CN117751113A - Aromatic acetylene derivative and preparation method and application thereof - Google Patents
Aromatic acetylene derivative and preparation method and application thereof Download PDFInfo
- Publication number
- CN117751113A CN117751113A CN202280052824.6A CN202280052824A CN117751113A CN 117751113 A CN117751113 A CN 117751113A CN 202280052824 A CN202280052824 A CN 202280052824A CN 117751113 A CN117751113 A CN 117751113A
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- CN
- China
- Prior art keywords
- phenyl
- methyl
- ethynyl
- pyrimidin
- group
- Prior art date
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- -1 Aromatic acetylene derivative Chemical class 0.000 title claims abstract description 511
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 150000003839 salts Chemical class 0.000 claims abstract description 35
- 125000001424 substituent group Chemical group 0.000 claims abstract description 25
- 239000003814 drug Substances 0.000 claims abstract description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 15
- 229940123346 LpxC inhibitor Drugs 0.000 claims abstract description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 78
- 150000001875 compounds Chemical class 0.000 claims description 75
- 125000000217 alkyl group Chemical group 0.000 claims description 66
- 125000003118 aryl group Chemical group 0.000 claims description 64
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 62
- 125000001072 heteroaryl group Chemical group 0.000 claims description 55
- 125000003545 alkoxy group Chemical group 0.000 claims description 40
- 229910052736 halogen Inorganic materials 0.000 claims description 33
- 150000002367 halogens Chemical class 0.000 claims description 33
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 28
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 24
- 241000894006 Bacteria Species 0.000 claims description 20
- 229910005965 SO 2 Inorganic materials 0.000 claims description 19
- 125000004429 atom Chemical group 0.000 claims description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
- 125000001188 haloalkyl group Chemical group 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
- 241000193830 Bacillus <bacterium> Species 0.000 claims description 8
- 241000588724 Escherichia coli Species 0.000 claims description 8
- 241000589517 Pseudomonas aeruginosa Species 0.000 claims description 8
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 8
- 201000010099 disease Diseases 0.000 claims description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- 230000001404 mediated effect Effects 0.000 claims description 7
- 208000035143 Bacterial infection Diseases 0.000 claims description 6
- 208000022362 bacterial infectious disease Diseases 0.000 claims description 6
- 150000007942 carboxylates Chemical group 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 241000589291 Acinetobacter Species 0.000 claims description 4
- 241000589242 Legionella pneumophila Species 0.000 claims description 4
- 241000588769 Proteus <enterobacteria> Species 0.000 claims description 4
- 241000607768 Shigella Species 0.000 claims description 4
- 241000607764 Shigella dysenteriae Species 0.000 claims description 4
- 241000607626 Vibrio cholerae Species 0.000 claims description 4
- 241000607734 Yersinia <bacteria> Species 0.000 claims description 4
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 229940115932 legionella pneumophila Drugs 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 229940118696 vibrio cholerae Drugs 0.000 claims description 4
- 241000588650 Neisseria meningitidis Species 0.000 claims description 3
- 208000037386 Typhoid Diseases 0.000 claims description 3
- 230000008878 coupling Effects 0.000 claims description 3
- 238000010168 coupling process Methods 0.000 claims description 3
- 238000005859 coupling reaction Methods 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 201000008297 typhoid fever Diseases 0.000 claims description 3
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 2
- 230000009471 action Effects 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- 229940007046 shigella dysenteriae Drugs 0.000 claims description 2
- 241000588832 Bordetella pertussis Species 0.000 claims 1
- 206010006500 Brucellosis Diseases 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 229940124597 therapeutic agent Drugs 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 234
- 239000000243 solution Substances 0.000 description 181
- 238000006243 chemical reaction Methods 0.000 description 166
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 165
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 117
- 239000012074 organic phase Substances 0.000 description 74
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 73
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 73
- 239000003480 eluent Substances 0.000 description 68
- 238000010898 silica gel chromatography Methods 0.000 description 59
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 50
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 48
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 41
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 40
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 39
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 37
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 36
- 239000007791 liquid phase Substances 0.000 description 31
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 29
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 28
- 239000012071 phase Substances 0.000 description 28
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 26
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 26
- 238000005191 phase separation Methods 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- 238000003756 stirring Methods 0.000 description 21
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 20
- 229920006395 saturated elastomer Polymers 0.000 description 20
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 239000005457 ice water Substances 0.000 description 16
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 15
- 238000005481 NMR spectroscopy Methods 0.000 description 15
- 238000004262 preparative liquid chromatography Methods 0.000 description 15
- 238000000746 purification Methods 0.000 description 15
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 15
- 125000002619 bicyclic group Chemical group 0.000 description 14
- 239000000203 mixture Substances 0.000 description 14
- 238000000926 separation method Methods 0.000 description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 12
- 239000008346 aqueous phase Substances 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- FXORZKOZOQWVMQ-UHFFFAOYSA-L dichloropalladium;triphenylphosphane Chemical compound Cl[Pd]Cl.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 FXORZKOZOQWVMQ-UHFFFAOYSA-L 0.000 description 11
- 125000003003 spiro group Chemical group 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 10
- 229910052786 argon Inorganic materials 0.000 description 10
- 230000005764 inhibitory process Effects 0.000 description 10
- 125000003367 polycyclic group Chemical group 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 10
- 235000017557 sodium bicarbonate Nutrition 0.000 description 10
- DNCYBUMDUBHIJZ-UHFFFAOYSA-N 1h-pyrimidin-6-one Chemical compound O=C1C=CN=CN1 DNCYBUMDUBHIJZ-UHFFFAOYSA-N 0.000 description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 9
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 239000011780 sodium chloride Substances 0.000 description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 239000001301 oxygen Substances 0.000 description 7
- 125000006413 ring segment Chemical group 0.000 description 7
- 239000012312 sodium hydride Substances 0.000 description 7
- 229910000104 sodium hydride Inorganic materials 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- OZKXSTLYLNSXRE-UHFFFAOYSA-N 4-[(4-ethynylphenyl)methyl]morpholine Chemical compound C1=CC(C#C)=CC=C1CN1CCOCC1 OZKXSTLYLNSXRE-UHFFFAOYSA-N 0.000 description 6
- DJXQYJXQDQXQTG-UHFFFAOYSA-N 4-hydroxythiomorpholine Chemical compound ON1CCSCC1 DJXQYJXQDQXQTG-UHFFFAOYSA-N 0.000 description 6
- VALZSZJVEFACEZ-UHFFFAOYSA-N azetidine-3-carboxamide Chemical compound NC(=O)C1CNC1 VALZSZJVEFACEZ-UHFFFAOYSA-N 0.000 description 6
- 125000004122 cyclic group Chemical group 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 125000002950 monocyclic group Chemical group 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 125000004076 pyridyl group Chemical group 0.000 description 6
- 239000012279 sodium borohydride Substances 0.000 description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- YQKWBFZGLGMZCT-UHFFFAOYSA-N (4-ethynylphenyl)-morpholin-4-ylmethanone Chemical compound C=1C=C(C#C)C=CC=1C(=O)N1CCOCC1 YQKWBFZGLGMZCT-UHFFFAOYSA-N 0.000 description 5
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 5
- LULBEMRHRASDFM-UHFFFAOYSA-N 4-(iodomethyl)-5,6-bis(phenylmethoxy)pyrimidine Chemical compound C(C1=CC=CC=C1)OC1=NC=NC(=C1OCC1=CC=CC=C1)CI LULBEMRHRASDFM-UHFFFAOYSA-N 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- YAMHXTCMCPHKLN-UHFFFAOYSA-N imidazolidin-2-one Chemical compound O=C1NCCN1 YAMHXTCMCPHKLN-UHFFFAOYSA-N 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- 238000004809 thin layer chromatography Methods 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- NVYLBKHPSREQBQ-WEVVVXLNSA-N (ne)-n-[(4-iodophenyl)methylidene]hydroxylamine Chemical compound O\N=C\C1=CC=C(I)C=C1 NVYLBKHPSREQBQ-WEVVVXLNSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- ZLADCUPTIDZBLX-UHFFFAOYSA-N 2-[4-(2-trimethylsilylethynyl)phenoxy]ethanol Chemical compound C[Si](C)(C)C#CC1=CC=C(OCCO)C=C1 ZLADCUPTIDZBLX-UHFFFAOYSA-N 0.000 description 4
- NSZBSAHNAGOSAW-UHFFFAOYSA-N 2-[4-[(1,1-dioxo-1,4-thiazinan-4-yl)methyl]phenyl]ethynyl-trimethylsilane Chemical compound C[Si](C)(C)C#CC1=CC=C(CN2CCS(CC2)(=O)=O)C=C1 NSZBSAHNAGOSAW-UHFFFAOYSA-N 0.000 description 4
- AZLBARIKNQPUJP-UHFFFAOYSA-N 4-[(4-ethynylphenyl)methyl]-1,4-thiazinane 1,1-dioxide Chemical compound C(#C)C1=CC=C(C=C1)CN1CCS(CC1)(=O)=O AZLBARIKNQPUJP-UHFFFAOYSA-N 0.000 description 4
- BFIZGNKQOJSJAA-UHFFFAOYSA-N 4-[(5-ethynylpyridin-2-yl)methyl]morpholine Chemical compound N1=CC(C#C)=CC=C1CN1CCOCC1 BFIZGNKQOJSJAA-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- 239000012300 argon atmosphere Substances 0.000 description 4
- 230000001580 bacterial effect Effects 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 239000000470 constituent Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 239000011698 potassium fluoride Substances 0.000 description 4
- 235000003270 potassium fluoride Nutrition 0.000 description 4
- 238000010791 quenching Methods 0.000 description 4
- NIDLJAPEZBFHGP-ZZXKWVIFSA-N (e)-3-(4-iodophenyl)prop-2-enoic acid Chemical compound OC(=O)\C=C\C1=CC=C(I)C=C1 NIDLJAPEZBFHGP-ZZXKWVIFSA-N 0.000 description 3
- SQWHBRPAXOERQR-UHFFFAOYSA-N 2-(4-ethynylphenoxy)ethanol Chemical compound OCCOC1=CC=C(C#C)C=C1 SQWHBRPAXOERQR-UHFFFAOYSA-N 0.000 description 3
- RETMUAMXYIIWAQ-UHFFFAOYSA-N 2-amino-1-(4-bromophenyl)ethanol Chemical compound NCC(O)C1=CC=C(Br)C=C1 RETMUAMXYIIWAQ-UHFFFAOYSA-N 0.000 description 3
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 3
- YIDGOFMCVVAHPY-UHFFFAOYSA-N 2-phenylmethoxypyrimidine Chemical compound C=1C=CC=CC=1COC1=NC=CC=N1 YIDGOFMCVVAHPY-UHFFFAOYSA-N 0.000 description 3
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- IWSNHXBESGDQMF-UHFFFAOYSA-N 3-amino-3-(4-iodophenyl)propanoic acid Chemical compound OC(=O)CC(N)C1=CC=C(I)C=C1 IWSNHXBESGDQMF-UHFFFAOYSA-N 0.000 description 3
- UZQDUXAJFTWMDT-UHFFFAOYSA-N 4-(2-trimethylsilylethynyl)benzaldehyde Chemical compound C[Si](C)(C)C#CC1=CC=C(C=O)C=C1 UZQDUXAJFTWMDT-UHFFFAOYSA-N 0.000 description 3
- NRDZZGZIDVLPNN-UHFFFAOYSA-N 4-(4-iodophenyl)pyrrolidin-2-one Chemical compound C1=CC(I)=CC=C1C1CC(=O)NC1 NRDZZGZIDVLPNN-UHFFFAOYSA-N 0.000 description 3
- NIEBHDXUIJSHSL-UHFFFAOYSA-N 4-iodobenzaldehyde Chemical compound IC1=CC=C(C=O)C=C1 NIEBHDXUIJSHSL-UHFFFAOYSA-N 0.000 description 3
- FWGFASQLOPSRHI-UHFFFAOYSA-N 5-(4-bromophenyl)-1,3-oxazolidin-2-one Chemical compound C1=CC(Br)=CC=C1C1OC(=O)NC1 FWGFASQLOPSRHI-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 241000606860 Pasteurella Species 0.000 description 3
- 201000005702 Pertussis Diseases 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- 125000004432 carbon atom Chemical group C* 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
- 238000001816 cooling Methods 0.000 description 3
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 230000002255 enzymatic effect Effects 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 description 3
- 125000001624 naphthyl group Chemical group 0.000 description 3
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000004808 supercritical fluid chromatography Methods 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- PAPFTCBBBUAHEW-UHFFFAOYSA-N 1-[(4-ethynylphenyl)methyl]-3-methoxyazetidine Chemical compound C(#C)C1=CC=C(CN2CC(C2)OC)C=C1 PAPFTCBBBUAHEW-UHFFFAOYSA-N 0.000 description 2
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 2
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- GZQKNULLWNGMCW-PWQABINMSA-N lipid A (E. coli) Chemical compound O1[C@H](CO)[C@@H](OP(O)(O)=O)[C@H](OC(=O)C[C@@H](CCCCCCCCCCC)OC(=O)CCCCCCCCCCCCC)[C@@H](NC(=O)C[C@@H](CCCCCCCCCCC)OC(=O)CCCCCCCCCCC)[C@@H]1OC[C@@H]1[C@@H](O)[C@H](OC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H](NC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H](OP(O)(O)=O)O1 GZQKNULLWNGMCW-PWQABINMSA-N 0.000 description 1
- 229920006008 lipopolysaccharide Polymers 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- IDATZIWFZZIKNZ-QPJJXVBHSA-N methyl (e)-3-(4-iodophenyl)prop-2-enoate Chemical compound COC(=O)\C=C\C1=CC=C(I)C=C1 IDATZIWFZZIKNZ-QPJJXVBHSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- LCEDQNDDFOCWGG-UHFFFAOYSA-N morpholine-4-carbaldehyde Chemical compound O=CN1CCOCC1 LCEDQNDDFOCWGG-UHFFFAOYSA-N 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- LAIZPRYFQUWUBN-UHFFFAOYSA-L nickel chloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].[Cl-].[Ni+2] LAIZPRYFQUWUBN-UHFFFAOYSA-L 0.000 description 1
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- 238000003305 oral gavage Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- MIPHRQMEIYLZFZ-UHFFFAOYSA-N oxolan-3-amine Chemical compound NC1CCOC1 MIPHRQMEIYLZFZ-UHFFFAOYSA-N 0.000 description 1
- 125000005476 oxopyrrolidinyl group Chemical group 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- GJVFBWCTGUSGDD-UHFFFAOYSA-L pentamethonium bromide Chemical compound [Br-].[Br-].C[N+](C)(C)CCCCC[N+](C)(C)C GJVFBWCTGUSGDD-UHFFFAOYSA-L 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- IWELDVXSEVIIGI-UHFFFAOYSA-N piperazin-2-one Chemical compound O=C1CNCCN1 IWELDVXSEVIIGI-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- JHHZLHWJQPUNKB-UHFFFAOYSA-N pyrrolidin-3-ol Chemical compound OC1CCNC1 JHHZLHWJQPUNKB-UHFFFAOYSA-N 0.000 description 1
- LMBZZTJQNYGICT-UHFFFAOYSA-N pyrrolidine-3-carbonitrile;hydrochloride Chemical compound Cl.N#CC1CCNC1 LMBZZTJQNYGICT-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000000611 regression analysis Methods 0.000 description 1
- 230000001105 regulatory effect Effects 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
- 230000036303 septic shock Effects 0.000 description 1
- 239000000779 smoke Substances 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000009210 therapy by ultrasound Methods 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 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
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical compound C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to an aromatic acetylene derivative, a preparation method thereof and application of a pharmaceutical composition containing the derivative in medicine. In particular, the invention relates to an aromatic acetylene derivative shown in a general formula (I), a preparation method and pharmaceutically acceptable salts thereof, and application thereof as a therapeutic agent, in particular to an LPXC inhibitor, wherein each substituent in the general formula (I) is defined as the specification.
Description
The present application claims priority from the following chinese patent applications: 1) The aromatic acetylene derivatives are submitted to China national intellectual property agency, application number 202110893756.3 and Chinese patent application with the name of aromatic acetylene derivatives, preparation method and application thereof in 2021, 8 and 5 days; 2) The aromatic acetylene derivatives are submitted to China national intellectual property agency, application number 202210596714.8 and Chinese patent application with the name of aromatic acetylene derivatives, preparation method and application thereof in 2022 and 5-30 days; 3) The aromatic acetylene derivatives and the preparation method and the application thereof are submitted to China national intellectual property agency, application number 202210756227.3 and Chinese patent application with the name of aromatic acetylene derivatives and the application of aromatic acetylene derivatives at the year of 2022 and the month of 6 and 29. The entire contents of the above-mentioned chinese patent application are incorporated herein by reference.
The invention relates to an aromatic acetylene derivative, a preparation method thereof, a pharmaceutical composition containing the aromatic acetylene derivative and application of the aromatic acetylene derivative or the pharmaceutical composition as a therapeutic agent, in particular as an LPXC inhibitor.
The thirty to sixty decades of the twentieth century are the golden period for the development of antibiotics, which are widely used worldwide, but bacterial resistance problems also continue to occur, and resistant bacteria have become a major problem threatening human health. The multi-drug resistant gram-negative bacteria is one of the main pathogens causing infection, and the drugs for treating the multi-drug resistant gram-negative bacteria infection are seriously deficient in clinic at present, and the drugs with higher toxicity are still adopted. In recent years, bacterial resistance has been a hot topic in the international medical community, but development speed is slow, and few compounds enter clinical researches at home and abroad, so finding a novel gram-negative bacterial antibacterial drug is an important problem to be solved urgently.
UDP-3-O- (R-3-hydroxymyristoyl) -N-acetylglucosamine deacetylase (LPXC) is a Zn-dependent enzyme 2+ Is the first rate limiting enzyme for the synthesis of lipid a, which is an important component of the outer membrane of gram-negative bacteria, and can anchor lipopolysaccharide to the outer membrane of cells, maintaining the integrity of cells themselves. Meanwhile, the antibacterial agent serves as a hydrophobic external barrier to prevent external factors such as antibiotics and the like from entering cells and protect bacteria from invasion. In addition, lipid A is also in bacteria The active ingredients of toxins, which are introduced into the blood through the intestinal mucosa, activate the immune response in humans and even cause severe septic shock, are also responsible for pathogenic infections caused by gram-negative bacteria. Thus, inhibition of LPXC can inhibit biosynthesis of lipid a of gram-negative bacteria, thereby effectively controlling infection with gram-negative bacteria.
At present, the further cognition of the structure and the characteristics of the LPXC is mostly obtained by separating, purifying and analyzing and identifying LPXC crystals of escherichia coli, pseudomonas aeruginosa and hyperthermophilic bacteria. The LPXC structures from these three different sources are highly similar and all contain two domains with the active region at the junction of the 2 domains. Each domain comprises an alpha helix and a beta sheet, which encloses the alpha helix, forming a sandwich of "beta-alpha-beta". The amino acid sequences of these two domains are slightly different, but have the same spatial structure. In addition, each domain has an insertion region corresponding thereto, which is formed by the beta sheet, forming a different functional region. Studies have shown that LPXC has high homology in gram-negative bacteria, has no common sequence with various enzyme systems of mammals, and from the biological point of view, inhibition of LPXC will be an ideal direction for studying antibacterial drugs due to its unique advantages of broad spectrum and low toxicity.
Inhibitors of LPXC are not yet marketed. Although research and application of LPXC inhibitors have advanced to some extent, there is still a great room for improvement in the treatment of people, and there is still a need to continue to research and develop new LPXC inhibitors.
Disclosure of Invention
Aiming at the technical problems, the invention provides an aromatic acetylene derivative shown in a general formula (I) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof:
wherein:
x and Y are each independently selected from C or N, and X, Y are not both N;
ring a is selected from 4-to 6-membered heteroaryl or 4-to 6-membered heterocyclyl, preferably 5-membered heteroaryl or 5-membered heterocyclyl;
L 1 selected from single bonds or-CH 2 -;
R 1 Identical or different, each independently selected from-G 1 -R 4 ;
G 1 Selected from single bond, -CH 2 -or-C (=o) -;
R 2 the same or different, each independently selected from hydroxy, cyano, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano or alkoxy;
R 3 identical or different, each independently selected from hydroxy, cyano, halogen, alkyl, cycloalkyl, heterocyclyl, alkoxy or-C (O) R 5 Wherein said alkyl, cycloalkyl, heterocyclyl OR alkoxy is optionally further substituted with one OR more groups selected from halogen, hydroxy, cyano, alkoxy, -C (O) OR 5 or-C (O) NR 6 R 7 Is substituted by a substituent of (2);
R 4 selected from cyano, halogen, alkyl, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R 5 、-C(O)OR 5 、-OC(O)R 5 、-NR 6 R 7 、-C(O)NR 6 R 7 、-SO 2 NR 6 R 7 or-NR 6 C(O)R 7 Wherein said alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more R A Substituted;
R A selected from halogen, hydroxy, amino, hydroxyalkyl, alkoxy, alkyl, cycloalkyl,Heterocyclyl, aryl, heteroaryl, -C (O) R 5 、-C(O)OR 5 、-OC(O)R 5 、-NR 6 R 7 、-C(O)NR 6 R 7 、-SO 2 NR 6 R 7 or-NR 6 C(O)R 7 Wherein said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally further substituted with one or more moieties selected from the group consisting of halogen, hydroxy, amino, haloalkyl, hydroxyalkyl, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R 5 、-C(O)OR 5 、-OC(O)R 5 、-NR 6 R 7 、-C(O)NR 6 R 7 、-SO 2 NR 6 R 7 or-NR 6 C(O)R 7 Is substituted by a substituent of (a);
R 5 selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted with one or more groups selected from a hydroxyl group, a halogen group, a nitro group, a cyano group, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, =o, -C (O) R 8 、-C(O)OR 8 、 -OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO 2 NR 9 R 10 or-NR 9 C(O)R 10 Is substituted by a substituent of (2);
R 6 and R is 7 Each independently selected from a hydrogen atom, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more groups selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =o, -C (O) R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO 2 NR 9 R 10 or-NR 9 C(O)R 10 Is substituted by a substituent of (2);
alternatively, R 6 And R is 7 Together with the atoms to which they are attached form a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group contains one or more N, O, S or SO 2 And said 4-8 membered heterocyclyl is optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =o, -C (O) R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO 2 NR 9 R 10 or-NR 9 C(O)R 10 Is substituted by a substituent of (2);
R 8 、R 9 and R is 10 Each independently selected from the group consisting of hydrogen, alkyl, amino, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl, or carboxylate;
m is 0, 1, 2 or 3;
n is 0, 1 or 2, n preferably being 0; and is also provided with
p is 0, 1 or 2.
According to a preferred embodiment of the present invention, there is provided a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is a compound of formula (II):
wherein: ring A, R 1 ~R 3 、L 1 The definitions of m, n and p are as described in the general formula (I).
According to a preferred embodiment of the present invention, there is provided a compound of formula (II) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is a compound of formula (III):
wherein:
R A selected from the group consisting of haloalkyl, hydroxyalkyl, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally further substituted with carboxyl;
q is 0, 1 or 2;
ring A, G 1 、R 2 、R 3 、L 1 The definition of n and p is as described in the general formula (I).
According to a preferred embodiment of the present invention there is provided a compound of formula (I), (II) or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein ring a is selected from:
According to a preferred embodiment of the present invention, there is provided a compound of the general formula (I), (II) or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein
Selected from:
according to a preferred embodiment of the present invention, there is provided a compound of the general formula (I) or (II) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein
Selected from:
according to a preferred embodiment of the present invention there is provided a compound of formula (I), (II) or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein n is selected from 0.
According to a preferred embodiment of the present invention, there is provided a compound of formula (I), (II) or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein L 1 Selected from-CH 2 -。
In a preferred embodiment of the invention, the compounds of formula (I) are selected from:
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
Note that: if there is a difference between the drawn structure and the name given to the structure, the drawn structure will be given greater weight.
