CN115403584B - 2-thio-2, 3-dihydropyrimidine-4-one derivatives, pharmaceutical compositions, preparation methods and applications thereof - Google Patents
2-thio-2, 3-dihydropyrimidine-4-one derivatives, pharmaceutical compositions, preparation methods and applications thereof Download PDFInfo
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- CN115403584B CN115403584B CN202210600006.7A CN202210600006A CN115403584B CN 115403584 B CN115403584 B CN 115403584B CN 202210600006 A CN202210600006 A CN 202210600006A CN 115403584 B CN115403584 B CN 115403584B
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- amino
- reaction
- pyrrole
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- 238000002360 preparation method Methods 0.000 title claims abstract description 273
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 77
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 32
- 102000003896 Myeloperoxidases Human genes 0.000 claims abstract description 24
- 108090000235 Myeloperoxidases Proteins 0.000 claims abstract description 24
- 201000010099 disease Diseases 0.000 claims abstract description 23
- 239000003814 drug Substances 0.000 claims abstract description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 82
- 125000000623 heterocyclic group Chemical group 0.000 claims description 58
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 36
- 125000003545 alkoxy group Chemical group 0.000 claims description 36
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 33
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 33
- 229910052739 hydrogen Inorganic materials 0.000 claims description 30
- 239000001257 hydrogen Substances 0.000 claims description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 17
- 125000001188 haloalkyl group Chemical group 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 11
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical group [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 9
- 208000035475 disorder Diseases 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 9
- 238000006467 substitution reaction Methods 0.000 claims description 9
- 238000011282 treatment Methods 0.000 claims description 9
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 6
- 239000003112 inhibitor Substances 0.000 claims description 6
- 208000001089 Multiple system atrophy Diseases 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 5
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 5
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 5
- 206010019280 Heart failures Diseases 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 230000004770 neurodegeneration Effects 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- 208000004476 Acute Coronary Syndrome Diseases 0.000 claims description 3
- 201000001320 Atherosclerosis Diseases 0.000 claims description 3
- 206010003658 Atrial Fibrillation Diseases 0.000 claims description 3
- 241000711573 Coronaviridae Species 0.000 claims description 3
- 206010012289 Dementia Diseases 0.000 claims description 3
- 208000023105 Huntington disease Diseases 0.000 claims description 3
- 208000018737 Parkinson disease Diseases 0.000 claims description 3
- 208000007536 Thrombosis Diseases 0.000 claims description 3
- 208000030886 Traumatic Brain injury Diseases 0.000 claims description 3
- 201000007201 aphasia Diseases 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 206010012601 diabetes mellitus Diseases 0.000 claims description 3
- 206010015037 epilepsy Diseases 0.000 claims description 3
- 201000006417 multiple sclerosis Diseases 0.000 claims description 3
- 208000002815 pulmonary hypertension Diseases 0.000 claims description 3
- 230000009529 traumatic brain injury Effects 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 2
- 229940125904 compound 1 Drugs 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 2
- 208000006011 Stroke Diseases 0.000 claims 1
- 208000024891 symptom Diseases 0.000 abstract description 6
- 230000005764 inhibitory process Effects 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 717
- -1 hydroxy, mercapto Chemical class 0.000 description 632
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 531
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 463
- 238000006243 chemical reaction Methods 0.000 description 408
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 267
- 239000000243 solution Substances 0.000 description 238
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 179
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 147
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 136
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 134
- 239000003208 petroleum Substances 0.000 description 128
- 238000005481 NMR spectroscopy Methods 0.000 description 126
- 239000000741 silica gel Substances 0.000 description 124
- 229910002027 silica gel Inorganic materials 0.000 description 124
- 239000007787 solid Substances 0.000 description 111
- 239000012074 organic phase Substances 0.000 description 110
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 106
- 239000012043 crude product Substances 0.000 description 96
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 95
- 239000011541 reaction mixture Substances 0.000 description 93
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 88
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 87
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 84
- 239000012230 colorless oil Substances 0.000 description 76
- 229910052757 nitrogen Inorganic materials 0.000 description 74
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 72
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 63
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 60
- 238000003756 stirring Methods 0.000 description 55
- 239000003921 oil Substances 0.000 description 52
- 238000002390 rotary evaporation Methods 0.000 description 49
- 125000003118 aryl group Chemical group 0.000 description 48
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 47
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 45
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 40
- 229920006395 saturated elastomer Polymers 0.000 description 39
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 39
- 238000000605 extraction Methods 0.000 description 38
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 37
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 36
- 125000000304 alkynyl group Chemical group 0.000 description 36
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 34
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 33
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 33
- 229960000583 acetic acid Drugs 0.000 description 32
- 125000003342 alkenyl group Chemical group 0.000 description 32
- 229910052736 halogen Inorganic materials 0.000 description 31
- 150000002367 halogens Chemical class 0.000 description 31
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 30
- 235000019270 ammonium chloride Nutrition 0.000 description 30
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 30
- SPNDLEQTZLQLTA-UHFFFAOYSA-N ethyl 3-amino-1h-pyrrole-2-carboxylate Chemical compound CCOC(=O)C=1NC=CC=1N SPNDLEQTZLQLTA-UHFFFAOYSA-N 0.000 description 29
- 230000002829 reductive effect Effects 0.000 description 29
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 28
- 125000004432 carbon atom Chemical group C* 0.000 description 25
- 239000000203 mixture Substances 0.000 description 25
- 125000006648 (C1-C8) haloalkyl group Chemical group 0.000 description 24
- 125000006708 (C5-C14) heteroaryl group Chemical group 0.000 description 24
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 24
- HBNYJWAFDZLWRS-UHFFFAOYSA-N ethyl isothiocyanate Chemical compound CCN=C=S HBNYJWAFDZLWRS-UHFFFAOYSA-N 0.000 description 22
- 125000001072 heteroaryl group Chemical group 0.000 description 22
- 239000012044 organic layer Substances 0.000 description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- 238000000746 purification Methods 0.000 description 20
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 20
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 19
- 125000003282 alkyl amino group Chemical group 0.000 description 18
- 239000007788 liquid Substances 0.000 description 18
- 150000003254 radicals Chemical class 0.000 description 18
- 238000000926 separation method Methods 0.000 description 18
- 125000000392 cycloalkenyl group Chemical group 0.000 description 17
- 150000002431 hydrogen Chemical class 0.000 description 17
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 16
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 16
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 16
- 125000004043 oxo group Chemical group O=* 0.000 description 16
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 16
- 239000000706 filtrate Substances 0.000 description 15
- 238000010898 silica gel chromatography Methods 0.000 description 15
- 125000003003 spiro group Chemical group 0.000 description 15
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 13
- 229930040373 Paraformaldehyde Natural products 0.000 description 12
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 12
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- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 11
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- 239000002904 solvent Substances 0.000 description 11
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- 125000004465 cycloalkenyloxy group Chemical group 0.000 description 10
- SNPMOXPMDVCCEM-UHFFFAOYSA-N ethyl 3-[(2-methylpropan-2-yl)oxycarbonylamino]-1h-pyrrole-2-carboxylate Chemical compound CCOC(=O)C=1NC=CC=1NC(=O)OC(C)(C)C SNPMOXPMDVCCEM-UHFFFAOYSA-N 0.000 description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 10
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
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- 229910052805 deuterium Inorganic materials 0.000 description 9
- 150000002430 hydrocarbons Chemical class 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
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- DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 description 8
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- JOFJLDMQBUWNGH-UHFFFAOYSA-N 2-propan-2-yloxyacetaldehyde Chemical compound CC(C)OCC=O JOFJLDMQBUWNGH-UHFFFAOYSA-N 0.000 description 7
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- 239000012453 solvate Substances 0.000 description 6
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- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 4
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- 125000003277 amino group Chemical group 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
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- BDTDECDAHYOJRO-UHFFFAOYSA-N ethyl n-(sulfanylidenemethylidene)carbamate Chemical compound CCOC(=O)N=C=S BDTDECDAHYOJRO-UHFFFAOYSA-N 0.000 description 4
- 239000012452 mother liquor Substances 0.000 description 4
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- BOTXQJAHRCGJEG-UHFFFAOYSA-N ethyl 5-methyl-1h-pyrazole-3-carboxylate Chemical compound CCOC(=O)C=1C=C(C)NN=1 BOTXQJAHRCGJEG-UHFFFAOYSA-N 0.000 description 1
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 1
- DBPFRRFGLYGEJI-UHFFFAOYSA-N ethyl glyoxylate Chemical compound CCOC(=O)C=O DBPFRRFGLYGEJI-UHFFFAOYSA-N 0.000 description 1
- QWYUCDFGDFQKJY-UHFFFAOYSA-N ethyl iodate Chemical compound CCOI(=O)=O QWYUCDFGDFQKJY-UHFFFAOYSA-N 0.000 description 1
- UVECLJDRPFNRRQ-UHFFFAOYSA-N ethyl trifluoromethanesulfonate Chemical compound CCOS(=O)(=O)C(F)(F)F UVECLJDRPFNRRQ-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 125000005549 heteroarylene group Chemical group 0.000 description 1
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 description 1
- QRRARMLFKAGUNA-UHFFFAOYSA-N isocyanatosulfanylethane Chemical compound CCSN=C=O QRRARMLFKAGUNA-UHFFFAOYSA-N 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropyl acetate Chemical compound CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 150000002540 isothiocyanates Chemical class 0.000 description 1
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 description 1
- 229910001623 magnesium bromide Inorganic materials 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 1
- OYEVFSJZQTUDDN-UHFFFAOYSA-N methanol;n-methylmethanamine Chemical compound OC.CNC OYEVFSJZQTUDDN-UHFFFAOYSA-N 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- GHDIHPNJQVDFBL-UHFFFAOYSA-N methoxycyclohexane Chemical compound COC1CCCCC1 GHDIHPNJQVDFBL-UHFFFAOYSA-N 0.000 description 1
- KPJWVJURYXOHOO-UHFFFAOYSA-N methyl 1-hydroxycyclopropane-1-carboxylate Chemical compound COC(=O)C1(O)CC1 KPJWVJURYXOHOO-UHFFFAOYSA-N 0.000 description 1
- CEKCJQBZVNIMLD-UHFFFAOYSA-N methyl 2-amino-4-methoxybenzoate Chemical compound COC(=O)C1=CC=C(OC)C=C1N CEKCJQBZVNIMLD-UHFFFAOYSA-N 0.000 description 1
- BIECSXCXIXHDBC-UHFFFAOYSA-N methyl 2-bromo-5-chlorobenzoate Chemical compound COC(=O)C1=CC(Cl)=CC=C1Br BIECSXCXIXHDBC-UHFFFAOYSA-N 0.000 description 1
- UTLPWTWCOSOPMX-UHFFFAOYSA-N methyl 3-aminofuran-2-carboxylate Chemical compound COC(=O)C=1OC=CC=1N UTLPWTWCOSOPMX-UHFFFAOYSA-N 0.000 description 1
- AZFQCTBZOPUVOW-UHFFFAOYSA-N methyl(triphenyl)phosphanium Chemical compound C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 AZFQCTBZOPUVOW-UHFFFAOYSA-N 0.000 description 1
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- KTMKRRPZPWUYKK-UHFFFAOYSA-N methylboronic acid Chemical compound CB(O)O KTMKRRPZPWUYKK-UHFFFAOYSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 210000000822 natural killer cell Anatomy 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- ZCYXXKJEDCHMGH-UHFFFAOYSA-N nonane Chemical compound CCCC[CH]CCCC ZCYXXKJEDCHMGH-UHFFFAOYSA-N 0.000 description 1
- BKIMMITUMNQMOS-UHFFFAOYSA-N normal nonane Natural products CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 1
- 125000002347 octyl 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])[H] 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- 239000002245 particle Substances 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
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 210000001539 phagocyte Anatomy 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- DLRJIFUOBPOJNS-UHFFFAOYSA-N phenetole Chemical compound CCOC1=CC=CC=C1 DLRJIFUOBPOJNS-UHFFFAOYSA-N 0.000 description 1
- 125000002265 phtalazinyl group Chemical group 0.000 description 1
- 238000000053 physical method Methods 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920000570 polyether Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- JIWDQJYCCQFDAF-UHFFFAOYSA-N potassium;2-methylpropan-2-olate;oxolane Chemical compound [K+].CC(C)(C)[O-].C1CCOC1 JIWDQJYCCQFDAF-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 125000004353 pyrazol-1-yl group Chemical group [H]C1=NN(*)C([H])=C1[H] 0.000 description 1
- 125000004289 pyrazol-3-yl group Chemical group [H]N1N=C(*)C([H])=C1[H] 0.000 description 1
- 125000004497 pyrazol-5-yl group Chemical group N1N=CC=C1* 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011369 resultant mixture Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- HYHCSLBZRBJJCH-UHFFFAOYSA-M sodium hydrosulfide Chemical compound [Na+].[SH-] HYHCSLBZRBJJCH-UHFFFAOYSA-M 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- RSIJVJUOQBWMIM-UHFFFAOYSA-L sodium sulfate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]S([O-])(=O)=O RSIJVJUOQBWMIM-UHFFFAOYSA-L 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- FUQHLUSGMOSPRQ-UHFFFAOYSA-N spiro[3.3]heptane-2-carboxylic acid Chemical compound C1C(C(=O)O)CC11CCC1 FUQHLUSGMOSPRQ-UHFFFAOYSA-N 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000013076 target substance Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- FJYBLMJHXRWDAQ-UHFFFAOYSA-N tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCOC(CO)C1 FJYBLMJHXRWDAQ-UHFFFAOYSA-N 0.000 description 1
- COUZDDDNQCVUDL-UHFFFAOYSA-N tert-butyl 3,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c]pyrrole-2-carboxylate Chemical compound C1CCC2CN(C(=O)OC(C)(C)C)CC21 COUZDDDNQCVUDL-UHFFFAOYSA-N 0.000 description 1
- JSOMVCDXPUXKIC-UHFFFAOYSA-N tert-butyl 3-oxopyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)C1 JSOMVCDXPUXKIC-UHFFFAOYSA-N 0.000 description 1
- LQTMEOSBXTVYRM-VIFPVBQESA-N tert-butyl n-[(2s)-1-hydroxy-4-methylpentan-2-yl]carbamate Chemical compound CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C LQTMEOSBXTVYRM-VIFPVBQESA-N 0.000 description 1
- JHLVEBNWCCKSGY-UHFFFAOYSA-N tert-butyl n-methylcarbamate Chemical compound CNC(=O)OC(C)(C)C JHLVEBNWCCKSGY-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical group C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000005556 thienylene group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 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
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
- 125000005455 trithianyl group Chemical group 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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- A—HUMAN NECESSITIES
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Abstract
The invention provides a 2-thio-2, 3-dihydropyrimidine-4-ketone derivative shown in a formula I, a pharmaceutical composition, a preparation method and application thereof. The compounds have good MPO inhibition and can be used for treating or preventing diseases and symptoms related to myeloperoxidase and preparing medicines for treating the diseases and symptoms.
Description
The invention claims priority to the prior application entitled "2-thio-2, 3-dihydropyrimidin-4-one derivatives, pharmaceutical compositions, methods for preparing them, and uses thereof," filed 5.26.2021 to the national intellectual property office, entitled "2-thio-2, 3-dihydropyrimidin-4-one derivatives, methods for preparing them, and uses thereof," and entitled "2-thio-2, 3-dihydropyrimidin-4-one derivatives, methods for preparing them, and uses thereof," filed 10.9.2021 to the national intellectual property office, entitled "202111179651.8. The entire contents of both prior applications are incorporated by reference into this invention.
Technical Field
The invention belongs to the field of medicine synthesis, and in particular relates to a 2-thio-2, 3-dihydropyrimidine-4-ketone derivative, a medicine composition, a preparation method and application thereof.
Background
Myeloperoxidase (MPO), also known as myeloperoxidase, is a heme protease that is a heme prosthetic group and is one of the members of the heme peroxidase superfamily. MPO is present in the eosinophil particles of myeloid cells (mainly neutrophils and monocytes) and is a specific marker for myeloid cells. The main function of MPO is to generate hypochlorite by hydrogen peroxide and chloride ions to form MPO-H 2 O 2 -a halogen system to kill microorganisms within phagocytes. In addition, MPO can be released outside cells to destroy various target substances such as tumor cells, platelets, NK cells, protozoa, toxins, etc., and plays a role in various aspects of body generation and regulation of inflammatory reactions, etc. However, under certain conditions, the MPO catalyzed reaction produces excessive oxidation products (hypochlorous acid, 3-chlorotyrosine, nitrotyrosine, etc.), which, in excess of the local antioxidant defensive reaction, can lead to oxidative stress and oxidative tissue damage. It has been found that MPO overactivation is closely related to cardiovascular disease, neurodegenerative disease, tumor, inflammation.
The MPO inhibitor can be combined with MPO enzyme in a reversible or irreversible way to inhibit the activity of the MPO enzyme, so as to achieve the aim of treating diseases. Currently no MPO inhibitors are marketed, and the MPO covalent inhibitors in clinical development are mainly BHV3241 of bioeaven (purchased from aliskir under the original number AZD 3241) and AZD4831 of aliskir. BHV3241 is in clinical stage three, with indications being Multiple System Atrophy (MSA) and Amyotrophic Lateral Sclerosis (ALS). AZD 48131 is in clinical stage II and is used for treating cardiovascular diseases such as heart failure. No non-covalent inhibitors are currently in clinical use.
Although significant research has been conducted in this area, there is a continuing need to develop more potent small molecule MPO inhibitors, which provide novel structural MPO inhibitors and find that compounds having such structures have good activity.
Disclosure of Invention
In order to solve the above technical problems, the present invention provides a compound represented by formula I, its racemate, stereoisomer, tautomer, isotopic label, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof:
wherein:
a is present or absent;
when A is absent, the carbon-carbon double bond may be substituted with one or two R's selected from hydrogen, deuterium, halogen, hydroxy, mercapto, nitro, cyano, unsubstituted or optionally substituted with one, two or more R' s a Substituted with the following groups: amino, C 1-40 Alkyl, C 1-40 Alkyloxy, C 1-40 Hydroxyalkyl, C 1-40 Haloalkyl, C 1-40 Alkylamino, (C) 1-8 Alkyl group 2 Amino, amino-C 1-40 Alkyl, C 2-40 Alkenyl, C 2-40 Alkynyl, C 3-40 Cycloalkyl, 3-20 membered heterocyclyl, C 6-20 Aryl, 5-20 membered heteroaryl, C 3-40 Cycloalkylamino, 3-to 20-membered heterocyclylamino, C 6-20 Arylamino, 5-20 membered heteroarylamino, C 3-40 Cycloalkyloxy, 3-20 membered heterocyclyloxy, C 6-20 Aryloxy or 5-20 membered heteroaryloxy;
when A is present, A is selected from unsubstituted or optionally substituted with one, two or more R a Substituted C 3-40 Cycloalkyl, C 3-40 Cycloalkenyl, C 3-40 Cycloalkynyl, 3-20 membered heterocyclyl, C 6-20 Aryl or 5-20 membered heteroaryl;
each R a The same or different, independently of one another, are selected from hydrogen, halogen, OH, CN, NO 2 Oxo (=o), thio (=s), unsubstituted or optionally substituted by one, two or more R a1 Substituted with the following groups: c (C) 1-40 Alkyl, C 1-40 Haloalkyl, C 2-40 Alkenyl, C 2-40 Alkynyl, C 3-40 Cycloalkyl, C 3-40 Cycloalkenyl, C 3-40 Cycloalkynyl radicals, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, C 1-40 Alkyloxy, C 2-40 Alkenyloxy, C 2-40 Alkynyloxy, C 3-40 Cycloalkyl oxy, C 3-40 Cycloalkenyl oxy, C 3-40 Cycloalkynyloxy, C 6-20 Aryloxy, 5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, NH 2 ;
Each R a1 The same or different, independently of one another, from hydrogen, halogen, OH, NH 2 、CN、NO 2 Oxo (=o), C 1-40 Alkyl, C 1-40 Haloalkyl, C 2-40 Alkenyl, C 2-40 Alkynyl, C 3-40 Cycloalkyl, C 3-40 Cycloalkenyl, C 3-40 Cycloalkynyl radicals, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, C 1-40 Alkylamino, (C) 1-40 Alkyl group 2 An amino group;
R is selected from unsubstituted or optionally substituted with one, two or more R b Substituted with the following groups: c (C) 1-40 Alkyl, C 1-40 Haloalkyl, C 2-40 Alkenyl, C 2-40 Alkynyl, C 3-40 Cycloalkyl, C 3-40 Cycloalkenyl, C 3-40 Cycloalkynyl radicals, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, C 1-40 Alkyloxy, C 2-40 Alkenyloxy, C 2-40 Alkynyloxy, C 3-40 Cycloalkyl oxy, C 3-40 Cycloalkenyl oxy, C 3-40 Cycloalkynyloxy, C 6-20 Aryloxy, 5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, NH 2 ;
Each R b The same or different, independently of one another, are selected from hydrogen, halogen, OH, CN, NO 2 Oxo (=o), thio (=s), unsubstituted or optionally substituted by one, two or more R b1 Substituted with the following groups: c (C) 1-40 Alkyl, C 1-40 Haloalkyl, C 2-40 Alkenyl, C 2-40 Alkynyl, C 3-40 Cycloalkyl, C 3-40 Cycloalkenyl, C 3-40 Cycloalkynyl radicals, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, C 1-40 Alkyloxy, C 2-40 Alkenyloxy, C 2-40 Alkynyloxy, C 3-40 Cycloalkyl oxy, C 3-40 Cycloalkenyl oxy, C 3-40 Cycloalkynyloxy, C 6-20 Aryloxy, 5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, NH 2 ;
Each R b1 The same or different, independently of one another, are selected from hydrogen, halogen, OH, CN, NO 2 Oxo (=o), thio (=s), unsubstituted or optionally substituted by one, two or more R b2 Substituted with the following groups: c (C) 1-40 Alkyl, C 1-40 Haloalkyl, C 2-40 Alkenyl, C 2-40 Alkynyl, C 3-40 Cycloalkyl, C 3-40 Cycloalkenyl, C 3-40 Cycloalkynyl radicals, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, C 1-40 Alkyloxy, C 2-40 Alkenyloxy, C 2-40 Alkynyloxy, C 3-40 Cycloalkyl oxy, C 3-40 Cycloalkenyl oxy, C 3-40 Cycloalkynyloxy, C 6-20 Aryloxy, 5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, NH 2 ;
Each R b2 The same or different, independently of one another, are selected from hydrogen, halogen, OH, CN, NO 2 Oxo (=o), thio (=s), unsubstituted or optionally substituted by one, two or more R b3 Substituted with the following groups: c (C) 1-40 Alkyl, C 1-40 Haloalkyl, C 2-40 Alkenyl, C 2-40 Alkynyl, C 3-40 Cycloalkyl, C 3-40 Cycloalkenyl, C 3-40 Cycloalkynyl radicals, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, C 1-40 Alkyloxy, C 2-40 Alkenyloxy, C 2-40 Alkynyloxy, C 3-40 Cycloalkyl oxy, C 3-40 Cycloalkenyl oxy, C 3-40 Cycloalkynyloxy, C 6-20 Aryloxy, 5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, NH 2 ;
Each R b3 The same or different, independently of one another, from hydrogen, halogen, OH, NH 2 、CN、NO 2 Oxo (=o), thio (=s), C 1-40 Alkyl, C 1-40 Haloalkyl, C 2-40 Alkenyl, C 2-40 Alkynyl, C 3-40 Cycloalkyl, C 3-40 Cycloalkenyl, C 3-40 Cycloalkynyl radicals, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl.
According to an embodiment of the invention, when A is absent, formula I has the structure shown in formula I-1:
wherein R' is selected from 3-10 membered heterocyclic groups, C 6-14 Aryl, 5-14 membered heteroaryl, 3-10 membered heterocyclylamino, C 6-14 Arylamino, 5-14 membered heteroarylamino, 3-10 membered heterocyclyloxy, C 6-14 Aryloxy or 5-14 membered heteroaryloxy;
when A is present, formula I has a structure represented by formula I-2, formula I-2', or formula I-3:
wherein:
represents a single bond or a double bond;
m is selected from integers from 0 to 4;
when formula I has a junction of formula I-2When the structure is formed, D is selected from O, C (O) and CH 2 Or NH; e is selected from C (O), CH or N;
when formula I has a structure shown in formula I-2', D is selected from O, C (O), CH 2 Or NH;selected from C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, 3-8 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl;
each R a The same or different, independently of one another, are selected from hydrogen, halogen, OH, CN, NO 2 Oxo (=o), thio (=s), unsubstituted or optionally substituted by one, two or more R a1 Substituted with the following groups: c (C) 1-8 Alkyl, C 1-8 Haloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkynyl radicals, C 6-14 Aryl, 5-14 membered heteroaryl, 3-8 membered heterocyclyl, C 1-8 Alkyloxy, C 2-8 Alkenyloxy, C 2-8 Alkynyloxy, C 3-8 Cycloalkyl oxy, C 3-8 Cycloalkenyl oxy, C 3-8 Cycloalkynyloxy, C 6-14 Aryloxy, 5-14 membered heteroaryloxy, 3-8 membered heterocyclyloxy, NH 2 ;
Each R a1 The same or different, independently of one another, from hydrogen, halogen, OH, NH 2 、CN、NO 2 Oxo (=o), thio (=s), C 1-8 Alkyl, C 1-8 Hydroxyalkyl, C 1-8 Haloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkynyl radicals, C 6-14 Aryl, 5-14 membered heteroaryl, 3-8 membered heterocyclyl, C 1-8 Alkylamino, (C) 1-8 Alkyl group 2 An amino group;
r is selected from unsubstituted or optionally substituted with one, two or more R b Substituted with the following groups: c (C) 1-8 Alkyl, C 1-8 Haloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkynyl radicals, C 6-14 Aryl, 5-14 membered heteroaryl, 3-8 membered heterocyclyl, C 1-8 Alkyloxy, C 2-8 Alkenyloxy, C 2-8 Alkynyloxy, C 3-8 Cycloalkyl oxy, C 3-8 Cycloalkenyl oxy, C 3-8 Cycloalkynyloxy, C 6-14 Aryloxy, 5-14 membered heteroaryloxy, 3-8 membered heterocyclyloxy, NH 2 ;
Each R b The same or different, independently of one another, are selected from hydrogen, halogen, OH, CN, NO 2 Oxo (=o), thio (=s), unsubstituted or optionally substituted by one, two or more R b1 Substituted with the following groups: c (C) 1-8 Alkyl, C 1-8 Haloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkynyl radicals, C 6-14 Aryl, 5-14 membered heteroaryl, 3-8 membered heterocyclyl, C 1-8 Alkyloxy, C 2-8 Alkenyloxy, C 2-8 Alkynyloxy, C 3-8 Cycloalkyl oxy, C 3-8 Cycloalkenyl oxy, C 3-8 Cycloalkynyloxy, C 6-14 Aryloxy, 5-14 membered heteroaryloxy, 3-8 membered heterocyclyloxy, NH 2 ;
Each R b1 The same or different, independently of one another, are selected from hydrogen, halogen, OH, CN, NO 2 Oxo (=o), thio (=s), unsubstituted or optionally substituted by one, two or more R b2 Substituted with the following groups: c (C) 1-8 Alkyl, C 1-8 Haloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkynyl radicals, C 6-14 Aryl, 5-14 membered heteroaryl, 3-8 membered heterocyclyl, C 1-8 Alkyloxy, C 2-8 Alkenyloxy, C 2-8 Alkynyloxy, C 3-8 Cycloalkyl oxy, C 3-8 Cycloalkenyl oxy, C 3-8 Cycloalkynyloxy, C 6-14 Aryloxy, 5-14 membered heteroaryloxy, 3-8 membered heterocyclyloxy, NH 2 ;
Each R b2 The same or different, independently of one another, from hydrogen, halogen, OH、CN、NO 2 Oxo (=o), thio (=s), unsubstituted or optionally substituted by one, two or more R b3 Substituted with the following groups: c (C) 1-8 Alkyl, C 1-8 Haloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkynyl radicals, C 6-14 Aryl, 5-14 membered heteroaryl, 3-8 membered heterocyclyl, C 1-8 Alkyloxy, C 2-8 Alkenyloxy, C 2-8 Alkynyloxy, C 3-8 Cycloalkyl oxy, C 3-8 Cycloalkenyl oxy, C 3-8 Cycloalkynyloxy, C 6-14 Aryloxy, 5-14 membered heteroaryloxy, 3-8 membered heterocyclyloxy, NH 2 ;
Each R b3 The same or different, independently of one another, from hydrogen, halogen, OH, NH 2 、CN、NO 2 Oxo (=o), thio (=s), C 1-8 Alkyl, C 1-8 Hydroxyalkyl, C 1-8 Haloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkynyl radicals, C 6-14 Aryl, 5-14 membered heteroaryl, 3-8 membered heterocyclyl.
