substances 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 230000003281 allosteric effect Effects 0.000 description 3
- 229940125797 compound 12 Drugs 0.000 description 3
- 230000029087 digestion Effects 0.000 description 3
- 238000007865 diluting Methods 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 229940088598 enzyme Drugs 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 229910000160 potassium phosphate Inorganic materials 0.000 description 3
- 235000011009 potassium phosphates Nutrition 0.000 description 3
- LFILDSDQMSCNBV-LURJTMIESA-N propane-2-sulfinamide Chemical compound CC(C)[S@@](N)=O LFILDSDQMSCNBV-LURJTMIESA-N 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 230000019491 signal transduction Effects 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- ZRHNALVSXAVNMX-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonyl-(2-phenylethyl)amino]acetic acid Chemical compound CC(C)(C)OC(=O)N(CC(O)=O)CCC1=CC=CC=C1 ZRHNALVSXAVNMX-UHFFFAOYSA-N 0.000 description 2
- KFYHXWDARZYYIS-UHFFFAOYSA-N 2-chloro-N-(2,2-dimethoxyethyl)-5-iodopyrimidin-4-amine Chemical compound COC(CNc1nc(Cl)ncc1I)OC KFYHXWDARZYYIS-UHFFFAOYSA-N 0.000 description 2
- BYHPOBHBBHWAIW-UHFFFAOYSA-N 3-[benzyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoic acid Chemical compound CC(C)(C)OC(=O)N(CCC(O)=O)CC1=CC=CC=C1 BYHPOBHBBHWAIW-UHFFFAOYSA-N 0.000 description 2
- NPDICENVXROWJV-UHFFFAOYSA-N 3-chloro-2-fluoro-4-iodopyridine Chemical compound FC1=NC=CC(I)=C1Cl NPDICENVXROWJV-UHFFFAOYSA-N 0.000 description 2
- GTTQRVGVEIXEHQ-UHFFFAOYSA-N 3-chloro-4-iodopyridin-2-amine Chemical compound NC1=NC=CC(I)=C1Cl GTTQRVGVEIXEHQ-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- XYEWTFOCPLSOIC-UHFFFAOYSA-N 5-bromo-[1,3]thiazolo[5,4-b]pyridin-2-amine Chemical compound C1=C(Br)N=C2SC(N)=NC2=C1 XYEWTFOCPLSOIC-UHFFFAOYSA-N 0.000 description 2
- SDMKKGSEIFPLDP-UHFFFAOYSA-N 5-chloro-8-iodoimidazo[1,2-c]pyrimidine Chemical compound ClC1=NC=C(I)C2=NC=CN12 SDMKKGSEIFPLDP-UHFFFAOYSA-N 0.000 description 2
- JGAVPFNFAUWIJY-UHFFFAOYSA-N 6-amino-3-methyl-1h-pyrimidine-2,4-dione Chemical compound CN1C(=O)C=C(N)NC1=O JGAVPFNFAUWIJY-UHFFFAOYSA-N 0.000 description 2
- BHKLNCGXKOSECR-UHFFFAOYSA-N 6-amino-5-iodo-3-methyl-1H-pyrimidine-2,4-dione Chemical compound CN1C(=O)NC(N)=C(I)C1=O BHKLNCGXKOSECR-UHFFFAOYSA-N 0.000 description 2
- UAZFZHXRKHSGLQ-UHFFFAOYSA-N 6-chloro-3-(2,3-dichlorophenyl)pyrazin-2-amine Chemical compound NC1=NC(Cl)=CN=C1C1=CC=CC(Cl)=C1Cl UAZFZHXRKHSGLQ-UHFFFAOYSA-N 0.000 description 2
- QYBVGWFSIYHZEG-UHFFFAOYSA-N 8-iodo-6H-imidazo[1,2-c]pyrimidin-5-one Chemical compound IC=1C=2N(C(NC=1)=O)C=CN=2 QYBVGWFSIYHZEG-UHFFFAOYSA-N 0.000 description 2
- SDZVRGYHXUIPEL-UHFFFAOYSA-N BrC1=CC=C2C(=N1)SC(=N2)Cl Chemical compound BrC1=CC=C2C(=N1)SC(=N2)Cl SDZVRGYHXUIPEL-UHFFFAOYSA-N 0.000 description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 2
- 102000043136 MAP kinase family Human genes 0.000 description 2
- 108091054455 MAP kinase family Proteins 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- 102000004142 Trypsin Human genes 0.000 description 2
- 108090000631 Trypsin Proteins 0.000 description 2
- 230000001028 anti-proliverative effect Effects 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- AUPNGYFUWFZWFC-UHFFFAOYSA-M sodium 5-chloropyrazine-2-thiolate Chemical compound ClC=1N=CC(=NC=1)[S-].[Na+] AUPNGYFUWFZWFC-UHFFFAOYSA-M 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 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 2
- 238000012360 testing method Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- JMXKSZRRTHPKDL-UHFFFAOYSA-N titanium ethoxide Chemical compound [Ti+4].CC[O-].CC[O-].CC[O-].CC[O-] JMXKSZRRTHPKDL-UHFFFAOYSA-N 0.000 description 2
- 239000012588 trypsin Substances 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 229910021642 ultra pure water Inorganic materials 0.000 description 2
- 239000012498 ultrapure water Substances 0.000 description 2
- 238000005303 weighing Methods 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
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-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
- TYIKXPOMOYDGCS-UHFFFAOYSA-N (2,3-dichlorophenyl)boronic acid Chemical compound OB(O)C1=CC=CC(Cl)=C1Cl TYIKXPOMOYDGCS-UHFFFAOYSA-N 0.000 description 1
- SUYJXERPRICYRX-UHFFFAOYSA-N (3-bromophenyl)methanamine Chemical compound NCC1=CC=CC(Br)=C1 SUYJXERPRICYRX-UHFFFAOYSA-N 0.000 description 1
- BJFPYGGTDAYECS-UHFFFAOYSA-N (3-chlorophenyl)methanamine Chemical compound NCC1=CC=CC(Cl)=C1 BJFPYGGTDAYECS-UHFFFAOYSA-N 0.000 description 1
- QVSVMNXRLWSNGS-UHFFFAOYSA-N (3-fluorophenyl)methanamine Chemical compound NCC1=CC=CC(F)=C1 QVSVMNXRLWSNGS-UHFFFAOYSA-N 0.000 description 1
- GRRIMVWABNHKBX-UHFFFAOYSA-N (3-methoxyphenyl)methanamine Chemical compound COC1=CC=CC(CN)=C1 GRRIMVWABNHKBX-UHFFFAOYSA-N 0.000 description 1
- RGXUCUWVGKLACF-UHFFFAOYSA-N (3-methylphenyl)methanamine Chemical compound CC1=CC=CC(CN)=C1 RGXUCUWVGKLACF-UHFFFAOYSA-N 0.000 description 1
- BXTWTBYGOKOWQX-UHFFFAOYSA-N (3-pyrrolidin-1-ylphenyl)methanamine Chemical compound NCC1=CC=CC(N2CCCC2)=C1 BXTWTBYGOKOWQX-UHFFFAOYSA-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
- 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 1
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- 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
- QKWWDTYDYOFRJL-UHFFFAOYSA-N 2,2-dimethoxyethanamine Chemical compound COC(CN)OC QKWWDTYDYOFRJL-UHFFFAOYSA-N 0.000 description 1
- JVSDZAGCHKCSGR-UHFFFAOYSA-N 2,5-dichloropyrazine Chemical compound ClC1=CN=C(Cl)C=N1 JVSDZAGCHKCSGR-UHFFFAOYSA-N 0.000 description 1
- AUCVZEYHEFAWHO-UHFFFAOYSA-N 2-(3-fluorophenyl)ethanamine Chemical compound NCCC1=CC=CC(F)=C1 AUCVZEYHEFAWHO-UHFFFAOYSA-N 0.000 description 1
- WJBMRZAHTUFBGE-UHFFFAOYSA-N 2-(3-methoxyphenyl)ethanamine Chemical compound COC1=CC=CC(CCN)=C1 WJBMRZAHTUFBGE-UHFFFAOYSA-N 0.000 description 1
- CESUXLKAADQNTB-SSDOTTSWSA-N 2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@](N)=O CESUXLKAADQNTB-SSDOTTSWSA-N 0.000 description 1
- SJIFOHPZHHKGLQ-UHFFFAOYSA-N 3-(aminomethyl)-n,n-dimethylaniline Chemical compound CN(C)C1=CC=CC(CN)=C1 SJIFOHPZHHKGLQ-UHFFFAOYSA-N 0.000 description 1
- ZDBWYUOUYNQZBM-UHFFFAOYSA-N 3-(aminomethyl)aniline Chemical compound NCC1=CC=CC(N)=C1 ZDBWYUOUYNQZBM-UHFFFAOYSA-N 0.000 description 1
- XFKPORAVEUOIRF-UHFFFAOYSA-N 3-(aminomethyl)benzonitrile Chemical compound NCC1=CC=CC(C#N)=C1 XFKPORAVEUOIRF-UHFFFAOYSA-N 0.000 description 1
- MEYHHNINZXLQDF-UHFFFAOYSA-N 3-amino-2-chlorobenzenethiol Chemical compound NC=1C(=C(C=CC1)S)Cl MEYHHNINZXLQDF-UHFFFAOYSA-N 0.000 description 1
- PKOHICLUFHSXDI-UHFFFAOYSA-N 3-chloro-4-(5-chloropyrazin-2-yl)sulfanylpyridin-2-amine Chemical compound ClC=1C(=NC=CC=1SC1=NC=C(N=C1)Cl)N PKOHICLUFHSXDI-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- LNDZXOWGUAIUBG-UHFFFAOYSA-N 6-aminouracil Chemical compound NC1=CC(=O)NC(=O)N1 LNDZXOWGUAIUBG-UHFFFAOYSA-N 0.000 description 1
- KLSJWNVTNUYHDU-UHFFFAOYSA-N Amitrole Chemical compound NC1=NC=NN1 KLSJWNVTNUYHDU-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 101800005151 Cholecystokinin-8 Proteins 0.000 description 1
- 102400000888 Cholecystokinin-8 Human genes 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 208000012239 Developmental disease Diseases 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- LXXNWCFBZHKFPT-UHFFFAOYSA-N Ethyl 2-mercaptopropionate Chemical compound CCOC(=O)C(C)S LXXNWCFBZHKFPT-UHFFFAOYSA-N 0.000 description 1
- CJQWLNNCQIHKHP-UHFFFAOYSA-N Ethyl 3-mercaptopropanoic acid Chemical compound CCOC(=O)CCS CJQWLNNCQIHKHP-UHFFFAOYSA-N 0.000 description 1
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 1
- 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 1
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 102000002727 Protein Tyrosine Phosphatase Human genes 0.000 description 1
- 102100028516 Receptor-type tyrosine-protein phosphatase U Human genes 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 101710097943 Viral-enhancing factor Proteins 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 1
- ZEEBGORNQSEQBE-UHFFFAOYSA-N [2-(3-phenylphenoxy)-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound C1(=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F)C1=CC=CC=C1 ZEEBGORNQSEQBE-UHFFFAOYSA-N 0.000 description 1
- LEKRFSJCHRYVQJ-UHFFFAOYSA-N [3-(4-fluorophenyl)phenyl]methanamine Chemical compound NCC1=CC=CC(C=2C=CC(F)=CC=2)=C1 LEKRFSJCHRYVQJ-UHFFFAOYSA-N 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 229940125528 allosteric inhibitor Drugs 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000004321 azepin-2-yl group Chemical group [H]N1C([H])=C([H])C([H])=C([H])C([H])=C1* 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940125773 compound 10 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
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- ARFLASKVLJTEJD-UHFFFAOYSA-N ethyl 2-bromopropanoate Chemical compound CCOC(=O)C(C)Br ARFLASKVLJTEJD-UHFFFAOYSA-N 0.000 description 1
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 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
- 239000010410 layer Substances 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000012982 microporous membrane Substances 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 230000006712 oncogenic signaling pathway Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 108020000494 protein-tyrosine phosphatase Proteins 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011535 reaction buffer Substances 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero 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
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Abstract
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to an aryl-containing aza-heptacyclic compound and a preparation method and application thereof. An aryloazepine heptacyclic compound having the general formula I and pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, polymorphs, or prodrugs thereof; the invention prepares a brand new compound of an aryl aza seven-membered ring based on SHP099 as a lead compound to solve the problem of SH at presentThe P2 inhibitor has single structural framework and the like; the invention has the important significance of providing a plurality of modification sites and providing a foundation for later structural modification. Meanwhile, the embodiment of the invention proves that the compound has allosteric inhibition effect on SHP2 phosphatase and provides framework support for the subsequent development of SHP2 phosphatase inhibitors.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to an aryl-containing aza-heptacyclic compound and a preparation method and application thereof.
