CN109328187B - 一种具有fgfr抑制活性的新型化合物及其制备和应用 - Google Patents
一种具有fgfr抑制活性的新型化合物及其制备和应用 Download PDFInfo
- Publication number
- CN109328187B CN109328187B CN201780037478.3A CN201780037478A CN109328187B CN 109328187 B CN109328187 B CN 109328187B CN 201780037478 A CN201780037478 A CN 201780037478A CN 109328187 B CN109328187 B CN 109328187B
- Authority
- CN
- China
- Prior art keywords
- pyrimidin
- pyrrolo
- amino
- methoxy
- preparation
- 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.)
- Active
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 244
- 150000001875 compounds Chemical class 0.000 title claims abstract description 167
- 108091008794 FGF receptors Proteins 0.000 title claims abstract description 43
- 230000002401 inhibitory effect Effects 0.000 title claims abstract description 26
- 102000052178 fibroblast growth factor receptor activity proteins Human genes 0.000 title claims abstract 6
- 201000010099 disease Diseases 0.000 claims abstract description 25
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 25
- 239000003814 drug Substances 0.000 claims abstract description 8
- -1 acyl halide compound Chemical class 0.000 claims description 171
- 238000000034 method Methods 0.000 claims description 36
- 239000008194 pharmaceutical composition Substances 0.000 claims description 33
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 32
- 230000000694 effects Effects 0.000 claims description 29
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 27
- 150000003839 salts Chemical class 0.000 claims description 27
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 23
- 229910052736 halogen Inorganic materials 0.000 claims description 19
- 150000002367 halogens Chemical class 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
- 238000006467 substitution reaction Methods 0.000 claims description 14
- 125000005842 heteroatom Chemical group 0.000 claims description 11
- 238000011282 treatment Methods 0.000 claims description 11
- 239000003937 drug carrier Substances 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 229940125829 fibroblast growth factor receptor inhibitor Drugs 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
- 125000006708 (C5-C14) heteroaryl group Chemical group 0.000 claims description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims description 6
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 5
- 125000005347 halocycloalkyl group Chemical group 0.000 claims description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- 125000002619 bicyclic group Chemical group 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 238000011321 prophylaxis Methods 0.000 claims description 3
- 238000006482 condensation reaction Methods 0.000 claims description 2
- 239000012442 inert solvent Substances 0.000 claims description 2
- 206010028980 Neoplasm Diseases 0.000 abstract description 43
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 132
- 238000005160 1H NMR spectroscopy Methods 0.000 description 115
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 99
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 90
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 84
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 81
- 239000003153 chemical reaction reagent Substances 0.000 description 80
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 76
- 239000002994 raw material Substances 0.000 description 53
- 239000000243 solution Substances 0.000 description 45
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 39
- 239000007787 solid Substances 0.000 description 38
- 239000007858 starting material Substances 0.000 description 38
- 102000044168 Fibroblast Growth Factor Receptor Human genes 0.000 description 37
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 34
- 238000006243 chemical reaction Methods 0.000 description 34
- 238000004440 column chromatography Methods 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 30
- 239000000203 mixture Substances 0.000 description 29
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 22
- 239000012074 organic phase Substances 0.000 description 22
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- NYCVCXMSZNOGDH-UHFFFAOYSA-N pyrrolidine-1-carboxylic acid Chemical compound OC(=O)N1CCCC1 NYCVCXMSZNOGDH-UHFFFAOYSA-N 0.000 description 18
- 229920006395 saturated elastomer Polymers 0.000 description 18
- HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical compound C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 description 17
- 230000005764 inhibitory process Effects 0.000 description 17
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 16
- 239000007864 aqueous solution Substances 0.000 description 16
- 125000001424 substituent group Chemical group 0.000 description 16
- 239000011780 sodium chloride Substances 0.000 description 15
- 238000003756 stirring Methods 0.000 description 15
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 239000000651 prodrug Substances 0.000 description 14
- 229940002612 prodrug Drugs 0.000 description 14
- 239000012453 solvate Substances 0.000 description 14
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 13
- 238000001914 filtration Methods 0.000 description 13
- APCBTRDHCDOPNY-UHFFFAOYSA-N tert-butyl 3-hydroxypyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(O)C1 APCBTRDHCDOPNY-UHFFFAOYSA-N 0.000 description 13
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 201000011510 cancer Diseases 0.000 description 12
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 11
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 11
- 238000001816 cooling Methods 0.000 description 11
- 229940126864 fibroblast growth factor Drugs 0.000 description 11
- 239000013642 negative control Substances 0.000 description 11
- UORVCLMRJXCDCP-UHFFFAOYSA-N propynoic acid Chemical compound OC(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-N 0.000 description 11
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 10
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 10
- 125000004567 azetidin-3-yl group Chemical group N1CC(C1)* 0.000 description 10
- LDHQCZJRKDOVOX-NSCUHMNNSA-N crotonic acid Chemical compound C\C=C\C(O)=O LDHQCZJRKDOVOX-NSCUHMNNSA-N 0.000 description 10
- 238000010438 heat treatment Methods 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 229910052760 oxygen Inorganic materials 0.000 description 9
- 239000003208 petroleum Substances 0.000 description 9
- XXHGDLJQCZLECB-UHFFFAOYSA-N pyrimidin-4-amine;hydrochloride Chemical compound Cl.NC1=CC=NC=N1 XXHGDLJQCZLECB-UHFFFAOYSA-N 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- 229910052717 sulfur Inorganic materials 0.000 description 9
- QMSRQVNGCIFRAP-UHFFFAOYSA-N (7-methoxy-5-methyl-1-benzothiophen-2-yl)boronic acid Chemical compound COC1=CC(C)=CC2=C1SC(B(O)O)=C2 QMSRQVNGCIFRAP-UHFFFAOYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 102100023593 Fibroblast growth factor receptor 1 Human genes 0.000 description 8
- 101710182386 Fibroblast growth factor receptor 1 Proteins 0.000 description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 235000019441 ethanol Nutrition 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- GKMJXFGEBGGQAG-UHFFFAOYSA-N tert-butyl 3-(4-amino-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC1N1C2=NC=NC(N)=C2C(I)=C1 GKMJXFGEBGGQAG-UHFFFAOYSA-N 0.000 description 8
- SPVHAGRWFNXBCU-UHFFFAOYSA-N 1-(2,2-diethoxyethylsulfanyl)-2-methoxy-4-methylbenzene Chemical compound CCOC(OCC)CSC1=CC=C(C)C=C1OC SPVHAGRWFNXBCU-UHFFFAOYSA-N 0.000 description 7
- ZEOWTGPWHLSLOG-UHFFFAOYSA-N Cc1ccc(cc1-c1ccc2c(n[nH]c2c1)-c1cnn(c1)C1CC1)C(=O)Nc1cccc(c1)C(F)(F)F Chemical compound Cc1ccc(cc1-c1ccc2c(n[nH]c2c1)-c1cnn(c1)C1CC1)C(=O)Nc1cccc(c1)C(F)(F)F ZEOWTGPWHLSLOG-UHFFFAOYSA-N 0.000 description 7
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 7
- 102100027844 Fibroblast growth factor receptor 4 Human genes 0.000 description 7
- 101000917134 Homo sapiens Fibroblast growth factor receptor 4 Proteins 0.000 description 7
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 7
- 229910052786 argon Inorganic materials 0.000 description 7
- 238000000605 extraction Methods 0.000 description 7
- 201000005202 lung cancer Diseases 0.000 description 7
- 208000020816 lung neoplasm Diseases 0.000 description 7
- 230000019491 signal transduction Effects 0.000 description 7
- AAAGPBPQCFWEQY-UHFFFAOYSA-N tert-butyl 3-(4-amino-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)azetidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC1N1C2=NC=NC(N)=C2C(I)=C1 AAAGPBPQCFWEQY-UHFFFAOYSA-N 0.000 description 7
- LPQZERIRKRYGGM-UHFFFAOYSA-N tert-butyl pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC1 LPQZERIRKRYGGM-UHFFFAOYSA-N 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- FMAMOHQHNNUMQJ-UHFFFAOYSA-N 7-methoxy-5-methyl-1-benzothiophene Chemical compound COC1=CC(C)=CC2=C1SC=C2 FMAMOHQHNNUMQJ-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 125000005915 C6-C14 aryl group Chemical group 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 6
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 125000004566 azetidin-1-yl group Chemical group N1(CCC1)* 0.000 description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 235000019198 oils Nutrition 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 230000035755 proliferation Effects 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- CBWBJFJMNBPWAL-UHFFFAOYSA-N 4-chloro-5-iodo-7h-pyrrolo[2,3-d]pyrimidine Chemical compound ClC1=NC=NC2=C1C(I)=CN2 CBWBJFJMNBPWAL-UHFFFAOYSA-N 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 208000034578 Multiple myelomas Diseases 0.000 description 5
- 206010035226 Plasma cell myeloma Diseases 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 208000005718 Stomach Neoplasms Diseases 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 125000003118 aryl group Chemical group 0.000 description 5
- 206010017758 gastric cancer Diseases 0.000 description 5
- 230000014509 gene expression Effects 0.000 description 5
- 150000004677 hydrates Chemical class 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 239000011259 mixed solution Substances 0.000 description 5
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 5
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 5
- 238000011580 nude mouse model Methods 0.000 description 5
- 201000011549 stomach cancer Diseases 0.000 description 5
- IRCJWWDRTXTAOL-UHFFFAOYSA-N tert-butyl 3-[4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,3-d]pyrimidin-7-yl]pyrrolidine-1-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1CC(CC1)N1C=C(C2=C1N=CN=C2N)C=1SC2=C(C=1)C=C(C=C2OC)C IRCJWWDRTXTAOL-UHFFFAOYSA-N 0.000 description 5
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 5
- 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 4
- PETRWTHZSKVLRE-UHFFFAOYSA-N 2-Methoxy-4-methylphenol Chemical compound COC1=CC(C)=CC=C1O PETRWTHZSKVLRE-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- 206010005003 Bladder cancer Diseases 0.000 description 4
- 206010006187 Breast cancer Diseases 0.000 description 4
- 208000026310 Breast neoplasm Diseases 0.000 description 4
- 206010009944 Colon cancer Diseases 0.000 description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 4
- 206010060862 Prostate cancer Diseases 0.000 description 4
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 4
- 208000006265 Renal cell carcinoma Diseases 0.000 description 4
- 101100331535 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) DIB1 gene Proteins 0.000 description 4
- 208000024313 Testicular Neoplasms Diseases 0.000 description 4
- 206010057644 Testis cancer Diseases 0.000 description 4
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 4
- 230000002159 abnormal effect Effects 0.000 description 4
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 description 4
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 230000004663 cell proliferation Effects 0.000 description 4
- 208000029742 colonic neoplasm Diseases 0.000 description 4
- 229940125782 compound 2 Drugs 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 4
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 208000005017 glioblastoma Diseases 0.000 description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- 201000007270 liver cancer Diseases 0.000 description 4
- 208000014018 liver neoplasm Diseases 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 201000001441 melanoma Diseases 0.000 description 4
- 201000002528 pancreatic cancer Diseases 0.000 description 4
- 208000008443 pancreatic carcinoma Diseases 0.000 description 4
- 235000018102 proteins Nutrition 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 201000003120 testicular cancer Diseases 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 208000013077 thyroid gland carcinoma Diseases 0.000 description 4
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 description 4
- 201000005112 urinary bladder cancer Diseases 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- KRQCXABUOQTMLT-UHFFFAOYSA-N (7-methoxy-1-benzothiophen-2-yl)boronic acid Chemical compound COC1=CC=CC2=C1SC(B(O)O)=C2 KRQCXABUOQTMLT-UHFFFAOYSA-N 0.000 description 3
- QXTSFEBXASFTLV-UHFFFAOYSA-N 1-(2,2-diethoxyethylsulfanyl)-2-methoxybenzene Chemical compound CCOC(OCC)CSC1=CC=CC=C1OC QXTSFEBXASFTLV-UHFFFAOYSA-N 0.000 description 3
- DXMQCYBZTUPOFT-UHFFFAOYSA-N 1-(2,2-diethoxyethylsulfanyl)-3-methoxybenzene Chemical compound CCOC(OCC)CSC1=CC=CC(OC)=C1 DXMQCYBZTUPOFT-UHFFFAOYSA-N 0.000 description 3
- ZQPFINBTTQSOBO-UHFFFAOYSA-N 1-(azetidin-3-yl)-3-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride Chemical compound Cl.COc1cc(C)cc2cc(sc12)-c1nn(C2CNC2)c2ncnc(N)c12 ZQPFINBTTQSOBO-UHFFFAOYSA-N 0.000 description 3
- ANOGFUSUQNPBFF-UHFFFAOYSA-N 1-[2-[[4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,3-d]pyrimidin-7-yl]methyl]pyrrolidin-1-yl]prop-2-en-1-one Chemical compound COc1cc(C)cc2cc(sc12)-c1cn(CC2CCCN2C(=O)C=C)c2ncnc(N)c12 ANOGFUSUQNPBFF-UHFFFAOYSA-N 0.000 description 3
- QRRSMCPHCUULNW-UHFFFAOYSA-N 1-[3-[[4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,3-d]pyrimidin-7-yl]methyl]pyrrolidin-1-yl]prop-2-en-1-one Chemical compound COc1cc(C)cc2cc(sc12)-c1cn(CC2CCN(C2)C(=O)C=C)c2ncnc(N)c12 QRRSMCPHCUULNW-UHFFFAOYSA-N 0.000 description 3
- SCQZHPMTSDVGKB-UHFFFAOYSA-N 2-morpholin-4-ylethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN1CCOCC1 SCQZHPMTSDVGKB-UHFFFAOYSA-N 0.000 description 3
- VUSDEMXXJKENHI-UHFFFAOYSA-N 3-[3-[4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,3-d]pyrimidin-7-yl]pyrrolidin-1-yl]-3-oxopropanenitrile Chemical compound NC=1C2=C(N=CN=1)N(C=C2C=1SC2=C(C=1)C=C(C=C2OC)C)C1CN(CC1)C(CC#N)=O VUSDEMXXJKENHI-UHFFFAOYSA-N 0.000 description 3
- WGDVDMKNSDCNGB-UHFFFAOYSA-N 6-methoxy-1-benzothiophene Chemical compound COC1=CC=C2C=CSC2=C1 WGDVDMKNSDCNGB-UHFFFAOYSA-N 0.000 description 3
- OSKWSQRKLNYRCT-UHFFFAOYSA-N 7-(azetidin-3-yl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,3-d]pyrimidin-4-amine hydrochloride Chemical compound Cl.COc1cc(C)cc2cc(sc12)-c1cn(C2CNC2)c2ncnc(N)c12 OSKWSQRKLNYRCT-UHFFFAOYSA-N 0.000 description 3
- RWWDZFRDYYQTFJ-UHFFFAOYSA-N 7-methoxy-1-benzothiophene Chemical compound COC1=CC=CC2=C1SC=C2 RWWDZFRDYYQTFJ-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 102100023600 Fibroblast growth factor receptor 2 Human genes 0.000 description 3
- 101710182389 Fibroblast growth factor receptor 2 Proteins 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 238000006751 Mitsunobu reaction Methods 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 108091000080 Phosphotransferase Proteins 0.000 description 3
- 239000004698 Polyethylene Substances 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 102000001253 Protein Kinase Human genes 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 108010087230 Sincalide Proteins 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000012300 argon atmosphere Substances 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000004327 boric acid Substances 0.000 description 3
- 238000010609 cell counting kit-8 assay Methods 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940125773 compound 10 Drugs 0.000 description 3
- 239000013078 crystal Chemical group 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- VYOHBZNTQBTZPN-UHFFFAOYSA-N ethyl 7-hydroxy-1-benzothiophene-5-carboxylate Chemical compound CCOC(=O)C1=CC(O)=C2SC=CC2=C1 VYOHBZNTQBTZPN-UHFFFAOYSA-N 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 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 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 3
- 125000001624 naphthyl group Chemical group 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 102000020233 phosphotransferase Human genes 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 description 3
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 3
- 229920000137 polyphosphoric acid Polymers 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 108060006633 protein kinase Proteins 0.000 description 3
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 3
- 229910052711 selenium Inorganic materials 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 239000007909 solid dosage form Substances 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- FYSDBBNBDBMFQL-SECBINFHSA-N tert-butyl (3r)-3-(4-chloro-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC[C@H]1N1C2=NC=NC(Cl)=C2C(I)=C1 FYSDBBNBDBMFQL-SECBINFHSA-N 0.000 description 3
- FJVXFVCBMHGHCE-UHFFFAOYSA-N tert-butyl 3-(4-amino-3-iodopyrazolo[3,4-d]pyrimidin-1-yl)azetidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC1N1C2=NC=NC(N)=C2C(I)=N1 FJVXFVCBMHGHCE-UHFFFAOYSA-N 0.000 description 3
- LTYMJJHSJFXWEM-UHFFFAOYSA-N tert-butyl 3-(4-chloro-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)azetidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC1N1C2=NC=NC(Cl)=C2C(I)=C1 LTYMJJHSJFXWEM-UHFFFAOYSA-N 0.000 description 3
- KWQRKOSMSFLBTJ-UHFFFAOYSA-N tert-butyl 3-methylsulfonyloxypyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)C1 KWQRKOSMSFLBTJ-UHFFFAOYSA-N 0.000 description 3
- WOZBHLASHCEWPR-UHFFFAOYSA-N tert-butyl 4-(4-amino-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1N1C2=NC=NC(N)=C2C(I)=C1 WOZBHLASHCEWPR-UHFFFAOYSA-N 0.000 description 3
- UAECUWVMVVADKD-UHFFFAOYSA-N tert-butyl 4-(4-chloro-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1N1C2=NC=NC(Cl)=C2C(I)=C1 UAECUWVMVVADKD-UHFFFAOYSA-N 0.000 description 3
- QUERMGFVJPRMJL-UHFFFAOYSA-N tert-butyl azetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC1 QUERMGFVJPRMJL-UHFFFAOYSA-N 0.000 description 3
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical compound CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- 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 2
- PNRDOYJXKKKYSU-UHFFFAOYSA-N (6-methoxy-1-benzothiophen-2-yl)boronic acid Chemical compound COC1=CC=C2C=C(B(O)O)SC2=C1 PNRDOYJXKKKYSU-UHFFFAOYSA-N 0.000 description 2
- PEIKPTUPZCRCBS-UHFFFAOYSA-N (7-methoxy-5-methyl-1-benzofuran-2-yl)boronic acid Chemical compound COC1=CC(=CC=2C=C(OC=21)B(O)O)C PEIKPTUPZCRCBS-UHFFFAOYSA-N 0.000 description 2
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 description 2
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 description 2
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 2
- VRGSTJQVRGRTCT-AATRIKPKSA-N (E)-1-[3-[4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,3-d]pyrimidin-7-yl]azetidin-1-yl]-4-(dimethylamino)but-2-en-1-one Chemical compound NC=1C2=C(N=CN=1)N(C=C2C=1SC2=C(C=1)C=C(C=C2OC)C)C1CN(C1)C(\C=C\CN(C)C)=O VRGSTJQVRGRTCT-AATRIKPKSA-N 0.000 description 2
- YXRXSDVBEKDBAZ-AATRIKPKSA-N (E)-1-[3-[4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,3-d]pyrimidin-7-yl]pyrrolidin-1-yl]-4-(4-ethylpiperazin-1-yl)but-2-en-1-one Chemical compound NC=1C2=C(N=CN=1)N(C=C2C=1SC2=C(C=1)C=C(C=C2OC)C)C1CN(CC1)C(\C=C\CN1CCN(CC1)CC)=O YXRXSDVBEKDBAZ-AATRIKPKSA-N 0.000 description 2