According to an embodiment of the invention, when a is absent, R' is selected from phenyl, pyridinyl, imidazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, thiazolyl, pyrrolyl, pyrazolyl, phenylamino, pyridinyl amino, imidazolylamino, 1,2, 3-triazolylamino, 1,2, 4-triazolylamino, thiazolylamino, pyrazolylamino, phenyloxy, pyridinyl oxy, imidazolyloxy, 1,2, 3-triazolyloxy, 1,2, 4-triazolyloxy, thiazolyloxy or pyrazolyloxy;
when A is present, A is selected from the group consisting of optionally one, two or more R a Substituted
Each R a Identical or different, independently of one another, from hydrogen, halogen, OH, unsubstituted or optionally substituted by one, two or more R a1 Substituted with the following groups: c (C) 1-8 Alkyl, C 1-8 Hydroxyalkyl, C 1-8 Haloalkyl, C 1-8 Alkyloxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkynyl radicals, C 6-14 Aryl, 5-14 membered heteroaryl, 3-8 membered heterocyclyl, NH 2 ;
Each R a1 The same or different, independently of one another, from the group halogen, OH, NH 2 、C 1-8 Alkyl, C 1-8 Hydroxyalkyl, C 1-8 Haloalkyl, C 3-8 Cycloalkyl, C 1-8 Alkylamino, (C) 1-8 Alkyl group 2 An amino group;
r is selected from unsubstituted or optionally substituted with one, two or more R b Substituted with the following groups: c (C) 1-8 An alkyl group;
each R b Identical or different, independently of one another, from halogen, OH, unsubstituted or optionally substituted by one, two or more R b1 Substituted with the following groups: c (C) 1-8 Alkyl, C 1-8 Haloalkyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, C 6-14 Aryl, 5-14 membered heteroaryl, 3-8 membered heterocyclyl, C 1-8 Alkyloxy, C 3-8 Cycloalkyloxy, 3-8 membered heterocyclyloxy, NH 2 ;
Each R b1 Identical or different, independently of one another, from halogen, OH, oxo (=o), unsubstituted or optionally substituted by one, two or more R b2 Substituted with the following groups: c (C) 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkyloxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, CN, NH 2 ;
Each R b2 Identical or different, independently of one another, from halogen, OH, unsubstituted or optionally substituted by one, two or more R b3 Substituted with the following groups: c (C) 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkyloxy, C 3-8 Cycloalkyl, CN, NH 2 ;
Each R b3 The same or different, independently of one another, from the group halogen, OH, NH 2 、C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkyloxy, C 3-8 Cycloalkyl groups.
According to an embodiment of the invention, the structure of the compound shown in the formula I is shown in the formula I-4, the formula I-5, the formula I-6, the formula I-7, the formula I-8, the formula I-9 or the formula I-10:
wherein m, R a With the definition described above.
According to an embodiment of the present invention, the compound of formula I has the structure shown in formula II:
wherein:
represents a single bond or a double bond;
m is a bond, O, S, NR 5 C (O) or CR 5 R 6 ;
R 1 And R is 2 The same or different, independently of one another, are selected from hydrogen, deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, C 1-8 Alkyl, C 1-8 Alkyloxy, C 1-8 Hydroxyalkyl, C 1-8 Haloalkyl, C 1-8 Alkylamino, (C) 1-8 Alkyl group 2 Amino, amino-C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said amino, C 1-8 Alkyl, C 1-8 Alkyloxy, C 1-8 Hydroxyalkyl, C 1-8 Haloalkyl, C 1-8 Alkylamino, (C) 1-8 Alkyl group 2 Amino, amino-C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, C 1-8 Alkyl, C 1-8 Alkyloxy, C 1-8 Hydroxyalkyl, C 1-8 Haloalkyl, C 1-8 Alkylamino, (C) 1-8 Alkyl group 2 Amino, amino-C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 One or more substituents in aryl and 5-14 membered heteroaryl;
R 3 and R is 4 The same or different, independently of one another, are selected from hydrogen, deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, C 1-8 Alkyl, C 1-8 Alkyloxy, C 1-8 Hydroxyalkyl, C 1-8 Haloalkyl, C 1-8 Alkylamino, (C) 1-8 Alkyl group 2 Amino, amino-C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said amino, C 1-8 Alkyl, C 1-8 Alkyloxy, C 1-8 Hydroxyalkyl, C 1-8 Haloalkyl, C 1-8 Alkylamino, (C) 1-8 Alkyl group 2 Amino, amino-C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, C 1-8 Alkyl, C 1-8 Alkyloxy, C 1-8 Hydroxyalkyl, C 1-8 Haloalkyl, C 1-8 Alkylamino, amino-C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 One or more substituents in aryl and 5-14 membered heteroaryl;
alternatively, R 3 And R is 4 Ligating to form C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, said C 3-8 Cycloalkyl and 3-8 membered heterocyclyl, optionally further substituted with deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, C 1-8 Alkyl, C 1-8 Alkyloxy, C 1-8 Hydroxyalkyl, C 1-8 Haloalkyl, C 1-8 Alkylamino, (C) 1-8 Alkyl group 2 Amino, amino-C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 One or more substituents in aryl and 5-14 membered heteroaryl;
R 5 and R is 6 The same or different, independently of one another, are selected from hydrogen, deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, C 1-8 Alkyl, C 1-8 Alkyloxy, C 1-8 Hydroxyalkyl, C 1-8 Haloalkyl, C 1-8 Alkylamino, (C) 1-8 Alkyl group 2 Amino, amino-C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said amino, C 1-8 Alkyl, C 1-8 Alkyloxy, C 1-8 Hydroxyalkyl, C 1-8 Haloalkyl, C 1-8 Alkylamino, (C) 1-8 Alkyl group 2 Amino, amino-C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, C 1-8 Alkyl, C 1-8 Alkyloxy, C 1-8 Hydroxyalkyl, C 1-8 Haloalkyl, C 1-8 Alkylamino, amino-C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 One or more substituents in aryl and 5-14 membered heteroaryl;
alternatively, R 5 And R is 6 Connection formationC 3-8 Cycloalkyl or 3-8 membered heterocyclyl, said C 3-8 Cycloalkyl and 3-8 membered heterocyclyl, optionally further substituted with deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, C 1-8 Alkyl, C 1-8 Alkyloxy, C 1-8 Hydroxyalkyl, C 1-8 Haloalkyl, C 1-8 Alkylamino, (C) 1-8 Alkyl group 2 Amino, amino-C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 One or more substituents in aryl and 5-14 membered heteroaryl;
E. m and R a With the definition described above.
According to an embodiment of the present invention, the compound of formula I has the structure shown in formula III:
wherein: m is N or CH;
n is 0, 1, 2, 3, 4 or 5;
m、R a and R is b1 With the definition described above.
According to an embodiment of the present invention, the compound of formula I has the structure shown in formula IV:
wherein G is selected from 3-8 membered heterocyclyl groups, e.g. G is selected fromX is the same or different and is independently selected from C, CH, N, NH, O, S; g may be specifically selected from the following groups: /> The 3-8 membered heterocyclic group is unsubstituted or optionally substituted with one, two or more R b1 Substituted heterocyclyl, R a M and R b1 With the definition described above.
According to an embodiment of the invention, said R is selected from the following groups:
according to an embodiment of the invention, theSelected from the following groups:
according to an embodiment of the invention, the structure of the compounds of formula I is as follows:
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the compounds of formula I of the present invention also exist as resonating structures represented by formula IA below, those skilled in the art will appreciate that resonating structures represented by formula IA are the same compounds as those of formula I:
the invention also provides a preparation method of the compound shown in the formula I, which comprises the following steps:
reacting the compound 1 under the action of alkali to obtain a compound shown in a formula I;
wherein a and R have the definitions described above; r is R 0 Identical or different, independently of one another, from C 1-6 Alkyl groups such as methyl, ethyl, propyl;
according to an embodiment of the present invention, the base in scheme 1 may be an inorganic base, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide;
According to an embodiment of the present invention, the reaction may be performed in the presence of a solvent such as an organic solvent or a mixed solvent of an organic solvent and water. For example, the organic solvent may be selected from at least one of the following: alcohols such as methanol, ethanol, isopropanol, and n-butanol; ethers such as ethyl propyl ether, n-butyl ether, anisole, phenetole, cyclohexylmethyl ether, dimethyl ether, diethyl ether, dimethylethylene glycol, diphenyl ether, propyl ether, isopropyl ether, isobutyl ether, isopentyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, methyl tert-butyl ether, tetrahydrofuran, methyltetrahydrofuran, dioxane, dichlorodiethyl ether, and polyethers of ethylene oxide and/or propylene oxide; aliphatic, cycloaliphatic or aromatic hydrocarbons, such as pentane, hexane, heptane, octane, nonane, and hydrocarbons which may be substituted by fluorine and/or chlorine atoms, such as methylene chloride, chloroform, carbon tetrachloride, fluorobenzene, chlorobenzene or dichlorobenzene; cyclohexane, methylcyclohexane, petroleum ether, acetone, octane, benzene, toluene, chlorobenzene, bromobenzene, xylene; esters such as methyl acetate, ethyl acetate, butyl acetate, isobutyl acetate, and dimethyl carbonate, dibutyl carbonate, or vinyl carbonate.
The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of a compound of formula I, racemate, stereoisomer, tautomer, isotopic label, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof.
According to an embodiment of the invention, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.
According to embodiments of the present invention, the pharmaceutical composition may further comprise one or more additional therapeutic agents.
The present invention also provides a method of treating a disease associated with myeloperoxidase, which comprises administering to a patient a prophylactically or therapeutically effective amount of at least one of a compound represented by formula I, racemate, stereoisomer, tautomer, isotopic label, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound thereof.
The invention also provides a method of treating a disease associated with myeloperoxidase comprising administering to a patient a prophylactically or therapeutically effective amount of the above pharmaceutical composition.
The myeloperoxidase-related diseases include neurodegenerative diseases (including but not limited to dementia, parkinson's disease, multiple sclerosis, huntington's disease, amyotrophic lateral sclerosis, multiple system atrophy, aphasia), stroke, epilepsy, depression, traumatic brain injury, cardiovascular diseases (including but not limited to heart failure, atrial fibrillation, atherosclerosis, thrombosis, acute coronary syndrome, pulmonary hypertension, diabetes), novel coronavirus-related disorders.
In some embodiments, the patient comprises a mammal, preferably a human.
The present invention also provides at least one of a compound of formula I, racemate, stereoisomer, tautomer, isotopic label, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof, or a pharmaceutical composition thereof, for use in a myeloperoxidase-related disease.
The invention also provides the use of at least one of a compound shown in formula I, a racemate, a stereoisomer, a tautomer, an isotopic label, a solvate, a polymorph, a pharmaceutically acceptable salt or a prodrug compound thereof in preparing a medicament.
According to an embodiment of the invention, the use may be in the manufacture of a medicament for the treatment of a myeloperoxidase-related disease, such as in the manufacture of a medicament for an MPO inhibitor.
According to embodiments of the present invention, the use may be in the preparation of a medicament for the treatment or prophylaxis of neurodegenerative disorders (including but not limited to dementia, parkinson's disease, multiple sclerosis, huntington's chorea, amyotrophic lateral sclerosis, multiple system atrophy, aphasia), stroke, epilepsy, depression, traumatic brain injury, cardiovascular disorders (including but not limited to heart failure, atrial fibrillation, atherosclerosis, thrombosis, acute coronary syndrome, pulmonary hypertension, diabetes), novel coronavirus related disorders.
The medicament may be used in diseases associated with myeloperoxidase.
Advantageous effects
The compound provided by the invention has good MPO inhibition effect, can be used for treating or preventing diseases and diseases of myeloperoxidase, and can be used for preparing medicines for treating the diseases and the diseases.
Definition and description of terms
Unless otherwise indicated, the radical and term definitions recited in the specification and claims of this application, including as examples, exemplary definitions, preferred definitions, definitions recited in tables, definitions of specific compounds in the examples, and the like, may be arbitrarily combined and coupled with each other. Such combinations and combinations of radical definitions and compound structures should be understood to be within the scope of the description and/or claims herein.
The numerical ranges recited in the specification and claims are equivalent to at least each specific integer number recited therein unless otherwise stated. For example, the numerical range "1 to 40" corresponds to each of the integer numbers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 in the numerical range "1 to 10", and each of the integer numbers 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 in the numerical range "11 to 40". Furthermore, when certain numerical ranges are defined as "numbers," it is to be understood that both endpoints of the range, each integer within the range, and each fraction within the range are delineated. For example, a "number of 0 to 10" should be understood to describe not only each integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, but also at least the sum of each integer with 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, respectively.
It should be understood that in the description of 1,2 or more herein, "more" shall mean an integer greater than 2, such as greater than or equal to 3, such as 3, 4, 5, 6, 7, 8, 9 or 10.
The term "halogen" means fluorine, chlorine, bromine and iodine.
The term "C 1-40 Alkyl "is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical having from 1 to 40 carbon atoms. For example, "C 1-10 Alkyl "means straight-chain and branched alkyl having 1,2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms," C 1-8 Alkyl "means straight and branched alkyl having 1,2, 3, 4, 5, 6, 7, or 8 carbon atoms," C 1-6 Alkyl "means havingStraight and branched alkyl groups having 1,2, 3, 4, 5 or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 2, 3-dimethylbutyl, 1, 3-dimethylbutyl, or 1, 2-dimethylbutyl, or the like, or an isomer thereof.
The term "C 2-40 Alkenyl "is understood to mean a straight-chain or branched monovalent hydrocarbon radical which contains one or more double bonds and has from 2 to 40 carbon atoms, preferably" C 2-10 Alkenyl groups). "C 2-10 Alkenyl "is understood to mean preferably a straight-chain or branched monovalent hydrocarbon radical which contains one or more double bonds and has 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, more preferably" C 2-8 Alkenyl groups). "C 2-10 Alkenyl "is understood to mean preferably a straight-chain or branched monovalent hydrocarbon radical which contains one or more double bonds and has 2, 3, 4, 5, 6, 7 or 8 carbon atoms, for example 2, 3, 4, 5 or 6 carbon atoms (i.e.C 2-6 Alkenyl) having 2 or 3 carbon atoms (i.e., C 2-3 Alkenyl). It will be appreciated that where the alkenyl group comprises more than one double bond, the double bonds may be separated from each other or conjugated. The alkenyl is, for example, vinyl, allyl, (E) -2-methylvinyl, (Z) -2-methylvinyl, (E) -but-2-enyl, (Z) -but-2-enyl, (E) -but-1-enyl, (Z) -but-1-enyl, pent-4-enyl, (E) -pent-3-enyl, (Z) -pent-3-enyl, (E) -pent-2-enyl, (E) -pent-1-enyl, (Z) -pent-1-enyl, hex-5-enyl, (E) -hex-4-enyl, (Z) -hex-4-enyl, (E) -hex-3-enyl, (Z) -hex-3-enyl, (E) -hex-2-enyl, (Z) -hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E) -1-methylprop-1-enyl, (Z) -1-methylpropan-1-enyl, 3-methylbutan-3-enyl, 2-methylbutan-3-enyl 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E) -2-methylbut-2-enyl, (Z) -2-methylbut-2-enyl, (E) -1-methylbut-2-enyl, (Z) -1-methylbut-2-enyl, (E) -3-methylbut-1-enyl, (Z) -3-methylbut-1-enyl, (E) -2-methylbut-1-enyl, (Z) -2-methylbut-1-enyl, (E) -1-methylbut-1-enyl, (Z) -1-methylbut-1-enyl, 1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl.
The term "C 2-40 Alkynyl "is understood to mean a monovalent hydrocarbon radical, directly or branched, containing one or more triple bonds and having from 2 to 40 carbon atoms, preferably" C 2-10 Alkynyl groups. The term "C 2-10 Alkynyl "is understood to mean preferably a straight-or branched-chain monovalent hydrocarbon radical which contains one or more triple bonds and has 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, for example 2, 3, 4, 5, 6, 7 or 8 carbon atoms (i.e." C 2-8 Alkynyl ") having 2, 3, 4, 5, or 6 carbon atoms (i.e.," C 2-6 Alkynyl ") having 2 or 3 carbon atoms (" C 2-3 Alkynyl "). The alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylpropan-2-ynyl, 2-methylbutan-3-ynyl, 1-methylbutan-2-ynyl, 3-methylbutan-1-ynyl, 1-ethylpropan-2-ynyl 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2-dimethylbbut-3-ynyl, 1, 1-dimethylbut-3-ynyl, 1-dimethylbut-2-ynyl or 3, 3-dimethylbut-1-ynyl. In particular, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.
The term "C 3-40 Cycloalkyl "is understood to mean a saturated monovalent monocyclic, bicyclic (e.g.Condensed, bridged, spiro) hydrocarbon or tricyclic hydrocarbon rings having 3 to 40 carbon atoms, preferably "C 3-10 Cycloalkyl ", more preferably" C 3-8 Cycloalkyl groups). The term "C 3-10 Cycloalkyl "is understood to mean a saturated monovalent monocyclic, bicyclic (e.g. bridged, spiro) hydrocarbon ring or tricycloalkane having 3,4, 5, 6, 7, 8, 9 or 10 carbon atoms. The C is 3-10 Cycloalkyl can be a monocyclic hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as campholyl, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo [2.1.1 ]]Hexyl, bicyclo [2.2.1]Heptyl, bicyclo [2.2.1]Heptenyl, 6-dimethylbicyclo [3.1.1]Heptyl, 2, 6-trimethylbicyclo [3.1.1]Heptyl, bicyclo [2.2.2]Octyl, 2, 7-diazaspiro [3,5 ]]Nonylalkyl, 2, 6-diazaspiro [3,4 ]]Octyl, or tricyclic hydrocarbon groups such as adamantyl.
The term "3-20 membered heterocyclyl" refers to a saturated or unsaturated, non-aromatic ring or ring system, unless otherwise defined, which is, for example, 4-, 5-, 6-, or 7-membered monocyclic, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic (e.g., fused, bridged, spiro) or 10-, 11-, 12-, 13-, 14-, or 15-membered tricyclic ring system, and which contains at least one, for example, 1, 2, 3,4, 5, or more heteroatoms selected from O, S and N, wherein N and S may also optionally be oxidized to various oxidation states to form nitrogen oxides, -S (O) -or-S (O) 2 -a state of the device. Preferably, the heterocyclic group may be selected from "3-10 membered heterocyclic groups". The term "3-10 membered heterocyclyl" means a saturated or unsaturated, non-aromatic ring or ring system and contains at least one heteroatom selected from O, S and N. The heterocyclic group may be attached to the remainder of the molecule through any of the carbon atoms or a nitrogen atom, if present. The heterocyclic group may include fused or bridged rings as well as spiro rings. In particular, the heterocyclic groups may include, but are not limited to: 4-membered rings such as azetidinyl, oxetanyl; a 5-membered ring such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered rings, e.g. tetrahydrochysenePyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or a 7-membered ring such as diazepanyl. Optionally, the heterocyclyl may be benzo-fused. The heterocyclic group may be bicyclic, such as, but not limited to, a 5,5 membered ring, such as hexahydrocyclopenta [ c ]]Pyrrol-2 (1H) -yl ring, or 5,6 membered bicyclic ring, e.g. hexahydropyrrolo [1,2-a ]]Pyrazin-2 (1H) -yl ring. The heterocyclic group may be partially unsaturated, i.e., it may contain one or more double bonds, such as, but not limited to, dihydrofuranyl, dihydropyranyl, 2, 5-dihydro-1H-pyrrolyl, 4H- [1,3,4 ]Thiadiazinyl, 1,2,3, 5-tetrahydrooxazolyl or 4H- [1,4]Thiazinyl, or it may be benzo-fused, such as, but not limited to, dihydroisoquinolinyl. When the 3-20 membered heterocyclic group is linked to other groups to form the compound of the present invention, the carbon atom on the 3-20 membered heterocyclic group may be linked to other groups, or the heterocyclic atom on the 3-20 membered heterocyclic ring may be linked to other groups. For example, when the 3-20 membered heterocyclic group is selected from piperazinyl, it may be that the nitrogen atom on the piperazinyl group is attached to other groups. Or when the 3-20 membered heterocyclic group is selected from piperidyl, it may be that the nitrogen atom on the piperidyl ring and the carbon atom at the para position thereof are attached to other groups.
The term "C 6-20 Aryl "is understood to mean preferably a mono-, bi-, e.g. fused-, bridged-, spiro-or tricyclic hydrocarbon ring of monovalent aromatic or partly aromatic character having 6 to 20 carbon atoms, which may be a monoaromatic ring or a polyaromatic ring fused together, preferably" C 6-14 Aryl group). The term "C 6-14 Aryl "is understood to mean preferably a mono-, bi-or tricyclic hydrocarbon ring (" C ") having a monovalent aromatic or partially aromatic character of 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms 6-14 Aryl), in particular a ring having 6 carbon atoms ("C) 6 Aryl "), such as phenyl; or biphenyl, or a ring having 9 carbon atoms ("C 9 Aryl "), e.g. indanyl or indenyl, or a ring having 10 carbon atoms (" C 10 Aryl "), such as tetralin, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms (" C " 13 Aryl "), e.g. fluorenyl, or having 1Rings of 4 carbon atoms ("C 14 Aryl "), such as anthracenyl. When said C 6-20 When aryl is substituted, it may be mono-substituted or poly-substituted. The substitution site is not limited, and may be, for example, ortho, para or meta substitution.
The term "5-20 membered heteroaryl" is understood to include such monovalent monocyclic, bicyclic (e.g., fused, bridged, spiro) or tricyclic aromatic ring systems: having 5 to 20 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O and S, such as "5-14 membered heteroaryl". The term "5-14 membered heteroaryl" is understood to include such monovalent monocyclic, bicyclic or tricyclic aromatic ring systems: it has 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and it contains 1 to 5, preferably 1 to 3 heteroatoms each independently selected from N, O and S and, in addition, can be benzo-fused in each case. "heteroaryl" also refers to groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, wherein the attached radical or point is on the heteroaromatic ring. Non-limiting examples include 1-, 2-, 3-, 5-, 6-, 7-, or 8-indolizinyl, 1-, 3-, 4-, 5-, 6-, or 7-isoindolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-indazolyl, 2-, 4-, 5-, 6-, 7-, or 8-purinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-quinolizinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolyl, 1-, 4-, 5-, 6-, 7-, or 8-phthalazinyl (phtalazinyl), 2-, 3-, 4-, 5-, or 6-naphthyridinyl, 2-, 3-, 5-, 6-, 7-, or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7-, or 8-naphthyridinyl, 2-, 4-, 6-, 7-, or 7-, 1-, 3-, 4-, 3-, 5-, 6-, 1-and 2-amino 4-, 5-, 6-, 7-or 8-carbazolylcarbazolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-or 9-carbolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-or 10-phenanthridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-or 9-acridinyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-or 9-pyrimidinyl, 2-, 3-, 4-, 5-, 6-, 8-, 9-or 10-phenanthrolinyl, 1-, 2-, 3-, 4-, 5-, 8-, 9-or 10-phenanthrolinyl 2-, 3-, 4-, 6-, 7-, 8-or 9-phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-or 10-phenothiazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-or 10-phenazinyl, 2-, 3-, 4-, 5-, 6-, or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9-or 10-benzisoquinolinyl, 2-, 3-, 4-or thieno [2,3-b ] furanyl, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-or 11-7H-pyrazino [2,3-c ] carbazolyl, 2-, 3-, 5-, 6-or 7-2H-furo [3,2-b ] -pyranyl, 2-, 3-, 4-, 5-, 7-or 8-5H-pyrido [2,3-d ] -o-oxazinyl, 1-, 3-or 5-1H-pyrazolo [4,3-d ] -oxazolyl, 2-, 4-or 54H-imidazo [4,5-d ] thiazolyl, 3-, 5-or 8-pyrazino [2,3-d ] pyridazinyl, 2-, 3-, 5-or 6-imidazo [2,1-b ] thiazolyl 1-, 3-, 6-, 7-, 8-or 9-furo [3,4-c ] cinnolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10-or 11-4H-pyrido [2,3-c ] carbazolyl, 2-, 3-, 6-or 7-imidazo [1,2-b ] [1,2,4] triazinyl, 7-benzo [ b ] thienyl, 2-, 4-, 5-, 6-or 7-benzoxazolyl, 2-, 4-, 5-, 6-or 7-benzimidazolyl, 2-, 4-, 5-, 6-or 7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-or 9-benzoxepin (benzoxapinyl), 2-, 4-, 5-, 6-, 7-or 8-benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-or 11-4H-pyrrolo [1,2-b ] [2] benzazapinyl. Typical fused heteroaryl groups include, but are not limited to, 2-, 3-, 4-, 5-, 6-, 7-or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-or 7-indolyl, 2-, 3-, 4-, 5-, 6-or 7-benzo [ b ] thienyl, 2-, 4-, 5-, 6-or 7-benzoxazolyl, 2-, 4-, 5-, 6-or 7-benzimidazolyl, and 2-, 4-, 5-, 6-or 7-benzothiazolyl. . When the 5-20 membered heteroaryl is attached to other groups to form the compounds of the invention, the carbon atom on the 5-20 membered heteroaryl ring may be attached to other groups, or the heteroatom on the 5-20 membered heteroaryl ring may be attached to other groups. When the 5-20 membered heteroaryl is substituted, it may be mono-substituted or poly-substituted. And, the substitution site thereof is not limited, and for example, hydrogen attached to a carbon atom on a heteroaryl ring may be substituted, or hydrogen attached to a heteroatom on a heteroaryl ring may be substituted.
The term "spiro" refers to a ring system in which two rings share 1 ring-forming atom.
The term "fused ring" refers to a ring system in which two rings share 2 ring atoms.
The term "bridged ring" refers to a ring system in which two rings share more than 3 ring members.
Unless otherwise indicated, heterocyclyl, heteroaryl or heteroarylene include all possible isomeric forms thereof, e.g. positional isomers thereof. Thus, for some illustrative non-limiting examples, forms that may include substitution at 1, 2, or more of its 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-positions, etc. (if present) or bonding to other groups include pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, and pyridin-4-yl; thienyl or thienylene include thiophen-2-yl, thienylene-2-yl, thiophen-3-yl and thienylene-3-yl; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, and pyrazol-5-yl.
The term "oxo" refers to the substitution of a carbon atom, nitrogen atom or sulfur atom in a substituent with an oxo group (=o) formed after oxidation.
The term "thio" refers to the substitution of a carbon or nitrogen atom in a substituent with an oxo (= S) formed after oxidation.
The term "alkylamino" refers to the radical-NH- (alkyl) wherein alkyl is as defined above. Non-limiting examples of alkylamino groups include: methylamino, ethylamino, propylamino, isopropylamino, butylamino, and the like.
The term "(alkyl) 2 Amino "means-N- (alkyl) 2 Wherein alkyl is as defined above. (alkyl) 2 Non-limiting examples of amino groups include: dimethylamino, methylethylamino, diethylamino, dipropylamino, methylpropylamino, diisopropylamino, dibutylamino, and the like.
The term "alkyloxy (alkoxy)" refers to the radical-O- (alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy. The alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkyloxy, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy or heterocycloalkyloxy.
"haloalkyl" refers to an alkyl group substituted with one or more halogens, where alkyl is as defined above.
Those skilled in the art will appreciate that the compounds of formula (I) may exist in various pharmaceutically acceptable salt forms. If these compounds have a basic center, they may form acid addition salts; if these compounds have an acidic center, they may form base addition salts; these compounds may also form internal salts if they contain both acidic (e.g., carboxyl) and basic (e.g., amino) centers.
The compounds of the invention may exist in the form of solvates (e.g. hydrates) wherein the compounds of the invention comprise a polar solvent as a structural element of the compound lattice, in particular, for example, water, methanol or ethanol. The polar solvent, in particular water, may be present in stoichiometric or non-stoichiometric amounts.
Depending on its molecular structure, the compound of the invention may be chiral and thus various enantiomeric forms may exist. These compounds may thus be present in racemic or optically active form. The compounds of the present invention encompass isomers or mixtures, racemates thereof wherein each chiral carbon is in the R or S configuration. The compounds of the invention or intermediates thereof may be isolated as enantiomer compounds by chemical or physical methods well known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are prepared from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g.N-benzoylproline or N-benzenesulfonylproline) or various optically active camphorsulfonic acids in R and S form. The chromatographic resolution can also advantageously be carried out with the aid of optically active resolving agents, such as dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chiral derivatized methacrylate polymers, immobilized on silica. Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example hexane/isopropanol/acetonitrile.