Background
Src homology 2-containing protein tyrosine phosphatase (SHP 2) belongs to the PTPs protein family and plays a key role in regulating the processes of cell growth, proliferation, differentiation and apoptosis. In human cells, SHP2 acts as an important junction linking multiple oncogenic signaling pathways, and its mutation and aberrant expression can cause a variety of diseases including developmental disorders, leukemia, and solid tumors. In recent years, SHP2 phosphatase has attracted considerable attention because targeting SHP2 is considered an effective anti-cancer strategy. On one hand, the SHP2 is used as an upstream core regulatory factor of a RAS/Raf/MAPK signal pathway, and the inhibition of SHP2 can block the activation of the RAS/Raf/MAPK signal pathway, thereby inhibiting the growth of tumor cells; on the other hand, SHP2 is an important synergistic factor for regulating tumor immunity, and inhibition of SHP2 can activate T cell immune function and specifically kill tumor cells.
In the research of the SHP2 inhibitor, the development of an inhibitor targeting the SHP2 catalytic domain was mainly focused at the beginning, but the inhibitor has the problems of low bioavailability, poor selectivity and the like, and subsequent clinical research is difficult to carry out. In view of this, researchers began to turn their eyes to the development of SHP2 allosteric inhibitors. In 2016, the first SHP2 allosteric inhibitor SHP099 was pioneered by nova corporation, and this finding greatly pushed the development of SHP2 inhibitors. Compared with a SHP2 inhibitor targeting a catalytic domain, the SHP099 has better activity, higher selectivity and better drugability. Currently, ten allosteric SHP2 inhibitors have entered clinical trials. However, no SHP2 small molecule inhibitor is yet available in the market. Therefore, the development of a novel SHP2 small-molecule inhibitor with good anti-tumor activity is of great significance.
Disclosure of Invention
One of the technical problems to be solved by the invention is to provide a series of aryl-containing aza-heptacyclic compounds for treating various related tumor diseases by inhibiting SHP2 protein and regulating KRAS-MEK-ERK signaling pathway.
The scheme for solving the technical problems is as follows:
an aromatic aza heptacyclic compound shown as general formula I, and pharmaceutically acceptable salt, enantiomer, non-isomer, tautomer, solvate, polymorph or prodrug thereof
X is N or CR4;
R1、R2And R4Independently hydrogen, halogen, amino;
l is a bond, C1-C2Carbon chain of (3), O or S;
when n is 1, m is 1;
when n is 2, m is 0;
R3is hydrogen, deuterium, halogen, amino, hydroxyl, nitro, cyano, amido, carboxyl, sulfonyl, -C (O) NR5R6、-C(O)R5、-C(O)OR5、-NR5C(O)R6、-NR5C(O)NR6R7、-NR5C(O)OR6、-NR5R6、-OC(O)R5、-OC(O)NR5R6、-SR5、-S(O)2R5、-S(O)R5、-S(O)2NR5R6、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C7Cycloalkyl radical, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C3-C7Epoxy group, C2-C6Alkenyl radical, C2-C6Alkynyl, C6-C10Aromatic ring heterocycle, C6-C10Heteroaromatic rings, mono-heterocycles, spirocycles, bridged rings, and fused rings; wherein R is5、R6And R7Independently hydrogen, deuterium, halogen, C1-C7Alkyl radical, C1-C7Haloalkyl, C1-C7Alkoxy radical, C1-C7Haloalkoxy, C2-C6Alkenyl radical, C2-C6Alkynyl, C6-C10Aromatic ring heterocycle, C6-C10A heteroaromatic ring;
an aromatic aza heptacyclic compound shown as general formula I, and pharmaceutically acceptable salt, enantiomer, non-isomer, tautomer, solvate, polymorph or prodrug thereof
X is N or CR4;
R1、R2And R4Independently hydrogen, halogen, amino;
l is a bond, C1-C2Carbon chain of (3), O or S;
when n is 1, m is 1;
when n is 2, m is 0;
R3is hydrogen, deuterium, halogen, amino, hydroxyl, nitro, cyano, amido, carboxyl, sulfonyl, -C (O) NR5R6、-C(O)R5、-C(O)OR5、-NR5C(O)R6、-NR5R6、-OC(O)R5、-SR5、C1-C6Alkyl radical, C3-C7Cycloalkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C6-C10Aromatic ring heterocycle, C6-C10A heteroaromatic ring; wherein R is5And R6Independently hydrogen, deuterium, halogen, C1-C6Alkyl radical, C3-C7Cycloalkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl;
the aromatic aza seven-membered ring compound is any one of the following structural formulas:
the pharmaceutical composition is characterized by comprising the aryl-aza-heptacyclic compound and pharmaceutically acceptable auxiliary materials.
The pharmaceutical composition is characterized in that the pharmaceutical composition is prepared into tablets, capsules, injection or freeze-dried powder.
The aryl aza seven-ring compound and the pharmaceutical composition are applied to the preparation of antitumor drugs, prodrugs of the antitumor drugs or intermediates of the antitumor drugs.
Advantageous effects
The aromatic nitrogen-containing aza-seven-membered ring compound with a brand-new framework is prepared based on SHP099 as a lead compound, has a novel structure, has enzyme activity remarkably superior to that of SHP099, and provides support for subsequent development of antitumor drugs.
Detailed Description
the method comprises the following steps: synthesis of 2-fluoro-3-chloro-4-iodopyridine (A-2):
n-butyllithium (76mL,1.25eq.) was slowly added dropwise to a solution of A-1(20.00g,152.6mmol) in THF (150mL) at-78 ℃. Slowly dropwise adding I after reacting for 1h2Of THF (60 mL). The reaction was monitored after 30 min. After monitoring the completion of the reaction, saturated Na was added dropwise2SO3Quenching the aqueous solution, concentrating to remove THF, extracting with ethyl acetate, drying over anhydrous sodium sulfate, concentrating, and separating by column chromatography to obtain compound A-2(12.21g, yield 32%).1H NMR(300MHz,CDCl3):δ7.77(dd,J=5.2,0.9Hz,1H),7.67(d,J=5.2Hz,1H).
Step two: synthesis of 3-chloro-4-iodo-2-pyridylamine (A-3)
Reacting NH3·H2O (30mL) was added slowly dropwise to a solution of A-2(12.2g,48.6mmol) in DMSO (40 mL). After the addition, the reaction was carried out at 60 ℃ for 48 hours. After completion of the reaction was monitored, the reaction system was poured into water (200mL), stirred for 30min, and dried by suction filtration to obtain Compound A-3(11.0g, yield 91%).1H NMR(300MHz,CDCl3):δ7.57(d,J=5.2Hz,1H),7.12(d,J=5.2Hz,1H),5.05(s,2H).
Step three: synthesis of ethyl 3- ((2-amino-3-chloropyridin-4-yl) thio) propionate (A-4)
Compound A-3(5.50g,22.1mmol,1.0eq.), Pd (OAc)2(248.0mg,5 mol%) and XantPhos (767.2mg,6 mol%) were placed in a 250mL single neck flask, the nitrogen was replaced by applying a vacuum to the system, ethyl mercaptopropionate (3.26g,24.3mmol,1.1eq.), 1, 4-dioxane (45mL) and DIPEA (7.7mL,44.2mmol,2.0eq.) were added and reacted overnight in an oil bath at 100 ℃ with monitoring that the conversion of the starting material was complete. Filtering with diatomaceous earth, concentrating the filtrate, adding 30mL ethyl acetate and 10mL water, extracting and separating, washing the organic phase with saturated saline 3 times, drying with anhydrous sodium sulfate, concentrating, and purifying by column chromatography to obtain compound A-4(4.10g, yield 81%).1H NMR(300MHz,CDCl3):δ7.87(d,J=5.5Hz,1H),6.53(d,J=5.5Hz,1H),4.89(s,2H),4.19(q,J=7.2Hz,2H),3.23(t,J=7.5Hz,2H),2.72(t,J=7.5Hz,2H),1.28(t,J=7.2Hz,3H).
Step four: synthesis of sodium 3-amino-2-chlorothiophenylate (A-5)
An ethanol solution of sodium ethoxide (5.88g,17.3mmol,1.1eq., ω ═ 20%) was slowly added dropwise to a solution of a-4(4.10g,15.7mmol) in THF (20 mL). The reaction was carried out at room temperature for 2 h. After the reaction was monitored to be complete, n-hexane (100mL) was added, and the mixture was slurried, filtered, and the solid was dried to give Compound A-5(3.20g, crude).