- VGTHQQRGUXGLLV-HWKANZROSA-N (E)-1-[3-[4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,3-d]pyrimidin-7-yl]pyrrolidin-1-yl]-4-(azetidin-1-yl)but-2-en-1-one Chemical compound NC=1C2=C(N=CN=1)N(C=C2C=1SC2=C(C=1)C=C(C=C2OC)C)C1CN(CC1)C(\C=C\CN1CCC1)=O VGTHQQRGUXGLLV-HWKANZROSA-N 0.000 description 2
- JKWPSZWWCDRXFP-AATRIKPKSA-N (E)-1-[3-[4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,3-d]pyrimidin-7-yl]pyrrolidin-1-yl]-4-(dimethylamino)but-2-en-1-one Chemical compound COc1cc(C)cc2cc(sc12)-c1cn(C2CCN(C2)C(=O)\C=C\CN(C)C)c2ncnc(N)c12 JKWPSZWWCDRXFP-AATRIKPKSA-N 0.000 description 2
- YGBUQWGIGSTYLG-VOTSOKGWSA-N (E)-1-[3-[4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,3-d]pyrimidin-7-yl]pyrrolidin-1-yl]-4-[ethyl(methyl)amino]but-2-en-1-one Chemical compound NC=1C2=C(N=CN=1)N(C=C2C=1SC2=C(C=1)C=C(C=C2OC)C)C1CN(CC1)C(\C=C\CN(C)CC)=O YGBUQWGIGSTYLG-VOTSOKGWSA-N 0.000 description 2
- OGKSNXUFWIHQHR-VOTSOKGWSA-N (E)-1-[3-[4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,3-d]pyrimidin-7-yl]pyrrolidin-1-yl]-4-[methyl(propan-2-yl)amino]but-2-en-1-one Chemical compound NC=1C2=C(N=CN=1)N(C=C2C=1SC2=C(C=1)C=C(C=C2OC)C)C1CN(CC1)C(\C=C\CN(C)C(C)C)=O OGKSNXUFWIHQHR-VOTSOKGWSA-N 0.000 description 2
- SFFNMJSDKNZMLZ-VOTSOKGWSA-N (E)-1-[3-[4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,3-d]pyrimidin-7-yl]pyrrolidin-1-yl]-4-piperidin-1-ylbut-2-en-1-one Chemical compound COc1cc(C)cc2cc(sc12)-c1cn(C2CCN(C2)C(=O)\C=C\CN2CCCCC2)c2ncnc(N)c12 SFFNMJSDKNZMLZ-VOTSOKGWSA-N 0.000 description 2
- HQIHNMMPXUSPOX-AATRIKPKSA-N (E)-1-[3-[4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,3-d]pyrimidin-7-yl]pyrrolidin-1-yl]-4-pyrrolidin-1-ylbut-2-en-1-one Chemical compound COc1cc(C)cc2cc(sc12)-c1cn(C2CCN(C2)C(=O)\C=C\CN2CCCC2)c2ncnc(N)c12 HQIHNMMPXUSPOX-AATRIKPKSA-N 0.000 description 2
- RLAMMVBKXXENEK-SNAWJCMRSA-N (E)-1-[3-[4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,3-d]pyrimidin-7-yl]pyrrolidin-1-yl]but-2-en-1-one Chemical compound NC=1C2=C(N=CN=1)N(C=C2C=1SC2=C(C=1)C=C(C=C2OC)C)C1CN(CC1)C(\C=C\C)=O RLAMMVBKXXENEK-SNAWJCMRSA-N 0.000 description 2
- DPZNOMCNRMUKPS-UHFFFAOYSA-N 1,3-Dimethoxybenzene Chemical compound COC1=CC=CC(OC)=C1 DPZNOMCNRMUKPS-UHFFFAOYSA-N 0.000 description 2
- DBPQZVOQSRHSRI-UHFFFAOYSA-N 1-(2,2-diethoxyethoxy)-2-methoxy-4-methylbenzene Chemical compound CCOC(OCC)COC1=CC=C(C)C=C1OC DBPQZVOQSRHSRI-UHFFFAOYSA-N 0.000 description 2
- HXRATNFKXKVAAU-UHFFFAOYSA-N 1-[(3-aminophenyl)methyl]-3-iodopyrazolo[3,4-d]pyrimidin-4-amine Chemical compound NC=1C=C(CN2N=C(C=3C2=NC=NC=3N)I)C=CC=1 HXRATNFKXKVAAU-UHFFFAOYSA-N 0.000 description 2
- ZMYXCQOKPQVAIY-OAHLLOKOSA-N 1-[(3R)-3-[4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,3-d]pyrimidin-7-yl]pyrrolidin-1-yl]prop-2-en-1-one Chemical compound NC=1C2=C(N=CN=1)N(C=C2C=1SC2=C(C=1)C=C(C=C2OC)C)[C@H]1CN(CC1)C(C=C)=O ZMYXCQOKPQVAIY-OAHLLOKOSA-N 0.000 description 2
- ZMYXCQOKPQVAIY-HNNXBMFYSA-N 1-[(3S)-3-[4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,3-d]pyrimidin-7-yl]pyrrolidin-1-yl]prop-2-en-1-one Chemical compound NC=1C2=C(N=CN=1)N(C=C2C=1SC2=C(C=1)C=C(C=C2OC)C)[C@@H]1CN(CC1)C(C=C)=O ZMYXCQOKPQVAIY-HNNXBMFYSA-N 0.000 description 2
- NIGCDPHSAAAETM-UHFFFAOYSA-N 1-[3-[4-amino-3-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrazolo[3,4-d]pyrimidin-1-yl]pyrrolidin-1-yl]prop-2-en-1-one Chemical compound COc1cc(C)cc2cc(sc12)-c1nn(C2CCN(C2)C(=O)C=C)c2ncnc(N)c12 NIGCDPHSAAAETM-UHFFFAOYSA-N 0.000 description 2
- MYSZTSPJXADVIF-UHFFFAOYSA-N 1-[3-[4-amino-5-(1H-indol-2-yl)pyrrolo[2,3-d]pyrimidin-7-yl]azetidin-1-yl]prop-2-en-1-one Chemical compound NC=1C2=C(N=CN=1)N(C=C2C=1NC2=CC=CC=C2C=1)C1CN(C1)C(C=C)=O MYSZTSPJXADVIF-UHFFFAOYSA-N 0.000 description 2
- XJYAEHFIXFRYPU-UHFFFAOYSA-N 1-[3-[4-amino-5-(5,7-dimethoxy-1-benzothiophen-2-yl)pyrrolo[2,3-d]pyrimidin-7-yl]pyrrolidin-1-yl]prop-2-en-1-one Chemical compound NC=1C2=C(N=CN=1)N(C=C2C=1SC2=C(C=1)C=C(C=C2OC)OC)C1CN(CC1)C(C=C)=O XJYAEHFIXFRYPU-UHFFFAOYSA-N 0.000 description 2
- SXXLGVGHYVRIAF-UHFFFAOYSA-N 1-[3-[4-amino-5-(6-methoxy-1-benzothiophen-2-yl)pyrrolo[2,3-d]pyrimidin-7-yl]azetidin-1-yl]prop-2-en-1-one Chemical compound NC=1C2=C(N=CN=1)N(C=C2C=1SC2=C(C=1)C=CC(=C2)OC)C1CN(C1)C(C=C)=O SXXLGVGHYVRIAF-UHFFFAOYSA-N 0.000 description 2
- WYSRIBSZOQNKSS-UHFFFAOYSA-N 1-[3-[4-amino-5-(7-methoxy-1-benzothiophen-2-yl)pyrrolo[2,3-d]pyrimidin-7-yl]azetidin-1-yl]prop-2-en-1-one Chemical compound NC=1C2=C(N=CN=1)N(C=C2C=1SC2=C(C=1)C=CC=C2OC)C1CN(C1)C(C=C)=O WYSRIBSZOQNKSS-UHFFFAOYSA-N 0.000 description 2
- OAKYQSJFJCQJAP-UHFFFAOYSA-N 1-[3-[4-amino-5-(7-methoxy-5-methyl-1-benzofuran-2-yl)pyrrolo[2,3-d]pyrimidin-7-yl]azetidin-1-yl]prop-2-en-1-one Chemical compound NC=1C2=C(N=CN=1)N(C=C2C=1OC2=C(C=1)C=C(C=C2OC)C)C1CN(C1)C(C=C)=O OAKYQSJFJCQJAP-UHFFFAOYSA-N 0.000 description 2
- HMJWDRNCIBKVLK-UHFFFAOYSA-N 1-[3-[4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,3-d]pyrimidin-7-yl]azetidin-1-yl]prop-2-en-1-one Chemical compound COc1cc(C)cc2cc(sc12)-c1cn(C2CN(C2)C(=O)C=C)c2ncnc(N)c12 HMJWDRNCIBKVLK-UHFFFAOYSA-N 0.000 description 2
- AZGPGOIEBOBKNI-UHFFFAOYSA-N 1-[3-[4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,3-d]pyrimidin-7-yl]piperidin-1-yl]prop-2-en-1-one Chemical compound NC=1C2=C(N=CN=1)N(C=C2C=1SC2=C(C=1)C=C(C=C2OC)C)C1CN(CCC1)C(C=C)=O AZGPGOIEBOBKNI-UHFFFAOYSA-N 0.000 description 2
- UTGGMJSSYPTPIU-UHFFFAOYSA-N 1-[3-[4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,3-d]pyrimidin-7-yl]pyrrolidin-1-yl]but-2-yn-1-one Chemical compound NC=1C2=C(N=CN=1)N(C=C2C=1SC2=C(C=1)C=C(C=C2OC)C)C1CN(CC1)C(C#CC)=O UTGGMJSSYPTPIU-UHFFFAOYSA-N 0.000 description 2
- ZMYXCQOKPQVAIY-UHFFFAOYSA-N 1-[3-[4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,3-d]pyrimidin-7-yl]pyrrolidin-1-yl]prop-2-en-1-one Chemical compound NC=1C2=C(N=CN=1)N(C=C2C=1SC2=C(C=1)C=C(C=C2OC)C)C1CN(CC1)C(C=C)=O ZMYXCQOKPQVAIY-UHFFFAOYSA-N 0.000 description 2
- IBHARKZDQBGJAJ-UHFFFAOYSA-N 1-[4-[4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,3-d]pyrimidin-7-yl]piperidin-1-yl]prop-2-en-1-one Chemical compound NC=1C2=C(N=CN=1)N(C=C2C=1SC2=C(C=1)C=C(C=C2OC)C)C1CCN(CC1)C(C=C)=O IBHARKZDQBGJAJ-UHFFFAOYSA-N 0.000 description 2
- PIQHCAIJDSYVKH-UHFFFAOYSA-N 1-iodo-2-methoxy-4-(trifluoromethyl)benzene Chemical compound IC1=C(C=C(C=C1)C(F)(F)F)OC PIQHCAIJDSYVKH-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 2
- KKFDCBRMNNSAAW-UHFFFAOYSA-N 2-(morpholin-4-yl)ethanol Chemical compound OCCN1CCOCC1 KKFDCBRMNNSAAW-UHFFFAOYSA-N 0.000 description 2
- GDHXJNRAJRCGMX-UHFFFAOYSA-N 2-fluorobenzonitrile Chemical compound FC1=CC=CC=C1C#N GDHXJNRAJRCGMX-UHFFFAOYSA-N 0.000 description 2
- CWSAPAHVCIIVDH-UHFFFAOYSA-N 2-iodo-5-(trifluoromethyl)phenol Chemical compound OC1=CC(C(F)(F)F)=CC=C1I CWSAPAHVCIIVDH-UHFFFAOYSA-N 0.000 description 2
- XCOUVPWGTSKINY-UHFFFAOYSA-N 2-methoxy-4-methyl-1-nitrobenzene Chemical compound COC1=CC(C)=CC=C1[N+]([O-])=O XCOUVPWGTSKINY-UHFFFAOYSA-N 0.000 description 2
- CJJLEUQMMMLOFI-UHFFFAOYSA-N 2-methoxy-4-methylaniline Chemical compound COC1=CC(C)=CC=C1N CJJLEUQMMMLOFI-UHFFFAOYSA-N 0.000 description 2
- PJRGDKFLFAYRBV-UHFFFAOYSA-N 2-phenylthiophene Chemical group C1=CSC(C=2C=CC=CC=2)=C1 PJRGDKFLFAYRBV-UHFFFAOYSA-N 0.000 description 2
- QNVKPJHZEBSGST-UHFFFAOYSA-N 3-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-1-pyrrolidin-3-ylpyrazolo[3,4-d]pyrimidin-4-amine hydrochloride Chemical compound Cl.COc1cc(C)cc2cc(sc12)-c1nn(C2CCNC2)c2ncnc(N)c12 QNVKPJHZEBSGST-UHFFFAOYSA-N 0.000 description 2
- HQAIUXZORKJOJY-UHFFFAOYSA-N 3-iodo-2h-pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound NC1=NC=NC2=NNC(I)=C12 HQAIUXZORKJOJY-UHFFFAOYSA-N 0.000 description 2
- WSXCJSFYYZMOCF-UHFFFAOYSA-N 4-[2-(4-chloro-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)ethyl]morpholine Chemical compound ClC=1C2=C(N=CN=1)N(C=C2I)CCN1CCOCC1 WSXCJSFYYZMOCF-UHFFFAOYSA-N 0.000 description 2
- ONMMXQOCWXUHJK-UHFFFAOYSA-N 4-chloro-1-iodo-2-methoxybenzene Chemical compound COC1=CC(Cl)=CC=C1I ONMMXQOCWXUHJK-UHFFFAOYSA-N 0.000 description 2
- WOXLPNAOCCIZGP-UHFFFAOYSA-N 4-chloro-2-methoxyaniline Chemical compound COC1=CC(Cl)=CC=C1N WOXLPNAOCCIZGP-UHFFFAOYSA-N 0.000 description 2
- WEGGBXZHIWVHOI-UHFFFAOYSA-N 4-chloro-2-methylsulfanyl-7h-pyrrolo[2,3-d]pyrimidine Chemical compound CSC1=NC(Cl)=C2C=CNC2=N1 WEGGBXZHIWVHOI-UHFFFAOYSA-N 0.000 description 2
- UVOGWAXIJDPGKG-UHFFFAOYSA-N 4-chloro-5-iodo-2-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidine Chemical compound ClC=1C2=C(N=C(N=1)SC)NC=C2I UVOGWAXIJDPGKG-UHFFFAOYSA-N 0.000 description 2
- BPTCCCTWWAUJRK-UHFFFAOYSA-N 4-chloro-7h-pyrrolo[2,3-d]pyrimidine Chemical compound ClC1=NC=NC2=C1C=CN2 BPTCCCTWWAUJRK-UHFFFAOYSA-N 0.000 description 2
- SMWFASGYGMSWCV-UHFFFAOYSA-N 7-(azetidin-3-yl)-5-(1H-indol-2-yl)pyrrolo[2,3-d]pyrimidin-4-amine hydrochloride Chemical compound Cl.Nc1ncnc2n(cc(-c3cc4ccccc4[nH]3)c12)C1CNC1 SMWFASGYGMSWCV-UHFFFAOYSA-N 0.000 description 2
- CHZGXRBSKNPVJW-UHFFFAOYSA-N 7-(azetidin-3-yl)-5-(6-methoxy-1-benzothiophen-2-yl)pyrrolo[2,3-d]pyrimidin-4-amine hydrochloride Chemical compound Cl.COc1ccc2cc(sc2c1)-c1cn(C2CNC2)c2ncnc(N)c12 CHZGXRBSKNPVJW-UHFFFAOYSA-N 0.000 description 2
- BJQMFVJWJZTWNT-UHFFFAOYSA-N 7-(azetidin-3-yl)-5-(7-methoxy-1-benzothiophen-2-yl)pyrrolo[2,3-d]pyrimidin-4-amine hydrochloride Chemical compound Cl.COc1cccc2cc(sc12)-c1cn(C2CNC2)c2ncnc(N)c12 BJQMFVJWJZTWNT-UHFFFAOYSA-N 0.000 description 2
- NRCUNBRHUYPYFB-UHFFFAOYSA-N 7-(azetidin-3-yl)-5-(7-methoxy-5-methyl-1-benzofuran-2-yl)pyrrolo[2,3-d]pyrimidin-4-amine hydrochloride Chemical compound Cl.COc1cc(C)cc2cc(oc12)-c1cn(C2CNC2)c2ncnc(N)c12 NRCUNBRHUYPYFB-UHFFFAOYSA-N 0.000 description 2
- LHCPRYRLDOSKHK-UHFFFAOYSA-N 7-deaza-8-aza-adenine Chemical class NC1=NC=NC2=C1C=NN2 LHCPRYRLDOSKHK-UHFFFAOYSA-N 0.000 description 2
- QZZBRTIQFYHWOK-UHFFFAOYSA-N 7-methoxy-1-benzothiophene-5-carboxylic acid Chemical compound COC1=CC(C(O)=O)=CC2=C1SC=C2 QZZBRTIQFYHWOK-UHFFFAOYSA-N 0.000 description 2
- FXPFLVMLMVBFPP-UHFFFAOYSA-N 7-methoxy-5-methyl-1-benzofuran Chemical compound COC1=CC(C)=CC2=C1OC=C2 FXPFLVMLMVBFPP-UHFFFAOYSA-N 0.000 description 2
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- WZNQHTWJCDJOCR-UHFFFAOYSA-N COC=1C=CC2=C(SC(=C2)OB(O)O)C1 Chemical compound COC=1C=CC2=C(SC(=C2)OB(O)O)C1 WZNQHTWJCDJOCR-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 229940125830 FGFR1 inhibitor Drugs 0.000 description 2
- 229940125408 FGFR4 inhibitor Drugs 0.000 description 2
- 102100027842 Fibroblast growth factor receptor 3 Human genes 0.000 description 2
- 101710182396 Fibroblast growth factor receptor 3 Proteins 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 241000699660 Mus musculus Species 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- JRJYJRWQFNROFA-UHFFFAOYSA-N N-[3-[[4-amino-3-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]phenyl]prop-2-enamide Chemical compound COc1cc(C)cc2cc(sc12)-c1nn(Cc2cccc(NC(=O)C=C)c2)c2ncnc(N)c12 JRJYJRWQFNROFA-UHFFFAOYSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 230000033115 angiogenesis Effects 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 2
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940126543 compound 14 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- MLIREBYILWEBDM-UHFFFAOYSA-N cyanoacetic acid Chemical group OC(=O)CC#N MLIREBYILWEBDM-UHFFFAOYSA-N 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 230000007783 downstream signaling Effects 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 2
- ZAVSJWMFJXEOBH-UHFFFAOYSA-N ethyl 7-methoxy-1-benzothiophene-5-carboxylate Chemical compound COC1=CC(=CC=2C=CSC=21)C(=O)OCC ZAVSJWMFJXEOBH-UHFFFAOYSA-N 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 125000002346 iodo group Chemical group I* 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 2
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 2
- 238000013508 migration Methods 0.000 description 2
- FLGCKPIDGVTCSU-UHFFFAOYSA-N n-[2-(dimethylamino)ethyl]acetamide Chemical compound CN(C)CCNC(C)=O FLGCKPIDGVTCSU-UHFFFAOYSA-N 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 239000004006 olive oil Substances 0.000 description 2
- 239000006186 oral dosage form Substances 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000004537 pulping Methods 0.000 description 2
- OYRRZWATULMEPF-UHFFFAOYSA-N pyrimidin-4-amine Chemical compound NC1=CC=NC=N1 OYRRZWATULMEPF-UHFFFAOYSA-N 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 239000011535 reaction buffer Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000008159 sesame oil Substances 0.000 description 2
- 235000011803 sesame oil Nutrition 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 235000010288 sodium nitrite Nutrition 0.000 description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 235000012222 talc Nutrition 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
- GKMJXFGEBGGQAG-SECBINFHSA-N tert-butyl (3r)-3-(4-amino-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC[C@H]1N1C2=NC=NC(N)=C2C(I)=C1 GKMJXFGEBGGQAG-SECBINFHSA-N 0.000 description 2
- GKMJXFGEBGGQAG-VIFPVBQESA-N tert-butyl (3s)-3-(4-amino-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC[C@@H]1N1C2=NC=NC(N)=C2C(I)=C1 GKMJXFGEBGGQAG-VIFPVBQESA-N 0.000 description 2
- FYSDBBNBDBMFQL-VIFPVBQESA-N tert-butyl (3s)-3-(4-chloro-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC[C@@H]1N1C2=NC=NC(Cl)=C2C(I)=C1 FYSDBBNBDBMFQL-VIFPVBQESA-N 0.000 description 2
- BOYYWVBZUOVEAW-UHFFFAOYSA-N tert-butyl 3-(4-amino-3-iodopyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC1N1C2=NC=NC(N)=C2C(I)=N1 BOYYWVBZUOVEAW-UHFFFAOYSA-N 0.000 description 2
- CREUBWCYHXMGFC-UHFFFAOYSA-N tert-butyl 3-[4-amino-3-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrazolo[3,4-d]pyrimidin-1-yl]azetidine-1-carboxylate Chemical compound COc1cc(C)cc2cc(sc12)-c1nn(C2CN(C2)C(=O)OC(C)(C)C)c2ncnc(N)c12 CREUBWCYHXMGFC-UHFFFAOYSA-N 0.000 description 2
- LODNEOKKZOOQOO-UHFFFAOYSA-N tert-butyl 3-[4-amino-5-(6-methoxy-1-benzothiophen-2-yl)pyrrolo[2,3-d]pyrimidin-7-yl]azetidine-1-carboxylate Chemical compound COc1ccc2cc(sc2c1)-c1cn(C2CN(C2)C(=O)OC(C)(C)C)c2ncnc(N)c12 LODNEOKKZOOQOO-UHFFFAOYSA-N 0.000 description 2
- AWNMUJQLNBGOLV-UHFFFAOYSA-N tert-butyl 3-[4-amino-6-chloro-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,3-d]pyrimidin-7-yl]pyrrolidine-1-carboxylate Chemical compound COc1cc(C)cc2cc(sc12)-c1c(Cl)n(C2CCN(C2)C(=O)OC(C)(C)C)c2ncnc(N)c12 AWNMUJQLNBGOLV-UHFFFAOYSA-N 0.000 description 2
- XXBDTKYKFFIAEY-UHFFFAOYSA-N tert-butyl 3-methylsulfonyloxyazetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1 XXBDTKYKFFIAEY-UHFFFAOYSA-N 0.000 description 2
- QGGKTCCQDJRXNI-UHFFFAOYSA-N tert-butyl formate pyrrolidin-3-ol Chemical compound OC1CCNC1.CC(C)(C)OC=O QGGKTCCQDJRXNI-UHFFFAOYSA-N 0.000 description 2
- YISWAJAOTHIFSW-UHFFFAOYSA-N tert-butyl formate pyrrolidine Chemical compound C(C)(C)(C)OC=O.N1CCCC1 YISWAJAOTHIFSW-UHFFFAOYSA-N 0.000 description 2
- OWPIFQXNMLDXKW-UHFFFAOYSA-N tert-butyl indole-1-carboxylate Chemical compound C1=CC=C2N(C(=O)OC(C)(C)C)C=CC2=C1 OWPIFQXNMLDXKW-UHFFFAOYSA-N 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Chemical compound O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- GCTFTMWXZFLTRR-GFCCVEGCSA-N (2r)-2-amino-n-[3-(difluoromethoxy)-4-(1,3-oxazol-5-yl)phenyl]-4-methylpentanamide Chemical compound FC(F)OC1=CC(NC(=O)[C@H](N)CC(C)C)=CC=C1C1=CN=CO1 GCTFTMWXZFLTRR-GFCCVEGCSA-N 0.000 description 1
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical class OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- XUIURRYWQBBCCK-UHFFFAOYSA-N (3,5-dimethoxyphenyl)boronic acid Chemical compound COC1=CC(OC)=CC(B(O)O)=C1 XUIURRYWQBBCCK-UHFFFAOYSA-N 0.000 description 1
- OJZQOQNSUZLSMV-UHFFFAOYSA-N (3-aminophenyl)methanol Chemical compound NC1=CC=CC(CO)=C1 OJZQOQNSUZLSMV-UHFFFAOYSA-N 0.000 description 1
- OOKAZRDERJMRCJ-KOUAFAAESA-N (3r)-7-[(1s,2s,4ar,6s,8s)-2,6-dimethyl-8-[(2s)-2-methylbutanoyl]oxy-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl]-3-hydroxy-5-oxoheptanoic acid Chemical compound C1=C[C@H](C)[C@H](CCC(=O)C[C@@H](O)CC(O)=O)C2[C@@H](OC(=O)[C@@H](C)CC)C[C@@H](C)C[C@@H]21 OOKAZRDERJMRCJ-KOUAFAAESA-N 0.000 description 1
- DECWLXUOZUMPBF-UHFFFAOYSA-N (4-cyano-3-fluorophenyl)boronic acid Chemical compound OB(O)C1=CC=C(C#N)C(F)=C1 DECWLXUOZUMPBF-UHFFFAOYSA-N 0.000 description 1
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 1
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 1
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 description 1
- 125000006714 (C3-C10) heterocyclyl group Chemical group 0.000 description 1
- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 description 1
- JKWPSZWWCDRXFP-QWNKOJSDSA-N (E)-1-[(3S)-3-[4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,3-d]pyrimidin-7-yl]pyrrolidin-1-yl]-4-(dimethylamino)but-2-en-1-one Chemical compound COC1=C2SC(=CC2=CC(C)=C1)C1=CN([C@H]2CCN(C2)C(=O)\C=C\CN(C)C)C2=C1C(N)=NC=N2 JKWPSZWWCDRXFP-QWNKOJSDSA-N 0.000 description 1
- WUFIKSYTVNYXHW-AATRIKPKSA-N (E)-1-[3-[4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,3-d]pyrimidin-7-yl]azetidin-1-yl]-4-pyrrolidin-1-ylbut-2-en-1-one Chemical compound NC=1C2=C(N=CN=1)N(C=C2C=1SC2=C(C=1)C=C(C=C2OC)C)C1CN(C1)C(\C=C\CN1CCCC1)=O WUFIKSYTVNYXHW-AATRIKPKSA-N 0.000 description 1
- FBRFPMODLGKJBC-ONEGZZNKSA-N (E)-1-[3-[4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,3-d]pyrimidin-7-yl]pyrrolidin-1-yl]-4-(3-fluoropyrrolidin-1-yl)but-2-en-1-one Chemical compound COc1cc(C)cc2cc(sc12)-c1cn(C2CCN(C2)C(=O)\C=C\CN2CCC(F)C2)c2ncnc(N)c12 FBRFPMODLGKJBC-ONEGZZNKSA-N 0.000 description 1
- OEZNWGXHRVJBGW-TYYBGVCCSA-N (E)-4-(3-fluoropyrrolidin-1-yl)but-2-enoic acid hydrochloride Chemical group Cl.OC(=O)\C=C\CN1CCC(F)C1 OEZNWGXHRVJBGW-TYYBGVCCSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- ITGIYLMMAABTHC-ONEGZZNKSA-N (e)-4-(dimethylazaniumyl)but-2-enoate Chemical group CN(C)C\C=C\C(O)=O ITGIYLMMAABTHC-ONEGZZNKSA-N 0.000 description 1
- 229940058015 1,3-butylene glycol Drugs 0.000 description 1
- DJMOXMNDXFFONV-UHFFFAOYSA-N 1,3-dimethyl-7-[2-(n-methylanilino)ethyl]purine-2,6-dione Chemical compound C1=NC=2N(C)C(=O)N(C)C(=O)C=2N1CCN(C)C1=CC=CC=C1 DJMOXMNDXFFONV-UHFFFAOYSA-N 0.000 description 1
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 1
- IQJPWAAWPFBLPZ-INIZCTEOSA-N 1-[(3S)-3-(4-amino-5-quinolin-3-ylpyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl]prop-2-en-1-one Chemical compound NC1=NC=NC2=C1C(=CN2[C@H]1CCN(C1)C(=O)C=C)C1=CC2=CC=CC=C2N=C1 IQJPWAAWPFBLPZ-INIZCTEOSA-N 0.000 description 1
- AIEJFFPKVRHDJZ-AWEZNQCLSA-N 1-[(3S)-3-[4-amino-3-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrazolo[3,4-d]pyrimidin-1-yl]pyrrolidin-1-yl]prop-2-yn-1-one Chemical compound NC1=C2C(=NC=N1)N(N=C2C=1SC2=C(C=1)C=C(C=C2OC)C)[C@@H]1CN(CC1)C(C#C)=O AIEJFFPKVRHDJZ-AWEZNQCLSA-N 0.000 description 1
- SRZVKCDOUAJEKY-AWEZNQCLSA-N 1-[(3S)-3-[4-amino-5-(5-chloro-7-methoxy-1-benzothiophen-2-yl)pyrrolo[2,3-d]pyrimidin-7-yl]pyrrolidin-1-yl]prop-2-en-1-one Chemical compound COC1=C2SC(=CC2=CC(Cl)=C1)C1=CN([C@H]2CCN(C2)C(=O)C=C)C2=C1C(N)=NC=N2 SRZVKCDOUAJEKY-AWEZNQCLSA-N 0.000 description 1
- QWGUTUKCPRERRM-AWEZNQCLSA-N 1-[(3S)-3-[4-amino-5-(7-methoxy-1-benzothiophen-2-yl)pyrrolo[2,3-d]pyrimidin-7-yl]pyrrolidin-1-yl]prop-2-en-1-one Chemical compound NC=1C2=C(N=CN=1)N(C=C2C=1SC2=C(C=1)C=CC=C2OC)[C@@H]1CN(CC1)C(C=C)=O QWGUTUKCPRERRM-AWEZNQCLSA-N 0.000 description 1
- KSJXHYQHYJPCLP-INIZCTEOSA-N 1-[(3S)-3-[5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-4-(methylamino)pyrrolo[2,3-d]pyrimidin-7-yl]pyrrolidin-1-yl]prop-2-en-1-one Chemical compound CNC1=NC=NC2=C1C(=CN2[C@H]1CCN(C1)C(=O)C=C)C1=CC2=CC(C)=CC(OC)=C2S1 KSJXHYQHYJPCLP-INIZCTEOSA-N 0.000 description 1
- JNTQGCDOWBHEAQ-UHFFFAOYSA-N 1-[3-[4-(dimethylamino)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,3-d]pyrimidin-7-yl]pyrrolidin-1-yl]prop-2-en-1-one Chemical compound COc1cc(C)cc2cc(sc12)-c1cn(C2CCN(C2)C(=O)C=C)c2ncnc(N(C)C)c12 JNTQGCDOWBHEAQ-UHFFFAOYSA-N 0.000 description 1
- KOCCHFAIPYNBNH-UHFFFAOYSA-N 1-[3-[4-amino-2-chloro-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,3-d]pyrimidin-7-yl]azetidin-1-yl]prop-2-en-1-one Chemical compound NC=1C2=C(N=C(N=1)Cl)N(C=C2C=1SC2=C(C=1)C=C(C=C2OC)C)C1CN(C1)C(C=C)=O KOCCHFAIPYNBNH-UHFFFAOYSA-N 0.000 description 1