The corresponding stable isomer may be isolated according to known methods, for example by extraction, filtration or column chromatography.
The term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses or primates, most preferably humans.
The term "therapeutically effective amount" refers to that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought by a researcher, veterinarian, medical doctor or other clinician in a tissue, system, animal, individual or human, which includes one or more of the following: (1) prevention of disease: for example, preventing a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but has not experienced or developed a pathology or symptomatology of the disease. (2) inhibition of disease: for example, inhibiting a disease, disorder or condition (i.e., preventing further development of pathology and/or symptoms) in an individual experiencing or presenting with the pathology or symptoms of the disease, disorder or condition. (3) alleviation of disease: for example, alleviating a disease, disorder or condition (i.e., reversing the pathology and/or symptoms) in an individual experiencing or presenting with the pathology or symptoms of the disease, disorder or condition.
Detailed Description
The technical scheme of the invention will be further described in detail below with reference to specific embodiments. It is to be understood that the following examples are illustrative only and are not to be construed as limiting the scope of the invention. All techniques implemented based on the above description of the invention are intended to be included within the scope of the invention.
Unless otherwise indicated, the starting materials and reagents used in the following examples were either commercially available or may be prepared by known methods.
The invention is further described below in connection with examples, which are not intended to limit the scope of the invention.
The structures of the compounds of the invention are determined by Nuclear Magnetic Resonance (NMR) and/or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (x) are given in parts per million (ppm). NMR was performed using Bruker AVANCE-400 nuclear magnetic resonance apparatus with deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated methanol (CD) 3 OD) and deuterated chloroform (CDCl) 3 ) The internal standard is Tetramethylsilane (TMS).
An Agilent 1200 affinity Series mass spectrometer was used for LC-MS measurement. HPLC was performed using Agilent 1200DAD high performance liquid chromatography (Sunfire C18X 4.6mm column) and Waters 2695-2996 high pressure liquid chromatography (Gimini C18X 4.6mm column).
The thin layer chromatography silica gel plate is prepared from yellow sea HSGF254 or Qingdao GF254 silica gel plate, and TLC has a specification of 0.15-0.20 mm, and the thin layer chromatography separation and purification product has a specification of 0.4-0.5 mm. Column chromatography generally uses 200-300 mesh silica gel of yellow sea as carrier.
The starting materials in the examples of the present invention are known and may be purchased commercially or may be synthesized using or according to methods known in the art.
Example 1
6-chloro-1- (2-isopropoxyethyl) -2-thio-1, 2,3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of 3- ((tert-Butoxycarbonyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester
3-amino-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-001A (1.0 g,6.5 mmol), di-tert-butyl dicarbonate (2.8 g,13.0 mmol) was dissolved in methanol (20 mL) and stirred at reflux for 4 hours. After the reaction is finished, the reaction solution is cooled to room temperature and concentrated under reduced pressure to obtain a crude product. Purification of the crude product by silica gel column chromatography (petroleum ether/ethyl acetate=5/1) gave compound 3- ((tert-butoxycarbonyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-001B (1.7 g, white solid), yield: 99%.
MS m/z(ESI):255[M+1] + .
Second step
Preparation of 3- ((tert-Butoxycarbonyl) amino) -5-chloro-1H-pyrrole-2-carboxylic acid ethyl ester
3- ((tert-Butoxycarbonyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-001B (500 mg,2.0 mmol) was dissolved in chloroform (10 mL) followed by N-chlorosuccinimide (276 mg,2.1 mmol). The reaction mixture was stirred at room temperature overnight. After the reaction is finished, the reaction mixture is decompressed and concentrated to obtain a crude product. Purification of the crude product by silica gel column chromatography (petroleum ether/ethyl acetate/=10/1) gave compound 3- ((tert-butoxycarbonyl) amino) -5-chloro-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-001C (456 mg, pale yellow oil), yield: 76%.
MS m/z(ESI):289[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.42(s,1H),8.36(s,1H),6.48(s,1H),4.25(q,J=7.1Hz,2H),1.45(s,9H),1.28(t,J=7.1Hz,3H).
Third step
Preparation of 3-amino-5-chloro-1H-pyrrole-2-carboxylic acid ethyl ester
3- ((tert-Butoxycarbonyl) amino) -5-chloro-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-001C (200 mg,25 mmol) was dissolved in methanol hydrochloride solution (1 mol/L,5 mL), stirred at room temperature for 2 hours, after the reaction was completed, the reaction solution was neutralized with aqueous sodium hydrogencarbonate solution, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated. 3-amino-5-chloro-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-001D (120 mg, white solid), yield: 92%. MS m/z (ESI): 189[ M+1 ]] + .
Fourth step
Preparation of 3- ((2-isopropoxyethyl) amino) -5-chloro-1H-pyrrole-2-carboxylic acid ethyl ester
Ethyl 3-amino-5-chloro-1H-pyrrole-2-carboxylate Cpd-001D (120 mg,0.64 mmol) was dissolved in methanol (3 mL), acetic acid (38 mg,0.64 mmol) and 2-isopropoxylacetaldehyde (65 mg,0.64 mmol) were added in this order, and stirred at room temperature for half an hour. Sodium cyanoborohydride (40 mg,0.64 mmol) was then added in portions, followed by stirring at room temperature for 16 hours. After the reaction was completed, 5mL of water was added to quench, extraction was performed with ethyl acetate, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and distilled to give crude product, which was purified by column to give 3- ((2-isopropoxyethyl) amino) -5-chloro-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-001E (60 mg, light brown oil), yield: 34%.
MS m/z(ESI):275[M+1] + .
Fifth step
Preparation of 3- (3- (ethoxycarbonyl) -1- (2-isopropoxyethyl) thiourea) -5-chloro-1H-pyrrole-2-carboxylic acid ethyl ester
3- ((2-isopropoxyethyl) amino) -5-chloro-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-001E (60 mg,0.22 mmol) was dissolved in dichloromethane (5 mL), cooled to 0℃and ethyl isothiocyanamide (72 mg,0.26 mmol) was added thereto, followed by stirring at room temperature for 3 hours. After completion of the reaction, the reaction mixture was washed once with water (5 mL), and the organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was isolated and purified by silica gel column (petroleum ether/ethyl acetate=3/1) to give 3- (3- (ethoxycarbonyl) -1- (2-isopropoxyethyl) thiourea) -5-chloro-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-001F (40 mg, light brown oil), yield: 45%.
MS m/z(ESI):406[M+1] + .
Sixth step
Preparation of 1- (2-isopropoxyethyl) -2-thio-1, 2,3, 5-tetrahydro-5-chloro-pyrrolo [3,2-d ] pyrimidin-4-one
3- (3- (ethoxycarbonyl) -1- (2-isopropoxyethyl) thiourea) -5-chloro-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-001F (40 mg,0.10 mmol) was dissolved in ethanol (3 mL), sodium ethoxide (13 mg,0.20 mmol) was added thereto, and the reaction solution was heated to 90℃for reaction for 1 hour. After the reaction was completed, cooled to room temperature and quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and concentrated, and the resulting residue was isolated from the preparation plate to give 1- (2-isopropoxyethyl) -2-thio-1, 2,3, 5-tetrahydro-6-chloro-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-001 (8 mg, white solid), yield: 28%.
MS m/z(ESI):288[M+1] + .
1 H NMR(400MHz,DMSO-d 6 )δ13.30(s,1H),12.33(s,1H),6.44(s,1H),4.44(t,J=6.0Hz,2H),3.70(t,J=6.0Hz,2H),3.58-3.52(m,1H),1.01(d,J=6.0Hz,6H).
Example 2
1- (2-isopropoxyethyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyridinyl [3',2':4,5] pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of ethyl (3-cyanopyridin-2-yl) glycinate
2-Chloricotinic acid Cpd-002A (10 g,72.2 mmol) was dissolved in ethanol (100 mL) with glycine ethyl ester hydrochloride (12.09 g,86.6 mmol) and triethylamine (14.61 g,144.4 mmol). The reaction was carried out at 80℃for 16 hours. After cooling to room temperature, the reaction solution was concentrated. The resulting residue was isolated and purified by silica gel column (petroleum ether/ethyl acetate=10/1) to give ethyl (3-cyanopyridin-2-yl) glycinate Cpd-002B (10.84 g, white solid), yield: 73%.
1 H NMR(400MHz,DMSO-d6)δ8.26(dd,J=4.8,1.6Hz,1H),7.96(dd,J=7.6,1.6Hz,1H),7.50(t,J=6.0Hz,1H),6.72(dd,J=7.6,4.8Hz,1H),4.17-3.89(m,4H),1.17(t,J=7.2Hz,3H).
Second step
Preparation of 3-amino-4H-pyrrolo [2,3-b ] pyridine-2-carboxylic acid ethyl ester
Ethyl (3-cyanopyridin-2-yl) glycinate Cpd-002B (1 g,4.9 mmol) was dissolved in N, N-dimethylformamide (5 mL) and potassium tert-butoxide (820 mg,7.35 mmol) was added thereto. The reaction was carried out at 25℃for 1 hour. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give 3-amino-4H-pyrrolo [2,3-b ] pyridine-2-carboxylic acid ethyl ester Cpd-002C (760 mg, yellow solid), yield: 76%.
1 H NMR(400MHz,DMSO-d6)δ10.93(s,1H),8.31(dd,J=4.4,1.6Hz,1H),8.19(d,J=8.0Hz,1H),6.96(dd,J=8.0,4.4Hz,1H),5.86(s,2H),4.29(q,J=7.2Hz,2H),1.32(t,J=7.2Hz,3H).
Third step
Preparation of ethyl 3- ((2-isopropoxyethyl) amino) -4H-pyrrolo [2,3-b ] pyridine-2-carboxylate
Ethyl 3-amino-4H-pyrrolo [2,3-b ] pyridine-2-carboxylate Cpd-002C (60 mg,5.79 mmol) was dissolved in methanol (3 mL) and 2-isopropoxylacetaldehyde (45 mg,0.44 mmol) and glacial acetic acid (17 mg,0.29 mmol) were added thereto. The reaction mixture was reacted at 25℃for 1 hour. Sodium cyanoborohydride (18.37 mg,0.29 mmol) was added to the reaction solution to continue the reaction for 16 hours. After the reaction was completed, methanol was removed by rotary evaporation, and the resulting residue was extracted with ethyl acetate (15 ml×3), and the organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give ethyl 3- ((2-isopropoxyethyl) amino) -4H-pyrrolo [2,3-b ] pyridine-2-carboxylate Cpd-002D (40 mg, yellow oil), yield: 47%.
MS m/z(ESI):292.1[M+1] +
Fourth step
Preparation of 1- (2-isopropoxyethyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyridinyl [3',2':4,5] pyrrolo [3,2-d ] pyrimidin-4-one
3- ((2-Isopropoxylethyl) amino) -4H-pyrrolo [2,3-b ] pyridine-2-carboxylic acid ethyl ester Cpd-002D (40 mg,0.13 mmol) was dissolved in dichloromethane (2 mL), and ethyl isothiocyanamide (45.9 mg,0.35 mmol) was added thereto, and the reaction solution was reacted at 25℃for 1 hour. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (15 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated. The residue obtained was dissolved in ethanol (2 mL), to which was added sodium ethoxide (148.8 mg,0.43 mmol), and the reaction solution was reacted at 100℃for 10 minutes in a microwave reactor. After cooling, the ethanol was removed by rotary evaporation, methylene chloride (5 mL) was added thereto, and a solid was precipitated, and the solid was filtered off to give 1- (2-isopropoxyethyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyridinyl [3',2':4,5] pyrrolo [3,2-d ] pyrimidin-4-one Cpd-002 (10 mg, yellow solid), yield: 23%.
MS m/z(ESI):305.1[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.85(br,2H),8.55(d,J=3.9Hz,1H),8.50(d,J=8.4Hz,1H),7.31(dd,J=8.3,4.5Hz,1H),4.91(s,2H),3.86(t,J=6.1Hz,2H),3.54(dt,J=12.1,6.1Hz,1H),0.93(d,J=6.0Hz,6H).
Example 3
5- (2-hydroxyethyl) -1- (2-isopropoxyethyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of 3- ((tert-Butoxycarbonyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester
3-amino-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-003A (1.1 g,7.1 mmol) and (BOC) 2 O (3.1 g,14.2 mmol) was dissolved in methanol (50 mL), heated to 60℃under nitrogen and stirred for 12 hours. After the reaction was completed, the reaction liquid was concentrated, and the crude product was separated and purified by silica gel column (petroleum ether/ethyl acetate=1/0-2/1) to give 3- ((t-butoxycarbonyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-003B (1.8 g, white solid), yield: 99%.
MS m/z(ESI):255.0[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ11.52(s,1H),8.32(s,1H),6.89(s,1H),6.51(s,1H),4.25(q,J=5.2Hz,2H),1.46(s,9H),1.29(t,J=5.2Hz,3H).
Second step
Preparation of ethyl 3- ((tert-Butoxycarbonyl) amino) -1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -1H-pyrrole-2-carboxylate
3- ((Boc) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-003B (600 mg,2.36 mmol) and cesium carbonate (1.5 g,4.71 mmol) were dissolved in dimethyl sulfoxide (8 mL), followed by addition of (2-bromoethoxy) (tert-butyl) dimethylsilane (480 mg,3.30 mmol) and stirring at room temperature under nitrogen for 1 hour. After the reaction was completed, the reaction mixture was poured into ice water (100 mL), extracted with ethyl acetate (50 ml×2), washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product, which was purified by separation on a silica gel column (petroleum ether/ethyl acetate=5/1) to give 3- ((t-butoxycarbonyl) amino) -1- (2- ((t-butyldimethylsilyl) oxy) ethyl) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-003C (900 mg, colorless oil), yield: 92%.
MS m/z(ESI):413.0[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ8.58(s,1H),6.97(d,J=2.8Hz,1H),6.49(s,1H),4.28-4.22(m,4H),3.76(t,J=5.3Hz,2H),1.45(s,9H),1.28(t,J=7.1Hz,3H),0.79(s,9H),-0.12(s,6H).
Third step
Preparation of 3-amino-1- (2-hydroxyethyl) -1H-pyrrole-2-carboxylic acid ethyl ester hydrochloride
3- ((tert-Butoxycarbonyl) amino) -1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-003C (1 g,2.4 mmol) was dissolved in 3 mol per liter of methanol hydrochloride (15 mL) and stirred at 40℃for half an hour. After completion of the reaction, the reaction mixture was concentrated to give crude 3-amino-1- (2-hydroxyethyl) -1H-pyrrole-2-carboxylic acid ethyl ester hydrochloride Cpd-003D (0.5 g, white solid), yield: 89%.
1 H NMR(400MHz,DMSO-d6)δ9.80(br,2H),7.13(d,J=2.8Hz,1H),6.23(d,J=2.8Hz,1H),4.35-4.23(m,4H),3.61(t,J=5.6Hz,2H),1.32(t,J=7.2Hz,3H).
Fourth step
Preparation of ethyl 1- (2-hydroxyethyl) -3- ((2-isopropoxyethyl) amino) -1H-pyrrole-2-carboxylate
3-amino-1- (2-hydroxyethyl) -1H-pyrrole-2-carboxylic acid ethyl ester hydrochloride Cpd-003D (700 mg,3.53 mmol), 2-isopropoxylacetaldehyde (721 mg,7.06 mmol) was dissolved in methanol (15 mL), and after two drops of trifluoroacetic acid were added dropwise, the mixture was stirred at room temperature under nitrogen atmosphere for 2 hours, followed by sodium cyanoborohydride (900 mg,14.12 mmol) and stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into water (200 mL), extracted twice with ethyl acetate (100 mL), washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product, which was purified by separation on a silica gel column (petroleum ether/ethyl acetate=2/1) to give 1- (2-hydroxyethyl) -3- ((2-isopropoxyethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-003E (1 g, colorless oil), yield: 40%.
MS m/z(ESI):285.0[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ6.85(d,J=2.8Hz,1H),5.59(d,J=2.8Hz,2H),4.71(t,J=5.2Hz,1H),4.21-4.08(m,4H),3.60-3.46(m,5H),3.14(q,J=5.6Hz,2H),1.26(t,J=7.2Hz,3H),1.09(d,J=6.0Hz,6H).
Fifth step
Preparation of 3- (3- (ethoxycarbonyl) -1- (2-isopropoxyethyl) thiourea) -1- (2-hydroxyethyl) -1H-pyrrole-2-carboxylic acid ethyl ester
1- (2-hydroxyethyl) -3- ((2-isopropoxyethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-003E (200 mg,0.70 mmol) was dissolved in dichloromethane (7 mL) followed by ethyl thioisocyanate (110 mg,0.84 mmol) and stirred under nitrogen at 30℃for 1 hour. After the reaction was completed, the mixture was concentrated at room temperature, and the crude product was purified by wet separation on a silica gel column (petroleum ether/ethyl acetate=1/1) to give 3- (3- (ethoxycarbonyl) -1- (2-isopropoxyethyl) thiourea) -1- (2-hydroxyethyl) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-003F (280 mg, colorless oil), yield: 96%.
MS m/z(ESI):416.0[M+1] + .
Sixth step
Preparation of 5- (2-hydroxyethyl) -1- (2-isopropoxyethyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
3- (3- (ethoxycarbonyl) -1- (2-isopropoxyethyl) thiourea) -1- (2-hydroxyethyl) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-003F (120 mg,0.289 mmol) was dissolved in absolute ethanol (2 mL), and a 20% sodium ethoxide ethanol solution (1.29 g,0.867 mmol) was added thereto and reacted at 100℃under nitrogen atmosphere for 1 hour. After completion of the reaction, quenched by pouring 1 mol per liter of diluted hydrochloric acid solution (100 mL), extracted twice with ethyl acetate (50 mL), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by separation over a silica gel column (petroleum ether/ethyl acetate=1/1) to give 5- (2-hydroxyethyl) -1- (2-isopropoxyethyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-003 (27 mg, white solid), yield: 31%.
MS m/z(ESI):298.0[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.16(s,1H),7.37(d,J=2.4Hz,1H),6.25(d,J=2.4Hz,1H),4.85(t,J=5.2Hz,1H),4.47(t,J=6.0Hz,2H),4.31(t,J=5.2Hz,2H),3.78-3.62(m,4H),3.58(dt,J=12.0,6.0Hz,1H),1.03(d,J=6.0Hz,6H).
Example 4
1- (cyclopropoxyethyl) -2-thio-1, 2,3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of 2-cyclopropyloxy ethanol
Magnesium powder (1.5 g,64 mmol) and elemental iodine (100 mg) were dispersed in anhydrous tetrahydrofuran (10 mL) under nitrogen atmosphere, a solution of dibromoethane (8.1 g,43 mmol) in tetrahydrofuran (15 mL) was slowly added dropwise at 40℃to 55℃and after the addition was completed, the reaction solution was kept warm for 20 minutes, cooled to room temperature, and a solution of 2- (2-bromoethyl) -1, 3-dioxane Cpd-004A (1.8 g,10 mmol) in tetrahydrofuran (10 mL) was slowly added dropwise and kept warm at 50℃overnight. After the reaction was completed, the reaction solution was cooled to room temperature, quenched with saturated aqueous ammonium chloride (50 mL), extracted with dichloromethane, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and rotary distilled to give crude 2-cyclopropylethanol Cpd-004B (500 mg, colorless oil), which was purified by column, yield: 49%.
1 H NMR(400MHz,CDCl 3 )δ3.74-3.68(m,2H),3.64-3.57(m,2H),3.32(tt,J=6.0,3.0Hz,1H),1.92(s,1H),0.62-0.43(m,4H).
Second step
Preparation of 2-cyclopropoxy ethyl trifluoro methane sulfonic acid
2-Cyclopropyloxyethanol Cpd-004B (100 mg,1.0 mmol) and triethylamine (303 mg,3.0 mmol) were dissolved in dry dichloromethane (5 mL). Cooling to 0 ℃, then slowly adding a solution of trifluoromethanesulfonic anhydride (564 mg,2.0 mmol) in dichloromethane (1 mL), stirring for 1 hour at 0 ℃ after the addition, adding water (10 mL) into the mixture after the reaction is finished, extracting the dichloromethane, washing the organic phase by saturated sodium chloride, drying by anhydrous sodium sulfate to obtain a crude product, and purifying by a column to obtain 2-cyclopropoxyethyl trifluoromethanesulfonic acid Cpd-004C (130 mg, light brown liquid), wherein the yield is: 57%.
1 H NMR(400MHz,CDCl 3 )δ4.61(t,J=4.0Hz,2H),3.82(t,J=4.0Hz,2H),3.50-3.45(m,1H),0.62-0.60(m,2H),0.52-0.50(m,2H).
Third step
Preparation of 3- ((2-cyclopropoxyethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester
Ethyl 3-amino-1H-pyrrole-2-carboxylate (66 mg,0.427 mmol) was dissolved in 1, 4-dioxane (4 mL), DIPEA (83 mg,0.64 mmol) and Cpd-004C 2-cyclopropoxyethyltriflate (100 mg,0.427 mmol) were added sequentially and then heated to 80℃for 2.5 hours. After the reaction was completed, 10mL of water was added to quench, extraction was performed with ethyl acetate, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and rotary distilled to obtain crude product, which was purified by column to obtain 3- ((2-cyclopropoxyethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-004D (60 mg, colorless oil), yield: 59%.
1 H NMR(400MHz,DMSO-d 6 )δ10.76(s,1H),6.75(t,J=3.0Hz,1H),5.66(t,J=2.5Hz,1H),5.31(s,1H),4.17(q,J=7.0Hz,2H),3.60-3.53(m,2H),3.48(t,J=6.1Hz,1H),3.20-3.14(m,2H),1.25(t,J=7.1Hz,3H),0.44-0.35(m,4H).
Fourth step
Preparation of 3- (3- (ethoxycarbonyl) -1- (2-cyclopropyloxyethyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester
3- ((2-Cyclopropyloxyethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-004D (60 mg,0.252 mmol) was dissolved in methylene chloride (50 mL), cooled to 0℃and ethyl isothiocyanamide (40 mg,0.302 mmol) was added thereto, followed by stirring at room temperature for 3 hours. After completion of the reaction, the reaction mixture was washed once with water (5 mL), and the organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was isolated and purified by silica gel column (petroleum ether/ethyl acetate=3/1) to give 3- (3- (ethoxycarbonyl) -1- (2-cyclopropyloxyethyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-004E (60 mg, light brown oil), yield: 64%.
1 H NMR(400MHz,CDCl 3 )δ9.32(s,1H),7.50(s,1H),6.99(s,1H),6.21(s,1H),4.66(s,1H),4.30(q,J=8.0Hz,2H),4.12(q,J=8.0Hz,2H),4.04-3.79(m,2H),3.72(s,1H),3.24(s,1H),1.34(t,J=7.1Hz,3H),1.26(t,J=7.1Hz,3H),0.48-0.44(m,4H).
Fifth step
Preparation of 1- (2-cyclopropoxyethyl) -2-thio-1, 2,3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one
3- (3- (ethoxycarbonyl) -1- (2-cyclopropyloxyethyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-004E (60 mg,0.163 mmol) was dissolved in ethanol (2 mL), and sodium ethoxide (16.6 mg,0.244 mmol) was added thereto, and the reaction solution was heated to 90℃for reaction for 1 hour. The reaction solution was cooled to room temperature, a saturated aqueous ammonium chloride solution (5 mL) was then added, extraction was performed with ethyl acetate (10 mL. Times.3), and the organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was isolated by prep. on a silica gel plate (DCM/meoh=20/1) to give 1- (2-cyclopropoxyethyl) -2-thio-1, 2,3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-004 (8 mg, white solid), yield: 20%.
MS m/z(ESI):252[M+1] + .
1 H NMR(400MHz,DMSO-d 6 )δ12.39(s,1H),12.23(s,1H),7.36(t,J=4.0Hz,1H),6.28(t,J=4.0Hz,1H),4.52(t,J=6.0Hz,2H),3.80(t,J=6.0Hz,2H),3.34(s,1H),0.40-0.38(m,4H).
Example 5
1- (4-chloro-2- (1-methylpyrrolidin-2-yl) benzyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of 3- (2-bromo-5-chlorobenzoyl) -1-vinylpyrrolidin-2-one
Sodium hydride (3.00 g,73.90mmol, 60%) was added to toluene (150 mL), warmed to 110℃under nitrogen, and a solution of methyl 2-bromo-5-chlorobenzoate Cpd-005A (15.00 g,56.90 mmol) and 1-vinylpyrrolidin-2-one (6.32 g,56.90 mmol) in toluene (50 mL) was added dropwise. After the completion of the dropwise addition, the reaction mixture was allowed to continue to react at 110℃for 3 hours. The reaction solution was cooled to room temperature and a saturated aqueous ammonium chloride solution (50 mL) was added dropwise thereto, followed by extraction with toluene (250 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=2/1) to give 3- (2-bromo-5-chlorobenzoyl) -1-vinylpyrrolidin-2-one Cpd-005B (3.00 g, yellow solid), yield: 14%.
MS m/z(ESI):328[M+1] + .
Second step
Preparation of 5- (2-bromo-5-chlorophenyl) -3, 4-dihydro-2H-pyrrole
3- (2-bromo-5-chlorobenzoyl) -1-vinylpyrrolidin-2-one Cpd-005B (2.2 g,6.1 mmol) was added to a hydrochloric acid solution (20 mL,5 mol/L), and the reaction mixture was reacted at 100℃for 16 hours. The reaction solution was cooled to 0℃and pH was adjusted to 12-13 with 50% sodium hydroxide solution, the aqueous phase obtained was extracted with dichloromethane (100 mL. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=3/1) to give 5- (2-bromo-5-chlorophenyl) -3, 4-dihydro-2H-pyrrole Cpd-005C (1.0 g, pale yellow oil), yield: 57%.
Third step
Preparation of 2- (2-bromo-5-chlorophenyl) pyrrolidine
5- (2-bromo-5-chlorophenyl) -3, 4-dihydro-2H-pyrrole Cpd-005C (1.0 g,3.9 mmol) was dissolved in methanol (8 mL) and water (2 mL) and sodium borohydride (290 mg,7.8 mmol) was added thereto, and the reaction solution was reacted at 25℃for 16 hours. To the reaction mixture was added a saturated aqueous ammonium chloride solution (20 mL), and the resulting aqueous phase was extracted with dichloromethane (50 mL. Times.2). All organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give 2- (2-bromo-5-chlorophenyl) pyrrolidine Cpd-005D (0.67 g, light yellow oil), yield: 59%.
1 H NMR(400MHz,CDCl 3 )δ7.66(d,J=2.4Hz,1H),7.42(d,J=8.4Hz,1H),7.05(dd,J=8.4,2.2Hz,1H),4.46(t,J=7.4Hz,1H),3.34-2.94(m,2H),2.37(td,J=13.7,7.8Hz,1H),1.85(tdd,J=19.9,12.8,7.0Hz,4H),1.50(dt,J=15.4,7.3Hz,1H).
Fourth step
Preparation of tert-butyl 2- (2-bromo-5-chlorophenyl) pyrrolidine-1-carboxylate
2- (2-bromo-5-chlorophenyl) pyrrolidine Cpd-005D (600 mg,2.53 mmol) was dissolved in methylene chloride (5 mL), to which di-tert-butyl dicarbonate (552.84 mg,2.53 mmol) and triethylamine (255.84 mg,2.53 mmol) were added and reacted at 25℃for 5 hours. The dichloromethane was removed by rotary evaporation and the resulting residue was purified by silica gel column (petroleum ether/ethyl acetate=33/1) to give tert-butyl 2- (2-bromo-5-chlorophenyl) pyrrolidine-1-carboxylate Cpd-005E (600 mg, colorless oil), yield: 68%.
1 H NMR(400MHz,CDCl 3 )δ7.43(d,J=8.5Hz,1H),7.17-7.00(m,2H),5.20-4.96(m,1H),3.74-3.43(m,2H),2.38(qd,J=15.2,7.1Hz,1H),1.88(dt,J=13.4,6.5Hz,2H),1.82-1.72(m,1H),1.46(s,3H),1.19(s,6H).
Fifth step
Preparation of tert-butyl 2- (5-chloro-2-formylphenyl) pyrrolidine-1-carboxylate
Tert-butyl 2- (2-bromo-5-chlorophenyl) pyrrolidine-1-carboxylate Cpd-005E (300 mg,0.83 mmol) was dissolved in dimethyl sulfoxide (3 mL), triethylsilane (337.59 mg,2.90 mmol), N, N-diisopropylethylamine (160.81 mg,1.24 mmol), and bis [ di-tert-butyl- (4-dimethylaminophenyl) phosphine ] palladium (II) dichloride (100 mg) were then added, and the reaction mixture was heated to 90℃for 16 hours. The reaction solution was cooled to room temperature, ethyl acetate (50 mL) was added, saturated sodium chloride solution was washed once, and the organic phase was dried over anhydrous sodium sulfate and concentrated, and the obtained residue was separated and purified by silica gel column (petroleum ether/ethyl acetate=5/1) to give tert-butyl 2- (5-chloro-2-formylphenyl) pyrrolidine-1-carboxylate Cpd-005F (130 mg, yellow oil), yield: 48%.