Still further, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I), (II) or (III), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The invention provides an application of a compound shown in a general formula (I), (II) or (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preparing an LPXC inhibitor.
The invention also provides the use of a compound of formula (I), (II) or (III), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment of a disease mediated by LPXC, wherein the disease mediated by LPXC is preferably a bacterial infection caused by gram-negative bacteria; wherein the LPXC-mediated disease is selected from bacterial infections caused by gram-negative bacteria such as Escherichia coli, pseudomonas aeruginosa, proteus, bacillus dysenteriae, bacillus pneumoniae, brucella, typhoid bacillus, acinetobacter, yersinia, legionella pneumophila, pertussis bacillus, shigella, pasteurella, vibrio cholerae, and Neisseria meningitidis.
The invention further provides application of the compound shown in the general formula (I), (II) or (III) or stereoisomer, tautomer or pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in preparing medicines for treating bacterial infection caused by gram-negative bacteria.
The invention provides an application of a compound shown in a general formula (I), (II) or (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in preparing medicines for treating bacterial infections caused by gram-negative bacteria such as escherichia coli, pseudomonas aeruginosa, bacillus proteus, shigella dysenteriae, pneumobacillus, bacillus typhi, acinetobacter, yersinia, legionella pneumophila, pertussis bacillus, shigella, pasteurella, vibrio cholerae, meningococcus and the like.
The present invention also provides a method of treating a disease mediated by LPXC comprising administering to a subject in need thereof a compound of formula (I), (II) or (III), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Preferably, the disease mediated by LPXC is a bacterial infection caused by gram negative bacteria; more preferably, the gram-negative bacteria are selected from the group consisting of E.coli, pseudomonas aeruginosa, proteus, bacillus dysenteriae, bacillus pneumoniae, brucella, typhoid bacillus, acinetobacter, yersinia, legionella pneumophila, pertussis bacillus, shigella, pasteurella, vibrio cholerae, and Neisseria meningitidis.
Detailed description of the invention
Unless stated to the contrary, some of the terms used in the specification and claims of the present invention are defined as follows:
"alkyl" when taken as a group or part of a group is meant to include C 1 -C 20 Straight chain or branched aliphatic hydrocarbon groups. Preferably C 1 -C 10 An alkyl group, a hydroxyl group,more preferably C 1 -C 6 Alkyl or C 1 -C 4 An alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. Alkyl groups may be substituted or unsubstituted.
"cycloalkyl" refers to a non-aromatic cyclic alkyl group wherein one or more of the ring-forming atoms are carbon atoms, including monocyclic, polycyclic, fused, bridged and spiro rings, preferably having 3 to 7 membered monocyclic or 7 to 10 membered bicyclic or tricyclic rings. Examples of "cycloalkyl" include, but are not limited to, cyclopropyl, cyclopentyl, cyclobutyl. Cycloalkyl groups may be substituted or unsubstituted. Preferably C 3 -C 7 Cycloalkyl, C 3 -C 6 Cycloalkyl or C 5 -C 7 Cycloalkyl groups.
"spirocycloalkyl" refers to a 5 to 18 membered, two or more cyclic structure, and monocyclic polycyclic groups sharing one carbon atom (called spiro atom) with each other, containing 1 or more double bonds within the ring, but no ring has a completely conjugated pi-electron aromatic system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The spirocycloalkyl group is classified into a single spiro group, a double spiro group or a multiple spirocycloalkyl group according to the number of common spiro atoms between rings, preferably single spiro group and double spirocycloalkyl group, preferably 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered. Non-limiting examples of "spirocycloalkyl" include, but are not limited to: spiro [4.5] decyl, spiro [4.4] nonyl, spiro [3.5] nonyl, spiro [2.4] heptyl.
"fused ring alkyl" refers to an all-carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms with each other, one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicycloalkyl group. Non-limiting examples of "fused ring alkyl" include, but are not limited to: bicyclo [3.1.0] hexyl, bicyclo [3.2.0] hept-1-enyl, bicyclo [3.2.0] heptyl, decalinyl, or tetradecahydrophenanthryl.
"bridged cycloalkyl" means an aromatic system having 5 to 18 members, containing two or more cyclic structures, sharing two all-carbon polycyclic groups with one another that are not directly attached to a carbon atom, one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi electron, preferably 6 to 12 members, more preferably 7 to 10 members. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Cycloalkyl groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to: (1 s,4 s) -bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl, (1 s,5 s) -bicyclo [3.3.1] nonyl, bicyclo [2.2.2] octyl, and (1 r,5 r) -bicyclo [3.3.2] decyl.
"heterocyclyl", "heterocycloalkyl", "heterocycle" or "heterocyclic" are used interchangeably herein to refer to a non-aromatic heterocyclic group in which one or more of the ring-forming atoms is a heteroatom such as oxygen, nitrogen or S (O) r (wherein r is selected from 0, 1 or 2), and the ring atoms optionally include-C (=o) -, including monocyclic, polycyclic, fused, bridged and spiro rings. Preferably having 5 to 7 membered mono-or 7 to 10 membered bi-or tricyclic ring, which may contain 1,2 or 3 groups selected from nitrogen, oxygen and/or S (O) r (wherein r is selected from an atom in 0, 1 or 2). Examples of "heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, 1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo [3.2.1]Octyl, piperazinyl, hexahydropyrimidine,
The heterocyclic group may be substituted or unsubstituted.
"spiroheterocyclyl" refers to a 5 to 18 membered, two or more cyclic structure, polycyclic group having single rings sharing one atom with each other, containing 1 or more double bonds within the ring, but no ring having a fully conjugated pi-electron aromatic system wherein one or more ring atoms are selected from nitrogen, oxygen, C (=o) or S (O) r (wherein r is selected from 0, 1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The spirocycloalkyl group is classified into a single spiro heterocyclic group, a double spiro heterocyclic group or a multiple spiro heterocyclic group according to the number of common spiro atoms between rings, and preferably a single spiro heterocyclic group and a double spiro heterocyclic group. More preferably a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered single spiro heterocyclic group. Non-limiting examples of "spiroheterocyclyl" include, but are not limited to: 1, 7-dioxaspiro [4.5 ] ]Decyl, 2-oxa-7-azaspiro [4.4 ]]Nonyl, 7-oxaspiro [3.5 ]]Nonyl, 5-oxaspiro [2.4 ]]A heptyl group.
"fused heterocyclyl" refers to a polycyclic group containing two or more cyclic structures sharing a pair of atoms with each other, one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system in which one or more of the ring atoms is selected from nitrogen, oxygen, C (=o) or S (O) r (wherein r is selected from 0, 1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting "fused heterocyclyl" groupsIllustrative embodiments include, but are not limited to: octahydropyrrolo [3,4-c ]]Pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo [3.1.0 ]]Hexyl, octahydrobenzo [ b ]][1,4]Dioxin (dioxin) is used,
"bridged heterocyclyl" means a 5 to 14 membered, 5 to 18 membered, polycyclic group containing two or more cyclic structures sharing two atoms not directly attached to each other, one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system in which one or more of the ring atoms is selected from nitrogen, oxygen, C (=o) or S (O) r (wherein r is selected from 0, 1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Heterocyclic groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged heterocyclyl" include, but are not limited to: 2-azabicyclo [2.2.1]Heptyl, 2-azabicyclo [2.2.2]Octyl, 2-azabicyclo [3.3.2]And (3) a decyl group.
"aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be linked together in a fused manner. The term "aryl" includes monocyclic or bicyclic aryl groups such as phenyl, naphthyl, tetrahydronaphthyl aromatic groups. Preferably aryl is C 6 -C 10 Aryl, more preferably aryl is phenyl and naphthyl, most preferably naphthyl. Aryl groups may be substituted or unsubstituted.
"heteroaryl" refers to an aromatic 5-to 6-membered monocyclic or 8-to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur. Preferred heteroaryl groups are C 6 -C 10 Heteroaryl groups containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of "heteroaryl" include, but are not limited to, furyl, pyridyl, 2-oxo-1, 2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, Oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2, 3-thiadiazolyl, benzodioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, 1, 3-dioxo-isoindolyl, quinolinyl, indazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, isothiazolyl, 1H-1,2, 4-triazolyl, 4H-1,2, 4-triazolyl, pyridinyl, pyrimidinyl, pyrazin-2 (1H) -one, pyrimidin-4 (3H) -one, pyridazin-3 (2H) -one, 1H-indolyl, 1H-benzo [ d ]]Imidazolyl, 1H-pyrrolo [2,3-c]Pyridyl, 3H-imidazo [4,5-c ]]Pyridinyl, isoquinolinyl, quinazolinyl, 2H-isoindolyl, and furan [3,2-b ]]Pyridyl and furan [2,3-c ]]Pyridinyl, thieno [2,3-c]Pyridyl, benzofuranyl and benzo [ b ]]Thienyl, 1H-pyrrolo [3,2-b]Pyridyl, 2H-pyrrolo [3,4-c]A pyridyl group. Heteroaryl groups may be substituted or unsubstituted.
"alkoxy" refers to a group of (alkyl-O-). Wherein alkyl is as defined herein. C (C) 1 -C 6 Or C 1 -C 4 Is preferably selected. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.
"nitro" means-NO 2 A group.
"hydroxy" refers to an-OH group.
"halogen" refers to fluorine, chlorine, bromine and iodine.
"amino" means-NH 2 。
"cyano" refers to-CN.
"benzyl" means-CH 2 -phenyl.
"carboxy" means-C (O) OH.
"carboxylate" refers to-C (O) O-alkyl or-C (O) O-cycloalkyl, wherein alkyl, cycloalkyl are as defined above.
"hydroxyalkyl" refers to hydroxy-substituted alkyl groups, wherein alkyl is as defined above.
"aminoalkyl" refers to an amino-substituted alkyl group, wherein the alkyl group is as defined above.
"haloalkyl" refers to a halogen substituted alkyl group, wherein alkyl is as defined above.
"haloalkoxy" refers to a halogen substituted alkoxy group, wherein the definition of alkoxy is as described above.
"DMSO" refers to dimethyl sulfoxide.
"BOC" refers to t-butoxycarbonyl.
"Bn" refers to benzyl.
"THP" refers to 2-tetrahydropyranyl.
"TFA" refers to trifluoroacetic acid.
"Ts" refers to p-toluenesulfonyl.
The term "leaving group", or "leaving group", is used in the term nucleophilic substitution reaction and elimination reaction as an atom or functional group that is released from a larger molecule in a chemical reaction. In nucleophilic substitution reactions, the reactant that is attacked by a nucleophile is referred to as a substrate (substrate), and the atom or group of atoms that breaks away from a pair of electrons in the substrate molecule is referred to as a leaving group. Groups that accept electrons easily and bear a strong negative charge are good leaving groups. The smaller the pKa of the leaving group conjugate acid, the easier the leaving group will be to disengage from the other molecule. The reason is that when the pKa of its conjugate acid is smaller, the corresponding leaving group does not need to be bound to other atoms, and the tendency to exist in anionic (or charge neutral leaving group) form is enhanced. Common leaving groups include, but are not limited to, halogen, methanesulfonyl, -OTs, or-OH.
"substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds.
The specification of the present applicationThe terms "substituted" or "substituted", unless otherwise indicated, mean that a group may be substituted with one or more groups selected from the group consisting of: alkyl, alkoxy, alkylthio, alkylamino, halogen, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, =o, -C (O) R 5 、-C(O)OR 5 、-OC(O)R 5 、-NR 6 R 7 、-C(O)NR 6 R 7 、-SO 2 NR 6 R 7 or-NR 6 C(O)R 7 ;
R 5 Selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted with one or more groups selected from a hydroxyl group, a halogen group, a nitro group, a cyano group, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, =o, -C (O) R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO 2 NR 9 R 10 or-NR 9 C(O)R 10 Is substituted by a substituent of (2);
R 6 and R is 7 Each independently selected from a hydrogen atom, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more groups selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =o, -C (O) R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO 2 NR 9 R 10 or-NR 9 C(O)R 10 Is substituted by a substituent of (2);
alternatively, R 6 And R is 7 Together with the atoms to which they are attached form a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group contains one or more N, O, S or SO 2 And said 4-8 membered heterocyclyl is optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =o, -C (O) R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO 2 NR 9 R 10 or-NR 9 C(O)R 10 Is substituted by a substituent of (2);
R 8 、R 9 and R is 10 Each independently selected from the group consisting of hydrogen, alkyl, amino, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl, and carboxylate.
"pharmaceutically acceptable salts" refers to certain salts of the above compounds which retain the original biological activity and are suitable for pharmaceutical use. The pharmaceutically acceptable salts of the compounds represented by the general formula (I) may be metal salts, amine salts with suitable acids.
"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as a physiologically acceptable carrier. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.
Synthesis method of compound of the invention
In order to achieve the purpose of the invention, the invention adopts the following technical scheme:
the present invention provides a process for the preparation of a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which process comprises:
coupling the compound of the general formula (I-a) with the compound of the general formula (I-b) under the action of a catalyst, and optionally removing the protecting group to obtain the compound of the general formula (I);
wherein:
X 1 selected from halogen;
ring A, X, Y, R 1 ~R 3 、L 1 The definitions of n, m and p are as described in the general formula (I).
The invention will be further described with reference to the following examples, which are not intended to limit the scope of the invention.
Examples
The preparation of representative compounds represented by formula (I) and related structural identification data are presented in the examples. It must be noted that the following examples are given by way of illustration and not by way of limitation. 1 The H NMR spectrum was determined with a Bruker instrument (400 MHz) and the chemical shifts were expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. 1 H NMR representation method: s=singlet, d=doublet, t=triplet, m=multiplet, br=broadened, dd=doublet of doublet, dt=doublet of triplet. If coupling constants are provided, they are in Hz.
The mass spectrum is measured by an LC/MS instrument, and the ionization mode can be ESI or APCI.
The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
Column chromatography generally uses tobacco stand yellow sea silica gel 200-300 mesh silica gel as a carrier.
In the following examples, unless otherwise indicated, all temperatures are in degrees celsius and, unless otherwise indicated, various starting materials and reagents are either commercially available or synthesized according to known methods, all of which are used without further purification and, unless otherwise indicated, commercially available manufacturers include, but are not limited to, aldrich Chemical Company, ABCR GmbH & co.kg, acros Organics, praise chemical technology limited, and vision chemical technology limited, etc.
CD 3 OD: deuterated methanol.
CDCl 3 : deuterated chloroform.
DMSO-d 6 : deuterated dimethyl sulfoxide.
The argon atmosphere means that the reaction flask is connected to an argon balloon of about 1L volume.
The examples are not particularly described, and the solution in the reaction is an aqueous solution.
Purifying the compound by using a silica gel column chromatography eluent system and thin layer chromatography, wherein the eluent system is selected from the group consisting of: a: petroleum ether and ethyl acetate systems; b: methylene chloride and methanol systems; c: dichloromethane and ethyl acetate systems; the volume ratio of the solvent is different according to the polarity of the compound, and can be adjusted by adding a small amount of acidic or alkaline reagent, such as acetic acid or triethylamine.
Example 1
5-hydroxy-6- (3- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -4, 5-dihydro-isoxazol-5-yl) pyrimidin-4 (3H) -one
First step
(E) -4-iodobenzaldehyde oxime
Hydroxylamine hydrochloride (5.99 g,86.20 mmol), potassium carbonate (11.9 g,86.20 mmol), 4-iodobenzaldehyde 1a (10 g,43.10 mmol) and water (80 mL) were added sequentially to ethanol (80 mL) and reacted overnight at room temperature. After the completion of the reaction, the organic phases were combined by extraction with ethyl acetate (100 mL. Times.3), and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give (E) -4-iodobenzaldehyde oxime 1b (8 g), yield: 75.14%.
MS m/z(ESI):247.8[M+1] +
Second step
(Z) -N-hydroxy-4-iodobenzilimide chloride
(E) -4-iodobenzaldehyde oxime 1b (1 g,4.05 mmol) was dissolved in N, N-dimethylformamide (10 mL), chlorosuccinimide (594.59 mg,4.45 mmol) was slowly added thereto, and the reaction was stirred at room temperature overnight. After the reaction was completed, the (Z) -N-hydroxy-4-iodobenzil chloride 1c was obtained, and the reaction solution was directly used for the next reaction without purification.
Third step
5- (5, 6-bis (benzyloxy) pyrimidin-4-yl) -3- (4-iodophenyl) -4, 5-dihydroisoxazole
4, 5-bis (benzyloxy) -6-vinyl pyrimidine 1d (1.1 g,3.46mmol, prepared according to patent WO 2020061375) and triethylamine (699.25 mg,6.91mmol, 957.87. Mu.L) were dissolved in N, N-dimethylformamide (14.04 mL), and a solution of (Z) -N-hydroxy-4-iodobenzil chloride 1c (972.54 mg,3.46 mmol) in N, N-dimethylformamide (10 mL) was slowly added dropwise and reacted at room temperature for 6 hours. After completion of the reaction, the reaction was quenched with water, extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give 5- (5, 6-bis (benzyloxy) pyrimidin-4-yl) -3- (4-iodophenyl) -4, 5-dihydroisoxazole 1e (1.4 g), yield: 71.92%.
MS m/z(ESI):563.8[M+1] +
Fourth step
4- (4- ((4- (5, 6-bis (benzyloxy)) pyrimidin-4-yl) -4, 5-dihydroisoxazol-3-yl) phenyl) ethynyl) benzyl) morpholine
5- (5, 6-bis (benzyloxy) pyrimidin-4-yl) -3- (4-iodophenyl) -4, 5-dihydroisoxazole 1e (0.8 g,1.42 mmol), 4- (4-ethynylbenzyl) morpholine 1f (285.79 mg,1.42 mmol), bis (triphenylphosphine) palladium dichloride (199.34 mg, 284.00. Mu. Mol), cuprous iodide (54.09 mg, 284.00. Mu. Mol) and triethylamine (431.07 mg,4.26 mmol) were dissolved in N, N-dimethylformamide (6 mL), replaced with argon three times and stirred at room temperature overnight. After completion of the reaction, the reaction was quenched with water, extracted with ethyl acetate (20 ml×3), the organic phases were combined, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: B system) to give 1g (0.85 g) of 4- (4- ((4- (5, 6-bis (benzyloxy)) pyrimidin-4-yl) -4, 5-dihydroisoxazol-3-yl) phenyl) ethynyl) benzyl) morpholine, yield: 94.01%.
MS m/z(ESI):637.0[M+1] +
Fifth step
5-hydroxy-6- (3- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -4, 5-dihydro-isoxazol-5-yl) pyrimidin-4 (3H) -one
1g (0.2 g, 314.10. Mu. Mol) of 4- (4- ((4- (5, 6-bis (benzyloxy)) pyrimidin-4-yl) -4, 5-dihydroisoxazol-3-yl) phenyl) ethynyl) benzyl) morpholine was dissolved in dichloromethane (2 mL) and boron trichloride (1.84 g,15.71mmol,5 mL) was slowly added dropwise and heated to 30℃for 6 hours. After the reaction is finished, adding a proper amount of methanol in an ice bath for quenching. Filtration under reduced pressure, followed by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) 2 O, mobile phase B: CH (CH) 3 CN) to give 5-hydroxy-6- (3- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -4, 5-dihydro-isoxazol-5-yl) pyrimidin-4 (3H) -one 1 (25 mg), yield: 13.67%.
MS m/z(ESI):457.2[M+1] +
Example 2
3- ((5-hydroxy-6-oxo-1, 6-dihydropyrimidin-4-yl) methyl) -5- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) oxazolidin-2-one 2
First step
2-amino-1- (4-bromophenyl) ethan-1-ol
To a solution of 2-amino-1- (4-bromophenyl) ethan-1-one hydrochloride 2a (5 g,17.42 mmol) in tetrahydrofuran (100 mL) was added sodium borohydride (1.98 g,52.27 mmol), then ethanol (50 mL) was added, the reaction was carried out at room temperature for 2 hours, after the completion of the reaction, 30mL of water was added, ethyl acetate (40 mL. Times.3) was extracted, a saturated sodium chloride solution (20 mL) was washed, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give 2-amino-1- (4-bromophenyl) ethan-1-ol 2b (3.76 g), yield: 100% of the reaction mixture was directly subjected to the next reaction without purification.
MS m/z(ESI):216.0[M+1] +
Second step
5- (4-bromophenyl) oxazolidin-2-one
To a solution of 2-amino-1- (4-bromophenyl) ethan-1-ol 2b (3.76 g,17.40 mmol) and triethylamine (3.52 g,34.80mmol,4.84 mL) in methylene chloride (80 mL) at-78deg.C was added bis (trichloromethyl) carbonate (2.58 g,8.70 mmol), and the mixture was allowed to react at low temperature for 20 minutes and then allowed to react overnight at room temperature. To the reaction solution was added 20mL of water, extracted with dichloromethane (60 mL. Times.3), washed with saturated sodium chloride solution (30 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: B system) to give 5- (4-bromophenyl) oxazolidin-2-one 2c (2.62 g), yield: 62.2%.
MS m/z(ESI):242.0[M+1] +
Third step
3- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -5- (4-bromophenyl) oxazolidin-2-one
Potassium carbonate (856.43 mg,6.20 mmol) was added to 5- (4-bromophenyl) oxazolidin-2-one 2c (500 mg,2.07 mmol) and 4, 5-bis (benzyloxy) -6- (iodomethyl) pyrimidine 2d (892.83 mg,2.07mmol, prepared according to patent WO 2020061375) in acetonitrile (40 mL), heated to reflux, reacted for 6 hours, after the reaction was completed, 20mL of water was added, ethyl acetate (20 mL. Times.3) was extracted, saturated sodium chloride solution (20 mL) was washed, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give 3- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -5- (4-bromophenyl) oxazolidin-2-one 2e (0.94 g), yield: 83.29%.
MS m/z(ESI):546.1[M+1] +
Fourth step
3- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -5- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) oxazolidin-2-one
3- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -5- (4-bromophenyl) oxazolidin-2-one 2e (910 mg,1.67 mmol), 4- (4-ethynylbenzyl) morpholine 1f (435.74 mg,2.17 mmol), bis (triphenylphosphine) palladium dichloride (58.45 mg, 83.27. Mu. Mol), tetrabutylammonium bromide (536.88 mg,1.67 mmol) and piperidine (425.43 mg,5.00 mmol) were added to water (20 mL), argon was displaced three times and heated to 85℃for 4 hours. After the completion of the reaction, ethyl acetate (30 ml×3) was added to the reaction mixture to extract, a saturated sodium chloride solution (20 mL) was washed, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: a system) to give 3- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -5- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) oxazolidin-2-one 2f (0.835 g), yield: 75.2%.
MS m/z(ESI):667.3[M+1] +
Fifth step
3- ((5-hydroxy-6-oxo-1, 6-dihydropyrimidin-4-yl) methyl) -5- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) oxazolidin-2-one
Boron trichloride (8 mL) was added to 3- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -5- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) oxazolidin-2-one 2f (860 mg,1.29 mmol) in dichloromethane (3 mL) under ice-water bath conditions, the temperature was slowly raised to 35℃and after the reaction was completed, the reaction was quenched with methanol and concentrated under reduced pressure to give a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) 2 O, mobile phase B: CH (CH) 3 CN) to give 3- ((5-hydroxy-6-oxo-1, 6-dihydropyrimidin-4-yl) methyl) -5- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) oxazolidin-2-one 2 (100 mg), yield: 12.34%。
MS m/z(ESI):487.2[M+1] +
1 H NMR(400MHz,DMSO-d 6 )δ10.17(s,1H),9.66(s,1H),7.80(s,1H),7.68(d,J=7.9Hz,2H),7.63(d,J=8.2Hz,2H),7.57(d,J=7.9Hz,2H),7.52(d,J=8.1Hz,2H),5.62(dd,J=8.8, 7.0Hz,1H),4.38(s,2H),4.32(s,2H),3.99(t,J=8.9Hz,3H),3.65(s,2H),3.43(dd,J=8.8,7.0Hz,1H),3.26(s,2H),3.13(s,2H).
example 3
3- ((5-hydroxy-6-oxo-1, 6-dihydropyrimidin-4-yl) methyl) -5- (4- ((4- (morpholin-4-carbonyl) phenyl) ethynyl) phenyl) oxazolin-2-one
First step
3- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -5- (4- (((4- (morpholine-4-carbonyl) phenyl) ethynyl) phenyl) oxazolidin-2-one
3- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -5- (4-bromophenyl) oxazolidin-2-one 2e (130 mg, 237.92. Mu. Mol), (4-ethynylphenyl) (morpholino) methanone 3a (51.21 mg, 237.92. Mu. Mol), bis (triphenylphosphine) palladium dichloride (8.35 mg, 11.90. Mu. Mol), tetrabutylammonium bromide (76.70 mg, 237.92. Mu. Mol) and piperidine (60.78 mg, 713.75. Mu. Mol) were added to water (3 mL), argon was displaced three times and heated to 85℃for 4 hours. After the completion of the reaction, ethyl acetate (20 mL. Times.3) was added to the reaction mixture to extract, a saturated sodium chloride solution (20 mL) was washed, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give 3- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -5- (4- (((4- (morpholin-4-carbonyl) phenyl) ethynyl) phenyl) oxazolidin-2-one 3b (130 mg), yield: 80.27%.