- ZTUAPVPZLCYLAP-UHFFFAOYSA-N 1-[3-[4-amino-3-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrazolo[3,4-d]pyrimidin-1-yl]azetidin-1-yl]prop-2-en-1-one Chemical compound COc1cc(C)cc2cc(sc12)-c1nn(C2CN(C2)C(=O)C=C)c2ncnc(N)c12 ZTUAPVPZLCYLAP-UHFFFAOYSA-N 0.000 description 1
- LTMQMQGCGOYYDY-UHFFFAOYSA-N 1-[3-[4-amino-3-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrazolo[3,4-d]pyrimidin-1-yl]azetidin-1-yl]prop-2-yn-1-one Chemical compound COc1cc(C)cc2cc(sc12)-c1nn(C2CN(C2)C(=O)C#C)c2ncnc(N)c12 LTMQMQGCGOYYDY-UHFFFAOYSA-N 0.000 description 1
- LOWQPOVYRCZDIP-UHFFFAOYSA-N 1-[3-[4-amino-3-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrazolo[3,4-d]pyrimidin-1-yl]pyrrolidin-1-yl]-2-chloroethanone Chemical compound COc1cc(C)cc2cc(sc12)-c1nn(C2CCN(C2)C(=O)CCl)c2ncnc(N)c12 LOWQPOVYRCZDIP-UHFFFAOYSA-N 0.000 description 1
- HLRISBLSHWIQBN-UHFFFAOYSA-N 1-[3-[4-amino-5-(1-benzothiophen-2-yl)pyrrolo[2,3-d]pyrimidin-7-yl]azetidin-1-yl]prop-2-en-1-one Chemical compound Nc1ncnc2n(cc(-c3cc4ccccc4s3)c12)C1CN(C1)C(=O)C=C HLRISBLSHWIQBN-UHFFFAOYSA-N 0.000 description 1
- QAHRYUQGKAWIJV-UHFFFAOYSA-N 1-[3-[4-amino-5-(3-amino-1H-indazol-6-yl)pyrrolo[2,3-d]pyrimidin-7-yl]pyrrolidin-1-yl]prop-2-en-1-one Chemical compound Nc1n[nH]c2cc(ccc12)-c1cn(C2CCN(C2)C(=O)C=C)c2ncnc(N)c12 QAHRYUQGKAWIJV-UHFFFAOYSA-N 0.000 description 1
- UKAGLCCFNDEZAF-UHFFFAOYSA-N 1-[3-[4-amino-5-(4,7-dimethoxy-1-benzothiophen-2-yl)pyrrolo[2,3-d]pyrimidin-7-yl]azetidin-1-yl]prop-2-en-1-one Chemical compound COc1ccc(OC)c2sc(cc12)-c1cn(C2CN(C2)C(=O)C=C)c2ncnc(N)c12 UKAGLCCFNDEZAF-UHFFFAOYSA-N 0.000 description 1
- DRNRSURPJMEOEL-UHFFFAOYSA-N 1-[3-[4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-2-(2-morpholin-4-ylethoxy)pyrrolo[2,3-d]pyrimidin-7-yl]pyrrolidin-1-yl]prop-2-en-1-one Chemical compound COc1cc(C)cc2cc(sc12)-c1cn(C2CCN(C2)C(=O)C=C)c2nc(OCCN3CCOCC3)nc(N)c12 DRNRSURPJMEOEL-UHFFFAOYSA-N 0.000 description 1
- YSMBBAKJHNAZTO-UHFFFAOYSA-N 1-[3-[4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,3-d]pyrimidin-7-yl]pyrrolidin-1-yl]prop-2-yn-1-one Chemical compound NC=1C2=C(N=CN=1)N(C=C2C=1SC2=C(C=1)C=C(C=C2OC)C)C1CN(CC1)C(C#C)=O YSMBBAKJHNAZTO-UHFFFAOYSA-N 0.000 description 1
- DOWBTQHWXGZIER-UHFFFAOYSA-N 1-[3-[4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,3-d]pyrimidin-7-yl]pyrrolidin-1-yl]propan-1-one Chemical compound NC=1C2=C(N=CN=1)N(C=C2C=1SC2=C(C=1)C=C(C=C2OC)C)C1CN(CC1)C(CC)=O DOWBTQHWXGZIER-UHFFFAOYSA-N 0.000 description 1
- VNADRHYCOKIGMT-UHFFFAOYSA-N 1-[3-[4-amino-5-(7-methyl-1-benzothiophen-2-yl)pyrrolo[2,3-d]pyrimidin-7-yl]pyrrolidin-1-yl]prop-2-en-1-one Chemical compound NC=1C2=C(N=CN=1)N(C=C2C=1SC2=C(C=1)C=CC=C2C)C1CN(CC1)C(C=C)=O VNADRHYCOKIGMT-UHFFFAOYSA-N 0.000 description 1
- XMQRYANXYWPPDH-UHFFFAOYSA-N 1-[3-[4-amino-5-[7-methoxy-5-(trifluoromethyl)-1-benzothiophen-2-yl]pyrrolo[2,3-d]pyrimidin-7-yl]pyrrolidin-1-yl]prop-2-en-1-one Chemical compound COc1cc(cc2cc(sc12)-c1cn(C2CCN(C2)C(=O)C=C)c2ncnc(N)c12)C(F)(F)F XMQRYANXYWPPDH-UHFFFAOYSA-N 0.000 description 1
- VULCMDJSLPODLG-UHFFFAOYSA-N 1-[3-[4-amino-6-chloro-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,3-d]pyrimidin-7-yl]-2,4-dihydropyrimidin-1-yl]prop-2-en-1-one Chemical compound NC=1C2=C(N=CN1)N(C(=C2C=2SC1=C(C2)C=C(C=C1OC)C)Cl)N1CN(C=CC1)C(C=C)=O VULCMDJSLPODLG-UHFFFAOYSA-N 0.000 description 1
- QUCWQWPYVVDMPX-UHFFFAOYSA-N 1-[4-[4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,3-d]pyrimidin-7-yl]-2-(hydroxymethyl)pyrrolidin-1-yl]prop-2-en-1-one Chemical compound COc1cc(C)cc2cc(sc12)-c1cn(C2CC(CO)N(C2)C(=O)C=C)c2ncnc(N)c12 QUCWQWPYVVDMPX-UHFFFAOYSA-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
- MZMNEDXVUJLQAF-SFYZADRCSA-N 1-o-tert-butyl 2-o-methyl (2s,4r)-4-hydroxypyrrolidine-1,2-dicarboxylate Chemical group COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C MZMNEDXVUJLQAF-SFYZADRCSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- GHXBPCSSQOKKGB-UHFFFAOYSA-N 2,4-dichloro-7h-pyrrolo[2,3-d]pyrimidine Chemical compound ClC1=NC(Cl)=C2C=CNC2=N1 GHXBPCSSQOKKGB-UHFFFAOYSA-N 0.000 description 1
- FZHTUELUUNCLRZ-UHFFFAOYSA-N 2,4-dimethoxybenzenethiol Chemical compound COC1=CC=C(S)C(OC)=C1 FZHTUELUUNCLRZ-UHFFFAOYSA-N 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- OLUDEMZRGNTBKV-UHFFFAOYSA-N 2-(2-methoxyphenyl)benzenethiol Chemical group COC1=CC=CC=C1C1=CC=CC=C1S OLUDEMZRGNTBKV-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical class NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- DSCJETUEDFKYGN-UHFFFAOYSA-N 2-Methoxybenzenethiol Chemical compound COC1=CC=CC=C1S DSCJETUEDFKYGN-UHFFFAOYSA-N 0.000 description 1
- LXUNZSDDXMPKLP-UHFFFAOYSA-N 2-Methylbenzenethiol Chemical compound CC1=CC=CC=C1S LXUNZSDDXMPKLP-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- CABSKTWHKWJRDE-UHFFFAOYSA-N 2-[3-[4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,3-d]pyrimidin-7-yl]pyrrolidine-1-carbonyl]-3-cyclopropylprop-2-enenitrile Chemical compound COC1=C2SC(=CC2=CC(C)=C1)C1=CN(C2CCN(C2)C(=O)C(=CC2CC2)C#N)C2=C1C(N)=NC=N2 CABSKTWHKWJRDE-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- PNDNJUUEMRVVER-UHFFFAOYSA-N 2-[4-amino-7-(1-prop-2-enoylpyrrolidin-3-yl)pyrrolo[2,3-d]pyrimidin-5-yl]-7-methoxy-1-benzothiophene-5-carboxylic acid Chemical compound C(C=C)(=O)N1CC(CC1)N1C=C(C2=C1N=CN=C2N)C=1SC2=C(C=1)C=C(C=C2OC)C(=O)O PNDNJUUEMRVVER-UHFFFAOYSA-N 0.000 description 1
- MLFIYYDKLNZLAO-UHFFFAOYSA-N 2-aminoethane-1,1-diol Chemical class NCC(O)O MLFIYYDKLNZLAO-UHFFFAOYSA-N 0.000 description 1
- LILXDMFJXYAKMK-UHFFFAOYSA-N 2-bromo-1,1-diethoxyethane Chemical compound CCOC(CBr)OCC LILXDMFJXYAKMK-UHFFFAOYSA-N 0.000 description 1
- VHCSBTPOPKFYIU-UHFFFAOYSA-N 2-chloroethanesulfonyl chloride Chemical compound ClCCS(Cl)(=O)=O VHCSBTPOPKFYIU-UHFFFAOYSA-N 0.000 description 1
- YBDVVSMQYQJAER-UHFFFAOYSA-N 2-methoxy-4-methylbenzenethiol Chemical compound COC1=CC(C)=CC=C1S YBDVVSMQYQJAER-UHFFFAOYSA-N 0.000 description 1
- BMIBJCFFZPYJHF-UHFFFAOYSA-N 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound COC1=NC=C(C)C=C1B1OC(C)(C)C(C)(C)O1 BMIBJCFFZPYJHF-UHFFFAOYSA-N 0.000 description 1
- YLZXOIATWSHVDK-UHFFFAOYSA-N 2-methylsulfanyl-1,7-dihydropyrrolo[2,3-d]pyrimidin-4-one Chemical compound N1C(SC)=NC(=O)C2=C1NC=C2 YLZXOIATWSHVDK-UHFFFAOYSA-N 0.000 description 1
- UGEJOEBBMPOJMT-UHFFFAOYSA-N 3-(trifluoromethyl)phenol Chemical compound OC1=CC=CC(C(F)(F)F)=C1 UGEJOEBBMPOJMT-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- ABEUJUYEUCCZQF-UHFFFAOYSA-N 4-chloro-2-methoxy-1-nitrobenzene Chemical compound COC1=CC(Cl)=CC=C1[N+]([O-])=O ABEUJUYEUCCZQF-UHFFFAOYSA-N 0.000 description 1
- RHVXSMCXTRVNJP-ZOWNYOTGSA-N 5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-[(3S)-pyrrolidin-3-yl]pyrrolo[2,3-d]pyrimidin-4-amine hydrochloride Chemical compound Cl.COc1cc(C)cc2cc(sc12)-c1cn([C@H]2CCNC2)c2ncnc(N)c12 RHVXSMCXTRVNJP-ZOWNYOTGSA-N 0.000 description 1
- VTXLFQCJWCDZSE-UHFFFAOYSA-N 5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-pyrrolidin-3-ylpyrrolo[2,3-d]pyrimidin-4-amine Chemical compound NC=1C2=C(N=CN=1)N(C=C2C=1SC2=C(C=1)C=C(C=C2OC)C)C1CNCC1 VTXLFQCJWCDZSE-UHFFFAOYSA-N 0.000 description 1
- FFNKBQRKZRMYCL-UHFFFAOYSA-N 5-amino-1h-pyrazole-4-carbonitrile Chemical compound NC1=NNC=C1C#N FFNKBQRKZRMYCL-UHFFFAOYSA-N 0.000 description 1
- 125000006163 5-membered heteroaryl group Chemical group 0.000 description 1
- NQXUSSVLFOBRSE-UHFFFAOYSA-N 5-methyl-2-nitrophenol Chemical compound CC1=CC=C([N+]([O-])=O)C(O)=C1 NQXUSSVLFOBRSE-UHFFFAOYSA-N 0.000 description 1
- LOWUCVWGIWOXOG-UHFFFAOYSA-N 7-(1-ethenylsulfonylazetidin-3-yl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,3-d]pyrimidin-4-amine Chemical compound COC1=CC(=CC=2C=C(SC=21)C1=CN(C=2N=CN=C(C=21)N)C1CN(C1)S(=O)(=O)C=C)C LOWUCVWGIWOXOG-UHFFFAOYSA-N 0.000 description 1
- QPLLPLLBBSWRTM-UHFFFAOYSA-N 7-methoxy-1-benzofuran Chemical compound COC1=CC=CC2=C1OC=C2 QPLLPLLBBSWRTM-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 125000005330 8 membered heterocyclic group Chemical group 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 235000003276 Apios tuberosa Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 235000010744 Arachis villosulicarpa Nutrition 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- OJNSSHZIVIFVFY-UHFFFAOYSA-N C(=O)OC(C)(C)C.OC1CNC1 Chemical group C(=O)OC(C)(C)C.OC1CNC1 OJNSSHZIVIFVFY-UHFFFAOYSA-N 0.000 description 1
- YORBOWQXTYHILG-UHFFFAOYSA-N C(=O)OC(C)(C)C.S(=O)(=O)(C)OC1CNC1 Chemical compound C(=O)OC(C)(C)C.S(=O)(=O)(C)OC1CNC1 YORBOWQXTYHILG-UHFFFAOYSA-N 0.000 description 1
- 125000000041 C6-C10 aryl group Chemical group 0.000 description 1
- IXKIQLNWDWYMDN-UHFFFAOYSA-N CC1=CC2=C(C(=C1)OC)SC(=C2)C3=NN(C=C3)C4CCNC4 Chemical compound CC1=CC2=C(C(=C1)OC)SC(=C2)C3=NN(C=C3)C4CCNC4 IXKIQLNWDWYMDN-UHFFFAOYSA-N 0.000 description 1
- BMEQOQISNGBGFF-UHFFFAOYSA-N CC1=CC2=C(C(=C1)OC)SC(=C2)C3=NN(C=C3)C4CNC4 Chemical compound CC1=CC2=C(C(=C1)OC)SC(=C2)C3=NN(C=C3)C4CNC4 BMEQOQISNGBGFF-UHFFFAOYSA-N 0.000 description 1
- NCSMSZLYSKPVKY-UHFFFAOYSA-N COC1=C2SC(=CC2=CC(C)=C1)C1=CN(C2CN(C2)C(=O)C(=CC2CC2)C#N)C2=C1C(N)=NC=N2 Chemical compound COC1=C2SC(=CC2=CC(C)=C1)C1=CN(C2CN(C2)C(=O)C(=CC2CC2)C#N)C2=C1C(N)=NC=N2 NCSMSZLYSKPVKY-UHFFFAOYSA-N 0.000 description 1
- QIQFEIKRPSWFBX-UHFFFAOYSA-N COC1=CC(=CC=2C=C(SC=21)OB(O)O)C Chemical compound COC1=CC(=CC=2C=C(SC=21)OB(O)O)C QIQFEIKRPSWFBX-UHFFFAOYSA-N 0.000 description 1
- LFDGFEUCCQELDJ-UHFFFAOYSA-N COC=1C=C(C=CC=1)C1=C(C=CC=C1)S Chemical group COC=1C=C(C=CC=1)C1=C(C=CC=C1)S LFDGFEUCCQELDJ-UHFFFAOYSA-N 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical class NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- 241000206672 Gelidium Species 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- JYBPARJXWMTCLP-UHFFFAOYSA-N N-[2-[4-amino-3-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrazolo[3,4-d]pyrimidin-1-yl]ethyl]prop-2-enamide Chemical compound COc1cc(C)cc2cc(sc12)-c1nn(CCNC(=O)C=C)c2ncnc(N)c12 JYBPARJXWMTCLP-UHFFFAOYSA-N 0.000 description 1
- MLGMVEAIWOTYGF-UHFFFAOYSA-N N-[2-[4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]prop-2-enamide Chemical compound NC=1C2=C(N=CN=1)N(C=C2C=1SC2=C(C=1)C=C(C=C2OC)C)CCNC(C=C)=O MLGMVEAIWOTYGF-UHFFFAOYSA-N 0.000 description 1
- MQNZARJVRSNEJL-UHFFFAOYSA-N N-[4-[4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl]prop-2-enamide Chemical compound NC=1C2=C(N=CN=1)N(C=C2C=1SC2=C(C=1)C=C(C=C2OC)C)C1CCC(CC1)NC(C=C)=O MQNZARJVRSNEJL-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 229910020700 Na3VO4 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 240000007817 Olea europaea Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 235000004443 Ricinus communis Nutrition 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- SSZBUIDZHHWXNJ-UHFFFAOYSA-N Stearinsaeure-hexadecylester Natural products CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC SSZBUIDZHHWXNJ-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical class OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 239000003655 absorption accelerator Substances 0.000 description 1
- 150000001241 acetals Chemical group 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000004450 alkenylene group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 230000035578 autophosphorylation Effects 0.000 description 1
- 210000001099 axilla Anatomy 0.000 description 1
- AKUXORNKVIRDKN-UHFFFAOYSA-N azetidine tert-butyl formate Chemical compound C(C)(C)(C)OC=O.N1CCC1 AKUXORNKVIRDKN-UHFFFAOYSA-N 0.000 description 1
- 125000000751 azo group Chemical group [*]N=N[*] 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 125000005620 boronic acid group Chemical class 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- LUEHNHVFDCZTGL-UHFFFAOYSA-N but-2-ynoic acid Chemical group CC#CC(O)=O LUEHNHVFDCZTGL-UHFFFAOYSA-N 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 230000019522 cellular metabolic process Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229940125900 compound 59 Drugs 0.000 description 1
- 239000000110 cooling liquid Substances 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- DMSZORWOGDLWGN-UHFFFAOYSA-N ctk1a3526 Chemical compound NP(N)(N)=O DMSZORWOGDLWGN-UHFFFAOYSA-N 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- JMYVMOUINOAAPA-UHFFFAOYSA-N cyclopropanecarbaldehyde Chemical compound O=CC1CC1 JMYVMOUINOAAPA-UHFFFAOYSA-N 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 150000001993 dienes Chemical class 0.000 description 1
- 150000005332 diethylamines Chemical class 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 150000004656 dimethylamines Chemical class 0.000 description 1
- 230000003467 diminishing effect Effects 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- AHKACZDKUNMFBD-UHFFFAOYSA-N ethyl 2-cyano-4,4-diethoxybutanoate Chemical compound CCOC(OCC)CC(C#N)C(=O)OCC AHKACZDKUNMFBD-UHFFFAOYSA-N 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 150000003947 ethylamines Chemical class 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 229930182478 glucoside Natural products 0.000 description 1
- 150000008131 glucosides Chemical class 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 230000009422 growth inhibiting effect Effects 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000002249 indol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([*])=C([H])C2=C1[H] 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 230000002601 intratumoral effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 238000006241 metabolic reaction Methods 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 150000003956 methylamines Chemical class 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- 150000005673 monoalkenes Chemical class 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- HVOYZOQVDYHUPF-UHFFFAOYSA-N n,n',n'-trimethylethane-1,2-diamine Chemical compound CNCCN(C)C HVOYZOQVDYHUPF-UHFFFAOYSA-N 0.000 description 1
- WFMDRIAQYUQXQQ-UHFFFAOYSA-M n-tert-butyl-n-(4-hydroxycyclohexyl)carbamate Chemical compound CC(C)(C)N(C([O-])=O)C1CCC(O)CC1 WFMDRIAQYUQXQQ-UHFFFAOYSA-M 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000005305 organ development Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 235000008729 phenylalanine Nutrition 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000000865 phosphorylative effect Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 230000004983 pleiotropic effect Effects 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- JCBJVAJGLKENNC-UHFFFAOYSA-M potassium ethyl xanthate Chemical compound [K+].CCOC([S-])=S JCBJVAJGLKENNC-UHFFFAOYSA-M 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 229960002429 proline Drugs 0.000 description 1
- 235000013930 proline Nutrition 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical group CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical class CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 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
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- APCBTRDHCDOPNY-SSDOTTSWSA-N tert-butyl (3r)-3-hydroxypyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC[C@@H](O)C1 APCBTRDHCDOPNY-SSDOTTSWSA-N 0.000 description 1
- APCBTRDHCDOPNY-ZETCQYMHSA-N tert-butyl (3s)-3-hydroxypyrrolidine-1-carboxylate Chemical group CC(C)(C)OC(=O)N1CC[C@H](O)C1 APCBTRDHCDOPNY-ZETCQYMHSA-N 0.000 description 1
- BFFLLBPMZCIGRM-UHFFFAOYSA-N tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate Chemical group CC(C)(C)OC(=O)N1CCCC1CO BFFLLBPMZCIGRM-UHFFFAOYSA-N 0.000 description 1
- KXOGFSKAAXBNCW-UHFFFAOYSA-N tert-butyl 2-[(4-chloro-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)methyl]pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC1CN1C2=NC=NC(Cl)=C2C(I)=C1 KXOGFSKAAXBNCW-UHFFFAOYSA-N 0.000 description 1
- WVIIUIJKRJCHHB-UHFFFAOYSA-N tert-butyl 2-[[tert-butyl(diphenyl)silyl]oxymethyl]-4-hydroxypyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(O)CC1CO[Si](C(C)(C)C)(C=1C=CC=CC=1)C1=CC=CC=C1 WVIIUIJKRJCHHB-UHFFFAOYSA-N 0.000 description 1
- VYFRMYRDVYLBIN-UHFFFAOYSA-N tert-butyl 3-(4-chloro-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC1N1C2=NC=NC(Cl)=C2C(I)=C1 VYFRMYRDVYLBIN-UHFFFAOYSA-N 0.000 description 1
- FYSDBBNBDBMFQL-UHFFFAOYSA-N tert-butyl 3-(4-chloro-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC1N1C2=NC=NC(Cl)=C2C(I)=C1 FYSDBBNBDBMFQL-UHFFFAOYSA-N 0.000 description 1
- HKIGXXRMJFUUKV-UHFFFAOYSA-N tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate Chemical group CC(C)(C)OC(=O)N1CCC(CO)C1 HKIGXXRMJFUUKV-UHFFFAOYSA-N 0.000 description 1
- JARWUNNMWXCNBE-UHFFFAOYSA-N tert-butyl 3-[(4-chloro-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)methyl]pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(Cn2cc(I)c3c(Cl)ncnc23)C1 JARWUNNMWXCNBE-UHFFFAOYSA-N 0.000 description 1
- WCDCWTJDKBRRBQ-UHFFFAOYSA-N tert-butyl 3-[4-amino-3-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrazolo[3,4-d]pyrimidin-1-yl]pyrrolidine-1-carboxylate Chemical compound COc1cc(C)cc2cc(sc12)-c1nn(C2CCN(C2)C(=O)OC(C)(C)C)c2ncnc(N)c12 WCDCWTJDKBRRBQ-UHFFFAOYSA-N 0.000 description 1
- SMZDJRVRSDELDO-UHFFFAOYSA-N tert-butyl 3-[4-amino-5-(3-amino-1H-indazol-6-yl)pyrrolo[2,3-d]pyrimidin-7-yl]pyrrolidine-1-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1CC(CC1)N1C=C(C2=C1N=CN=C2N)C1=CC=C2C(=NNC2=C1)N SMZDJRVRSDELDO-UHFFFAOYSA-N 0.000 description 1
- JYZAVBWHUUGCQZ-UHFFFAOYSA-N tert-butyl 3-[4-amino-5-(7-methoxy-5-methyl-1-benzofuran-2-yl)pyrrolo[2,3-d]pyrimidin-7-yl]azetidine-1-carboxylate Chemical compound COc1cc(C)cc2cc(oc12)-c1cn(C2CN(C2)C(=O)OC(C)(C)C)c2ncnc(N)c12 JYZAVBWHUUGCQZ-UHFFFAOYSA-N 0.000 description 1
- LXZVPZYWTIRTSI-UHFFFAOYSA-N tert-butyl 3-[4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,3-d]pyrimidin-7-yl]azetidine-1-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1CC(C1)N1C=C(C2=C1N=CN=C2N)C=1SC2=C(C=1)C=C(C=C2OC)C LXZVPZYWTIRTSI-UHFFFAOYSA-N 0.000 description 1
- XRRXRQJQQKMFBC-UHFFFAOYSA-N tert-butyl 3-hydroxyazetidine-1-carboxylate Chemical group CC(C)(C)OC(=O)N1CC(O)C1 XRRXRQJQQKMFBC-UHFFFAOYSA-N 0.000 description 1
- UIJXHKXIOCDSEB-UHFFFAOYSA-N tert-butyl 3-hydroxypiperidine-1-carboxylate Chemical group CC(C)(C)OC(=O)N1CCCC(O)C1 UIJXHKXIOCDSEB-UHFFFAOYSA-N 0.000 description 1
- WUCQUEBUUBZOGN-UHFFFAOYSA-N tert-butyl 4-[4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,3-d]pyrimidin-7-yl]-2-(hydroxymethyl)pyrrolidine-1-carboxylate Chemical compound COc1cc(C)cc2cc(sc12)-c1cn(C2CC(CO)N(C2)C(=O)OC(C)(C)C)c2ncnc(N)c12 WUCQUEBUUBZOGN-UHFFFAOYSA-N 0.000 description 1
- UFJNFQNQLMGUTQ-UHFFFAOYSA-N tert-butyl 4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(O)CC1CO UFJNFQNQLMGUTQ-UHFFFAOYSA-N 0.000 description 1
- PWQLFIKTGRINFF-UHFFFAOYSA-N tert-butyl 4-hydroxypiperidine-1-carboxylate Chemical group CC(C)(C)OC(=O)N1CCC(O)CC1 PWQLFIKTGRINFF-UHFFFAOYSA-N 0.000 description 1
- TZRQZPMQUXEZMC-UHFFFAOYSA-N tert-butyl n-(2-bromoethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCBr TZRQZPMQUXEZMC-UHFFFAOYSA-N 0.000 description 1
- KTQKOGBTMNDCFG-UHFFFAOYSA-N tert-butyl(diphenyl)silicon Chemical compound C=1C=CC=CC=1[Si](C(C)(C)C)C1=CC=CC=C1 KTQKOGBTMNDCFG-UHFFFAOYSA-N 0.000 description 1
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical class CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 150000005671 trienes Chemical class 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- UAEJRRZPRZCUBE-UHFFFAOYSA-N trimethoxyalumane Chemical compound [Al+3].[O-]C.[O-]C.[O-]C UAEJRRZPRZCUBE-UHFFFAOYSA-N 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical class CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- XPFJYKARVSSRHE-UHFFFAOYSA-K trisodium;2-hydroxypropane-1,2,3-tricarboxylate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].[Na+].OC(=O)CC(O)(C(O)=O)CC(O)=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O XPFJYKARVSSRHE-UHFFFAOYSA-K 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- WCJYTPVNMWIZCG-UHFFFAOYSA-N xylylcarb Chemical group CNC(=O)OC1=CC=C(C)C(C)=C1 WCJYTPVNMWIZCG-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- 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