1 H NMR(400MHz,CDCl 3 )δ10.15(s,1H),7.75(d,J=8.2Hz,1H),7.48-7.28(m,2H),5.77-5.60(m,1H),3.74-3.49(m,2H),2.52(d,J=6.9Hz,1H),1.96-1.77(m,2H),1.74-1.66(m,1H),1.46(s,3H),1.17(s,6H).
Sixth step
Preparation of 3- ((4-chloro-3- (1-methylpyrrolidin-2-yl) benzyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester
Tert-butyl 2- (5-chloro-2-formylphenyl) pyrrolidine-1-carboxylate Cpd-005F (130 mg,0.41 mmol) was dissolved in methanol (5 mL) and ethyl 3-amino-1H-pyrrole-2-carboxylate (70.94 mg,0.46 mmol) was added. The reaction was stirred at 25℃for 30 minutes, sodium cyanoborohydride (39.43 mg,0.62 mmol) was added, and stirring was continued at 25℃for 4 hours. After the reaction was completed, the reaction was quenched with water (1 mL), and ethanol was removed by rotary evaporation. Saturated sodium bicarbonate was added to the residue to adjust its pH to 8, followed by extraction with methylene chloride (50 mL. Times.2). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated. The resulting residue was isolated and purified by silica gel column (petroleum ether/ethyl acetate=5/1) to give ethyl 3- ((2- (1- (tert-butoxycarbonyl) pyrrolidin-2-yl) -4-chlorobenzyl) amino) -1H-pyrrole-2-carboxylate Cpd-005G (120 mg, yellow oil), yield: 57%.
MS m/z(ESI):448[M+1] +
Seventh step
Preparation of tert-butyl 2- (5-chloro-2- ((4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) methyl) phenyl) pyrrolidine-1-carboxylate
3- ((2- (1- (tert-Butoxycarbonyl) pyrrolidin-2-yl) -4-chlorobenzyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-005G (100 mg,0.22 mmol) was dissolved in methanol (5 mL). Ethyl isothiocyanamide (35.05 mg,0.26 mmol) was added. The reaction mixture was reacted at 25℃for 12 hours. Cesium carbonate (217.68 mg,0.66 mmol) was added to the reaction solution, and the mixture was heated to 70℃for 4 hours. The reaction solution was cooled to room temperature, ethyl acetate (10 mL) was added, the saturated sodium chloride solution was washed once, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the obtained residue was separated and purified by silica gel column (petroleum ether/ethyl acetate=6/1) to give Cpd-005H (50 mg, yellow oil), yield: 44%.
1 H NMR(400MHz,CDCl 3 )δ7.32(d,J=2.6Hz,1H),7.18(d,J=7.5Hz,1H),7.07(s,1H),6.76-6.64(m,1H),6.03-5.48(m,3H),5.14(s,1H),3.63(s,1H),3.47(s,1H),1.95-1.68(m,3H),1.42(s,3H),1.17(s,6H).
Eighth step
Preparation of 1- (4-chloro-2- (pyrrolidin-2-yl) benzyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one hydrochloride
Tert-butyl 2- (5-chloro-2- ((4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) methyl) phenyl) pyrrolidine-1-carboxylate Cpd-005H (50 mg,0.11 mmol) was added to a methanol solution of hydrochloric acid (2 mL,2 mol/L), and the reaction was allowed to react at 25℃for 4 hours. After the reaction was completed, the reaction solution was concentrated to give 1- (4-chloro-2- (pyrrolidin-2-yl) benzyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one hydrochloride Cpd-005I (30.0 mg, white solid), yield: 73%.
MS m/z(ESI):361[M+1] + .
Ninth step
Preparation of 1- (4-chloro-2- (1-methylpyrrolidin-2-yl) benzyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
1- (4-chloro-2- (pyrrolidin-2-yl) benzyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one hydrochloride Cpd-005I (20 mg,0.05 mmol) was dissolved in methanol (2 mL), paraformaldehyde (9 mg,0.1 mg) was added, stirred at room temperature for 1 hour, sodium cyanoborohydride (6 mg,0.1 mmol) was added, and stirred at room temperature for 3 hours. The reaction solution was concentrated to give silica gel plate separation (DCM/meoh=10/1) to give 1- (4-chloro-2- (1-methylpyrrolidin-2-yl) benzyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-005 (10 mg, white solid), yield: 53%
MS m/z(ESI):375[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.50(s,1H),12.40(s,1H),7.56(s,1H),7.32(s,1H),7.16(d,J=8.0Hz,1H),6.65(s,1H),5.94(s,1H),5.71(s,1H),3.50(t,J=8.0Hz,1H),3.20(t,J=8.0Hz,1H),2.33-2.30(m,2H),2.21(s,3H),1.84-1.82(m,2H),1.65-1.50(m,1H).
Example 6
1- (4-chloro-2- (1-methylpyrrolidin-2-yl) benzyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of 3- (5-bromo-2-chlorobenzoyl) -1-vinylpyrrolidin-2-one
Sodium hydride (1.04 g,26.1mmol, 60%) was added to toluene (25 mL), warmed to 110℃under nitrogen, and a mixture of ethyl 2-chloro-5-bromobenzoate Cpd-006A (5.0 g,20.0 mmol) and 1-vinylpyrrolidin-2-one (2.36 g,21.2 mmol) was added dropwise. After the completion of the dropwise addition, the reaction mixture was allowed to continue to react at 110℃for 3 hours. The reaction solution was cooled to room temperature and a saturated aqueous ammonium chloride solution (10 mL) was then added dropwise thereto, followed by extraction with toluene (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The resulting residue was isolated and purified by silica gel column (petroleum ether/ethyl acetate=2/1) to give 3- (2-bromo-5-chlorobenzoyl) -1-vinylpyrrolidin-2-one Cpd-006B (3.00 g, brown oil), yield: 41%.
MS m/z(ESI):328[M+1] + .
Second step
Preparation of 5- (2-chloro-5-bromophenyl) -3, 4-dihydro-2H-pyrrole
3- (2-chloro-5-bromobenzoyl) -1-vinylpyrrolidin-2-one Cpd-006B (3.0 g,9.1 mmol) was added to a 5 mol/L hydrochloric acid solution (30 mL) and the reaction stirred at 100deg.C for 16 hours. The reaction solution was cooled to 0℃and pH was adjusted to 12-13 with 50% sodium hydroxide solution, the aqueous phase obtained was extracted with dichloromethane (100 mL. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated. The resulting residue was isolated and purified by silica gel column (petroleum ether/ethyl acetate=10/1) to give 5- (2-chloro-5-bromophenyl) -3, 4-dihydro-2H-pyrrole Cpd-006C (1.7 g, pale yellow oil), yield: 65%.
1 H NMR(400MHz,CDCl 3 )δ7.76(d,J=2.4Hz,1H),7.43(dd,J=8.4,2.4Hz,1H),7.27-7.24(m,1H),4.07-4.02(m,2H),3.08-2.94(m,2H),2.10-2.01(m,2H).
Third step
Preparation of 2- (2-bromo-5-chlorophenyl) pyrrolidine
5- (2-chloro-5-bromophenyl) -3, 4-dihydro-2H-pyrrole Cpd-006C (1.7 g,6.6 mmol) was dissolved in methanol (20 mL) and water (4 mL), and sodium borohydride (0.5 g,13.2 mmol) was added thereto, and the reaction solution was reacted at 25℃for 16 hours. After the reaction was completed, the reaction was quenched with water (10 mL) and methanol was removed by rotary evaporation. Saturated sodium bicarbonate was added to the residue to adjust its pH to 8, followed by extraction with methylene chloride (50 mL. Times.2). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated. The resulting residue was isolated and purified by silica gel column (petroleum ether/ethyl acetate=10/1) to give 2- (2-bromo-5-chlorophenyl) pyrrolidine Cpd-006D (800 mg, yellow oil), yield: 57%.
1 H NMR(400MHz,CDCl 3 )δ7.84(d,J=2.4Hz,1H),7.42(dd,J=8.4,2.4Hz,1H),7.35(d,J=8.4Hz,1H),4.35(t,J=7.2Hz,1H),3.02-2.92(m,3H),2.32-2.23(m,1H),1.71(dd,J=13.6,7.2Hz,2H),1.32(dd,J=12.4,7.2Hz,1H).
Fourth step
Preparation of 2- (5-bromo-2-chlorophenyl) -1-methylpyrrolidine
2- (2-bromo-5-chlorophenyl) pyrrolidine Cpd-006D (800 mg,3.07 mmol) was dissolved in methanol (20 mL), and paraformaldehyde (147.37 mg,4.91 mmol) was added thereto, and the reaction mixture was reacted at 25℃for 1 hour. Sodium cyanoborohydride (308.7 mg,4.91 mmol) was added and stirring was continued for 16 hours at 25 ℃. To the reaction solution was added ethyl acetate (100 mL), the organic phase was washed with saturated sodium bicarbonate (50 mL), dried over anhydrous sodium sulfate, and concentrated, and the obtained residue was separated and purified by silica gel column (petroleum ether/ethyl acetate=10/1) to give (5-bromo-2-chlorophenyl) -1-methylpyrrolidine Cpd-006E (500 mg, colorless oil), yield: 46%.
1 H NMR(400MHz,CDCl 3 )δ7.77(d,J=2.4Hz,1H),7.29-7.26(m,1H),7.18(d,J=8.4Hz,1H),3.56(t,J=8.4Hz,1H),3.28-3.20(m,1H),2.42-2.33(m,2H),2.23(s,3H)1.91-1.73(m,2H),1.55-1.47(m,1H).
Fifth step
Preparation of 4-chloro-3- (1-methylpyrrolidin-2-yl) benzaldehyde
(5-bromo-2-chlorophenyl) -1-methylpyrrolidine Cpd-006E (700 mg,2.55 mmol) was dissolved in dimethyl sulfoxide (5 mL), triethylsilane (1037 mg,8.92 mmol), N, N-diisopropylethylamine (494 mg,3.82 mmol), and bis [ di-t-butyl- (4-dimethylaminophenyl) phosphine ] palladium (II) dichloride (100 mg) were then added, and the reaction mixture was heated to 90℃for 16 hours. The reaction solution was cooled to room temperature, ethyl acetate (50 mL) was added, the saturated sodium chloride solution was washed once, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the obtained residue was separated and purified by silica gel column (petroleum ether/ethyl acetate=5/1) to give 4-chloro-3- (1-methylpyrrolidin-2-yl) benzaldehyde Cpd-006F (100 mg, yellow oil), yield: 17%.
MS m/z(ESI):224[M+1] + .
Sixth step
Preparation of 3- ((4-chloro-3- (1-methylpyrrolidin-2-yl) benzyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester
4-chloro-3- (1-methylpyrrolidin-2-yl) benzaldehyde Cpd-006F (60 mg,0.27 mmol) was dissolved in methanol (5 mL) and 3-amino-1H-pyrrole-2-carboxylic acid ethyl ester (45.48 mg,0.30 mmol) was added. The reaction solution was stirred at 25℃for 30 minutes, and sodium cyanoborohydride (25.28 mg,0.40 mmol) was added thereto, followed by stirring for 4 hours. After the reaction was completed, the reaction was quenched with water (0.5 mL) and ethanol was removed by rotary evaporation. Saturated sodium bicarbonate was added to the residue to adjust its pH to 8, followed by extraction with methylene chloride (30 mL. Times.2). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated. The resulting residue was isolated and purified by silica gel column (petroleum ether/ethyl acetate=5/1) to give ethyl 3- ((4-chloro-3- (1-methylpyrrolidin-2-yl) benzyl) amino) -1H-pyrrole-2-carboxylate Cpd-006G (30 mg, yellow oil), yield: 30%.
MS m/z(ESI):362[M+1] + .
Seventh step
Preparation of 1- (4-chloro-3- (1-methylpyrrolidin-2-yl) benzyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
3- ((4-chloro-3- (1-methylpyrrolidin-2-yl) benzyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-006G (30 mg,0.08 mmol) was dissolved in methanol (2 mL). Ethyl isothiocyanamide (13.02 mg,0.13 mmol) was added. The reaction mixture was reacted at 25℃for 12 hours. Cesium carbonate (161.66 mg,0.50 mmol) was added to the reaction solution, and the mixture was heated to 70℃to react for 4 hours. The reaction solution was cooled to room temperature, ethyl acetate (10 mL), saturated sodium chloride solution was added, washed once, and the organic phase was dried over anhydrous sodium sulfate and concentrated, and the obtained residue was separated and purified by preparative plate (dichloromethane/methanol=20/1) to give 1- (4-chloro-3- (1-methylpyrrolidin-2-yl) benzyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-006 (10.0 mg, pale oil), yield: 16%.
MS m/z(ESI):375[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.57-12.17(m,2H),7.59(d,J=1.6Hz,1H),7.32(dd,J=8.4,5.6Hz,2H),7.12(dd,J=8.0,2.0Hz,1H),6.11(d,J=2.8Hz,1H),5.71(s,2H),3.43(t,J=8.4Hz,1H),3.17-3.11(m,1H),2.27(dd,J=16.8,8.0Hz,2H),2.07(s,3H),1.75(dd,J=14.4,7.2Hz,2H),1.36(dd,J=12.0,7.2Hz,1H).
Example 7
1- (2-isopropoxyethyl) -2-thio-furo [3,2-d ] pyrimidin-4 (1H) -one
First step
Preparation of methyl 3- ((2-isopropoxyethyl) amino) furan-2-carboxylate
Methyl 3-aminofuran-2-carboxylate Cpd-007A (460 mg,3.3 mmol), N, N-diisopropylethylamine (1.26 g,9.8 mmol) and isopropoxyethyl triflate (924 mg,3.9 mmol) were dissolved in dioxane (10 mL) and then heated to 90℃under nitrogen with stirring for 2 hours. After the reaction was completed, the reaction mixture was poured into water (100 mL), extracted twice with ethyl acetate (50 mL), washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was separated and purified by a silica gel column (petroleum ether/ethyl acetate=5/1) to obtain 3- ((2-isopropoxyethyl) amino) furan-2-carboxylic acid methyl ester Cpd-007B (275 mg, colorless oil), yield: 37%.
MS m/z(ESI):228.0[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ7.62(d,J=4.0Hz,1H),6.49(d,J=4.0Hz,1H),5.74(s,1H),3.72(s,3H),3.60-3.53(m,1H),3.49-3.46(m,2H),3.33-3.25(m,2H),1.08(d,J=8.0Hz,6H).
Second step
Preparation of methyl 3- (3- (ethoxycarbonyl) -1- (2-isopropoxyethyl) thiourea) furan-2-carboxylate
Methyl 3- ((2-isopropoxyethyl) amino) furan-2-carboxylate Cpd-007B (200 mg,0.88 mmol) and ethyl isothiocyanato (139 mg,1.06 mmol) were dissolved in dichloromethane (5 mL) and stirred at room temperature under nitrogen for half an hour. After the reaction was completed, the crude product obtained by concentration of the reaction solution was separated and purified by a silica gel column (petroleum ether/ethyl acetate=1/1) to obtain methyl 3- (3- (ethoxycarbonyl) -1- (2-isopropoxyethyl) thiourea) furan-2-carboxylate Cpd-007C (200 mg, brown oil), yield: 63%.
MS m/z(ESI):359.0[M+1] +
Third step
Preparation of 1- (2-isopropoxyethyl) -2-thio-furo [3,2-d ] pyrimidin-4 (1H) -one
Methyl 3- (3- (ethoxycarbonyl) -1- (2-isopropoxyethyl) thiourea) furan-2-carboxylate Cpd-007C (70 mg,0.20 mmol) was dissolved in ethanol (3 mL) followed by sodium ethoxide (53 mg,0.78 mmol) under nitrogen blanket and heated to 100deg.C with microwave stirring for half an hour. After the reaction was completed, the reaction solution was quenched with hydrochloric acid (2 mol/L,20 mL), extracted twice with ethyl acetate (50 mL), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the obtained crude product was separated and purified by a silica gel column (petroleum ether/ethyl acetate=2/1) to give 1- (2-isopropoxyethyl) -2-thio-furo [3,2-d ] pyrimidin-4 (1H) -one Cpd-007 (10 mg, white solid), yield: 19%.
MS m/z(ESI):255.0[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.74(s,1H),8.19(d,J=1.5Hz,1H),7.02(d,J=1.7Hz,1H),4.48(t,J=5.5Hz,2H),3.74(t,J=5.5Hz,2H),3.52(dt,J=12.1,6.0Hz,1H),0.98(d,J=6.0Hz,6H).
Example 8
1- (3-cyclopropyl-2-yn-1-methylene) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of 3-cyclopropyl-2-propyne-1-aldehyde
3-cyclopropyl-2-propyn-1-ol Cpd-008A (500 mg,5.20 mmol) and manganese dioxide (3165 mg,36.40 mmol) were dissolved in chloroform (10 mL) and stirred at 40℃for 1 hour under nitrogen. After the reaction, the reaction solution is filtered through diatomite, filter residues are washed by methylene dichloride, and the filtrate is concentrated at room temperature to obtain a crude product. After separation and purification on a silica gel column (petroleum ether/ethyl acetate=10/1), 3-cyclopropyl-2-propyne-1-aldehyde Cpd-008B (330 mg, colorless oil) was obtained, yield: 67%.
1 H NMR(400MHz,DMSO-d6)δ9.11(d,J=1.2Hz,1H),1.68-1.61(m,1H),1.09-1.03(m,2H),0.92-0.88(m,2H).
Second step
Preparation of 3- ((3-cyclopropyl-2-alkynyl-1-methylene) amino) -1H-pyrrole-2-carboxylic acid ethyl ester
3-cyclopropyl-2-propyne-1-al (330 mg,3.50 mmol) and 3-amino-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-008B (541 mg,3.50 mmol) were dissolved in methanol (5 mL), two drops of acetic acid were added dropwise, and stirred at room temperature under nitrogen for 1 hour, followed by sodium cyanoborohydride (661mg, 10.51 mmol) and stirred for half an hour. The reaction solution was poured into water (100 mL), ethyl acetate (50 mL) was added to extract twice, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was purified by separation over a silica gel column (petroleum ether/ethyl acetate=4/1) to give 3- ((3-cyclopropyl-2-ynyl-1-methylene) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-008C (360 mg, colorless oil), yield: 40%.
MS m/z(ESI):233.0[M+1] + .
Third step
Preparation of 3- (1- (3-cyclopropyl-2-yne-1-methylene) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester
3- (3-cyclopropyl-2-alkyne-1-methylene) amino-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-008C (230 mg,0.95 mmol) was dissolved in dichloromethane (7 mL), followed by dropwise addition of ethyl isothiocyanate (149 mg,1.14 mmol) at room temperature, stirring under nitrogen for half an hour, concentrating at room temperature after completion of the reaction, and passing the crude product directly through a silica gel column (petroleum ether/ethyl acetate=1/2) by wet method to give 3- (1- (3-cyclopropyl-2-alkyne-1-methylene) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-008D (230 mg, colorless oil), yield: 67%.
MS m/z(ESI):364.0[M+1] + .
Fourth step
Preparation of 1- (3-cyclopropyl-2-yn-1-methylene) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
3- (1- (3-cyclopropyl-2-yne-1-methylene) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-008D (230 mg,0.63 mmol) was dissolved in absolute ethanol (2 mL), and 20% sodium ethoxide ethanol solution (295 mg,1.90 mmol) was added thereto and reacted at 100℃under nitrogen atmosphere for 1 hour. After completion of the reaction, quenched by pouring into a dilute hydrochloric acid solution (100 mL,1 mol/L), extracted twice with ethyl acetate (50 mL), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by a silica gel column (petroleum ether/ethyl acetate=9/1) to give 1- (3-cyclopropyl-2-yn-1-methylene) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-008 (15 mg, white solid), yield: 13%.
MS m/z(ESI):246.0[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.65(s,1H),8.26(s,1H),7.52(t,J=2.8Hz,1H),6.86(t,J=2.4Hz,1H),2.73(d,J=7.2Hz,2H),1.18-0.98(m,1H),0.68-0.52(m,2H),0.40-0.23(m,2H).
Example 9
2-thio-1- [2- (2, 2-trifluoroethoxy) ethyl ] -5H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of ethyl 2- (2, 2-trifluoroethoxy) trifluoromethanesulfonate
2- (2, 2-trifluoroethoxy) ethanol Cpd-009A (300 mg,2.0 mmol), N, N-diisopropylethylamine (800 mg,6.2 mmol) was dissolved in anhydrous dichloromethane (20 mL), stirred under a nitrogen atmosphere at 0℃and trifluoromethanesulfonic anhydride (700 mg,2.5 mmol) was added dropwise thereto. The reaction solution was stirred at room temperature for 1 hour. After the completion of the reaction, ice water (20 mL) was added thereto, followed by extraction with methylene chloride (30 mL. Times.3). The organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude product. The crude product obtained was purified by Flash column (petroleum ether/ethyl acetate=10/1) to give compound 2- (2, 2-trifluoroethoxy) ethyl triflate Cpd-009B (359 mg, pale yellow liquid), yield: 63%.
1 H NMR(400MHz,DMSO-d6)δ4.55-4.42(m,2H),4.18(q,J=9.2Hz,2H),3.87(dd,J=5.2,3.2Hz,2H).
Second step
Preparation of ethyl 3- { [2- (2, 2-trifluoroethoxy) ethyl ] amino } -1H-pyrrole-2-carboxylate
Ethyl 2- (2, 2-trifluoroethoxy) trifluoromethanesulfonate Cpd-009B (300 mg,1.1 mmol), ethyl 3-amino-1H-pyrrole-2-carboxylate (200 mg,1.3 mmol) and N, N-diisopropylethylamine (426 mg,3.3 mmol) were dissolved in 1, 4-dioxane (20 mL), and the reaction mixture was stirred under nitrogen at 80℃for 4 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate (30 mL. Times.3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product obtained was purified by separation on a Flash column (petroleum ether/ethyl acetate=85/15) to give compound 3- { [2- (2, 2-trifluoroethoxy) ethyl ] amino } -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-009C (200 mg, yellow liquid), yield: 66%.
MS m/z(ESI):281[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ10.77(s,1H),6.76(t,J=3.0Hz,1H),5.68(t,J=2.5Hz,1H),5.35(s,1H),4.17(q,J=7.1Hz,2H),4.09(q,J=9.4Hz,2H),3.72(t,J=5.4Hz,2H),3.25(q,J=5.5Hz,2H),1.25(t,J=7.1Hz,3H).
Third step
Preparation of 3- (3- (ethoxycarbonyl) -1- (2, 2-trifluoroethoxy) ethyl) thioureido) -1H-pyrrole-2-carboxylic acid ethyl ester
Ethyl 3- { [2- (2, 2-trifluoroethoxy) ethyl ] amino } -1H-pyrrole-2-carboxylate Cpd-009C (200 mg,0.7 mmol) ethyl isothiocyanamide (112 mmol,0.8 mmol) was dissolved in dichloromethane (20 mL) and the reaction mixture was reacted under nitrogen atmosphere at room temperature for 1 hour. The reaction mixture was quenched with water and extracted with ethyl acetate (30 mL. Times.3). The organic phases were combined and dried over anhydrous sodium sulfate, and concentrated to give crude product. The crude product obtained was isolated and purified using Flash column (petroleum ether/ethyl acetate=85/15) to give compound 3- (3- (ethoxycarbonyl) -1- (2, 2-trifluoroethoxy) ethyl) thioureido) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-009D (200 mg, yellow viscous liquid), yield: 68%.
MS m/z(ESI):413[M+1] + .
Fourth step
Preparation of 2-thio-1- [2- (2, 2-trifluoroethoxy) ethyl ] -5H-pyrrolo [3,2-d ] pyrimidin-4-one
3- (3- (ethoxycarbonyl) -1- (2, 2-trifluoroethoxy) ethyl) thioureido) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-009D (190 mg,0.4607 mmol) was dissolved in ethanol (3 mL) in a microwave tube, and reacted for 30 minutes at 100℃with sodium ethoxide (470 mg,20% ethanol solution). After the completion of the reaction, it was quenched with 5mL of a saturated aqueous ammonium chloride solution, and the precipitated solid was collected by filtration and washed with pure water several times to give the title compound, 2-thio-1- [2- (2, 2-trifluoroethoxy) ethyl ] -5H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-009 (25 mg, white solid), yield: 19%.
MS m/z(ESI):294[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.39(s,1H),12.24(s,1H),7.37(d,J=2.8Hz,1H),6.32(d,J=2.8Hz,1H),4.59(t,J=5.6Hz,2H),4.10(q,J=9.2Hz,2H),3.98(t,J=5.6Hz,2H).
Example 10
2-thio-1- (4, 4-trifluoro-3-hydroxybutyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of ethyl 3- ((tert-butyldimethylsilyl) hydroxy) -4, 4-trifluorobutyrate
Ethyl 3-hydroxy-4, 4-trifluorobutyrate (0.5 g,2.7 mmol) was dissolved in dry N, N-dimethylformamide (2 mL) and cooled to 0deg.C. Imidazole (0.46 g,6.8 mmol) and t-butyldimethylsilyl chloride (0.49 g,3.3 mmol) were then added to the reaction solution. The reaction solution was slowly warmed to room temperature and stirred overnight, then diluted with ethyl acetate and washed twice with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/1) to give compound 3- ((tert-butyldimethylsilyl) hydroxy) -4, 4-trifluorobutyrate Cpd-010B (610 mg, colorless oil), yield: 67%.
1 H NMR(400MHz,DMSO-d6)δ4.66-4.54(m,1H),4.16-4.03(m,2H),2.82(dd,J=15.6,3.2Hz,2H),1.20(t,J=7.2Hz,3H),0.83(s,9H),0.11(s,3H),0.06(s,3H).
Second step
Preparation of 3- ((tert-butyldimethylsilyl) hydroxy) -4, 4-trifluoro-1-butanol
3- ((tert-Butyldimethylsilyl) hydroxy) -ethyl 4, 4-trifluorobutyrate Cpd-010B (500 mg,1.7 mmol) and lithium chloride (280 mg,6.7 mmol) were dispersed in dry ethanol (20 mL), cooled to 0deg.C and stirred for 1 hour, followed by slow addition of sodium borohydride (250 mg,6.7 mmol). The reaction was slowly warmed to room temperature and stirred overnight. After completion of the reaction, water (10 mL) was added, followed by extraction with ethyl acetate (50 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound 3- ((tert-butyldimethylsilyl) hydroxy) -4, 4-trifluoro-1-butanol Cpd-010C (430 mg, colorless oil), yield: 70%.
Third step
Preparation of 3- ((tert-butyldimethylsilyl) hydroxy) -4, 4-trifluorobutanal
3- ((tert-Butyldimethylsilyl) hydroxy) -4, 4-trifluoro-1-butanol Cpd-010C (430 mg,1.7 mmol) was dissolved in dichloromethane (25 mL) and cooled to 0deg.C followed by slow addition of dess-Martin oxidant (470 mg,1.7 mmol). The reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was washed with a saturated sodium thiosulfate solution (10 ml×2) and saturated sodium bicarbonate (10 ml×2), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, the residue was again dispersed in a mixed solvent of petroleum ether/ethyl acetate=5/1, suction-filtered, and the filtrate was collected and concentrated under reduced pressure to give the title compound 3- ((tert-butyldimethylsilyl) hydroxy) -4, 4-trifluorobutyraldehyde Cpd-010D (440 mg, yellow oil), yield: 61%.
Fourth step
Preparation of ethyl 3- ((3- ((tert-butyldimethylsilyl) hydroxy) -4, 4-trifluorobutyl) amino) -1H-pyrrole-2-carboxylate
Ethyl 3-amino-1H-pyrrole-2-carboxylate (250 mg,1.7 mmol) was dissolved in methanol (10 mL) followed by the sequential addition of 3- ((tert-butyldimethylsilyl) hydroxy) -4, 4-trifluorobutyraldehyde Cpd-010D (430 mg,1.7 mmol), acetic acid (100 mg,1.7 mmol) and sodium cyanoborohydride (105 mg,1.7 mmol). The reaction was stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to give the title compound 3- ((3- ((tert-butyldimethylsilyl) hydroxy) -4, 4-trifluorobutyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-010E (330 mg, colorless oil), yield: 47%.