MS m/z(ESI):681.3[M+1] +
Second step
3- ((5-hydroxy-6-oxo-1, 6-dihydropyrimidin-4-yl) methyl) -5- (4- ((4- (morpholin-4-carbonyl) phenyl) ethynyl) phenyl) oxazolin-2-one
Boron trichloride (1.5 mL) was added dropwise to 3- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -5- (4- (((4- (morpholin-4-carbonyl) phenyl) ethynyl) phenyl) oxazolidin-2-one 3b (130 mg, 190.97. Mu. Mol) dichloromethane (2 mL) under ice-water bath conditions, heated to 35℃and reacted for 5 hours, after the reaction was completed, the methanol quenched reaction was concentrated under reduced pressure to prepare a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) 2 O, mobile phase B: CH (CH) 3 CN) to give 3- ((5-hydroxy-6-oxo-1, 6-dihydropyrimidin-4-yl) methyl) -5- (4- ((4- (morpholine-4-carbonyl) phenyl) ethynyl) phenyl) oxazolin-2-one 3 (11.97 mg), yield: 9.96%.
MS m/z(ESI):501.2[M+1] +
1 H NMR(400MHz,DMSO-d 6 )δ9.14-9.51(m,4H),8.44(dd,J=5.2,1.7Hz,1H),8.14(s,4H),7.20(dd,J=16.8,11.0Hz,1H),6.62(dd,J=16.9,1.7Hz,1H),5.92(dd,J=10.8,1.8Hz,1H),5.09(d,J=7.5Hz,2H),4.95(t,J=7.5Hz,2H),4.88(t,J=7.6Hz,1H),3.91(t,J=6.7Hz,1H),3.64(s,1H),3.52(d,J=6.1Hz,1H),3.45(s,1H),3.32(s,1H),3.29(d,J=7.3Hz,2H).
Example 4
5-hydroxy-6- ((4- (4- ((4- (morpholin-4-carbonyl) phenyl) ethynyl) phenyl) -2-oxoimidazolin-1-yl) methyl) pyrimidin-4 (3H) -one
First step
(E) -3- (4-iodophenyl) acrylic acid
4-iodobenzaldehyde 1a (10 g,43.10 mmol), malonic acid (5.38 g,51.72 mmol) and ammonium acetate (6.64 g,86.20 mmol) were added to ethanol (10 mL), the mixture was refluxed for 6 hours, cooled to room temperature, after the reaction was completed, filtered, and the filter cake was washed once with ethanol and n-hexane 40mL each, and dried to give (E) -3- (4-iodophenyl) acrylic acid 4a (9.8 g), yield: 82.97%.
MS m/z(ESI):275.0[M+1] +
Second step
3-amino-3- (4-iodophenyl) propionic acid
(E) -3- (4-iodophenyl) acrylic acid 4a (6 g,21.89 mmol), ammonium acetate (5.06 g,65.68 mmol) and ethanol (50 mL) were added to the pressure tube, heated to reflux, reacted for 6 hours, cooled to room temperature after the reaction was completed, filtered, the filter cake was washed once with ethanol and n-hexane 40mL each, and the filter cake was dried to give 3-amino-3- (4-iodophenyl) propionic acid 4b (5 g), yield: 78.16%. MS m/z (ESI): 292.0[ M+1 ]] +
Third step
3- ((tert-Butoxycarbonyl) amino) -3- (4-iodophenyl) propanoic acid
Di-tert-butyl dicarbonate (5.51 g,25.25 mmol) was added to 4b 3-amino-3- (4-iodophenyl) propionic acid (4.9 g,16.83 mmol) in 50mL dioxane, followed by 50mL saturated sodium bicarbonate solution and stirred overnight at room temperature. After the reaction was completed, filtration, washing the cake with 50mL of n-hexane twice, acidifying the filtrate with citric acid solution, extracting with ethyl acetate (40 ml×3), washing with saturated sodium chloride solution (20 mL), drying the organic phase over anhydrous sodium sulfate, filtration, concentrating under reduced pressure, to give 3- ((t-butoxycarbonyl) amino) -3- (4-iodophenyl) propionic acid 4c (4.85 g), yield: 73.65%, and the next reaction was directly carried out without purification.
MS m/z(ESI):414.0[M+23] +
Fourth step
5- (4-iodophenyl) -2-oxoimidazoline-1-carboxylic acid tert-butyl ester
3- ((Boc) amino) -3- (4-iodophenyl) propanoic acid 4c (1 g,2.56 mmol), diphenyl azide phosphate (844.17 mg,3.07 mmol) and triethylamine (646.66 mg,6.39 mmol) were added to toluene (25 mL) and stirred at room temperature for 30 min. After the reaction was completed, 20mL of water was added to the reaction mixture, which was then extracted with ethyl acetate (20 mL. Times.3), and the saturated sodium chloride solution (20 mL) was washed, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl 5- (4-iodophenyl) -2-oxoimidazoline-1-carboxylate 4d (992 mg), yield: 99.97%, and the next reaction was directly carried out without purification.
MS m/z(ESI):333.0[M-55] +
Fifth step
3- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -5- (4-iodophenyl) -2-oxoimidazoline-1-carboxylic acid tert-butyl ester
5- (4-iodophenyl) -2-oxoimidazoline-1-carboxylic acid tert-butyl ester 4d (800 mg,2.06 mmol), 4, 5-bis (benzyloxy) -6- (iodomethyl) pyrimidine 2d (890.79 mg,2.06 mmol), potassium carbonate (854.47 mg,6.18 mmol) were added to acetonitrile (5 mL), heated to 90 ℃ and reacted for 10 hours, after the reaction was completed, 20mL of water was added to the reaction solution, ethyl acetate (20 mL. Times.3) was extracted, saturated sodium chloride solution (20 mL) was washed, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give 3- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -5- (4-iodophenyl) -2-oxoimidazoline-1-carboxylic acid tert-butyl ester 4e (510 mg), yield: 35.73%.
MS m/z(ESI):637.1[M-55] +
Sixth step
3- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -5- (4- ((4- (morpholine-4-carbonyl) phenyl) ethynyl) phenyl) -2-oxoimidazoline-1-carboxylic acid tert-butyl ester
3- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -5- (4-iodophenyl) -2-oxoimidazoline-1-carboxylic acid tert-butyl ester 4e (100 mg, 154.91. Mu. Mol), (4-ethynylphenyl) (morpholino) methanone 3a (33.34 mg, 154.91. Mu. Mol), bis (triphenylphosphine) palladium dichloride (5.44 mg, 7.75. Mu. Mol), tetrabutylammonium bromide (49.94 mg, 154.91. Mu. Mol) and piperidine (39.57 mg, 464.73. Mu. Mol) were added to water (2 mL), argon was displaced three times, heated to 85℃and after the reaction was completed, 20mL of water was added to the reaction solution, ethyl acetate (20 mL. Times.3) was extracted, saturated sodium chloride solution (20 mL) was washed, the organic phase was dried over anhydrous sodium sulfate, filtered, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give 3- ((5, 6-bis (benzyloxy) pyrimidine-4-methyl) -4- (4-ethynylphenyl) -4-carboxylic acid tert-butyl ester (4-ethynylphenyl) -1-carboxylic acid) yield, 60mg, after the reaction was completed, the reaction was extracted, saturated sodium chloride solution was saturated sodium chloride solution (20 mL). 49.66%.
MS m/z(ESI):780.5[M+1] +
Seventh step
5-hydroxy-6- ((4- (4- ((4- (morpholin-4-carbonyl) phenyl) ethynyl) phenyl) -2-oxoimidazolin-1-yl) methyl) pyrimidin-4 (3H) -one
Boron trichloride (1 mL) was added to 3- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -5- (4- ((4- (morpholin-4-carbonyl) phenyl) ethynyl) phenyl) -2-oxoimidazoline-1-carboxylic acid tert-butyl ester 4f (60 mg, 76.94. Mu. Mol) in methylene chloride (1 mL), heated to 35℃and reacted for 6 hours, after the reaction was completed, quenched with methanol, concentrated under reduced pressure to give a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) 2 O, mobile phase B: CH (CH) 3 CN) to give 5-hydroxy-6- ((4- (4- ((4- (morpholine-4-carbonyl) phenyl) ethynyl) phenyl) -2-oxoimidazol-1-yl) methyl) pyrimidin-4 (3H) -one 4 (8.58 mg), yield: 17.78%.
MS m/z(ESI):500.2[M+1] +
1 H NMR(400MHz,DMSO-d 6 )δ12.65(s,1H),9.31-9.76(m,1H),7.78(s,1H),7.59(dd,J=18.8,8.0Hz,4H),7.45(dd,J=12.0,8.0Hz,4H),7.10(d,J=14.3Hz,1H),4.72(t,J=8.1Hz,1H),4.19(d,J=6.7Hz,2H),3.80(s,1H),3.63(s,8H),3.09(s,1H).
Example 5
5-hydroxy-6- ((3- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -4, 5-dihydroisoxazol-5-yl) methyl) pyrimidin-4 (3H) -one
Example 6
5-hydroxy-6- ((3- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -4, 5-dihydroisoxazol-4-yl) methyl) pyrimidin-4 (3H) -one
First step
4-allyl-5, 6-bis (benzyloxy) pyrimidine
Potassium phosphate (6.50 g,30.60 mmol), bis (triphenylphosphine) palladium dichloride (859.18 mg,1.22 mmol), 4, 5-dibenzyloxy-6-chloropyrimidine 5a (2.0 g,6.12mmol, prepared according to patent WO 2020102572) and 2-allyl-4, 5-tetramethyl-1, 3, 2-dioxaborane (4.11 g,24.48 mmol) were added sequentially to a mixed solution of tetrahydrofuran (20 mL) and water (4 mL), argon was replaced three times, and heated to 90℃for 20 hours. After completion of the reaction, water (10 mL) was added, extracted with ethyl acetate (10 mL. Times.3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give 4-allyl-5, 6-bis (benzyloxy) pyrimidine 5b (250 mg), yield: 21.6%.
MS m/z(ESI):333.1[M+1] +
Second step
5- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3- (4-iodophenyl) -4, 5-dihydroisoxazole 5c
4- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3- (4-iodophenyl) -4, 5-dihydroisoxazole 5d
Pyridine (24.02 mg, 303.60. Mu. Mol), (E) -4-iodobenzaldehyde oxime 1b (250 mg,1.01 mmol) and 4-allyl-5, 6-bis (benzyloxy) pyrimidine 5b (504.58 mg,1.52 mmol) were successively added to a chloroform (5 mL) solution, and sodium hypochlorite solution (1.61 g,3.04 mmol) was slowly added dropwise under ice water bath cooling, and then warmed to room temperature and stirred for 3 hours. After completion of the reaction, water (10 mL) was added, extracted with ethyl acetate (10 mL. Times.3), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give a mixture (470 mg) of 5- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3- (4-iodophenyl) -4, 5-dihydroisoxazole 5c and 4- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3- (4-iodophenyl) -4, 5-dihydroisoxazole 5d, yield: 80.4%.
MS m/z(ESI):578.1[M+1] +
Third step
4- (4- ((4- (5- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4, 5-dihydro-isoxazol-3-yl) phenyl) ethynyl) benzyl) morpholine 5e
4- (4- ((4- (4- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4, 5-dihydro-isoxazol-3-yl) phenyl) ethynyl) benzyl) morpholine 5f
A mixture (470 mg, 813.98. Mu. Mol) of the above 5- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3- (4-iodophenyl) -4, 5-dihydroisoxazole 5c and 4- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3- (4-iodophenyl) -4, 5-dihydroisoxazole 5d, 4- (4-ethynylbenzyl) morpholine 1f (163.82 mg, 813.98. Mu. Mol), allylpalladium chloride dimer (29.78 mg, 81.40. Mu. Mol), 1, 4-diazabicyclooctane (182.61 mg,1.63 mmol) and tri-tert-butylphosphine (16.47 mg, 81.40. Mu. Mol) was added to a solution of acetonitrile (10 mL), argon was replaced three times, and reacted at room temperature for 20 hours. After completion of the reaction, water (10 mL) was added. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the resulting residue was purified by column chromatography on silica gel (eluent: A system) to give 4- (4- ((4- (5- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4, 5-dihydroisoxazol-3-yl) phenyl) ethynyl) benzyl) morpholine 5e (210 mg) and 4- (4- ((4- (4- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4, 5-dihydroisoxazol-3-yl) phenyl) ethynyl) benzyl) morpholine 5f (110 mg) in 39.6% and 20.8% yields, respectively.
MS m/z(ESI):651.2[M+1] +
MS m/z(ESI):651.0[M+1] +
Fourth step
5-hydroxy-6- ((3- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -4, 5-dihydroisoxazol-5-yl) methyl) pyrimidin-4 (3H) -one
4- (4- ((4- (5- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4, 5-dihydroisoxazol-3-yl) phenyl) ethynyl) benzyl) morpholine 5e (100 mg, 153.67. Mu. Mol) was dissolved in dichloromethane (2 mL) and 1M solution of boron trichloride in dichloromethane (2 mL) was slowly added dropwise with ice water bath cooling, then warmed to room temperature and stirred for 20 hours. After completion of the reaction, quenched with methanol (2 mL), concentrated under reduced pressure to give a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) 2 O, mobile phase B: CH (CH) 3 CN) to give 5-hydroxy-6- ((3- (4- ((4- (morpholinomethyl) phenyl) ethynyl)) Phenyl) -4, 5-dihydro-isoxazol-5-yl-methyl) pyrimidin-4 (3H) -one 5 (6.7 mg), yield: 18.5%.
MS m/z(ESI):470.8[M+1] +
Fifth step
5-hydroxy-6- ((3- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -4, 5-dihydroisoxazol-4-yl) methyl) pyrimidin-4 (3H) -one
4- (4- ((4- (4- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4, 5-dihydroisoxazol-3-yl) phenyl) ethynyl) benzyl) morpholine 5f (110 mg, 169. Mu. Mol) was added to a solution of dichloromethane (2 mL), 1M solution of boron trichloride in dichloromethane (2 mL) was slowly added dropwise with ice water bath cooling, then warmed to room temperature and stirred for 20 hours. After completion of the reaction, quenched with methanol (2 mL), concentrated under reduced pressure to give a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) 2 O, mobile phase B: CH (CH) 3 CN) to give 5-hydroxy-6- ((3- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -4, 5-dihydro-isoxazol-4-yl) methyl) pyrimidin-4 (3H) -one 6 (27 mg), yield: 27.2%.
MS m/z(ESI):471.1[M+1] +
Example 7
5-hydroxy-6- ((4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -2-oxopyrrolidin-1-yl) methyl) pyrimidin-4 (3H) -one
First step
(E) -3- (4-iodophenyl) acrylic acid methyl ester
To a solution of potassium t-butoxide (2.90 g,25.86 mmol) in tetrahydrofuran (50 mL) was slowly added dropwise methyl 2- (ethoxy (propyl) phosphoryl) acetate 7a (5.43 g,25.86 mmol) under an argon atmosphere at zero degrees Celsius for 30 minutes, and a solution of 4-iodobenzaldehyde 1a (5 g,21.55 mmol) in tetrahydrofuran (10 mL) was added. The mixture was warmed to room temperature and stirred for 3 hours. After the completion of the reaction, the reaction was quenched with water (30 mL), extracted with ethyl acetate (30 mL. Times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give methyl (E) -3- (4-iodophenyl) acrylate 7b (6 g), yield: 96.65%, and the next reaction was directly carried out without purification.
MS m/z(ESI):288.6[M+1] +
Second step
3- (4-iodophenyl) -4-nitrobutanoic acid methyl ester
To nitromethane (15 mL) was added 1, 8-diazabicyclo [5.4.0] undec-7-ene (1.59 g,10.41 mmol) and methyl (E) -3- (4-iodophenyl) acrylate 7b (3 g,10.41 mmol) at-10deg.C, stirred for 1 hour, slowly warmed to room temperature and stirred for 5 hours. After the completion of the reaction, the reaction was quenched with water (10 mL), the system was acidified with a dilute hydrochloric acid solution, extracted with ethyl acetate (30 mL. Times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give methyl 3- (4-iodophenyl) -4-nitrobutyrate 7c (3.1 g), yield: 85.27%.
1 H NMR(400MHz,DMSO-d 6 )δ7.62-7.72(m,2H),7.12-7.19(m,2H),4.96(dd,J=13.3,5.9Hz,1H),4.85(dd,J=13.3,9.5Hz,1H),3.77(ddd,J=9.1,6.0,3.0Hz,1H),3.52(s,3H),2.82(dd,J=16.3,6.3Hz,1H),2.71(dd,J=16.3,8.6Hz,1H).
Third step
4- (4-iodophenyl) pyrrolidin-2-one
Methyl 3- (4-iodophenyl) -4-nitrobutanoate 7c (500 mg,1.43 mmol) was added to methanol (10 mL), nickel chloride (92.80 mg, 716.08. Mu. Mol) was added, and after 5 minutes of reaction, sodium borohydride (108.36 mg,2.86 mmol) was added and the reaction was carried out at room temperature overnight. Saturated aqueous ammonium chloride solution was added at zero degrees celsius, followed by extraction with ethyl acetate (30 ml×2), the aqueous layer was separated, the combined organic phases were washed sequentially with saturated aqueous sodium chloride solution (30 ml×2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: a system) to give 4- (4-iodophenyl) pyrrolidin-2-one 7d (200 mg), yield: 48.64%.
MS m/z(ESI):287.9[M+1] +
Fourth step
1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4-iodophenyl) pyrrolidin-2-one
4- (4-iodophenyl) pyrrolidin-2-one 7d (184 mg, 640.90. Mu. Mol) and 4, 5-bis (benzyloxy) -6- (iodomethyl) pyrimidine 2d (277.03 mg, 640.90. Mu. Mol) were added to acetonitrile (5 mL), cesium carbonate (835.27 mg,2.56 mmol) was added, and the mixture was heated to 100℃and reacted for 4 hours. The reaction solution was extracted with ethyl acetate (30 mL. Times.2), the aqueous layer was removed, the combined organic phases were washed successively with saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: B system) to give 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4-iodophenyl) pyrrolidin-2-one 7e (110 mg), yield: 29.02%.
MS m/z(ESI):591.8[M+1] +
Fifth step
1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) pyrrolidin-2-one
To an aqueous solution of 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4-iodophenyl) pyrrolidin-2-one 7e (100 mg, 169.08. Mu. Mol) was added bis (triphenylphosphine) palladium dichloride (4.75 mg, 6.76. Mu. Mol), tetrabutylammonium bromide (54.51 mg, 169.08. Mu. Mol) and piperidine (43.19 mg, 507.24. Mu. Mol) at room temperature. The reaction was warmed to 70℃and stirred for 5 hours. The reaction solution was extracted with ethyl acetate (30 ml×2), the aqueous layer was separated, the combined organic phases were washed successively with saturated sodium chloride solution (30 ml×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: B system) to give 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) pyrrolidin-2-one 7f (60 mg), yield: 53.38%.
MS m/z(ESI):665.0[M+1] +
Sixth step
5-hydroxy-6- ((4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -2-oxopyrrolidin-1-yl) methyl) pyrimidin-4 (3H) -one
Boron trichloride (1 mL) was added dropwise to 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) pyrrolidin-2-one 7f (60 mg, 90.25. Mu. Mol) in dichloromethane (2 mL) under ice-water bath conditions, reacted at room temperature for 2 hours, after completion of the reaction, quenched with methanol (2 mL), concentrated under reduced pressure to give a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) 2 O, mobile phase B: CH (CH) 3 CN) to give 5-hydroxy-6- ((4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -2-oxopyrrolidin-1-yl) methyl) pyrimidin-4 (3H) -one 7 (13 mg), yield: 22.47%.
MS m/z(ESI):485.2[M+1] +
1 H NMR(400MHz,DMSO-d 6 )δ10.22(s,1H),9.57(s,1H),7.77(s,1H),7.66(d,J=7.9Hz,2H),7.54(dd,J=14.6,8.0Hz,4H),7.39(d,J=8.0Hz,2H),4.37(q,J=9.0,8.6Hz,4H),3.96(s,2H),3.74(t,J=8.8Hz,2H),3.60-3.65(m,2H),3.29-3.33(m,1H),3.06-3.26(m,4H),2.75(dd,J=16.5,9.0Hz,1H),2.38(dd,J=16.5,8.1Hz,1H).
Example 8
5-hydroxy-6- ((4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -2-oxoimidazolin-1-yl) methyl) pyrimidin-4 (3H) -one
First step
3- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -5- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -2-oxoimidazoline-1-carboxylic acid tert-butyl ester
3- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -5- (4-iodophenyl) -2-oxoimidazoline-1-carboxylic acid tert-butyl ester 4e (1 g,1.44 mmol), 4- (4-ethynylbenzyl) morpholine 1f (311.77 mg,1.55 mmol), bis (triphenylphosphine) palladium dichloride (54.37 mg, 77.45. Mu. Mol), tetrabutylammonium bromide (499.38 mg,1.55 mmol) and piperidine (395.71 mg,4.65 mmol) were added to water (2 mL), replaced three times with argon, heated to 85 ℃ C., reacted for 4 hours, 20mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL. Times.3), the saturated sodium chloride solution (20 mL) was washed, the organic phase was dried over anhydrous sodium sulfate, filtered and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give 3- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -5- (4-methylphenyl) -morpholine tert-8- ((8-ethynylmorpholine) yield (660 mg): 55.63%.
MS m/z(ESI):766.4[M+1] +
Second step
5-hydroxy-6- ((4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -2-oxoimidazolin-1-yl) methyl) pyrimidin-4 (3H) -one
Boron trichloride (0.5 mL) and 3- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -5- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -2-oxoimidazoline-1-carboxylic acid tert-butyl ester 8a (60 mg, 78.34. Mu. Mol) in dichloromethane (1 mL) were slowly warmed to room temperature under ice-water bath conditions and reacted overnight. After completion of the reaction, quenched with methanol (2 mL), concentrated under reduced pressure to give a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) 2 O, mobile phase B: CH (CH) 3 CN) to give 5-hydroxy-6- ((4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -2-oxoimidazolin-1-yl) methyl) pyrimidin-4 (3H) -one 8 (11.54 mg), yield: 23.78%.
MS m/z(ESI):486.2[M+1] +
1 H NMR(400MHz,DMSO-d 6 )δ10.64(s,1H),9.57(s,1H),7.83(s,1H),7.71(d,J=8.0Hz,2H),7.57-7.69(m,4H),7.49(d,J=8.1Hz,2H),7.14(s,1H),4.79(t,J=8.1Hz,1H),4.44(s,2H),4.25(d,J=9.6Hz,2H),3.86(s,2H),3.77(s,2H),3.23-3.44(m,3H),3.04-3.24(m,3H).