- C07D403/12—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 linked by a chain containing hetero atoms as chain links
-
- 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
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/58—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems with hetero atoms directly attached to the ring nitrogen atom
-
- 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
- C07D401/02—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 two hetero rings
- C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
本发明涉及一种具有FGFR抑制活性的新型化合物及其制备和应用。具体地,本发明所述化合物具有式I所示结构,其中各基团和取代基如说明书中所定义。本发明还公开了所述化合物的制备方法及其在制备治疗和/或预防肿瘤相关疾病和/或FGFR相关疾病的药物中的用途。
Description
技术领域
本发明涉及药物领域,具体地涉及一种具有FGFR抑制活性的新型化合物及其制备和应用。
背景技术
蛋白激酶是一种通过对蛋白质上特定氨基酸的磷酸化来调节各种细胞功能的蛋白质(酶)。蛋白质通过构象的改变来调节活性以及与其他组分结合能力。蛋白质激酶的活性指的是,激酶将磷酸基团结合到底物上的速率,该速率可以通过检测一定时间内转化为产物的底物的量来进行测定。底物的磷酸化发生在蛋白质激酶的活化位点上。
酪氨酸激酶是一种可以催化将三磷酸腺苷转移到蛋白质酪氨酸残基的蛋白质酶。这些激酶在生长因子传导引发细胞增殖、分化和迁移过程中扮演着重要的角色。
成纤维细胞生长因子(FGF)已经被确认在许多生理过程中有重要的调节作用,例如器官生成和血管生成等等。目前已知,在FGF家族中有超过25种亚型,成纤维细胞生长因子受体(FGFR)家族共包含四个亚型(FGFR1-4),他们都是糖蛋白,包含细胞外的类免疫球蛋白区域、跨膜的疏水区域和细胞质内的酪氨酸激酶区域。FGF的结合引发FGFR二聚,进而发生受体的自磷酸化和下游信号通路的活化。下游信号通路的某些特定组分对于细胞生长、代谢和存活有非常重要的作用。因此,FGFR信号通路对于肿瘤细胞的繁殖、迁移、浸润和血管生成有多效性的重要生理作用。
目前,已有证据表明FGF信号通路与人类癌症有直接的关联。在不同种类的癌细胞中(膀胱癌、肾癌和***癌等等)都被报道出有不同的FGF过表达现象。因此,FGF信号通路是一个有前景的治疗靶点。
综上所述,本领域急需开发新型的FGFR抑制剂。
发明内容
本发明的目的在于提供一种具有FGFR抑制活性的新型化合物及其制备和应用。
本发明的第一方面,提供了一种式I所示化合物或其立体异构体、几何异构体、互变异构体、其药用盐、其前药及其水合物或溶剂合物,
式中,R1选自下组:取代或未取代的含有1-3个选自S、O、N和Se杂原子的5-14元杂芳基和取代或未取代的6-14元芳基,并且所述取代指被选自下组的1个或多个基团取代:C1-C6烷基、卤代的C1-C6烷基、C3-C8环烷基、卤代的C3-C8环烷基、羟基、C1-C6烷氧基、卤代的C1-C6烷氧基、-O-(C3-C8环烷基)、-O-(C3-C8的卤代环烷基)、-NR6R7、卤素、-(C1-C6亚烷基)-L1、C(=O)R8;并且当R1为含N的5-14元杂芳基时,R1不是选自下组的基团:未取代的喹啉基、未取代的异喹啉基;
R2和R3可相同或不同,分别独立地选自:H、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、C(=O)R8和S(=O)2R9;
R4选自H、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、NR6R7、卤素、羟基、氰基、取代或未取代的C1-C6烷氧基和取代或未取代的C1-C6烷硫基;
X1和X2可相同或不同,分别独立地选自N和CR10;R10选自H、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、卤素、羟基、氰基、取代或未取代的C1-C6烷氧基和取代或未取代的C1-C6烷硫基;
n为0、1、2、3、4或5;
Y选自取代或未取代的含有1-3个选自N、O和S杂原子的3-10元杂环基、-NR6R7、取代或未取代的C3-C8环烷基和-L2-(取代或未取代的C6-C10芳基)-,并且所述取代指被选自下组的1个或多个基团独立地取代:C1-C6烷基、卤代的C1-C6烷基、C3-C8环烷基、卤代的C3-C8环烷基、羟基、C1-C6烷氧基、卤代的C1-C6烷氧基、-O-(C3-C8环烷基)、-O-(C3-C8的卤代环烷基)、NR11R12、卤素、含有1-3个选自N、O和S杂原子的4-10元杂环基、-(C1-C6亚烷基)-L1、C(=O)R8和-Boc,
E选自下组:无、C(=O)、S(=O)2、C(=S)和S(=O);
Z选自下组:无、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、-(R13)-N(R11)-(R14)-(取代或未取代的C1-C6烷氧基);
R6和R7可相同或不同,分别独立地选自:H、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、C(=O)R8、-(C1-C6亚烷基)-L1、-(C1-C6亚烷基)-(取代或未取代的含1-3个选自N、O和S杂原子的4-8元杂环基)、-CN、卤素、-OH、-(C1-C6亚烷基)-(取代或未取代的C4-C8环烷基)、或-(C1-C6亚烷基)-L2-(C1-C6亚烷基)-(取代或未取代的C1-C6烷氧基);
R8和R9可相同或不同,分别独立地选自:H、羟基、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C2-C4烯基、取代或未取代的C2-C4炔基、-L2-(C1-C6亚烷基)-L1和-NR11R12;
L1选自-OH、C1-C4烷氧基、-NR11R12、或含1或2个N原子的4-7元杂环;和
L2选自下组:-NR11-、或-N(取代或未取代的C3-C6环烷基);
对于R2至R10、X1、X2、E、Z和L2,所述取代指被选自下组的1个或多个基团独立地取代:C1-C6烷基、卤代的C1-C6烷基、C3-C8环烷基、卤代的C3-C8环烷基、羟基、C1-C6烷氧基、卤代的C1-C6烷氧基、-O-(C3-C8环烷基)、-O-(C3-C8的卤代环烷基)、NR11R12、卤素、-CN、含有1-3个选自N、O和S杂原子的4-10元杂环基、-(C1-C6亚烷基)-L1和C(=O)R8;其中,所述的4-10元杂环基可任选地具有1-3个选自下组的取代基:C1-C3烷基、卤素、-OH、C1-C3卤代烷基、C3-C4环烷基;
R11和R12独立地选自H、C1-C6烷基、C1-C6卤代烷基、C3-C6环烷基、C3-C6卤代环烷基、-CO(C2-C4烯基)、或-CO(C2-C4炔基);或R11和R12与相邻的N构成含1-2个N原子和0-2个O或S原子的4-7元杂环;
R13和R14独立地选自取代或未取代的C1-C6亚烷基、或取代或未取代的C2-C6亚烯基。
在另一优选例中,当Z为具有1、2或3个取代基AA的C2-C6烯基,其中所述的取代基AA选自下组:NR11R12、-(C1-C6亚烷基)-L1、C3-C8环烷基、卤代的C3-C8环烷基、-CN、卤素。
在另一优选例中,当Z为具有1-2个取代基AA取代的C2-C4烯基,其中取代基AA选自下组:NR11R12、-(C1-C6亚烷基)-L1、C3-C8环烷基、-CN、卤素。
在另一优选例中,当Z具有下式结构:
式中,RA、RB和RC独立地选自下组:H、上述取代基AA;
并且,RA、RB和RC不同时为H。
在另一优选例中,RA或RB为取代基AA。
在另一优选例中,RC为取代基AA。
在另一优选例中,所述的R1为下式的二环基团:
式中,环A为取代或未取代的5元杂芳环;而环B为取代或未取代的6元杂芳环或取代或未取代的苯基。
在另一优选例中,所述的R1为下式的二环基团:
在另一优选例中,所述的环A为含S的5元杂芳环。
在另一优选例中,所述的R1为下式的二环基团:
在另一优选例中,所述的环A为含一个或两个N原子的5元杂芳环。
在另一优选例中,R1为取代的5-14元杂芳基或取代的6-14元芳基。
在另一优选例中,R1为取代的5-14元杂芳基或取代的6-14元芳基,且所述取代为具有选自下组的1个或多个取代基:C1-C6烷基、卤代的C1-C6烷基、C3-C8环烷基、卤代的C3-C8环烷基、羟基、C1-C6烷氧基、卤代的C1-C6烷氧基、-O-(C3-C8环烷基)、-O-(C3-C8的卤代环烷基)、-NR6R7、卤素、C(=O)R8。
在另一优选例中,所述的R1为取代的5-14元杂芳基或取代的6-14元芳基,且所述取代为具有选自下组的1个或多个取代基:C1-C6烷基、羟基、C1-C6烷氧基、卤代的C1-C6烷氧基、-NH2、卤素。
在另一优选例中,对于R1,所述取代为具有至少一个选自下组的取代基:C1-C6烷氧基、卤代的C1-C6烷氧基。
在另一优选例中,对于R1,所述取代为具有至少一个选自下组的取代基:C1-C6烷氧基、卤代的C1-C6烷氧基、羟基和-NH2;以及具有至少一个选自下组的取代基:C1-C6烷基、C3-C8环烷基和卤素。
在另一优选例中,R1为取代的选自下组的基团:苯并噻吩基、苯并呋喃基、吲哚基、苯并咪唑基、苯并硒吩基、吲唑基和苯并噻唑基。
在另一优选例中,R1为取代的苯并噻吩基。
在另一优选例中,R1为取代的苯并噻吩基,并且在7位具有选自下组的取代基:C1-C6烷氧基、卤代的C1-C6烷氧基、羟基和-NH2。
在另一优选例中,所述的式I所示化合物选自表1所列化合物。
本发明的第二方面,提供了一种药物组合物,所述药物组合物包含治疗有效量的本发明第一方面所述的化合物或其立体异构体、几何异构体、互变异构体、其药用盐、其前药及其水合物或溶剂合物中的一种或多种以及任选的药学上可接受的载体。
在另一优选例中,所述药物组合物是用于预防和/或治疗癌症的药物组合物,或用于预防和/或治疗FGFR相关疾病的药物组合物。
在另一优选例中,所述的FGFR选自下组:FGFR1、FGFR2、FGFR3、FGFR4、或组合。
在另一优选例中,所述药物组合物用于预防和/或治疗FGF/FGFR信号通路异常表达相关疾病。
在另一优选例中,所述药物组合物的剂型选自下组:口服剂型、冻干制剂、注射剂。
本发明的第三方面,提供了一种本发明第一方面所述的化合物或其立体异构体、几何异构体、互变异构体、其药用盐、其前药及其水合物或溶剂合物或本发明第二方面所述药物组合物的用途,用于制备预防和/或治疗选自下组的疾病的药物:
a)肿瘤相关疾病;
b)蛋白酪氨酸激酶活性相关疾病。
在另一优选例中,所述肿瘤相关疾病选自下组:乳腺癌、肺癌、膀胱癌、胃癌、胰腺癌、***癌、结肠癌、多发性骨髓瘤AML、肝癌、黑色素瘤、头颈癌、甲状腺癌、肾细胞癌、胶质母细胞癌和睾丸癌。
在另一优选例中,所述肺癌为非小细胞肺癌。
在另一优选例中,所述蛋白酪氨酸激酶活性相关疾病选自下组:FGFR相关疾病。
本发明的第四方面,提供了一种FGFR抑制剂,所述FGFR抑制剂包含抑制有效量的本发明第一方面所述的化合物或其立体异构体、几何异构体、互变异构体、其药用盐、其前药及其水合物或溶剂合物中的一种或多种。
在另一优选例中,所述FGFR抑制剂为FGFR1抑制剂和FGFR4抑制剂。
本发明的第五方面,提供了一种本发明第一方面所述的化合物或其立体异构体、几何异构体、互变异构体、其药用盐、其前药及其水合物或溶剂合物的制备方法,所述方法包括如下步骤:
(i)在惰性溶剂中,将式4化合物或其盐与式15所示的酰卤化合物或者酸进行缩合反应,从而形成式I化合物;
各式中,R1、R2、R3、R4、n、X1、X2、Y、E和Z的定义同上;
X选自下组:卤素、羟基。
在另一优选例中,步骤(i)所述反应在碱性条件下进行,优选为在三乙胺、吡啶、N,N-二异丙基乙胺、4-二甲氨基吡啶、N-甲基***啉等存在的条件下进行。
在另一优选例中,所述酰卤化合物优选为酰氯化合物。
在另一优选例中,所述酸为羧酸。
本发明的第六方面,提供了一种本发明第二方面所述药物组合物的制备方法,包括步骤:将药学上可接受的载体与本发明第一方面所述的化合物或其立体异构体、几何异构体、互变异构体、其药用盐、其前药及其水合物或溶剂合物进行混合,从而形成药物组合物。
本发明的第七方面,提供了一种非诊断性、非治疗性抑制FGFR活性的方法,所述方法包括向所需患者施用抑制有效量的本发明第一方面所述的化合物或其立体异构体、几何异构体、互变异构体、其药用盐、其前药及其水合物或溶剂合物或本发明第二方面所述药物组合物。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
具体实施方式
本发明人经过长期而深入的研究,意外地制备得到一种结构新颖、FGFR抑制作用显著的式I化合物。与现有FGFR抑制剂相比,以本发明化合物制备的FGFR抑制剂可在nM水平上实现对FGFR1-4酶活性的明显抑制作用,并且所述抑制剂在细胞水平对FGFR1-4诱导的各种癌细胞增殖也具有显著抑制作用,这对于开发新型抗肿瘤药物具有重要意义。在此基础上,发明人完成了本发明。
术语
在本文中,除特别说明之处,术语“取代”指基团上的一个或多个氢原子被选自下组的取代基取代:C1-C6烷基、卤代的C1-C6烷基、C3-C8环烷基、卤代的C3-C8环烷基、羟基、C1-C6烷氧基、卤代的C1-C6烷氧基、-O-(C3-C8环烷基)、-O-(C3-C8的卤代环烷基)、卤素、含有1-3个选自S、O、N和Se杂原子的4-10元杂环基、氨基、苯基、氰基、C2-C6烯基、C2-C6炔基;所述的苯基包括未取代的苯基或具有1-3个取代基的取代苯基,所述取代基选自:卤素、C1-C6烷基、C3-C8环烷基、C1-C6烷氧基、OH、氰基、硝基、氨基。
除特别说明之处,本发明的所有化合物之中,各手性碳原子可以任选地为R构型或S构型,或R构型和S构型的混合物。
术语“5-14元杂芳基”指具有选自下组的1-3个杂原子的5-14元芳基失去一个氢原子形成的基团:N、S、O、Se,其中每个杂芳基的环状体系可以是单环或多环的;例如苯并噻吩基、苯并呋喃基、吲哚基、萘基、苯并咪唑基、苯并硒吩基、吡啶基、呋喃基、苯基、吲唑基、噻吩基、吡咯基、咪唑基、吡唑基、吡嗪基、噁唑基、噻唑基、苯并噻唑基、或类似基团。
术语“6-14元芳基”指6-14元芳基失去一个氢原子形成的基团;例如苯基、萘基,或类似基团。
术语“C1-C6烷基”指具有1-6个碳原子的直链或支链烷基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、或类似基团。
术语“C1-C6烷氧基”指具有1-6个碳原子的直链或支链烷氧基,例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基、叔丁氧基、或类似基团。
术语“C2-C6烯基”指具有2-6个碳原子的烯烃失去一个或两个氢原子所形成的基团,所述的烯烃可以是单烯烃、二烯烃或三烯烃,例如-CH=CH2、-C2H4=CH2、-CH=C2H4,或类似基团。
术语“卤素”指F、Cl、Br和I。
此外,在本发明中,术语“烷基”包括饱和或不饱和、直链、支链、环状的1-10个碳原子的全碳烷基或其中的1-3个碳原子被氧、氮、硫等杂原子取代的烷基,以及通过1个或1个以上碳原子连接的芳烷基。此外,所述的烷基是未取代的或取代的。
如本文所用,术语“芳基”包括稠合或非稠合的芳基,通常含有6-30个碳原子,代表性的芳基包括苯基、萘基,或含氧、氮、硫等杂原子的芳香基团。
除非特别说明,本发明所描述的结构式意在包括所有的同分异构形式(如对映异构,非对映异构和几何异构体(或构象异构体):例如含有不对称中心的R、S构型,双键的(Z)、(E)异构体和(Z)、(E)的构象异构体。因此本发明的化合物的单个立体化学异构体或其对映异构体、非对映异构体或几何异构体(或构象异构体)的混合物都属于本发明的范围。
术语“互变异构体”表示具有不同能量的结构同分异构体可以超过低能垒,从而互相转化。比如,质子互变异构体(即质子移变)包括通过质子迁移进行互变,如1H-吲唑与2H-吲唑、1H-苯并[d]咪唑与3H-苯并[d]咪唑,化合价互变异构体包括通过一些成键电子重组而进行互变。
式I化合物
本发明人设计合成了一系列结构新颖的FGFR抑制剂化合物,通过结构优化,发现了在酶、细胞以及动物体内均有优异活性的小分子FGFR抑制剂,并且对FGFR1-4均有强烈抑制作用,该系列化合物有望在临床上用于治疗FGF/FGFR信号通路异常表达所引起的疾病,如癌症等。
具体地,本发明提供了一种如下式I所示化合物:
在另一优选例中,R1、R2、R3、R4、R6、R7、R8、R9、R10、R11、R12、R13、R14、X1、X2、L1、L2、Y、E、Z中任一个分别为实施例中各具体化合物中所对应的基团。
在另一优选例中,所述化合物优选为实施例中所制备的化合物。
在另一优选例中,所述化合物NO.1-NO.56分别为实施例1-56制备所得化合物。
在另一优选例中,所述化合物选自表1所列化合物。
表1
在另一优选例中,所述化合物具有显著的FGFR抑制活性。
在另一优选例中,所述化合物基本无EGFR抑制活性。
如本文所用,术语“药用盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。所述药用盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于:盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸;甲酸、乙酸、三氟乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、苯甲酸、甲磺酸、乙磺酸、甲烷磺酸、三氟甲烷磺酸、乙烷磺酸、对甲苯磺酸、苯磺酸、萘磺酸等有机酸;以及脯氨酸、苯丙氨酸、天冬氨酸、谷氨酸等氨基酸。
另一类优选的盐是本发明化合物与碱形成的盐,例如碱金属盐(例如钠盐或钾盐)、碱土金属盐(例如镁盐或钙盐)、铵盐(如低级的烷醇铵盐以及其它药学上可接受的胺盐),例如甲胺盐、乙胺盐、丙胺盐、二甲基胺盐、三甲基胺盐、二乙基胺盐、三乙基胺盐、叔丁基胺盐、乙二胺盐、羟乙胺盐、二羟乙胺盐、三羟乙胺盐,以及分别由吗啉、哌嗪、赖氨酸形成的胺盐。
术语“溶剂合物”指本发明化合物与溶剂分子配位形成特定比例的配合物。“水合物”是指本发明化合物与水进行配位形成的配合物。
术语“前药”包括其本身可以是具有生物学活性的或非活性的,当用适当的方法服用后,其在人体内进行代谢或化学反应而转变成式I化合物的一类化合物,或式I的一个化合物所组成的盐或溶液。所述的前药包括(但不局限于)所述化合物的羧酸酯、碳酸酯、磷酸酯、硝酸酯、硫酸酯、砜酯、亚砜酯、氨基化合物、氨基甲酸盐、偶氮化合物、磷酰胺、葡萄糖苷、醚、乙缩醛等形式。
式I化合物制备方法
下面更具体地描述本发明式I结构化合物的制备方法,但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得,这样的组合可由本发明所属领域的技术人员容易地进行。
典型地,本发明化合物的制备工艺流程如下,其中所用原料和试剂如无特殊说明,均可通过商业途径购买。
其中,R1、R2、R3、R4、n、X1、X2、Y、E和Z的定义同上,P是任何可做为氨基保护基的基团,L是发生亲核取代时的离去基团。
从化合物1出发通过光延反应或者亲核取代连接制成化合物2,然后偶联,去保护基后缩合得到目标产物。
具体的说,所述制备方法包括如下步骤:
1.化合物1通过光延反应或者亲核取代生成化合物2,或者化合物13通过光延反应或者亲核取代生成化合物14,化合物14与NHR2R3或其盐反应生成化合物2;
2.化合物2与相应的硼酸在钯催化剂作用下进行偶联反应得到化合物3;
3.化合物3在酸性条件下脱保护基得到化合物4;
4.化合物4与相应的酰氯化合物或者羧酸缩合得到目标产物。
其中,所述的中间体1可以通过本领域的常规方法制备,或通过市售途径获得。在本发明的一个优选例中,所述化合物(1a)由如下方法制备:
其中R2、R3的定义同上。
从化合物5出发做成碘代物,再氨化得到中间体(1a)。
具体的说,所述制备方法包括如下步骤:
1.化合物5在N-碘代丁二酰亚胺条件下生成相应的碘代物6;
2.化合物6与适当的胺(氨)在适当的溶剂中加热或者微波反应得到中间体(1a);
在本发明的另一个优选例中,所述化合物(1b)由如下方法制备:
从化合物7出发环合后做成碘代物得到中间体(1b)。
具体的说,所述制备方法包括如下步骤:
1.化合物7在甲酰胺溶剂中180度环合生成相应的8;
2.化合物8与N-碘代丁二酰亚胺反应得到中间体(1b);
在制备通式I结构的方法中所需的相应硼酸可以通过本领域的常规方法制备,或通过市售途径获得。在本发明的一个优选例中,由如下方法制备:
Ra是上述R1中的取代基,定义如上述。
从化合物9出发通过亲核取代连接制成化合物10,然后在氯苯在多聚磷酸条件下得到化合物11,11再在常规反应条件中(正丁基锂和三异丙基硼酸酯)制成相应硼酸。
具体的说,所述制备方法包括如下步骤:
1.化合物9通过亲核取代生成化合物10;
2.化合物10在氯苯等适当溶剂中与多聚磷酸回流得到化合物11;
3.化合物11在正丁基锂和三异丙基硼酸酯条件下得到硼酸化合物。
本发明化合物的制备方法具有反应条件温和、原料丰富易得、操作及后处理简单等优点。
药物组合物及其制备方法
本发明还提供了一种药物组合物,所述药物组合物包含治疗有效量的所述的化合物或其立体异构体、几何异构体、互变异构体、其药用盐、其前药及其水合物或溶剂合物中的一种或多种以及任选的药学上可接受的载体。
在另一优选例中,所述药物组合物是用于预防和/或治疗癌症的药物组合物,或用于预防和/或治疗FGFR相关疾病的药物组合物。
在另一优选例中,所述的FGFR选自下组:FGFR1、FGFR2、FGFR3、FGFR4、或组合。
在另一优选例中,所述药物组合物用于预防和/或治疗FGF/FGFR信号通路异常表达相关疾病。
在另一优选例中,所述药物组合物的剂型选自下组:口服剂型、冻干制剂、注射剂。
由于本发明化合物具有优异的对FGFR激酶(Kinase)例如FGFR1和FGFR4的抑制活性,因此本发明化合物及其各种晶型,药学上可接受的无机或有机盐,水合物或溶剂合物,以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解由与FGFR活性或表达量相关的疾病,例如预防和/或治疗与FGF/FGFR信号通路异常表达相关的疾病。根据现有技术,本发明化合物可用于治疗以下疾病:所述的癌症包括乳腺癌、肺癌、膀胱癌、胃癌、胰腺癌、***癌、结肠癌、多发性骨髓瘤AML、肝癌、黑色素瘤、头颈癌、甲状腺癌、肾细胞癌、胶质母细胞癌和睾丸癌。更特别的是,这些癌症选自:乳腺癌、非小细胞肺癌、膀胱癌、胃癌、胰腺癌、***癌、结肠癌、多发性骨髓瘤、肝癌、黑色素瘤、头颈癌、甲状腺癌、肾细胞癌、胶质母细胞癌和睾丸癌。最特别的是,该癌症是非小细胞肺癌、胃癌或多发性骨髓瘤。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是:化合物的量足以明显改善病情,而不至于产生严重的副作用。通常,药物组合物含有1-2000mg本发明化合物/剂,更佳地,含有5-200mg本发明化合物/剂。较佳地,所述的“一剂”为一个胶囊或药片。
“药学上可接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和,而不明显降低化合物的药效。药学上可接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和***胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药,或者与其他治疗手段和/或其它治疗药物联用。
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重的人而言,日给药剂量通常为1-2000mg,优选5-500mg。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
此外,本发明还提供了一种所述药物组合物的制备方法,包括步骤:将药学上可接受的载体与所述的化合物或其立体异构体、几何异构体、互变异构体、其药用盐、其前药及其水合物或溶剂合物进行混合,从而形成药物组合物。
用途
本发明还提供了一种所述的化合物或所述药物组合物的用途,用于制备预防和/或治疗选自下组的疾病的药物:
a)肿瘤相关疾病;
b)蛋白酪氨酸激酶活性相关疾病。
在另一优选例中,所述肿瘤相关疾病选自下组:乳腺癌、肺癌、膀胱癌、胃癌、胰腺癌、***癌、结肠癌、多发性骨髓瘤AML、肝癌、黑色素瘤、头颈癌、甲状腺癌、肾细胞癌、胶质母细胞癌和睾丸癌。
在另一优选例中,所述肺癌为非小细胞肺癌。
在另一优选例中,所述蛋白酪氨酸激酶活性相关疾病选自下组:FGFR相关疾病。
此外,本发明提供了一种FGFR抑制剂,所述FGFR抑制剂包含抑制有效量的所述的化合物或其立体异构体、几何异构体、互变异构体、其药用盐、其前药及其水合物或溶剂合物中的一种或多种。
在另一优选例中,所述FGFR抑制剂为FGFR1抑制剂和FGFR4抑制剂。
治疗方法
本发明还提供了一种治疗FGFR相关疾病的方法,包括向所需患者施用抑制有效量的所述的化合物或其立体异构体、几何异构体、互变异构体、其药用盐、其前药及其水合物或溶剂合物或所述药物组合物。
本发明还提供了一种非诊断性、非治疗性抑制FGFR活性的方法,所述方法包括向所需患者施用抑制有效量的所述的化合物或其立体异构体、几何异构体、互变异构体、其药用盐、其前药及其水合物或溶剂合物或所述药物组合物。
与现有技术相比,本发明具有以下主要优点:
(1)以所述化合物制备所得抑制剂对FGFR酶活性有显著的抑制作用;
(2)所述化合物可在nM水平上实现对FGFR1-4酶活性的明显抑制作用;
(3)所述化合物在细胞水平上对FGFR1-4诱导的各种癌细胞增殖也具有显著抑制作用。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件如Sambrook等人,分子克隆:实验室手册(New York:Cold Spring Harbor LaboratoryPress,1989)中所述的条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
除非另行定义,文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外,任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
实施例1:
1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)丙-2-烯-1-酮
步骤1:制备2-甲氧基-4-甲基硝基苯
将7.5克5-甲基-2-硝基苯酚和10.2克碳酸钾混悬于80毫升丙酮中,再加入8.3克碘甲烷,加热回流5小时后停止加热,硅藻土过滤掉不溶物,滤液旋干得7.7克橘色结晶,直接投下一步。
1H NMR(300MHz,DMSO-d6)δ7.76(d,J=8.2Hz,1H),6.86(s,1H),6.79(d,J=8.2Hz,1H),3.92(s,3H),2.39(s,3H).
步骤2:制备2-甲氧基-4-甲基苯胺
将7.7克2-甲氧基-4-甲基硝基苯和32克二氯亚锡二水化合物溶于250毫升甲醇,加热回流3小时后停止反应,旋掉大部分甲醇反应液后用乙酸乙酯稀释,然后用饱和碳酸氢钠溶液中和,过滤掉不溶物后再用乙酸乙酯萃取,分液后有机相用饱和氯化钠水溶液洗涤后无水硫酸钠干燥,过滤浓缩得5.2克红褐色油状物,直接投下一步。
1H NMR(300MHz,DMSO-d6)δ6.45-6.63(m,3H),4.46(s,2H),3.72(s,3H),2.16(s,3H).
步骤3:制备2-甲氧基-4-甲基苯硫酚
将5.2克2-甲氧基-4-甲基苯胺溶于32毫升水和11.4毫升浓盐酸,冰浴冷却至0-5℃,再将2.88克亚硝酸钠溶于9毫升水中滴加至上述冷却液中,冰浴下搅拌10分钟后再加入5.6克乙酸钠。将上述反应液滴加至热的(75℃左右)11克乙基黄原酸钾溶于51毫升水的溶液中,继续搅拌1小时后冷却至室温,用乙酸乙酯萃取,分液后有机相用饱和氯化钠水溶液洗涤后无水硫酸钠干燥,过滤浓缩后溶于1.3N氢氧化钾乙醇溶液中,加入3克葡萄糖一起加热回流3小时,浓缩反应液,冰浴冷却下用6N硫酸调PH至1左右,再加入5.7克锌粉50℃加热搅拌30分钟,过滤掉不溶物后乙酸乙酯萃取,分液后有机相用饱和氯化钠水溶液洗涤后无水硫酸钠干燥过滤浓缩,残余物柱层析(100%石油醚)分离得4.15克油状物,收率71%。
1H NMR(300MHz,DMSO-d6)δ7.17(s,1H),6.81(s,1H),6.66(s,1H),4.63(s,1H),3.80(s,3H),2.26(s,3H).
步骤4:制备(2,2-二乙氧基乙基)(2-甲氧基-4-甲基苯基)硫醚
将4.15克2-甲氧基-4-甲基苯硫酚和5.91克2-溴-1,1-二乙氧基乙烷溶于40毫升N,N-二甲基甲酰胺,加入15.8克碳酸铯后室温搅拌过夜,加水后用乙酸乙酯萃取,有机相用饱和氯化钠水溶液洗涤后无水硫酸钠干燥过滤浓缩,残余物柱层析(100%石油醚)分离得6.6克油状物,收率90%。
1H NMR(300MHz,DMSO-d6)δ7.16(s,1H),6.82(s,1H),6.73(s,1H),4.55(t,J=4.86Hz,1H),3.80(s,3H),3.52-3.64(m,2H)3.39-3.51(m,2H)2.96(m,2H),2.33(s,3H),1.09(t,j=7.0Hz,6H).
步骤5:制备7-甲氧基-5-甲基苯并噻吩
将17克多聚磷酸溶于150毫升氯苯中回流,将6.6克(2,2-二乙氧基乙基)(2-甲氧基-4-甲基苯基)硫醚滴加至反应液中回流过夜,次日倒出溶液,残留物用乙酸乙酯冲洗后合并有机相,浓缩柱层析(100%石油醚)分离得1.85克油状物,收率42%。
1H NMR(300MHz,DMSO-d6)δ7.68(s,1H),7.34(s,1H),7.28(s,1H),6.78(s,1H),3.93(s,3H),2.43(s,3H).
步骤6:制备(7-甲氧基-5-甲基苯并噻吩-2-基)硼酸
将1.5克7-甲氧基-5-甲基苯并噻吩溶于20毫升干燥的四氢呋喃,冷却至-70℃后滴加1.5当量的正丁基锂溶液,保持-70℃搅拌1小时后,滴加3当量的三异丙基硼酸酯,保持-70℃搅拌1小时后缓慢升至室温,饱和氯化铵水溶液淬灭反应,室温搅拌半小时后用乙酸乙酯萃取,有机相用饱和氯化钠水溶液洗涤后无水硫酸钠干燥,过滤浓缩,残余物柱层析(二氯甲烷∶甲醇=98∶2)分离得1.7克米色固体,收率94%。
步骤7:制备4-氯-5-碘-7H-吡咯[2,3-d]嘧啶
将1.53克4-氯-7H-吡咯[2,3-d]嘧啶和2.7克N-碘代丁二酰亚胺溶于35毫升二氯甲烷中,室温搅拌1小时后用饱和硫代硫酸钠溶液洗,加入乙酸乙酯萃取,有机相用饱和氯化钠水溶液洗涤后无水硫酸钠干燥,过滤浓缩干得2.5克灰白色固体,直接投下一步。
1H NMR(300MHz,DMSO-d6)δ12.95(brs,1H),8.60(s,1H),7.91(d,J=2.5Hz,1H).
步骤8:制备3-(4-氯-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯
氩气氛围中将500毫克4-氯-5-碘-7H-吡咯[2,3-d]嘧啶,505毫克3-羟基吡咯烷-1-甲酸叔丁酯和945毫克三苯基膦溶于干燥的四氢呋喃溶液中,冰浴冷却下滴加0.7毫升偶氮二甲酸二异丙酯,滴加完后移至室温下搅拌2小时,反应液浓缩至干,残余物柱层析(乙酸乙酯∶石油醚=10∶90)分离得1.05克淡黄色固体。
步骤9:制备3-(4-氨基-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯
将120毫克3-(4-氯-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯溶于2毫升1,4-二氧六环和1毫升氨水的混合溶液中,封管100℃加热反应16小时,冷却至室温后加水,用乙酸乙酯萃取,有机相用饱和氯化钠水溶液洗涤后无水硫酸钠干燥,过滤浓缩,残余物柱层析(二氯甲烷∶甲醇=98∶2)分离得113毫克米色固体,收率80%。
步骤10:制备3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯
将178毫克的3-(4-氨基-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯,95毫克的(7-甲氧基-5-甲基苯并噻吩-2-基)硼酸,90毫克的碳酸钠和25毫克的四三苯基膦钯溶于4毫升的1,4-二氧六环和1毫升水的混合溶液中,置换氩气后80℃加热反应5小时,反应液浓缩至干,残余物柱层析(二氯甲烷∶甲醇=98∶2)分离定量得200毫克淡黄色固体。
1H NMR(400MHz,CDCl3)δ8.34(s,1H),7.24(s,1H),7.23(s,1H),7.16(s,1H),6.65(s,1H),5.68(s,2H),5.52-5.43(m,1H),4.01(s,3H),3.99-3.91(m,1H),3.81-3.53(m,3H),2.50(s,3H),2.48-2.38(m,1H),2.35-2.27(m,1H),1.49(s,9H).
步骤11:制备5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7-(吡咯烷-3-基)-7H-吡咯[2,3-d]嘧啶-4-氨基盐酸盐
将95毫克的3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯溶于4N的盐酸1,4-二氧六环溶液中,室温搅拌2小时,反应液浓缩至干,直接投下一反应。
步骤12:制备1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)丙-2-烯-1-酮
将步骤11制得的5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7-(吡咯烷-3-基)-7H-吡咯[2,3-d]嘧啶-4-氨基盐酸盐混悬于2毫升干燥的二氯甲烷中,加入0.15毫升的三乙胺,冰浴冷却下滴加17微升的丙烯酰氯,滴加完后移至室温搅拌过夜,次日反应液浓缩至干,残余物柱层析(二氯甲烷∶甲醇=97∶3)分离得59毫克白色固体,收率70%。
1H NMR(400MHz,CDCl3)δ8.33(s,1H),7.23-7.19(m,2H),7.11(d,J=14.3Hz,1H),6.64(s,1H),6.51-6.39(m,2H),5.79-5.69(m,1H),5.50(m,3H),4.22-4.09(m,1H),4.04-3.90(m,1H),3.99(s,3H),3.86-3.75(m,2H),2.68-2.53(m,1H),2.48(s,3H),2.43(m,1H).
实施例2:
1-(3-(4-氨基-3-(7-甲氧基-5-甲基苯并噻吩-2-基)-1H-吡唑[3,4-d]嘧啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮
步骤1:制备1H-吡唑[3,4-d]嘧啶-4-胺
将1克3-氨基-4-氰基吡唑溶于甲酰胺中,氩气保护下加热至170℃反应5小时,冷却至室温后倒入30毫升水中打浆,过滤后滤饼干燥得1.15克棕色固体。
1H NMR(300MHz,DMSO-d6)δ13.34(s,1H),8.13(s,1H),8.07(s,1H),7.61(s,2H).
步骤2:制备3-碘-1H-吡唑[3,4-d]嘧啶-4-胺
将500毫克1H-吡唑[3,4-d]嘧啶-4-胺和1.25克N-碘代丁二酰亚胺溶于5毫升N,N-二甲基甲酰胺,氩气保护下加热至80℃反应18小时,冷却至室温后倒入20毫升饱和硫代硫酸钠水溶液中打浆,过滤,滤饼干燥得1.2克棕色固体。
1H NMR(300MHz,DMSO-d6)δ13.81(s,1H),8.13(s,1H),8.17(s,1H).
步骤3:制备3-((甲磺酰基)氧)吡咯烷-1-甲酸叔丁酯
将136毫克3-羟基吡咯烷-1-甲酸叔丁酯溶于1毫升二氯甲烷中,加入0.15毫升的三乙胺,冰浴冷却下滴加67微升的甲磺酰氯,加料完毕后移至室温下搅拌2小时停止反应。加水后用乙酸乙酯萃取,有机相用饱和氯化钠水溶液洗涤后无水硫酸钠干燥,过滤浓缩后定量得190毫克油状物。
1H NMR(300MHz,CDCl3)δ5.25-5.28(m,1H),3.49-3.68(m,4H),3.05(s,3H),2.12-2.28(m,2H),1.47(s,9H).
步骤4:制备3-(4-氨基-3-碘-1H-吡唑[3,4-d]嘧啶-1-基)吡咯烷-1-甲酸叔丁酯
将110毫克3-碘-1H-吡唑[3,4-d]嘧啶-4-胺和110毫克3-((甲磺酰基)氧)吡咯烷-1-甲酸叔丁酯溶于2毫升N,N-二甲基甲酰胺,再加入270毫克碳酸铯,氩气保护下加热至90℃过夜,次日加水后用乙酸乙酯萃取,有机相用饱和氯化钠水溶液洗涤后无水硫酸钠干燥,过滤浓缩,残余物柱层析(二氯甲烷∶甲醇=97∶3)分离得100毫克黄色固体,收率57%。
1H NMR(300MHz,CDCl3)δ8.32(s,1H),6.05(s,2H),5.40-5.39(m,1H),3.90-3.68(m,3H),3.58-3.47(m,1H),2.58-2.26(m,2H),1.48(s,9H).
步骤5:制备3-(4-氨基-3-(7-甲氧基-5-甲基苯并噻吩-2-基)-1H-吡唑[3,4-d]嘧啶-1-基)吡咯烷-1-甲酸叔丁酯
将3-(4-氨基-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯替换成3-(4-氨基-3-碘-1H-吡唑[3,4-d]嘧啶-1-基)吡咯烷-1-甲酸叔丁酯,其余所需原料、试剂及制备方法同实施例1中的步骤10,得3-(4-氨基-3-(7-甲氧基-5-甲基苯并噻吩-2-基)-1H-吡唑[3,4-d]嘧啶-1-基)吡咯烷-1-甲酸叔丁酯。
步骤6:制备3-(7-甲氧基-5-甲基苯并噻吩-2-基)-1-(吡咯烷-3-基)-1H-吡唑[3,4-d]嘧啶-4-胺盐酸盐
将3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯替换成3-(4-氨基-3-(7-甲氧基-5-甲基苯并噻吩-2-基)-1H-吡唑[3,4-d]嘧啶-1-基)吡咯烷-1-甲酸叔丁酯,其余所需原料、试剂及制备方法同实施例1中的步骤11,得3-(7-甲氧基-5-甲基苯并噻吩-2-基)-1-(吡咯烷-3-基)-1H-吡唑[3,4-d]嘧啶-4-胺盐酸盐。
步骤7:制备1-(3-(4-氨基-3-(7-甲氧基-5-甲基苯并噻吩-2-基)-1H-吡唑[3,4-d]嘧啶-1-基)吡咯烷-1-基)丙基-2-烯-1-酮
将5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7-(吡咯烷-3-基)-7H-吡咯[2,3-d]嘧啶-4-氨基盐酸盐替换成3-(7-甲氧基-5-甲基苯并噻吩-2-基)-1-(吡咯烷-3-基)-1H-吡唑[3,4-d]嘧啶-4-胺盐酸盐,其余所需原料、试剂及制备方法同实施例1中的步骤12,得1-(3-(4-氨基-3-(7-甲氧基-5-甲基苯并噻吩-2-基)-1H-吡唑[3,4-d]嘧啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮,收率53%。
1H NMR(300MHz,DMSO-d6)δ8.29(s,1H),7.67(s,1H),7.34(s,1H),6.85(s,1H),6.74-6.51(m,1H),6.17(d,J=16.4Hz,1H),5.68(dd,J=16.9,11.0Hz,1H),5.51(d,J=21.5Hz,1H),4.18-4.05(m,1H),3.95(s,3H),3.84(m,3H),2.44(s,3H),2.39(m,2H).
实施例3:
1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)丙-2-炔-1-酮
将100毫克5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7-(吡咯烷-3-基)-7H-吡咯[2,3-d]嘧啶-4-氨基盐酸,20微升丙炔酸和145毫克2-(7-偶氮苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯溶于2毫升N,N-二甲基甲酰胺,滴加0.2毫升的N,N-二异丙基乙胺,室温下搅拌8小时停止反应,加水后用乙酸乙酯萃取,有机相用饱和氯化钠水溶液洗涤后无水硫酸钠干燥,过滤浓缩,残余物柱层析(二氯甲烷∶甲醇=97∶3)分离得48毫克黄色固体,收率44%。
1H NMR(300MHz,CDCl3)δ8.33(s,1H),7.22(s,2H),7.11(d,J=9.3Hz,1H),6.65(s,1H),5.69(s,2H),5.59-5.40(m,1H),4.37-3.57(m,4H),4.00(s,3H),3.09(d,J=15.2Hz,1H),2.64-2.24(m,2H),2.49(s,3H).
实施例4:
(E)1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)-4-(二甲氨基)丁-2-烯-1-酮
将丙炔酸替换成反式-4-二甲基胺基巴豆酸盐酸盐,其余所需原料、试剂及制备方法同实施例3,得(E)1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)-4-(二甲氨基)丁-2-烯-1-酮,收率43%。
1H NMR(300MHz,CDCl3)δ8.32(s,1H),7.22(s,2H),7.11(d,J=11.4Hz,1H),7.03-6.86(m,1H),6.78(d,J=15.9Hz,0.5H),6.61(d,J=17.7Hz,1.5H),5.57(s,2H),5.53-5.39(m,1H),4.33-3.81(m,4H),3.99(s,3H),3.52(m,2H),2.63(s,3H),2.57(s,3H),2.53-2.44(m,5H).
实施例5:
(E)1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)-4-(乙基(甲基)氨基)丁-2-烯-1-酮
将丙炔酸替换成反式-4-(乙基(甲基)胺基)巴豆酸盐酸盐,其余所需原料、试剂及制备方法同实施例3,得(E)1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)-4-(乙基(甲基)氨基)丁-2-烯-1-酮,收率45%。
1H NMR(300MHz,CDCl3)δ8.32(s,1H),7.22(s,2H),7.11(d,J=12.3Hz,1H),6.99-6.71(m,2H),6.64(s,1H),5.61(s,2H),5.56-5.38(m,1H),4.40-3.88(m,4H),3.99(s,3H),3.81-3.62(m,2H),2.75-2.59(m,3H),2.48(s,3H),2.62-2.34(m,2H),1.52-1.33(m,3H).
实施例6:
(E)1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)-4-(异丙基基(甲基)氨基)丁-2-烯-1-酮
将丙炔酸替换成反式-4-(异丙基(甲基)胺基)巴豆酸盐酸盐,其余所需原料、试剂及制备方法同实施例3,得(E)1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)-4-(异丙基(甲基)氨基)丁-2-烯-1-酮,收率42%。
1H NMR(300MHz,CDCl3)δ8.32(s,1H),7.21(s,2H),7.11(d,J=10.8Hz,1H),6.98-6.85(m,1.5H),6.78-6.67(m,0.5H),6.64(s,1H),5.54(s,2H),5.50-5.38(m,1H),4.33-3.84(m,4H),3.99(s,3H),3.71-3.52(m,2H),3.45-3.22(m,1H),2.54(d,J=16.3Hz,3H),2.48(s,3H),1.36-1.21(m,6H).
实施例7:
(E)1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)-4-(吡咯烷-1-基)丁-2-烯-1-酮
将丙炔酸替换成反式-4-(吡咯烷-1-基)巴豆酸盐酸盐,其余所需原料、试剂及制备方法同实施例3,得(E)1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)-4-(吡咯烷-1-基)丁-2-烯-1-酮,收率43%。
1H NMR(300MHz,CDCl3)δ8.32(s,1H),7.22(s,2H),7.11(d,J=11.1Hz,1H),6.92(m,1H),6.79(d,J=17.6Hz,0.5H),6.61(d,J=12.3Hz,1.5H),5.54-5.40(m,3H),4.32-3.81(m,4H),3.99(s,3H),3.61(dd,J=19.1,6.0Hz,2H),3.11-2.85(m,4H),2.53-2.40(m,5H),2.11-1.77(m,4H).