MS m/z(ESI):395[M+1] +
1 H NMR(400MHz,DMSO-d6)δ10.80(s,1H),6.78(d,J=2.4Hz,1H),5.62(s,1H),5.29(s,1H),4.33(s,1H),4.18(q,J=7.2Hz,2H),3.18(d,J=6.4Hz,2H),1.91(dd,J=13.2,3.6Hz,1H),1.75(td,J=14.0,7.2Hz,1H),1.25(t,J=7.2Hz,3H),0.88(s,9H),0.10(d,J=5.6Hz,6H).
Fifth step
Preparation of ethyl 3- (1- (3- ((tert-butyldimethylsilyl) hydroxy) -4, 4-trifluorobutyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylate
- ((3- ((tert-butyldimethylsilyl) hydroxy) -4, 4-trifluorobutyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-010E (150 mg,0.38 mmol) was dissolved in dichloromethane (10 mL) followed by ethyl isothiocyanate (60 mg,0.46 mmol). The reaction was stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was separated with a silica gel preparation plate (dichloromethane/methanol=20/1) to give the title compound, 3- (1- (3- ((tert-butyldimethylsilyl) hydroxy) -4, 4-trifluorobutyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-010F (177 mg, yellow solid), yield: 84%.
MS m/z(ESI):526[M+1] + .
Sixth step
Preparation of 2-thio-1- (4, 4-trifluoro-3-hydroxybutyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
3- (1- (3- ((tert-Butyldimethylsilyl) hydroxy) -4, 4-trifluorobutyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-010F (100 mg,0.19 mmol) was dissolved in methanol (25 mL) followed by cesium carbonate (310 mg,0.95 mmol) and stirred at 65℃for 4 hours. After the reaction was completed, water (10 mL) and ethyl acetate (10 mL) were added, followed by extraction of the aqueous phase with ethyl acetate (10 ml×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated using a silica gel preparation plate (dichloromethane/methanol=20/1) to give the title compound 2-thio-1- (4, 4-trifluoro-3-hydroxybutyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-010 (70 mg, white solid), yield: 97%.
MS m/z(ESI):294[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.45(s,1H),12.20(s,1H),7.40(t,J=2.8Hz,1H),6.43(d,J=6.4Hz,1H),6.32(s,1H),4.58-4.41(m,2H),4.19(dd,J=14.0,7.2Hz,1H),2.12-1.98(m,1H),1.89-1.84(m,1H).
Example 11
1- ((2-azabicyclo [2.2.2] oct-3-yl) methyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of ethyl 2-tolyl-2-azabicyclo [2.2.2] oct-5-ene-3-carboxylate
Ethyl 2-oxoacetate Cpd-011A (7.86 g,77.00 mmol) and 4-toluenesulfonyl isocyanate (7.60 g,38.50 mmol) were dissolved in dry toluene (25 mL), the reaction was reacted at 105℃for 24 hours, then 1, 3-cyclohexadiene (4.63 g,57.75 mmol) was added and the reaction was continued at 105℃for 18 hours. After the reaction was completed, the mixture was cooled to 0 ℃ and a large amount of solid was removed, and the mixture was filtered, and the cake was slurried with petroleum ether/ethyl acetate=10/1, and twice filtered to give ethyl 2-tolyl-2-azabicyclo [2.2.2] oct-5-ene-3-carboxylate Cpd-011B (4.60 g, white solid), yield: 36%.
MS m/z(ESI):335.9[M+1] + .
Second step
Preparation of ethyl 2-tolyl-2-azabicyclo [2.2.2] octane-3-carboxylate
Ethyl 2-tolyl-2-azabicyclo [2.2.2] oct-5-ene-3-carboxylate Cpd-011B (4.60 g,13.67 mmol) was dissolved in a mixed solvent of ethanol (50 mL) and ethyl acetate (250 mL), 10% palladium on carbon (460 mg) was added, the reaction was carried out at room temperature under a hydrogen atmosphere for 18 hours, palladium on carbon was filtered off after the reaction was completed, and the mother liquor was concentrated to give ethyl 2-tolyl-2-azabicyclo [2.2.2] octane-3-carboxylate Cpd-011C (4.50 g, white solid), yield: 97%.
MS m/z(ESI):337.9[M+1] + .
Third step
Preparation of ethyl 2-azabicyclo [2.2.2] octane-3-carboxylate
Ethyl 2-tolyl-2-azabicyclo [2.2.2] octane-3-carboxylate Cpd-011C (2.00 g,5.90 mmol) and phenol (5.55 g,59.00 mmol) were dissolved in ethyl acetate (50 mL), then a solution of hydrogen bromide in acetic acid (30%, 50 mL) was added and reacted at room temperature for 18 hours. After the reaction, acetic acid was removed by rotary evaporation, and extracted with ethyl acetate (30 ml×3) and saturated aqueous sodium bicarbonate (30 mL), and the organic phase was concentrated by drying to give ethyl 2-azabicyclo [2.2.2] octane-3-carboxylate Cpd-011D (1.00 g, pale yellow oil), yield: 93%.
MS m/z(ESI):183.9[M+1] + .
Fourth step
Preparation of 2-azabicyclo [2.2.2] octane-2-carboxylic acid tert-butyl ester-3-carboxylic acid ethyl ester
2-azabicyclo [2.2.2]Ethyl octane-3-carboxylate Cpd-011D (1.00 g,5.50 mmol) was dissolved in dichloromethane (50 mL) and then added (Boc) 2 O (1.80 g,8.25 mmol) and DIEA (1.42 g,11.00 mmol) were reacted at room temperature for 18 hours. After the completion of the reaction, dichloromethane was removed by rotary evaporation, ethyl acetate (50 mL. Times.3) and saturated aqueous potassium hydrogen sulfate (30 mL) were then used for extraction, and the organic phase was concentrated by drying, and the obtained residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate=4/1) to give 2-azabicyclo [ 2.2.2:2:]ethyl octane-2-carboxylate Cpd-011E (1.00 g, colorless oil), yield: 64%.
MS m/z(ESI):228.0(M-56+1).
Fifth step
Preparation of 3- (hydroxymethyl) -2-azabicyclo [2.2.2] octane-2-carboxylic acid tert-butyl ester
Ethyl 2-azabicyclo [2.2.2] octane-2-carboxylate Cpd-011E (1.00 g,3.50 mmol) was dissolved in tetrahydrofuran (10 mL), then a solution of aluminum lithium hydrogen in tetrahydrofuran (17.50 mL,17.50mmol, 1M) was carefully added dropwise under ice bath, the reaction was carried out at room temperature for 18 hours, sodium sulfate decahydrate was added after the reaction was completed, stirred for half an hour, and then filtration was carried out, and the mother liquor was dried and concentrated to give 3- (hydroxymethyl) -2-azabicyclo [2.2.2] octane-2-carboxylate Cpd-011F (0.55 g, colorless oil), yield: 67%.
MS m/z(ESI):242.2[M+1] + .
Sixth step
Preparation of 3-formyl-2-azabicyclo [2.2.2] octane-2-carboxylic acid tert-butyl ester
3- (hydroxymethyl) -2-azabicyclo [2.2.2] octane-2-carboxylic acid tert-butyl ester Cpd-011F (550 mg,2.28 mmol) was dissolved in dichloromethane (20 mL), dess-Martin reagent (1.93G, 4.56 mmol) was added, the reaction was carried out at room temperature for 18 hours, after the completion of the reaction, the solution was filtered, the mother liquor was washed with saturated sodium bicarbonate solution and saturated sodium bisulfite solution in sequence, dichloromethane was removed by spinning, and the obtained residue was separated and purified by silica gel column (petroleum ether/ethyl acetate=100/10) to obtain 3-formyl-2-azabicyclo [2.2.2] octane-2-carboxylic acid tert-butyl ester Cpd-011G (400 mg, colorless oil), yield: 73%.
MS m/z(ESI):184.0(M-56+1).
Seventh step
Preparation of 3- ((2- (ethoxycarbonyl) -1H-pyrrol-3-yl) amino) methyl-2-azabicyclo [2.2.2] octane-2-carboxylic acid tert-butyl ester
3-formyl-2-azabicyclo [2.2.2] octane-2-carboxylic acid tert-butyl ester Cpd-011G (400 mg,1.67 mmol) was dissolved in anhydrous methanol (20 mL), followed by the sequential addition of ethyl 3-amino-1H-pyrrole-2-carboxylate (309 mg,2.01 mmol), sodium cyanoborohydride (315 mg,5.01 mmol) and acetic acid (3 drops) and stirring at room temperature for 3 hours. After the reaction was completed, methanol was removed by rotary evaporation, and the obtained residue was separated and purified by silica gel column (petroleum ether/ethyl acetate=100/10) to give 3- ((2- (ethoxycarbonyl) -1H-pyrrol-3-yl) amino) methyl-2-azabicyclo [2.2.2] octane-2-carboxylic acid tert-butyl ester Cpd-011H (600 mg, colorless oil), yield: 95%.
MS m/z(ESI):378.1[M+1] + .
Eighth step
Preparation of tert-butyl 3- ((2-thio-4-oxo-1, 2,3, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) methyl) -2-azabicyclo [2.2.2] octane-2-carboxylate
3- ((2- (ethoxycarbonyl) -1H-pyrrol-3-yl) amino) methyl-2-azabicyclo [2.2.2] octane-2-carboxylic acid tert-butyl ester Cpd-011H (600 mg,1.59 mmol) was dissolved in anhydrous methanol (20 mL), followed by addition of oxyethyl isothiocyanate (250 mg,1.91 mmol) and stirring at room temperature for 8 hours. Cesium carbonate (1.56 g,4.77 mmol) was added and the reaction was continued for 3 hours at 65℃and after the completion of the reaction, extracted with ethyl acetate (50 mL. Times.3) and saturated brine solution (30 mL), the organic phase was concentrated to give 3- ((2-thio-4-oxo-1, 2,3, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) methyl) -2-azabicyclo [2.2.2] octane-2-carboxylic acid tert-butyl ester Cpd-011I (400 mg, white solid), yield: 65%.
MS m/z(ESI):391.1[M+1] + .
Ninth step
Preparation of 1- ((2-azabicyclo [2.2.2] oct-3-yl) methyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
3- ((2-thio-4-oxo-1, 2,3, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) methyl) -2-azabicyclo [2.2.2] octane-2-carboxylic acid tert-butyl ester Cpd-011I (300 mg,0.77 mmol) was dissolved in anhydrous methanol (10 mL), followed by addition of a methanol solution of hydrochloric acid (1.93 mL,7.70mmol, 4M) and stirring for 2 hours at 65 ℃. After the reaction was completed, methanol was distilled off, the obtained solid was slurried with ethyl acetate, filtered, and the cake was washed with aqueous sodium hydrogencarbonate solution, extracted with ethyl acetate and dried to give Cpd-011 (150 mg, white solid), yield: 67%
MS m/z(ESI):291.0[M+1] + .
Example 12
2-thio-1- ((2-methyl-2-azabicyclo [2.2.2] oct-3-yl) methyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
1- ((2-azabicyclo [2.2.2] oct-3-yl) methyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-011 (50 mg,0.17 mmol) was dissolved in methanol (10 mL), paraformaldehyde (15 mg,0.52 mmol) and sodium cyanoborohydride (33 mg,0.52 mmol) were added sequentially, after 1 hour reaction at room temperature, methanol was removed by spinning, and the residue was prepared to purify (aqueous solution/acetonitrile=100/25 (formic acid 1 mill)) to give 2-thio-1- ((2-methyl-2-azabicyclo [2.2.2] oct-3-yl) methyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-012 (5 mg, white solid), yield: 10%.
MS m/z(ESI):304.9[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.40(s,1H),12.16(s,1H),8.20(s,1H),7.36(s,1H),6.25(d,J=2.4Hz,1H),4.48-4.35(m,1H),4.25-4.22(m,1H),2.81-2.78(m,1H),2.33-2.32(m,4H),2.02-1.78(m,4H),1.47-1.29(m,5H).
Example 13
1- (quinin-4-ylmethyl) -2-thioxy-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of quinine-4-methanol
Quinine-4-ethyl formate Cpd-013A (500 mg,2.73 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) under nitrogen atmosphere, the temperature was controlled between 0℃and 10℃and lithium aluminum hydride (4.1mL,4.1mmol,1M in THF) was slowly reacted at 70℃for 2 hours after the addition. After the reaction was completed, the reaction solution was cooled to 0 ℃, quenched by slowly adding aqueous sodium hydroxide (1 m,0.5 mL) and water (0.5 mL), then added with anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to give Cpd-013B (300 mg, white solid), yield: 78%.
1 H NMR(400MHz,CDCl 3 )δ3.29(s,2H),2.91(t,J=8.0Hz,6H),1.40(t,J=8.0Hz,6H).
Second step
Preparation of quinine-4-carbaldehyde
Quinine-4-methanol Cpd-013B (100 mg,0.71 mmol) was dissolved in dry dichloromethane (5 mL). Cooling to 0 ℃, then adding dess-martin oxidant (361 mg,0.85 mmol) in portions, stirring at room temperature for 1 hour after the addition, adding 10mL of water after the reaction, taking a water phase, washing with dichloromethane, and freeze-drying the water phase to obtain a product Cpd-013C (80 mg, white solid), yield: 80%.
Third step
Preparation of 3- (quinine-4-methylamino) -1H-pyrrole-2-carboxylic acid ethyl ester
Ethyl 3-amino-1H-pyrrole-2-carboxylate (88.5 mg,0.575 mmol) was dissolved in methanol (3 mL), acetic acid (34.5 mg,0.575 mmol) and Cpd-013C (80 mg,0.575 mmol) were added sequentially and stirred at room temperature for 0.5 hours. Sodium cyanoborohydride (36 mg,0.575 mmol) was then added in portions and stirred at room temperature for 16 hours. After the reaction was completed, 5mL of water was added to quench, extraction was performed with ethyl acetate, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and rotary distilled to obtain crude product, which was purified by column to obtain 3- (quinine-4-methylamino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-013D (60 mg, light brown oil), yield: 38%.
MS m/z(ESI):278[M+1] + .
Fourth step
Preparation of 3- (3- (ethoxycarbonyl) -1- (quinine-4-methyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester
3- (quinine-4-methylamino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-013D (60 mg,0.217 mmol) was dissolved in dichloromethane (5 mL) and ethyl isothiocyanamide (34 mg,0.260 mmol) was added thereto, followed by stirring at room temperature for 3 hours. After completion of the reaction, the reaction mixture was washed once with water (5 mL), and the organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was isolated and purified by silica gel column (petroleum ether/ethyl acetate=3/1) to give 3- (3- (ethoxycarbonyl) -1- (quinine-4-methyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-013E (70 mg, light brown oil), yield: 79%.
MS m/z(ESI):409[M+1] + .
Fifth step
Preparation of 1- (quinine-4-methyl) -2-thio-1, 2,3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one
3- (3- (ethoxycarbonyl) -1- (quinine-4-methyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-013E (70 mg,0.171 mmol) was dissolved in methanol (2 mL), cesium carbonate (167 mg, 0.515mmol) was added thereto, and the reaction solution was heated to 65℃for 3 hours. The reaction was cooled to room temperature, saturated aqueous ammonium chloride was then added, DCM/MeOH (10/1) (10 mL. Times.3) was added, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was isolated by prep. on a silica gel plate (DCM/meoh=10/1) to give 1- (quinine-4-methyl) -2-thio-1, 2,3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-013 (30 mg, white solid), yield: 60%.
MS m/z(ESI):291[M+1] + .
1 H NMR(400MHz,DMSO-d 6 )δ12.39(s,1H),12.10(s,1H),7.33(s,1H),6.33(s,1H),5.06(s,1H),3.69(s,1H),2.76(t,J=8.0Hz,6H),1.59-1.51(m,6H).
Example 14
(S) -1- (2-amino-4-methylpentyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of tert-butyl (S) - (4-methyl-1-oxopentan-2-yl) carbamate
Tert-butyl (S) - (1-hydroxy-4-methylpentan-2-yl) carbamate Cpd-014A (1.6 g,7.3 mmol) was dissolved in dichloromethane (20 mL), and dessert (3.7 g,8.8 mmol) was added in portions under ice bath, followed by removal of the ice bath and natural reversion to room temperature under nitrogen protection with stirring for 1 hour. After the reaction was completed, the reaction cloudy solution was filtered through celite, the residue was washed with methylene chloride, and the obtained mother liquor was concentrated to obtain crude product, which was separated and purified by silica gel column (petroleum ether/ethyl acetate=6/1) to obtain tert-butyl (S) - (4-methyl-1-oxopentan-2-yl) carbamate Cpd-014B (1.2 g, colorless oil), yield: 73%.
1 H NMR(400MHz,DMSO-d6)δ9.43(s,1H),7.27(d,J=7.5Hz,1H),3.92-3.80(m,1H),1.63(td,J=13.4,6.6Hz,1H),1.41-1.34(m,11H),0.87(dd,J=10.1,6.6Hz,6H).
Second step
Preparation of (S) -3- ((2- ((tert-Butoxycarbonyl) amino) -4-methylpentyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester
Tert-butyl (S) - (4-methyl-1-oxopentan-2-yl) carbamate Cpd-014B (1.1 g,5.3 mmol), ethyl 3-amino-1H-pyrrole-2-carboxylate (0.8 g,5.3 mmol) and two drops of acetic acid were dissolved in methanol (15 mL), stirred at room temperature under nitrogen for 1 hour, followed by addition of sodium cyanoborohydride (213 mg,3.4 mmol) and stirred at room temperature overnight. After the reaction was completed, the reaction mixture was poured into water (100 mL), ethyl acetate (50 mL) was extracted, the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was purified by separation with a silica gel column (petroleum ether/ethyl acetate=2/1) to give (S) -3- ((2- ((tert-butoxycarbonyl) amino) -4-methylpentyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-014C (1.5 g, colorless oil), yield: 75%.
MS m/z(ESI):354[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ10.69(s,1H),6.74(d,J=8Hz,1H),6.68(d,J=8Hz,1H),5.67(s,1H),5.34(s,1H),4.17-1.14(m,2H),3.62(s,1H),3.12-2.89(m,2H),1.70-1.54(m,1H),1.37(s,9H),1.36-1.26(m,5H),0.85-0.82(m,6H).
Third step
Preparation of (S) -3- (1- (2- ((tert-butoxycarbonyl) amino) -4-methylpentyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester
(S) -3- ((2- ((tert-Butoxycarbonyl) amino) -4-methylpentyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-014C (1.3 g,3.7 mmol) and ethoxycarbonyl isothiocyanate (0.5 g,4.1 mmol) were dissolved in dichloromethane (20 mL) and stirred at room temperature under nitrogen for half an hour. After the reaction was completed, the crude product obtained by concentration of the reaction mixture was purified by silica gel column (petroleum ether/ethyl acetate=1/2) to give (S) -3- (1- (2- ((t-butoxycarbonyl) amino) -4-methylpentyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-014D (1.5 g, colorless oil), yield: 78%.
MS m/z(ESI):485[M+1] + .
Fourth step
Preparation of tert-butyl (S) - (4-methyl-1- (4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) pentan-2-yl) carbamate
(S) -3- (1- (2- ((tert-butoxycarbonyl) amino) -4-methylpentyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-014D (1.5 g,3.0 mmol) was dissolved in ethanol (10 mL) followed by addition of sodium ethoxide (3.1 g,9.0 mmol) under nitrogen protection and microwave heating to 100deg.C for half an hour with stirring. After the completion of the reaction, the reaction mixture was quenched with an aqueous ammonium chloride solution (200 mL), the mixed solvent (dichloromethane/methanol=10/1, 100ml×2) was extracted, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated, and the obtained crude product was separated and purified by a silica gel column (petroleum ether/ethyl acetate=1/1) to give tert-butyl (S) - (4-methyl-1- (4-oxo-2-thio-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) pentan-2-yl) carbamate Cpd-014E (0.8 g, white solid), yield: 70%.
MS m/z(ESI):367[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.26(s,1H),12.09(s,1H),7.35(t,J=2.8Hz,1H),6.60(d,J=9.4Hz,1H),6.40(s,1H)4.65(d,J=11.1Hz,1H),4.36-4.13(m,1H),3.83(s,1H),1.64-1.59(m,1H),1.51-1.39(m,1H),1.27-1.18(m,1H),1.11-1.08(m,9H),0.94-0.79(m,6H).
Fifth step
Preparation of (S) -1- (2-amino-4-methylpentyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Tert-butyl (S) - (4-methyl-1- (4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) pentan-2-yl) carbamate Cpd-014E (400 mg,1.1 mmol) was dissolved in methanol hydrochloride (10 mL, 3M) and the reaction was heated to 30deg.C under nitrogen and stirred for half an hour. After the reaction was completed, the reaction solution was concentrated, and the crude product was purified by C18 reverse phase column (methanol/water (1%fa) =3/7-7/3) to give (S) -1- (2-amino-4-methylpentyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-014 (100 mg, white solid), yield: 34%.
MS m/z(ESI):267[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ7.37(d,J=2.8Hz,1H),6.41(d,J=2.8Hz,1H),4.48(dd,J=13.6,4.7Hz,1H),4.28-4.14(m,1H),3.62-3.54(m,1H),1.95-1.73(m,1H),1.47-1.23(m,2H),0.86(dd,J=38.4,6.5Hz,6H).
Example 15
(S) -1- (2- (dimethylamino) -4-methylpentyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of (S) -1- (2- (dimethylamino) -4-methylpentyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
(S) -1- (2-amino-4-methylpentyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-014 (50 mg,0.18 mmol) was dissolved in methanol (3 mL), followed by addition of paraformaldehyde (322 mg,3.75 mmol) with two drops of acetic acid, followed by addition of sodium cyanoborohydride (94 mg,1.50 mmol) at room temperature and stirring at room temperature for half an hour. After the completion of the reaction, the reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (50 ml×2), and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered to obtain a crude product, which was purified by separation with a silica gel column (petroleum ether/ethyl acetate=1/1) to obtain (S) -1- (2- (dimethylamino) -4-methylpentyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-015 (11 mg, white solid), yield: 19%.
MS m/z(ESI):295[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.36(s,1H),12.11(s,1H),7.36(s,1H),6.29(s,1H),4.35(s,2H),3.41(s,1H),2.23(s,6H),1.66(s,1H),1.48-1.35(m,1H),1.02(d,J=5.8Hz,1H),0.81(dd,J=31.0,5.0Hz,6H).
Example 16
(S) -1- (4-methyl-2- (methylamino) pentyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step preparation of (S, E) -N, N-dimethyl-N' - (4-methyl-1- (4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) pentan-2-yl) carboxamide
Preparation method
(S) -1- (2-amino-4-methylpentyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-014 (70 mg,0.26 mmol) and N, N-dimethylformamide dimethyl acetal (94 mg,0.78 mmol) were dissolved in N, N-dimethylformamide (2 mL) and stirred at room temperature under nitrogen for 2 hours. After the completion of the reaction, the reaction mixture was quenched with water (100 mL), extracted with ethyl acetate (50 ml×2), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give (S, E) -N, N-dimethyl-N' - (4-methyl-1- (4-oxo-2-thio-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) pentan-2-yl) carboxamide Cpd-016A (70 mg, white solid), yield: 58%.
MS m/z(ESI):322[M+1] + .
Second step
Preparation of (S) -1- (4-methyl-2- (methylamino) pentyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
(S, E) -N, N-dimethyl-N' - (4-methyl-1- (4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) pentan-2-yl) carboxamide Cpd-016A (45 mg,0.14 mmol) was dissolved in absolute ethanol (2 mL), sodium borohydride (53 mg,1.40 mmol) was added portionwise under ice-bath followed by stirring for half an hour under nitrogen. After the completion of the reaction, the reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (50 ml×2), and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to Prep-HPLC to give (S) -1- (4-methyl-2- (methylamino) pentyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-016 (5 mg, white solid), yield: 12%.
MS m/z(ESI):281[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.29(br,2H),7.35(d,J=2.7Hz,1H),6.32(d,J=2.7Hz,1H),4.29(s,2H),3.26-3.17(m,1H),2.24(s,3H),1.72(dt,J=13.3,6.5Hz,1H),1.37(dt,J=13.7,6.9Hz,1H),1.16-1.06(m,1H),0.92-0.75(m,6H).
Example 17
1- (spiro [3.3] heptane-2-methyl) -2-thio-1, 2,3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of spiro [3.3] heptane-2-methanol
Spiro [3.3] heptane-2-carboxylic acid Cpd-017A (300 mg,2.14 mmol) was dissolved in tetrahydrofuran (5 mL), cooled to 0 ℃, borane tetrahydrofuran complex (10.7 mL,10.7mmol,1 m) was slowly added, and after completion of the reaction, cooled to 0 ℃, quenched by slow addition of methanol, the reaction was concentrated and the next Cpd-017B (250 mg, white solid) was directly purified without purification, yield: 92%.
1 H NMR(400MHz,CDCl 3 )δ3.55(d,J=8.0Hz,2H),2.37-2.27(m,1H),2.09-2.05(m,2H),2.02-1.96(m,2H),1.91-1.87(m,2H),1.82-1.77(m,2H),1.71-1.67(m,2H).
Second step
Preparation of spiro [3.3] heptane-2-carbaldehyde
Spiro [3.3] heptane-2-methanol Cpd-017B (100 mg,0.79 mmol) was dissolved in dry dichloromethane (5 mL), sodium bicarbonate (80 mg,0.95 mmol) was added, cooled to 0 ℃, then dessert-martin oxidant (402 mg,0.95 mmol) was added slowly in portions, stirred at room temperature for 1 hour after the addition was completed, after the reaction was completed, filtered, the filtrate was washed with aqueous sodium bicarbonate solution, aqueous sodium thiosulfate solution, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate to give crude product, and purified by column to give spiro [3.3] heptane-2-formaldehyde Cpd-017C (80 mg, colorless oil), yield: 81%.
Third step
Preparation of 3- (spiro [3.3] heptane-2-methylamino) -1H-pyrrole-2-carboxylic acid ethyl ester
3-amino-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-017C (99 mg, 0.640 mmol) was dissolved in methanol (50 mL), acetic acid (38.7 mg, 0.640 mmol) and spiro [3.3] heptane-2-carbaldehyde (80 mg, 0.640 mmol) were added sequentially, and stirred at room temperature for 0.5 hours. Sodium cyanoborohydride (40.5 mg, 0.640 mmol) was then added in portions and stirred at room temperature for 16 hours. After the reaction was completed, 5mL of water was added to quench, extraction was performed with ethyl acetate, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and rotary distilled to obtain crude product, which was purified by column to obtain 3- (spiro [3.3] heptane-2-methylamino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-017D (80 mg, light brown oil), yield: 47%.
MS m/z(ESI):263[M+1] + .
Fourth step
Preparation of 3- (3- (ethoxycarbonyl) -1- (spiro [3.3] heptane-2-methyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester
3- (spiro [3.3] heptane-2-methylamino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-017D (80 mg,0.305 mmol) was dissolved in dichloromethane (5 mL), cooled to 0℃and ethyl isothiocyanamide (48 mg,0.366 mmol) was added thereto, followed by stirring at room temperature for 3 hours. After completion of the reaction, the reaction mixture was washed once with water (5 mL), and the organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was isolated and purified by silica gel column (petroleum ether/ethyl acetate=3/1) to give ethyl 3- (3- (ethoxycarbonyl) -1- (spiro [3.3] heptane-2-methyl) thiourea) -1H-pyrrole-2-carboxylate Cpd-017E (40 mg, light brown oil), yield: 33%.
1 H NMR(400MHz,CDCl 3 )δ9.28(s,1H),7.40(s,1H),7.01(t,J=3.1Hz,1H),6.16(t,J=2.8Hz,1H),4.41-4.27(m,3H),4.15-4.10(m,2H),4.04-3.92(m,1H),2.58-2.48(m,1H),1.97-1.88(m,4H),1.84-1.80(m,2H),1.75-1.70(m,2H),1.63-1.56(m,2H),1.35(t,J=7.1Hz,3H),1.20(t,J=7.1Hz,3H).
Fifth step
Preparation of 1- (spiro [3.3] heptane-2-methyl) -2-thio-1, 2,3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one
3- (3- (ethoxycarbonyl) -1- (spiro [3.3] heptane-2-methyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-017E (20 mg,0.051 mmol) was dissolved in ethanol (2 mL), sodium ethoxide (5.2 mg,0.076 mmol) was added thereto, and the reaction mixture was heated to 90℃for 1 hour. The reaction solution was cooled to room temperature, a saturated aqueous ammonium chloride solution was then added thereto, extraction was performed with ethyl acetate (10 mL. Times.3), and the organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was isolated by preparative silica gel plate (DCM/meoh=20/1) to give 1- (spiro [3.3] heptane-2-methyl) -2-thio-1, 2,3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-017 (8 mg, white solid), yield: 57%.