Example 9
5-hydroxy-6- ((3- (2-fluoroethyl) -4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -2-oxoimidazolin-1-yl) methyl) pyrimidin-4 (3H) -one
First step
1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) imidazolin-2-one
Hydrochloric acid (457.00 mg,12.53 mmol) was added to a solution of 3- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -5- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -2-oxoimidazoline-1-carboxylic acid tert-butyl ester 8a (480 mg, 626.72. Mu. Mol) in ethyl acetate (4 mL), stirred at room temperature for 4 hours, after completion of the reaction, the reaction solution was concentrated under reduced pressure, 20mL of saturated sodium bicarbonate solution was added, extracted with ethyl acetate (20 mL. Times.3), the saturated sodium chloride solution (20 mL) was washed, the organic phase was dried over anhydrous sodium sulfate, filtered and the resulting residue concentrated under reduced pressure was purified by silica gel column chromatography (eluent: B system) to give 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) imidazolin-2-one 9a (200 mg), yield: 47.93%.
MS m/z(ESI):666.3[M+1] +
Second step
1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3- (2-fluoroethyl) -4- (4- (((4- (morpholinomethyl) phenyl) ethynyl) phenyl) imidazolin-2-one
To a solution of 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) imidazolin-2-one 9a (80 mg, 120.16. Mu. Mol) in N, N-dimethylformamide (2 mL) was added sodium hydride (6.25 mg, 144.19. Mu. Mol,60% purity), stirred for 20 minutes, 1-fluoro-2-iodoethane (25.08 mg, 144.19. Mu. Mol) was added and stirred at room temperature for 2 hours, after the end of the reaction, the reaction mixture was quenched with 20mL of ice water, extracted with ethyl acetate (20 mL. Times.3), washed with saturated sodium chloride solution (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3- (2-fluoroethyl) -4- (4- (((4- (morpholinomethyl) phenyl) ethynyl) imidazolin-2-one) 9b (99.38%) and the following purification was carried out without direct purification.
MS m/z(ESI):712.3[M+1] +
Third step
5-hydroxy-6- ((3- (2-fluoroethyl) -4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -2-oxoimidazolin-1-yl) methyl) pyrimidin-4 (3H) -one
Boron trichloride (1 mL) was added to a solution of 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3- (2-fluoroethyl) -4- (4- (((4- (morpholinomethyl) phenyl) ethynyl) phenyl) imidazolin-2-one 9b (85 mg, 119.41. Mu. Mol) in methylene chloride (1 mL) under ice-water bath conditions, reacted at room temperature for 5 hours, after completion of the reaction, quenched with methanol (2 mL) and concentrated under reduced pressure to prepare a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) 2 O, mobile phase B: CH (CH) 3 CN) to give 5-hydroxy-6- ((3- (2-fluoroethyl) -4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -2-oxoimidazol-1-yl) methyl) pyrimidin-4 (3H) -one 9 (4.4 mg), yield: 5.51%.
MS m/z(ESI):532.2[M+1] +
1 H NMR(400MHz,DMSO-d 6 )δ10.30(s,1H),9.51(s,1H),7.78(s,1H),7.66(d,J=7.9Hz,2H),7.52-7.63(m,4H),7.46(d,J=8.0Hz,2H),4.77(dd,J=9.1,7.0Hz,1H),4.21-4.50(m,6H),3.95(s,2H),3.77(t,J=9.0Hz,2H),3.67(s,2H),3.22(s,2H),3.13(dd,J=8.9,6.9Hz,3H),2.91(dddd,J=25.0,15.0,6.4,3.5Hz,1H).
Example 10
5-hydroxy-6- ((3-methyl-4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -2-oxoimidazolin-1-yl) methyl) pyrimidin-4 (3H) -one
First step
1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-methyl-4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) imidazolin-2-one
To a solution of 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) imidazolin-2-one 9a (80 mg, 120.16. Mu. Mol) in N, N-dimethylformamide (2 mL) was added sodium hydride (6.25 mg, 144.19. Mu. Mol,60% purity), stirred for 20 min, methyl iodide (20.47 mg, 144.19. Mu. Mol) was added, stirred at room temperature for 2 h, after the end of the reaction, the reaction mixture was quenched with 20mL of ice water, extracted with ethyl acetate (20 mL. Times.3), the saturated sodium chloride solution (20 mL) was washed, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-methyl-4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) imidazolin-2-one 10a (81 mg), yield: 99.16%, without purification, the next reaction was directly carried out.
MS m/z(ESI):680.3[M+1] +
Second step
5-hydroxy-6- ((3-methyl-4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -2-oxoimidazolin-1-yl) methyl) pyrimidin-4 (3H) -one
Boron trichloride (1 mL) was added to a solution of 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-methyl-4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) imidazolin-2-one 10a (81 mg,119.15 μmol) in dichloromethane (1 mL) under ice-water bath conditions and reacted overnight at room temperature. After completion of the reaction, quenched with methanol (2 mL), concentrated under reduced pressure to give a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) 2 O, mobile phase B: CH (CH) 3 CN) to give 5-hydroxy-6- ((3-methyl-4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -2-oxoimidazol-1-yl) methyl) pyrimidin-4 (3H) -one 10 (4.38 mg), yield: 5.87%.
MS m/z(ESI):500.2[M+1] +
1 H NMR(400MHz,DMSO-d 6 )δ10.52(s,1H),9.51(s,1H),7.79(s,1H),7.66(d,J=8.0Hz,2H),7.60(p,J=4.9,4.4Hz,4H),7.44(d,J=8.0Hz,2H),4.53(t,J=8.4Hz,1H),4.39(s,2H),4.25(s,2H),3.83-4.15(m,4H),3.72(s,1H),3.70(s,3H),3.20(d,J=23.5Hz,4H),3.06(t,J=8.3Hz,1H).
Example 11
5-hydroxy-6- ((3-isopropyl-4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -2-oxoimidazolin-1-yl) methyl) pyrimidin-4 (3H) -one
First step
1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) imidazolin-2-one
To a solution of 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) imidazolin-2-one 9a (70 mg, 105.14. Mu. Mol) in N, N-dimethylformamide (2 mL) was added sodium hydride (5.47 mg, 126.17. Mu. Mol,60% purity), stirred under ice bath for 20 minutes, 2-iodopropane (19.66 mg, 115.65. Mu. Mol) was further added, stirred at room temperature for 2 hours, after completion of the reaction, 20mL of ice water was added to quench the reaction solution, extracted with ethyl acetate (20 mL. Times.3), washed with saturated sodium chloride solution (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) imidazolin-2-one (74 mg) yield: 99.43%, without purification, the next reaction was directly carried out.
MS m/z(ESI):708.3[M+1] +
Second step
5-hydroxy-6- ((3-isopropyl-4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -2-oxoimidazolin-1-yl) methyl) pyrimidin-4 (3H) -one
Boron trichloride (1.5 mL) was added to 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) imidazoline under ice-water bath conditions2-Ketone 11a (74 mg, 104.54. Mu. Mol) in dichloromethane (1 mL) was reacted overnight at room temperature, after completion of the reaction, quenched with methanol (2 mL), concentrated under reduced pressure to give a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mM I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) 2 O, mobile phase B: CH (CH) 3 CN) to give 5-hydroxy-6- ((3-isopropyl-4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -2-oxoimidazol-1-yl) methyl) pyrimidin-4 (3H) -one 11 (1.36 mg), yield: 1.95%.
MS m/z(ESI):528.2[M+1] +
1 H NMR(400MHz,Methanol-d 4 )δ7.79(s,1H),7.65(d,J=8.0Hz,2H),7.52-7.59(m,4H),7.49(d,J=8.3Hz,2H),4.93-4.94(m,1H),4.79(q,J=2.3Hz,1H),4.35-4.43(m,3H),4.05(s,2H),3.77-3.89(m,2H),3.75(d,J=14.2Hz,2H),3.36(d,J=9.6Hz,2H),3.24(dd,J=15.7,6.0Hz,2H),3.17-3.21(m,1H),1.23(d,J=6.8Hz,3H),0.89(d,J=6.8Hz,3H).
Example 12
5-hydroxy-6- ((3- (2-hydroxyethyl) -4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -2-oxoimidazolin-1-yl) methyl) pyrimidin-4 (3H) -one
First step
1- ((5- (benzyloxy) -6-hydroxypyrimidin-4-yl) methyl) -3- (2-hydroxyethyl) -4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) imidazolin-2-one
Cesium carbonate (101.0 mg,310.0 μmol) and 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) imidazolin-2-one 9a (70 mg,105.14 μmol) were added to N, N-dimethylformamide (2 mL), 2-iodoethanol (19.89 mg,115.65 μmol) was then added, the reaction was heated to 120 ℃ for 3 hours, after completion of the reaction, extracted with ethyl acetate (20 ml×3), washed with water (20 mL) and saturated sodium chloride solution (20 mL), respectively, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1- ((5- (benzyloxy) -6-hydroxypyrimidin-4-yl) methyl) -3- (2-hydroxyethyl) -4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) imidazolin-2-one 12a (65 mg) in yield: 99.76%, and the next reaction was directly carried out without purification.
MS m/z(ESI):620.3[M+1] +
Second step
5-hydroxy-6- ((3- (2-hydroxyethyl) -4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -2-oxoimidazolin-1-yl) methyl) pyrimidin-4 (3H) -one
Boron trichloride (1.5 mL) was added to 1- ((5- (benzyloxy) -6-hydroxypyrimidin-4-yl) methyl) -3- (2-hydroxyethyl) -4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) imidazolin-2-one 12a (20 mg, 32.27. Mu. Mol) in dichloromethane (1 mL) under ice-water bath conditions, reacted at room temperature for 5 hours, after completion of the reaction, quenched with methanol (2 mL), concentrated under reduced pressure, and a liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) was prepared 2 O, mobile phase B: CH (CH) 3 CN) to give 5-hydroxy-6- ((3- (2-hydroxyethyl) -4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -2-oxoimidazol-1-yl) methyl) pyrimidin-4 (3H) -one 12 (9.53 mg), yield: 43.49%.
MS m/z(ESI):530.2[M+1] +
1 H NMR(400MHz,Methanol-d 4 )δ7.76(s,1H),7.65(d,J=7.9Hz,2H),7.54(dd,J=8.2,3.7Hz,4H),7.41-7.47(m,2H),4.95-4.92(m,2H),4.39(d,J=2.4Hz,4H),3.99-4.15(m,3H),3.92(t,J=9.1Hz,2H),3.66-3.82(m,3H),3.37(s,2H),3.20-3.29(m,3H).
Example 13 and example 14
(R)-5-hydroxy-6-((3-isopropyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one 13
(R) -5-hydroxy-6- ((3-isopropyl-4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -2-oxoimidazol-1-yl) methyl) pyrimidin-4 (3H) -one 13
(S)-5-hydroxy-6-((3-isopropyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidaz olidin-1-yl)methyl)pyrimidin-4(3H)-one 14
(S) -5-hydroxy-6- ((3-isopropyl-4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -2-oxoimidazol-1-yl) methyl) pyrimidin-4 (3H) -one 14
First step
5-hydroxy-6- ((3-isopropyl-4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -2-oxoimidazolin-1-yl) methyl) pyrimidin-4 (3H) -one 11 (412 MG) was purified by preparative supercritical fluid chromatography (model: MG II preparation SFC (SFC-14), column: chiralCel OX (250X 30mm I.D.,10 μm), mobile phase: A phase CO 2 Phase B was Ethanol (0.1% NH) 3 H 2 O), gradient: phase B40%, flow rate: 80mL/min, backpressure: 100bar, column temperature: 38 c) and the separated fractions were subjected to separation and purification by rotary evaporator and the solvent was removed at a bath temperature of 40 c to give (R) -5-hydroxy-6- ((3-isopropyl-4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -2-oxoimidazolin-1-yl) methyl) pyrimidin-4 (3H) -one 13 (114 mg,215 μmol,27.6% yield) and (S) -5-hydroxy-6- ((3-isopropyl-4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -2-oxoimidazolin-1-yl) methyl) pyrimidin-4 (3H) -one 14 (122 mg,28.6% yield).
13MS m/z(ESI):528.0[M+1] +
1 H NMR(400MHz,DMSO-d 6 )δ7.78(s,1H),7.64–7.41(m,6H),7.36(d,J=8.0Hz,2H),4.70(dd,J=9.2,7.2Hz,1H),4.26(d,J=15.6Hz,1H),4.19(d,J=15.2Hz,1H),3.74–3.66(m,2H),3.59–3.57(m,4H),3.49(s,2H),3.04(t,J=8.0Hz,1H),2.35(t,J=4.7Hz,4H),1.13(d,J=6.8Hz,3H),0.77(d,J=7.2Hz,3H).
14MS m/z(ESI):528.0[M+1] +
Example 15
5-hydroxy-6-((3-isopropyl-2-oxo-4-(4-((4-(((tetrahydrofuran-3-yl)amino)methyl)phenyl)ethynyl)phenyl)imidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-hydroxy-6- ((3-isopropyl-2-oxo-4- (4- ((4- (((tetrahydrofuran-3-yl) amino) methyl) phenyl) ethynyl) phenyl) imidazolin-1-yl) methyl) pyrimidin-4 (3H) -one
First step
1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((4-(((tetrahydrofuran-3-yl)amino)methyl)phenyl)ethynyl)phenyl)imidazolidin-2-one
1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-4- (4- ((4- (((tetrahydrofuran-3-yl) amino) methyl) phenyl) ethynyl) phenyl) imidazolin-2-one
4- ((4- (1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-2-oxoimidazolin-4-yl) phenyl) ethynyl) benzaldehyde 4e (50 mg, 78.53. Mu. Mol), tetrahydrofuran-3-amine 15b (13.68 mg, 157.05. Mu. Mol) was dissolved in 1, 2-dichloroethane (5 mL), acetic acid (0.2 mL) was added, stirring was continued for 30 min, sodium borohydride acetate (49.93 mg, 235.58. Mu. Mol) was added, and stirring was continued at room temperature for 12 h. 15mL of saturated aqueous sodium bicarbonate solution was added to quench, dichloromethane (30 mL) and water (15 mL) were added, the solution was separated, the aqueous phase was extracted with dichloromethane (30 mL. Times.2), the combined organic phases were washed with saturated aqueous sodium chloride (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and the residue was purified by preparative liquid chromatography to give 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-4- (4- ((4- (((tetrahydrofuran-3-yl) amino) methyl) phenyl) ethynyl) phenyl) imidazolin-2-one 15c (40 mg,71.96% yieldd).
MS m/z(ESI):708.0[M+1] +
Second step
5-hydroxy-6-((3-isopropyl-2-oxo-4-(4-((4-(((tetrahydrofuran-3-yl)amino)methyl)phenyl)ethynyl)phenyl)imidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-hydroxy-6- ((3-isopropyl-2-oxo-4- (4- ((4- (((tetrahydrofuran-3-yl) amino) methyl) phenyl) ethynyl) phenyl) imidazolin-1-yl) methyl) pyrimidin-4 (3H) -one
Boron trichloride (0.4 mL) was added dropwise to a solution of 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-4- (4- ((4- (((tetrahydrofuran-3-yl) amino) methyl) phenyl) ethynyl) phenyl) imidazolin-2-one 15c (40 mg,56.51 μmol) in dichloromethane (1 mL) under ice bath conditions, and the reaction was quenched with methanol at room temperature for 2 hours. Preparation of liquid chromatography purification yielded 5-hydroxy-6- ((3-isopropyl-2-oxo-4- (4- ((4- (((tetrahydrofuran-3-yl) amino) methyl) phenyl) ethynyl) phenyl) imidazolin-1-yl) methyl) pyrimidin-4 (3H) -one 15 (6 mg,15.14% yieldd, 91.5% purity).
MS m/z(ESI):528.0[M+1] +
Example 16
5-hydroxy-6-((3-isopropyl-4-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-hydroxy-6- ((3-isopropyl-4- (4- ((4- ((3-methoxyazetidin-1-yl) methyl) phenyl) ethynyl) phenyl) -2-oxoimidazolin-1-yl) methyl) pyrimidinyl 4 (3H) -one
First step
3-methoxy-1-(4-((trimethylsilyl)ethynyl)benzyl)azetidine
3-methoxy-1- (4- ((trimethylsilyl) ethynyl) benzyl) azetidine
After 4- (2-trimethylsilylethynyl) benzaldehyde 16a (400 mg,1.98 mmol) was dissolved in 1, 2-dichloroethane (10 mL), 3-methoxyazetidine hydrochloride 16b (488.65 mg,3.95mmol, and acetic acid (1.2 mL) were added, reacted at room temperature for 30 minutes, sodium triacetoxyborohydride (1.26 g,5.93 mmol) was added at 0℃and reacted at room temperature for 2 hours, 50mL of saturated sodium bicarbonate solution was added to the reaction solution, dichloromethane (100 mL) was extracted, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was further separated and purified by silica gel column chromatography (eluent: system A) to give 3-methoxy-1- (4- ((trimethylsilyl) ethynyl) benzyl) azetidine 16c (mg, 73.99% yield).
MS m/z(ESI):274.0[M+1] +
Second step
1-(4-ethynylbenzyl)-3-methoxyazetidine
1- (4-ethynylbenzyl) -3-methoxyazetidine
3-methoxy-1- (4- ((trimethylsilyl) ethynyl) benzyl) azetidine 16c (400 mg,1.46 mmol) was added to methanol (10 mL), potassium fluoride (339.96 mg,5.85 mmol) was added, and the reaction was carried out at room temperature for 4 hours. After completion of the reaction, the residue obtained was purified by silica gel column chromatography (eluent: system A) to give 1- (4-ethynylbenzyl) -3-3-methoxyazetidine 16d (280 mg,95.10% yield).
MS m/z(ESI):202.0[M+1] +
Third step
1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)imidazolidin-2-one
1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-4- (4- ((4- ((3-methoxyazetidin-1-yl) methyl) phenyl) ethynyl) phenyl) imidazolin-2-one
To a solution of 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4-iodophenyl) -3-isopropylimidazolin-2-one 16e (55 mg, 86.68. Mu. Mol) and 1- (4-ethynylbenzyl) -3-3-methoxyazetidine 16d (34.9 mg, 173. Mu. Mol) in water (1 mL) was added bis (triphenylphosphine) palladium chloride (2.43 mg, 3.47. Mu. Mol), tetrabutylammonium bromide (27.94 mg, 86.68. Mu. Mol) and piperidine (22.14 mg, 260.04. Mu. Mol) in this order, and the mixture was stirred at 70℃for 5 hours. The reaction solution was extracted with ethyl acetate (30 mL x 2), the aqueous layer was separated, the combined organic phases were washed successively with saturated sodium chloride solution (30 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system B) to give 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-4- (4- ((4- ((3-methoxyazetidin-1-yl) methyl) phenyl) ethynyl) phenyl) imidazolin-2-one 16f (29 mg,47.26% yield).
MS m/z(ESI):708.4[M+1] +
Fourth step
5-hydroxy-6-((3-isopropyl-4-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-hydroxy-6- ((3-isopropyl-4- (4- ((4- ((3-methoxyazetidin-1-yl) methyl) phenyl) ethynyl) phenyl) -2-oxoimidazolin-1-yl) methyl) pyrimidinyl 4 (3H) -one
Boron trichloride (0.8 mL) was added dropwise to a solution of 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-4- (4- ((4- ((3-methoxyazetidinyl-1-yl) methyl) phenyl) ethynyl) phenyl) imidazolin-2-one 16f (29 mg, 40.97. Mu. Mol) in dichloromethane (2 mL) at room temperature for 2 hours, quenched with methanol, and purified by preparative liquid chromatography to give 5-hydroxy-6- ((3-isopropyl-4- (4- ((4- ((3-methoxyazetidin-1-yl) methyl) phenyl) ethynyl) phenyl) -2-oxoimidazolin-1-yl) methyl) pyrimidin-4 (3H) -one 16 (2 mg,7.55% yield,99.26% purity).
MS m/z(ESI):528.3[M+1] +
Example 17
5-hydroxy-6-((3-isopropyl-4-(4-((4-(morpholine-4-carbonyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-hydroxy-6- ((3-isopropyl-4- (4- ((4- (morpholin-4-carbonyl) phenyl) ethynyl) phenyl) -2-oxoimidazol-1-yl) methyl) pyrimidinyl 4 (3H) -one
First step
(4-ethynylphenyl)(morpholino)methanone
(4-Acetylylphenyl) (morpholinyl) methanone
4-Acetylylbenzoic acid 17a (1 g,6.84 mmol) and morpholine 17b (3.58 g,41.06 mmol) were added to 5mL of dichloromethane, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.10 g,10.95 mmol) was added and reacted overnight at room temperature. After completion of the reaction, the reaction mixture was extracted with methylene chloride (30 mL. Times.2), the aqueous layer was separated, the combined organic phases were washed successively with a saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system A) to give (4-ethynylphenyl) (morpholinyl) methanone 17c (600 mg,40.74% yield).
MS m/z(ESI):216.2[M+1] +
Second step
1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((4-(morpholine-4-carbonyl)phenyl)ethynyl)phenyl)imidazolidin-2-one
1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-4- (4- ((4- (morpholine-4-carbonyl) phenyl) ethynyl) phenyl) imidazolin-2-one
To a 1.5mL aqueous solution of 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4-iodophenyl) -3-isopropylimidazolin-2-one 17d and (4-ethynylphenyl) (morpholinyl) methanone 17c (67.85 mg, 315.21. Mu. Mol) were added bis (triphenylphosphine) palladium chloride (4.42 mg, 6.30. Mu. Mol), tetrabutylammonium bromide (50.81 mg, 157.60. Mu. Mol) and piperidine (40.26 mg, 472.81. Mu. Mol) at room temperature, and the reaction was warmed to 70℃and stirred for 5 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (30 mL x 2), the aqueous layer was separated, the combined organic phases were washed successively with saturated sodium chloride solution (30 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system B) to give 1- ((5, 6-di (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-4- (4- ((4- (morpholine-4-carbonyl) phenyl) ethynyl) phenyl) imidazolin-2-one 17e (100 mg,87.90% yield).
MS m/z(ESI):722.0[M+1] +
Third step
5-hydroxy-6-((3-isopropyl-4-(4-((4-(morpholine-4-carbonyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-hydroxy-6- ((3-isopropyl-4- (4- ((4- (morpholine-4-carbonyl) phenyl) ethynyl) phenyl) -2-oxoimidazolin-1-yl) methyl) pyrimidinyl 4 (3H) -one
1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-4- (4- ((4- (morpholine-4-carbonyl) phenyl) ethynyl) phenyl) imidazolin-2-one 17e (99.86 mg,138.35 μmol) was added to dichloromethane (5 mL), boron trichloride (2 mL) was added and reacted at room temperature for 1 hour. The reaction was complete, concentrated under reduced pressure, and the prepared liquid phase was separated and purified to give 5-hydroxy-6- ((3-isopropyl-4- (4- ((4- (morpholine-4-carbonyl) phenyl) ethynyl) phenyl) -2-oxoimidazolin-1-yl) methyl) pyrimidinyl 4 (3H) -one 17 (23 mg,24.57% yield,96.88% purity).
MS m/z(ESI):542.3[M+1] +
Example 20
5-hydroxy-6-((4-methyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxopyrrolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-hydroxy-6- ((4-methyl-4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -2-oxopyrrolidin-1-yl) methyl) pyrimidin-4 (3H) -one
First step
methyl(E)-3-(4-iodophenyl)but-2-enoate
(E) -3- (4-iodophenyl) but-2-enoic acid methyl ester
To a solution of sodium hydride (1.32 g,30.48mmol,60% purity) in tetrahydrofuran (60 mL) was slowly added dropwise methyl 2- (ethoxyphosphoryl) acetate 20b (6.11 g,33.53 mmol) at 0℃and warmed to room temperature, a solution of 1- (4-iodophenyl) ethanone 20a (5 g,20.32 mmol) in tetrahydrofuran (20 mL) was added dropwise and the reaction was completed at room temperature for 16 hours by LC-MS detection. The reaction mixture was quenched with 60mL of water, extracted with ethyl acetate (30 mL. Times.3), the combined organic phases were successively washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system A) to give methyl (E) -3- (4-iodophenyl) but-2-enoate 20c (2.8 g,9.27mmol,45.61% yield).