实施例8:
(E)1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)-4-(哌啶-1-基)丁-2-烯-1-酮
将丙炔酸替换成反式-4-(哌啶-1-基)巴豆酸盐酸盐,其余所需原料、试剂及制备方法同实施例3,得(E)1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)-4-(哌啶-1-基)丁-2-烯-1-酮,收率44%。
1H NMR(300MHz,DMSO-d6)δ8.19(s,1H),7.48(s,1H),7.31(d,J=6.6Hz,1H),7.27(s,1H),6.80(s,1H),6.48(s,2H),5.46-5.35(m,2H),5.29-5.26(m,1H),4.05-3.62(m,4H),3.94(s,3H),3.40-3.20(m,6H),2.43(s,3H),2.42(s,2H),1.42-1.18(m,6H).
实施例9:
5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7-(吡咯烷-3-基)-7H-吡咯[2,3-d]嘧啶-4-胺
将95毫克的3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯溶于4N的盐酸1,4-二氧六环溶液中,室温搅拌2小时,反应液浓缩至干,用饱和碳酸氢钠水溶液洗,加入乙酸乙酯萃取,有机相用饱和氯化钠水溶液洗涤后无水硫酸钠干燥,过滤浓缩,残余物柱层析(二氯甲烷∶甲醇(含1%氨水)=95∶5)分离得48毫克黄色固体,收率44%。
1H NMR(300MHz,DMSO-d6)δ8.20(s,1H),7.59(d,J=17.3Hz,1H),7.32(s,1H),7.27(s,1H),6.79(s,1H),6.49(s,2H),5.46-5.26(m,1H),4.19-4.06(m,0.5H),3.94(s,3H),3.85-4.0(m,1H),3.80-3.68(m,1.5H),3.58-3.45(m,1H),2.43(s,3H),2.43-2.34(m,2H).
实施例10:
3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯
制备同实施例1步骤10。
1H NMR(300MHz,DMSO-d6)δ8.20(s,1H),7.59(d,J=17.3Hz,1H),7.32(s,1H),7.27(s,1H),6.79(s,1H),6.49(s,2H),5.46-5.26(m,1H),4.19-4.06(m,0.5H),3.94(s,3H),3.85-4.0(m,1H),3.80-3.68(m,1.5H),3.58-3.45(m,1H),2.43(s,3H),2.43-2.34(m,2H),1.48(s,9H).
实施例11:
(R)-1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)丙-2-烯-1-酮
步骤1:制备(R)-3-(4-氯-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯
将3-羟基吡咯烷-1-甲酸叔丁酯替换成(S)-3-羟基吡咯烷-1-甲酸叔丁酯,其余所需原料、试剂及制备方法同实施例1中的步骤8,得(R)-3-(4-氯-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯
步骤2:制备(R)-3-(4-氨基-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯
将3-(4-氯-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯替换成(R)-3-(4-氯-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯,其余所需原料、试剂及制备方法同实施例1中的步骤9,得(R)-3-(4-氨基-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯。
步骤3:制备(R)3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯
将3-(4-氨基-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯替换成(R)-3-(4-氨基-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯,其余所需原料、试剂及制备方法同实施例1中的步骤10,得(R)3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯。
步骤4:制备(R)-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7-(吡咯烷-3-基)-7H-吡咯[2,3-d]嘧啶-4-氨基盐酸盐
将3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯替换成(S)-3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯,其余所需原料、试剂及制备方法同实施例1中的步骤11,得(R)-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7-(吡咯烷-3-基)-7H-吡咯[2,3-d]嘧啶-4-氨基盐酸盐。
步骤5:制备(R)-1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)丙-2-烯-1-酮
将5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7-(吡咯烷-3-基)-7H-吡咯[2,3-d]嘧啶-4-氨基盐酸盐替换成(R)-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7-(吡咯烷-3-基)-7H-吡咯[2,3-d]嘧啶-4-氨基盐酸盐,其余所需原料、试剂及制备方法同实施例1中的步骤12,得(R)-1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)丙-2-烯-1-酮,收率51%。
1H NMR(400MHz,CDCl3)δ8.33(s,1H),7.23-7.19(m,2H),7.11(d,J=14.3Hz,1H),6.64(s,1H),6.51-6.39(m,2H),5.79-5.69(m,1H),5.50(m,3H),4.22-4.09(m,1H),4.04-3.90(m,1H),3.99(s,3H),3.86-3.75(m,2H),2.68-2.53(m,1H),2.48(s,3H),2.43(m,1H).
实施例12:
(S)-1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)丙-2-烯-1-酮
步骤1:制备(S)-3-(4-氯-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯
将3-羟基吡咯烷-1-甲酸叔丁酯替换成(R)-3-羟基吡咯烷-1-甲酸叔丁酯,其余所需原料、试剂及制备方法同实施例1中的步骤8,得(S)-3-(4-氯-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯
步骤2:制备(S)-3-(4-氨基-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯
将3-(4-氯-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯替换成(S)-3-(4-氯-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯,其余所需原料、试剂及制备方法同实施例1中的步骤9,得(S)-3-(4-氨基-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯。
步骤3:制备(S)3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯
将3-(4-氨基-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯替换成(S)-3-(4-氨基-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯,其余所需原料、试剂及制备方法同实施例1中的步骤10,得(S)3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯。
步骤4:制备(S)-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7-(吡咯烷-3-基)-7H-吡咯[2,3-d]嘧啶-4-氨基盐酸盐
将3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯替换成(S)-3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯,其余所需原料、试剂及制备方法同实施例1中的步骤11,得(S)-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7-(吡咯烷-3-基)-7H-吡咯[2,3-d]嘧啶-4-氨基盐酸盐。
步骤5:制备(S)-1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)丙-2-烯-1-酮
将5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7-(吡咯烷-3-基)-7H-吡咯[2,3-d]嘧啶-4-氨基盐酸盐替换成(S)-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7-(吡咯烷-3-基)-7H-吡咯[2,3-d]嘧啶-4-氨基盐酸盐,其余所需原料、试剂及制备方法同实施例1中的步骤12,得(S)-1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)丙-2-烯-1-酮,收率53%。
1H NMR(400MHz,CDCl3)δ8.33(s,1H),7.23-7.19(m,2H),7.11(d,J=14.3Hz,1H),6.64(s,1H),6.51-6.39(m,2H),5.79-5.69(m,1H),5.50(m,3H),4.22-4.09(m,1H),4.04-3.90(m,1H),3.99(s,3H),3.86-3.75(m,2H),2.68-2.53(m,1H),2.48(s,3H),2.43(m,1H).
实施例13:
1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-基)丙-2-烯-1-酮
步骤1:制备3-(4-氯-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯
将3-羟基吡咯烷-1-甲酸叔丁酯替换成3-羟基氮杂环丁烷-1-甲酸叔丁酯,其余所需原料、试剂及制备方法同实施例1中的步骤8,得3-(4-氯-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯。
步骤2:制备3-(4-氨基-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯
将3-(4-氯-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯替换成3-(4-氯-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯,其余所需原料、试剂及制备方法同实施例1中的步骤9,得3-(4-氨基-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯。
1H NMR(300MHz,CDCl3)δ8.22(d,J=1.7Hz,1H),7.35(d,J=1.3Hz,1H),6.02-5.86(m,2H),5.50(d,J=4.0Hz,1H),4.45(m,2H),4.15(m,2H),1.47(s,9H).
步骤3:制备3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯
将3-(4-氨基-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯替换成3-(4-氨基-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯,其余所需原料、试剂及制备方法同实施例1中的步骤10,得3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯。
步骤4:制备5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7-(氮杂环丁烷-3-基)-7H-吡咯[2,3-d]嘧啶-4-胺盐酸盐
将3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯替换成3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯,其余所需原料、试剂及制备方法同实施例1中的步骤11,得5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7-(氮杂环丁烷-3-基)-7H-吡咯[2,3-d]嘧啶-4-胺盐酸盐。
步骤5:制备1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-基)丙-2-烯-1-酮
将5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7-(吡咯烷-3-基)-7H-吡咯[2,3-d]嘧啶-4-氨基盐酸盐替换成5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7-(氮杂环丁烷-3-基)-7H-吡咯[2,3-d]嘧啶-4-氨基盐酸盐,其余所需原料、试剂及制备方法同实施例1中的步骤12,得1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-基)丙-2-烯-1-酮,收率61%。
1H NMR(300MHz,CDCl3)δ8.30(s,1H),7.35(s,1H),7.23(d,J=2.8Hz,2H),6.64(s,1H),6.47-6.37(m,1H),6.24(dd,J=17.0,10.1Hz,1H),5.71(dd,J=25.2,12.1Hz,4H),4.78(s,1H),4.66(s,1H),4.54(d,J=14.2Hz,2H),3.99(s,3H),2.48(s,3H)..
实施例14:
1-(4-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)哌啶-1-基)丙-2-烯-1-酮
步骤1:制备4-(4-氯-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)哌啶-1-甲酸叔丁酯
将3-羟基吡咯烷-1-甲酸叔丁酯替换成4-羟基哌啶-1-甲酸叔丁酯,其余所需原料、试剂及制备方法同实施例1中的步骤8,得4-(4-氯-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)哌啶-1-甲酸叔丁酯。
步骤2:制备4-(4-氨基-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)哌啶-1-甲酸叔丁酯
将3-(4-氯-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯替换成4-(4-氯-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)哌啶-1-甲酸叔丁酯,其余所需原料、试剂及制备方法同实施例1中的步骤9,得4-(4-氨基-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)哌啶-1-甲酸叔丁酯。
1H NMR(300MHz,CDCl3)δ8.26(s,1H),7.09(s,1H),5.64(s,2H),4.75-4.85(m,1H),4.25-4.35(m,2H),2.85-2.95(m,2H),1.98-2.04(m,2H),1.78-1.90(m,2H),1.48(s,9H).
步骤3:制备4-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)哌啶-1-甲酸叔丁酯
将3-(4-氨基-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯替换成4-(4-氨基-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)哌啶-1-甲酸叔丁酯,其余所需原料、试剂及制备方法同实施例1中的步骤10,得4-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)哌啶-1-甲酸叔丁酯。
1H NMR(300MHz,CDCl3)δ8.32(s,1H),7.20(s,2H),7.16(s,1H),6.63(s,1H),5.63(s,2H),4.82-4.92(m,1H),4.25-4.40(m,2H),3.99(s,3H),2.88-3.02(m,2H),2.48(s,3H),2.15-1.80(m,4H),1.48(s,9H).
步骤4:制备5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7-(哌啶-4-基)-7H-吡咯[2,3-d]嘧啶-4-氨基盐酸盐
将3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯替换成4-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)哌啶-1-甲酸叔丁酯,其余所需原料、试剂及制备方法同实施例1中的步骤11,得5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7-(哌啶-4-基)-7H-吡咯[2,3-d]嘧啶-4-氨基盐酸盐。
步骤5:制备1-(4-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)哌啶-1-基)丙-2-烯-1-酮
将5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7-(吡咯烷-3-基)-7H-吡咯[2,3-d]嘧啶-4-氨基盐酸盐替换成5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7-(哌啶-4-基)-7H-吡咯[2,3-d]嘧啶-4-氨基盐酸盐,其余所需原料、试剂及制备方法同实施例1中的步骤12,得1-(4-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)哌啶-1-基)丙-2-烯-1-酮,收率56%。
1H NMR(300MHz,CDCl3)δ8.32(s,1H),7.20(d,J=4.1Hz,2H),7.14(s,1H),6.62(m,2H),6.32(m,1H),5.73(m,1H),5.62(s,2H),4.97(m,2H),4.18(d,J=11.4Hz,1H),3.99(s,3H),3.32(s,1H),2.85(s,1H),2.48(s,3H),1.99(m,4H).
实施例15:
1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)哌啶-1-基)丙-2-烯-1-酮
步骤1:制备3-(4-氯-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)哌啶-1-甲酸叔丁酯
将3-羟基吡咯烷-1-甲酸叔丁酯替换成3-羟基哌啶-1-甲酸叔丁酯,其余所需原料、试剂及制备方法同实施例1中的步骤8,得3-(4-氯-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)哌啶-1-甲酸叔丁酯。
步骤2:制备3-(4-氨基-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)哌啶-1-甲酸叔丁酯
将3-(4-氯-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯替换成3-(4-氯-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)哌啶-1-甲酸叔丁酯,其余所需原料、试剂及制备方法同实施例1中的步骤9,得3-(4-氨基-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)哌啶-1-甲酸叔丁酯。
步骤3:制备3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)哌啶-1-甲酸叔丁酯
将3-(4-氨基-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯替换成3-(4-氨基-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)哌啶-1-甲酸叔丁酯,其余所需原料、试剂及制备方法同实施例1中的步骤10,得3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)哌啶-1-甲酸叔丁酯。
步骤4:制备5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7-(哌啶-3-基)-7H-吡咯[2,3-d]嘧啶-4-氨基盐酸盐
将3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯替换成3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)哌啶-1-甲酸叔丁酯,其余所需原料、试剂及制备方法同实施例1中的步骤11,得5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7-(哌啶-3-基)-7H-吡咯[2,3-d]嘧啶-4-氨基盐酸盐。
步骤5:制备1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)哌啶-1-基)丙-2-烯-1-酮
将5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7-(吡咯烷-3-基)-7H-吡咯[2,3-d]嘧啶-4-氨基盐酸盐替换成5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7-(哌啶-3-基)-7H-吡咯[2,3-d]嘧啶-4-氨基盐酸盐,其余所需原料、试剂及制备方法同实施例1中的步骤12,得1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)哌啶-1-基)丙-2-烯-1-酮,收率50%。
1H NMR(300MHz,CDCl3)δ8.33(s,1H),7.22(d,J=3.2Hz,2H),7.17(s,1H),6.63(q,J=10.3Hz,2H),6.32(d,J=16.9Hz,1H),5.72(d,J=10.1Hz,1H),5.53(s,2H),4.74(s,2H),4.32(s,1H),3.25(s,1H),2.84(s,1H),2.28(s,1H),2.17(s,1H),1.95(s,1H),1.77(s,4H).
实施例16:
1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)丙-1-酮
将丙烯酰氯替换成丙酰氯,其余所需原料、试剂及制备方法同实施例1中的步骤12,得1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)丙-1-酮,收率46%。
1H NMR(300MHz,CDCl3)δ8.33(s,1H),7.22(s,2H),7.10(d,J=14.8Hz,1H),6.64(s,1H),5.55(s,2H),5.52-5.39(m,1H),4.10-4.02(m,1H),4.00(s,3H),3.86(dd,J=16.1,7.0Hz,1H),3.74-3.62(m,2H),2.49(s,3H),2.44-2.22(m,4H),1.18(m,3H).
实施例17:
(E)-1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-基)-4-(吡咯烷-1-基)丁-2-烯-1-酮
将80毫克5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7-(氮杂环丁烷-3-基)-7H-吡咯[2,3-d]嘧啶-4-氨基盐酸盐,116毫克反式-4-(吡咯烷-1-基)巴豆酸盐酸盐和228毫克2-(7-偶氮苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯溶于2毫升N,N-二甲基甲酰胺,滴加0.26毫升的N,N-二异丙基乙胺,室温下搅拌过夜,次日加水后用乙酸乙酯萃取,有机相用饱和氯化钠水溶液洗涤后无水硫酸钠干燥,过滤浓缩,残余物柱层析(二氯甲烷∶甲醇(含1%氨水)=95∶5)分离得30毫克黄色固体,收率23%。
1H NMR(300MHz,CD3OD)δ8.13(s,1H),7.56(s,1H),7.22(s,1H),7.16(s,1H),6.76(dd,J=14.8,7.5Hz,1H),6.69(s,1H),6.46(d,J=15.1Hz,1H),5.60-5.50(m,1H),4.80(d,J=8.2Hz,2H),4.55(dd,J=17.1,8.5Hz,2H),3.94(s,3H),3.83(d,J=6.8Hz,2H),3.18(s,4H),2.42(s,3H),2.01(d,J=3.7Hz,4H).
实施例18:
(E)-1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)丁-2-烯-1-酮
将丙烯酰氯替换成巴豆酰氯,其余所需原料、试剂及制备方法同实施例1中的步骤12,得(E)-1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)丁-2-烯-1-酮,收率36%。
1H NMR(300MHz,CDCl3)δ8.31(s,1H),7.20(s,2H),7.09(dd,J=13.6,4.4Hz,1H),7.04-6.88(m,1H),6.62(s,1H),6.12(dd,J=22.6,15.1Hz,1H),5.73(s,2H),5.55-5.38(m,1H),4.20-4.04(m,1H),3.98(s,4H),3.81(dd,J=13.8,7.8Hz,1H),3.74(dd,J=13.8,6.7Hz,2H),2.49(d,J=10.5Hz,4H),2.45-2.33(m,2H),1.88(dd,J=10.8,7.5Hz,3H).
实施例19:
(E)-1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-基)-4-(二甲氨基)丁-2-烯-1-酮
将反式-4-(吡咯烷-1-基)巴豆酸盐酸盐替换成反式-4-(二甲氨基)巴豆酸盐酸盐,其余所需原料、试剂及制备方法同实施例17,得(E)-1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-基)-4-(二甲氨基)丁-2-烯-1-酮,收率40%。
1H NMR(300MHz,CDCl3)δ8.29(s,1H),7.35(s,1H),7.23(s,2H),7.00-6.86(m,1H),6.64(s,1H),6.32(d,J=15.8Hz,1H),5.65(s,2H),4.82(s,1H),4.65(s,2H),4.49(s,1H),3.99(s,3H),3.36(d,J=6.0Hz,2H),2.47(s,9H),1.25(s,4H).
实施例20:
1-(3-((4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)甲基)吡咯烷-1-基)丙-2-烯-1-酮
步骤1:制备3-((4-氯-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)甲基)吡咯烷-1-甲酸叔丁酯
将3-羟基吡咯烷-1-甲酸叔丁酯替换成3-羟甲基吡咯烷-1-甲酸叔丁酯,其余所需原料、试剂及制备方法同实施例1中的步骤8,得3-((4-氯-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)甲基)吡咯烷-1-甲酸叔丁酯。
步骤2:制备3-((4-氨基-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)甲基)吡咯烷-1-甲酸叔丁酯
3-(4-氯-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯替换成3-((4-氯-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)甲基)吡咯烷-1-甲酸叔丁酯,其余所需原料、试剂及制备方法同实施例1中的步骤9,得3-((4-氨基-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)甲基)吡咯烷-1-甲酸叔丁酯。
步骤3:制备3-((4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)甲基)吡咯烷-1-甲酸叔丁酯
将3-(4-氨基-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯替换成3-((4-氨基-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)甲基)吡咯烷-1-甲酸叔丁酯,其余所需原料、试剂及制备方法同实施例1中的步骤10,得3-((4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)甲基)吡咯烷-1-甲酸叔丁酯。
步骤4:制备5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7-(吡咯烷-3-亚甲基)-7H-吡咯[2,3-d]嘧啶-4-胺盐酸盐
将3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯替换成3-((4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)甲基)吡咯烷-1-甲酸叔丁酯,其余所需原料、试剂及制备方法同实施例1中的步骤11,得5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7-(吡咯烷-3-亚甲基)-7H-吡咯[2,3-d]嘧啶-4-胺盐酸盐。
步骤5:制备1-(3-((4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)甲基)吡咯烷-1-基)丙-2-烯-1-酮
将5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7-(吡咯烷-3-基)-7H-吡咯[2,3-d]嘧啶-4-氨基盐酸盐替换成5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7-(吡咯烷-3-亚甲基)-7H-吡咯[2,3-d]嘧啶-4-胺盐酸盐,其余所需原料、试剂及制备方法同实施例1中的步骤12,得1-(3-((4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)甲基)吡咯烷-1-基)丙-2-烯-1-酮,收率37%。
1H NMR(300MHz,CDCl3)δ8.32(s,1H),7.22(s,2H),7.11(d,J=7.2Hz,1H),6.64(s,1H),6.39(dd,J=14.4,7.6Hz,2H),5.67(dd,J=9.9,5.4Hz,1H),5.55(s,2H),4.38-4.15(m,2H),4.00(s,3H),3.75(s,2H),3.65-3.47(m,1H),3.38(m,1H),2.89(m,1H),2.49(s,3H),2.17-1.96(m,1H).
实施例21:
1-(3-(4-氨基-5-(6-甲氧基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-基)丙-2-烯-1-酮
步骤1:制备(2,2-二乙氧基乙基)(3-甲氧基苯基)硫醚
将2-甲氧基-4-甲基苯硫酚替换成3-甲氧基苯硫酚,其余所需原料、试剂及制备方法同实施例1中的步骤4,得(2,2-二乙氧基乙基)(3-甲氧基苯基)硫醚。
1H NMR(300MHz,CDCl3)7.19(t,J=7.9Hz,1H),6.94(m,2H),6.75-6.68(m,1H),4.65(t,J=5.5Hz,1H),3.79(s,3H),3.68(m,2H),3.55(m,2H),3.14(d,J=5.6Hz,2H),1.20(t,J=7.0Hz,6H).
步骤2:制备6-甲氧基苯并噻吩
将(2,2-二乙氧基乙基)(2-甲氧基-4-甲基苯基)硫醚替换成(2,2-二乙氧基乙基)(3-甲氧基苯基)硫醚,其余所需原料、试剂及制备方法同实施例1中的步骤5,得6-甲氧基苯并噻吩。
1H NMR(300MHz,CDCl3)δ7.70(d,J=8.7Hz,1H),7.36(d,J=2.0Hz,1H),7.00(dd,J=8.7,2.0Hz,1H),3.88(s,3H).
步骤3:制备(6-甲氧基苯并噻吩-2-基)硼酸
将7-甲氧基-5-甲基苯并噻吩替换成6-甲氧基苯并噻吩,其余所需原料、试剂及制备方法同实施例1中的步骤6,得(6-甲氧基苯并噻吩-2-基)硼酸。
步骤4:制备3-(4-氨基-5-(6-甲氧基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯
将3-(4-氨基-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯替换成3-(4-氨基-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯,(7-甲氧基-5-甲基苯并噻吩-2-基)硼酸替换成(6-甲氧基苯并噻吩-2-基)硼酸,其余所需原料、试剂及制备方法同实施例1中的步骤10,得3-(4-氨基-5-(6-甲氧基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯。
步骤5:制备5-(6-甲氧基苯并噻吩-2-基)-7-(氮杂环丁烷-3-基)-7H-吡咯[2,3-d]嘧啶-4-胺盐酸盐
将3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯替换成3-(4-氨基-5-(6-甲氧基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯,其余所需原料、试剂及制备方法同实施例1中的步骤11,得5-(6-甲氧基苯并噻吩-2-基)-7-(氮杂环丁烷-3-基)-7H-吡咯[2,3-d]嘧啶-4-胺盐酸盐。
步骤6:制备1-(3-(4-氨基-5-(6-甲氧基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-基)丙-2-烯-1-酮
将5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7-(吡咯烷-3-基)-7H-吡咯[2,3-d]嘧啶-4-氨基盐酸盐替换成5-(6-甲氧基苯并噻吩-2-基)-7-(氮杂环丁烷-3-基)-7H-吡咯[2,3-d]嘧啶-4-胺盐酸盐,其余所需原料、试剂及制备方法同实施例1中的步骤12,得1-(3-(4-氨基-5-(6-甲氧基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-基)丙-2-烯-1-酮,收率65%。
1H NMR(300MHz,CDCl3)δ8.32(s,1H),7.68(d,J=8.7Hz,1H),7.34(s,2H),7.24(s,1H),7.07-7.00(m,1H),6.42(d,J=17.0Hz,1H),6.25(dd,J=16.9,10.3Hz,1H),5.73(dd,J=16.6,8.0Hz,2H),5.52(s,2H),4.77(d,J=7.6Hz,1H),4.72-4.62(m,1H),4.53(s,2H),3.90(s,3H).
实施例22:
1-(3-(4-氨基-5-(7-甲氧基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-基)丙-2-烯-1-酮
步骤1:制备(2,2-二乙氧基乙基)(2-甲氧基苯基)硫醚
将2-甲氧基-4-甲基苯硫酚替换成2-甲氧基苯硫酚,其余所需原料、试剂及制备方法同实施例1中的步骤4,得(2,2-二乙氧基乙基)(2-甲氧基苯基)硫醚。
步骤2:制备7-甲氧基苯并噻吩
将(2,2-二乙氧基乙基)(2-甲氧基-4-甲基苯基)硫醚替换成(2,2-二乙氧基乙基)(2-甲氧基苯基)硫醚,其余所需原料、试剂及制备方法同实施例1中的步骤5,得7-甲氧基苯并噻吩。
1H NMR(300MHz,CDCl3)δ7.49-7.41(m,2H),7.33(m,2H),6.78(d,J=7.9Hz,1H),4.01(s,3H).
步骤3:制备(7-甲氧基苯并噻吩-2-基)硼酸
将7-甲氧基-5-甲基苯并噻吩替换成7-甲氧基苯并噻吩,其余所需原料、试剂及制备方法同实施例1中的步骤6,得(6-甲氧基苯并噻吩-2-基)硼酸。
步骤4:制备3-(4-氨基-5-(6-甲氧基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯
将3-(4-氨基-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯替换成3-(4-氨基-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯,(7-甲氧基-5-甲基苯并噻吩-2-基)硼酸替换成(7-甲氧基苯并噻吩-2-基)硼酸,其余所需原料、试剂及制备方法同实施例1中的步骤10,得3-(4-氨基-5-(7-甲氧基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯。
步骤5:制备5-(7-甲氧基苯并噻吩-2-基)-7-(氮杂环丁烷-3-基)-7H-吡咯[2,3-d]嘧啶-4-胺盐酸盐
将3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯替换成3-(4-氨基-5-(7-甲氧基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯,其余所需原料、试剂及制备方法同实施例1中的步骤11,得5-(7-甲氧基苯并噻吩-2-基)-7-(氮杂环丁烷-3-基)-7H-吡咯[2,3-d]嘧啶-4-胺盐酸盐。
步骤6:制备1-(3-(4-氨基-5-(7-甲氧基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-基)丙-2-烯-1-酮
将5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7-(吡咯烷-3-基)-7H-吡咯[2,3-d]嘧啶-4-氨基盐酸盐替换成5-(7-甲氧基苯并噻吩-2-基)-7-(氮杂环丁烷-3-基)-7H-吡咯[2,3-d]嘧啶-4-胺盐酸盐,其余所需原料、试剂及制备方法同实施例1中的步骤12,得1-(3-(4-氨基-5-(7-甲氧基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-基)丙-2-烯-1-酮,收率55%。
1H NMR(300MHz,CDCl3)δ8.31(s,1H),7.42(d,J=7.6Hz,1H),7.37(t,J=3.8Hz,2H),7.33(d,J=3.3Hz,1H),6.81(d,J=7.5Hz,1H),6.42(dd,J=16.9,1.6Hz,1H),6.24(dd,J=17.0,10.2Hz,1H),5.80-5.57(m,4H),4.78-4.62(m,2H),4.55(m,2H),4.02(s,3H).
实施例23:
1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并呋喃-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-基)丙-2-烯-1-酮
步骤1:制备1-(2,2-二乙氧基乙氧基)-2-甲氧基-4-甲基苯
将2-甲氧基-4-甲基苯硫酚替换成2-甲氧基-4-甲基苯酚,其余所需原料、试剂及制备方法同实施例1中的步骤4,得1-(2,2-二乙氧基乙氧基)-2-甲氧基-4-甲基苯。
1H NMR(300MHz,CDCl3)δ6.83(d,J=7.9Hz,1H),6.68(d,J=10.8Hz,2H),4.86(t,J=5.1Hz,1H),4.03(d,J=5.2Hz,2H),3.83(s,3H),3.74-3.57(m,4H),2.29(s,3H),1.23(t,J=7.0Hz,6H).
步骤2:制备7-甲氧基-5-甲基苯并呋喃
将(2,2-二乙氧基乙基)(2-甲氧基-4-甲基苯基)硫醚替换成1-(2,2-二乙氧基乙氧基)-2-甲氧基-4-甲基苯,其余所需原料、试剂及制备方法同实施例1中的步骤5,得7-甲氧基-5-甲基苯并呋喃。
步骤3:制备(7-甲氧基-5-甲基苯并呋喃-2-基)硼酸
将7-甲氧基-5-甲基苯并噻吩替换成7-甲氧基苯并呋喃,其余所需原料、试剂及制备方法同实施例1中的步骤6,得(7-甲氧基-5-甲基苯并呋喃-2-基)硼酸。
步骤4:制备3-(4-氨基-5-(7-甲氧基-5-甲基苯并呋喃-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯
将3-(4-氨基-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯替换成3-(4-氨基-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯,(7-甲氧基-5-甲基苯并噻吩-2-基)硼酸替换成(7-甲氧基-5-甲基苯并呋喃-2-基)硼酸,其余所需原料、试剂及制备方法同实施例1中的步骤10,得3-(4-氨基-5-(7-甲氧基-5-甲基苯并呋喃-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯。
步骤5:制备5-(7-甲氧基-5-甲基苯并呋喃-2-基)-7-(氮杂环丁烷-3-基)-7H-吡咯[2,3-d]嘧啶-4-胺盐酸盐
将3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯替换成3-(4-氨基-5-(7-甲氧基-5-甲基苯并呋喃-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯,其余所需原料、试剂及制备方法同实施例1中的步骤11,得5-(7-甲氧基-5-甲基苯并呋喃-2-基)-7-(氮杂环丁烷-3-基)-7H-吡咯[2,3-d]嘧啶-4-胺盐酸盐。
步骤6:制备1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并呋喃-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-基)丙-2-烯-1-酮
将5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7-(吡咯烷-3-基)-7H-吡咯[2,3-d]嘧啶-4-氨基盐酸盐替换成5-(7-甲氧基-5-甲基苯并呋喃-2-基)-7-(氮杂环丁烷-3-基)-7H-吡咯[2,3-d]嘧啶-4-胺盐酸盐,其余所需原料、试剂及制备方法同实施例1中的步骤12,得1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并呋喃-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-基)丙-2-烯-1-酮,收率56%。
1H NMR(300MHz,CD3OD)δ8.14(s,1H),8.00(s,1H),6.94(s,2H),6.71(s,1H),6.38(m,2H),5.79(d,J=10.0Hz,1H),5.63(s,1H),4.85-4.54(m,4H),3.98(s,3H),2.42(s,3H).