MS m/z(ESI):276[M+1] + .
1 H NMR(400MHz,DMSO-d 6 )δ12.39(s,1H),12.12(s,1H),7.35(s,1H),6.33(s,1H),4.42(d,J=6.8Hz,2H),2.87-2.63(m,1H),2.02-1.84(m,8H),1.79-1.58(m,2H).
Example 18
1- ((hexahydrocyclopentyl [ c ] pyrrol-5-yl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of 5-methylenehexahydrocyclopentyl [ c ] pyrrole-2- (1H) -carboxylic acid tert-butyl ester
Methyl triphenylphosphine Cpd-018A (160 mg,4.44 mmol) was dispersed in 10mL of anhydrous diethyl ether under ice bath, potassium tert-butoxide (500 mg,4.44 mmol) was added, after stirring for one hour, an ether solution (5 mL) of 5-oxo-hexahydrocyclopentyl [ c ] pyrrole-2- (1H) -carboxylic acid tert-butyl ester (500 mg,2.22 mmol) was added to the reaction flask, reacted for 1 hour under ice bath, then stirred at room temperature for 3 hours, 20mL of water was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the residue obtained after concentrating under reduced pressure was chromatographed on (petroleum ether/ethyl acetate=5/1) to give 5-methylene-hexahydrocyclopentyl [ c ] pyrrole-2- (1H) -carboxylic acid tert-butyl ester Cpd-018B (332 mg, colorless oil, yield: 67%.
1 H NMR(400MHz,CDCl 3 )δ4.90-4.87(m,2H),3.55-3.50(m,2H),3.13-3.09(m,2H),2.70-2.65(m,2H),2.59-2.52(m,2H),2.21-2.16(m,2H),1.45(s,9H).
Second step
Preparation of tert-butyl 5- (hydroxymethyl) hexahydrocyclopentyl [ c ] pyrrole-2- (1H) -carboxylate
To a solution of 5-methylenehexahydrocyclopentyl [ C ] pyrrole-2- (1H) -carboxylic acid tert-butyl ester Cpd-018B (330 mg,1.5 mmol) in diethyl ether (10 mL) was slowly added dropwise a 2M solution of borane in tetrahydrofuran (7.5 mL,7.5mmol, 1.0M) at-15 ℃ for 2 hours, 1mol/L sodium oxide solution was added dropwise at low temperature for 1.5mL, after 1 hour at room temperature, 30% hydrogen peroxide 0.5mL was added dropwise to the reaction system, stirred at room temperature for 1 hour, the solvent was concentrated under reduced pressure, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the residue obtained after concentration under reduced pressure was subjected to column chromatography with (petroleum ether/ethyl acetate=1/2) to give 5- (hydroxymethyl) hexahydrocyclopentyl [ C ] pyrrole-2- (1H) -carboxylic acid tert-butyl ester Cpd-018C (200 mg, colorless oil), yield: 56%.
MS m/z(ESI):242.0[M+1] + .
Third step
Preparation of tert-butyl 5- (formyloxy) hexahydrocyclopentyl [ c ] pyrrole-2- (1H) -carboxylate
Tert-butyl 5- (hydroxymethyl) hexahydrocyclopentyl [ C ] pyrrole-2- (1H) -carboxylate Cpd-018C (200 mg,0.83 mmol) was dissolved in dichloromethane (10 mL) and Dess-Martine oxidant (424 mg,1.0 mmol) was added in portions and reacted at room temperature for 1 hour. The reaction solution was filtered, the filtrate was washed with aqueous sodium bicarbonate, aqueous sodium thiosulfate, dried over anhydrous sodium sulfate, and the residue obtained after concentration under reduced pressure was subjected to column chromatography (petroleum ether/ethyl acetate=4/1) to give tert-butyl 5- (carbaldehyde) pyrrole [ c ] 2- (1H) -carboxylate Cpd-018D (120 mg, colorless oil), yield: 60%.
1 H NMR(400MHz,CDCl 3 )δ9.64(s,1H),3.51-3.46(m,2H),3.21-3.14(m,2H),2.89-2.82(m,1H),2.71-2.65(m,2H),2.18-2.10(m,2H),1.46(s,9H).
Fourth step
Preparation of 3- ((5- (methoxy) hexahydrocyclopentyl [ c ] pyrrole-2- (1H) -carboxylic acid tert-butyl ester) amino) -1H-pyrrole-2-carboxylic acid ethyl ester
Ethyl 3-amino-1H-pyrrole-2-carboxylate (77 mg,0.5 mmol) was dissolved in methanol (5 mL), acetic acid (30 mg,0.5 mmol) and tert-butyl 5- (carbaldehyde) hexahydrocyclopentyl [ c ] pyrrole-2- (1H) -carboxylate Cpd-018D (120 mg,0.5 mmol) were added sequentially and stirred at room temperature for 0.5H. Sodium cyanoborohydride (31 mg,0.5 mmol) was then added in portions and stirred at room temperature for 16 hours. After the reaction was completed, 5mL of water was added to quench, extraction was performed with ethyl acetate, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and rotary distilled to obtain crude product, which was purified by column to obtain 5- ((((2- (ethoxycarbonyl) -1H-pyrrol-3-yl) amino) methyl) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester Cpd-018E (70 mg, light brown oil), yield: 48%.
MS m/z(ESI):378.0[M+1] + .
Fifth step
Preparation of ethyl 3- [ 3-ethoxycarbonyl-1- (5- (methoxy) hexahydrocyclopentyl [ c ] pyrrole-2- (1H) -carboxylate) ] -1H-pyrrole-2-carboxylate
Tert-butyl 5- ((((2- (ethoxycarbonyl) -1H-pyrrol-3-yl) amino) methyl) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylate Cpd-018E (70 mg,0.185 mmol) was dissolved in dichloromethane (5 mL), cooled to 0℃and ethyl isothiocyanamide (29 mg,0.223 mmol) was added thereto, followed by stirring at room temperature for 3 hours.
MS m/z(ESI):509.0[M+1] + .
Sixth step
Preparation of 1- (5- (methoxy) hexahydrocyclopentyl [ c ] pyrrole-2- (1H) -carboxylic acid tert-butyl ester) -2-thio-1, 2,3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one
Tert-butylcyclopentyl [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl Cpd-018F (50 mg,0.1 mmol) was dissolved in methanol (2 mL), cesium carbonate (100 mg,0.3 mmol) was added thereto, the reaction mixture was heated to 65 ℃ for 3 hours, the reaction mixture was cooled to room temperature, saturated aqueous ammonium chloride solution (5 mL) was added, ethyl acetate (10 ml×3) was extracted, the organic layer was dried over anhydrous sodium sulfate and concentrated, and the crude product was isolated (DCM/meoh=20/1) by preparative silica gel plate to give tert-butyl 5- (((4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) methyl) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl Cpd-018G (18 mg, white solid) in 47% yield.
MS m/z(ESI):391[M+1] + .
Seventh step
Preparation of 1- ((hexahydrocyclopentyl [ c ] pyrrol-5-yl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Tert-butyl 5- (((4-oxo-2-thiooxo 2,3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) methyl) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylate Cpd-018G (18 mg,0.046 mmol) was dissolved in a solution of hydrogen chloride in dioxane (4 m,2 ml) and stirred at room temperature for 3 hours after completion of the reaction, concentrated, neutralized with saturated sodium bicarbonate, DCM/meoh=10/1 extracted, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the prepared silica gel plate was isolated (DCM/meoh=10/1) to give 1- ((hexahydrocyclopentyl [ c ] pyrrol-5-yl) methyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-018 (10 mg, 75%).
MS m/z(ESI):291[M+1] + .
1 H NMR(400MHz,DMSO-d 6 )δ10.30(br,2H),7.37(s,1H),6.44-6.36(m,1H),4.37(s,2H),3.17-3.13(m,1H),2.86(s,2H),2.74-2.60(m,2H),2.58-2.51(m,2H),1.90-1.84(m,1H),1.67-1.63(m,1H),1.50-1.48(m,1H),1.37-1.34(m,1H).
Example 19
1- ((2-methylhexahydrocyclopentyl [ c ] pyrrol-5-yl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
1- ((hexahydrocyclopentyl [ c ] pyrrol-5-yl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one (8 mg,0.027 mmol) was dissolved in methanol (2 mL), paraformaldehyde (5 mg,0.055 mol) was added, stirred at room temperature for 1 hour, sodium cyanoborohydride (3.5 mg,0.055 mmol) was added, and stirred at room temperature for 3 hours. The reaction was concentrated and separated on a silica gel plate (DCM/meoh=10/1) to give 1- ((2-methylhexahydrocyclopentyl [ c ] pyrrol-5-yl) methyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-019 (5 mg, 59%).
MS m/z(ESI):305[M+1] + .
1 H NMR(400MHz,DMSO-d 6 )δ12.42(s,1H),12.15(s,1H),7.39(s,1H),6.37(s,1H),4.41(s,2H),3.39-3.29(m,2H),3.23-2.98(m,3H),2.93-2.75(m,2H),2.74(s,3H),1.68-1.54(m,2H),1.45-1.41(m,2H).
Example 20
1- (bicyclo [2.2.2] oct-1-ylmethyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of bicyclo [2.2.2] octane-1-methanol
Bicyclo [2.2.2] octane-1-carboxylic acid Cpd-020A (200 mg,1.3 mmol) was dissolved in dry tetrahydrofuran (5 mL) and borane-tetrahydrofuran solution (6.5 mL,1.3 mmol) was slowly added. The reaction was stirred at 30℃overnight. After the reaction was completed, methanol (3 mL) was added to quench the reaction, followed by concentrating the reaction solution under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to give bicyclo [2.2.2] octane-1-methanol Cpd-020B (160 mg, colorless oil), yield: 83%.
1 H NMR(400MHz,DMSO-d6)δ4.25(t,J=5.4Hz,1H),2.97(d,J=5.4Hz,2H),1.48(dd,J=9.2,6.0Hz,7H),1.28(dd,J=10.0,5.6Hz,6H).
Second step
Preparation of bicyclo [2.2.2] octane-1-carbaldehyde
Bicyclo [2.2.2] octane-1-methanol Cpd-020B (160 mg,1.1 mmol) was dissolved in dichloromethane (20 mL) and cooled to 0deg.C, followed by slow addition of dessmartin oxidant (580 mg,1.4 mmol) and stirring of the reaction mixture at room temperature for 1h. After the reaction was completed, the reaction solution was washed with a saturated sodium thiosulfate solution (10 ml×2) and saturated sodium bicarbonate (10 ml×2), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, the residue was again dispersed in a mixed solvent of petroleum ether/ethyl acetate=5/1, suction filtration, and the filtrate was collected and concentrated under reduced pressure to give bicyclo [2.2.2] octane-1-carbaldehyde Cpd-020C (145 mg, yellow oily substance), yield: 45%.
Third step
Preparation of 3- ((bicyclo [2.2.2] octane-1-methyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester
Ethyl 3-amino-1H-pyrrole-2-carboxylate (110 mg,0.7 mmol) was dissolved in methanol (5 mL), followed by the sequential addition of bicyclo [2.2.2] octane-1-carbaldehyde Cpd-020C (100 mg,0.7 mmol), acetic acid (40 mg,0.7 mmol) and sodium cyanoborohydride (45 mg,0.7 mmol). The reaction was stirred at room temperature overnight and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to give the title compound 3- ((bicyclo [2.2.2] octane-1-methyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-020D (85 mg, colorless oil), yield: 40%.
MS m/z(ESI):277[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ10.66(s,1H),6.72(d,J=2.8Hz,1H),5.60(t,J=2.4Hz,1H),5.50-4.86(m,1H),4.18(q,J=7.2Hz,2H),2.74(d,J=6.4Hz,2H),1.57-1.46(m,7H),1.36(dd,J=10.0,5.2Hz,6H),1.26(t,J=7.2Hz,3H).
Fourth step
Preparation of 3- (1- (bicyclo [2.2.2] octane-1-methyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester
3- ((bicyclo [2.2.2] octane-1-methyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-020D (80 mg,0.29 mmol) was dissolved in dichloromethane (10 mL) followed by ethyl isothiocyanate (38 mg,0.29 mmol). The reaction was stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was separated with a silica gel preparation plate (dichloromethane/methanol=20/1) to give the title compound, 3- (1- (bicyclo [2.2.2] octane-1-methyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-020E (40 mg, white solid), yield: 32%.
MS m/z(ESI):408[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ11.91(s,1H),9.05(s,1H),6.97(t,J=2.9Hz,1H),6.22(d,J=2.5Hz,1H),4.23(d,J=8.5Hz,2H),4.18-4.03(m,2H),2.69(s,2H),1.48-1.28(m,13H),1.25(t,J=7.1Hz,3H),1.07(t,J=7.1Hz,3H).
Fifth step
Preparation of 1- (bicyclo [2.2.2] octane-1-methyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
3- (1- (bicyclo [2.2.2] octane-1-methyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-020E (40 mg,0.1 mmol) was dissolved in methanol (5 mL) followed by cesium carbonate (160 mg,0.5 mmol). The reaction solution was heated to 65℃and stirred for 4 hours. After the reaction was completed, water (10 mL) and ethyl acetate (10 mL) were added, followed by extraction of the aqueous phase with ethyl acetate (10 ml×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated using a silica gel preparation plate (dichloromethane/methanol=20/1) to give the title compound 1- (bicyclo [2.2.2] octane-1-methyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-020 (6 mg, white solid), yield: 20%.
MS m/z(ESI):290[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.34(s,1H),12.11(s,1H),7.32(d,J=2.8Hz,1H),6.30(d,J=2.8Hz,1H),5.00(s,1H),3.58(s,1H),1.46(s,13H).
Example 21
1- (2-isopropoxyethyl) -2-thio-7-methyl-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of 3- ((tert-Butoxycarbonyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester
3-amino-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-021A (5 g,32.4 mmol) and di-tert-butyl dicarbonate (14.14 g,64.8 mmol) were dissolved in methanol (50 mL) and reacted at 70℃for 6 hours. The reaction solution was cooled to room temperature, and methanol was removed by rotary evaporation. The resulting residue was isolated and purified by silica gel column (petroleum ether/ethyl acetate=4/1) to give 3- ((tert-butoxycarbonyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-021B (7.6 g, white solid), yield: 87%.
MS m/z(ESI):255[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ11.50(s,1H),8.31(s,1H),6.89(t,J=3.2Hz,1H),6.51(s,1H),4.26(q,J=7.2Hz,2H),1.46(s,9H),1.29(t,J=7.2Hz,3H).
Second step
Preparation of 3- ((tert-Butoxycarbonyl) amino) -4-iodo-1H-pyrrole-2-carboxylic acid ethyl ester
3- ((tert-Butoxycarbonyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-021B (3 g,11.8 mmol) was dissolved in chloroform (30 mL) and N-iodosuccinimide (2.79 g,12.4 mmol) was added thereto. The reaction mixture was reacted at 25℃for 16 hours. The chloroform was removed by rotary evaporation and the resulting residue was purified by silica gel column (petroleum ether/ethyl acetate=5/1) to give 3- ((tert-butoxycarbonyl) amino) -4-iodo-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-021C (1.94 g, yellow solid), yield: 41%.
MS m/z(ESI):381[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.04(s,1H),8.15(s,1H),7.06(d,J=3.3Hz,1H),4.19(q,J=7.1Hz,2H),1.41(s,9H),1.25(t,J=7.1Hz,3H).
Third step
Preparation of 3- ((tert-Butoxycarbonyl) amino) -4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester
3- ((Boc) amino) -4-iodo-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-021C (300 mg,0.78 mmol) was dissolved in a mixed solution of acetone (10 mL) and water (3 mL), to which was added methylboronic acid (51.96 mg,0.86 mmol), potassium carbonate (2793 mg,1.97 mmol) and palladium acetate (18 mg,0.08 mmol). The reaction solution was reacted for 16 hours under the protection of nitrogen at 40 ℃. The reaction solution was cooled to room temperature and the solvent was removed by rotary evaporation, and the obtained residue was separated and purified by silica gel column (petroleum ether/ethyl acetate=9/1) to give 3- ((tert-butoxycarbonyl) amino) -4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-021D (115 mg, white solid), yield: 52%.
MS m/z(ESI):269[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ11.30(s,1H),7.97(s,1H),6.69(d,J=3.2Hz,1H),4.17(q,J=7.2Hz,2H),1.86(s,3H),1.41(s,9H),1.25(t,J=7.2Hz,3H).
Fourth step
Preparation of 3-amino-4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester
3- ((tert-Butoxycarbonyl) amino) -4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-021D (230 mg,0.85 mmol) was dissolved in methanol (3 mL), to which was added 3M methanolic hydrochloride solution (3 mL), and the reaction solution was reacted at 25℃for 16 hours. The acid was neutralized with saturated sodium bicarbonate solution, and then methanol was distilled off, followed by extraction of the residue with ethyl acetate (15 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give 3-amino-4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-021E (126 mg, yellow solid), yield: 79%.
MS m/z(ESI):169[M+1] + .
Fifth step
Preparation of 3- ((2-isopropoxyethyl) amino) -4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester
3-amino-4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-021E (80 mg,0.48 mmol) was dissolved in methanol (3 mL) and 2-isopropoxylacetaldehyde (48 mg,0.48 mmol) and glacial acetic acid (28.5 mg,0.48 mmol) were added thereto. The reaction mixture was reacted at 25℃for 1 hour. Sodium cyanoborohydride (29.8 mg,0.48 mmol) was added to the reaction solution to continue the reaction for 16 hours. After the reaction was completed, methanol was removed by rotary evaporation, the resulting residue was extracted with ethyl acetate (15 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give crude 3- ((2-isopropoxyethyl) amino) -4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-021F (100 mg, yellow oil), yield: 50%.
MS m/z(ESI):255[M+1] + .
Sixth step
Preparation of 3- (3- (ethoxycarbonyl) -1- (2-isopropoxyethyl) thiourea) -4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester
The crude 3- ((2-isopropoxyethyl) amino) -4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-021F (100 mg,0.39 mmol) was dissolved in dichloromethane (5 mL) and ethyl isothiocyanato (62 mg,0.47 mmol) was added thereto for reaction at 25℃for 2 hours. After completion of the reaction, dichloromethane was removed by rotary evaporation, and the resulting residue was separated and purified by a preparative plate (petroleum ether/ethyl acetate=2/1) to give 3- (3- (ethoxycarbonyl) -1- (2-isopropoxyethyl) thiourea) -4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-021G (35 mg, colorless oil), yield: 21%.
MS m/z(ESI):386[M+1] + .
Seventh step
Preparation of 1- (2-isopropoxyethyl) -2-thio-7-methyl-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
3- (3- (ethoxycarbonyl) -1- (2-isopropoxyethyl) thiourea) -4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-021G (35 mg,0.03 mmol) was dissolved in methanol (3 mL), and cesium carbonate (89 mg,0.27 mmol) was added thereto. After the reaction solution was heated to 65 ℃ for 6 hours, the reaction solution was cooled to room temperature to remove methanol by rotary evaporation, water was added to the obtained residue, and after standing and filtration, the cake was dried to obtain 1- (2-isopropoxyethyl) -2-thio-7-methyl-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-021 (10 mg, pale yellow solid), yield: 39%.
MS m/z(ESI):268[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.20(s,1H),12.13(s,1H),7.17(d,J=2.4Hz,1H),4.65(s,2H),3.72(t,J=6.4Hz,2H),3.54-3.51(m,1H),2.31(s,3H),1.02(d,J=6.0Hz,6H).
Example 22
5-hydroxy-1- (2-isopropoxyethyl) -7-methoxy-2-thio-2, 3-dihydro-quinazolin-4 (1H) -one
First step
Preparation of methyl 2-amino-4, 6-dimethoxybenzoate
2-amino-4, 6-dimethoxybenzoic acid Cpd-022A (400 mg,2.03 mmol) was dissolved in DMF (10 mL), potassium carbonate (308 mg,2.23 mmol), methyl iodide (317 mg,2.23 mmol) was added sequentially, the reaction was carried out at room temperature for 2 hours, after the completion of the reaction, quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate (50 mL. Times.3), and the organic phase was concentrated by dryness, and the obtained residue was separated and purified by silica gel column (petroleum ether/ethyl acetate=4/1) to give methyl 2-amino-4, 6-dimethoxybenzoate Cpd-022B (300 mg, white solid), yield: 70%.
MS m/z(ESI):212.0[M+1] + .
Second step
Preparation of methyl 2- ((2-isopropoxyethyl) amino) -4, 6-dimethoxybenzoate
Methyl 2-amino-4, 6-dimethoxybenzoate Cpd-022B (300 mg,1.42 mmol) was dissolved in anhydrous methanol (10 mL), then 2-isopropoxylacetaldehyde (174 mg,1.70 mmol), sodium cyanoborohydride (268 mg,4.26 mmol) and acetic acid (3 drops) were added in this order, and stirred at room temperature for 3 hours. After the reaction was completed, methanol was removed by rotary evaporation, and the obtained residue was separated and purified by silica gel column (petroleum ether/ethyl acetate=100/15) to give methyl 2- ((2-isopropoxyethyl) amino) -4, 6-dimethoxybenzoate Cpd-022C (300 mg, pale yellow oil), yield: 71%.
MS m/z(ESI):298.1[M+1] + .
Third step
Preparation of methyl 2- (3- (ethoxycarbonyl) -1- (2-isopropoxyethyl) thiourea) -4, 6-dimethoxy benzoate
Methyl 2- ((2-isopropoxyethyl) amino) -4, 6-dimethoxybenzoate Cpd-022C (60 mg,0.20 mmol) was dissolved in methanol (10 mL), followed by addition of ethyl isothiocyanamide (32 mg,0.24 mmol), and the reaction mixture was used directly in the next step after completion of the reaction at room temperature for 1 hour.
MS m/z(ESI):429.3[M+1] + .
Fourth step
Preparation of 1- (2-isopropoxyethyl) -5, 7-dimethoxy-2-thio-2, 3-dihydroquinazolin-4 (1H) -one
Cesium carbonate (114 mg,0.35 mmol) was added to methyl 2- (3- (ethoxycarbonyl) -1- (2-isopropoxyethyl) thiourea) -4, 6-dimethoxybenzoate Cpd-022D (50 mg,0.12 mmol) in methanol (10 mL), heated to 65 ℃ and stirred for 3 hours, methanol was removed by rotary evaporation after the reaction was completed, and the resulting residue was separated and purified by silica gel column (petroleum ether/ethyl acetate=1/1) to give 1- (2-isopropoxyethyl) -5, 7-dimethoxy-2-thio-2, 3-dihydro-quinazolin-4 (1H) -one Cpd-022E (15 mg, white solid), yield: 39%.
MS m/z(ESI):324.9[M+1] + .
Fifth step
Preparation of 5-hydroxy-1- (2-isopropoxyethyl) -7-methoxy-2-thio-2, 3-dihydroquinazolin-4 (1H) -one
1- (2-isopropoxyethyl) -5, 7-dimethoxy-2-thio-2, 3-dihydroquinazolin-4 (1H) -one Cpd-022E (10 mg,0.03 mmol) was added to pyridine (1 mL), then magnesium bromide (28 mg,0.15 mmol) was added, the reaction was warmed to 105℃for 2 hours, pyridine was removed by spin evaporation after the reaction was completed, and the obtained residue was separated and purified by silica gel column (petroleum ether/ethyl acetate=4/1) to obtain 5-hydroxy-1- (2-isopropoxyethyl) -7-methoxy-2-thio-2, 3-dihydroquinazolin-4 (1H) -one Cpd-022 (4 mg, white solid), yield: 41%.
MS m/z(ESI):311.0[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.92(s,1H),12.10(d,J=1.2Hz,1H),6.60(s,1H),6.41(s,1H),4.71(s,2H),3.87(d,J=0.8Hz,3H),3.71(t,J=6.0Hz,2H),3.62-3.56(m,1H),1.05(dd,J=6.0,1.2Hz,6H).
Example 23
1- (2-isopropoxyethyl) -7-methoxy-2-thio-2, 3-dihydro-quinazolin-4 (1H) -one
First step
Preparation of methyl 2- ((2-isopropoxyethyl) amino) -4-methoxybenzoate
Methyl 2-amino-4-methoxybenzoate Cpd-023A (100 mg,0.55 mmol) was dissolved in methanol (2 mL) and 2-isopropoxylacetaldehyde (67.6 mg,0.81 mmol) and glacial acetic acid (33.1 mg,0.55 mmol) were added thereto. The reaction mixture was reacted at 25℃for 1 hour. Sodium cyanoborohydride (34.6 mg,0.55 mmol) was added to the reaction solution to continue the reaction for 16 hours. After the reaction was completed, methanol was removed by rotary evaporation, and the obtained residue was separated and purified by silica gel column (petroleum ether/ethyl acetate=9/1) to give methyl 2- ((2-isopropoxyethyl) amino) -4-methoxybenzoate Cpd-023B (90 mg, colorless oil), yield: 55%.
MS m/z(ESI):268[M+1] + .
Second step
Preparation of methyl 2- (3- (ethoxycarbonyl) -1- (2-isopropoxyethyl) thiourea) -4-methoxybenzoate
Methyl 2- ((2-isopropoxyethyl) amino) -4-methoxybenzoate Cpd-023B (80 mg,0.29 mmol) was dissolved in methylene chloride (5 mL), and ethyl isothiocyanamide (117.7 mg,0.89 mmol) was added thereto for reaction at 30℃for 24 hours. After the completion of the reaction, methylene chloride was distilled off, and the obtained residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate=2/1) to give methyl 2- (3- (ethoxycarbonyl) -1- (2-isopropoxyethyl) thiourea) -4-methoxybenzoate Cpd-023C (57 mg, colorless oil), yield: 45%.
MS m/z(ESI):399[M+1] + .
Third step
Preparation of 1- (2-isopropoxyethyl) -7-methoxy-2-thio-2, 3-dihydro-quinazolin-4 (1H) -one
Methyl 2- (3- (ethoxycarbonyl) -1- (2-isopropoxyethyl) thiourea) -4-methoxybenzoate Cpd-023C (50 mg,0.12 mmol) was dissolved in methanol (2 mL), and cesium carbonate (122.6 mg,0.37 mmol) was added thereto. The reaction solution was heated to 65℃and reacted for 6 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature, methanol was removed by rotary evaporation, and the resulting residue was separated and purified by a preparative plate (petroleum ether/ethyl acetate=4/1) to give 1- (2-isopropoxyethyl) -7-methoxy-2-thio-2, 3-dihydroquinazolin-4 (1H) -one Cpd-023 (35 mg, pale yellow solid), yield: 90%.
MS m/z(ESI):295[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.58(s,1H),7.96(d,J=8.8Hz,1H),7.15(d,J=2.0Hz,1H),7.00(dd,J=8.8,2.0Hz,1H),4.80(s,2H),3.92(s,3H),3.77(t,J=6.0Hz,2H),3.59(dt,J=12.0,6.0Hz,1H),1.04(d,J=6.0Hz,6H).
Example 24
1- (2-isopropoxyethyl) -5- (phenylamino) -2-thio-2, 3-dihydropyrimidin-4 (1H) -one
First step
Preparation of 5-iodo-2- (methylthio) pyrimidin-4 (3H) -one
2- (methylthio) -3H-pyrimidin-4-one Cpd-024A (1.0 g,7.0 mmol) was dissolved with iodosuccinimide (1.7 g,7.7 mmol) in tetrahydrofuran (100 mL) and then reacted for two hours at 70℃under nitrogen. After the reaction, the reaction solution was concentrated, ethyl acetate (50 mL) and water (50 mL) were added to the crude product and stirred and beaten, and the mixture was filtered, and the filter cake was rinsed with ethyl acetate to obtain compound 5-iodo-2- (methylthio) pyrimidin-4 (3H) -one 043B (1.5 g, white solid), yield: 80%.
MS m/z(ESI):269[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ13.15(s,1H),8.32(s,1H),2.48(s,3H).
Second step
Preparation of 5-iodo-1- (2-isopropoxyethyl) -2- (methylthio) pyrimidin-4-one
5-iodo-2- (methylsulfanyl) -3H-pyrimidin-4-one Cpd-024B (0.8 g,3.0 mmol) and N, N-diisopropylethylamine (0.8 g,6.0 mmol) were dissolved in dichloromethane (15 mL), followed by dropwise addition of isopropyloxyethyl triflate (0.9 g,3.6 mmol) under ice bath and stirring at room temperature under nitrogen for half an hour after addition. After the reaction was completed, the reaction mixture was diluted with dilute hydrochloric acid (100 mL,1 m), dichloromethane (50 ml×2) was extracted, the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was separated and purified by silica gel column (petroleum ether/ethyl acetate=10/1) to give 5-iodo-1- (2-isopropoxyethyl) -2- (methylthio) pyrimidin-4-one Cpd-024C (1.5 g, colorless oil), yield: 75%.