MS m/z(ESI):303.0[M+1] +
Second step
methyl 3-(4-iodophenyl)-3-methyl-4-nitrobutanoate
3- (4-iodophenyl) -3-methyl-4-nitrobutanoic acid methyl ester
To methyl (E) -3- (4-iodophenyl) but-2-enoate 20c (1.7 g,5.63 mmol) in nitromethane (20 mL) was added tetrabutylammonium fluoride (1M, 5.63 mL) dropwise and the reaction was allowed to proceed overnight at 100℃and was detected by LC-MS. The reaction solution was concentrated under reduced pressure, 12mL of ethyl acetate was added, and the system was acidified with 1M hydrochloric acid solution. Extraction with ethyl acetate (30 mL. Times.3), washing the combined organic phases with saturated brine, drying over anhydrous sodium sulfate, and filtration, the resulting residue was further separated and purified by silica gel column chromatography (eluent: system A) to give methyl 3- (4-iodophenyl) -3-methyl-4-nitrobutanoate 20d (800 mg,2.20mmol,39.15% yield).
MS m/z(ESI):361.8[M-1] +
Third step
4-(4-iodophenyl)-4-methylpyrrolidin-2-one
4- (4-iodophenyl) -4-methylpyrrolidin-2-one
Methyl 3- (4-iodophenyl) -3-methyl-4-nitrobutanoate 20d (100 mg, 275.37. Mu. Mol) was added to 1mL of methanol, nickel (II) chloride hexahydrate (17.84 mg, 137.69. Mu. Mol) was added, and after 5 minutes of reaction, sodium borohydride (20.83 mg, 550.74. Mu. Mol) was added at 0℃and the reaction was continued overnight at room temperature. Saturated ammonium chloride solution was added at 0deg.C, followed by extraction with dichloromethane (30 mL x 2), the aqueous layer was separated, the combined organic phases were successively washed with saturated sodium chloride solution (30 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system A) to give 4- (4-iodophenyl) -4-methylpyrrolidin-2-one 20e (40 mg, 132.84. Mu. Mol,48.24% yield).
MS m/z(ESI):301.8[M+1] +
Fourth step
1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-iodophenyl)-4-methylpyrrolidin-2-one
1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4-iodophenyl) -4-methylpyrrolidin-2-one
4- (4-iodophenyl) -4-methylpyrrolidin-2-one 20e (137 mg, 454.96. Mu. Mol) was added to 5mL of acetonitrile, 4, 5-dibenzyloxy-6- (iodomethyl) pyrimidine 20f (196.66 mg, 454.96. Mu. Mol) and cesium carbonate (370.59 mg,1.14 mmol) were sequentially added, and the reaction solution was heated to 90℃to react for 4 hours. The reaction solution was extracted with ethyl acetate (30 mL. Times.2), the aqueous layer was separated, the combined organic phases were successively washed with supersaturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system A and system B) to give 20g (130 mg, 214.71. Mu. Mol,47.19% yieldof 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4-iodophenyl) -4-methylpyrrolidin-2-one.
MS m/z(ESI):606.1[M+1] +
Fifth step
1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-methyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)pyrrolidin-2-one
1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4-methyl-4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) pyrrolidin-2-one
To a solution of 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4-iodophenyl) -4-methylpyrrolidin-2-one 20g (80 mg, 132.13. Mu. Mol) and 4- (4-ethynylbenzyl) morpholine 20h (26.6 mg,132. Mu. Mol) in 1mL of water at room temperature was added successively bis triphenylphosphine palladium dichloride (3.71 mg, 5.29. Mu. Mol) tetrabutylammonium bromide (42.59 mg, 132.13. Mu. Mol), piperidine (33.75 mg, 396.39. Mu. Mol). The reaction was warmed to 70 ℃ and stirred for 5 hours. The reaction solution was extracted with ethyl acetate (30 mL. Times.2), the aqueous layer was separated, the combined organic phases were washed successively with saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system B) to give 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4-methyl-4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) pyrrolidin-2-one 20j (50 mg, 73.66. Mu. Mol,55.75% yield).
MS m/z(ESI):679.0[M+1] +
Sixth step
5-hydroxy-6-((4-methyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxopyrrolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-hydroxy-6- ((4-methyl-4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -2-oxopyrrolidin-1-yl) methyl) pyrimidin-4 (3H) -one
Boron trichloride (0.8 mL) was added dropwise to a solution of 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4-methyl-4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) pyrrolidin-2-one 20j (50 mg, 73.66. Mu. Mol) in 2mL of dichloromethane at room temperature, reacted for 2 hours, quenched with methanol, concentrated under reduced pressure, and the residue was purified by preparative liquid phase separation to give 5-hydroxy-6- ((4-methyl-4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -2-oxopyrrolidin-1-yl) methyl) pyrimidin-4 (3H) -one 20 (10 mg, 15.12. Mu. Mol,20.52% yield, 92.6%)
MS m/z(ESI):499.2[M+1] +
Example 21
6-((4-(4-((4-(((1,1-dioxidotetrahydrothiophen-3-yl)amino)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolidin-1-yl)methyl)-5-hydroxypyrimidin-4(3H)-one
6- ((4- (4- ((4- (((1, 1-tetrahydroxythiophen-3-yl) amino) methyl) phenyl) ethynyl) phenyl) -3-isopropyl-2-oxoimidazolin-1-yl) methyl) -5-hydroxypyrimidin-4 (3H) -one
First step
tert-butyl
3-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-5-(4-iodophenyl)-2-oxoimidazolidine-1-carboxylate
3- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -5- (4-iodophenyl) -2-oxoimidazoline-1-carboxylic acid tert-butyl ester
5- (4-iodophenyl) -2-oxoimidazoline-1-carboxylic acid tert-butyl ester 21a (4.2 g,10.82 mmol), 4, 5-dibenzyloxy-6- (iodomethyl) pyrimidine 21b (4.68 g,10.82 mmol), potassium carbonate (4.49 g,32.46 mmol) were added to 70mL of acetonitrile, and the reaction solution was heated to 98℃and refluxed overnight, and the reaction was monitored to completion. Water (20 mL) was added to the reaction solution, ethyl acetate was extracted (30 mL. Times.3), the combined organic phases were washed successively with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system A) to give tert-butyl 3- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -5- (4-iodophenyl) -2-oxoimidazoline-1-carboxylate 21c (3 g,4.33mmol,40.04% yield).
MS m/z(ESI):592.8[M-100+H]
Second step
1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-iodophenyl)imidazolidin-2-one
1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4-iodophenyl) imidazolin-2-one
A solution of 3- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -5- (4-iodophenyl) -2-oxoimidazoline-1-carboxylic acid tert-butyl ester 21c (1.5 g,2.17 mmol) in 1, 4-dioxane (20 mL) was added dropwise to a solution of 1, 4-dioxane in hydrochloric acid (4M, 10.83 mL) under ice, the ice was removed, the reaction was monitored for completion at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, 30mL of saturated sodium bicarbonate solution was added to the residue, ethyl acetate was used for extraction (30 mL. Times.3), the combined organic phases were washed successively with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4-iodophenyl) imidazolin-2-one 21d (1 g,1.69mmol,77.93% yield).
MS m/z(ESI):592.8[M+1] +
Third step
1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-iodophenyl)-3-isopropylimidazolidin-2-one
1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4-iodophenyl) -3-isopropylimidazolin-2-one
To a solution of 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4-iodophenyl) imidazolin-2-one 21d (1 g,1.69 mmol) in N, N-dimethylformamide (30 mL) under argon was added sodium hydride (146.35 mg,3.38mmol,60% purity) under an ice bath, and after stirring for 20 minutes under an ice bath, 2-iodopropane (573.88 mg,3.38mmol, 336.98. Mu.L) was added and stirring was carried out at room temperature for 2 hours, and the reaction was monitored to completion. To the reaction solution was added 20mL of ice water, extracted with ethyl acetate (20 mL. Times.3), the combined organic phases were washed successively with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system A) to give 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4-iodophenyl) -3-isopropylimidazolin-2-one 21e (450 mg, 709.21. Mu. Mol,42.02% yieldd).
MS m/z(ESI):634.8[M+1]
Fourth step
3-((4-((trimethylsilyl)ethynyl)benzyl)amino)tetrahydrothiophene 1,1-dioxide
3- ((4- ((trimethylsilyl) ethynyl) phenyl) amino) tetrahydrothiophene 1, 1-dioxide
After 4- (2-trimethylsilylethynyl) benzaldehyde 21f (400 mg,1.98 mmol) was dissolved in 1, 2-dichloroethane (20L), 21g (678.70 mg,3.95 mmol) of 1, 1-dioxotetrahydrothiophene-3-amine hydrochloride and acetic acid (1.25 mL) were added, and after 30 minutes at room temperature, sodium triacetoxyborohydride (1.26 g,5.93 mmol) was added and reacted at 0℃for 2 hours at room temperature. The reaction was added 50mL of saturated sodium bicarbonate solution, extracted with dichloromethane (100 mL), the combined organic phases dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was further isolated and purified by silica gel column chromatography (eluent: system B) to give 3- ((4- ((trimethylsilyl) ethynyl) phenyl) amino) tetrahydrothiophene 1, 1-dioxide 21h (290 mg, 902.00. Mu. Mol,45.62% yield).
MS m/z(ESI):321.9[M+1] +
Fifth step
3-((4-ethynylbenzyl)amino)tetrahydrothiophene 1,1-dioxide
3- ((4-ethynylbenzyl) amino) tetrahydrothiophene 1, 1-dioxide
To a solution of 3- ((4- ((trimethylsilyl) ethynyl) phenyl) amino) tetrahydrothiophene 1, 1-dioxide 21h (280 mg, 870.89. Mu. Mol) in 30mL methanol was added potassium fluoride (202.40 mg,3.48 mmol) and reacted at room temperature for 4 hours. The reaction solution was extracted with ethyl acetate (30 mL. Times.2), the aqueous layer was separated, the combined organic phases were washed successively with saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system B) to give 3- ((4-ethynylbenzyl) amino) tetrahydrothiophene 1, 1-dioxide 21j (180 mg, 721.94. Mu. Mol,82.90% yieldd).
MS m/z(ESI):250.0[M+1] +
Sixth step
1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-(((1,1-dioxidotetrahydrothiophen-3-yl)amino)methyl)phenyl)ethynyl)phenyl)-3-isopropylimidazolidin-2-one
1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4- ((4- (((1, 1-dioxotetrahydrothiophen-3-yl) amino) methyl) phenyl) ethynyl) phenyl) -3-isopropylimidazolin-2-one
To a solution of 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4-iodophenyl) -3-isopropylimidazolin-2-one 21e (45 mg, 70.92. Mu. Mol) and 3- ((4-ethynylbenzyl) amino) tetrahydrothiophene 1, 1-dioxide 21j (21.22 mg, 85.11. Mu. Mol) in water (1 mL) at room temperature was added bis triphenylphosphine palladium dichloride (1.99 mg, 2.84. Mu. Mol), tetrabutylammonium bromide (22.86 mg, 70.92. Mu. Mol) and piperidine (18.12 mg, 212.76. Mu. Mol) in this order, and the reaction was warmed to 70℃and stirred for 5 hours. The reaction solution was extracted with ethyl acetate (30 mL. Times.2), the aqueous layer was separated, the combined organic phases were washed successively with saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system B) to give 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4- ((4- (((1, 1-dioxotetrahydrothiophen-3-yl) amino) methyl) phenyl) ethynyl) phenyl) -3-isopropylimidazolin-2-one 21k (50 mg, 66.14. Mu. Mol,93.26% yield).
MS m/z(ESI):755.9[M+1] +
Seventh step
6-((4-(4-((4-(((1,1-dioxidotetrahydrothiophen-3-yl)amino)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolidin-1-yl)methyl)-5-hydroxypyrimidin-4(3H)-one
6- ((4- (4- ((4- (((1, 1-tetrahydroxythiophen-3-yl) amino) methyl) phenyl) ethynyl) phenyl) -3-isopropyl-2-oxoimidazolin-1-yl) methyl) -5-hydroxypyrimidin-4 (3H) -one
Boron trichloride (0.8 mL) was added dropwise to a solution of 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4- ((4- (((1, 1-dioxotetrahydrothiophen-3-yl) amino) methyl) phenyl) ethynyl) phenyl) -3-isopropylimidazolin-2-one 21k (60 mg, 79.37. Mu. Mol) in dichloromethane (2 mL) under ice bath, reacted for 2 hours at room temperature, quenched with methanol, concentrated under reduced pressure, and the residue was purified by preparative liquid phase separation to give 6- ((4- (((1, 1-tetrahydrothiophen-3-yl) amino) methyl) phenyl) ethynyl) -3-isopropyl-2-oxoimidazolin-1-yl) methyl) -5-hydroxypyrimidinyl-4 (3H) -one 21 (2 mg, 2.81. Mu. Mol,3.54% yieldd).
MS m/z(ESI):575.9[M+1] +
Example 22
6-((4-(4-((4-((1,1-dioxidothiomorpholino)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolidin-1-yl)methyl)-5-hydroxypyrimidin-4(3H)-one
6- ((4- (4- ((4- ((1, 1-thiomorpholino) methyl) phenyl) ethynyl) phenyl) -3-isopropyl-2-oxoimidazol-1-yl) methyl) -5-hydroxypyrimidin-4 (3H) -one
First step
4-(4-((trimethylsilyl)ethynyl)benzyl)thiomorpholine 1,1-dioxide
4- (4- ((trimethylsilyl) ethynyl) benzyl) thiomorpholine 1, 1-dioxide
4- (2-Trisilylethynyl) benzaldehyde 22a (400 mg,1.98 mmol) was dissolved in 1, 2-dichloroethane (15 mL), thiomorpholine 1, 1-dioxide 22b (534.53 mg,3.95 mmol) and acetic acid (1.25 mL) were added in this order, and after 30 minutes at room temperature, sodium triacetoxyborohydride (1.26 g,5.93 mmol) was added and the reaction was carried out at 0℃for two hours at room temperature. The reaction mixture was taken up in 50mL of saturated sodium bicarbonate solution, extracted with dichloromethane (100 mL), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the resulting residue was further separated and purified by column chromatography on silica gel (eluent: system A) to give 4- (4- ((trimethylsilyl) ethynyl) benzyl) thiomorpholine 1, 1-dioxide 22c (157 mg, 488.32. Mu. Mol,24.70% yield)
MS m/z(ESI):321.9[M+1] +
Second step
4-(4-ethynylbenzyl)thiomorpholine 1,1-dioxide
4- (4-ethynylbenzyl) thiomorpholine 1, 1-dioxide
4- (4- ((trimethylsilyl) ethynyl) benzyl) thiomorpholine 1, 1-dioxide 22c (157 mg, 488.32. Mu. Mol) was added to methanol (5 mL), potassium fluoride (113.49 mg,1.95 mmol) was added and reacted at room temperature for 4 hours. After completion of the reaction, the resulting residue was purified by silica gel column chromatography (eluent: system A) to give 4- (4-ethynylbenzyl) thiomorpholine 1, 1-dioxide 22d (90 mg, 360.97. Mu. Mol,73.92% yield).
MS m/z(ESI):249.9[M+1] +
Third step
1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-((1,1-dioxidothiomorpholino)methyl)phenyl)ethynyl)phenyl)-3-isopropylimidazolidin-2-one
1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4- ((4- ((1, 1-thiomorpholino) methyl) phenyl) ethynyl) phenyl) -3-isopropylimidazolin-2-one
To a solution of 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4-iodophenyl) -3-isopropylimidazolin-2-one 21e (45 mg, 70.92. Mu. Mol) and 4- (4-ethynylbenzyl) thiomorpholine 1, 1-dioxide 22d (21.22 mg, 85.11. Mu. Mol) in water (1 mL) at room temperature was added bis triphenylphosphine palladium dichloride (1.99 mg, 2.84. Mu. Mol), tetrabutylammonium bromide (22.86 mg, 70.92. Mu. Mol) and piperidine (18.12 mg, 212.76. Mu. Mol) in this order, and the mixture was stirred at 70℃for 5 hours. The reaction solution was extracted with ethyl acetate (30 mL. Times.2), the aqueous layer was separated, the combined organic phases were washed successively with saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system B) to give 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4- ((4- ((1, 1-thiomorpholinomethyl) phenyl) ethynyl) phenyl) -3-isopropylimidazolin-2-one 22e (26 mg, 34.40. Mu. Mol,48.50% yieldd).
MS m/z(ESI):755.9[M+1] +
Fourth step
6-((4-(4-((4-((1,1-dioxidothiomorpholino)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolidin-1-yl)methyl)-5-hydroxypyrimidin-4(3H)-one
6- ((4- (4- ((4- ((1, 1-thiomorpholino) methyl) phenyl) ethynyl) phenyl) -3-isopropyl-2-oxoimidazol-1-yl) methyl) -5-hydroxypyrimidin-4 (3H) -one
To a solution of 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4- ((4- ((1, 1-thiomorpholino) methyl) phenyl) ethynyl) phenyl) -3-isopropylimidazolin-2-one 22e (26 mg, 34.40. Mu. Mol) in dichloromethane (1 mL) was added dropwise boron trichloride (0.4 mL) under ice bath, reacted for 2 hours at room temperature, quenched with methanol, concentrated under reduced pressure, and the residue was purified by preparative liquid phase separation to give 6- ((4- (4- ((4- ((1, 1-thiomorpholino) methyl) phenyl) ethynyl) phenyl) -3-isopropyl-2-oxoimidazolin-1-yl) methyl) -5-hydroxypyrimidino-4 (3H) -one 22 (3 mg, 4.11. Mu. Mol,11.96% yield).
MS m/z(ESI):575.9[M+1] +
Example 23
5-hydroxy-6-((3-isopropyl-2-oxo-4-(4-((4-((tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methyl)phenyl)ethynyl)phenyl)imidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-hydroxy-6- ((3-isopropyl-2-oxo-4- (4- ((4- ((tetrahydro-1H-furan [3,4-c ] pyrrol-5 (3H) -yl) methyl) phenyl) ethynyl) phenyl) imidazolin-1-yl) methyl) pyrimidin-4 (3H) -one
First step
5-(4-((trimethylsilyl)ethynyl)benzyl)hexahydro-1H-furo[3,4-c]pyrrole
5- (4- ((trimethylsilyl) ethynyl l) benzyl) hexahydro-1H-furo [3,4-c ] pyrrole
4- (2-trimethylsilylethynyl) benzaldehyde 22a (400 mg,1.98 mmol) was dissolved in 1, 2-dichloroethane (20 mL), hexahydro-1H-furo [3,4-c ] pyrrole 23a (335.57 mg,2.97 mmol) and acetic acid (1.25 mL) were added sequentially, and after reacting at room temperature for 2 hours, sodium triacetoxyborohydride (1.26 g,5.93 mmol) was added and reacted at room temperature for 2 hours. The reaction mixture was added with 50mL of saturated sodium bicarbonate solution, extracted with dichloromethane (100 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was further separated and purified by silica gel column chromatography (eluent: system B) to give 5- (4- ((trimethylsilyl) ethynyl) benzyl) hexahydro-1H-furo [3,4-c ] pyrrole 23B (460 mg,1.54mmol,77.69% yield).
MS m/z(ESI):300.0[M+1] +
Second step
5-(4-ethynylbenzyl)hexahydro-1H-furo[3,4-c]pyrrole
5- (4-ethynylbenzyl) hexahydro-1H-furo [3,4-c ] pyrrole
To a solution of 5- (4- ((trimethylsilyl) ethynyl) benzyl) hexahydro-1H-furo [3,4-c ] pyrrole 23b (460 mg,1.54 mmol) in methanol (20 mL) was added potassium fluoride (356.96 mg,6.14 mmol) and reacted at room temperature for 4 hours. The reaction solution was extracted with ethyl acetate (30 mL. Times.2), the aqueous layer was separated, the combined organic phases were washed successively with a saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system A) to give 5- (4-ethynylbenzyl) hexahydro-1H-furo [3,4-c ] pyrrole 23c (311 mg,1.37mmol,89.08% yieldd).
MS m/z(ESI):228.0[M+1] +
Third step
1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((4-((tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methyl)phenyl)ethynyl)phenyl)imidazolidin-2-one
1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-4- (4- ((4- ((tetrahydro-1H-furo [3,4-c ] pyrrol-5 (3H) -yl) methyl) phenyl) ethynyl) phenyl) imidazolin-2-one
To a solution of 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4-iodophenyl) -3-isopropylimidazolin-2-one 21e (45.81 mg, 72.20. Mu. Mol) and 5- (4-ethynylbenzyl) hexahydro-1H-furo [3,4-c ] pyrrole 23c (19.7 mg, 87. Mu. Mol) in water (1 mL) at room temperature was added, successively, bis triphenylphosphine palladium dichloride (2.03 mg, 2.89. Mu. Mol), tetrabutylammonium bromide (23.27 mg, 72.20. Mu. Mol) and piperidine (18.44 mg, 216.59. Mu. Mol). The reaction was warmed to 70 ℃ and stirred for 5 hours. The reaction solution was extracted with ethyl acetate (30 mL. Times.2), the aqueous layer was separated, the combined organic phases were washed successively with saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system B) to give 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-4- (4- ((4- ((tetrahydro-1H-furo [3,4-c ] pyrrol-5 (3H) -yl) methyl) phenyl) ethynyl) phenyl) imidazolin-2-one 23d (45 mg, 61.32. Mu. Mol,84.93% yield).
MS m/z(ESI):734.0[M+1] +
Fourth step
5-hydroxy-6-((3-isopropyl-2-oxo-4-(4-((4-((tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methyl)phenyl)ethynyl)phenyl)imidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-hydroxy-6- ((3-isopropyl-2-oxo-4- (4- ((4- ((tetrahydro-1H-furan [3,4-c ] pyrrol-5 (3H) -yl) methyl) phenyl) ethynyl) phenyl) imidazolin-1-yl) methyl) pyrimidin-4 (3H) -one
1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-4- (4- ((4- ((tetrahydro-1H-furo [3,4-c ] pyrrol-5 (3H) -yl) methyl) phenyl) ethynyl) phenyl) imidazolin-2-one 23d (45 mg, 61.32. Mu. Mol) in dichloromethane (1 mL) was added dropwise boron trichloride (0.4 mL) under ice bath, reacted at room temperature for 2 hours, quenched with methanol, concentrated under reduced pressure, and the residue was purified by preparative liquid phase separation to give 5-hydroxy-6- ((3-isopropyl-2-oxo-4- (4- ((4- ((tetrahydro-1H-furo [3,4-c ] pyrrol-5 (3H) -yl) methyl) phenyl) ethynyl) phenyl) imidazolin-1-yl) methyl) pyrimidin-4 (3H) -one 23 (5 mg, 7.38. Mu. Mol,12.04% yield.
MS m/z(ESI):554.0[M+1] +
Example 24
5-hydroxy-6-((4-(4-((4-((4-hydroxypiperidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-hydroxy-6- ((4- (4- ((4- ((4-hydroxypiperidin-1-yl) methyl) phenyl) ethynyl) phenyl) -3-isopropyl-2-oxoimidazolin-1-yl) methyl) pyrimidin-4 (3H) -one
First step
4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)benzaldehyde
4- ((4- (1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-2-oxoimidazolin-4-yl) phenyl) ethynyl) benzaldehyde
To a solution of 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4-iodophenyl) imidazolin-2-one 21d (300 mg, 472.81. Mu. Mol) and 4-ethynylbenzaldehyde 24a (73.8 mg, 567. Mu. Mol) in water (1 mL) at room temperature were added 13.27mg of ditriphenylphosphine palladium dichloride, 18.91. Mu. Mol), tetrabutylammonium bromide (152.42 mg, 472.81. Mu. Mol) and piperidine (120.78 mg,1.42 mmol) in this order, and the reaction was warmed to 70℃and stirred for 5 hours. The reaction solution was extracted with ethyl acetate (30 mL. Times.2), the aqueous layer was separated, the combined organic phases were washed successively with saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system B) to give 4- ((4- (1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-2-oxoimidazolin-4-yl) phenyl) ethynyl) benzaldehyde 24B (230 mg, 361.22. Mu. Mol,76.40% yield).