Step five: synthesis of 3-amino-2-chlorobenzenethiol (A)
Compound a-5(1.60g, crude) was dissolved in water (10mL) and hydrochloric acid (3M) was added dropwise to pH 6. The reaction solution was extracted with ethyl acetate, and the organic phase was washed with saturated sodium chloride solution 3 times, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give intermediate a (1.05g, yield in two steps 75%).1H NMR(300MHz,DMSO-d6):δ11.46(s,1H),7.09(d,J=6.9Hz,1H),6.76(s,2H),6.67(d,J=6.9Hz,1H).
the method comprises the following steps: synthesis of ethyl 3- ((5-chloropyrazin-2-yl) thio) propionate (B-2) ethyl 3-mercaptopropionate (4.45mL,1.05eq.) was added slowly dropwise to 2, 5-dichloropyrazine (5.00g,33.6mmol) and K2CO3(4.64g,1.0eq.) in DMF (42 mL). The reaction was carried out at room temperature for 4 hours. After completion of the reaction was monitored, 200mL of ethyl acetate was added to dilute the reaction mixture, the mixture was washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate, concentrated and subjected to column chromatography to obtain Compound B-2(7.78g, yield 94%).1H NMR(300MHz,CDCl3):δ8.39(d,J=1.5Hz,1H),8.22(d,J=1.5Hz,1H),5.17(q,J=7.2Hz,2H),3.42(t,J=7.0Hz,2H),2.75(t,J=7.0Hz,2H),1.27(t,J=7.2Hz,3H).
Step two: synthesis of sodium 5-chloropyrazine-2-thiolate (B-3)
An ethanol solution of sodium ethoxide (11.22g,33.0mmol,1.1eq., ω ═ 20%) was slowly added dropwise to a solution of B-3(7.38g,30.0mmol) in THF (100 mL). The reaction was carried out at room temperature for 2 h. After the reaction was monitored to be complete, n-hexane (100mL) was added, and the mixture was slurried, filtered, and the solid was dried to give Compound B-3(5.13g, crude).
Step three: synthesis of 3-chloro-4- ((5-chloropyrazin-2-yl) thio) pyridin-2-amine (B)
Compound A-3(5.50g,22.1mmol,1.0eq.), compound B-3(4.47g,26.5mmol,1.2eq.), and compound Pd2dba3(303.5mg,1.5 mol%) and Xantphos (383.6mg,3 mol%) were placed in a 100mL single neck flask, the nitrogen was replaced by applying a vacuum to the system, 1, 4-dioxane (45mL) and DIPEA (7.7mL,44.2mmol,2.0eq.) were added and the reaction was allowed to proceed overnight in a 100 ℃ oil bath and monitored for complete conversion of the starting material. Filtering with celite, concentrating the filtrate, adding 50mL ethyl acetate and 10mL water, extracting and separating, washing the organic phase with saturated brine for 3 times, drying with anhydrous sodium sulfate, concentrating, and purifying by column chromatography to obtain intermediate compound B (4.4g, yield 73%).1H NMR(300MHz,CDCl3):δ8.52(d,J=1.5Hz,1H),8.36(d,J=1.5Hz,1H),7.90(d,J=5.2Hz,1H),6.58(d,J=5.2Hz,1H),5.04(brs,2H).
the method comprises the following steps: synthesis of 3- (benzyl (tert-butoxycarbonyl) amino) propionic acid (1-2):
ethyl acrylate (5.34mL,50.0mmol,1.0eq.) was slowly added dropwise to a solution of 1-1(6.05g,50.0mmol) in ethanol (100 mL). The reaction was carried out at room temperature for 12 hours, after completion of the reaction was monitored, the reaction mixture was concentrated, and DCM (100mL), triethylamine (13.8mL,100.0mmol,2.0eq.) and Boc were added to the mixture in this order2O (12.01g,55.0mmol,1.1 eq.). Reacting for half an hour at room temperature, monitoring the reaction completion, concentrating, and adding THF/H into the mixture in sequence2O/EtOH (25/25/25mL) mixed solution and lithium hydroxide (3.62g, 150.0mmol,3.0 eq.). Reacting at room temperature for 6h, monitoring the reaction completion, concentrating, adding 30mL of water and 30mL of ethyl acetateThe mixture was extracted, separated, and the aqueous phase was adjusted to pH 3 with hydrochloric acid (3M), and then extracted twice with ethyl acetate. The organic phase was washed with an appropriate amount of saturated brine for 3 times, dried over anhydrous sodium sulfate, and concentrated to give compound 1-2(13.60g, crude).
Step two: synthesis of tert-butyl 5-oxo-1, 3,4, 5-tetrahydro-2H-benzo [ c ] aza-2-carboxylate (1-3):
thionyl chloride (10.8mL,150.0mmol,3.0eq.) was slowly added dropwise to a 1-2 solution of anhydrous DCM (100mL) at 0 ℃ for 2h at room temperature, after completion of the reaction was monitored, concentrated and pumped with an oil pump for half an hour. The mixture was dissolved in anhydrous DCM (100mL), and aluminum trichloride (19.85g,150.0mml,3.0eq.) was added at 0 ℃ to react overnight at room temperature. The reaction was poured into ice aqueous sodium hydroxide (6M,100mL), filtered, the filter residue was washed twice with DCM (20mL), the liquid separated and the organic phase washed 3 times with saturated brine. To the organic phase was added triethylamine (7.6mL,55.0mmol,1.1eq.) and Boc sequentially2O (10.92g,50.0mmol,1.0 eq.). Reacting for half an hour at room temperature, washing the reaction solution with an appropriate amount of saturated sodium chloride solution for 3 times, drying with anhydrous sodium sulfate, concentrating, and purifying by column chromatography to obtain compound 1-3(3.10g, yield 23% in six steps).1H NMR(300MHz,CDCl3):δ7.89(dd,J=7.8,1.5Hz,1H),7.49-7.44(m,1H),7.42-7.29(m,2H),4.70(d,J=16.0Hz,2H),3.79-3.66(m,2H),3.08-2.98(m,2H),1.39(s,9H).
Step three: synthesis of tert-butyl (S) -5- (((R) -tert-butylsulfinyl) amino) -1,3,4, 5-tetrahydro-2H-benzo [ c ] aza-2-carboxylate (1-4)
(R) -2-methylpropane-2-sulfinamide (2.86g,23.6mmol,2.0eq.) and tetraethyltitanate (5.38g,23.6mmol,2.0eq.) were added to a solution of 1-3(3.10g,11.8mmol) in THF (20mL) and reacted at 75 ℃ overnight. After monitoring the reaction completion, LiBH (iBu) was slowly added dropwise at-50 ℃3The reaction solution (23.6mL,1M,2.0eq.) was allowed to react at room temperature for 2 h. After completion of the reaction was monitored, water (1mL) was slowly added dropwise to the reaction system. Filtration was carried out, and the filter cake was washed with ethyl acetate (10mL), followed by liquid separation, and the organic phase was washed with saturated brine 3 times, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain compounds 1 to 4(2.85g, yield 66%).1H NMR(300MHz,CDCl3):δ7.42-7.36(m,1H),7.30-7.17(m,3H),4.76(dd,J=6.0,1.4Hz,2H),4.52(d,J=15.1Hz,1H),4.38(d,J=15.1Hz,1H),3.79-3.63(m,2H),2.32-2.19(m,1H),2.06-1.93(m,1H),1.39(s,9H),1.23(s,9H).
Step four: synthesis of (R) -N- ((S) -2- (5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -2,3,4, 5-tetrahydro-1H-benzo [ c ] azepin-5-yl) -2-methylpropylamine-2-sulfinamide (1-5)
Trifluoroacetic acid (0.5mL) was slowly added dropwise to a solution of 1-4(118.6mg,0.33mmol,1.3eq.) in DCM (2mL) and reacted at room temperature for 2 h. After monitoring the reaction completion, concentrate. DMSO (1mL), DIPEA (1mL) and Compound B (68.3mg,0.25mmol) were added sequentially. Reacting for 2h at 100 ℃. After monitoring the reaction for completion, 25mL of ethyl acetate and 10mL of water were added. The organic phase was washed with saturated brine 5 times, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to give compounds 1 to 6(42.0mg, yield 33%).1H NMR(300MHz,CDCl3):δ8.23(d,J=1.3Hz,1H),8.21(d,J=1.3Hz,1H),7.65(d,J=5.5Hz,1H),7.46-7.34(m,2H),7.33-7.23(m,2H),5.98(d,J=5.5Hz,1H),5.06(s,2H),4.87(d,J=15.5Hz,1H),4.76(d,J=15.5Hz,1H),4.38-4.23(m,1H),4.08-3.93(m,1H),3.73(d,J=4.1Hz,1H),2.46-2.35(m,1H),2.17-2.02(m,1H),1.23(s,9H).