MS m/z(ESI):355[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ8.20(s,1H),4.03(t,J=5.3Hz,2H),3.64(t,J=5.3Hz,2H),3.53(dt,J=12.1,6.1Hz,1H),2.49(s,3H),1.04(d,J=6.1Hz,6H).
Third step
Preparation of 1- (2-isopropoxyethyl) -2- (methylthio) -5- (phenylamino) pyrimidin-4-one
5-iodo-1- (2-isopropoxyethyl) -2- (methylthio) pyrimidin-4-one Cpd-024C (560 mg,1.6 mmol), aniline (254 mg,3.2 mmol), tris (dibenzylideneacetone) dipalladium (72 mg,0.08 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (91 mg,0.16 mmol) and cesium carbonate (1.0 g,3.2 mmol) were dissolved in anhydrous dioxane (80 mL) and reacted at 90℃under nitrogen atmosphere for 4 hours. After the reaction was completed, the reaction solution was filtered through celite, and the filtrate was concentrated, and the obtained crude product was separated and purified by silica gel column (petroleum ether/ethyl acetate=1/1) to obtain 1- (2-isopropoxyethyl) -2- (methylsulfanyl) -5- (phenylamino) pyrimidin-4-one Cpd-024D (1.2 g, white solid), yield: 83%.
MS m/z(ESI):320[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ7.62(s,1H),7.35(s,1H),7.28-7.16(m,4H),6.86(t,J=6.8Hz,1H),4.10(t,J=5.1Hz,2H),3.69(t,J=5.2Hz,2H),3.58(dt,J=12.2,6.1Hz,1H),2.53(s,3H),1.07(d,J=6.1Hz,6H).
Fourth step
Preparation of 1- (2-isopropoxyethyl) -5- (phenylamino) -2-thio-2, 3-dihydropyrimidin-4 (1H) -one
1- (2-Isopropoxylethyl) -2- (methylthio) -5- (phenylamino) pyrimidin-4-one Cpd-024D (100 mg,0.31 mmol) was dissolved in N-methylpyrrolidone (2 mL) with sodium hydrosulfide solid (88 mg,1.56 mmol) followed by heating to 100deg.C under nitrogen and stirring for 1 hour. After the completion of the reaction, the reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (50 ml×2), and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was separated and purified by silica gel column (petroleum ether/ethyl acetate=1/1) to give 1- (2-isopropoxyethyl) -5- (phenylamino) -2-thio-2, 3-dihydropyrimidin-4 (1H) -one Cpd-024 (50 mg, white solid), yield: 52%.
MS m/z(ESI):306[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.81(s,1H),7.62(s,1H),7.48(s,1H),7.21(t,J=7.8Hz,2H),7.11(d,J=7.9Hz,2H),6.83(t,J=7.2Hz,1H),4.35(t,J=5.0Hz,2H),3.71(t,J=5.0Hz,2H),3.57(dt,J=12.2,6.1Hz,1H),1.07(d,J=6.1Hz,6H).
Example 25
1- (1-adamantylmethyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of 1-adamantane-formaldehyde
1-adamantanemethanol Cpd-025A (300 mg,1.8 mmol) was dissolved in anhydrous dichloromethane (20 mL) and dess-Martin oxidant (918 mg,2.2 mmol) was slowly added. The reaction solution was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was quenched by addition of a saturated sodium thiosulfate solution (30 mL), and the organic phase was washed with a saturated sodium carbonate solution (30 mL. Times.2), dried over anhydrous sodium sulfate, and filtered through celite. The filtrate was concentrated under reduced pressure to give the title compound 1-adamantanecarbaldehyde Cpd-025B (274 mg, pale yellow liquid), yield: 92%. The crude product is directly used for the next reaction without further treatment.
1 H NMR(400MHz,DMSO-d6)δ9.29(s,1H),2.02(s,4H),1.74-1.63(m,12H).
Second step
Preparation of 3- ((1-adamantylmethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester
1-Adamantadine carbaldehyde Cpd-025B (270 mg,1.6 mmol), ethyl 3-amino-1H-pyrrole-2-carboxylate (200 mg,1.3 mmol), acetic acid (78 mg,1.3 mmol) and methanol (5 mL) were added to the flask, and stirred at room temperature under nitrogen atmosphere for 1 hour, followed by adding sodium cyanoborohydride (413 mg,6.6 mmol) to the flask, and the reaction was continued for 1 hour. After the completion of the reaction, the reaction mixture was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate (30 mL. Times.3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product was isolated and purified using a Flash column (petroleum ether/ethyl acetate=85/15) to give 3- ((1-adamantylmethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-025C (256 mg, yellow liquid), yield: 51%.
MS m/z(ESI):303[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ10.65(s,1H),6.72(s,1H),5.76(d,J=0.7Hz,1H),5.62(t,J=2.3Hz,1H),4.18(q,J=7.2Hz,2H),2.74(d,J=6.2Hz,2H),1.73-1.55(m,9H),1.50(s,6H),1.26(t,J=7.2Hz,3H).
Third step
Preparation of ethyl 3- (1-adamantylmethyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylate
Ethyl 3- ((1-adamantylmethyl) amino) -1H-pyrrole-2-carboxylate Cpd-025C (150 mg,0.5 mmol) ethyl isothiocyanate (98 mg,0.7 mmol) was dissolved in dichloromethane (20 mL) and the reaction mixture was reacted at room temperature under nitrogen atmosphere for 1 hour. After the reaction, the reaction mixture was quenched with water, extracted with ethyl acetate (30 mL. Times.3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give a crude product. The crude product was isolated and purified using Flash column (petroleum ether/ethyl acetate=85/15) to give 3- (1-adamantylmethyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-025D (180 mg, yellow viscous liquid), yield: 84%.
MS m/z(ESI):434[M+1] + .
Fourth step
Preparation of 1- (1-adamantylmethyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
3- (1-adamantylmethyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-025D (65 mg,0.15 mmol) sodium ethoxide (153 mg,20% in ethanol) was dissolved in ethanol (1 mL) in a microwave tube and reacted at 100deg.C for 30 min. Quenched with 5mL of saturated aqueous ammonium chloride solution, the precipitated solid was collected by filtration, and washed with pure water several times to give the title compound 1- (1-adamantylmethyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-025 (8 mg, white solid), yield: 17%.
MS m/z(ESI):316[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.34(s,1H),12.11(s,1H),7.31(s,1H),6.33(s,1H),5.01(d,J=10.4Hz,1H),3.55(d,J=10.8Hz,1H),1.89(s,3H),1.73(s,3H),1.59(s,9H).
Example 26
1- (2-1, 1-Trifluoroisopropoxyethyl) -2-thio-1, 2,3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one (Cpd-026)
(R) -1- (2-1, 1-trifluoroisopropoxyethyl) -2-thioxo-1, 2,3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one (Cpd-026R)
(S) -1- (2-1, 1-trifluoroisopropoxyethyl) -2-thioxo-1, 2,3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one (Cpd-026S)
First step
Preparation of (2- (1, 1-trifluoroisopropoxy) ethoxy) -tert-butyldimethylsilane
1, 1-trifluoroisopropanol Cpd-026A (1 g,8.77 mmol) was dissolved in dry DMF (10 mL), cooled to 0deg.C, sodium hydrogen (426 mg,10.5 mmol) was added in portions, reacted at 0deg.C for 1 hour, then (2-bromoethoxy) -tert-butyldimethylsilane (2.3 g,9.65 mmol) was slowly added dropwise and stirred at room temperature for 16 hours after the addition. After the reaction was completed, it was quenched with saturated aqueous ammonium chloride (50 mL), extracted with dichloromethane, and the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and rotary distilled to give crude product, which was directly used as the next step Cpd-026B (1 g, light brown oil) without purification, yield: 42%.
1 H NMR(400MHz,CDCl 3 )δ3.91-3.82(m,1H),3.80-3.71(m,3H),3.67-3.61(m,1H),1.32(d,J=8.0Hz,3H),0.89(s,9H),0.06(s,6H).
Second step
Preparation of 2- (1, 1-trifluoroisopropoxy) -ethanol
(2- (1, 1-Trifluoroisopropoxy) ethoxy) -tert-butyldimethylsilane Cpd-026B (1 g,3.67 mmol) was dissolved in tetrahydrofuran solution (1M, 10 mL) of TBAF, stirred at room temperature for 1 hour, after the reaction was completed, and water (20 mL) was added thereto, dichloromethane was used for extraction, and the organic phase was washed with saturated sodium chloride and dried over anhydrous sodium sulfate to give crude product, which was purified by column to give 2- (1, 1-Trifluoroisopropoxy) -ethanol Cpd-026C (230 mg, pale yellow liquid), yield: 40%.
1 H NMR(400MHz,CDCl 3 )δ3.83-3.69(m,5H),1.88(s,1H),1.35(d,J=8.0Hz,3H).
Third step
Preparation of ethyl 2- (1, 1-trifluoroisopropoxy) -trifluoromethanesulfonate
2- (1, 1-Trifluoroisopropoxy) -ethanol Cpd-026C (100 mg,0.63 mmol) and pyridine (75 mg,0.94 mmol) were dissolved in dry dichloromethane (5 mL) under nitrogen, cooled to 0deg.C, and trifluoromethanesulfonic anhydride (213 mg,0.75 mmol) was slowly added, after the addition was completed, reacted at 0deg.C for 1 hour, after the reaction was completed, and water (10 mL) was added thereto, dichloromethane was extracted, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated to give the product, the next step Cpd-026D (150 mg, pale brown liquid) without purification, yield: 82%.
Fourth step
Preparation of 3- ((1, 1-trifluoroisopropoxyethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester
Ethyl 3-amino-1H-pyrrole-2-carboxylate (80 mg,0.517 mmol) was dissolved in 1, 4-dioxane (4 mL), DIPEA (100 mg,0.776 mmol) and ethyl 2- (1, 1-trifluoroisopropoxy) -trifluoromethanesulfonate Cpd-026D (150 mg,0.517 mmol) were added sequentially, and then heated to 80℃for 2.5 hours. After the reaction was completed, 10mL of water was added to quench, extraction was performed with ethyl acetate, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and rotary distilled to obtain crude product, which was purified by column to obtain 3- ((1, 1-trifluoroisopropoxyethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-026E (70 mg, colorless oil), yield: 46%.
MS m/z(ESI):295[M+1] + .
Fifth step
Preparation of 3- (3- (ethoxycarbonyl) -1- (1, 1-trifluoroisopropoxyethyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester
3- ((1, 1-Trifluoroisopropoxyethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-026E (70 mg,0.238 mmol) was dissolved in dichloromethane (5 mL), cooled to 0℃and ethyl isothiocyanato (37 mg, 0.284 mmol) was added thereto, followed by stirring at room temperature for 3 hours. After completion of the reaction, the reaction mixture was washed once with water (5 mL), and the organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was isolated and purified by silica gel column (petroleum ether/ethyl acetate=3/1) to give 3- (3- (ethoxycarbonyl) -1- (1, 1-trifluoroisopropoxyethyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-026F (80 mg, light brown oil), yield: 79%.
MS m/z(ESI):426[M+1] + .
Sixth step
Preparation of 1- (2-1, 1-trifluoroisopropoxyethyl) -2-thio-1, 2,3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one
3- (3- (ethoxycarbonyl) -1- (1, 1-trifluoroisopropoxyethyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-026F (80 mg,0.188 mmol) was dissolved in methanol (2 mL), cesium carbonate (184 mg, 0.514 mmol) was added thereto, and the reaction solution was heated to 65℃for 3 hours. The reaction solution was cooled to room temperature, a saturated aqueous ammonium chloride solution (5 mL) was then added, extraction was performed with ethyl acetate (10 mL. Times.3), and the organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was isolated by prep. on a silica gel plate (DCM/meoh=20/1) to give 1- (2-1, 1-trifluoroisopropoxyethyl) -2-thio-1, 2,3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-026 (30 mg, white solid), yield: 52%.
MS m/z(ESI):308[M+1] + .
1 H NMR(400MHz,DMSO-d 6 )δ12.38(s,1H),12.24(s,1H),7.36(s,1H),6.31(d,J=2.7Hz,1H),4.63-4.46(m,2H),4.22-4.10(m,1H),3.98(t,J=5.9Hz,2H),1.15(d,J=6.5Hz,3H).
The compound Cpd-026 of the example was obtained by chiral resolution to give (R) -1- (2-1, 1-trifluoroisopropoxyethyl) -2-thio-1, 2,3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one (Cpd-026R) and (S) -1- (2-1, 1-trifluoroisopropoxyethyl) -2-thio-1, 2,3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one (Cpd-026S). The chiral resolution conditions were as follows:
LC-30AD SFC.
Column chromatography, daicel CHIRALPAK AD-H250 mm X20 mm I.D., 5. Mu.mm.
Mobile phase CO 2 /EtOH=77/23.
The flow rate was 38.0mL/min.
Wavelength of UV 214nm &254nm.
Column temperature 40 ℃.
Cpd-026R:
t R :4.644min.
1 H NMR(400MHz,DMSO-d6)δ12.28(s,2H),7.35(s,1H),6.30(s,1H),4.69-4.43(m,2H),4.27-4.08(m,1H),3.98(t,J=5.6Hz,2H),1.15(d,J=6.4Hz,3H).
Cpd-026S:
t R :5.289min.
1 H NMR(400MHz,DMSO-d6)δ12.26(s,2H),7.36(s,1H),6.30(s,1H),4.63-4.46(m,2H),4.23-4.09(m,1H),3.98(t,J=5.8Hz,2H),1.15(d,J=6.4Hz,3H).
Example 27
1- [2- (2-trifluoromethyl-2-propoxyethyl) ] -2-thioxo-1, 2,3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of (2- (2-trifluoromethyl-2-propoxy) ethoxy) -tert-butyldimethylsilane
2-trifluoromethyl-2-propanol Cpd-027A (1 g,7.81 mmol) was dissolved in dry DMF (10 mL), cooled to 0deg.C, sodium hydrogen (375 mg,9.37 mmol) was added in portions, reacted at 0deg.C for 1 hour, then (2-bromoethoxy) -tert-butyldimethylsilane (2.05 g,8.59 mmol) was slowly added dropwise and stirred at room temperature for 16 hours after the addition. After the reaction was completed, it was quenched with saturated aqueous ammonium chloride (50 mL), extracted with dichloromethane, and the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and rotary distilled to give crude product, which was directly used as the next step Cpd-027B (1.5 g, light brown oil) without purification, yield: 68%.
1 H NMR(400MHz,CDCl 3 )δ3.88(t,J=6.0Hz,1H),3.71(t,J=4.0Hz,1H),3.55(t,J=6.0Hz,1H),3.38(t,J=6.0Hz,1H),0.89(s,9H),0.85(s,6H),0.05(s,6H).
Second step
Preparation of 2- (2-trifluoromethyl-2-propoxy) -ethanol
(2- (2-trifluoromethyl-2-propoxy) ethoxy) -tert-butyldimethylsilane Cpd-027B (1.0 g,3.5 mmol) was dissolved in tetrahydrofuran solution (1M, 10 mL) of TBAF, stirred at room temperature for 1 hour, after the reaction was completed, and water (20 mL) was added thereto, dichloromethane was used for extraction, and the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate to obtain crude product, which was purified by column to obtain 2- (2-trifluoromethyl-2-propoxy) -ethanol Cpd-027C (180 mg, pale yellow liquid), yield: 30%.
1 H NMR(400MHz,CDCl 3 )δ3.75-3.71(m,2H),3.62(t,J=4.0Hz,2H),1.93(s,1H),1.38(s,6H).
Third step
Preparation of ethyl 2- (2-trifluoromethyl-2-propoxy) -trifluoromethanesulfonate
2- (2-trifluoromethyl-2-propoxy) -ethanol Cpd-027C (100 mg,0.58 mmol) and pyridine (70 mg,0.87 mmol) were dissolved in dry dichloromethane (5 mL) under nitrogen, cooled to 0deg.C, and trifluoromethanesulfonic anhydride (200 mg,0.70 mmol) was slowly added, after the addition was completed, reacted at 0deg.C for 1 hour, after the reaction was completed, and water (10 mL) was added thereto, dichloromethane extraction was performed, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated to obtain the product, and the next step Cpd-027D (157 mg, pale brown liquid) was directly obtained without purification, yield: 89%.
Fourth step
Preparation of 3- ((2-trifluoromethyl-2-propoxyethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester
Ethyl 3-amino-1H-pyrrole-2-carboxylate (80 mg,0.517 mmol) was dissolved in 1, 4-dioxane (4 mL), DIPEA (100 mg,0.776 mmol) and ethyl 2- (2-trifluoromethyl-2-propoxy) -trifluoromethanesulfonate Cpd-027D (157 mg,0.517 mmol) were added sequentially, and then heated to 80℃for 2.5 hours. After the reaction was completed, 10mL of water was added to quench, extraction was performed with ethyl acetate, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and rotary distilled to obtain crude product, which was purified by column to obtain 3- ((2-trifluoromethyl-2-propoxyethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-027E (70 mg, colorless oil), yield: 43.7%.
MS m/z(ESI):309[M+1] + .
Fifth step
Preparation of 3- (3- (ethoxycarbonyl) -1- (2-trifluoromethyl-2-propoxyethyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester
3- ((2-trifluoromethyl-2-propoxyethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-027E (70 mg,0.227 mmol) was dissolved in dichloromethane (5 mL), cooled to 0℃and ethyl isothiocyanate (35.7 mg, 0.279 mmol) was added thereto, followed by stirring at room temperature for 3 hours. After completion of the reaction, the reaction mixture was washed once with water (5 mL), and the organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was isolated and purified by silica gel column (petroleum ether/ethyl acetate=3/1) to give 3- (3- (ethoxycarbonyl) -1- (2-trifluoromethyl-2-propoxyethyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-027F (80 mg, light brown oil), yield: 80%.
MS m/z(ESI):440[M+1] + 。
Sixth step
Preparation of 1- (2-2-trifluoromethyl-2-propoxyethyl) -2-thio-1, 2,3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one
3- (3- (ethoxycarbonyl) -1- (2-trifluoromethyl-2-propoxyethyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-027F (80 mg,0.182 mmol) was dissolved in methanol (2 mL), cesium carbonate (178 mg,0.546 mmol) was added thereto, and the reaction solution was heated to 65℃for 3 hours. The reaction solution was cooled to room temperature, a saturated aqueous ammonium chloride solution (5 mL) was then added, extraction was performed with ethyl acetate (10 mL. Times.3), and the organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was isolated by prep. on a silica gel plate (DCM/meoh=20/1) to give 1- (2-2-trifluoromethyl-2-propoxyethyl) -2-thio-1, 2,3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-027 (20 mg, white solid), yield: 34%.
MS m/z(ESI):322[M+1] + .
1 H NMR(400MHz,DMSO-d 6 )δ12.36(s,1H),12.23(s,1H),7.36(s,1H),6.27(s,1H),4.51(t,J=6.0Hz,2H),3.90(t,J=4.0Hz,2H),1.22(s,6H).
Example 28
1- (2-isopropoxyethyl) -2-thio-7-cyclopropyl-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of 3- ((tert-Butoxycarbonyl) amino) -4-cyclopropyl-1H-pyrrole-2-carboxylic acid ethyl ester
3- ((tert-Butoxycarbonyl) amino) -4-iodo-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-028A (500 mg,1.3 mmol) was dissolved in dioxane (5 mL). And to it was added cyclopropylboric acid (560 mg,6.8 mmol), potassium carbonate (454 mg,3.3 mmol), palladium acetate (30 mg,0.1 mmol) and tricyclohexylphosphorus (74 mg,0.3 mmol). The reaction solution was subjected to microwave reaction at 120℃under nitrogen protection for 1 hour. The reaction solution was cooled to room temperature and the solvent was removed by rotary evaporation. The resulting residue was isolated and purified using prep. plate (petroleum ether/ethyl acetate=4/1) to give 3- ((tert-butoxycarbonyl) amino) -4-cyclopropyl-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-028B (80 mg, brown oil), yield: 16%.
MS m/z(ESI):295[M+1] + .
Second step
Preparation of 3-amino-4-cyclopropyl-1H-pyrrole-2-carboxylic acid ethyl ester
3- ((Boc) amino) -4-cyclopropyl-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-028B (80 mg,0.27 mmol) was dissolved in dioxane (1 mL), 4M dioxane hydrochloride solution (1 mL) was added thereto, and the reaction solution was reacted at 25℃for 16 hours. The acid was neutralized with saturated sodium bicarbonate solution, and the dioxane was distilled off, followed by extraction of the residue with ethyl acetate (3X 15 mL). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give 3-amino-4-cyclopropyl-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-028C (18 mg, pale yellow solid), yield: 32%.
MS m/z(ESI):195[M+1] + .
Third step
Preparation of 3- ((2-isopropoxyethyl) amino) -4-cyclopropyl-1H-pyrrole-2-carboxylic acid ethyl ester
Ethyl 3-amino-4-cyclopropyl-1H-pyrrole-2-carboxylate Cpd-028C (18 mg,0.09 mmol) was dissolved in methanol (2 mL), acetic acid (5.6 mg,0.09 mmol) and 2-isopropoxylacetaldehyde (10 mg,0.09 mmol) were added sequentially and stirred at room temperature for 0.5 hours. Sodium cyanoborohydride (6 mg,0.09 mmol) was then added in portions and stirred at room temperature for 16 hours. After the reaction was completed, quenched by addition of water (2 mL), extracted with ethyl acetate, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and evaporated in vacuo to give crude product, which was purified by column to give 3- ((2-isopropoxyethyl) amino) -4-cyclopropyl-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-028D (20 mg, colorless oil), yield: 77%.
MS m/z(ESI):281[M+1] + .
Fourth step
Preparation of 3- (3- (ethoxycarbonyl) -1- (2-isopropoxyethyl) thiourea) -4-cyclopropyl-1H-pyrrole-2-carboxylic acid ethyl ester
3- ((2-isopropoxyethyl) amino) -4-cyclopropyl-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-028D (20 mg,0.07 mmol) was dissolved in dichloromethane (2 mL), cooled to 0℃and ethyl isothiocyanate (11.2 mg,0.09 mmol) was added thereto, followed by stirring at room temperature for 3 hours. After completion of the reaction, the reaction mixture was washed once with water (2 mL), and the organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was isolated and purified by silica gel column (petroleum ether/ethyl acetate=3/1) to give 3- (3- (ethoxycarbonyl) -1- (2-isopropoxyethyl) thiourea) -4-cyclopropyl-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-028E (18 mg, colorless oil), yield: 62%.
MS m/z(ESI):412[M+1] + .
Fifth step
Preparation of 1- (2-isopropoxyethyl) -2-thio-7-cyclopropyl-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
3- (3- (ethoxycarbonyl) -1- (2-isopropoxyethyl) thiourea) -4-cyclopropyl-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-028E (18 mg,0.04 mmol) was dissolved in methanol (3 mL), and cesium carbonate (43 mg,0.13 mmol) was added thereto. The reaction solution was heated to 65℃and reacted for 6 hours. After the reaction was completed, the reaction solution was cooled to room temperature and quenched with ammonium chloride, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue preparation plate was separated to give 1- (2-isopropoxyethyl) -2-thio-7-cyclopropyl-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-028 (6 mg, white solid), yield: 47%.
MS m/z(ESI):294[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.22(s,1H),12.16(s,1H),7.13(s,1H),4.94(t,J=6.4Hz,2H),3.78(t,J=6.4Hz,2H),3.56-3.53(m,1H),2.02-1.93(m,1H),1.02(d,J=6.0Hz,6H),0.87-0.8(m,2H),0.70-0.65(m,2H).
Example 29
2-thio-1- (2- ((1, 1-trifluoro-3- (methylamino) propan-2-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of 1, 1-trifluoro-3- ((4-methoxybenzyl) amino) propan-2-ol
3-amino-1, 1-trifluoropropan-2-ol Cpd-029A (1.50 g,11.60 mmol) and p-methoxybenzyl chloride (1.91 g,12.18 mmol) and triethylamine (2.35 g,23.2 mmol) were added sequentially to acetonitrile (60 mL), the reaction was warmed to 70℃for 2 hours, acetonitrile was removed by rotary evaporation after the reaction was completed, and the resulting residue was isolated and purified by silica gel column (petroleum ether/ethyl acetate=2/1) to give 1, 1-trifluoro-3- ((4-methoxybenzyl) amino) propan-2-ol Cpd-029B (700 mg, colorless oil), yield: 24%.
MS m/z(ESI):250.0[M+1] + .
Second step
Preparation of 1, 1-trifluoro-3- ((4-methoxybenzyl) (methyl) amino) propan-2-ol
1, 1-trifluoro-3- ((4-methoxybenzyl) amino) propan-2-ol Cpd-029B (500 mg,2.01 mmol) was dissolved in dry methanol (15 mL), followed by addition of paraformaldehyde (121 mg,4.02 mmol) and sodium cyanoborohydride (252 mg,4.02 mmol) for 2 hours at room temperature. After the reaction was completed, methanol was removed by rotary evaporation, and the obtained residue was separated and purified by silica gel column (petroleum ether/ethyl acetate=4/1) to give 1, 1-trifluoro-3- ((4-methoxybenzyl) (methyl) amino) propan-2-ol Cpd-029C (500 mg, white solid), yield: 94%.
1 H NMR(400MHz,DMSO-d6)δ7.21(d,J=8.4Hz,2H),6.87(d,J=8.4Hz,2H),6.13(d,J=6.4Hz,1H),4.16-4.09(m,1H),3.73(s,3H),3.48(s,2H),2.60-2.51(m,2H),2.16(s,3H).
Third step
Preparation of 2- (2- ((tert-butyldimethylsilyloxy) ethoxy) -3, 3-trifluoro-N- (4-methoxybenzyl) -N-methylpropan-1-amine
1, 1-trifluoro-3- ((4-methoxybenzyl) (methyl) amino) propan-2-ol Cpd-029C (500 mg,1.90 mmol) was dissolved in anhydrous DMF (10 mL), cooled to zero, sodium hydrogen (91 mg,3.80 mmol) was carefully added, the reaction was continued at room temperature for 10 min, (2-bromoethoxy) (tert-butyl) dimethylsilane (909 mg,3.80 mmol) was added, then the reaction was continued at room temperature for 2 h, after completion of the reaction quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate (50 ml×3), the organic phase was concentrated by dryness, and the resulting residue was isolated and purified using a silica gel column (petroleum ether/ethyl acetate=10/1) to give 2- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) -3, 3-trifluoro-N- (4-methoxybenzyl) -N-methylpropan-1-amine Cpd-029D (500 mg, colorless oil, yield): 62%.
MS m/z(ESI):422.2[M+1] + .
Fourth step
Preparation of 2- ((1, 1-trifluoro-3- ((4-methoxybenzyl) (methyl) amino) propan-2-yl) oxy) ethan-1-ol
2- (2- ((tert-Butyldimethylsilyloxy) ethoxy) -3, 3-trifluoro-N- (4-methoxybenzyl) -N-methylpropan-1-amine Cpd-029D (500 mg,1.19 mmol) was dissolved in tetrahydrofuran (15 mL), then tetrabutylammonium fluoride in tetrahydrofuran (1M, 5.95mL,5.95 mmol) was added, the reaction was quenched with saturated aqueous ammonium chloride solution after completion of the reaction for 2 hours at room temperature, extracted with ethyl acetate (50 mL. Times.3), and the organic phase was concentrated by dryness and the resulting residue was isolated and purified on a silica gel column (petroleum ether/ethyl acetate=2/1) to give 2- ((1, 1-trifluoro-3- ((4-methoxybenzyl) (methyl) amino) propan-2-yl) oxy) ethane-1-ol Cpd-029E (350 mg, colorless oil), yield: 96%.
MS m/z(ESI):308.0[M+1] + .
Fifth step
Preparation of 2- ((1, 1-trifluoro-3- ((4-methoxybenzyl) (methyl) amino) propan-2-yl) oxy) acetaldehyde
Oxalyl chloride (4966 mg,3.91 mmol) was dissolved in dry dichloromethane (12 mL) and dry dimethyl sulfoxide (610 mg,7.81 mmol) dissolved in dichloromethane was added thereto under nitrogen protection at-55deg.C. After stirring for 10 minutes, 2- ((1, 1-trifluoro-3- ((4-methoxybenzyl) (methyl) amino) propan-2-yl) oxy) ethan-1-ol Cpd-029E (300 mg,0.98 mmol) in dichloromethane was added thereto. After the reaction solution was stirred at-55℃for 30 minutes, triethylamine (790 mg,7.81 mmol) was added thereto. The reaction solution was stirred and returned to room temperature. After the reaction was completed, the mixture was washed with water, and the organic phase was dried over sodium sulfate and concentrated to give crude 2- ((1, 1-trifluoro-3- ((4-methoxybenzyl) (methyl) amino) propan-2-yl) oxy) acetaldehyde Cpd-029F (300 mg, yellow oil). Yield: 50%.