MS m/z(ESI):637.3[M+1] +
Second step
1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-((4-hydroxypiperidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-isopropylimidazolidin-2-one
1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4- ((4- ((4-hydroxypiperidin-1-yl) methyl) phenyl) ethynyl) phenyl) -3-isopropylimidazolin-2-one
4- ((4- (1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-2-oxoimidazol-4-yl) phenyl) ethynyl) benzaldehyde 24b (50 mg, 78.53. Mu. Mol), piperidin-4-ol (15.89 mg, 157.05. Mu. Mol) was dissolved in 5mL of 1, 2-dichloroethane, acetic acid (0.2 mL) was added, stirring was performed for 30 min, sodium borohydride acetate (49.93 mg, 235.58. Mu. Mol) was added, and stirring was continued at room temperature for 12 h. 15mL of saturated aqueous sodium bicarbonate solution was added to quench, dichloromethane (30 mL) and water (15 mL) were added, the solution was separated, the aqueous phase was extracted with dichloromethane (30 mL. Times.2), the combined organic phases were washed with saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system B) to give 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4- ((4- ((4-hydroxypiperidin-1-yl) methyl) phenyl) ethynyl) phenyl) -3-isopropylimidazolin-2-one 24c (20 mg, 27.71. Mu. Mol,35.28% yield).
MS m/z(ESI):722.0[M+1] +
Third step
5-hydroxy-6-((4-(4-((4-((4-hydroxypiperidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-hydroxy-6- ((4- (4- ((4- ((4-hydroxypiperidin-1-yl) methyl) phenyl) ethynyl) phenyl) -3-isopropyl-2-oxoimidazolin-1-yl) methyl) pyrimidin-4 (3H) -one
To a solution of 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4- ((4- ((4-hydroxypiperidin-1-yl) methyl) phenyl) ethynyl) phenyl) -3-isopropylimidazolin-2-one 24c (20 mg, 27.71. Mu. Mol) in dichloromethane (2 mL) in an ice bath was added dropwise boron trichloride (0.8 mL), reacted at room temperature for 2 hours, quenched with methanol, concentrated under reduced pressure, and the residue was purified by preparative liquid phase separation to give 5-hydroxy-6- ((4- (4- ((4- ((4-hydroxypiperidin-1-yl) methyl) phenyl) ethynyl) phenyl) -3-isopropyl-2-oxoimidazolin-1-yl) methyl) pyrimidin-4 (3H) -one 24 (1 mg, 1.41. Mu. Mol,5.08% yield).
MS m/z(ESI):542.0[M+1] +
Example 25
5-hydroxy-6-((3-isopropyl-4-(4-((6-(morpholinomethyl)pyridin-3-yl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-hydroxy-6- ((3-isopropyl-4- (4- ((6- (morpholinomethyl) pyridin-3-yl) ethynyl) phenyl) -2-oxoimidazol-1-yl) methyl) pyrimidin-4 (3H) -one
First step
4-((5-ethynylpyridin-2-yl)methyl)morpholine
4- ((5-ethynylpyridin-2-yl) methyl) morpholine
5-Acetylylpyridine-2-carbaldehyde 25a (200 mg,1.53 mmol) was dissolved in 1, 2-dichloroethane (3 mL), and morpholine 25b (398.62 mg,4.58 mmol), acetic acid (0.2 mL) and sodium borohydride acetate (969.75 mg,4.58 mmol) were added in this order and reacted at room temperature for 4 hours. The reaction was quenched with water at 0deg.C, extracted with dichloromethane (30 ml×2), the aqueous layer was separated, the combined organic phases were washed sequentially with saturated sodium chloride solution (30 ml×2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system A) to give 4- ((5-ethynylpyridin-2-yl) methyl) morpholine 25c (170 mg, 840.54. Mu. Mol,55.11% yieldd).
MS m/z(ESI):203.1[M+1] +
Second step
1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((6-(morpholinomethyl)pyridin-3-yl)ethynyl)phenyl)imidazolidin-2-one
1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-4- (4- ((6- (morpholinomethyl) pyridin-3-yl) ethynyl) phenyl) imidazolin-2-one
1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4-iodophenyl) -3-isopropylimidazolin-2-one 21e (50 mg, 78.80. Mu. Mol) and 4- ((5-ethynylpyridin-2-yl) methyl) morpholine 25c (19.13 mg, 94.56. Mu. Mol) were added to a solution of bis triphenylphosphine palladium dichloride (2.21 mg, 3.15. Mu. Mol), tetrabutylammonium bromide (25.40 mg, 78.80. Mu. Mol) and piperidine (20.13 mg, 236.40. Mu. Mol) in this order at room temperature, and the reaction was warmed to 70℃and stirred for 5 hours. The reaction solution was extracted with ethyl acetate (30 mL. Times.2), the aqueous layer was separated, the combined organic phases were washed successively with saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system B) to give 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-4- (4- ((6- (morpholinomethyl) pyridin-3-yl) ethynyl) phenyl) imidazolin-2-one 25d (55 mg, 77.59. Mu. Mol,98.46% yield).
MS m/z(ESI):709.3[M+1] +
Third step
5-hydroxy-6-((3-isopropyl-4-(4-((6-(morpholinomethyl)pyridin-3-yl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-hydroxy-6- ((3-isopropyl-4- (4- ((6- (morpholinomethyl) pyridin-3-yl) ethynyl) phenyl) -2-oxoimidazol-1-yl) methyl) pyrimidin-4 (3H) -one
To a solution of 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-4- (4- ((6- (morpholinomethyl) pyridin-3-yl) ethynyl) phenyl) imidazolin-2-one 25d (50 mg, 70.54. Mu. Mol) in dichloromethane (2 mL) was added dropwise boron trichloride (0.8 mL) under ice bath, reacted at room temperature for 2 hours, quenched with methanol, concentrated under reduced pressure, and the residue was purified by preparative liquid phase separation to give 5-hydroxy-6- ((3-isopropyl-4- (4- ((6- (morpholinomethyl) pyridin-3-yl) ethynyl) phenyl) -2-oxoimidazolin-1-yl) methyl) pyrimidinyl-4 (3H) -one 25 (10 mg, 14.83. Mu. Mol,21.03% yield).
MS m/z(ESI):529.0[M+1] +
Example 26
6-((3-cyclopropyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)-5-hydroxypyrimidin-4(3H)-one
6- ((3-cyclopropyl-4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -2-oxoimidazolin-1-yl) methyl) -5-hydroxypyrimidin-4 (3H) -one
First step
tert-butyl
3-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidine-1-carboxylate
3- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -5- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -2-oxoimidazoline-1-carboxylic acid tert-butyl ester
3- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -5- (4-iodophenyl) -2-oxoimidazoline-1-carboxylic acid tert-butyl ester 21c (4 g,5.78 mmol), 4- (4-ethynylbenzyl) morpholine 26a (1.39 g,6.93 mmol), bis triphenylphosphine palladium dichloride (203 mg, 289. Mu. Mol), tetrabutylammonium bromide (1.86 g,5.78 mmol) and piperidine (1.48 g,17.33 mmol) were added to 50mL of water under argon and reacted at 75℃for 5 hours. After completion of the reaction, water (20 mL), ethyl acetate extraction (40 mL. Times.3) and washing of the combined organic phases with saturated sodium chloride solution (20 mL), drying over anhydrous sodium sulfate, filtration and concentration under reduced pressure were added, and the resulting residue was purified by silica gel column chromatography (eluent: system A) to give tert-butyl 3- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -5- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -2-oxoimidazoline-1-carboxylate 26b (3 g,3.92mmol,67.8% yield).
MS m/z(ESI):766.5[M+1] +
Second step
1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)imidazolidin-2-one
1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) imidazolin-2-one
Concentrated hydrochloric acid (3.0 mL) was added to a 30mL solution of 3- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -5- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -2-oxoimidazoline-1-carboxylic acid tert-butyl ester 26b (3 g,3.92 mmol) in 30mL of 1, 4-dioxane at room temperature for 2 hours. After completion of the reaction, saturated sodium bicarbonate solution was added to basicity, the organic solvent was removed by concentration under reduced pressure, extraction with ethyl acetate (40 mL. Times.3), washing with saturated sodium chloride solution (20 mL) in this order, drying over anhydrous sodium sulfate, filtration, concentration under reduced pressure, and purification of the resulting residue by silica gel column chromatography (eluent: system B) gave 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) imidazolin-2-one 26c (2.34 g,3.51mmol,89.7% yield).
MS m/z(ESI):666.3[M+1] +
Third step
1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-cyclopropyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)imidazolidin-2-one
1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-cyclopropyl-4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) imidazolin-2-one
1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) imidazolin-2-one 26c (200 mg, 300. Mu. Mol) in tetrahydrofuran (1.5 mL) was added cyclopropylboronic acid (77.4 mg, 901. Mu. Mol), copper acetate (164 mg, 901. Mu. Mol) and heated to 80℃for reaction overnight. After completion of the reaction, ethyl acetate (50 mL) was added, the filtrate was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system A) to give 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-cyclopropyl-4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) imidazolin-2-one 26d (40 mg, 56.7. Mu. Mol,18.9% yieldd).
MS m/z(ESI):706.3[M+1] +
Fourth step
6-((3-cyclopropyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)-5-hydroxypyrimidin-4(3H)-one
6- ((3-cyclopropyl-4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -2-oxoimidazolin-1-yl) methyl) -5-hydroxypyrimidin-4 (3H) -one
To a solution of 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-cyclopropyl-4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) imidazolin-2-one 26d (60 mg, 85. Mu. Mol) in dichloromethane (1.2 mL) was added dropwise boron trichloride (2.5 mL) at room temperature for 5 hours under ice bath. After completion of the reaction, quenched with methanol, concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography to give 6- ((3-cyclopropyl-4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -2-oxoimidazol-1-yl) methyl) -5-hydroxypyrimidin-4 (3H) -one 26 (11.7 mg,18.3 μmol,21.5% yieldd).
MS m/z(ESI):526.2[M+1] +
Example 27
2-(3-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)acetonitrile
2- (3- ((5-hydroxy-6-oxo-1, 6-dihydropyrimidin-4-yl) methyl) -5- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -2-oxoimidazolin-1-yl) acetonitrile
First step
2-(3-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)acetonitrile
2- (3- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -5- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -2-oxoimidazolin-1-yl) acetonitrile
To a solution of 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) imidazolin-2-one 26h (620 mg, 931. Mu. Mol) in 10mL of N, N-dimethylformamide under an argon atmosphere was added sodium hydride (121 mg,2.79mmol,60% purity), and the mixture was allowed to react at room temperature for 20 minutes, and 2-chloroacetonitrile (211 mg,2.79 mmol) was added to continue the reaction for 3 hours. After completion of the reaction, the reaction was quenched by addition of water (20 mL). The combined organic phases were extracted with ethyl acetate (30 mL. Times.3), washed successively with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by column chromatography on silica gel (eluent: system A) to give 2- (3- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -5- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -2-oxoimidazolin-1-yl) acetonitrile 27a (270 mg, 383. Mu. Mol,41.1% yield)
MS m/z(ESI):705.3[M+1] +
Second step
2-(3-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)acetonitrile
2- (3- ((5-hydroxy-6-oxo-1, 6-dihydropyrimidin-4-yl) methyl) -5- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -2-oxoimidazolin-1-yl) acetonitrile
Boron trichloride (3 mL) was added to a solution of 2- (3- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -5- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -2-oxoimidazolin-1-yl) acetonitrile 27a (130 mg, 184. Mu. Mol) in 1.2mL dichloromethane at room temperature, and stirred for 5 hours. After completion of the reaction, the reaction was quenched with a small amount of ice water, concentrated, and the residue was purified by preparative liquid chromatography to give 2- (3- ((5-hydroxy-6-oxo-1, 6-dihydropyrimidin-4-yl) methyl) -5- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -2-oxoimidazolin-1-yl) acetonitrile 27 (31.5 mg, 49.0. Mu. Mol,26.6% yield).
MS m/z(ESI):525.3[M+1] +
Example 28
2-(3-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)acetamide
2- (3- ((5-hydroxy-6-oxo-1, 6-dihydropyrimidin-4-yl) methyl) -5- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -2-oxoimidazolin-1-yl) acetamide
Potassium hydroxide (3.21 mg, 57.2. Mu. Mol) was added to a solution of 2- (3- ((5-hydroxy-6-oxo-1, 6-dihydropyrimidin-4-yl) methyl) -5- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -2-oxoimidazolin-1-yl) acetonitrile 27 (15 mg, 28.6. Mu. Mol) in dimethyl sulfoxide (1 mL) under ice bath, hydrogen peroxide (30%, 0.5 mL) was added dropwise, and the mixture was allowed to react at room temperature for 1 hour. After completion of the reaction, the reaction mixture was neutralized with 1M hydrochloric acid and concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography to give 2- (3- ((5-hydroxy-6-oxo-1, 6-dihydropyrimidin-4-yl) methyl) -5- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -2-oxoimidazolin-1-yl) acetamide 28 (13.0 mg, 19.0. Mu. Mol,66.5% yield)
MS m/z(ESI):543.2[M+1] +
Example 29
6-((3-(2,2-difluoroethyl)-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)-5-hydroxypyrimidin-4(3H)-one
6- ((3- (2, 2-difluoroethyl) -4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -2-oxoimidazol-1-yl) methyl) -5-hydroxypyrimidin-4 (3H) -one
First step
1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-(2,2-difluoroethyl)-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)imidazolidin-2-one
1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3- (2, 2-difluoroethyl) -4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) imidazolin-2-one
Sodium hydride (7.81 mg, 180. Mu. Mol,60% purity) was added to a solution of 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) imidazolin-2-one (80 mg, 120. Mu. Mol) in N, N-dimethylformamide (2 mL) under an argon atmosphere, and after stirring for 10 minutes, trifluoromethanesulfonic acid (2, 2-difluoroethyl ester) (51.5 mg, 240. Mu. Mol) was added and the reaction was continued for 2 hours. After completion of the reaction, water (20 mL) was added, the organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system A) to give 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3- (2, 2-difluoroethyl) -4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) imidazolin-2-one 29a (80 mg, 110. Mu. Mol,91.2% yield)
MS m/z(ESI):730.3[M+1] +
Second step
6-((3-(2,2-difluoroethyl)-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)-5-hydroxypyrimidin-4(3H)-one
6- ((3- (2, 2-difluoroethyl) -4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -2-oxoimidazol-1-yl) methyl) -5-hydroxypyrimidin-4 (3H) -one
Boron trichloride (3 mL) was added to a 1.5mL dichloromethane solution of 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3- (2, 2-difluoroethyl) -4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) imidazolin-2-one 29a (100 mg,137 μmol) and reacted overnight at room temperature. After completion of the reaction, the reaction was quenched with methanol, concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography to give 6- ((3- (2, 2-difluoroethyl) -4- (4- ((4- (morpholinomethyl) phenyl) ethynyl) phenyl) -2-oxoimidazol-1-yl) methyl) -5-hydroxypyrimidin-4 (3H) -one 29 (34.8 mg,50.3 μmol,36.7% yieldd). MS m/z (ESI) 550.3[ M+1 ]] +
Example 30
5-hydroxy-6-((4-(4-((4-(((2-hydroxyethyl)amino)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-hydroxy-6- ((4- (4- ((4- (((2-hydroxyethyl) amino) methyl) phenyl) ethynyl) phenyl) -3-isopropyl-2-oxoimidazol-1-yl) methyl) pyrimidin-4 (3H) -one
First step
1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-(((2-hydroxyethyl)amino)methyl)phenyl)ethynyl)phenyl)-3-isopropylimidazolidin-2-one
1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4- ((4- (((2-hydroxyethyl) amino) methyl) phenyl) ethynyl) phenyl) -3-isopropylimidazolin-2-one
24g (62 mg, 97.37. Mu. Mol) of 4- ((4- (1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-2-oxoimidazolin-4-yl) phenyl) ethynyl) benzaldehyde and 30a (11.90 mg, 194.74. Mu. Mol) of 2-aminoethanol were dissolved in 3mL of 1, 2-dichloroethane, acetic acid (1 mL) was added, stirring was carried out at room temperature for 30 minutes, and sodium triacetylborohydride (41.27 mg, 194.74. Mu. Mol) was added, stirring was carried out at room temperature for 12 hours. After completion of the reaction, 15mL of saturated aqueous sodium bicarbonate solution was added, extracted with dichloromethane (30 mL. Times.2), the combined organic phases were washed sequentially with saturated aqueous sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by preparative liquid chromatography (eluent: system B) to give 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4- ((4- (((2-hydroxyethyl) amino) methyl) phenyl) ethynyl) phenyl) -3-isopropylimidazolin-2-one 30B (25 mg, 36.67. Mu. Mol,37.66% yieldd).
MS m/z(ESI):682.0[M+1] +
Second step
5-hydroxy-6-((4-(4-((4-(((2-hydroxyethyl)amino)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-hydroxy-6- ((4- (4- ((4- (((2-hydroxyethyl) amino) methyl) phenyl) ethynyl) phenyl) -3-isopropyl-2-oxoimidazol-1-yl) methyl) pyrimidin-4 (3H) -one
1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4- ((4- (((2-hydroxyethyl) amino) methyl) phenyl) ethynyl) phenyl) -3-isopropylimidazolin-2-one 30b (25 mg, 36.67. Mu. Mol) was added to 2mL of dichloromethane, boron trichloride (0.8 mL) was added and reacted at room temperature for 2 hours. After completion of the reaction, concentrated under reduced pressure, and the residue was purified by preparative liquid phase separation to give 5-hydroxy-6- ((4- (4- ((4- (((2-hydroxyethyl) amino) methyl) phenyl) ethynyl) phenyl) -3-isopropyl-2-oxoimidazol-1-yl) methyl) pyrimidin-4 (3H) -one 30 (7 mg,10.81 μmol,29.48% yieldd).
MS m/z(ESI):502.0[M+1] +
Example 31
2-((4-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)benzyl)amino)acetamide
2- ((4- ((4- (1- ((5-hydroxy-6-oxo-1, 6-dihydropyrimidin-4-yl) methyl) -3-isopropyl-2-oxoimidazolin-4-yl) phenyl) ethynyl) benzyl) amino) acetamide
First step
2-((4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)benzyl)amino)acetamide
2- ((4- ((4- (1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-2-oxoimidazolin-4-yl) phenyl) ethynyl) benzyl) amino) acetamide
24g (73 mg, 114.65. Mu. Mol) of 4- ((4- (1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-2-oxoimidazolin-4-yl) phenyl) ethynyl) benzaldehyde and 2-aminoacetamide 31a (16.99 mg, 229.29. Mu. Mol) were dissolved in 2mL of 1, 2-dichloroethane, acetic acid (0.5 mL) was added, stirring was continued at room temperature for 30 min, and sodium triacetylborohydride (48.60 mg, 229.29. Mu. Mol) was added, stirring was continued at room temperature for 12 h. After completion of the reaction, 15mL of saturated aqueous sodium bicarbonate solution was added, quenched, dichloromethane (30 mL) and water (15 mL) were added, the aqueous phase was separated, the aqueous phase was extracted with dichloromethane (30 mL. Times.2), the combined organic phases were washed with saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by preparative liquid chromatography (eluent: system B) to give 2- ((4- ((4- (1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-2-oxoimidazolin-4-yl) phenyl) ethynyl) benzyl) amino) acetamide 31B (50 mg, 71.96. Mu. Mol,62.77% yield).
MS m/z(ESI):695.4[M+1] +
Second step
2-((4-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)benzyl)amino)acetamide
2- ((4- ((4- (1- ((5-hydroxy-6-oxo-1, 6-dihydropyrimidin-4-yl) methyl) -3-isopropyl-2-oxoimidazolin-4-yl) phenyl) ethynyl) benzyl) amino) acetamide
2- ((4- ((4- (1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-2-oxoimidazolin-4-yl) phenyl) ethynyl) benzyl) amino) acetamide 31b (50 mg, 71.96. Mu. Mol) was added to 2mL of dichloromethane, boron trichloride (0.8 mL) was added and reacted at room temperature for 1 hour. After completion of the reaction, concentrated under reduced pressure and the residue purified by preparative liquid phase separation to give 2- ((4- ((4- (1- ((5-hydroxy-6-oxo-1, 6-dihydropyrimidin-4-yl) methyl) -3-isopropyl-2-oxoimidazolin-4-yl) phenyl) ethynyl) benzyl) amino) acetamide 31 (16 mg, 24.53. Mu. Mol,34.09% yield).
MS m/z(ESI):515.0[M+1] +
Example 32
5-hydroxy-6-((4-(4-((4-((3-hydroxypyrrolidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-hydroxy-6- ((4- (4- ((4- ((3-hydroxypyrrolidin-1-yl) methyl) phenyl) ethynyl) phenyl) -3-isopropyl-2-oxoimidazolin-1-yl) methyl) pyrimidin-4 (3H) -one
First step
1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-((3-hydroxypyrrolidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-isopropylimidazolidin-2-one
1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4- ((4- ((3-hydroxypyrrolidin-1-yl) methyl) phenyl) ethynyl) phenyl) -3-isopropylimidazolin-2-one
24g (50 mg, 78.53. Mu. Mol) of 4- ((4- (1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-2-oxoimidazolin-4-yl) phenyl) ethynyl) benzaldehyde and pyrrolidin-3-ol 32a (13.68 mg, 157.05. Mu. Mol) were dissolved in 1mL of 1, 2-dichloroethane, acetic acid (0.2 mL) was added, stirring was continued for 30 minutes, and sodium triacetylborohydride (33.29 mg, 157.05. Mu. Mol) was added and stirring was continued at room temperature for 12 hours. After completion of the reaction, 15mL of saturated aqueous sodium bicarbonate solution was added, quenched, dichloromethane (30 mL) and water (15 mL) were added, the solution was separated, the aqueous phase was extracted with dichloromethane (30 mL. Times.2), the combined organic phases were washed with saturated aqueous sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (eluent: system A) to give 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4- ((4- ((3-hydroxypyrrolidin-1-yl) methyl) phenyl) ethynyl) phenyl) -3-isopropylimidazolin-2-one 32b (40 mg, 56.51. Mu. Mol,71.96% yieldd).
MS m/z(ESI):708.5[M+1] +
Second step
5-hydroxy-6-((4-(4-((4-((3-hydroxypyrrolidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-hydroxy-6- ((4- (4- ((4- ((3-hydroxypyrrolidin-1-yl) methyl) phenyl) ethynyl) phenyl) -3-isopropyl-2-oxoimidazolin-1-yl) methyl) pyrimidin-4 (3H) -one
1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4- ((4- ((3-hydroxypyrrolidin-1-yl) methyl) phenyl) ethynyl) phenyl) -3-isopropylimidazolin-2-one 32b (40 mg, 56.51. Mu. Mol) was added to 2mL of dichloromethane, boron trichloride (0.8 mL) was added and reacted at room temperature for 1 hour. After completion of the reaction, concentrated under reduced pressure, and the residue was purified by preparative liquid phase separation to give 5-hydroxy-6- ((4- (4- ((4- ((3-hydroxypyrrolidin-1-yl) methyl) phenyl) ethynyl) phenyl) -3-isopropyl-2-oxoimidazol-1-yl) methyl) pyrimidin-4 (3H) -one 32 (9.78 mg,15.20 μmol,26.91% yieldd).