Step five: synthesis of (S) -2- (5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -2,3,4, 5-tetrahydro-1H-benzo [ c ] azepin-5-amine (1)
A2M ethyl acetate hydrogen chloride solution (1.0mL) was slowly added dropwise to a solution of 1-5(42.0mg,0.08mmol) in ethyl acetate (2mL) and allowed to react overnight at room temperature. After the reaction was monitored to be complete, 20mL of purified water and 10mL of ethyl acetate were added, extracted, the aqueous phase was adjusted to pH 6 with saturated sodium carbonate, and the aqueous phase was washed with ethyl acetate until all impurities were washed off. The aqueous phase was further adjusted to pH 8, extracted twice with 15mL of ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and lyophilized to give compound 1(21.1mg, yield 63%).1H NMR(300MHz,CDCl3):δ8.24(d,J=1.4Hz,1H),8.20(d,J=1.4Hz,1H),7.67(d,J=5.5Hz,1H),7.44-7.33(m,2H),7.32-7.28(m,1H),7.26-7.18(m,1H),6.00(d,J=5.5Hz,1H),5.03(d,J=15.1Hz,1H),4.89(s,2H),4.73(d,J=15.1Hz,1H),4.43(dd,J=5.6,2.3Hz,1H),4.25-4.02(m,2H),2.23-2.09(m,1H),1.92-1.81(m,1H)。
detailed procedures referring to the synthesis of compound 1, compound 2 is finally obtained by five-step reactions using 3-methoxybenzylamine as the starting material instead of 1-1.1H NMR(300MHz,CDCl3):δ8.24(d,J=1.4Hz,1H),8.20(d,J=1.4Hz,1H),7.68(d,J=5.5Hz,1H),7.29(d,J=8.4Hz,1H),6.92(d,J=2.7Hz,1H),6.77(dd,J=8.4,2.7Hz,1H),6.01(d,J=5.5Hz,1H),5.00(d,J=15.1Hz,1H),4.87(s,2H),4.69(d,J=15.1Hz,1H),4.38(dd,J=7.8,2.7Hz,1H),4.20-4.09(m,2H),3.81(s,3H),2.19-2.05(m,1H),1.96-1.77(m,1H)。
detailed procedures referring to the synthesis of compound 1, compound 3 is finally obtained by five-step reactions using 3-methylbenzylamine as a starting material instead of 1-1.1H NMR(300MHz,CDCl3):δ8.24(d,J=1.4Hz,1H),8.21(d,J=1.5Hz,1H),7.68(d,J=5.4Hz,1H),7.27(d,J=8.0Hz,1H),7.16(d,J=1.2Hz,1H),7.08(dd,J=8.0,1.2Hz,1H),6.02(d,J=5.4Hz,1H),4.99(d,J=15.2Hz,1H),4.86(s,2H),4.68(d,J=15.2Hz,1H),4.39(dd,J=7.8,2.6Hz,1H),4.19-4.11(m,2H),2.33(s,3H),2.21-2.05(m,1H),1.92-1.79(m,1H)。
detailed procedures referring to the synthesis of compound 1, compound 4 is finally obtained by five-step reactions using 3-fluorobenzylamine as the starting material instead of 1-1.1H NMR(300MHz,CDCl3):δ8.25(d,J=1.4Hz,1H),8.18(d,J=1.4Hz,1H),7.68(d,J=5.5Hz,1H),7.35(dd,J=8.5,5.6Hz,1H),7.10(dd,J=8.9,2.7Hz,1H),6.94(ddd,J=8.5,8.2,2.7Hz,1H),6.01(d,J=5.5Hz,1H),5.03(d,J=15.1Hz,1H),4.87(s,2H),4.71(d,J=15.1Hz,1H),4.42(dd,J=7.8,2.6Hz,1H),4.23-4.08(m,2H),2.24-2.09(m,1H),1.92-1.80(m,1H)。
detailed operation steps refer to the synthesis of the compound 1, 3-chlorobenzylamine is used as a starting material to replace 1-1, and the compound 5 is finally obtained through five-step reaction.1H NMR(300MHz,CDCl3):δ8.26(d,J=1.4Hz,1H),8.18(d,J=1.4Hz,1H),7.68(d,J=5.5Hz,1H),7.38-7.31(m,2H),7.24(dd,J=8.2,2.2Hz,1H),6.02(d,J=5.5Hz,1H),5.02(d,J=15.1Hz,1H),4.96(s,2H),4.69(d,J=15.1Hz,1H),4.41(d,J=7.7Hz,1H),4.22-4.01(m,2H),2.22-2.08(m,1H),1.92-1.78(m,1H)。
the detailed operation steps refer to the synthesis of the compound 1, 3-bromobenzylamine is used as a starting material to replace 1-1, and the compound 6 is finally obtained through five-step reaction.1H NMR(300MHz,CDCl3):δ8.26(d,J=1.4Hz,1H),8.18(d,J=1.4Hz,1H),7.68(d,J=5.5Hz,1H),7.51(d,J=2.1Hz,1H),7.40(dd,J=8.1,2.1Hz,1H),7.28(d,J=8.1Hz,1H),6.02(d,J=5.5Hz,1H),5.01(d,J=15.1Hz,1H),4.93(s,2H),4.69(d,J=15.1Hz,1H),4.39(dd,J=8.1,2.7Hz,1H),4.23-4.01(m,2H),2.21-2.08(m,1H),1.93-1.79(m,1H)。
detailed procedures referring to the synthesis of compound 1, compound 7 was finally obtained by five-step reactions using 3-cyanobenzylamine as the starting material in place of 1-1.1H NMR(300MHz,DMSO-d6):δ8.50(d,J=1.4Hz,1H),8.28(d,J=1.4Hz,1H),7.99(d,J=1.7Hz,1H),7.75(dd,J=8.0,1.7Hz,1H),7.64(d,J=8.0Hz,1H),7.62(d,J=5.4Hz,1H),6.35(s,2H),5.75(d,J=5.4Hz,1H),5.08(d,J=15.3Hz,1H),4.81(d,J=15.3Hz,1H),4.45(dd,J=8.7,2.0Hz,1H),4.30-4.14(m,1H),4.04-3.85(m,1H),2.07-1.93(m,1H),1.77-1.61(m,1H)。
detailed operation steps referring to the synthesis of the compound 1, 3-aminobenzylamine is used as a starting material to replace 1-1, and the compound 8 is finally obtained through five-step reaction.1H NMR(300MHz,CDCl3):δ8.23(d,J=1.4Hz,1H),8.19(d,J=1.4Hz,1H),7.68(d,J=5.5Hz,1H),7.14(d,J=8.1Hz,1H),6.69(d,J=2.5Hz,1H),6.56(dd,J=8.1,2.5Hz,1H),6.02(d,J=5.4Hz,1H),4.93(d,J=15.1Hz,1H),4.87(s,1H)4.62(d,J=15.1Hz,1H),4.32(dd,J=7.5,2.5Hz,1H),4.20-4.06(m,2H),3.67(s,2H),2.18-2.04(m,1H),1.91-1.77(m,1H)。
detailed procedures refer to the synthesis of compound 1, replacing 1-1 with 3- (pyrrolidin-1-yl) benzylamine as starting material, and obtaining compound 9 through five-step reactions.1H NMR(300MHz,CDCl3):δ8.25(d,J=1.4Hz,1H),8.22(d,J=1.4Hz,1H),7.68(d,J=5.5Hz,1H),7.19(d,J=8.2Hz,1H),6.56(d,J=2.5Hz,1H),6.41(dd,J=8.2,2.5Hz,1H),6.02(d,J=5.5Hz,1H),5.00(d,J=15.1Hz,1H),4.86(s,2H),4.66(d,J=15.1Hz,1H),4.34(dd,J=7.6,2.4Hz,1H),4.27-4.10(m,2H),3.36-3.22(m,4H),2.18-2.05(m,1H),2.02-1.92(m,4H),1.93-1.81(m,1H)。
detailed procedures refer to the synthesis of compound 1, and 3-dimethylaminobenzylamine is used as a starting material to replace 1-1, and compound 10 is finally obtained through five-step reactions.1H NMR(300MHz,CDCl3):δ8.23(s,2H),7.68(d,J=5.5Hz,1H),7.22(d,J=8.4Hz,1H),6.73(d,J=2.7Hz,1H),6.58(dd,J=8.4,2.7Hz,1H),6.02(d,J=5.5Hz,1H),5.00(d,J=15.1Hz,1H),4.86(s,2H),4.68(d,J=15.1Hz,1H),4.34(dd,J=7.4,2.5Hz,1H),4.22-4.09(m,2H),2.95(s,6H),2.19-2.05(m,1H),1.90-1.81(m,1H)。
detailed description of the preferred embodimentsreferring to the synthesis of compound 1, compound 11 was finally obtained by a five-step reaction starting with 3- (4-fluorophenyl) benzylamine instead of 1-1.1H NMR(400MHz,CDCl3):δ8.25(d,J=1.4Hz,1H),8.23(d,J=1.4Hz,1H),7.65(d,J=5.4Hz,1H),7.58-7.50(m,3H),7.49-7.39(m,2H),7.18-7.07(m,2H),6.01(d,J=5.4Hz,1H),5.10(d,J=15.1Hz,1H),4.87(s,2H),4.79(d,J=15.1Hz,1H),4.76(brs,1H),4.47(dd,J=7.8,2.6Hz,1H),4.27-4.10(m,2H),2.25-2.14(m,1H),1.96-1.85(m,1H)。
the method comprises the following steps: synthesis of N- (tert-butoxycarbonyl) -N-phenethylglycine (12-2):
ethyl bromopropionate (1.18mL,10.0mmol,1.0eq.) and triethylamine (2.78mL,20.0mmol,2.0eq.) were added dropwise in that order to a solution of 12-1(1.21g,10.0mmol) in THF (20 mL). The reaction was carried out at room temperature for 4h, after completion of the reaction was monitored, the reaction mixture was concentrated, and DCM (20mL), triethylamine (2.78mL,20.0mmol,2.0eq.) and Boc were added to the mixture in this order2O (2.40g,11.0mmol,1.1 eq.). Reacting for half an hour at room temperature, monitoring the reaction completion, concentrating, and adding THF/H into the mixture in sequence2O/EtOH (5/5/5mL) mixed solution and lithium hydroxide (0.72g, 30.0mmol, 3.0 eq.). After the reaction was completed for 6 hours at room temperature, the reaction mixture was concentrated, 20mL of water and 20mL of ethyl acetate were added, the mixture was extracted, the aqueous phase was separated, the pH was adjusted to 3 with hydrochloric acid (3M), and then an appropriate amount of ethyl acetate was added and the mixture was extracted twice.The organic phase was washed with an appropriate amount of saturated brine for 3 times, dried over anhydrous sodium sulfate, and concentrated to give compound 12-2(2.01g, crude).
Step two: synthesis of 1-oxo-1, 2,4, 5-tetrahydro-3H-benzo [ d ] aza-3-carboxylic acid tert-butyl ester (12-3):
referring to step two of the synthetic route of example 1, 12-2 was substituted for 1-2 to give compound 12-3(0.31g, 16% yield over six steps).1H NMR(300MHz,CDCl3):δ7.77(d,J=7.6,1.2Hz,1H),7.43(ddd,J=7.5,7.4,1.2Hz,1H),7.36(ddd,J=7.6,7.4,1.0Hz,1H),7.23(dd,J=7.5,1.0Hz,1H),4.17(d,J=17.7Hz,2H),3.79-3.68(m,2H),3.08-2.97(m,2H),1.22(s,9H).
Step three: synthesis of tert-butyl (R) -1- (((R) -tert-butylsulfinyl) amino) -1,2,4, 5-tetrahydro-3H-benzo [ d ] aza-3-carboxylate (12-4):
referring to step three of the synthetic route of example 1, 12-3 was substituted for 1-3 to give compound 12-4(0.14g, yield 32%). LC-MS (ESI):367.2(M + H)+.