实施例24:
1-(2-((4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)甲基)吡咯烷-1-基)丙-2-烯-1-酮
步骤1:制备2-((4-氯-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)甲基)吡咯烷-1-甲酸叔丁酯
将3-羟基吡咯烷-1-甲酸叔丁酯替换成2-羟甲基吡咯烷-1-甲酸叔丁酯,其余所需原料、试剂及制备方法同实施例1中的步骤8,得2-((4-氯-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)甲基)吡咯烷-1-甲酸叔丁酯。
步骤2:制备2-((4-氨基-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)甲基)吡咯烷-1-甲酸叔丁酯
3-(4-氯-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯替换成2-((4-氯-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)甲基)吡咯烷-1-甲酸叔丁酯,其余所需原料、试剂及制备方法同实施例1中的步骤9,得2-((4-氨基-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)甲基)吡咯烷-1-甲酸叔丁酯。
步骤3:制备2-((4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)甲基)吡咯烷-1-甲酸叔丁酯
将3-(4-氨基-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯替换成2-((4-氨基-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)甲基)吡咯烷-1-甲酸叔丁酯,其余所需原料、试剂及制备方法同实施例1中的步骤10,得2-((4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)甲基)吡咯烷-1-甲酸叔丁酯。
步骤4:制备5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7-(吡咯烷-2-亚甲基)-7H-吡咯[2,3-d]嘧啶-4-胺盐酸盐
将3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯替换成2-((4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)甲基)吡咯烷-1-甲酸叔丁酯,其余所需原料、试剂及制备方法同实施例1中的步骤11,得5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7-(吡咯烷-2-亚甲基)-7H-吡咯[2,3-d]嘧啶-4-胺盐酸盐。
步骤5:制备1-(2-((4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)甲基)吡咯烷-1-基)丙-2-烯-1-酮
将5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7-(吡咯烷-3-基)-7H-吡咯[2,3-d]嘧啶-4-氨基盐酸盐替换成5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7-(吡咯烷-2-亚甲基)-7H-吡咯[2,3-d]嘧啶-4-胺盐酸盐,其余所需原料、试剂及制备方法同实施例1中的步骤12,得1-(2-((4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)甲基)吡咯烷-1-基)丙-2-烯-1-酮,收率61%。
1H NMR(300MHz,CDCl3)δ8.34(d,J=9.2Hz,1H),7.23-7.16(m,3H),6.63(s,1H),6.47(d,J=8.7Hz,2H),5.75(dd,J=8.2,3.6Hz,1H),5.55(m,3H),4.53(s,3H),3.99(s,3H),3.55-3.43(m,2H),2.48(s,3H),1.93(m,4H).
实施例25:
2-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-羰基)-3-环丙基丙烯腈
步骤1:制备3-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)-3-氧代丙腈
将反式-4-(吡咯烷-1-基)巴豆酸盐酸盐替换成氰乙酸,其余所需原料、试剂及制备方法同实施例17,得3-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)-3-氧代丙腈。
1H NMR(300MHz,DMSO-d6)δ8.29(s,1H),7.69m,1H),7.35(s,1H),7.28(s,1H),6.96(s,2H),6.81(s,1H),5.39(m,1H),4.05-3.30(m,11H),2.44(s,3H).
步骤2:制备2-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-羰基)-3-环丙基丙烯腈
将50毫克3-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)-3-氧代丙腈,17微升环丙基甲醛和10微升哌啶溶于1毫升甲醇,室温下搅拌过夜,次日有固体析出,过滤,滤饼干燥得13毫克米色固体,收率80%。
1H NMR(300MHz,CDCl3)δ8.32(s,1H),7.22(s,2H),7.11(s,1H),6.91(m,1H),6.64(s,1H),5.62(s,2H),5.48(s,1H),4.38-4.34(m,0.5H),4.00(s,3H),3.85-4.1(m,2.5H),3.80-3.68(m,1H),,2.48(s,3H),2.6-2.43(m,2H),1.3-1.25(m,1H),1.0-0.8(m,4H).
实施例26:
1-(3-(4-氨基-3-(7-甲氧基-5-甲基苯并噻吩-2-基)-1H-吡唑[3,4-d]嘧啶-1-基)氮杂环丁烷-1-基)丙-2-烯-1-酮
步骤1:制备3-((甲磺酰基)氧)氮杂环丁烷-1-甲酸叔丁酯
将3-羟基吡咯烷-1-甲酸叔丁酯替换成3-羟基氮杂环丁烷-1-甲酸叔丁酯,其余所需原料、试剂及制备方法同实施例2中的步骤3,得3-((甲磺酰基)氧)氮杂环丁烷-1-甲酸叔丁酯。
1H NMR(300MHz,CDCl3)δ5.23-5.04(m,1H),4.23(m,2H),4.05(m,2H),3.03(s,3H),1.40(s,9H).
步骤2:制备3-(4-氨基-3-碘-1H-吡唑[3,4-d]嘧啶-1-基)氮杂环丁烷-1-甲酸叔丁酯
将3-((甲磺酰基)氧)吡咯烷-1-甲酸叔丁酯替换成3-((甲磺酰基)氧)氮杂环丁烷-1-甲酸叔丁酯,其余所需原料、试剂及制备方法同实施例2中的步骤4,得3-(4-氨基-3-碘-1H-吡唑[3,4-d]嘧啶-1-基)氮杂环丁烷-1-甲酸叔丁酯。
步骤3:制备3-(4-氨基-3-(7-甲氧基-5-甲基苯并噻吩-2-基)-1H-吡唑[3,4-d]嘧啶-1-基)氮杂环丁烷-1-甲酸叔丁酯
将3-(4-氨基-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯替换成3-(4-氨基-3-碘-1H-吡唑[3,4-d]嘧啶-1-基)氮杂环丁烷-1-甲酸叔丁酯,其余所需原料、试剂及制备方法同实施例1中的步骤10,得3-(4-氨基-3-(7-甲氧基-5-甲基苯并噻吩-2-基)-1H-吡唑[3,4-d]嘧啶-1-基)氮杂环丁烷-1-甲酸叔丁酯。
步骤4:制备3-(7-甲氧基-5-甲基苯并噻吩-2-基)-1-(氮杂环丁烷-3-基)-1H-吡唑[3,4-d]嘧啶-4-胺盐酸盐
将3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯替换成3-(4-氨基-3-(7-甲氧基-5-甲基苯并噻吩-2-基)-1H-吡唑[3,4-d]嘧啶-1-基)氮杂环丁烷-1-甲酸叔丁酯,其余所需原料、试剂及制备方法同实施例1中的步骤11,得3-(7-甲氧基-5-甲基苯并噻吩-2-基)-1-(氮杂环丁烷-3-基)-1H-吡唑[3,4-d]嘧啶-4-胺盐酸盐。
步骤5:制备1-(3-(4-氨基-3-(7-甲氧基-5-甲基苯并噻吩-2-基)-1H-吡唑[3,4-d]嘧啶-1-基)氮杂环丁烷-1-基)丙基-2-烯-1-酮
将5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7-(吡咯烷-3-基)-7H-吡咯[2,3-d]嘧啶-4-氨基盐酸盐替换成3-(7-甲氧基-5-甲基苯并噻吩-2-基)-1-(氮杂环丁烷-3-基)-1H-吡唑[3,4-d]嘧啶-4-胺盐酸盐,其余所需原料、试剂及制备方法同实施例1中的步骤12,得1-(3-(4-氨基-3-(7-甲氧基-5-甲基苯并噻吩-2-基)-1H-吡唑[3,4-d]嘧啶-1-基)氮杂环丁烷-1-基)丙基-2-烯-1-酮,收率54%。
1H NMR(300MHz,DMSO-d6)δ8.29(s,1H),7.71(s,1H),7.36(s,1H),6.86(s,1H),6.40(dd,J=17.0,10.5Hz,1H),6.17(d,J=17.2Hz,1H),5.73(d,J=11.7Hz,2H),4.76-4.67(m,2H),4.53-4.35(m,2H),3.96(s,3H),2.45(s,3H).
实施例27:
1-(3-(4-氨基-3-(7-甲氧基-5-甲基苯并噻吩-2-基)-1H-吡唑[3,4-d]嘧啶-1-基)氮杂环丁烷-1-基)丙-2-炔-1-酮
将100毫克3-(7-甲氧基-5-甲基苯并噻吩-2-基)-1-(氮杂环丁烷-3-基)-1H-吡唑[3,4-d]嘧啶-4-胺盐酸盐,20微升丙炔酸和145毫克苯并***-1-三(三甲氨基)-三氟磷酸酯溶于2毫升N,N-二甲基甲酰胺,滴加0.2毫升的N,N-二异丙基乙胺,室温下搅拌8小时停止反应,加水后用乙酸乙酯萃取,有机相用饱和氯化钠水溶液洗涤后无水硫酸钠干燥,过滤浓缩,残余物柱层析(二氯甲烷∶甲醇=97∶3)分离得48毫克淡黄色固体,收率44%。
1H NMR(300MHz,DMSO-d6)δ8.30(s,1H),7.72(s,1H),7.36(s,1H),6.87(s,1H),5.76(s,1H),4.73-4.58(m,2H),4.55(s,1H),4.53-4.37(m,1H),3.97(s,3H),2.45(s,3H).
实施例28:
5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7-(1-(乙烯磺酰基)氮杂环丁烷-3-基)-7H-吡咯[2,3-d]嘧啶-4-胺
将100毫克5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7-(氮杂环丁烷-3-基)-7H-吡咯[2,3-d]嘧啶-4-胺盐酸盐混悬于2毫升干燥的二氯甲烷中,加入0.18毫升的三乙胺,冰浴冷却下滴加31微升的2-氯乙基磺酰氯,滴加完后移至室温搅拌过夜,次日反应液浓缩至干,残余物柱层析(二氯甲烷∶甲醇=97∶3)分离得46毫克白色固体,收率52%。
1H NMR(300MHz,CDCl3)δ8.30(s,1H),7.39(s,1H),7.24(s,2H),6.73(dd,J=16.6,9.9Hz,1H),6.65(s,1H),6.43(d,J=16.6Hz,1H),6.24(d,J=9.9Hz,1H),5.62-5.54(m,3H),4.45-4.35(m,4H),4.01(s,3H),2.49(s,3H).
实施例29:
1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-基)-2-氟-丙-2-炔-1-酮
将60毫克5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7-(氮杂环丁烷-3-基)-7H-吡咯[2,3-d]嘧啶-4-胺盐酸盐,17毫克2-氟-丙炔酸和80毫克苯并***-1-三(三甲氨基)-三氟磷酸酯溶于2毫升N,N-二甲基甲酰胺,滴加0.12毫升的N,N-二异丙基乙胺,室温下搅拌8小时停止反应,加水后用乙酸乙酯萃取,有机相用饱和氯化钠水溶液洗涤后无水硫酸钠干燥,过滤浓缩,残余物柱层析(二氯甲烷∶甲醇=97∶3)分离得46毫克淡黄色固体,收率61%。
1H NMR(300MHz,DMSO-d6)δ8.19(s,1H),7.97(s,1H),7.35(s,1H),7.28(s,1H),6.80(s,1H),6.53(s,2H),5.70-60(m,2H),5.39-5.26(m,1H),4.85(s,2H),4.56-4.33(m,2H),3.95(s,3H),2.43(s,3H).
实施例30:
1-(3-(4-氨基-5-(1H-吲哚-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-基)丙-2-烯-1-酮
步骤1:制备1H-吲哚-1-甲酸叔丁酯
将200毫克吲哚,0.7毫升三乙胺和48毫克的4-二甲氨基吡啶溶于2毫升二氯甲烷,再加入375毫克的二碳酸二叔丁酯,放至室温搅拌1小时候后浓缩反应液,柱层析(石油醚100%)分得370毫克油状物。
1H NMR(300MHz,CDCl3)δ8.16(d,J=8.0Hz,1H),7.59(dd,J=10.5,5.6Hz,2H),7.32(td,J=8.0,1.3Hz,1H),7.27-7.19(m,1H),6.58(d,J=3.7Hz,1H),1.68(s,9H).
步骤2:制备(1-甲酸叔丁酯-1H-吲哚-2-基)硼酸
氩气保护下将370毫克的1H-吲哚-1-甲酸叔丁酯和0.6毫升三异丙基硼酸酯溶于3毫升干燥的四氢呋喃,冰浴冷却下滴加1.2当量的二异丙基氨基锂,冰浴下搅拌2小时,用3毫升的1N盐酸水溶液淬灭,加水后用乙酸乙酯萃取,有机相用饱和氯化钠水溶液洗涤后无水硫酸钠干燥,过滤浓缩,直接投下一步。
步骤3:制备2-(4-氨基-7-(1-(甲酸叔丁酯)氮杂环丁烷-3-基)-7H-吡咯[2,3-d]嘧啶-5-基)-1H-吲哚-1-甲酸叔丁酯
将3-(4-氨基-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯替换成3-(4-氨基-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯,(7-甲氧基-5-甲基苯并噻吩-2-基)硼酸替换成(1-甲酸叔丁酯-1H-吲哚-2-基)硼酸,其余所需原料、试剂及制备方法同实施例1中的步骤10,得2-(4-氨基-7-(1-(甲酸叔丁酯)氮杂环丁烷-3-基)-7H-吡咯[2,3-d]嘧啶-5-基)-1H-吲哚-1-甲酸叔丁酯。
1H NMR(300MHz,CDCl3)δ8.32(s,1H),8.29(d,J=8.2Hz,1H),7.59(d,J=7.3Hz,1H),7.42-7.29(m,3H),6.68(s,1H),5.65-5.56(m,1H),4.97(s,2H),4.55-4.49(m,2H),4.27-4.22(m,2H),1.48(s,9H),1.19(s,9H).
步骤4:制备7-(氮杂环丁烷-3-基)-5-(1H-吲哚-2-基)-7H-吡咯[2,3-d]嘧啶-4-胺盐酸盐
将3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯替换成2-(4-氨基-7-(1-(甲酸叔丁酯)氮杂环丁烷-3-基)-7H-吡咯[2,3-d]嘧啶-5-基)-1H-吲哚-1-甲酸叔丁酯,其余所需原料、试剂及制备方法同实施例1中的步骤11,得7-(氮杂环丁烷-3-基)-5-(1H-吲哚-2-基)-7H-吡咯[2,3-d]嘧啶-4-胺盐酸盐。
步骤5:制备1-(3-(4-氨基-5-(1H-吲哚-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-基)丙-2-烯-1-酮
将5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7-(吡咯烷-3-基)-7H-吡咯[2,3-d]嘧啶-4-氨基盐酸盐替换成7-(氮杂环丁烷-3-基)-5-(1H-吲哚-2-基)-7H-吡咯[2,3-d]嘧啶-4-胺盐酸盐,其余所需原料、试剂及制备方法同实施例1中的步骤12,得1-(3-(4-氨基-5-(1H-吲哚-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-基)丙-2-烯-1-酮,33%。
1H NMR(300MHz,DMSO-d6)δ11.38(s,1H),8.20(s,1H),7.88(s,1H),7.56(d,J=7.9Hz,1H),7.39(d,J=7.8Hz,1H),7.10(t,J=7.5Hz,1H),7.02(t,J=7.3Hz,1H),6.61(s,1H),6.55(s,1H),6.40(dd,J=17.0,10.3Hz,1H),6.17(d,J=16.8Hz,1H),5.78-5.59(m,3H),4.79(t,J=8.7Hz,1H),4.65(d,J=6.1Hz,1H),4.55-4.44(m,1H),4.37(d,J=5.9Hz,1H).
实施例31:
1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-基)-2-(***啉亚甲基)丙-2-烯-1-酮
步骤1:制备2-(***啉亚甲基)丙烯酸
将0.66克多聚甲醛和1克丙二酸溶于1,4二氧六环溶液中,再加入***啉,加热至70℃反应2小时,反应液浓缩柱层析(二氯甲烷∶甲醇=98∶2),分离得850毫克白色固体,产率52%
1H NMR(300MHz,CDCl3)δ11.15(s,1H),6.38(s,1H),5.62(s,1H),3.78(s,4H),3.37(s,2H),2.66(s,4H).
步骤2:制备1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-基)-2-(***啉亚甲基)丙-2-烯-1-酮
将2-氟-丙炔酸替换成2-(***啉亚甲基)丙烯酸,其余所需原料、试剂及制备方法同实施例28,得1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-基)-2-(***啉亚甲基)丙-2-烯-1-酮,45%。
1H NMR(300MHz,DMSO-d6)δ8.19(s,1H),7.83(s,1H),7.35(s,1H),7.27(s,1H),6.80(s,1H),6.54(s,2H),5.59(d,J=20.1Hz,3H),4.66(s,2H),4.50-4.32(m,2H),3.95(s,3H),3.55(s,4H),3.11(s,2H),2.43(s,3H),2.37(s,4H).
实施例32:
(E)-1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)-4-(4-乙基哌嗪-1-基)丁-2-烯-1-酮
将丙炔酸替换成反式-4-(4-乙基哌嗪-1-基)巴豆酸盐酸盐,其余所需原料、试剂及制备方法同实施例3,得(E)-1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)-4-(4-乙基哌嗪-1-基)丁-2-烯-1-酮,收率44%。
1H NMR(300MHz,CDCl3)δ8.33(s,1H),7.21(d,J=2.5Hz,2H),7.10(d,J=13.3Hz,1H),6.94(dd,J=15.0,6.2Hz,1H),6.63(s,1H),6.30(dd,J=23.5,15.2Hz,1H),5.50(d,J=5.5Hz,3H),3.99(s,3H),4.32-3.58(m,4H),3.19(dd,J=11.9,6.1Hz,2H),2.72(s,3H),2.83-2.59(m,10H),2.58-2.29(m,2H),2.48(s,3H),1.30-1.07(m,3H).
实施例33:
(E)-1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)-4-(氮杂环丁烷-1-基)丁-2-烯-1-酮
将丙炔酸替换成反式-4-(氮杂环丁烷-1-基)巴豆酸盐酸盐,其余所需原料、试剂及制备方法同实施例3,得(E)-1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)-4-(氮杂环丁烷-1-基)丁-2-烯-1-酮,收率47%。
1H NMR(300MHz,CDCl3)δ8.33(s,1H),7.24-7.18(m,2H),7.10(d,J=11.0Hz,1H),6.94-6.79(m,1H),6.64(s,1H),6.37(dd,J=38.3,15.0Hz,1H),5.56-5.39(m,3H),4.29-3.65(m,4H),3.99(s,3H),3.48-3.20(m,6H),2.48(s,3H),2.65-2.09(m,4H).
实施例34:
1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)丁-2-炔-1-酮
将丙炔酸替换成2-丁炔酸,其余所需原料、试剂及制备方法同实施例3,得1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)丁-2-炔-1-酮,收率33%。
1H NMR(300MHz,CDCl3)δ8.32(d,J=3.8Hz,1H),7.24-7.19(m,2H),7.11(d,J=11.6Hz,1H),6.64(s,1H),5.62(s,2H),5.55-5.40(m,1H),4.32-3.61(m,4H),4.00(s,3H),2.49(s,3H),2.68-2.22(m,2H),2.00(d,J=15.2Hz,3H).
实施例35:
(S)-1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)丙-2-炔-1-酮
将100毫克(S)-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7-(吡咯烷-3-基)-7H-吡咯[2,3-d]嘧啶-4-氨基盐酸,20微升丙炔酸和145毫克2-(7-偶氮苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯溶于2毫升N,N-二甲基甲酰胺,滴加0.2毫升的N,N-二异丙基乙胺,室温下搅拌8小时停止反应,加水后用乙酸乙酯萃取,有机相用饱和氯化钠水溶液洗涤后无水硫酸钠干燥,过滤浓缩,残余物柱层析(二氯甲烷∶甲醇=97∶3)分离得48毫克黄色固体,收率44%。
1H NMR(300MHz,CDCl3)δ8.33(s,1H),7.22(s,2H),7.11(d,J=9.3Hz,1H),6.65(s,1H),5.69(s,2H),5.59-5.40(m,1H),4.37-3.57(m,4H),4.00(s,3H),3.09(d,J=15.2Hz,1H),2.64-2.24(m,2H),2.49(s,3H).
实施例36:
1-(3-(4-氨基-5-(2-甲基-1H-苯并咪唑-5-基)-7H-吡咯[2,3-d]嘧啶-7-y1)吡咯烷-1-基)丙-2-烯-1-酮
将(7-甲氧基-5-甲基苯并噻吩-2-基)硼酸替换成2-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)-1H-苯并咪唑-1-甲酸叔丁酯(制备方法见专利WO2011055215),其余所需原料、试剂及制备方法同实施例1,收率37%。
1H NMR(400MHz,DMSO)δ8.17(s,1H),7.55(d,J=8.1Hz,1H),7.50(s,1H),7.39(s,0.5H),7.34(s,0.5H),7.23(d,J=8.1Hz,1H),6.62(m,1H),6.22-6.12(m,1H),5.73-5.63(m,1H),5.45-5.30(m,1H),3.85-3.75(m,1H),3.65-3.48(m,3H),2.50(s,3H),2.48-2.25(m,2H).
实施例37
(S)-1-(3-(5-(7-甲氧基-5-甲基苯并噻吩-2-基)-4-甲氨基-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)丙-2-烯-1-酮
制备方法同实施例12,收率55%。
1H NMR(300MHz,DMSO-d)δ8.28(s,1H),7.55(d,J=17.7Hz,1H),7.28(d,J=6.9Hz,2H),6.79(s,1H),6.71-6.53(m,1H),6.16(d,J=16.8Hz,2H),5.71(dd,J=22.5,9.6Hz,1H),5.37(d,J=25.8Hz,1H),4.21-3.99(m,1H),3.94(s,3H),3.73(d,J=6.9Hz,2H),3.54(dd,J=15.4,8.9Hz,1H),2.95(d,J=3.7Hz,3H),2.46-2.31(m,5H).
实施例38
(S,E)-1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)-4-二甲氨基-丁-2-烯-1-酮
制备方法同实施例26,收率47%。
1H NMR(300MHz,DMSO-d)δ8.29(s,1H),7.67(s,1H),7.34(s,1H),6.85(s,1H),6.69-6.42(m,2H),5.59-5.41(m,1H),4.10(s,1H),3.95(s,3H),3.86(d,J=7.2Hz,3H),3.23(d,J=12.7Hz,2H),2.47-2.34(m,5H),2.30(s,3H),2.27(s,3H).
实施例39
(S)-1-(3-(4-氨基-3-(7-甲氧基-5-甲基苯并噻吩-2-基)1H-吡唑并[3,4-d]嘧啶-1-基)吡咯烷-1-基)丙-2-炔-1-酮
制备方法同实施例26,收率39%。
1H NMR(300MHz,DMSO-d)δ8.29(s,1H),7.68(s,1H),7.35(s,1H),6.85(s,1H),5.52(s,1H),4.51(d,J=23.6Hz,1H),4.10(d,J=16.8Hz,1H),3.96(s,3H),3.91-3.51(m,3H),2.44(s,5H).
实施例40
(S)-3-(7-甲氧基-5-甲基苯并噻吩-2-基)-1-(1-乙烯磺酰基)吡咯烷-3-基)-1H-吡唑[3,4-d]嘧啶-4-胺)
制备方法同实施例27,收率46%。
1H NMR(300MHz,DMSO-d)δ8.29(s,1H),7.69(s,1H),7.36(s,1H),6.88(dd,J=17.9,8.4Hz,2H),6.10(dd,J=16.8,13.4Hz,2H),5.48(dt,J=10.7,5.4Hz,1H),3.97(s,3H),3.79(dd,J=10.6,7.1Hz,1H),3.59(dd,J=15.8,6.2Hz,2H),3.46(dd,J=9.9,6.8Hz,1H),2.47-2.35(m,5H).
实施例41
1-(3-(4-氨基-5-(4,7-二甲氧基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-基)丙-2-烯-1-酮
制备方法同实施例13,收率60%。
1H NMR(300MHz,DMSO-d)δ8.19(s,1H),7.95(s,1H),7.40(s,1H),6.86(s,2H),6.54(s,2H),6.45-6.30(m,1H),6.15(d,J=17.1Hz,1H),5.71(d,J=10.2Hz,1H),5.62(s,1H),4.72(d,J=8.2Hz,2H),4.42(d,J=9.2Hz,2H),3.91(s,3H),3.88(s,3H).
实施例42
1-(3-(4-氨基-5-(6-甲氧基苯并噻吩-2-基)-7H-吡咯[2,3-d嘧啶-7-基)氮杂环丁烷-1-基)丙-2-烯-1-酮
制备方法同实施例1,收率45%。
1H NMR(300MHz,DMSO-d)δ8.18(s,1H),7.93(d,J=8.8Hz,2H),7.87(d,J=9.1Hz,1H),7.80(s,1H),7.63(d,J=8.3Hz,1H),7.38(s,1H),7.21(d,J=8.9Hz,1H),6.38(dd,J=17.1,10.3Hz,1H),6.16(d,J=17.1Hz,1H),5.71(d,J=12.4Hz,1H),5.62(d,J=8.7Hz,1H),4.72(m,J=2H),4.42(m,2H),3.89(s,3H).
实施例43
1-(3-(4-氨基-5-(苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁基-1-基)丙-2-烯-1-酮
制备方法同实施例1,收率43%。
1H NMR(300MHz,DMSO-d)δ8.18(s,1H),7.97(d,J=7.3Hz,1H),7.90(s,1H),7.85(d,J=7.0Hz,1H),7.44(s,1H),7.36(td,J=13.1,6.5Hz,2H),6.54(s,2H),6.36(dd,J=17.0,10.2Hz,1H),6.19-6.08(m,1H),5.74(s,1H),5.72-5.67(m,1H),5.61(dt,J=13.8,6.8Hz,1H),4.77-4.64(m,2H),4.48-4.32(m,2H).
实施例44
1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-基)-2-(吡咯烷-1-亚甲基)丙-2-烯-1-酮
制备方法同实施例31,收率45%。
1H NMR(300MHz,DMSO-d6)δ8.19(s,1H),7.93(s,1H),7.35(s,1H),7.28(s,1H),6.81(s,1H),6.52(s,2H),5.59(d,J=20.1Hz,3H),4.77(s,2H),4.50-4.35(m,2H),3.95(s,3H),3.4-3.2(6H),2.44(s,3H),1.89(s,4H).
实施例45
(S)1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)-2-(***啉亚甲基)丙-2-烯-1-酮
制备方法同实施例31,收率47%。
1H NMR(300MHz,DMSO-d6)δ8.19(s,1H),7.50(d,J=9.4Hz,1H),7.31(d,J=6.6Hz,1H),7.27(s,1H),6.80(s,1H),6.48(s,2H),5.46-5.35(m,2H),5.29-5.26(m,1H),4.05-3.62(m,4H),3.94(s,3H),3.40-3.20(m,6H),2.43(s,3H),2.37(s,4H),2.24(s,2H).
实施例46
(S)1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)-2-((二乙胺基)亚甲基)丙-2-烯-1-酮
制备方法同实施例31,收率49%。
1H NMR(300MHz,DMSO-d6)δ8.19(s,1H),7.50(d,J=9.4Hz,1H),7.31(d,J=6.6Hz,1H),7.27(s,1H),6.80(s,1H),6.48(s,2H),5.46-5.35(m,2H),5.29-5.26(m,1H),4.05-3.62(m,4H),3.94(s,3H),3.40-3.20(m,6H),2.43(s,3H),2.40(s,2H),1.02-0.68(m,6H).
实施例47
(S)1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)-2-((二甲胺基)亚甲基)丙-2-烯-1-酮
制备方法同实施例31,收率43%
1H NMR(300MHz,DMSO-d6)δ8.19(s,1H),7.53(d,J=9.4Hz,1H),7.31(d,J=6.6Hz,1H),7.27(s,1H),6.80(s,1H),6.48(s,2H),5.52-5.41(m,2H),5.38-5.29(m,1H),4.05-3.62(m,4H),3.94(s,3H),3.40-3.20(m,6H),2.43(s,3H),2.40(s,2H),2.22(s,3H),2.11(s,3H).
实施例48
(S)1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)-2-(哌啶-1-亚甲基)丙-2-烯-1-酮
制备方法同实施例31,收率44%。
1H NMR(300MHz,DMSO-d6)δ8.19(s,1H),7.48(s,1H),7.31(d,J=6.6Hz,1H),7.27(s,1H),6.80(s,1H),6.48(s,2H),5.46-5.35(m,2H),5.29-5.26(m,1H),4.05-3.62(m,4H),3.94(s,3H),3.40-3.20(m,6H),2.43(s,3H),2.42(s,2H),1.42-1.18(m,6H).
实施例49
(S)1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)-2-((4-甲基哌嗪-1-基)-亚甲基)丙-2-烯-1-酮
制备方法同实施例31,收率49%
1H NMR(300MHz,DMSO-d6)δ8.19(s,1H),7.48(d,J=9.4Hz,1H),7.31(d,J=6.6Hz,1H),7.27(s,1H),6.80(s,1H),6.48(s,2H),5.46-5.35(m,2H),5.29-5.26(m,1H),4.05-3.62(m,4H),3.94(s,3H),3.40-3.20(m,2H),2.43(s,3H),2.50(m,8H),2.24(s,3H).
实施例50
N-(2-(4-氨基-3-(7-甲氧基-5-甲基苯并噻吩-2-基)-1H-吡唑[3,4-d]嘧啶-1-基)乙基)丙烯酰胺
制备方法同实施例31,收率46%。
1H NMR(300MHz,DMSO-d6)δ8.37(s,1H),7.53(s,1H),7.27(s,1H),6.91(s,1H),6.69(s,1H),6.26(d,J=17.2Hz,1H),6.15-6.01(m,3H),5.63(d,J=10.2Hz,1H),4.69-4.59(m,2H),4.01(s,3H),3.88(dd,J=10.2,5.3Hz,2H),2.50(s,3H).
实施例51
1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-基)-2-((二乙胺基)亚甲基)丙-2-烯-1-酮
制备方法同实施例31
1H NMR(300MHz,DMSO-d6)δ8.18(s,1H),7.83(s,1H),7.34(s,1H),7.28(s,1H),6.80(s,1H),6.51(s,2H),5.65-5.45(m,3H),4.67(s,2H),4.45-4.37(m,2H),3.94(s,3H),3.40-3.20(m,6H),2.43(s,3H),1.02-0.68(m,6H).