MS m/z(ESI):528.0[M+1] +
Example 33
5-hydroxy-6-((4-(4-((4-(((3-hydroxycyclobutyl)amino)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-hydroxy-6- ((4- (4- ((4- (((3-hydroxycyclobutyl) amino) methyl) phenyl) ethynyl) phenyl) -3-isopropyl-2-oxoimidazol-1-yl) methyl) pyrimidin-4 (3H) -one
First step
1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-(((3-hydroxycyclobutyl)amino)methyl)phenyl)ethynyl)phenyl)-3-isopropylimidazolidin-2-one
1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4- ((4- (((3-hydroxycyclobutyl) amino) methyl) phenyl) ethynyl) phenyl) -3-isopropylimidazolin-2-one
24g (50 mg, 78.53. Mu. Mol) of 4- ((4- (1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-2-oxoimidazolin-4-yl) phenyl) ethynyl) benzaldehyde and 33a (19.41 mg, 157.05. Mu. Mol) of 3-aminocyclobutane-1-ol hydrochloride were dissolved in 1mL of 1, 2-dichloroethane, acetic acid (0.2 mL) was added, stirring was carried out for 30 minutes, and sodium triacetylborohydride (33.29 mg, 157.05. Mu. Mol) was added, and stirring was continued at room temperature for 12 hours. After completion of the reaction, 15mL of saturated aqueous sodium bicarbonate solution was added, quenched, dichloromethane (30 mL) and water (15 mL) were added, the aqueous phase was separated, the aqueous phase was extracted with dichloromethane (30 mL. Times.2), the combined organic phases were washed with saturated aqueous sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by preparative liquid chromatography (eluent: system B) to give 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4- ((4- (((3-hydroxycyclobutyl) amino) methyl) phenyl) ethynyl) phenyl) -3-isopropylimidazolin-2-one 33B (20 mg, 28.25. Mu. Mol,35.98% yieldd).
MS m/z(ESI):708.0[M+1] +
Second step
5-hydroxy-6-((4-(4-((4-(((3-hydroxycyclobutyl)amino)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-hydroxy-6- ((4- (4- ((4- (((3-hydroxycyclobutyl) amino) methyl) phenyl) ethynyl) phenyl) -3-isopropyl-2-oxoimidazol-1-yl) methyl) pyrimidin-4 (3H) -one
1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4- ((4- (((3-hydroxycyclobutyl) amino) methyl) phenyl) ethynyl) phenyl) -3-isopropylimidazolin-2-one 33b (20 mg, 28.25. Mu. Mol) was added to 2mL of dichloromethane, boron trichloride (0.8 mL) was added and reacted at room temperature for 1 hour. After completion of the reaction, concentrated under reduced pressure, and the residue was purified by preparative liquid phase separation to give 5-hydroxy-6- ((4- (4- ((4- (((3-hydroxycyclobutyl) amino) methyl) phenyl) ethynyl) phenyl) -3-isopropyl-2-oxoimidazol-1-yl) methyl) pyrimidin-4 (3H) -one 33 (11 mg,17.08 μmol,60.45% yieldd).
MS m/z(ESI):528.0[M+1] +
Example 34
1-(4-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)benzyl)azetidine-3-carbonitrile
1- (4- ((4- (1- ((5-hydroxy-6-oxo-1, 6-dihydropyrimidin-4-yl) methyl) -3-isopropyl-2-oxoimidazolin-4-yl) phenyl) ethynyl) benzyl) azetidine-3-carbonitrile
First step
1-(4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)benzyl)azetidine-3-carbonitrile
1- (4- ((4- (1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-2-oxoimidazolin-4-yl) phenyl) ethynyl) benzyl) azetidine-3-carbonitrile
24g (43 mg, 67.53. Mu. Mol) of 4- ((4- (1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-2-oxoimidazolin-4-yl) phenyl) ethynyl) benzaldehyde and 34a (12.01 mg, 101.30. Mu. Mol) of azetidine-3-carbonitrile hydrochloride were dissolved in 1, 2-dichloroethane (999.73. Mu.L), acetic acid (4.06 mg, 67.53. Mu. Mol, 3.86. Mu.L) was added, stirred for 30 minutes, and sodium triacetylborohydride (28.63 mg, 135.06. Mu. Mol) was added and stirring was continued at room temperature for 12 hours. After completion of the reaction, 15mL of saturated aqueous sodium bicarbonate solution was added, quenched, dichloromethane (30 mL) and water (15 mL) were added, the solution was separated, the aqueous phase was extracted with dichloromethane (30 mL. Times.2), the combined organic phases were washed with saturated aqueous sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (eluent: system B) to give 1- (4- ((4- (1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-2-oxoimidazolin-4-yl) phenyl) ethynyl) benzyl) azetidine-3-carbonitrile 34B (26 mg, 36.99. Mu. Mol,54.78% yieldd).
MS m/z(ESI):703.3[M+1] +
Second step
1-(4-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)benzyl)azetidine-3-carbonitrile
1- (4- ((4- (1- ((5-hydroxy-6-oxo-1, 6-dihydropyrimidin-4-yl) methyl) -3-isopropyl-2-oxoimidazolin-4-yl) phenyl) ethynyl) benzyl) azetidine-3-carbonitrile
1- (4- ((4- (1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-2-oxoimidazolin-4-yl) phenyl) ethynyl) benzyl) azetidine-3-carbonitrile 34b (26 mg, 36.99. Mu. Mol) was added to 2.5mL of dichloromethane, boron trichloride (0.1 mL) was added and reacted at room temperature for 1 hour. After completion of the reaction, quenched with methanol, concentrated under reduced pressure, and the residue was purified by preparative liquid phase separation to give 1- (4- ((4- (1- ((5-hydroxy-6-oxo-1, 6-dihydropyrimidin-4-yl) methyl) -3-isopropyl-2-oxoimidazolin-4-yl) phenyl) ethynyl) benzyl) azetidine-3-carbonitrile 34 (6.8 mg,10.62 μmol,28.70% yieldd).
MS m/z(ESI):523.4[M+1] +
Example 35
1-(4-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)benzyl)pyrrolidine-3-carbonitrile
1- (4- ((4- (1- ((5-hydroxy-6-oxo-1, 6-dihydropyrimidin-4-yl) methyl) -3-isopropyl-2-oxoimidazolin-4-yl) phenyl) ethynyl) benzyl) pyrrolidine-3-carbonitrile
First step
1-(4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)benzyl)pyrrolidine-3-carbonitrile
1- (4- ((4- (1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-2-oxoimidazolin-4-yl) phenyl) ethynyl) benzyl) pyrrolidine-3-carbonitrile
24g (40 mg, 62.82. Mu. Mol) of 4- ((4- (1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-2-oxoimidazolin-4-yl) phenyl) ethynyl) benzaldehyde and 35a (9.06 mg, 68.32. Mu. Mol) of pyrrolidine-3-carbonitrile hydrochloride were dissolved in 1mL of 1, 2-dichloroethane, acetic acid (3.77 mg, 62.82. Mu. Mol, 3.59. Mu.L) was added and stirred for 30 minutes, sodium triacetylborohydride (26.63 mg, 125.64. Mu. Mol) was added and stirring was continued at room temperature for 12 hours. After completion of the reaction, 15mL of saturated aqueous sodium bicarbonate solution was added, quenched, dichloromethane (30 mL) and water (15 mL) were added, the solution was separated, the aqueous phase was extracted with dichloromethane (30 mL. Times.2), the combined organic phases were washed with saturated aqueous sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (eluent: system B) to give 1- (4- ((4- (1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-2-oxoimidazolin-4-yl) phenyl) ethynyl) benzyl) pyrrolidine-3-carbonitrile 35B (40 mg, 55.80. Mu. Mol,88.82% yieldd).
MS m/z(ESI):717.4[M+1] +
Second step
1-(4-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)benzyl)pyrrolidine-3-carbonitrile
1- (4- ((4- (1- ((5-hydroxy-6-oxo-1, 6-dihydropyrimidin-4-yl) methyl) -3-isopropyl-2-oxoimidazolin-4-yl) phenyl) ethynyl) benzyl) pyrrolidine-3-carbonitrile
1- (4- ((4- (1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-2-oxoimidazolin-4-yl) phenyl) ethynyl) benzyl) pyrrolidine-3-carbonitrile 35b (40 mg, 55.80. Mu. Mol) was added to 2mL of dichloromethane, boron trichloride (0.5 mL) was added and reacted at room temperature for 1 hour. After completion of the reaction, quenched with methanol, concentrated under reduced pressure, and the residue purified by preparative liquid phase separation to give 1- (4- ((4- (1- ((5-hydroxy-6-oxo-1, 6-dihydropyrimidin-4-yl) methyl) -3-isopropyl-2-oxoimidazolin-4-yl) phenyl) ethynyl) benzyl) pyrrolidine-3-carbonitrile 35 (8 mg,12.10 μmol,21.69% yieldd).
MS m/z(ESI):537.0[M+1] +
Example 36
5-hydroxy-6-((3-isopropyl-4-(4-((4-((1-oxidothiomorpholino)methyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-hydroxy-6- ((3-isopropyl-4- (4- ((4- ((1-thiomorpholin oxide) methyl) phenyl) ethynyl) phenyl) -2-oxoimidazolin-1-yl) methyl) pyrimidin-4 (3H) -one
First step
1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((4-((1-oxidothiomorpholino)methyl)phenyl)ethynyl)phenyl)imidazolidin-2-one
1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-4- (4- ((4- ((1-thiomorpholin oxide) methyl) phenyl) ethynyl) phenyl) imidazolin-2-one
24g (40 mg, 62.82. Mu. Mol) of 4- ((4- (1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-2-oxoimidazolin-4-yl) phenyl) ethynyl) benzaldehyde and thiomorpholine 1-oxide 36a (14.67 mg, 94.23. Mu. Mol) were dissolved in 1ml of 1, 2-dichloroethane, acetic acid (3.77 mg, 62.82. Mu. Mol, 3.59. Mu.L) was added, stirred for 30 minutes, sodium triacetylborohydride (26.63 mg, 125.64. Mu. Mol) was added and stirring was continued at room temperature for 12 hours. After completion of the reaction, 15mL of saturated aqueous sodium bicarbonate solution was added, quenched, dichloromethane (30 mL) and water (15 mL) were added, the aqueous phase was separated, the aqueous phase was extracted with dichloromethane (30 mL. Times.2), the combined organic phases were washed with saturated aqueous sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (eluent: system B) to give 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-4- (4- ((4- ((1-thiomorpholinomethyl) phenyl) ethynyl) phenyl) imidazolin-2-one 36B (20 mg, 27.03. Mu. Mol,43.03% yield).
MS m/z(ESI):740.0[M+1] +
Second step
5-hydroxy-6-((3-isopropyl-4-(4-((4-((1-oxidothiomorpholino)methyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-hydroxy-6- ((3-isopropyl-4- (4- ((4- ((1-thiomorpholin oxide) methyl) phenyl) ethynyl) phenyl) -2-oxoimidazolin-1-yl) methyl) pyrimidin-4 (3H) -one
1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-4- (4- ((4- ((1-thiomorpholino oxide) methyl) phenyl) ethynyl) phenyl) imidazolin-2-one 36b (20 mg, 27.03. Mu. Mol) was added to 2mL dichloromethane, boron trichloride (0.5 mL) was added and reacted at room temperature for 1 hour. After completion of the reaction, quenched with methanol, concentrated under reduced pressure, and the residue purified by preparative liquid phase separation to give 5-hydroxy-6- ((3-isopropyl-4- (4- ((4- ((1-thiomorpholin oxide methyl) phenyl) ethynyl) phenyl) -2-oxoimidazolin-1-yl) methyl) pyrimidin-4 (3H) -one 36 (4 mg,5.90 μmol,21.83% yieldd).
MS m/z(ESI):560.0[M+1] +
According to the synthetic methods of examples 1-36, the following compounds were prepared, including:
example 88
1-((5-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)pyridin-2-yl)methyl)azetidine-3-carboxamide
1- ((5- ((4- (1- ((5-hydroxy-6-oxo-1, 6-dihydroxypyrimidin-4-yl) methyl) -3-isopropyl-2-oxoimidazolin-4-yl) phenyl) ethynyl) pyridin-2-yl) methyl) azetidine-3-carboxamide
First step
1-(4-ethynylbenzyl)azetidine-3-carboxamide
1- (4-ethynylphenyl) azetidine-3-carboxamide
4-Acetylbenzaldehyde 88a (200 mg,1.54 mmol) and azetidine-3-carboxamide hydrochloride 88b (307.72 mg,2.25 mmol) were dissolved in 1, 2-dichloroethane (2.00 mL), acetic acid (92.28 mg,1.54mmol, 87.89. Mu.L) was added, stirred for 30 minutes, sodium triacetoxyborohydride (651.41 mg,3.07 mmol) was added, and stirring was continued at room temperature for 12 hours. After completion of the reaction, the reaction mixture was quenched by adding 15mL of saturated aqueous sodium hydrogencarbonate, dichloromethane (30 mL) and water (15 mL) in this order, the solution was separated, the aqueous phase was extracted with dichloromethane (30 mL. Times.2), the combined organic phases were washed with saturated aqueous sodium chloride (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and the residue was purified by preparative liquid chromatography (eluent: system B) to give 1- (4-ethynylphenyl) azetidine-3-carboxamide 88c (100 mg, 466.72. Mu. Mol,30.37% yield).
MS m/z(ESI):214.9[M+1]
Second step
1-(4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)benzyl)azetidine-3-carboxamide
1- (4- ((4- (1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-2-oxoimidazolin-4-yl) methyl) ethynyl) benzyl) azetidine-3-carboxamide
To a solution of 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4-iodophenyl) -3-isopropylimidazolin-2-one 21e (50 mg, 78.80. Mu. Mol) and 1- (4-ethynylphenyl) azetidine-3-carboxamide 88c (33.77 mg, 157.60. Mu. Mol) in water (2 mL) was added bis triphenylphosphine palladium dichloride (2.21 mg, 3.15. Mu. Mol), tetrabutylammonium bromide (25.40 mg, 78.80. Mu. Mol) and piperidine (20.13 mg, 236.40. Mu. Mol) at room temperature. After the reaction was warmed to 70℃and stirred for 5 hours, the reaction mixture was extracted with ethyl acetate (30 mL. Times.2), the aqueous layer was separated, the combined organic phases were washed successively with saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system B) to give 1- (4- ((4- (1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-2-oxoimidazolin-4-yl) methyl) ethynyl) benzyl) azetidine-3-carboxamide 88d (30 mg, 41.62. Mu. Mol,52.81% yield).
MS m/z(ESI):721.0[M+1]
Third step
1-((5-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)pyridin-2-yl)methyl)azetidine-3-carboxamide
1- ((5- ((4- (1- ((5-hydroxy-6-oxo-1, 6-dihydroxypyrimidin-4-yl) methyl) -3-isopropyl-2-oxoimidazolin-4-yl) phenyl) ethynyl) pyridin-2-yl) methyl) azetidine-3-carboxamide
1- (4- ((4- (1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-2-oxoimidazolin-4-yl) methyl) ethynyl) benzyl) azetidine-3-carboxamide 88d (30 mg, 41.62. Mu. Mol) was added to 2mL of dichloromethane followed by boron trichloride (0.8 mL) and reacted at room temperature for 1 hour. After completion of the reaction, quenched with methanol, concentrated under reduced pressure, and the residue is further isolated and purified by preparation of a liquid phase to give 1- ((5- ((4- (1- ((5-hydroxy-6-oxo-1, 6-dihydroxypyrimidin-4-yl) methyl) -3-isopropyl-2-oxoimidazol-4-yl) phenyl) ethynyl) pyridin-2-yl) methyl) azetidine-3-carboxamide 88 (7 mg,9.88 μmol,23.75% yieldd).
MS m/z(ESI):541.3[M+1]
Example 89
5-hydroxy-6-((4-(4-((4-(2-hydroxyethoxy)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-hydroxy-6- ((4- (4- ((4- (2-hydroxyethoxy) phenyl) ethynyl) phenyl) -3-isopropyl-2-oxoimidazolin-1-yl) methyl) pyrimidin-4 (3H) -one
First step
2-(4-((trimethylsilyl)ethynyl)phenoxy)ethan-1-ol
2- (4- ((trimethylsilyl) ethynyl) phenoxy) ethan-1-ol
To a solution of 2- (4-bromophenoxy) ethanol 89a (600 mg,2.76 mmol) and ethynyl (trimethyl) silane 89b (298.65 mg,3.04mmol, 429.71. Mu.L) in triethylamine (10.29 mL) were added copper iodide (52.64 mg, 276.42. Mu. Mol) and ditolylphosphine palladium dichloride (194.02 mg, 276.42. Mu. Mol) at room temperature. After stirring overnight at room temperature and completion of the reaction, the reaction mixture was extracted with ethyl acetate (30 mL. Times.2), the aqueous layer was separated, the combined organic phases were washed successively with saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system B) to give 2- (4- ((trimethylsilyl) ethynyl) phenoxy) ethan-1-ol 89c (250 mg,1.07mmol,38.59% yieldd).
MS m/z(ESI):235.1[M+1]
Second step
2-(4-ethynylphenoxy)ethan-1-ol
2- (4-Acetylylphenoxy) ethan-1-ol
2- (4- ((trimethylsilyl) ethynyl) phenoxy) ethan-1-ol 89c (236 mg,1.01 mmol) was added to methanol, potassium carbonate (417.52 mg,3.02 mmol) was added and reacted at room temperature for 1 hour. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (30 mL. Times.2), the aqueous layer was separated, the combined organic phases were washed successively with saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system A) to give 2- (4-ethynylphenoxy) ethan-1-ol 89d (120 mg, 739.90. Mu. Mol,73.48% yieldd).
MS m/z(ESI):163.0[M+1]
Third step
1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-(2-hydroxyethoxy)phenyl)ethynyl)phenyl)-3-isopropylimidazolidin-2-one
1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4- ((4- (2-hydroxyethyl) phenyl) ethynyl) phenyl) -3-isopropylimidazolin-2-one
To a solution of 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4-iodophenyl) -3-isopropylimidazolin-2-one 21e (60 mg, 94.56. Mu. Mol) 2- (4-ethynylphenoxy) ethan-1-ol 89d (30.67 mg, 189.12. Mu. Mol) in water (2 mL) was added bis triphenylphosphine palladium dichloride (2.65 mg, 3.78. Mu. Mol), tetrabutylammonium bromide (30.48 mg, 94.56. Mu. Mol) and piperidine (24.16 mg, 283.69. Mu. Mol) at room temperature. After the reaction was warmed to 70℃and stirred for 5 hours, the reaction was completed, the reaction solution was extracted with ethyl acetate (30 mL. Times.2), the aqueous layer was separated, the combined organic phases were washed successively with saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4- ((4- (2-hydroxyethyl) phenyl) ethynyl) phenyl) -3-isopropylimidazolin-2-one 89e (30 mg, 44.86. Mu. Mol,47.44% yieldd).
MS m/z(ESI):669.3[M+1]
Fourth step
5-hydroxy-6-((4-(4-((4-(2-hydroxyethoxy)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-hydroxy-6- ((4- (4- ((4- (2-hydroxyethoxy) phenyl) ethynyl) phenyl) -3-isopropyl-2-oxoimidazolin-1-yl) methyl) pyrimidin-4 (3H) -one
1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4- ((4- (2-hydroxyethyl) phenyl) ethynyl) phenyl) -3-isopropylimidazolin-2-one 89e (30 mg, 44.86. Mu. Mol) was added to 2mL of dichloromethane, boron trichloride (0.5 mL) was added and reacted at room temperature for 1 hour. After completion of the reaction, quenched with methanol, concentrated under reduced pressure, and the residue was further isolated and purified by preparation of a liquid phase to give 5-hydroxy-6- ((4- (4- ((4- (2-hydroxyethoxy) phenyl) ethynyl) phenyl) -3-isopropyl-2-oxoimidazol-1-yl) methyl) pyrimidin-4 (3H) -one 89 (4 mg,6.48 μmol,14.44% yield).
MS m/z(ESI):488.9[M+1]
1 H NMR(400MHz,DMSO)δ12.60(s,1H),9.48(s,1H),7.79(s,1H),7.60–7.40(m,6H),6.99(d,J=8.4Hz,2H),4.69(t,J=8.2Hz,1H),4.26(d,J=15.6Hz,1H),4.19(d,J=15.6Hz,1H),4.02(t,J=4.8Hz,2H),3.73–3.67(m,4H),3.04(t,J=8.0Hz,1H),1.13(d,J=6.8Hz,3H),0.77(d,J=6.4Hz,3H).
Example 90
5-hydroxy-6-((3-isopropyl-4-(4-((4-(3-methoxyazetidine-1-carbonyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-hydroxy-6- ((3-isopropyl-4- (4- ((4- (3-methoxyazetidine-1-carbonyl) phenyl) ethynyl) phenyl) -2-oxoimidazolin-1-yl) methyl) pyrimidin-4 (3H) -one
First step
(4-ethynylphenyl)(3-methoxyazetidin-1-yl)methanone
(4-Acetylylphenyl) (3-methoxyazetidin-1-yl) methanone
4-Acetylylbenzoic acid 90a (500 mg,3.42 mmol) and 3-methoxyazacyclo-completed hydrochloride 90b (845.62 mg,6.84 mmol) were added to 5mL of methylene chloride, followed by 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.05 g,5.47 mmol), 4-dimethylaminopyridine (41.80 mg, 342.13. Mu. Mol) and reacted overnight at room temperature. The reaction solution was extracted with methylene chloride (30 mL. Times.2), the aqueous layer was separated, the combined organic phases were successively washed with a saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was further separated and purified by silica gel column chromatography (eluent: system C) to give (4-ethynylphenyl) (3-methoxyazetidin-1-yl) methanone 90C (500 mg,2.32mmol,67.90% yield).
MS m/z(ESI):216.2[M+1] +
Second step
1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((4-(3-methoxyazetidine-1-carbonyl)phenyl)ethynyl)phenyl)imidazolidin-2-one
1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-4- (4- ((4- (3-methoxyazetidine-1-carbonyl) phenyl) ethynyl) phenyl) imidazolin-2-one
To a solution of 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4-iodophenyl) -3-isopropylimidazolin-2-one 21e (60 mg, 94.56. Mu. Mol) and (4-ethynylphenyl) (3-methoxyazetidin-1-yl) methanone 90c (40.71 mg, 189.12. Mu. Mol) in water (1.5 mL) was added, followed by stirring for 5 hours at 70℃with ditolylphosphine palladium dichloride (2.65 mg, 3.78. Mu. Mol), tetrabutylammonium bromide (30.48 mg, 94.56. Mu. Mol) and piperidine (24.16 mg, 283.69. Mu. Mol). The reaction solution was extracted with ethyl acetate (30 mL. Times.2), the aqueous layer was separated, the combined organic phases were washed successively with saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was further separated and purified by silica gel column chromatography (eluent: system B) to give 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-4- (4- ((4- (3-methoxyazetidine-1-carbonyl) phenyl) ethynyl) phenyl) imidazolin-2-one 90d (35 mg, 48.49. Mu. Mol,51.28% yieldd).
MS m/z(ESI):722.0[M+1] +
Third step
5-hydroxy-6-((3-isopropyl-4-(4-((4-(3-methoxyazetidine-1-carbonyl)phenyl)ethynyl)phenyl)-2-o xoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-hydroxy-6- ((3-isopropyl-4- (4- ((4- (3-methoxyazetidine-1-carbonyl) phenyl) ethynyl) phenyl) -2-oxoimidazolin-1-yl) methyl) pyrimidin-4 (3H) -one
1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-4- (4- ((4- (3-methoxyazetidine-1-carbonyl) phenyl) ethynyl) phenyl) imidazolin-2-one 90d (35 mg,48.49 μmol) was added to 2mL dichloromethane, boron trichloride (0.5 mL) was added and reacted at room temperature for 1 hour. After completion of the reaction, quenched with methanol, concentrated under reduced pressure, and the residue is further isolated and purified by preparation of a liquid phase to give 5-hydroxy-6- ((3-isopropyl-4- (4- ((4- (3-methoxyazetidine-1-carbonyl) phenyl) ethynyl) phenyl) -2-oxoimidazolin-1-yl) methyl) pyrimidin-4 (3H) -one 90 (6 mg,8.40 μmol,17.33% yield).
MS m/z(ESI):542.3[M+1] +
1 H NMR(400MHz,DMSO)δ12.59(br,1H),9.50(s,1H),7.79(s,1H),7.68(d,J=8.3Hz,2H),7.61(d,J=8.4Hz,2H),7.58(d,J=8.4Hz,2H),7.52(d,J=8.4Hz,2H),4.71(dd,J=9.2,7.2Hz,1H),4.45(dt,J=6.4,3.3Hz,1H),4.29–4.12(m,5H),3.85(q,J=7.1Hz,1H),3.74-3.67(m,2H),3.22(s,3H),3.04(t,J=8.0Hz,1H),1.13(d,J=6.8Hz,3H),0.78(d,J=6.8Hz,3H).