Step four: synthesis of (R) -N- ((R) -3- (5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -2,3,4, 5-tetrahydro-1H-benzo [ c ] azepin-5-yl) -2-methylpropylamine-2-sulfinamide (12-5):
referring to step four of the synthetic route of example 1, 12-4 was substituted for 1-4 to give compound 12-5(98.2mg, yield 66%).1H NMR(300MHz,CDCl3):δ8.36(d,J=1.4Hz,1H),8.30(d,J=1.4Hz,1H),7.70(d,J=5.4Hz,1H),7.46-7.39(m,1H),7.35-7.29(m,1H),7.25-7.19(m,1H),7.14-7.09(m,1H),5.98(d,J=5.4Hz,1H),5.14(dd,J=14.6,5.6Hz,1H),4.96(s,2H),4.83-4.78(m,1H),4.36(dd,J=14.6,5.3Hz,1H),4.26(d,J=2.2Hz,1H),3.61-3.20(m,3H),2.97-2.85(m,1H),0.98(s,9H).
Step five: synthesis of (R) -3- (5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -2,3,4, 5-tetrahydro-1H-benzo [ d ] azepin-1-amine (12):
referring to step five of the synthetic route of example 1, substituting 12-5 for 1-5, Compound 12(45.2mg, 58% yield) was obtained.1H NMR(300MHz,CDCl3):δ8.28(d,J=1.3Hz,1H),8.26(d,J=1.3Hz,1H),7.69(d,J=5.5Hz,1H),7.36-7.29(m,1H),7.26-7.19(m,2H),7.19-7.14(m,1H),6.00(d,J=5.5Hz,1H),4.92(s,2H),4.36(dd,J=7.2,2.9Hz,1H),4.20(dd,J=14.3,7.2Hz,1H),4.05(ddd,J=13.3,6.4,2.8Hz,1H),3.92(dd,J=14.3,2.9Hz,1H),3.69(ddd,J=13.3,9.7,2.5Hz,1H),3.37(ddd,J=15.2,9.7,2.8Hz,1H),2.99(ddd,J=15.2,6.4,2.5Hz,1H)。
detailed procedures referring to the synthesis of compound 12, compound 13 was finally obtained by five-step reaction using 3-fluorophenethylamine as starting material instead of 12-1.1H NMR(300MHz,CDCl3)δ8.28(d,J=1.2Hz,1H),8.26(d,J=1.2Hz,1H),7.70(d,J=5.4Hz,1H),7.30(dd,J=8.2,7.0Hz,1H),6.98-6.82(m,2H),6.00(d,J=5.4Hz,1H),4.89(s,2H),4.35(dd,J=7.1,2.7Hz,1H),4.20(dd,J=14.3,7.1Hz,1H),4.08(ddd,J=14.5,6.5,2.6Hz,1H),3.88(dd,J=14.3,2.7Hz,1H),3.68(ddd,J=14.5,9.8,2.1Hz,1H),3.36(ddd,J=15.2,9.8,2.6Hz,1H),3.94(ddd,J=15.2,6.5,2.1Hz,1H)。
detailed procedures referring to the synthesis of compound 12, compound 14 is finally obtained by five-step reactions using 3-methoxyphenethylamine as starting material instead of 12-1.1H NMR(300MHz,CDCl3):δ8.28(d,J=1.4Hz,1H),8.26(d,J=1.4Hz,1H),7.70(d,J=5.5Hz,1H),7.24(d,J=8.1Hz,1H),6.78-6.69(m,2H),6.01(d,J=5.5Hz,1H),4.87(s,2H),4.32(dd,J=6.9,2.6Hz,1H),4.22(dd,J=14.1,6.9Hz,1H),4.10(ddd,J=14.5,7.1,2.8Hz,1H),3.85(dd,J=14.1,2.6Hz,1H),3.80(s,3H),3.65(ddd,J=14.5,10.2,2.0Hz,1H),3.35(ddd,J=15.4,10.2,2.8Hz,1H),2.91(ddd,J=15.4,7.1,2.0Hz,1H)。
the method comprises the following steps: synthesis of 3- ((2-amino-3-chloropyridin-4-yl) thio) -6-chloropyrazin-2-amino (15-2):
placing compounds 15-1(208.4mg,1.0mmol), a (192.7mg,1.2mmol,1.2eq.), cuprous iodide (38.9mg,0.2mmol,0.2eq.), 1, 10-phenanthroline (54.2mg,0.3mmol,0.3eq.) and potassium phosphate (424.5mg,2.0mmol,2.0eq.) in a 15mL sealed tube, vacuumizing the system to replace nitrogen, adding 1, 4-dioxane (4mL) to react in an oil bath at 85 ℃ overnight, and monitoring until the conversion of the raw materials is complete. Filtering with diatomaceous earth, concentrating the filtrate, adding 20mL ethyl acetate and 10mL water, extracting, separating, washing the organic phase with saturated saline solution for 3 times, drying with anhydrous sodium sulfate, concentrating, and purifying by column chromatography to obtain compound 15-2(216.2mg, yield 75%).1H NMR(300MHz,CDCl3):δ8.01(s,1H),7.77(d,J=5.4Hz,1H),6.09(d,J=5.4Hz,1H),5.23(s,2H),4.96(s,2H).
Step two: synthesis of (R) -N- ((S) -2- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -2,3,4, 5-tetrahydro-1H-benzo [ c ] azepin-5-yl) -2-methylpropane-2-sulfinamide (15-3):
trifluoroacetic acid (0.5mL) was slowly added dropwise to a solution of 1-4(186.0mg,0.52mmol,1.3eq.) in DCM (2mL) and reacted at room temperature for 2 h. After monitoring the reaction completion, concentrate. NMP (1mL), potassium carbonate (220.8mg,1.6mmol,4.0eq.) and compound 15-3(115.3mg,0.4mmol) were added sequentially. The reaction is carried out for 10h at 100 ℃. After monitoring the reaction for completion, 25mL of ethyl acetate and 10mL of water were added. The organic phase was washed with saturated brine 5 times, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to give compound 15-3(95.2mg, yield 46%).1H NMR(300MHz,CDCl3):δ8.24(d,J=1.3Hz,1H),8.20(d,J=1.3Hz,1H),7.67(d,J=5.5Hz,1H),7.45-7.34(m,2H),7.33-7.27(m,2H),5.99(d,J=5.5Hz,1H),5.02-4.72(m,6H),4.40-4.23(m,1H),4.05-3.93(t,J=11.5Hz,1H),3.46(d,J=4.0Hz,1H),2.37-2.31(m,1H),2.18-2.03(m,1H),1.22(s,9H).
Step three: synthesis of (S) -2- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -2,3,4, 5-tetrahydro-1H-benzo [ c ] azepin-5-amine (15):
referring to step five of the synthetic route of example 1, substituting 15-3(80.9mg,0.16mmol) for 1-5 gave compound 15(44.2mg, yield 67%).1H NMR(300MHz,CDCl3):δ7.67(d,J=5.4Hz,1H),7.64(s,1H),7.41(d,J=7.8Hz,1H),7.36-7.28(m,2H),7.25-7.18(m,1H),6.01(d,J=5.4Hz,1H),4.92(d,J=15.2Hz,1H),4.87(s,2H),4.79(s,2H),4.68(d,J=15.2Hz,1H),4.40(dd,J=8.2,2.5Hz,1H),4.17-3.88(m,2H),2.23-2.10(m,1H),1.88-1.76(m,1H)。
the method comprises the following steps: synthesis of 6-chloro-3- (2, 3-dichlorophenyl) pyrazin-2-amine (16-2):
compound 16-1(0.21g,1.0mmol), 2, 3-dichlorophenylboronic acid (0.21g,1.1mmol,1.1eq.), pd (dppf) Cl2(14.6mg,2 mol%) and potassium phosphate (0.42g,2.0mmol,2.0eq.) were placed in a 15mL sealed tube, the system was evacuated to replace nitrogen, 1, 4-dioxane (2mL) and water (0.2mL) were added and reacted overnight in a 120 ℃ oil bath with TLC monitoring until complete conversion of the starting material. Filtering with celite, concentrating the filtrate, extracting with 20mL ethyl acetate, washing with an appropriate amount of saturated brine for 3 times, drying with anhydrous sodium sulfate, concentrating, and separating by column chromatography to obtain compound 16-2(0.25g, yield 91%).1H NMR(300MHz,CDCl3):δ8.03(s,1H),7.60(dd,J=7.6,2.0Hz,1H),7.36(dd,J=7.7,7.6Hz,1H),7.32(dd,J=7.6,2.0Hz,1H),4.65(s,2H).
Step two: synthesis of 6-chloro-3- (2, 3-dichlorophenyl) pyrazine-2-amino-tert-butyl ester (16-3):
compound 17-2(0.25g,0.91mmol,1.0eq.) and DMAP (5.6mg,0.05mmol,0.05eq.) were placed in a 10mL single vial, DCM (5mL) and di-tert-butyl dicarbonate (0.44g,1.91mmol,2.1eq.) were added sequentially, after addition, the reaction was carried out at room temperature for 2h, and TLC was monitored as it wasThe conversion of the material is complete. Washing with saturated salt for 3 times, drying the organic phase with anhydrous sodium sulfate, concentrating, and separating by column chromatography to obtain compound 16-3(0.35g, yield 80%).1H NMR(300MHz,CDCl3):δ8.68(s,1H),7.57(d,J=7.5Hz,1H),7.46-7.24(m,2H),1.37(s,18H).
Step three: synthesis of tert-butyl (6- ((S) -5- (((R) -tert-butylsulfinyl) amino) -1,3,4, 5-tetrahydro-2H-benzo [ c ] azepin-2-yl) -3- (2, 3-dichlorophenyl) pyrazin-2-yl) carbamate (16-4)
Referring to step four of the synthetic route of example 1, substituting 16-3(0.19g,0.4mmol) for B gave compound 16-4(0.15g, yield 55%).1H NMR(300MHz,CDCl3):δ8.18(s,1H),7.46(dd,J=7.9,1.7Hz,1H),7.43-7.35(m,2H),7.34-7.23(m,3H),7.20(t,J=7.8Hz,1H),4.91(d,J=15.4Hz,1H)4.85-4.78(m,1H),4.74(d,J=15.4Hz,1H),4.44-4.23(m,1H),4.07-3.93(m,1H),3.47(d,J=3.8Hz,1H),2.47-2.30(m,1H),2.19-2.10(m,1H),1.34(s,18H),1.24(s,9H).