实施例52
1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-基)-2-((4-甲基哌嗪-1-基)亚甲基)丙-2-烯-1-酮
制备方法同实施例31
1H NMR(300MHz,DMSO-d6)δ8.19(s,1H),7.78(s,1H),7.34(s,1H),7.28(s,1H),6.80(s,1H),6.51(s,2H),5.60-5.53(m,3H),4.70-4.62(m,2H),4.48-4.31(m,2H),3.94(s,3H),3.40-3.20(m,4H),3.12(s,2H),2.43(s,7H),2.18(s,3H).
实施例53
1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-基)-2-((二甲胺基)亚甲基)丙-2-烯-1-酮
制备方法同实施例31,收率47%
1H NMR(300MHz,DMSO-d6)δ8.18(s,1H),7.85(s,1H),7.35(s,1H),7.28(s,1H),6.81(s,1H),6.51(s,2H),5.75-5.68(m,2H),5.60-5.52(m,1H),4.72-4.71(m,2H),4.50-4.42(m,1H),4.38-4.32(m,1H),3.95(s,3H),3.40-3.20(m,2H),2.44(s,3H),2.31(s,6H).
实施例54
(S)1-(3-(4-氨基-3-(7-甲氧基-5-甲基苯并噻吩-2-基)-1H-吡唑[3,4-d]嘧啶-1-基)吡咯烷-1-基)-2-(***啉亚甲基)丙-2-烯-1-酮
制备方法同实施例31,收率46%。
1H NMR(300MHz,DMSO-d6)δ8.29(s,1H),7.67(s,1H),7.34(s,1H),7.25(s,2H),6.85(s,1H),5.57-5.30(m,3H),4.11(m,1H),3.96(s,3H),3.81(m,3H),3.40-3.20(m,6H),2.44(s,3H),2.43-2.34(m,2H),2.37(m,4H).
实施例55
1-(3-(4-氨基-3-(7-甲氧基-5-甲基苯并噻吩-2-基)-1H-吡唑[3,4-d]嘧啶-1-基)氮杂环丁烷-1-基)-2-(***啉亚甲基)丙-2-烯-1-酮
制备方法同实施例31,收率45%
1H NMR(300MHz,DMSO-d6)δ8.29(s,1H),7.71(s,1H),7.36(s,1H),7.25(s,2H),6.86(s,1H),5.75-5.65(m,1H),5.75(s,2H),4.75-4.67(m,2H),4.48-4.38(m,2H),3.96(s,3H),3.59(s,3H),3.40-3.20(m,2H),2.45(s,3H),2.37(m,4H).
实施例56
(S)1-(3-(4-氨基-3-(7-甲氧基-5-甲基苯并噻吩-2-基)-1H-吡唑[3,4-d]嘧啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮
制备方法同实施例2,收率55%。
1H NMR(300MHz,DMSO-d6)δ8.29(s,1H),7.67(s,1H),7.34(s,1H),7.25(s,2H),6.85(s,1H),6.75-6.48(m,2H),6.16(d,J=16.9Hz,1H),5.75-5.61(m,2H),5.51(d,J=20.1Hz,1H),4.11(m,1H),3.94(d,J=9.9Hz,3H),3.81(m,3H),2.44(s,3H),2.43-2.34(m,2H).
实施例57
1-(3-(4-氨基-5-(5,7-二甲氧基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)丙-2-烯-1-酮
步骤1:将实施例1步骤4中的原料2-甲氧基-4-甲基苯硫酚替换成2,4-二甲氧基苯硫酚,其余步骤同实施例1,可制备得到标题化合物1-(3-(4-氨基-5-(5,7-二甲氧基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)丙-2-烯-1-酮。
1H NMR(300MHz,CDCl3)δ8.33(s,1H),7.21(s,1H),7.11(d,J=10.2Hz,1H),6.87(s,1H),6.48(s,2H),6.42(d,J=5.6Hz,1H),5.74(s,1H),5.60(s,2H),5.49(s,1H),4.05(s,2H),3.97(s,3H),3.88(s,3H),3.81(s,2H),2.45(s,3H).
实施例58
1-(3-(4-氨基-5-(7-甲氧基-5-(三氟甲基)苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)丙-2-烯-1-酮
步骤1:制备2-碘-5-(三氟甲基)苯酚
将495mg钠氢(60%)混选于40ml干燥得甲苯中,冰浴冷却。缓慢滴加3-三氟甲基苯酚,滴加完后搅拌10分钟后再加入2.08g单质碘。放置室温搅拌16小时。3N盐酸水溶液稀释,乙酸乙酯萃取,硫代硫酸钠水溶液洗,合并有机相浓缩柱层析(石油醚∶乙酸乙酯=98∶2)可获得2.35g油状物。
1H NMR(300MHz,CDCl3)δ5.68(s,1H),6.93(dd,J=8.4,2.1Hz,1H),7.22(d,J=2.1Hz,1H),7.79(d,J=8.4Hz,1H).
步骤2:制备1-碘-2-甲氧基-4-(三氟甲基)苯
将步骤1获得的2-碘-5-(三氟甲基)苯酚2.35g溶于25ml乙醇,加入3.9g碳酸钾和1.4g碘甲烷,氩气保护下回流13小时。硅藻土过滤,滤液浓缩干柱层析(石油醚100%)可定量获得2g油状物。
1H NMR(300MHz,CDCl3)δ3.92(s,3H),6.94(d,J=8.1Hz,1H),6.99(s,1H),7.86(d,J=8.1Hz,1H).
步骤3:制备(2,2-二乙氧基)(2-甲氧基-4-(三氟甲基)苯)硫烷
以步骤2获得的1-碘-2-甲氧基-4-(三氟甲基)苯为原料,通过Adv.Synth.Catal.2015,357,2205-2212报道的方法可获得(2,2-二乙氧基)(2-甲氧基-4-(三氟甲基)苯)硫烷。
1H NMR(300MHz,CDCl3)δ7.37(d,J=8.1Hz,1H),7.17(d,J=8.1Hz,1H),7.00(s,1H),4.68(t,J=5.5Hz,1H),3.93(s,3H),3.69(tt,J=14.1,7.1Hz,2H),3.62-3.46(m,2H),3.14(d,J=5.5Hz,2H),1.20(t,J=7.1Hz,6H).
步骤4:将实施例1步骤5的原料(2,2-二乙氧基乙基)(2-甲氧基-4-甲基苯基)硫醚替换成(2,2-二乙氧基)(2-甲氧基-4-(三氟甲基)苯)硫烷,按照实施例1的步骤可获得标题化合物。
1H NMR(300MHz,CDCl3)δ8.35(s,1H),7.70(s,1H),7.35(s,1H),7.15(d,J=10.1Hz,1H),6.96(s,1H),6.49(d,J=8.6Hz,1H),6.43(d,J=7.1Hz,1H),5.80-5.68(m,1H),5.53(m,3H),4.24-4.09(m,1H),4.07(s,3H),3.85(m,3H),2.59(m,1H),2.44(m,1H).
实施例59
(S)-1-(3-(4-氨基-5-(5-氯-7-甲氧基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)丙-2-烯-1-酮
步骤1:制备4-氯-2-甲氧基苯胺
将3g的铁粉和375mg的氯化铵固体在50ml水中加热回流15分钟,再加入2g的4-氯-2-甲氧基硝基苯。回流反应1.5个小时后冷至室温,饱和碳酸氢钠水溶液调节PH至中性。硅藻土过滤后,滤液用乙酸乙酯萃取,无水硫酸钠干燥得1.45g产物,收率86%。
步骤2:制备4-氯-1-碘-2-甲氧基苯
将1.45g的4-氯-2-甲氧基苯胺溶于60ml水和10ml浓硫酸的溶液中,冰浴冷却至5摄氏度以下。再将634mg亚硝酸钠溶于1ml水中缓慢滴加至反应液,冰浴冷却下搅拌45分钟后,再滴加1.98g的碘化钾水溶液5ml。移至室温搅拌1小时后,乙酸乙酯萃取,饱和硫代硫酸钠水溶液洗,无水硫酸钠干燥后柱层析(PE100%)得2.17g液体,收率88%。
步骤3:制备(4-氯-2-甲氧基苯)(2,2-二乙氧基乙基)硫醚
以步骤2获得的4-氯-1-碘-2-甲氧基苯为原料,通过Adv.Synth.Catal.2015,357,2205-2212报道的方法可获得(4-氯-2-甲氧基苯)(2,2-二乙氧基乙基)硫醚。
1H NMR(300MHz,CDCl3)δ7.27(d,J=8.3Hz,1H),6.89(dd,J=8.3,2.1Hz,1H),6.83(d,J=2.0Hz,1H),4.62(t,J=5.6Hz,1H),3.88(s,3H),3.72-3.47(m,4H),3.06(d,J=5.6Hz,2H),1.20(m,6H).
步骤4:将实施例1步骤5的原料(2,2-二乙氧基乙基)(2-甲氧基-4-甲基苯基)硫醚替换成(4-氯-2-甲氧基苯)(2,2-二乙氧基乙基)硫醚,按照实施例1的步骤可获得标题化合物。
1H NMR(300MHz,CDCl3)δ8.34(s,1H),7.40(s,1H),7.22(s,1H),7.12(d,J=10.4Hz,1H),6.78(s,1H),6.48(d,J=8.5Hz,1H),6.42(d,J=5.0Hz,1H),5.70-5.80(m,1H),5.57(s,2H),5.45-5.55(m,1H),4.05-4.14(m,2H),4.00(s,3H),3.75-3.90(m,3H),2.40-2.60(m,2H).
以下化合物的制备方法与化合物59类似。
实施例61
1-(3-(4-氨基-2-氯-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-基)丙-2-烯-1-酮
将实施例13中步骤1的原料4-氯-7H-吡咯[2,3-d]嘧啶替换成2,4-二氯-7H-吡咯[2,3-d]嘧啶,操作步骤同实施例13。可制备得1-(3-(4-氨基-2-氯-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)氮杂环丁烷-1-基)丙-2-烯-1-酮,收率45%。
1H NMR(300MHz,CDCl3)δ7.36(s,1H),7.23(s,2H),6.66(s,1H),6.42(d,J=16.9Hz,1H),6.27(d,J=10.3Hz,1H),5.80-5.65(m,4H),4.73(m,2H),4.45(s,2H),4.00(s,3H),2.49(s,3H).
以下化合物的制备方法与化合物61类似。
实施例63
1-(3-(4-(二甲氨基)-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)丙-2-烯-1-酮
将实施例12中步骤2的原料氨水替换成二甲胺的水溶液,其余步骤同实施例12。制备得1-(3-(4-(二甲氨基)-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)丙-2-烯-1-酮。收率59%。
1H NMR(300MHz,CDCl3)δ8.42(s,1H),7.22-7.08(m,3H),6.62(s,1H),6.45(m,2H),5.73(m,1H),5.53(m,1H),4.25-4.03(m,2H),4.00(s,3H),3.79(s,2H),2.94(s,6H),2.54(s,1H),2.48(s,3H),2.44-2.36(m,1H).
实施例66
1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-2-(2-***啉乙氧基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)丙-2-烯-1-酮
步骤1:制备6-氨基-5-(2,2-二乙氧基)-2-巯基嘧啶-4-醇
将2.15g的2-氰基-4,4-二乙氧基丁酸乙酯溶于5.3ml的20%乙醇钠乙醇溶液中,再加入1.2g硫脲,加热回流过夜。次日浓缩干反应液,再用38ml的水稀释,***洗涤。水相用醋酸调节PH至中性,大量固体析出,过滤,收集固体干燥,得1.5g浅黄色固体,收率62%。
1H NMR(300MHz,DMSO-d6)δ11.75(s,1H),11.44(s,1H),6.07(s,2H),4.50(t,J=5.6,1H),3.59(dq,J=7.0,9.5,2H),3.40(dq,J=7.0,9.6,2H),2.44(d,J=5.6,2H),1.07(t,J=7.0,6H);
步骤2:制备2-硫代-1,2,3,7-四氢-4H-吡咯[2,3-d]嘧啶-4-酮。
将步骤2得到的6-氨基-5-(2,2-二乙氧基)-2-巯基嘧啶-4-醇1g于12ml的0.2NHCl水溶液中室温搅拌24小时,大量固体析出,过滤干燥定量得到2-硫代-1,2,3,7-四氢-4H-吡咯[2,3-d]嘧啶-4-酮。
1H NMR(300MHz,DMSO-d6)δ13.20(s,1H),11.86(s,1H),11.26(s,1H),6.72(s,1H),6.33(d,J=2.8Hz,1H).
步骤3:制备2-(甲硫基)-3,7-二氢-4H-吡咯[2,3-d]嘧啶-4-酮。
320mg氢氧化钠溶于15ml乙醇中,将步骤3得到的2-硫代-1,2,3,7-四氢-4H-吡咯[2,3-d]嘧啶-4-酮660mg溶于该溶液中,冰浴冷却下滴加0.25ml碘甲烷。完毕后恢复室温,搅拌3小时。浓缩反应液,少量水溶解,用5N的HCl调节PH至弱酸性,大量固体析出。过滤收集固体,干燥得700mg白色固体。收率97%。
1H NMR(300MHz,DMSO-d6)δ12.02(s,1H),11.74(s,1H),6.89-6.91(m,1H),6.34-6.36(m,1H),2.09(s,3H).
步骤4:制备4-氯-2-(甲硫基)-7H-吡咯[2,3-d]嘧啶。
将700mg步骤3得到的2-(甲硫基)-3,7-二氢-4H-吡咯[2,3-d]嘧啶-4-酮于10ml三氯氧磷中加热回流过夜,次日浓缩反应液,加水稀释后乙酸乙酯萃取,饱和氯化钠水洗,无水硫酸钠干燥有机相,浓缩干定量得4-氯-2-(甲硫基)-7H-吡咯[2,3-d]嘧啶。
1H NMR(300MHz,DMSO-d6)δ12.40(s,1H),7.52(d,J=3.4Hz,1H),6.51(s,1H),2.55(s,3H).
步骤5:制备4-氯-5-碘-2-(甲硫基)-7H-吡咯[2,3-d]嘧啶。
将上述制备的4-氯-2-(甲硫基)-7H-吡咯[2,3-d]嘧啶100mg和146mgN-碘代丁二酰亚胺溶于2mlN,N-二甲基甲酰胺中,室温搅拌18小时。用水稀释,大量固体析出,过滤干燥的140mg紫色固体,收率91%。
1H NMR(300MHz,DMSO-d6)δ12.72(s,1H),7.75(s,1H),2.55(s,3H).
步骤6:制备3-(4-氯-5-碘-2-(甲硫基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯。
将实施例1中步骤8的4-氯-5-碘-7H-吡咯[2,3-d]嘧啶替换成4-氯-5-碘-2-(甲硫基)-7H-吡咯[2,3-d]嘧啶,其余所需原料、操作步骤同实施例1步骤8,定量得到3-(4-氯-5-碘-2-(甲硫基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯。
1H NMR(300MHz,CDCl3)δ7.20(s,1H),5.37(s,1H),3.88(dd,J=11.7,6.9Hz,1H),3.55(s,3H),2.60(s,3H),2.42(td,J=13.9,7.2Hz,1H),2.22(td,J=13.2,6.7Hz,1H),1.48(s,9H).
步骤7:制备3-(4-氨基-5-碘-2-(甲硫基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯。
制备方法同实施例1中的步骤9。
1H NMR(300MHz,CDCl3)δ6.91(s,1H),5.55(s,2H),5.31(s,1H),3.91-3.77(m,1H),3.53(s,3H),2.55(s,3H),2.37(dd,J=13.5,6.5Hz,1H),2.28-2.13(m,1H),1.48(s,9H).
步骤8:制备3-(4-氨基-5-碘-2-(甲磺酰基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯。
将上述制备的3-(4-氨基-5-碘-2-(甲硫基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯1.2g溶于乙醇中,分批加入2.5当量的间氯过氧苯甲酸室温搅拌过夜。次日浓缩干柱层析(二氯甲烷∶甲醇=98∶2),得1.28g的3-(4-氨基-5-碘-2-(甲磺酰基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯。
1H NMR(300MHz,CDCl3)δ7.21(s,1H),6.20(s,2H),5.46(s,1H),3.87(s,1H),3.70-3.50(m,3H),3.30(s,3H),2.42(s,1H),2.19(s,1H),1.49(s,9H).
步骤9:制备3-(4-氨基-5-碘-2-(2-***啉乙氧基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯。
将413mg的2-***啉乙醇和384mg叔丁醇钾溶于四氢呋喃,室温搅拌10分钟后加入3-(4-氨基-5-碘-2-(甲磺酰基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯800mg,80℃封管过夜。次日浓缩干反应液,柱层析(二氯甲烷∶甲醇=98∶2+0.1%氨水),得到780mg固体,收率89%。
1H NMR(300MHz,CDCl3)δ6.87(s,1H),5.56(s,2H),5.24(s,1H),4.45(t,J=6.0Hz,2H),3.80(s,1H),3.75-3.69(m,4H),3.65-3.45(m,3H),2.80(t,J=6.0Hz,2H),2.64-2.50(m,4H),2.41-2.25(m,1H),2.18(dd,J=13.5,6.6Hz,1H),1.48(s,9H).
步骤10:将实施例1步骤10中的3-(4-氨基-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯替换成3-(4-氨基-5-碘-2-(2-***啉乙氧基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯,其余步骤与实施例1类似,可以制备得到标题化合物。
1H NMR(300MHz,CDCl3)δ7.19(d,J=4.4Hz,2H),6.93(d,J=9.2Hz,1H),6.62(s,1H),6.51-6.37(m,2H),5.78-5.65(m,1H),5.44(s,2H),5.41-5.26(m,1H),4.48(t,J=5.8Hz,2H),4.17-4.03(m,1H),3.98(s,3H),3.79(d,J=8.6Hz,3H),3.72(s,4H),2.82(t,J=5.8Hz,2H),2.59(s,4H),2.47(s,3H),2.44-2.31(m,2H).
实施例68
1-(3-(4-氨基-5-(7-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)丙-2-烯-1-酮
将实施例22中步骤1的原料2-甲氧基苯硫酚替换成2-甲基苯硫酚,其余操作步骤类似实施例22。制备得1-(3-(4-氨基-5-(7-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)丙-2-烯-1-酮,收率56%。
1H NMR(300MHz,CDCl3)δ8.34(s,1H),7.65(d,J=8.0Hz,1H),7.33(m,2H),7.20-7.09(m,2H),6.53-6.45(m,1H),6.45-6.39(m,1H),5.78-5.68(m,1H),5.58(s,2H),5.51(dd,J=12.1,5.9Hz,1H),4.26-4.04(m,2H),3.88-3.76(m,2H),2.58(s,3H),2.55-2.35(m,2H).
实施例69
(E)-1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)-4-(3-氟吡咯烷-1-基)丁-2-烯-1-酮
将实施例7中的反式-4-(吡咯烷-1-基)巴豆酸盐酸盐替换成反式-4-(3-氟吡咯烷-1-基)丁-2-烯酸盐酸盐,其余步骤与实施例7类似。制备得(E)-1-(3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)-4-(3-氟吡咯烷-1-基)丁-2-烯-1-酮
以下化合物的制备方法与化合物69类似。
实施例70
1-(4-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)-2-(羟甲基)吡咯烷-1-基)丙-2-烯-1-酮
步骤1:制备2-(((叔丁基二苯基硅)氧)甲基)-4-羟基吡咯烷-1-甲酸叔丁酯
将4-羟基-2-(羟甲基)吡咯烷-1-甲酸叔丁酯500mg和164mg咪唑溶于N,N-二甲基甲酰胺中。冰浴冷却下滴加叔丁基二苯基氯硅烷0.62ml。室温下搅拌1小时后加水淬灭反应,乙酸乙酯萃取后柱层析(石油醚∶乙酸乙酯=85∶15),得900mg油状物,收率86%。[M+H]+:456
步骤2:制备4-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)-2-(((叔丁基二苯基硅)氧)亚甲基)吡咯烷-1-甲酸叔丁酯。
将实施例1中步骤8的3-羟基吡咯烷-1-甲酸叔丁酯替换成2-(((叔丁基二苯基硅)氧)甲基)-4-羟基吡咯烷-1-甲酸叔丁酯,其余步骤与实施例1中步骤8至步骤10类似。[M+H]+:748
步骤3:制备4-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)-2-(羟甲基)吡咯烷-1-甲酸叔丁酯。
将4-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)-2-(((叔丁基二苯基硅)氧)亚甲基)吡咯烷-1-甲酸叔丁酯300mg溶于3ml四氢呋喃,再加入2.5当量的四丁基氟化铵,室温搅拌过夜。次日浓缩干柱层析(二氯甲烷∶甲醇=98∶2)得170mg固体,收率83%。[M+H]+:510
步骤4:以步骤3获得的4-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)-2-(羟甲基)吡咯烷-1-甲酸叔丁酯为原料,制备方法同实施例1步骤11至步骤12可获得标题化合物。
1H NMR(300MHz,CDCl3)δ8.30(s,1H),7.20(m,3H),6.64(s,1H),6.43(m,2H),5.80-5.73(m,1H),5.62(s,2H),5.26(m,1H),4.50-4.29(m,2H),3.99(s,3H),3.94(m,2H),3.88-3.76(m,2H),2.72-2.65(m,1H),2.48(s,3H),2.40-2.25(m,1H).
实施例71
1-(3-(4-氨基-6-氯-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)嘧啶-1-基)丙-2-烯-1-酮
步骤1:制备3-(4-氯-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯
将实施例1中步骤10中的3-(4-氨基-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯替换成3-(4-氯-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯,其他原料不变可制备得3-(4-氯-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯。[M+H]=499
步骤2:制备3-(4,6-二氯-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯
将步骤1得到的3-(4-氯-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯50mg和3mg的三苯硫磷溶于1ml二氯甲烷中,室温搅拌5分钟后加入16mg的N-氯代丁二酰亚胺,室温搅拌1小时。浓缩干后柱层析(PE:EA)=55∶45,可以得到3-(4,6-二氯-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯。[M+H]=533
步骤3:制备3-(4-氨基-6-氯-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯
将步骤2得到的3-(4,6-二氯-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯40mg于2ml氨水和2ml二氧六环混合溶液中110℃加热反应48小时。浓缩干后柱层析(二氯甲烷∶甲醇=98∶2),以78%收率得到3-(4-氨基-6-氯-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯。[M+H]=514
步骤4:根据实施例1,将实施例1步骤11的原料3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯替换成3-(4-氨基-6-氯-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯可制备得到标题化合物。
1H NMR(300MHz,CDCl3)δ8.34(s,1H),7.41(d,J=2.0Hz,1H),7.14(d,J=11.4Hz,1H),6.68(s,1H),6.51-6.39(m,2H),5.80-5.69(m,1H),5.57(s,2H),5.54-5.43(m,1H),4.24-4.03(m,2H),3.98(s,3H),3.91-3.75(m,2H),2.60-2.52(m,1H),2.51(s,3H),2.45(s,1H).
实施例72
N-(2-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)乙基)丙烯酰胺
步骤1:制备(2-(4-氯-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)乙基)氨基甲酸叔丁酯
将实施例1步骤7得到的4-氯-5-碘-7H-吡咯[2,3-d]嘧啶100mg,108mg的N-Boc-溴乙胺和200mg碳酸铯于2ml的N,N-二甲基甲酰胺中加热80℃反应6小时。加水稀释后用乙酸乙酯萃取,有机相用无水硫酸钠干燥。浓缩干后柱层析(PE∶EA=85∶15),得145mg(2-(4-氯-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)乙基)氨基甲酸叔丁酯,收率85%。
1H NMR(300MHz,CDCl3)δ8.60(s,1H),7.38(s,1H),4.75(s,1H),4.40(s,2H),3.52(dd,J=12.9,7.0Hz,2H),1.40(s,9H).
步骤2:制备标题化合物
根据实施例1,将步骤1获得的中间体为原料替换实施例1步骤9中的3-(4-氯-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯,可制备得到标题化合物。
1H NMR(300MHz,CDCl3)δ8.31(s,1H),7.20(d,J=3.8Hz,2H),7.11(s,2H),6.64(s,1H),6.25(d,J=17.3Hz,1H),6.14-6.01(m,1H),5.63(d,J=16.7Hz,3H),4.47-4.36(m,2H),4.00(s,3H),3.77(dd,J=10.4,4.9Hz,2H),2.48(s,3H).
实施例73
N-(4-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)环己基)丙烯酰胺
将实施例1中步骤8的3-羟基吡咯烷-1-甲酸叔丁酯替换成(4-羟基环己基)氨基甲酸叔丁酯,其他步骤同实施例1可获得标题化合物。
1H NMR(300MHz,CDCl3)δ8.31(s,1H),7.20(m,3H),6.64(s,1H),6.35(d,J=16.6Hz,1H),6.24(d,J=10.1Hz,1H),6.18(d,J=9.9Hz,1H),5.69(d,J=10.1Hz,1H),5.55(s,2H),4.62(s,1H),4.34(s,1H),3.99(s,3H),2.48(s,3H),2.06(s,4H),1.85(s,4H).
实施例75
(4S)-1-丙烯酰胺-4-(4-氨基-3-(7-甲氧基-5-甲基苯并噻吩-2-基)-1H-吡唑[3,4-d]嘧啶-1-基)-N-(2-(二甲胺)乙基-N-甲基吡咯烷-2-甲酰胺
步骤1:制备1-(叔丁基2-甲基(4S)-4-(4-氨基-3-(7-甲氧基-5-甲基苯并噻吩-2-基)-1H-吡唑[3,4-d]嘧啶-1-基)吡咯烷-1,2-二甲酸酯
将实施例2步骤3中的3-羟基吡咯烷-1-甲酸叔丁酯替换成N-Boc-反式-4-羟基-L-脯氨酸甲酯,其余步骤同实施例2得1-(叔丁基2-甲基(4S)-4-(4-氨基-3-(7-甲氧基-5-甲基苯并噻吩-2-基)-1H-吡唑[3,4-d]嘧啶-1-基)吡咯烷-1,2-二甲酸酯。[M+H]+:539
步骤2:制备(4S)-4-(4-氨基-3-(7-甲氧基-5-甲基苯并噻吩-2-基)-1H-吡唑[3,4-d]嘧啶-1-基)-1-(甲酸叔丁酯)吡咯烷-2-甲酸。
将步骤1得到的1-(叔丁基2-甲基(4S)-4-(4-氨基-3-(7-甲氧基-5-甲基苯并噻吩-2-基)-1H-吡唑[3,4-d]嘧啶-1-基)吡咯烷-1,2-二甲酸酯670mg溶于6ml甲醇,冰浴冷却。滴加4N氢氧化钠水溶液3.8ml,室温搅拌5小时。稀盐酸调节PH至弱酸性,乙酸乙酯萃取,无水硫酸钠干燥。浓缩干得530mg粗品。
步骤3:制备(4S)-4-(4-氨基-3-(7-甲氧基-5-甲基苯并噻吩-2-基)-1H-吡唑[3,4-d]嘧啶-1-基)-2-((2-(二甲氨基)乙基)(甲基)甲酰胺)吡咯烷-1-甲酸叔丁酯
将步骤2获得的(4S)-4-(4-氨基-3-(7-甲氧基-5-甲基苯并噻吩-2-基)-1H-吡唑[3,4-d]嘧啶-1-基)-1-(甲酸叔丁酯)吡咯烷-2-甲酸200mg、N,N,N’-三甲基乙烷-1,2-二胺50微升、BOP252mg和0.12ml二异丙基乙胺溶于5ml乙腈中,室温搅拌过夜。次日浓缩干,柱层析(二氯甲烷∶甲醇=95∶5+0.1%氨水)得100mg黄色固体。[M+H]+:609
步骤4:将步骤3获得的(4S)-4-(4-氨基-3-(7-甲氧基-5-甲基苯并噻吩-2-基)-1H-吡唑[3,4-d]嘧啶-1-基)-2-((2-(二甲氨基)乙基)(甲基)甲酰胺)吡咯烷-1-甲酸叔丁酯替换掉实施例2步骤6的3-(4-氨基-3-(7-甲氧基-5-甲基苯并噻吩-2-基)-1H-吡唑[3,4-d]嘧啶-1-基)吡咯烷-1-甲酸叔丁酯,获得标题化合物。[M+H]+:563
实施例76
5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7-(2-***啉乙基)-7H-吡咯[2,3-d]嘧啶-4-氨
步骤1:制备2-吗啉基乙基甲磺酸酯
将实施例2步骤3中的3-羟基吡咯烷-1-甲酸叔丁酯替换成2-吗啉乙醇获得2-吗啉基乙基甲磺酸酯,直接投下一步。
步骤2:制备4-(2-(4-氯-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)乙基)吗啉
将200毫克4-氯-5-碘-7H-吡咯[2,3-d]嘧啶和步骤1获得的480毫克2-吗啉基乙基甲磺酸酯溶于2毫升N,N-二甲基甲酰胺,再加入456毫克碳酸铯,氩气保护下加热至90℃过夜,次日加水后用乙酸乙酯萃取,有机相用饱和氯化钠水溶液洗涤后无水硫酸钠干燥,过滤浓缩,残余物柱层析(二氯甲烷∶甲醇=97∶3)分离得38毫克黄色固体。
1H NMR(300MHz,CDCl3)δ8.60(s,1H),7.50(s,1H),4.37(t,J=6.1Hz,2H),3.67(s,4H),2.74(t,J=6.3Hz,2H),2.50(s,4H).
步骤3将实施例1步骤9中的3-(4-氯-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯替换成步骤2获得的4-(2-(4-氯-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)乙基)吗啉,按照实施例1步骤9至步骤10可获得标题化合物。
1H NMR(300MHz,CDCl3)δ8.33(s,1H),7.25(s,1H),7.22(d,J=2.3Hz,2H),6.64(s,1H),5.56(s,2H),4.34(t,J=6.3Hz,2H),4.00(s,3H),3.74-3.65(m,4H),2.79(t,J=6.3Hz,2H),2.53(s,4H),2.49(s,3H).
实施例78
N-(3-((4-氨基-3-(7-甲氧基-5-甲基苯并噻吩-2-基)-1H-吡唑[3,4-d]嘧啶-1-基)甲基)苯基)丙烯酰胺
步骤1:制备1-(3-氨基苄基)-3-碘-1H-吡唑[3,4-d]嘧啶-4-胺
将实施例1步骤8中的原料4-氯-5-碘-7H-吡咯[2,3-d]嘧啶替换成3-碘-1H-吡唑[3,4-d]嘧啶-4-胺,3-羟基吡咯烷-1-甲酸叔丁酯替换成(3-氨基苯基)甲醇,可获得1-(3-氨基苄基)-3-碘-1H-吡唑[3,4-d]嘧啶-4-胺。[M+H]+:367
步骤2:将实施例1步骤10的原料3-(4-氨基-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯替换成步骤1得到的1-(3-氨基苄基)-3-碘-1H-吡唑[3,4-d]嘧啶-4-胺,其余步骤同实施例1,可获得标题化合物N-(3-((4-氨基-3-(7-甲氧基-5-甲基苯并噻吩-2-基)-1H-吡唑[3,4-d]嘧啶-1-基)甲基)苯基)丙烯酰胺。
1H NMR(300MHz,DMSO-d6)δ10.14(s,1H),8.31(s,1H),7.67(d,J=11.4Hz,2H),7.50(s,1H),7.35(s,1H),7.33-7.25(m,2H),7.03(d,J=7.8Hz,1H),6.85(s,1H),6.39(dd,J=16.9,9.9Hz,2H),6.22(d,J=16.7Hz,1H),5.72(d,J=9.9Hz,1H),5.54(s,2H),3.95(s,3H),2.44(s,3H).