Example 91
5-hydroxy-6-((3-isopropyl-4-(4-((4-(1-oxidothiomorpholine-4-carbonyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-hydroxy-6- ((3-isopropyl-4- (4- ((4- (1-thiomorpholin-4-carbonyl) phenyl) ethynyl) phenyl) -2-oxoimidazolin-1-yl) methyl) pyrimidin-4 (3H) -one
First step
(4-ethynylphenyl)(1-oxidothiomorpholino)methanone
(4-Acetylylphenyl) (1-thiomorpholine oxide) methanone
4-Acetylylbenzoic acid 90a (150 mg,1.03 mmol) and thiomorpholine 1-oxide hydrochloride 36a (255.61 mg,1.64 mmol) were added to 1mL of dichloromethane, followed by 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (314.82 mg,1.64 mmol) and 4-dimethylaminopyridine (12.54 mg, 102.64. Mu. Mol) and reacted overnight at room temperature. The reaction solution was extracted with methylene chloride (30 mL. Times.2), the aqueous layer was separated, the combined organic phases were washed successively with a saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was further separated and purified by silica gel column chromatography (eluent: system A) to give (4-ethynylphenyl) (1-thiomorpholine oxide) methanone 91a (100 mg, 404.35. Mu. Mol,39.39% yield).
MS m/z(ESI):247.9[M+1] +
Second step
1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((4-(1-oxidothiomorpholine-4-carbonyl)phenyl)ethynyl)phenyl)imidazolidin-2-one
1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-4- (4- ((4- (1-thiomorpholine-4-carbonyl) phenyl) ethynyl) phenyl) imidazolin-2-one
To a solution of 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4-iodophenyl) -3-isopropylimidazolin-2-one 21e (50 mg, 78.80. Mu. Mol) and (4-ethynylphenyl) (1-thiomorpholine oxide) methanone 91a (38.98 mg, 157.60. Mu. Mol) in water (1.5 mL) at room temperature was added successively bis triphenylphosphine palladium dichloride (2.21 mg, 3.15. Mu. Mol), tetrabutylammonium bromide (25.40 mg, 78.80. Mu. Mol) and piperidine (20.13 mg, 236.40. Mu. Mol). The reaction was warmed to 70 ℃ and stirred for 5 hours. The reaction solution was extracted with ethyl acetate (30 mL. Times.2), the aqueous layer was separated, the combined organic phases were washed successively with saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-4- (4- ((4- (1-thiomorpholine-4-carbonyl) phenyl) ethynyl) phenyl) imidazolin-2-one 91B (30 mg, 39.79. Mu. Mol,50.50% yield).
MS m/z(ESI):754.9[M+1] +
Third step
5-hydroxy-6-((3-isopropyl-4-(4-((4-(1-oxidothiomorpholine-4-carbonyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one
5-hydroxy-6- ((3-isopropyl-4- (4- ((4- (1-thiomorpholin-4-carbonyl) phenyl) ethynyl) phenyl) -2-oxoimidazolin-1-yl) methyl) pyrimidin-4 (3H) -one
1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-4- (4- ((4- (1-thiomorpholine-4-carbonyl) phenyl) ethynyl) phenyl) imidazolin-2-one 91b (30 mg, 39.79. Mu. Mol) was added to 2mL dichloromethane, boron trichloride (0.8 mL) was added and reacted at room temperature for 1 hour. After completion of the reaction, quenched with methanol, concentrated under reduced pressure, and the residue is further isolated and purified by preparation of a liquid phase to give 5-hydroxy-6- ((3-isopropyl-4- (4- ((4- (1-thiomorpholine-4-carbonyl) phenyl) ethynyl) phenyl) -2-oxoimidazolin-1-yl) methyl) pyrimidin-4 (3H) -one 91 (8 mg,11.57 μmol,29.08% yield).
MS m/z(ESI):574.2[M+1] +
Example 92
2-hydroxy-N-(4-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)benzyl)acetamide
2-hydroxy-N- (4- ((4- (1- ((5-hydroxy-6-oxo-1, 6-dihydropyrimidin-4-yl) methyl) -3-isopropyl-2-oxoimidazolin-4-yl) phenyl) ethynyl) benzyl) acetamide
First step
N-(4-ethynylbenzyl)-2-hydroxyacetamide
N- (4-ethynylbenzyl) -2-hydroxyacetamide
(4-Acetylylphenyl) methylamine 92a (600 mg,3.58mmol, S02) and 2-glycolic acid 92b (326.64 mg,4.30 mmol) were added to 2mL of methylene chloride, followed by 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.10 g,5.73 mmol), 4-dimethylaminopyridine (43.73 mg, 357.92. Mu. Mol) and reacted overnight at room temperature. After completion of the reaction, the reaction mixture was extracted with methylene chloride (30 mL. Times.2), the aqueous layer was separated, the combined organic phases were washed successively with a saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give N- (4-ethynylbenzyl) -2-hydroxyacetamide 92C (300 mg,1.59mmol,44.30% yieldd).
MS m/z(ESI):190.2[M+1] +
Second step
N-(4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)benzyl)-2-hydroxyacetamide
N- (4- ((4- (1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-2-oxoimidazolin-4-yl) phenyl) ethynyl) benzyl) -2-hydroxyacetamide
To a solution of 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4-iodophenyl) -3-isopropylimidazolin-2-one 21e (60 mg, 94.56. Mu. Mol) and N- (4-ethynylbenzyl) -2-hydroxyacetamide 92c (35.78 mg, 189.12. Mu. Mol) in water (1 mL) at room temperature was added bis triphenylphosphine palladium dichloride (2.65 mg, 3.78. Mu. Mol), tetrabutylammonium bromide (30.48 mg, 94.56. Mu. Mol) and piperidine (24.16 mg, 283.69. Mu. Mol) in this order, and the reaction was warmed to 70℃and stirred for 5 hours. The reaction solution was extracted with ethyl acetate (30 mL. Times.2), the aqueous layer was separated, the combined organic phases were washed successively with saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give N- (4- ((4- (1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-2-oxoimidazolin-4-yl) phenyl) ethynyl) benzyl) -2-hydroxyacetamide 92d (30 mg, 43.12. Mu. Mol,45.60% yieldd).
MS m/z(ESI):696.3[M+1] +
Third step
2-hydroxy-N-(4-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)benzyl)acetamide
2-hydroxy-N- (4- ((4- (1- ((5-hydroxy-6-oxo-1, 6-dihydropyrimidin-4-yl) methyl) -3-isopropyl-2-oxoimidazolin-4-yl) phenyl) ethynyl) benzyl) acetamide
N- (4- ((4- (1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-2-oxoimidazolin-4-yl) phenyl) ethynyl) benzyl) -2-hydroxyacetamide 92d (20 mg, 28.74. Mu. Mol) was added to 1.5mL of dichloromethane, boron trichloride (0.8 mL) was added, and the mixture was reacted at room temperature for 1 hour. After completion of the reaction, quenched with methanol, concentrated under reduced pressure, and the residue is further separated and purified by preparative liquid phase to give 2-hydroxy-N- (4- ((4- (1- ((5-hydroxy-6-oxo-1, 6-dihydropyrimidin-4-yl) methyl) -3-isopropyl-2-oxoimidazolin-4-yl) phenyl) ethynyl) benzyl) acetamide 92 (8 mg,12.03 μmol,41.86% yieldd).
MS m/z(ESI):516.0[M+1] +
1 H NMR(400MHz,DMSO)δ12.57(br,1H),9.48(s,1H),8.37(t,J=6.4Hz,1H),7.79(s,1H),7.59–7.45(m,6H),7.31(d,J=8.4Hz,2H),4.70(dd,J=9.2,7.2Hz,1H),4.33(d,J=6.3Hz,2H),4.26(d,J=15.6Hz,1H),4.18(d,J=15.6Hz,1H),3.87(s,2H),3.74-3.67(m,4H),3.04(t,J=8.0Hz,1H),1.13(d,J=6.8Hz,3H),0.77(d,J=6.8Hz,3H).
Example 93
4-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)-N-(2-methoxyethyl)benzamide
4- ((4- (1- ((5-hydroxy-6-oxo-1, 6-dihydropyrimidin-4-yl) methyl) -3-isopropyl-2-oxoimidazolin-4-yl) phenyl) ethynyl) -N- (2-methoxyethyl) benzamide
First step
4-ethynyl-N-(2-methoxyethyl)benzamide
4-ethynyl-N- (2-methoxyethyl) benzamide
4-Acetylylbenzoic acid 90a (500 mg,3.42 mmol) and methoxyethylamine 93a (513.95 mg,6.84 mmol) were added to 2mL of methylene chloride, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (655.87 mg,3.42 mmol) and 4-dimethylaminopyridine (41.80 mg, 342.13. Mu. Mol) were added in this order and reacted overnight at room temperature. The reaction solution was extracted with dichloromethane (30 ml×2), the aqueous layer was separated, the combined organic phases were washed successively with saturated sodium chloride solution (30 ml×2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was further separated and purified by silica gel column chromatography (eluent: system A) was purified to give 4-ethynyl-N- (2-methoxyethyl) benzamide 93b (360 mg,1.77mmol,51.77% yield).
MS m/z(ESI):204.2[M+1] +
Second step
4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)-N-(2-methoxyethyl)benzamide
4- ((4- (1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-2-oxoimidazolin-4-yl) phenyl) ethynyl) -N- (2-methoxyethyl) benzamide
To a solution of 1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -4- (4-iodophenyl) -3-isopropylimidazolin-2-one 21e (60 mg, 94.56. Mu. Mol) and 4-ethynyl-N- (2-methoxyethyl) benzamide 93b (38.44 mg, 189.12. Mu. Mol) in water (1 mL) at room temperature was added bis triphenylphosphine palladium dichloride (2.65 mg, 3.78. Mu. Mol), tetrabutylammonium bromide (30.48 mg, 94.56. Mu. Mol) and piperidine (24.16 mg, 283.69. Mu. Mol) in this order, and the reaction was warmed to 70℃and stirred for 5 hours. The reaction solution was extracted with ethyl acetate (30 mL. Times.2), the aqueous layer was separated, the combined organic phases were washed successively with saturated sodium chloride solution (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system B) to give 4- ((4- (1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-2-oxoimidazolin-4-yl) phenyl) ethynyl) -N- (2-methoxyethyl) benzamide 93d (40 mg, 56.35. Mu. Mol,59.59% yieldd).
MS m/z(ESI):710.3[M+1] +
Third step
4-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)-N-(2-methoxyethyl)benzamide
4- ((4- (1- ((5-hydroxy-6-oxo-1, 6-dihydropyrimidin-4-yl) methyl) -3-isopropyl-2-oxoimidazolin-4-yl) phenyl) ethynyl) -N- (2-methoxyethyl) benzamide
4- ((4- (1- ((5, 6-bis (benzyloxy) pyrimidin-4-yl) methyl) -3-isopropyl-2-oxoimidazolin-4-yl) phenyl) ethynyl) -N- (2-methoxyethyl) benzamide 93d (40 mg,56.35 μmol) was added to 2mL dichloromethane, boron trichloride (0.8 mL) was added and reacted at room temperature for 1 hour. After completion of the reaction, quenched with methanol, concentrated under reduced pressure, and the residue is further isolated and purified by preparation of a liquid phase to give 4- ((4- (1- ((5-hydroxy-6-oxo-1, 6-dihydropyrimidin-4-yl) methyl) -3-isopropyl-2-oxoimidazolin-4-yl) phenyl) ethynyl) -N- (2-methoxyethyl) benzamide 93 (1.82 mg,2.68 μmol,4.75% yield).
MS m/z(ESI):530.2[M+1] +
1H NMR(400MHz,DMSO)δ9.61(br,1H),8.65(s,1H),7.92-7.89(m,3H),7.64(d,J=8.0,2H),7.58(d,J=8.0Hz,2H),7.52(d,J=8.0Hz,2H),4.71(t,J=8.0,1H),4.24(d,J=15.6Hz,,1H),4.22(d,J=15.6Hz,,1H),3.72-3.67(m,2H),3.47–3.42(m,4H),3.27(s,3H),3.05(t,J=8.0Hz,1H),1.13(d,J=6.8Hz,3H),0.78(d,J=6.4Hz,3H).
According to the synthetic methods of examples 1-93, the following compounds were prepared, including:
biological evaluation
Test example 1 inhibition assay of LpxC enzymatic Activity by Compounds of the invention
The following methods were used to determine the extent of inhibition of the enzymatic activity of the compounds of the invention on recombinant Pseudomonas aeruginosa LpxC under in vitro conditions.
The experimental procedure is briefly described as follows: test compounds were first dissolved in DMSO to prepare 10mM stock solutions. Reactions were performed in 96-well microplates, first 20 μl of recombinant Pseudomonas aeruginosa LpxC (available from Signalway Antibody under the trade designation AP 74647-2) was added to the wells at a final concentration of 5nM, respectively; adding 5 mu L of a compound to be tested, diluting the compound 4 times, and 8 concentration points, wherein the concentration range is 0.61-10000nM; mu.L of the LpxC substrate UDP-3-O- (R-3-hydroxydecanoyl) -GlcNAc (available from Biosynth Carbosynth under the trade name mu 75071) was added thereto at a final substrate concentration of 10. Mu.M and incubated at 25℃for 120 minutes. Then 20. Mu.L of 2.0mg/mL fluoroscamine (purchased from Sigma-Aldrich under the trade name F9015 and 1:1 dimethylformamide/acetonite) was added to the reaction system, and the mixture was stirred and reacted for 10 minutes; finally, 50. Mu.L of 200mM sodium phosphate buffer was added (pH 8.0) the reaction was stopped and read using a microplate reader (BMG) with excitation and emission wavelengths of 390nm and 495nm, respectively. The percent inhibition of the compounds at each concentration was calculated by comparison with the fluorescence intensity ratio of the control group (0.1% dmso) and nonlinear regression analysis was performed on the compound concentration vs. inhibition by GraphPad Prism 5 software to obtain IC of the compounds 50 The values are shown in Table 1 below.
TABLE 1 inhibition of LpxC enzymatic Activity by Compounds of the invention
Numbering of compounds | IC 50 /nM |
Example 7 | 42.45 |
Example 9 | 13.12 |
Example 10 | 22.99 |
Example 11 | 8.00 |
Example 13 | 15.72 |
Example 15 | 33.17 |
Example 16 | 24.69 |
Example 17 | 23.17 |
Example 22 | 36.1 |
Example 23 | 32.08 |
Example 24 | 20.58 |
Example 25 | 28.88 |
Example 26 | 9.55 |
Example 27 | 15.84 |
Example 28 | 35.53 |
Example 31 | 37.4 |
Example 36 | 52.02 |
Example 88 | 14.92 |
Example 90 | 19.99 |
Example 92 | 55.43 |
Example 93 | 60.9 |
Conclusion: IC with recombinant Pseudomonas aeruginosa LpxC enzyme activity inhibition by the compounds of the invention 50 All are less than 100nM, and have remarkable inhibition effect on LpxC enzyme activity.
Test example 2 evaluation of antibacterial Activity of the Compounds of the invention
In vitro minimum inhibitory concentration (minimum inhibitory concentration, MIC) assays were performed according to the guidelines of CLSI, using a mini broth dilution method.
The experimental procedure is briefly described as follows: test compounds were dissolved in DMSO to prepare 12.8mg/mL stock solution, and then 11 double dilutions of 100 Xhigh concentration working solution (final system concentration of 64. Mu.g/mL-0.06. Mu.g/mL) were prepared using DMSO. The strain frozen by glycerol at-80 deg.C (K.Pneumoniae ATCC13883 and E.coli ATCC 25922) is connected to a solid agar culture medium, placed in an incubator at 35 deg.C for culturing for 18-24 h to finish the preparation of the strain, then a proper amount of solid flat culture is collected and resuspended in physiological saline, and the mixture is uniformly mixed, and the turbidity of the bacterial suspension is regulated to a proper turbidity by a turbidity meter to be about 1X 10 8 cfu/mL bacteria, and then diluting the turbidity-adjusted bacterial suspension with a test medium to a bacterial concentration of 5×10 5 cfu/ml, the inoculum preparation is completed. Inoculating 198. Mu.L of the inoculating solution into a 96-well plate, adding 2. Mu.L of 100 Xhigh-concentration working solution of the compound, culturing the 96-well plate at 35 ℃ for 18-24 h, and observing the test plate by naked eyes after culturingThe long minimum drug concentration is the Minimum Inhibitory Concentration (MIC) of the compound, as specified in table 2 below.
TABLE 2 antibacterial Activity test results of the inventive Compounds
Conclusion: the compound has better inhibition effect on both pneumobacillus (K.Pneumoniae ATCC 13883) and escherichia coli (E.coli ATCC 25922).
Remarks: ND represents not measured.
Test example 3 ICR mouse pharmacokinetic study of the Compound of the invention
1. Purpose of experiment
The ICR mice are taken as test animals, the LC/MS/MS method is adopted to determine the intravenous injection or the intragastric administration of the compound 13 of the invention, the drug concentration in plasma at different times is determined, and the pharmacokinetic characteristics of the compound of the invention in the mice are studied.
2. Experimental protocol
2.1 experimental drugs and animals;
the compound of example 13;
ICR mice, male, 29.0-33.8 g, purchased from Peking Vitre Liwa laboratory animal technologies Co.
2.2 pharmaceutical formulation
Intravenous injection group: weighing a proper amount of medicine, adding 10% HP-beta-CD water solution, vortex and ultrasonic for 60 min. Adding 10 μl of 1M HCl, vortexing, mixing, and filtering with (Rephile, nylon,0.45 μm) pH 3.5-4.0 to obtain colorless solution, and preparing final concentration of 0.2mg/mL;
oral gavage group: weighing a proper amount of medicine, adding 10% Solutol HS15-20% HP-beta-CD, vortexing, and performing ultrasonic treatment for 30 minutes to obtain a colorless solution, and preparing the final preparation concentration of 0.5mg/kg.
2.3 administration of drugs
ICR mice, each test compound was divided into intravenous (9 per group) and intragastric (9 per group), and fed by orbital intravenous (1 mg/kg dose, 5mL/kg dose volume) and intragastric (5 mg/kg dose, 10mL/kg dose volume) administration after overnight fast, respectively, 4 hours after administration.
3. Operation of
About 0.1mL of blood was collected via the cervical orbit before and after 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours and 24 hours, and whole blood samples were placed in an anticoagulant tube containing EDTA-K2. After blood sample collection, the plasma was centrifuged (centrifugation conditions: 1500g,10 min). The collected plasma was stored at-40 to-20℃prior to analysis.
The LC-MS/MS was used to determine the amount of test compound in the plasma of mice following intravenous and intragastric administration of the different compounds.
4. Pharmacokinetic parameter results
The pharmacokinetic parameters of the compounds of the invention are shown in table 3.
TABLE 3 pharmacokinetic parameter results for the compounds of the invention
Conclusion: the compound of the embodiment 13 of the invention has higher blood concentration and area under the curve, higher bioavailability and better pharmacokinetic property.
Claims (14)
- A compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:wherein:x and Y are each independently selected from C or N, and X, Y are not both N;ring a is selected from 4-to 6-membered heteroaryl or 4-to 6-membered heterocyclyl, preferably 5-membered heteroaryl or 5-membered heterocyclyl;L 1 selected from single bonds or-CH 2 -;R 1 Identical or different, each independently selected from-G 1 -R 4 ;G 1 Selected from single bond, -CH 2 -or-C (=o) -;R 2 the same or different, each independently selected from hydroxy, cyano, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more halogen, hydroxy, cyano, or alkoxy substituents;R 3 identical or different, each independently selected from hydroxy, cyano, halogen, alkyl, cycloalkyl, heterocyclyl, alkoxy or-C (O) R 5 Wherein said alkyl, cycloalkyl, heterocyclyl OR alkoxy is optionally further substituted with one OR more groups selected from halogen, hydroxy, cyano, alkoxy, -C (O) OR 5 or-C (O) NR 6 R 7 Is substituted by a substituent of (2);R 4 selected from cyano, halogen, alkyl, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R 5 、-C(O)OR 5 、-OC(O)R 5 、-NR 6 R 7 、-C(O)NR 6 R 7 、-SO 2 NR 6 R 7 or-NR 6 C(O)R 7 Wherein said alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more R A Substituted;R A selected from halogen, hydroxy, amino, hydroxyalkyl, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R 5 、-C(O)OR 5 、-OC(O)R 5 、-NR 6 R 7 、-C(O)NR 6 R 7 、-SO 2 NR 6 R 7 or-NR 6 C(O)R 7 Wherein said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally further substituted with one or more substituents selected from halogen, hydroxy, amino, haloalkyl, hydroxyalkyl, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R 5 、-C(O)OR 5 、-OC(O)R 5 、-NR 6 R 7 、-C(O)NR 6 R 7 、-SO 2 NR 6 R 7 or-NR 6 C(O)R 7 Is substituted by a substituent of (a);R 5 selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted with one or more groups selected from a hydroxyl group, a halogen group, a nitro group, a cyano group, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, =o, -C (O) R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO 2 NR 9 R 10 or-NR 9 C(O)R 10 Is substituted by a substituent of (2);R 6 and R is 7 Each independently selected from a hydrogen atom, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more groups selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =o, -C (O) R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO 2 NR 9 R 10 or-NR 9 C(O)R 10 Is substituted by a substituent of (2);Alternatively, R 6 And R is 7 Together with the atoms to which they are attached form a 4-8 membered heterocyclic group, where the 4-8 membered heterocyclic group contains one or more N, O, S or SO 2 And said 4-8 membered heterocyclyl is optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =o, -C (O) R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO 2 NR 9 R 10 or-NR 9 C(O)R 10 Is substituted by a substituent of (2);R 8 、R 9 and R is 10 Each independently selected from the group consisting of hydrogen, alkyl, amino, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl, or carboxylate;m is 0,1,2 or 3;n is 0,1 or 2; n is preferably 0; and is also provided withp is 0,1 or 2.
- The compound of claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which is a compound of formula (II):wherein: ring A, R 1 ~R 3 、L 1 The definitions of m, n and p are as defined in claim 1.
- A compound according to claim 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which is a compound of formula (III):wherein:R A selected from the group consisting of haloalkyl, hydroxyalkyl, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally further substituted with a substituent of carboxyl;q is 0,1 or 2;ring A, G 1 、R 2 、R 3 、L 1 The definitions of n and p are as defined in claim 1.
- A compound according to any one of claims 1 to 3, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein ring a is selected from:
- a compound according to any one of claims 1 to 3, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, whereinSelected from:
- a compound according to any one of claims 1 to 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, whereinSelected from:
- a compound according to any one of claims 1 to 3, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein n is selected from 0.
- A compound according to any one of claims 1 to 3, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein L 1 Selected from-CH 2 -。
- A compound according to any one of claims 1 to 8, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound is:
- a process for the preparation of a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which process comprises:coupling the compound of the general formula (I-a) with the compound of the general formula (I-b) under the action of a catalyst, and optionally removing the protecting group to obtain the compound of the general formula (I);wherein:X 1 selected from halogen;ring A, X, Y, R 1 ~R 3 、L 1 The definitions of n, m and p are as defined in claim 1.
- A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 9, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or combination thereof.
- Use of a compound according to any one of claims 1 to 9, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11, for the preparation of an LPXC inhibitor.
- Use of a compound according to any one of claims 1 to 9, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11, for the manufacture of a medicament for the treatment of a disease mediated by LPXC, wherein the disease mediated by LPXC is selected from bacterial infections caused by gram-negative bacteria.
- The use according to claim 13, wherein the gram-negative bacteria are selected from the group consisting of escherichia coli, pseudomonas aeruginosa, proteus, shigella dysenteriae, pneumobacillus, bacillus brucellosis, typhoid bacillus, acinetobacter, yersinia, legionella pneumophila, bordetella pertussis, shigella, pasteur, vibrio cholerae, neisseria meningitidis.
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