Step four: synthesis of (S) -2- (6-amino-5- (2, 3-dichlorophenyl) pyrazin-2-yl) -2,3,4, 5-tetrahydro-1H-benzo [ c ] aza-5-amine (16):
referring to step five of the synthetic route of example 1, substituting 16-4 for 1-5, Compound 16 was obtained (46.5mg, yield 52%).1H NMR(300MHz,CDCl3):δ7.58(s,1H),7.47(dd,J=7.0,2.6Hz,1H),7.41(d,J=7.4Hz,1H),7.36(dd,J=7.1,1.7Hz,1H),7.32-7.19(m,4H),4.89(d,J=15.6Hz,1H),4.67(d,J=15.6Hz,1H),4.40(dd,J=8.3,2.8Hz,1H),4.20(s,2H),4.10-3.90(m,2H),2.26-2.21(m,1H),1.91-1.83(m,1H)。
the method comprises the following steps: synthesis of 2-chloro-N- (2, 2-dimethoxyethyl) -5-iodopyrimidin-4-amine (17-2): triethylamine (2.77mL,20.0mmol,2.0eq.) was added dropwise to a solution of 17-1(2.74g,10.0mmol) and 2, 2-dimethoxyethane-1-amine (2.10g,20.0mmol,2.0eq.) in ethanol (40mL) at 0 ℃. The reaction was allowed to proceed overnight at room temperature and monitored by TLC until complete conversion of starting material. After concentration, 30mL of ethyl acetate and 10mL of water were added, the mixture was separated, and the organic phase was washed 3 times with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain Compound 17-2(3.64g, crude product).
Step two: synthesis of 8-iodoimidazo [1,2-c ] pyrimidin-5-ol (17-3):
17-2(3.64g, crude) was added to concentrated sulfuric acid (40 mL). The reaction was allowed to proceed overnight at room temperature and monitored by TLC until complete conversion of starting material. The reaction solution was poured into ice water, pH was adjusted to 6 with sodium hydroxide, and filtered to give compound 17-3(2.55g, crude product).
Step three: synthesis of 5-chloro-8-iodoimidazo [1,2-c ] pyrimidine (17-4):
DIPEA (1mL) was added dropwise to a solution of 17-3(0.52g,2.0mmol) in phosphorus oxychloride (8 mL). The reaction was carried out at 120 ℃ for 5h and TLC monitored until complete conversion of starting material. After concentration, 20mL of dichloromethane was added, and the mixture was poured into 10mL of ice water, followed by liquid separation, the organic phase was washed with saturated brine 3 times, dried over anhydrous sodium sulfate, concentrated, and column chromatography to give compound 17-4(0.34g, 63%).1H NMR(300MHz,CDCl3):δ8.21(s,1H),7.89(d,J=1.5Hz,1H),7.82(d,J=1.5Hz,1H).
Step four: synthesis of (R) -N- ((S) -2- (8-iodoimidazo [1,2-c ] pyrimidin-5-yl) -2,3,4, 5-tetrahydro-1H-benzo [ c ] azepin-5-yl) -2-methylpropane-2-sulfinamide (17-5):
trifluoroacetic acid (0.5mL) was slowly added dropwise to a solution of 1-4(0.44g,1.2mmol,1.2eq.) in DCM (2mL) and reacted at room temperature for 2 h. After monitoring the reaction to completion, concentrate. Acetonitrile (2mL), DIPEA (0.35mL,2.0mmol,2.0eq.) and compound 17-5(279.5mg,1.0mmol) were added sequentially. The reaction was carried out at room temperature for 4 hours. After monitoring the reaction for completion, 25mL of ethyl acetate and 10mL of water were added. The organic phase was washed with saturated brine 3 times, dried over anhydrous sodium sulfate, concentrated, and isolated by column chromatography to give compound 17-5(0.35g, yield 69%).1H NMR(300MHz,CDCl3):δ8.01(s,1H),7.66(d,J=1.5Hz,1H),7.58(d,J=1.5Hz,1H),7.47(dd,J=7.4,1.4Hz,1H),7.38(ddd,J=7.5,7.4,1.4Hz,1H),7.31(ddd,J=7.5,7.4,1.4Hz,1H),7.14(dd,J=7.4,1.4Hz,1H),4.90-4.83(m,1H),4.78(d,J=15.8Hz,1H),4.62(d,J=15.8Hz,1H),4.08-3.84(m,2H),3.72(d,J=5.9Hz,1H),2.64-2.51(m,1H),2.50-2.35(m,1H),1.17(s,9H).
Step five: synthesis of (R) -N- ((S) -2- (8- ((2-amino-3-chloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -2,3,4, 5-tetrahydro-1H-benzo [ c ] azepin-5-yl) -2-methylpropane-2-sulfinamide (17-6)
Compound 17-5(127.3mg,0.25mmol), A-5(54.5mg,0.30mmol,1.2eq.), Pd2dba3(23.0mg,10 mol%) and Xantphos (29.0mg,20 mol%) were placed in a 15mL sealed tube, the system was evacuated to replace nitrogen, 1, 4-dioxane (2mL) and DIPEA (87. mu.L, 0.5mmol,2.0eq.) were added and reacted in a 100 ℃ oil bath overnight, monitored until complete conversion of the starting material. Diluting with 10mL ethyl acetate, filtering with diatomaceous earth, concentrating the filtrate, adding 15mL ethyl acetate and 5mL water, extracting and layering, washing the organic phase with saturated saline solution for 3 times, drying with anhydrous sodium sulfate, concentrating, and purifying by column chromatography to obtain compound 17-6(42.1mg, yield 31%).1H NMR(300MHz,CDCl3):δ7.98(s,1H),7.63(d,J=1.3Hz,1H),7.60(d,J=5.4Hz,1H),7.57(d,J=1.3Hz,1H),7.50(dd,J=7.7,1.4Hz,1H),7.38(ddd,J=7.7,7.6,1.4Hz,1H),7.32(ddd,J=7.6,7.5,1.4Hz,1H),7.17(dd,J=7.5,1.4Hz,1H),5.84(d,J=5.4Hz,1H),4.94(d,J=15.4Hz,1H),4.91(s,2H),4.79(d,J=15.4Hz,1H),4.16-4.03(m,2H),3.66(d,J=5.4Hz,1H),2.71-2.58(m,1H),2.53-2.38(m,1H),1.19(s,9H).
Step six: synthesis of (S) -2- (8- ((2-amino-3-chloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -2,3,4, 5-tetrahydro-1H-benzo [ c ] azepin-5-amine (17):
referring to step five of the synthetic route of example 1, substituting 17-6 for 1-5, Compound 17(25.0mg, yield 72%) was obtained.1H NMR(300MHz,CDCl3):δ7.97(s,1H),7.64-7.54(m,3H),7.48(dd,J=7.5,1.1Hz,1H),7.36(ddd,J=7.8,7.5,1.3Hz,1H),7.25(ddd,J=7.8,7.4,1.1Hz,1H),7.16(ddd,J=7.4,1.3Hz,1H),5.86(d,J=5.4Hz,1H),5.05(d,J=15.6Hz,1H),4.89(s,2H),4.73(d,J=15.6Hz,1H),4.48(dd,J=7.8,1.4Hz,1H),4.20-4.09(m,1H),4.01-3.89(m,1H),2.43-2.32(m,1H),2.28-2.15(m,1H)。
the method comprises the following steps: synthesis of 6-amino-3-methylpyrimidine-2, 4(1H,3H) -dione (18-2)
Concentrated sulfuric acid (0.05mL) was added slowly dropwise to a solution of 4-amino-2, 6-dihydroxypyrimidine (0.52g,4.1mmol) in HMDS (2.5 mL). After 6h reaction at 130 ℃ the mixture was concentrated to remove HMDS. DMF (2.5mL) and methyl iodide (0.85mL,14.4mmol,3.5eq.) were added in this order and reacted at room temperature overnight. After completion of the reaction was monitored, a saturated solution of sodium hydrogencarbonate was added dropwise until no bubble was generated, followed by suction filtration, water washing of the cake and drying to obtain Compound 18-2(0.36g, yield 63%).1H NMR(300MHz,DMSO-d6):δ10.43(s,1H),6.23(brs,2H),4.59(s,1H),3.00(s,3H).
Step two: synthesis of 6-amino-5-iodo-3-methylpyrimidine-2, 4(1H,3H) -dione (18-3)
Compound 18-2(0.19g,1.4mmol) was dissolved in DMF (2mL) and AcOH (4mL) and NIS (0.37g,1.68mmol,1.2eq.) was added. Reacting for 2h at room temperature, monitoring the reaction, filtering, washing the filter cake with water, and drying to obtain a compound 18-3(0.30g, crude product).
Step three: synthesis of (R) -2-methyl-N- ((S) -2,3,4, 5-tetrahydro-1H-benzo [ c ] azepin-5-yl) propane-2-sulfinamide (18-4)
Trifluoroacetic acid (0.5mL) was added to a solution of 1-5(0.36g,1.0mmol) in DCM (2mL) and reacted at room temperature for 2 h. The reaction was monitored for completion, concentrated, 5mL of water was added and the pH was adjusted to 9 with saturated aqueous sodium carbonate solution. Ethyl acetate (10mL) was extracted twice and concentrated to give 18-4 which was directly used for the next reaction.
Step four: synthesis of (R) -N- ((S) -2- (4-amino-5-iodo-1-methyl-6-oxo-1, 6-dihydropyrimidin-2-yl) -2,3,4, 5-tetrahydro-1H-benzo [ c ] azepin-5-yl) -2-methylpropane-2-sulfinamide (18-5)
DBU (0.8mL,5.25mmol,7.0eq.) was added dropwise to 18-3(0.2g, 0.7.)5mmol), 18-4 (from step three), and Bop (0.66g,1.5mmol,2.0eq.) in DMF (2mL) at room temperature for 8 h. After completion of the reaction was monitored, 20mL of ethyl acetate and 5mL of water were added, followed by liquid separation, and the organic phase was washed with an appropriate amount of saturated brine 5 times, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to give 18-5(0.11g, yield 28%). LC-MS (ESI) 516.2(M + H)+.
Step five: synthesis of (R) -N- ((S) -2- (4-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) -1-methyl-6-oxo-1, 6-dihydropyrimidin-2-yl) -2,3,4, 5-tetrahydro-1H-benzo [ c ] azepin-5-yl) -2-methylpropane-2-sulfinamide (18-6):
compounds 18-5(0.1g,0.19mmol), a (62.6mg,0.39mmol,2.0eq.), cuprous iodide (7.4mg,0.04mmol,0.2eq.), TMEDA (12 μ L,0.08mmol,0.4eq.), and potassium phosphate (120.9mg,0.57mmol,3.0eq.) were placed in a 15mL sealed tube, the system was evacuated to replace nitrogen, 1, 4-dioxane (1mL) was added and reacted in a 100 ℃ oil bath overnight, monitored until the conversion of the starting material was complete. Diluting with 10mL of ethyl acetate, filtering with celite, concentrating the filtrate, adding 10mL of ethyl acetate and 10mL of water, extracting and separating, washing the organic phase with saturated brine for 3 times, drying with anhydrous sodium sulfate, concentrating, and purifying by column chromatography to obtain compound 18-6(46.7mg, yield 40%).1H NMR(300MHz,CDCl3):δ7.70(d,J=5.4Hz,1H),7.45(dd,J=7.5,1.4Hz,1H),7.39-7.31(m,2H),7.20(dd,J=8.0,1.5Hz,1H),6.15(d,J=5.4Hz,1H),4.86(s,2H),4.84-4.74(m,1H),4.63(d,J=15.7Hz,1H),4.50(d,J=15.7Hz,1H),3.87-3.73(m,2H),3.57(d,J=5.9Hz,1H),3.42(s,3H),2.60-2.44(m,1H),2.41-2.27(m,1H),1.23(s,9H).