实施例79
1-(3-(4-氨基-5-(3,5-二甲氧基苯)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)丙-2-烯-1-酮
步骤1:将实施例1步骤10的原料(7-甲氧基-5-甲基苯并噻吩-2-基)硼酸替换成3,5-二甲氧基苯基硼酸频那醇酯,其余步骤同实施例1,可获得标题化合物1-(3-(4-氨基-5-(3,5-二甲氧基苯)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)丙-2-烯-1-酮。
以下化合物的制备方法与化合物79类似。
实施例80
1-(3-(4-氨基-5-(3-氨基-1H-吲唑-6-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)丙-2-烯-1-酮
步骤1:制备3-(4-氨基-5-(4-氰基-3-氟苯)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯
将200毫克的3-(4-氨基-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯,91毫克的4-氰基-3-氟苯硼酸,98毫克的碳酸钠和27毫克的四三苯基膦钯溶于4毫升的1,4-二氧六环和1毫升水的混合溶液中,置换氩气后80℃加热反应过夜,反应液浓缩至干,残余物柱层析(二氯甲烷∶甲醇=98∶2)分离定量得150毫克淡黄色固体。[M+H]+:423
步骤2:制备3-(4-氨基-5-(3-氨基-1H-吲唑-6-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯
将上一步得到的3-(4-氨基-5-(4-氰基-3-氟苯)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯100mg溶于4ml正丁醇中,加入1ml水合肼,氩气保护下回流12小时。浓缩干后柱层析(二氯甲烷∶甲醇=98∶2),可获得62mg固体3-(4-氨基-5-(3-氨基-1H-吲唑-6-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯。
1H NMR(300MHz,CDCl3)δ8.33(s,1H),7.65(d,J=8.2Hz,1H),7.38(s,1H),7.18(d,J=8.2Hz,1H),7.03(s,1H),5.49(s,1H),5.30(s,2H),4.20(s,2H),3.97-3.87(m,1H),3.70-3.50(m,3H),2.50-2.38(m,1H),2.35-2.23(m,1H),1.47(s,9H).
步骤3:将实施例1步骤11中的3-(4-氨基-5-(7-甲氧基-5-甲基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯替换成上一步获得的3-(4-氨基-5-(3-氨基-1H-吲唑-6-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯,按相同步骤可获得标题化合物。
1H NMR(300MHz,CDCl3)δ8.34(s,1H),7.65(d,J=8.2Hz,1H),7.37(s,1H),7.17(d,J=9.0Hz,1H),7.00(d,J=8.2Hz,1H),6.54-6.36(m,2H),5.74(s,1H),5.52(s,1H),5.29(s,2H),4.13(m,2H),3.81(s,2H),2.44(s,2H).
实施例84
1-(3-(4-氨基-3-(7-甲氧基-5-甲基苯并噻吩-2-基)-1H-吡唑[3,4-d]嘧啶-1-基)吡咯烷-1-基)-2-氯乙烷-1-酮
步骤1:将实施例2步骤7中的丙烯酰氯替换成氯乙酰氯,可制备得到标题化合物。
1H NMR(300MHz,CDCl3)δ8.38(s,1H),7.52(s,1H),7.27(s,1H),6.68(s,1H),5.89(d,J=7.8Hz,2H),5.58(s,1H),4.20-4.03(m,4H),4.01(s,3H),3.74(s,2H),2.67(s,2H),2.50(s,3H).
实施例85
2-(7-(1-丙烯酰基吡咯烷-3-基)-4-氨基-7H-吡咯[2,3-d]嘧啶-5-基)-7-甲氧基苯并噻吩-5-甲酸
步骤1:制备7-羟基苯并噻吩-5-甲酸乙酯
根据文献J.AM.CHEM.SOC.2007,129,14092-14099类似方法可得到7-羟基苯并噻吩-5-甲酸乙酯。
步骤2:7-甲氧基基苯并噻吩-5-甲酸乙酯
将上述得到的7-羟基苯并噻吩-5-甲酸乙酯200mg、150mg碳酸钾和155mg碘甲烷溶于乙腈中,封管加热回流20小时。过滤后滤液浓缩柱层析(石油醚100%)可定量获得230mg油状物。
1H NMR(300MHz,CDCl3)δ8.19(d,J=1.0Hz,1H),7.50(d,J=5.4Hz,1H),7.43(s,1H),7.40(d,J=5.4Hz,1H),4.43(q,J=7.1Hz,2H),4.06(s,3H),1.44(t,J=7.1Hz,3H).
步骤3:制备7-甲氧基基苯并噻吩-5-甲酸
将步骤2获得的200mg7-甲氧基基苯并噻吩-5-甲酸乙酯溶于4ml四氢呋喃、1ml甲醇和1ml水的混合溶液中,加入36mg氢氧化锂搅拌24小时。用2N稀盐酸调节PH至2,乙酸乙酯萃取。有机相浓缩干柱层析(二氯甲烷∶甲醇=98∶2),可获得165mg白色固体,收率93%。
1H NMR(300MHz,CDCl3)δ8.30(s,1H),7.53(d,J=5.4Hz,1H),7.49(s,1H),7.44(d,J=5.3Hz,1H),4.09(s,3H).
步骤4:将实施例1步骤6的7-甲氧基-5-甲基苯并噻吩和正丁基锂分别替换成7-甲氧基基苯并噻吩-5-甲酸和二异丙基氨基锂,按照实施例1相同步骤可制备得到标题化合物。
1H NMR(300MHz,DMSO-d6)δ12.96(s,1H),8.21(s,1H),8.12(s,1H),7.65(d,J=17.5Hz,1H),7.55(s,1H),7.40(s,1H),6.70-6.47(m,3H),6.17(d,J=16.4Hz,1H),5.67(d,J=12.6Hz,1H),5.37(m,1H),4.12(m,1H),4.03(s,3H),3.90(m,1H),3.79-3.68(m,1H),3.54(m,1H),2.39(m,2H).
实施例86
(S)-1-(3-(4-氨基-5-(7-甲氧基苯并噻吩-2-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)丙-2-烯-1-酮
将实施例12步骤3中的(7-甲氧基-5-甲基苯并噻吩-2-基)硼酸替换成实施例22中得到的(7-甲氧基苯并噻吩-2-基)硼酸,可制备得到标题化合物。
1H NMR(300MHz,CDCl3)δ8.34(s,1H),7.45-7.31(m,2H),7.29(d,J=1.7Hz,1H),7.12(d,J=10.7Hz,1H),6.81(d,J=7.8Hz,1H),6.51-6.45(m,1H),6.45-6.39(m,1H),5.81-5.68(m,1H),5.58(s,2H),5.51(dd,J=14.3,6.9Hz,1H),4.25-4.04(m,2H),4.02(s,3H),3.75-3.93(m,2H),2.40-2.60(m,2H).
对照化合物
(S)-1-(3-(4-氨基-5-(喹啉-3-基)-7H-吡咯[2,3-d]嘧啶-7-基)吡咯烷-1-基)丙-2-烯-1-酮
制备方法参照实施例1。
1H NMR(300MHz,DMSO-d)δ9.05(s,1H),8.35(s,1H),8.21(s,1H),8.11-7.96(m,2H),7.76(d,J=7.2Hz,1H),7.69(d,J=16.2Hz,1H),7.66-7.59(m,1H),6.72-6.53(m,1H),6.39(s,2H),6.17(d,J=16.5Hz,1H),5.69(t,J=11.4Hz,1H),5.51-5.31(m,1H),4.22-4.09(m,0.5H),4.05-3.86(m,1.5H),3.76(dd,J=12.4,6.2Hz,1.5H),3.55(dd,J=20.0,7.9Hz,0.5H),2.41(dd,J=16.2,8.9Hz,2H).
化合物分子水平对FGFR1、FGFR4酶活的影响
1、试验方法
将酶反应底物Poly(Glu,Tyr)4∶1用无钾离子的PBS(10mM磷酸钠缓冲液,150mMNaCl,pH 7.2-7.4)稀释成20μg/mL,125μL/孔包被酶标板,置37℃反应12-16小时。弃去孔中液体后洗板,用200μL/孔的T-PBS(含0.1%Tween-20的PBS)洗板三次,每次5分钟。于37℃烘箱中干燥酶标板1-2小时。
每孔加入用反应缓冲液(50mM HEPES pH 7.4,50mM MgCl2,0.5mM MnCl2,0.2mMNa3VO4,1mM DTT)稀释的ATP溶液50μL,终浓度5μM。化合物用DMSO稀释成合适的浓度,1μL/孔或者或含相应浓度的DMSO(阴性对照孔),再加入用49μL反应缓冲液稀释的FGFR1、FGFR4激酶域重组蛋白启动反应,每次实验需设无ATP对照孔两孔。置37℃摇床(100rpm)反应1小时。T-PBS洗板三次。加入一抗PY99稀释液100μL/孔,37℃摇床反应0.5小时。T-PBS洗板三次。加入二抗辣根过氧化物酶标记羊抗鼠的IgG稀释液100μL/孔,37℃摇床反应0.5小时。T-PBS洗板三次。加入2mg/ml的OPD显色液100μL/孔(用含有0.03%H2O2的0.1M柠檬酸-柠檬酸钠缓冲液(pH=5.4)稀释),25℃避光反应1-10分钟。(OPD溶解时需用超声,显色液需现配现用)。加入2M H2SO4 50μL/孔中止反应,用可调波长式微孔板酶标仪SPECTRA MAX 190读数,波长为490nm。
样品的抑制率通过下列公式求得:
IC50值采用酶标仪随机附带软件以四参数法回归求得。
2、实验结果
表2.化合物对FGFR1和FGFR4酶活抑制活性
表3.化合物对EGFR酶活抑制活性
实施例 | EGFR |
NO.12 | >1000nM |
其中:A表示IC50小于(≤)10nM
B表示IC50小于(≤)100nM且大于(>)10nM
C表示IC50大于(>)100nM
从表2可以看出:本发明化合物对FGFR1和FGFR4酶在nM水平具有明显的抑制作用,由于FGFR1和FGFR2、3具有很高的同源性,可以预见本发明化合物对于FGFR1-4都具有显著的抑制作用。
此外,从表2还可以得出如下结论:
i)对比化合物NO.1-8(含取代的苯丙噻吩基团且Y-E-Z结构较复杂)和化合物NO.9-10以及NO.50(含取代的苯丙噻吩基团,但是Y-E-Z结构较简单)可知,当Y-E-Z结构较为复杂时,所述化合物具有更高的FGFR抑制活性;类似的结论也可从化合物NO.2和化合物NO.50的测试结果对比得出;
ii)对比化合物NO.13(含取代的苯丙噻吩基)和化合物NO.23(含取代的苯丙呋喃基)可知,当所述化合物包含取代的苯丙噻吩基时,其将具有更高的FGFR抑制活性;
iii)对比化合物NO.43和化合物NO.22可知,苯丙噻吩上甲氧基的取代是利于增强所述化合物的FGFR抑制活性的;
iv)对比化合物NO.43和化合物NO.13可知,苯丙噻吩上甲氧基和甲基的取代是利于增强所述化合物的FGFR抑制活性的;
v)对比化合物NO.12(R1为取代的苯丙噻吩基)和对照化合物(R1为未取代的喹啉基)可知,相比于R1为取代的苯丙噻吩基的化合物,当R1为未取代的喹啉基时,所得化合物对FGFR的抑制活性将显著降低;换言之,当R1为未取代的喹啉基时,所得化合物基本不具有FGFR抑制活性。
从表3可以看出:化合物NO.12作为本发明的代表性的化合物,其基本不具有EGFR抑制活性。
化合物对SNU16细胞增殖的影响
1、试验方法
化合物对SNU16细胞的增殖抑制作用以CCK-8细胞计数试剂盒(Dojindo)检测。具体步骤如下:处于对数生长期的SNU16细胞按合适密度接种至96孔培养板中,每孔90μL,培养过夜后,加入不同浓度的化合物作用72hr,并设定溶剂对照组(阴性对照)。待化合物作用细胞72h后,化合物对细胞增殖的影响采用CCK-8细胞计数试剂盒(Dojindo)检测,每孔加入10μL CCK-8试剂,置于37℃培养箱中放置2-4小时后,用全波长式微孔板酶标仪SpectraMax190读数,测定波长为450nm。采用以下列公式计算化合物对肿瘤细胞生长的抑制率(%):抑制率(%)=(OD阴性对照孔-OD给药孔)/OD阴性对照孔×100%。IC50值采用酶标仪随机附带软件以四参数法回归求得。
2、实验结果
表4.化合物对SNU16细胞增殖的影响
其中:A表示IC50小于(≤)10nM
B表示IC50小于(≤)100nM且大于(>)10nM
C表示IC50大于(>)100nM
从表4可以看出:本发明化合物对于FGFR依赖性的细胞株的生殖活性具有显著的抑制作用。
化合物对非小细胞肺癌细胞NCI-H1581裸小鼠移植瘤生长的影响
实验方法
取生长旺盛期的瘤组织剪切成1.5mm3左右,在无菌条件下,接种于裸小鼠右侧腋窝皮下。裸小鼠皮下移植瘤用游标卡尺测量移植瘤直径,待肿瘤生长至平均体积约为90mm3组左右后将动物随机分组。将实施例12所得化合物NO.12分别按照100mg/kg和20mg/kg的剂量,每天口服给药一次,连续给药14天,测量化合物NO.12对人肺癌NCI-H1581裸小鼠皮下移植瘤的生长抑制作用。
溶剂对照组则给以等量生理盐水。整个实验过程中,每周2次测量移植瘤直径,同时称量小鼠体重。肿瘤体积(tumor volume,TV)的计算公式为:TV=1/2×a×b2,其中a、b分别表示长、宽。根据测量的结果计算出相对肿瘤体积(relative tumor volume,RTV),计算公式为:RTV=Vt/V0,其中V0为分笼给药时(即d0)测量所得肿瘤体积,Vt为每一次测量时的肿瘤体积。
抗肿瘤活性的评价指标为:1)相对肿瘤增殖率T/C(%),计算公式如下:T/C(%)=(TRTV/CRTV)×100%,TRTV:治疗组RTV;CRTV:阴性对照组RTV;2)肿瘤体积增长抑制率GI%,计算公式如下:GI%=[1-(TVt-TV0)/(CVt-CV0)]×100%,TVt为治疗组每次测量的瘤体积;TV0为治疗组分笼给药时所得瘤体积;CVt为对照组每次测量的瘤体积;CV0为对照组分笼给药时所得瘤体积;3)瘤重抑制率,计算公式如下:瘤重抑制率%=(Wc-WT)/Wc×100%,Wc:对照组瘤重,WT:治疗组瘤重。
实验结束当天给药2小时后,各组收集血液样本及肿瘤组织保存。
实验结果
表5.化合物NO.12对人肺癌NCI-H1581裸小鼠移植瘤的实验治疗作用
从表5可以得出如下结论:
i)相比于阴性对照组,施用化合物NO.1214天后,动物的体重变化分别为-5.9%(100mg/kg,po)和24.2%(20mg/kg,po),远小于阴性对照组的36.8%;
ii)相比于阴性对照组,施用化合物NO.1214天后,动物的肿瘤体积变化分别为54.8%(100mg/kg,po)和1500%(20mg/kg,po),远小于阴性对照组的5223%;
iii)相比于阴性对照组,施用化合物NO.1214天后,动物的相对肿瘤体积分别为1.51(100mg/kg,po)和16.33(20mg/kg,po),远小于阴性对照组的52.22;
iv)相比于阴性对照组,施用化合物NO.1214天后,动物的相对肿瘤增殖率分别为2.9%(100mg/kg,po)和31.28%(20mg/kg,po)。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
1.一种式I所示化合物或其立体异构体、几何异构体,
式中,R1选自下组:取代或未取代的含有1个S杂原子的5-14元杂芳基,并且所述取代指被选自下组的1个或多个基团取代:C1-C6烷基、卤代的C1-C6烷基、C3-C8环烷基、卤代的C3-C8环烷基、羟基、C1-C6烷氧基、卤代的C1-C6烷氧基、-O-(C3-C8环烷基)、-O-(C3-C8的卤代环烷基)、卤素;
并且R1同时满足如下条件:
R2和R3为H;
R4为H;
X1为N;
X2为CR10;
R10选自H、卤素;
n为0;
Y为未取代的含有1个N杂原子的3-10元杂环基,
E选自下组:C(=O)、S(=O)2、C(=S)和S(=O);
Z选自下组:取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基;
对于Z,所述取代指被选自下组的1个或多个基团独立地取代:C3-C8环烷基、卤代的C3-C8环烷基、-CN。
3.一种药物组合物,其特征在于,所述药物组合物包含治疗有效量的权利要求1所述的化合物或其立体异构体、几何异构体中的一种或多种以及任选的药学上可接受的载体。
4.一种药物组合物,其特征在于,所述药物组合物包含治疗有效量的权利要求2所述的化合物或其立体异构体、几何异构体中的一种或多种以及任选的药学上可接受的载体。
5.一种权利要求1所述的化合物或其立体异构体、几何异构体或权利要求3所述药物组合物的用途,其特征在于,用于制备预防和/或治疗FGFR激酶活性相关疾病的药物。
6.一种权利要求2所述的化合物或其立体异构体、几何异构体或权利要求4所述药物组合物的用途,其特征在于,用于制备预防和/或治疗FGFR激酶活性相关疾病的药物。
7.一种FGFR抑制剂,其特征在于,所述FGFR抑制剂包含抑制有效量的权利要求1所述的化合物或其立体异构体、几何异构体中的一种或多种。
8.一种FGFR抑制剂,其特征在于,所述FGFR抑制剂包含抑制有效量的权利要求2所述的化合物或其立体异构体、几何异构体中的一种或多种。
10.一种权利要求3所述药物组合物的制备方法,其特征在于,包括步骤:将药学上可接受的载体与权利要求1所述的化合物或其立体异构体、几何异构体进行混合,从而形成药物组合物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2016104287654 | 2016-06-16 | ||
CN201610428765.4A CN107513068A (zh) | 2016-06-16 | 2016-06-16 | 一种具有fgfr抑制活性的新型化合物及其制备和应用 |
PCT/CN2017/087222 WO2017215485A1 (zh) | 2016-06-16 | 2017-06-05 | 一种具有fgfr抑制活性的新型化合物及其制备和应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN109328187A CN109328187A (zh) | 2019-02-12 |
CN109328187B true CN109328187B (zh) | 2022-04-26 |
Family
ID=60663365
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201610428765.4A Pending CN107513068A (zh) | 2016-06-16 | 2016-06-16 | 一种具有fgfr抑制活性的新型化合物及其制备和应用 |
CN201780037478.3A Active CN109328187B (zh) | 2016-06-16 | 2017-06-05 | 一种具有fgfr抑制活性的新型化合物及其制备和应用 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201610428765.4A Pending CN107513068A (zh) | 2016-06-16 | 2016-06-16 | 一种具有fgfr抑制活性的新型化合物及其制备和应用 |
Country Status (5)
Country | Link |
---|---|
US (1) | US20190367520A1 (zh) |
EP (1) | EP3486244A4 (zh) |
JP (1) | JP2019521992A (zh) |
CN (2) | CN107513068A (zh) |
WO (2) | WO2017215464A1 (zh) |
Families Citing this family (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9694084B2 (en) | 2014-12-23 | 2017-07-04 | Dana-Farber Cancer Institute, Inc. | Methods to induce targeted protein degradation through bifunctional molecules |
CN107459476B (zh) | 2016-06-03 | 2022-06-24 | 中国科学院上海药物研究所 | 反吲哚啉环丙胺类化合物及其制备方法、药物组合物和用途 |
BR112020000827A2 (pt) | 2017-08-03 | 2020-07-21 | Oryzon Genomics, S.A. | métodos de tratamento de alterações de comportamento |
US11512072B2 (en) | 2018-04-19 | 2022-11-29 | University Of Virginia Patent Foundation | Compositions and methods for preparing and using azetidines |
US20220151999A1 (en) | 2019-03-20 | 2022-05-19 | Oryzon Genomics, S.A. | Methods of treating attention deficit hyperactivity disorder using kdm1a inhibitors such as the compound vafidemstat |
CN113613653A (zh) | 2019-03-20 | 2021-11-05 | 奥莱松基因组股份有限公司 | 治疗边缘型人格障碍的方法 |
JP2022546908A (ja) | 2019-07-05 | 2022-11-10 | オリゾン・ゲノミクス・ソシエダッド・アノニマ | Kdm1a阻害剤を使用した小細胞肺がんの個別化された処置のためのバイオマーカーおよび方法 |
WO2021089005A1 (zh) * | 2019-11-08 | 2021-05-14 | 石药集团中奇制药技术(石家庄)有限公司 | 一种fgfr抑制剂的用途 |
CN112961159B (zh) * | 2020-03-05 | 2022-07-01 | 四川大学华西医院 | 氨基嘧啶并吡唑/吡咯类衍生物及其制备方法和用途 |
CN113527300B (zh) * | 2020-06-04 | 2023-02-03 | 广州百霆医药科技有限公司 | 布鲁顿酪氨酸蛋白激酶抑制剂 |
CN112574216B (zh) * | 2020-12-16 | 2022-03-08 | 天津济坤医药科技有限公司 | 一种化合物及其制备方法以及其在制备治疗抗癌药物中的应用 |
CN115433190A (zh) * | 2021-06-02 | 2022-12-06 | 药雅科技(上海)有限公司 | 不可逆杂环化合物fgfr抑制剂的制备方法和用途 |
US20240109896A1 (en) * | 2021-02-03 | 2024-04-04 | Ya Therapeutics Inc | Fgfr kinase inhibitor and use thereof |
WO2022212326A1 (en) | 2021-03-29 | 2022-10-06 | Halia Therapeutics, Inc. | Nek7 inhibitors |
CN115141176B (zh) * | 2021-03-31 | 2023-08-22 | 药雅科技(上海)有限公司 | 炔代吲哚类fgfr抑制剂及其制备方法和用途 |
WO2022216680A1 (en) | 2021-04-05 | 2022-10-13 | Halia Therapeutics, Inc. | Nek7 inhibitors |
JP2024513260A (ja) | 2021-04-08 | 2024-03-22 | オリゾン ジェノミックス ソシエダッド アノニマ | 骨髄癌処置のためのlsd1阻害剤の組み合わせ |
CN115215868A (zh) * | 2021-04-14 | 2022-10-21 | 药雅科技(上海)有限公司 | 杂环化合物fgfr抑制剂的制备方法和用途 |
CN113501806B (zh) * | 2021-06-30 | 2022-06-28 | 深圳大学 | 查尔酮基荧光探针及其制备方法与应用 |
WO2023217758A1 (en) | 2022-05-09 | 2023-11-16 | Oryzon Genomics, S.A. | Methods of treating malignant peripheral nerve sheath tumor (mpnst) using lsd1 inhibitors |
WO2023217784A1 (en) | 2022-05-09 | 2023-11-16 | Oryzon Genomics, S.A. | Methods of treating nf1-mutant tumors using lsd1 inhibitors |
Family Cites Families (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DK0888353T3 (da) * | 1996-03-15 | 2003-10-27 | Novartis Ag | N-7-Heterocyclyl-pyrrolo[2,3-d]pyrimidiner og deres anvendelse |
ATE310001T1 (de) * | 1998-09-18 | 2005-12-15 | Abbott Gmbh & Co Kg | 4-aminopyrrolopyrimidine als kinaseinhibitoren |
AU2000240570A1 (en) * | 2000-03-29 | 2001-10-08 | Knoll Gesellschaft Mit Beschraenkter Haftung | Pyrrolopyrimidines as tyrosine kinase inhibitors |
MXPA03008560A (es) * | 2001-03-22 | 2004-06-30 | Abbot Gmbh & Co Kg | Pirazolopirimidinas como agentes terapeuticos. |
WO2005047289A1 (en) * | 2003-11-17 | 2005-05-26 | Pfizer Products Inc. | Pyrrolopyrimidine compounds useful in treatment of cancer |
WO2009062118A2 (en) * | 2007-11-07 | 2009-05-14 | Foldrx Pharmaceuticals, Inc. | Modulation of protein trafficking |
US8993580B2 (en) * | 2008-03-14 | 2015-03-31 | Intellikine Llc | Benzothiazole kinase inhibitors and methods of use |
CN102124009B (zh) * | 2008-07-08 | 2014-07-23 | 因特利凯公司 | 激酶抑制剂及其使用方法 |
US8476431B2 (en) * | 2008-11-03 | 2013-07-02 | Itellikine LLC | Benzoxazole kinase inhibitors and methods of use |
KR102052670B1 (ko) * | 2011-05-17 | 2019-12-06 | 더 리젠츠 오브 더 유니버시티 오브 캘리포니아 | 키나아제 저해제 |
CN104080786A (zh) * | 2011-11-08 | 2014-10-01 | 因特利凯有限责任公司 | 使用多种药剂的治疗方案 |
UY34484A (es) * | 2011-12-15 | 2013-07-31 | Bayer Ip Gmbh | Benzotienilo-pirrolotriazinas disustituidas y sus usos |
US8377946B1 (en) * | 2011-12-30 | 2013-02-19 | Pharmacyclics, Inc. | Pyrazolo[3,4-d]pyrimidine and pyrrolo[2,3-d]pyrimidine compounds as kinase inhibitors |
CN104854107A (zh) * | 2012-11-15 | 2015-08-19 | 药品循环公司 | 作为激酶抑制剂的吡咯并嘧啶化合物 |
EP2740474A1 (en) * | 2012-12-05 | 2014-06-11 | Instituto Europeo di Oncologia S.r.l. | Cyclopropylamine derivatives useful as inhibitors of histone demethylases kdm1a |
JP6084292B2 (ja) * | 2013-07-18 | 2017-02-22 | 大鵬薬品工業株式会社 | Fgfr阻害剤耐性癌の治療薬 |
CA2922044A1 (en) * | 2013-10-18 | 2015-05-14 | Medivation Technologies, Inc. | Pyrazolo-, imidazolo- and pyrrolo-pyridine or -pyrimidine derivatives as inhibitors o brutons kinase (btk) |
BR112016016844A2 (pt) * | 2014-02-03 | 2017-08-08 | Cadila Healthcare Ltd | Compostos heterocíclicos |
US9493442B2 (en) * | 2014-02-13 | 2016-11-15 | Incyte Corporation | Cyclopropylamines as LSD1 inhibitors |
CN106045862B (zh) * | 2015-04-10 | 2019-04-23 | 上海迪诺医药科技有限公司 | 环丙胺类螺(杂)环化合物、其药物组合物及应用 |
-
2016
- 2016-06-16 CN CN201610428765.4A patent/CN107513068A/zh active Pending
-
2017
- 2017-06-02 WO PCT/CN2017/087081 patent/WO2017215464A1/zh active Application Filing
- 2017-06-05 US US16/310,394 patent/US20190367520A1/en not_active Abandoned
- 2017-06-05 WO PCT/CN2017/087222 patent/WO2017215485A1/zh unknown
- 2017-06-05 JP JP2018566299A patent/JP2019521992A/ja active Pending
- 2017-06-05 CN CN201780037478.3A patent/CN109328187B/zh active Active
- 2017-06-05 EP EP17812596.9A patent/EP3486244A4/en not_active Withdrawn
Also Published As
Publication number | Publication date |
---|---|
EP3486244A4 (en) | 2020-04-08 |
CN107513068A (zh) | 2017-12-26 |
US20190367520A1 (en) | 2019-12-05 |
EP3486244A1 (en) | 2019-05-22 |
WO2017215485A1 (zh) | 2017-12-21 |
WO2017215464A1 (zh) | 2017-12-21 |
JP2019521992A (ja) | 2019-08-08 |
CN109328187A (zh) | 2019-02-12 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN109328187B (zh) | 一种具有fgfr抑制活性的新型化合物及其制备和应用 | |
CN109422755B (zh) | 一种含氮杂环化合物、制备方法、中间体、组合物和应用 | |
KR101532256B1 (ko) | 키나제 억제제로서의 이미다조트리아진 및 이미다조피리미딘 | |
JP5576802B2 (ja) | C−Metチロシンキナーゼ介在疾患の治療用のイミダゾ[1,2−b]ピリダジン誘導体 | |
CA2900748C (en) | Novel pyrimidine and pyridine compounds and their usage | |
CN106928219B (zh) | 含氮稠杂环化合物、制备方法、中间体、组合物和应用 | |
WO2022174031A1 (en) | Cdk inhibitors and methods of use thereof | |
AU2010310786B2 (en) | AKT inhibitors | |
EP2945623A1 (en) | Hedgehog pathway signaling inhibitors and therapeutic applications thereof | |
EP2528920A2 (en) | Bicyclic heteroaryl derivatives having inhibitory activity for protein kinase | |
CN114539245A (zh) | 含嘧啶并环类衍生物调节剂、其制备方法和应用 | |
JP2023513854A (ja) | 大環状化合物およびその使用 | |
KR20210124961A (ko) | 티로신 키나제 억제제, 조성물 및 방법 | |
EP3556761A1 (en) | Pyrrolo-aromatic heterocyclic compound, preparation method therefor, and medical use thereof | |
CN113234079B (zh) | 用作prmt5抑制剂的核苷类似物 | |
AU2021323844B2 (en) | FGFR and mutation inhibitor thereof, preparation method therefor and use thereof | |
TW202214634A (zh) | 雜環化合物及其衍生物 | |
TWI819470B (zh) | Fgfr激酶抑制劑及其應用 | |
KR20230171440A (ko) | 약학적 화합물 | |
CN117460723A (zh) | 药物化合物 | |
TW202328128A (zh) | Cdk7抑制劑及治療癌症之方法 | |
CN117136052A (zh) | Cdk抑制剂和其使用方法 | |
CN116514806A (zh) | 含丙烯酮类生物抑制剂、其制备方法和应用 | |
CN117715642A (zh) | 杂环化合物和使用方法 |
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 |