Step six: synthesis of (S) -6-amino-2- (5-amino-1, 3,4, 5-tetrahydro-2H-benzo [ c ] azepin-2-yl) -5- ((2-amino-3-chloropyridin-4-yl) thio) -3-methylpyrimidin-4 (3H) -one (18):
referring to step five of the synthetic route of example 1, substituting 18-6 for 1-5, Compound 18(17.6mg, yield 46%) was obtained.1H NMR(300MHz,CDCl3):δ7.67(d,J=5.4Hz,1H),7.43(dd,J=7.6,1.4Hz,1H),7.33(ddd,J=7.6,7.4,1.4Hz,1H),7.23(ddd,J=7.6,7.4,1.0Hz,1H),7.16(dd,J=7.6,1.0Hz,1H)6.14(d,J=5.4Hz,1H),5.23(s,2H),4.93(s,2H),4.72(d,J=15.5Hz,1H),4.46(d,J=15.5Hz,1H),4.41(dd,J=8.1,2.0Hz,1H),3.91-3.77(m,1H),3.70-3.57(m,1H),3.41(s,3H),2.31-3.16(m,1H),2.16-2.06(m,1H)。
the method comprises the following steps: synthesis of 5-bromothiazolo [5,4-b ] pyridin-2-amine (19-2)
19-1(1.0g,5.78mmol) was slowly added to a solution of KSCN (2.2g,22.8mmol,4.0eq.) in acetic acid (10 mL). After stirring at room temperature for fifteen minutes, a solution of bromine (0.38mL,7.51mmol,1.3eq.) in acetic acid (10mL) was slowly added dropwise. The reaction was carried out at room temperature for 3h and the completion of the reaction was monitored. The reaction was quenched dropwise with water, filtered, and the filtrate was concentrated, adjusted to pH 7 with saturated aqueous sodium carbonate solution, extracted twice with ethyl acetate (20mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give compound 19-2(1.33g, crude product).
Step two: synthesis of 5-bromo-2-chlorothiazolo [5,4-b ] pyridine (19-3)
The chloroidene (0.65g,4.9mmol,1.5eq.) was added to a solution of 19-2(0.75g,3.2mmol) in acetonitrile (10mL) at 0 ℃. After stirring at this temperature for fifteen minutes, a solution of tBuONO (0.57mL,4.9mmol,1.5eq.) in acetonitrile (2mL) was slowly added dropwise. The reaction was allowed to proceed overnight at room temperature and was monitored for completion. After concentration, ethyl acetate (20mL) and water (5mL) were added to separate the layers, and the organic layer was washed with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to give compound 19-3(0.63g, 44% yield in two steps).1H NMR(300MHz,CDCl3):δ8.06(d,J=8.5Hz,1H),7.63(d,J=8.5Hz,1H).
Step three: synthesis of 3-chloro-4- ((2-chlorothiazolo [5,4-b ] pyridin-5-yl) thio) pyridin-2-amine (19-4)
Mixing the compound 19-3(0.63g,2.5mmol), A-5(0.59g,3.25mmol,1.3eq.), Pd2dba3(0.23g,10 mol%) and Xantphos (0.29g,20 mol%) were placed at 15mIn an L sealed tube, the system was evacuated to replace nitrogen, 1, 4-dioxane (2mL) and DIPEA (0.85mL,5.0mmol,2.0eq.) were added, reacted overnight in an oil bath at 100 ℃ and monitored until complete conversion of the starting material. Diluting with 10mL of ethyl acetate, filtering with celite, concentrating the filtrate, adding 15mL of ethyl acetate and 5mL of water, extracting and layering, washing the organic phase with saturated brine for 3 times, drying with anhydrous sodium sulfate, concentrating, and purifying by column chromatography to obtain compound 19-4(0.15g, yield 18%). LC-MS (ESI) 329.0(M + H)+.
Step four: synthesis of (R) -N- ((S) -2- (5- ((2-amino-3-chloropyridin-4-yl) thio) thiazole [5,4-b ] pyridin-2-yl-2, 3,4, 5-tetrahydro-1H-benzo [ c ] azepin-5-yl) -2-methylpropane-2-sulfinamide (19-5):
trifluoroacetic acid (0.5mL) was slowly added dropwise to a solution of 1-4(0.22g,0.59mmol,1.3eq.) in DCM (2mL) and reacted at room temperature for 2 h. After monitoring the reaction completion, concentrate. DMF (2mL), cesium carbonate (0.24g,0.9mmol,2.0eq.) and compound 19-4(0.15g,0.45mmol) were added sequentially. The reaction was carried out at room temperature for 4 hours. After monitoring the reaction for completion, 25mL of ethyl acetate and 10mL of water were added. The organic phase was washed with saturated brine 3 times, dried over anhydrous sodium sulfate, concentrated, and isolated by column chromatography to give compound 19-5(56.2mg, yield 27%).1H NMR(300MHz,CDCl3):δ7.70(d,J=8.3Hz,1H),7.59(d,J=5.6Hz,1H),7.50(d,J=8.3Hz,1H),7.46-7.39(m,2H),7.38-7.30(m,2H),6.04(d,J=5.6Hz,1H),5.54(s,2H),4.93(d,J=15.4Hz,1H),4.87-4.79(s,1H),4.71(d,J=15.4Hz,1H),4.36-4.19(m,2H),3.77(d,J=4.0Hz,1H),2.54-2.40(m,2H),1.25(s,9H).
Step five: synthesis of (S) -2- (5- ((2-amino-3-chloropyridin-4-yl) thio) thiazolo [5,4-b ] pyridin-2-yl) -2,3,4, 5-tetrahydro-1H-benzo [ c ] azepin-5-amine (19):
referring to step five of the synthetic route of example 1, substituting 19-5 for 1-5, Compound 19(33.0mg, yield 72%) was obtained.1H NMR(300MHz,CDCl3):δ7.68(d,J=8.2Hz,1H),7.66(d,J=5.4Hz,1H),7.46(d,J=8.2Hz,1H),7.40(dd,J=7.3,1.3Hz,2H),7.30(ddd,J=7.6,7.3,1.3Hz,1H),7.25(ddd,J=7.6,7.3,1.6Hz,1H),6.04(d,J=5.4Hz,1H),5.10(d,J=15.1Hz,1H),4.90(s,2H),4.68(d,J=15.1Hz,1H),4.45(dd,J=7.9,2.6Hz,1H),4.29-4.16(m,1H),4.15-3.99(m,1H),2.31-2.15(m,1H),1.99-1.84(m,1H)。
The present invention is further described and explained below in conjunction with test examples, which are not intended to limit the scope of the present invention.
Example 21 in vitro SHP2 enzyme level Activity assay
The compounds of the above examples were tested for activity at the SHP2 enzyme level by the following specific procedures:
1 preparation of the Compound
The compound was dissolved in DMSO to prepare a 30mM stock solution, which was stored in a-20 ℃ freezer under dark conditions.
2SHP2 reaction process
(1) A1 XReactionbuffer was prepared.
(2) Preparation of compound concentration gradient: test compounds were tested at an initial concentration of 30 μ M, 3-fold dilution, 10 concentrations, single well assay. 100% DMSO solution diluted to 100-fold final concentration in 384source plates, compounds were diluted 3-fold with Precision, 10 concentrations. 250nL of 100-fold final concentration of compound was transferred to the target 384 plates using a dispenser Echo 550. 250nL DMSO was added to the positive control, and 250nL of 1mM SHP099 was added to the negative control.
(3) 5-fold final concentration of the activated peptide solution was prepared using 1 × ReactionBuffer, and 5 μ L of the solution was added to each reaction plate and centrifuged at 1000rpm for 1 min.
(4) A2.5-fold final concentration of enzyme solution was prepared using 1 XReactionBuffer, and 10. mu.L of each solution was added to the reaction plate, centrifuged at 1000rpm for 1min, and incubated at room temperature for 60 minutes.
(5) A substrate solution of 2.5 times final concentration was prepared using 1 XReactionBuffer, and 10. mu.L of each was added to the reaction plate, centrifuged at 1000rpm for 1min, and incubated at room temperature for 20 minutes.
(6) Ex355/Em460 fluorescence values were read with EnSight
3 data analysis
Formula for calculation
Wherein: RFU: fluorescence value of the sample; mean (nc): mean fluorescence values for control wells containing 10 μ M SHP 099;
mean (pc): mean fluorescence values of positive control wells.
Fitting dose-effect curve
The log value of the concentration is taken as an X axis, the percent inhibition rate is taken as a Y axis, and a dose-effect curve is fitted by adopting the log (inhibitor) vs. response-Variable slope of the GraphPad Prism 5 analysis software, so as to obtain the IC of each compound on the enzyme activity50The value is obtained.
The calculation formula is Y ═ Bottom + (Top-Bottom)/(1+10^ ((LogIC)50-X)*HillSlope))
4. Results of the experiment
The specific results are shown in the table:
compound numbering | SHP2IC50(nM) | Compound numbering | SHP2IC50(nM) |
1 | A | 10 | A |
2 | A | 11 | A |
3 | A | 12 | C |
4 | B | 13 | C |
5 | B | 14 | C |
6 | A | 15 | C |
7 | B | 16 | A |
8 | B | 17 | C |
9 | A | 18 | C |
SHP099 | 107 | 19 | C |
A<50nM,50nM≤B≤100nM,C>100nM。
And (4) experimental conclusion: the above data show that the examples of the invention have allosteric inhibitory effects on SHP2 phosphatase, and that many of the examples are significantly superior to the positive control SHP 099.
EXAMPLE 22 in vitro antiproliferative Activity of Compounds
1. Experimental procedure
(1) The PBS solution was autoclaved and stored in a refrigerator at 4 ℃.
(2) Weighing trypsin and pancreatin digestive juice, adding ultrapure water to fully dissolve, filtering with a microporous filter to obtain liquid, and storing in a refrigerator at-20 ℃.
(3) Respectively weighing culture medium powder and NaHCO3Adding ultrapure water for full dissolution, adding 10% double antibody, filtering with microporous membrane to obtain culture solution, storing at 4 deg.C in refrigerator, and adding 10% fetal calf serum before use.
(4) Taking the NCI-H358 cells or KYSE520 cells out of the liquid nitrogen tank, immediately placing the cells in a constant-temperature water bath kettle at 37 ℃, shaking the cells to melt the cells, pouring the cells into a culture bottle, and adding a culture solution (containing 10% fetal calf serum) for dilution. Transferring the diluted culture medium into a centrifuge tube, centrifuging for 5 minutes at 1000r/min, discarding the supernatant, adding fresh culture medium, blowing, mixing, transferring into a culture bottle, and culturing in 5% CO2And cultured in an incubator at 37 ℃. When the cells are attached to the wall and spread to the bottom of the bottle, passage is started, a small amount of fresh culture medium (containing 10% fetal calf serum) is added to stop digestion, the liquid in the culture bottle is poured out, PBS is washed twice, the fresh culture medium is added to blow and beat uniformly, and the cells are evenly distributed into two culture bottles to continue culture.
(5) Taking the logarithmic phase cells, pouring off the old culture medium, adding a trypsin solution for digestion for 3 minutes, adding a fresh culture medium containing 10% fetal calf serum to stop digestion, transferring the solution to a centrifuge tube, centrifuging for 5 minutes at 1000r/min, and discarding the supernatant. Adding culture medium to prepare cell suspension, and counting cells. After counting was complete, cells were plated in 96-well plates at 5000-. Placing the 96-well plate with the cells at 37 ℃ and 5% CO2The incubator continues to culture for 24 h. Gradient dilution of drug with culture mediumThey were then added to 96 well plates at 90. mu. mol/L, 30. mu. mol/L, 10. mu. mol/L, 3.3. mu. mol/L, 1.1. mu. mol/L, 0.37. mu. mol/L, 100. mu.L per well, with three duplicate wells per concentration. Adding corresponding concentration of culture medium containing solvent into control group, adding blank culture medium with the same volume into zero setting hole, and placing in 5% CO2And incubating in an incubator at 37 ℃ for 48 h. Adding 20. mu.L of CCK8 reagent into each well, mixing well, adding 5% CO2And culturing in a 37 ℃ incubator for 1h in a dark place. The 96-well plate was then placed in a microplate reader for detection and absorbance was measured at 450 nm.
2. Data processing
Drawing a curve and calculating the inhibition rate of the drug on cells and IC50。
The inhibition ratio was [ (control average OD value-experimental average OD value)/(control average OD value-blank control average OD value) ] × 100%.
3. Results of the experiment
The inhibitory activity of the compound on non-small cell lung cancer cell strain NCI-H358 cells and esophageal cancer cell strain KYSE520 cells is as follows:
compound numbering | NCI-H358(IC50,μM) | KYSE520(IC50,μM) |
1 | 8.3 | 9.7 |
3 | 8.6 | 6.3 |
9 | 11.5 | 6.3 |
11 | 3.2 | 1.2 |
SHP099 | 33.4 | 38.1 |
And (4) experimental conclusion: the data show that the compounds of the embodiment of the invention have good inhibition effect on the proliferation of NCI-H358 and KYSE520 cells. Various embodiments of the present invention have novel structures and superior in vitro anti-proliferative activity compared to SHP 099.
Claims (6)
1. An aromatic aza-heptacyclic compound shown as a general formula I, and pharmaceutically acceptable salts, enantiomers, non-isomers, tautomers, solvates, polymorphs or prodrugs thereof,
X is N or CR4;
R1、R2And R4Independently hydrogen, halogen, amino;
l is a bond, C1-C2Carbon chain of (3), O or S;
when n is 1, m is 1;
when n is 2, m is 0;
R3is hydrogen, deuterium, halogen, ammoniaRadical, hydroxyl, nitro, cyano, amido, carboxyl, sulfonyl, -C (O) NR5R6、-C(O)R5、-C(O)OR5、-NR5C(O)R6、-NR5C(O)NR6R7、-NR5C(O)OR6、-NR5R6、-OC(O)R5、-OC(O)NR5R6、-SR5、-S(O)2R5、-S(O)R5、-S(O)2NR5R6、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C7Cycloalkyl radical, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C3-C7Epoxy group, C2-C6Alkenyl radical, C2-C6Alkynyl, C6-C10Aromatic ring heterocycle, C6-C10Heteroaromatic rings, mono-heterocycles, spirocycles, bridged rings, and fused rings; wherein R is5、R6And R7Independently hydrogen, deuterium, halogen, C1-C7Alkyl radical, C1-C7Haloalkyl, C1-C7Alkoxy radical, C1-C7Haloalkoxy, C2-C6Alkenyl radical, C2-C6Alkynyl, C6-C10Aromatic ring heterocycle, C6-C10A heteroaromatic ring.
2. The aromatic aza heptacyclic compound of claim 1, wherein:
X is N or CR4;
R1、R2And R4Independently hydrogen, halogen, amino;
l is a bond, C1-C2Carbon chain of (3), O or S;
when n is 1, m is 1;
when n is 2, m is 0;
R3is hydrogen, deuterium, halogen, amino, hydroxyl, nitro, cyano, amido, carboxyl, sulfonyl, -C (O) NR5R6、-C(O)R5、-C(O)OR5、-NR5C(O)R6、-NR5R6、-OC(O)R5、-SR5、C1-C6Alkyl radical, C3-C7Cycloalkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C6-C10Aromatic ring heterocycle, C6-C10A heteroaromatic ring; wherein R is5And R6Independently hydrogen, deuterium, halogen, C1-C6Alkyl radical, C3-C7Cycloalkyl, C2-C6Alkenyl radical, C2-C6Alkynyl.
4. a pharmaceutical composition comprising the aryloazepine heptacyclic compound according to any one of claims 1 to 3 and a pharmaceutically acceptable excipient.
5. The pharmaceutical composition of claim 3, wherein the pharmaceutical composition is in the form of a tablet, capsule, injection, or lyophilized powder.
6. Use of the aryloazepine heptacyclic compound according to any one of claims 1 to 3, the pharmaceutical composition according to claim 4 or 5 for the preparation of a therapeutic antitumor agent, as a prodrug of an antitumor agent or as an intermediate of an antitumor agent.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210194719.8A CN114539223B (en) | 2022-03-01 | 2022-03-01 | Aryl-containing aza-seven-membered ring compound and preparation method and application thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210194719.8A CN114539223B (en) | 2022-03-01 | 2022-03-01 | Aryl-containing aza-seven-membered ring compound and preparation method and application thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
CN114539223A true CN114539223A (en) | 2022-05-27 |
CN114539223B CN114539223B (en) | 2024-04-09 |
Family
ID=81662458
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202210194719.8A Active CN114539223B (en) | 2022-03-01 | 2022-03-01 | Aryl-containing aza-seven-membered ring compound and preparation method and application thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN114539223B (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115974841A (en) * | 2023-01-09 | 2023-04-18 | 中国药科大学 | Substituted benzoazepine amino compound and preparation method and application thereof |
WO2023172940A1 (en) | 2022-03-08 | 2023-09-14 | Revolution Medicines, Inc. | Methods for treating immune refractory lung cancer |
WO2023240263A1 (en) | 2022-06-10 | 2023-12-14 | Revolution Medicines, Inc. | Macrocyclic ras inhibitors |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113646049A (en) * | 2019-04-08 | 2021-11-12 | 默克专利有限公司 | Pyrimidone derivatives as SHP2 antagonists |
-
2022
- 2022-03-01 CN CN202210194719.8A patent/CN114539223B/en active Active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113646049A (en) * | 2019-04-08 | 2021-11-12 | 默克专利有限公司 | Pyrimidone derivatives as SHP2 antagonists |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023172940A1 (en) | 2022-03-08 | 2023-09-14 | Revolution Medicines, Inc. | Methods for treating immune refractory lung cancer |
WO2023240263A1 (en) | 2022-06-10 | 2023-12-14 | Revolution Medicines, Inc. | Macrocyclic ras inhibitors |
CN115974841A (en) * | 2023-01-09 | 2023-04-18 | 中国药科大学 | Substituted benzoazepine amino compound and preparation method and application thereof |
Also Published As
Publication number | Publication date |
---|---|
CN114539223B (en) | 2024-04-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN111153901B (en) | Nitrogen-containing fused heterocyclic SHP2 inhibitor compound, preparation method and application | |
JP6600365B2 (en) | JAK inhibitor | |
CN114539223B (en) | Aryl-containing aza-seven-membered ring compound and preparation method and application thereof | |
US10160771B2 (en) | Hepatitis C virus inhibitors and uses thereof in preparation of drugs | |
RU2763898C9 (en) | Lsd1 inhibitor, as well as its production method and its application | |
CA2829939C (en) | Tricyclic gyrase inhibitors | |
CN109415341B (en) | Benzotriazole-derived alpha, beta unsaturated amide compounds as TGF-beta R1 inhibitor | |
WO2015073767A1 (en) | Substituted 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine derivatives as casein kinase 1 d/e inhibitors | |
NO332005B1 (en) | New pyridopyrazines, their use, medicament containing at least one such compound and process for the preparation of such a medicament | |
CN112292374B (en) | Novel phosphoinositide 3-kinase inhibitor and preparation method and application thereof | |
EP3157925A1 (en) | Imidazo-pyridazne derivatives as casein kinase 1 delta/epsilon inhibitors | |
JP7168149B2 (en) | Pyrazin-2(1H)-one compounds as FGFR inhibitors | |
KR20220066074A (en) | Triazolopyrimidines as A2A/A2B inhibitors | |
KR20210113287A (en) | Halo-allylamine compounds and uses thereof | |
TW202204351A (en) | Compounds having a macrocyclic structure and uses thereof | |
JP2011529085A (en) | Antiviral compounds | |
JP6900406B2 (en) | Dihydropyrazoloazepine compounds as Akt inhibitors | |
CN116768861A (en) | SOS1 protein degradation targeting chimeric and composition, preparation and application thereof | |
AU2017359819B2 (en) | FGFR4 inhibitor and preparation method and use thereof | |
CN114478403A (en) | Compound containing aromatic guanidyl as well as preparation method and application thereof | |
CN110283174B (en) | PI3K delta inhibitor and application thereof | |
CN116456987A (en) | Compounds useful as CDK kinase inhibitors and uses thereof | |
CN115974841A (en) | Substituted benzoazepine amino compound and preparation method and application thereof | |
TW202334132A (en) | Sarm1 enzyme activity inhibitor and its application | |
CN117003734A (en) | Pyrimidine ring derivative and preparation method and application thereof |
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 | ||
GR01 | Patent grant | ||
GR01 | Patent grant |