MS m/z(ESI):346.0(M+41).
Sixth step
Preparation of ethyl 3- ((2- ((1, 1-trifluoro-3- ((4-methoxybenzyl) (methyl) amino) propan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate
2- ((1, 1-trifluoro-3- ((4-methoxybenzyl) (methyl) amino) propan-2-yl) oxy) acetaldehyde Cpd-029F (300 mg,0.98 mmol) was dissolved in methanol (5 mL) and ethyl 3-amino-1H-pyrrole-2-carboxylate (167 mg,1.08 mmol) and glacial acetic acid (1 drop) were added thereto. The reaction mixture was reacted at 25℃for 1 hour. Sodium cyanoborohydride (93 mg,1.47 mmol) was added to the reaction solution to continue the reaction for 16 hours. After the reaction was completed, methanol was removed by rotary evaporation, and the resulting residue was separated and purified by silica gel column (petroleum ether/ethyl acetate=1/1) to give 3- ((2- ((1, 1-trifluoro-3- ((4-methoxybenzyl) (methyl) amino) propan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-029G (80 mg, yellow oil), yield: 16%.
MS m/z(ESI):444[M+1] + .
Seventh step
Preparation of ethyl 3- ((2- ((1, 1-trifluoro-3- (methylamino) propan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate
3- ((2- ((1, 1-trifluoro-3- ((4-methoxybenzyl) (methyl) amino) propan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-029G (80 mg) was dissolved in methanol (5 mL) and Pd (OH) was added thereto 2 Reaction at room temperature under nitrogen for 16 hours at/C (10 mg). The reaction solution was filtered, the filter cake was rinsed with a small amount of methanol, and the filtrate was concentrated to give ethyl 3- ((2- ((1, 1-trifluoro-3- (methylamino) propan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-029H (45 mg, yellow oil), yield: 61%.
MS m/z(ESI):324[M+1] + .
Eighth step
Preparation of ethyl 3- ((2- ((3- ((tert-butoxycarbonyl) (methyl) amino) -1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate
3- ((2- ((1, 1-trifluoro-3- (methylamino) propan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-029H (45 mg,0.14 mmol) was dissolved in dichloromethane (1 mL) and di-tert-butyl dicarbonate (33 mg,0.15 mmol) was added thereto and reacted at room temperature for 16 hours. The reaction solution was concentrated, to the residue was added saturated sodium bicarbonate solution (2 mL), extracted with dichloromethane (5 ml×3), dried over anhydrous sodium sulfate, 3- ((2- ((3- ((tert-butoxycarbonyl) (methyl) amino) -1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-029I (15 mg, yellow oil), yield: 25%.
MS m/z(ESI):424(M-100+1).
Ninth step
Preparation of ethyl 3- (1- (2- ((3- ((tert-butoxycarbonyl) (methyl) amino) -1, 1-trifluoropropan-2-yl) oxy) ethyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylate
3- ((2- ((1- (tert-Butoxycarbonyl) -3-methylpyrrolidin-3-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-029I (15 mg,0.035 mmol) was dissolved in dichloromethane (1 mL) and ethyl isothiocyanate (9 mg,0.071 mmol) was added thereto. The reaction solution was reacted at 25℃for 2 hours. After the reaction, dichloromethane was distilled off. The resulting residue was extracted with ethyl acetate (3×5 mL), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give crude product, which was prepared to give ethyl 3- (1- (2- ((3- ((tert-butoxycarbonyl) (methyl) amino) -1, 1-trifluoropropan-2-yl) oxy) ethyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylate Cpd-029J (10 mg, yellow oil), yield: 46%.
MS m/z(ESI):555[M+1] + .
Preparation of tenth step methyl (3, 3-trifluoro-2- (2- (2-thio-4-oxo-1, 2,3, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) ethoxy) propyl) carbamic acid tert-butyl ester
Preparation of ethyl 3- (1- (2- ((3- ((tert-butoxycarbonyl) (methyl) amino) -1, 1-trifluoropropan-2-yl) oxy) ethyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylate Cpd-029J (10 mg,0.019 mmol) was dissolved in methanol (0.5 mL), and cesium carbonate (12 mg,0.037 mmol) was added thereto. The reaction solution was heated to 65℃and reacted for 6 hours. After the completion of the reaction, methylene chloride (5 mL) was added to the reaction mixture, which was washed with water (2 mL) and saturated brine (2 mL) in this order, dried over anhydrous sodium sulfate, and concentrated to give Cpd-029K (10 mg, yellow oil) as a yield of tert-butyl methyl (3, 3-trifluoro-2- (2- (2-thio-4-oxo-1, 2,3, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) ethoxy) propyl) carbamate: 100%.
MS m/z(ESI):459(M+23).
Eleventh step
Preparation of 2-thio-1- (2- ((1, 1-trifluoro-3- (methylamino) propan-2-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Tert-butyl methyl (3, 3-trifluoro-2- (2- (2-thio-4-oxo-1, 2,3, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) ethoxy) propyl) carbamate Cpd-029K was dissolved in methanol (0.5 mL), and 4N methanolic hydrochloride solution (1 mL) was added thereto. The reaction solution was reacted at room temperature for 1 hour. After the reaction, the reaction mixture was concentrated, neutralized with aqueous sodium bicarbonate, extracted with ethyl acetate, and the organic phase was concentrated, and the residue was purified by reverse phase preparation to give 2-thio-1- (2- ((1, 1-trifluoro-3- (methylamino) propan-2-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-029 (1.39 mg, white solid), yield: 2%.
MS m/z(ESI):337[M+1] + .
Example 30
1- (2- ((3-amino-1, 1-trifluoropropan-2-yl) oxy) ethyl) -2-mercapto-1, 5-dihydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of 3- (bis (4-methoxybenzyl) amino) -1, 1-trifluoropropan-2-ol
3-amino-1, 1-trifluoropropan-2-ol Cpd-030A (4.00 g,31.00 mmol) and p-methoxybenzyl chloride (12.14 g,77.50 mmol) and diisopropylethylamine (12.02 g,93.00 mmol) were added sequentially to acetonitrile (100 mL), the reaction was warmed to 75℃for 18 hours, acetonitrile was removed by rotary evaporation after the reaction was completed, and the resulting residue was separated and purified by silica gel column (petroleum ether/ethyl acetate=100/15) to give 3- (bis (4-methoxybenzyl) amino) -1, 1-trifluoropropan-2-ol Cpd-030B (2.00 g, colorless oil), yield: 17%.
MS m/z(ESI):370.1[M+1] + .
Second step
Preparation of 2- (2- ((tert-butyldimethylsilyloxy) ethoxy) -3, 3-trifluoro-N, N-bis (4-methoxybenzyl) propan-1-amine
3- (bis (4-methoxybenzyl) amino) -1, 1-trifluoropropan-2-ol Cpd-030B (2.00 g,5.40 mmol) was dissolved in anhydrous DMF (15 mL), cooled to 0deg.C, sodium hydrogen (390 mg,16.20 mmol) was carefully added, after 10 minutes at RT, (2-bromoethoxy) (tert-butyl) dimethylsilane (1.94 g,8.10 mmol) was added and the reaction continued at RT for 2 hours. After the reaction was completed, the reaction was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate (50 ml×3), and concentrated by organic phase drying, and the obtained residue was separated and purified by silica gel column (petroleum ether/ethyl acetate=10/1) to give 2- (2- ((tert-butyldimethylsilyloxy) oxy) ethoxy) -3, 3-trifluoro-N, N-bis (4-methoxybenzyl) propan-1-amine Cpd-030C (2.00 g, white solid), yield: 70%.
MS m/z(ESI):528.3[M+1] + .
Third step
Preparation of 2- ((3- (bis (4-methoxybenzyl) amino) -1, 1-trifluoropropan-2-yl) oxy) ethan-1-ol
2- (2- ((tert-Butyldimethylsilyloxy) ethoxy) -3, 3-trifluoro-N, N-bis (4-methoxybenzyl) propan-1-amine Cpd-030C (2.00 g,3.80 mmol) was dissolved in tetrahydrofuran (50 mL), then tetrabutylammonium fluoride in tetrahydrofuran (1M, 7.60mL,7.60 mmol) was added, the reaction was quenched with saturated aqueous ammonium chloride solution after completion of the reaction for 2 hours at room temperature, extracted with ethyl acetate (50 mL. Times.3), and the organic phase was concentrated by dryness, and the resulting residue was isolated and purified using a silica gel column (petroleum ether/ethyl acetate=4/1) to give 2- ((3- (bis (4-methoxybenzyl) amino) -1, 1-trifluoropropan-2-yl) oxy) ethane-1-ol Cpd-030D (1.10 g, white solid) yield: 70%.
MS m/z(ESI):414.1[M+1] + .
Fourth step
Preparation of 2- ((3- (bis (4-methoxybenzyl) amino) -1, 1-trifluoropropan-2-yl) oxy) acetaldehyde
Oxalyl chloride (690 mg,5.40 mmol) was dissolved in dry dichloromethane (20 mL), cooled to-78 ℃, then a solution of dimethyl sulfoxide (630 mg,8.10 mmol) in dichloromethane (5 mL) was slowly added, the temperature was controlled below-65 ℃, stirring was carried out at-78℃for 30 minutes after the addition was completed, then a solution of 2- ((3- (bis (4-methoxybenzyl) amino) -1, 1-trifluoropropan-2-yl) oxy) ethan-1-ol Cpd-030D (1.10 g,2.70 mmol) in dichloromethane (5 mL) was added dropwise, and the mixture was incubated for 2 hours after the addition. Triethylamine (1.64 g,16.20 mmol) was then added dropwise, after the addition was completed, the temperature was slowly raised to 0℃and water (100 mL) was added thereto, the solution was separated, the organic phase was washed with saturated sodium chloride and dried over anhydrous sodium sulfate to obtain 30mL of a methylene chloride solution containing 2- ((3- (bis (4-methoxybenzyl) amino) -1, 1-trifluoropropan-2-yl) oxy) acetaldehyde Cpd-030E, and the next step was directly carried out without treatment.
MS m/z(ESI):412.1[M+1] + .
Fifth step
Preparation of ethyl 3- ((2- ((3- (bis (4-methoxybenzyl) amino) -1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate
2- ((3- (bis (4-methoxybenzyl) amino) -1, 1-trifluoropropan-2-yl) oxy) acetaldehyde Cpd-030E (800 mg,1.94 mmol) was dissolved in anhydrous methanol (20 mL) and then ethyl 3-amino-1H-pyrrole-2-carboxylate (300 mg,1.94 mmol), sodium cyanoborohydride (367 mg,5.83 mmol) and acetic acid (3 drops) were added in sequence and stirred at room temperature for 3 hours. After completion of the reaction, methanol was removed by rotary evaporation, and the resulting residue was separated and purified by silica gel column (petroleum ether/ethyl acetate=100/10) to give ethyl 3- ((2- ((3- (bis (4-methoxybenzyl) amino) -1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-030F (400 mg, pale yellow solid), yield: 38%.
MS m/z(ESI):550.2[M+1] + .
Sixth step
Preparation of ethyl 3- ((2- ((3-amino-1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate
3- ((2- ((3- (bis (4-methoxybenzyl) amino) -1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-030F (400 mg,0.73 mmol) was dissolved in methanol (20 mL), palladium on carbon hydroxide (100 mg) was then added, after three hydrogen substitutions, the temperature was raised to 65℃for 18 hours, after the reaction was completed the catalyst was filtered off and dried and concentrated to give 3- ((2- ((3-amino-1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-030G (200 mg, light yellow oil), yield: 89%.
MS m/z(ESI):310.0[M+1] + .
Seventh step
Preparation of ethyl 3- ((2- ((3- ((tert-butoxycarbonyl) amino) -1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate
3- ((2- ((3-amino-1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-030G (200 mg,0.65 mmol) was dissolved in dichloromethane (20 mL) and then added (Boc) 2 O (212 mg,0.97 mmol) and triethylamine (196 mg,1.94 mmol) were reacted at room temperature for 2 hours. After the completion of the reaction, methylene chloride was removed by rotary evaporation, followed by extraction with ethyl acetate (20 mL. Times.3) and saturated aqueous potassium hydrogen sulfate (20 mL), drying and concentration of the organic phase, and the obtained residue was purified by a silica gel column (petroleum ether/acetic acid) Ethyl=100/15) to give 3- ((2- ((3- ((tert-butoxycarbonyl) amino) -1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-030H (160 mg, colorless oil), yield: 60%. MS m/z (ESI) 410.0[ M+1 ]] + .
Eighth step
Preparation of ethyl 3- (1- (2- ((3- ((tert-butoxycarbonyl) amino) -1, 1-trifluoropropan-2-yl) oxy) ethyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylate
3- ((2- ((3- ((tert-Butoxycarbonyl) amino) -1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-030H (150 mg,0.37 mmol) was dissolved in methanol (10 mL), then ethyl isothiocyanato (58 mg,0.44 mmol) was added and reacted at room temperature for 1 hour, and after the reaction was completed, the reaction solution was directly used in the next step.
MS m/z(ESI):541.2[M+1] + .
Preparation of ninth step (3, 3-trifluoro-2- (2- (2-thio-4-oxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-1-yl) ethoxy) propyl) carbamic acid tert-butyl ester
Cesium carbonate (271mg, 0.83 mmol) was added to a solution of 3- (1- (2- ((3- ((tert-butoxycarbonyl) amino) -1, 1-trifluoropropan-2-yl) oxy) ethyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-030I (150 mg,0.28 mmol) in methanol (10 mL) and stirred for 3 hours at 65 ℃, methanol was removed by rotary evaporation after completion of the reaction, and the resulting residue was isolated and purified by silica gel column (petroleum ether/ethyl acetate=1/1) to give tert-butyl (3, 3-trifluoro-2- (2- (2-thio-4-oxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-1-yl) ethoxy) propyl) carbamate Cpd-030J (100 mg, white solid), yield: 85%.
MS m/z(ESI):423.1[M+1] + .
Tenth step
Preparation of 1- (2- ((3-amino-1, 1-trifluoropropan-2-yl) oxy) ethyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Tert-butyl (3, 3-trifluoro-2- (2- (2-thio-4-oxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-1-yl) ethoxy) propyl) Cpd-030J (100 mg,0.24 mmol) was added to methanol hydrochloride (5 ml,4m,20.00 mmol) for 2 hours at 50 ℃, methanol was removed by rotary evaporation after reaction, the residue was washed with aqueous sodium bicarbonate solution, dried after extraction with ethyl acetate, and the residue was isolated and purified using a silica gel column (dichloromethane/methanol=10/1) to give 1- (2- ((3-amino-1, 1-trifluoropropan-2-yl) oxy) ethyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-030 (50 mg, white solid), yield: 65%.
MS m/z(ESI):323.0[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ7.37(d,J=2.8Hz,1H),6.36(d,J=2.8Hz,1H),4.71-4.51(m,2H),4.16-3.99(m,2H),3.93-3.82(m,1H),2.75-2.67(m,1H),2.59-2.53(m,1H).
Example 31
1- (2- ((3- (dimethylamino) -1, 1-trifluoropropan-2-yl) oxy) ethyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
1- (2- ((3-amino-1, 1-trifluoropropan-2-yl) oxy) ethyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-030 (15 mg,0.047 mmol) was dissolved in anhydrous methanol (5 mL), then paraformaldehyde (3 mg,0.094 mmol) and sodium cyanoborohydride (6 mg,0.094 mmol) were added in sequence and stirred at room temperature for 3 hours. After the reaction was completed, methanol was removed by rotary evaporation, and the resulting residue was separated and purified by silica gel column (dichloromethane/methanol=100/5) to give 1- (2- ((3- (dimethylamino) -1, 1-trifluoropropan-2-yl) oxy) ethyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-031 (4 mg, white solid), yield: 23%.
MS m/z(ESI):351.0[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.35(s,1H),12.21(s,1H),7.36(t,J=2.8Hz,1H),6.30(s,1H),4.55(t,J=5.6Hz,2H),4.21-4.17(m,1H),4.09(t,J=5.6Hz,2H),2.38-2.37(m,2H),2.11(s,6H).
Example 32
1- (3-amino-2- (2, 2-trifluoroethoxy) propyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of 3- (bis (4-methoxybenzyl) amino) propane-1, 2-diol
3-aminopropane-1, 2-diol Cpd-032A (1 g,11 mmol), N, N-diisopropylethylamine (4.26 g,33 mmol) and potassium iodide (0.37 g,2.2 mol) were dissolved in acetonitrile (20 mL) followed by heating to 90℃under nitrogen and stirring for two hours. After completion of the reaction, the reaction mixture was poured into water (200 mL), extracted with ethyl acetate (100 mL), the combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was separated and purified by silica gel column (petroleum ether/ethyl acetate=1/1) to give 3- (bis (4-methoxybenzyl) amino) propane-1, 2-diol Cpd-032B (2.9 g, colorless oil), yield: 80%.
MS m/z(ESI):332.0[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ7.23(d,J=8.4Hz,4H),6.88(d,J=8.4Hz,4H),4.41(t,J=5.6Hz,1H),4.36(d,J=4.4Hz,1H),3.73(s,6H),3.65(dd,J=10.5,4.9Hz,1H),3.47(dd,J=42.8,13.5Hz,4H),3.36-3.30(m,1H),3.16(dt,J=11.2,5.8Hz,1H),2.42-2.48(m,2H).
Second step
Preparation of 1- (bis (4-methoxybenzyl) amino) -3- ((tert-butyldimethylsilyl) oxy) propan-2-ol
3- (bis (4-methoxybenzyl) amino) propane-1, 2-diol Cpd-032B (2.94 g,8.9 mmol) and imidazole (1.21 g,17.8 mmol) were dissolved in tetrahydrofuran (40 mL), t-butyldimethylchlorosilane (1.34 g,8.9 mmol) was added portionwise under ice, stirred under nitrogen for ten minutes, followed by removal of the ice bath and stirring for 1 hour. After completion of the reaction, the reaction mixture was poured into water (200 mL), extracted twice with ethyl acetate (100 mL), and the combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was separated and purified by silica gel column (petroleum ether/ethyl acetate=4/1) to give 1- (bis (4-methoxybenzyl) amino) -3- ((tert-butyldimethylsilyloxy) propan-2-ol Cpd-032C (3.4 g, colorless oil), yield: 85%.
MS m/z(ESI):446.0[M+1] + .
Third step
Preparation of 2-bromo-3- ((tert-butyldimethylsilyl) oxy) -N, N-bis (4-methoxybenzyl) propan-1-amine
1- (bis (4-methoxybenzyl) amino) -3- ((tert-butyldimethylsilyl) oxy) propan-2-ol Cpd-032C (500 mg,1.1 mmol) and triphenylphosphine (382 mg,1.5 mmol) were dissolved in dichloromethane (10 mL), carbon tetrabromide (284 mg,1.5 mmol) was added portionwise under ice bath, followed by removal of ice bath nitrogen protection and stirring for half an hour. After the reaction was completed, the reaction solution was poured into 100mL of water, extracted twice with ethyl acetate (50 mL), the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was separated and purified by a silica gel column (petroleum ether/ethyl acetate=10/1) to give 1- (bis (4-methoxybenzyl) amino) -3- ((tert-butyldimethylsilyloxy) propan-2-ol Cpd-032D (430 mg, colorless oil), yield: 75%.
MS m/z(ESI):508.0[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ7.25(d,J=8.0Hz,4H),6.89(d,J=8.0Hz,4H),4.22-4.12(m,1H),3.86-3.78(m,1H),3.74(s,6H),3.70-3.66(m,1H),3.57-3.43(m,4H),2.83-2.69(m,2H),0.82(s,9H),0.02-0.00(m,6H).
Fourth step
Preparation of 3- ((tert-butyldimethylsilyl) oxy) -N, N-bis (4-methoxybenzyl) -2- (2, 2-trifluoroethoxy) propan-1-amine
2-bromo-3- ((tert-butyldimethylsilyl) oxy) -N, N-bis (4-methoxybenzyl) propan-1-amine Cpd-032D (2.2 g,4.3 mmol) was dissolved in trifluoroethanol (8.7 g,86 mmol) followed by the addition of potassium tert-butoxide (0.97 g,8.6 mol) under nitrogen and heated at 70℃for half an hour. After the completion of the reaction, the reaction mixture was poured into a saturated aqueous ammonium chloride solution (100 mL), extracted twice with ethyl acetate (50 mL), the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was separated and purified by a silica gel column (petroleum ether/ethyl acetate=10/1) to give 3- ((tert-butyldimethylsilyl) oxy) -N, N-bis (4-methoxybenzyl) -2- (2, 2-trifluoroethoxy) propan-1-amine Cpd-032E (2.0 g, colorless oil), yield: 79%.
MS m/z(ESI):528.0[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ7.23(d,J=8.4Hz,4H),6.86(d,J=8.1Hz,4H),4.16-3.94(m,2H),3.82-3.78(m,1H),3.76-3.66(m,9H),3.63(d,J=2.1Hz,3H),3.52-3.39(m,1H),2.85-2.80(m,1H),0.85(s,9H),0.00(s,6H).
Fifth step
Preparation of 3- (bis (4-methoxybenzyl) amino) -2- (2, 2-trifluoroethoxy) propanol
3- ((tert-Butyldimethylsilyl) oxy) -N, N-bis (4-methoxybenzyl) -2- (2, 2-trifluoroethoxy) propan-1-amine Cpd-032E (2.0 g,3.7 mmol) was dissolved in tetrahydrofuran (15 mL), tetrabutylammonium fluoride (1M, 7.4mL,7.4 mmol) was added and stirred at room temperature under nitrogen for half an hour. After the completion of the reaction, the reaction mixture was poured into 100mL of an aqueous solution, extracted twice with ethyl acetate (50 mL), and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was separated and purified by a silica gel column (petroleum ether/ethyl acetate=4/1) to give 3- (bis (4-methoxybenzyl) amino) -2- (2, 2-trifluoroethoxy) propanol Cpd-032F (1.3 g, colorless oil), yield: 84%.
MS m/z(ESI):414.0[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ7.24(d,J=8.5Hz,4H),6.86(d,J=8.5Hz,4H),4.52-4.45(m,1H),4.06-3.96(m,2H),3.82(dd,J=9.9,7.1Hz,1H),3.72(d,J=5.3Hz,8H),3.62(s,3H),3.58-3.41(m,3H),2.86-2.76(m,1H).
Sixth step
Preparation of 3- (bis (4-methoxybenzyl) amino) -2- (2, 2-trifluoroethoxy) propanal
Oxalyl chloride (0.51 g,4.0 mmol) was dissolved in dichloromethane (15 mL) with anhydrous sodium sulfate (200 mg) under nitrogen and a solution of anhydrous dimethyl sulfoxide (0.63 g,8.1 mmol) diluted with dichloromethane (0.5 mL) was added dropwise at-60 ℃. After 5 minutes, a solution of 3- (bis (4-methoxybenzyl) amino) -2- (2, 2-trifluoroethoxy) propanol Cpd-032F (1.1 g,2.7 mmol) dissolved in dichloromethane (3 mL) was dropwise added at-55 ℃. The mixture was stirred at the same temperature for half an hour, and then triethylamine (1.09 g,10.8 mmol) was added dropwise at a temperature of not higher than-55℃and, after the completion of the addition, the mixture was stirred at room temperature for 10 minutes. After the completion of the reaction, the reaction mixture was poured into 100mL of an aqueous solution, extracted twice with methylene chloride (100 mL), the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude 3- (bis (4-methoxybenzyl) amino) -2- (2, 2-trifluoroethoxy) propanal Cpd-032G (1.2G, colorless oil), which was used directly in the next reaction without further purification.
MS m/z(ESI):412.0[M+1] + .
Seventh step
Preparation of 3- ((3- (bis (4-methoxybenzyl) amino) -2- (2, 2-trifluoroethoxy) propyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester
Ethyl 3-amino-1H-pyrrole-2-carboxylate (0.6G, 3.8 mmol) and 3- (bis (4-methoxybenzyl) amino) -2- (2, 2-trifluoroethoxy) propanal Cpd-032G (1.2G, 2.9 mmol) were dissolved in methanol (15 mL), and two drops of glacial acetic acid were added dropwise under nitrogen and stirred at room temperature for half an hour, followed by sodium cyanoborohydride (0.7G, 11.6 mmol) and stirred at room temperature for half an hour. After the reaction was completed, the reaction mixture was poured into 100mL of water, extracted twice with ethyl acetate (50 mL), the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product which was separated and purified by a silica gel column (petroleum ether/ethyl acetate=4/1) to give 3- ((3- (bis (4-methoxybenzyl) amino) -2- (2, 2-trifluoroethoxy) propyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-032H (1 g, colorless oil), yield: 62%.
MS m/z(ESI):550.0[M+1] + .
Eighth step
Preparation of 3- ((3-amino-2- (2, 2-trifluoroethoxy) propyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester
3- ((3- (bis (4-methoxybenzyl) amino) -2- (2, 2-trifluoroethoxy) propyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-032H (700 mg,1.27 mmol) was dissolved in methanol (50 mL), palladium on carbon hydroxide (70 mg) was added, and after four times the gas was replaced with a double-layered hydrogen balloon, the temperature was raised to 60℃and heated for two hours. After the reaction was completed, the reaction mixture was filtered through celite, the residue was washed with methanol (20 ml×2), and the combined organic phases were concentrated to give crude 3- ((3-amino-2- (2, 2-trifluoroethoxy) propyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-032I (330 mg, colorless oil) which was used in the next step without purification.
MS m/z(ESI):310.0[M+1] + .
Ninth step
Preparation of 3- ((3- ((tert-Butoxycarbonyl) amino) -2- (2, 2-trifluoroethoxy) propyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester
3- ((3-amino-2- (2, 2-trifluoroethoxy) propyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-032I (330 mg,1.1 mmol), triethylamine (348 mg,1.6 mmol) and (Boc) 2 O (348 mg,1.1 mmol) was dissolved in dichloromethane (10 mL) and stirred overnight at room temperature under nitrogen. After the reaction was completed, the reaction mixture was poured into water (100 mL), extracted twice with ethyl acetate (50 mL), and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product which was separated and purified by silica gel column (petroleum ether/ethyl acetate=1/1) to give 3- ((3- ((tert-butoxycarbonyl) amino) -2- (2, 2-trifluoroethoxy) propyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-032J (423 mg, colorless oil), yield: 97%.
MS m/z(ESI):410.0[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ10.73(s,1H),6.87(d,J=8.0Hz,1H),6.76(s,1H),5.68-5.63(m,1H),5.40(s,1H),4.23-4.11(m,3H),3.77-3.70(m,1H),3.55(dd,J=12.3,6.6Hz,2H),3.21-2.99(m,3H),1.37(s,9H),1.26(t,J=6.0Hz,3H).
Tenth step
Preparation of ethyl 3- (1- (3- ((tert-butoxycarbonyl) amino) -2- (2, 2-trifluoroethoxy) propyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylate
3- ((3- ((tert-Butoxycarbonyl) amino) -2- (2, 2-trifluoroethoxy) propyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-032J (420 mg,1.0 mmol) was dissolved in dichloromethane (7 mL), followed by dropwise addition of ethyl isothiocyanato formate (161 mg,1.2 mmol) at room temperature and stirring at room temperature for half an hour. After the reaction was completed, the mixture was concentrated to give crude 3- (1- (3- ((t-butoxycarbonyl) amino) -2- (2, 2-trifluoroethoxy) propyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-032K (554 mg, colorless oil), yield: 100%.
MS m/z(ESI):541.0[M+1] + .
Preparation of tert-butyl (3- (2-thio-4-oxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-1-yl) -2- (2, 2-trifluoroethoxy) propyl) carbamate
3- (1- (3- ((tert-Butoxycarbonyl) amino) -2- (2, 2-trifluoroethoxy) propyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-032K (450 mg,0.8 mmol) was dissolved in methanol (10 mL), cesium carbonate (2.7 g,8.3 mmol) was added and heated to 70℃under nitrogen and stirred for 4 hours. After the completion of the reaction, the reaction mixture was poured into an aqueous ammonium chloride solution (100 mL), extracted twice with ethyl acetate (50 mL), and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product, which was separated and purified by a silica gel column (petroleum ether/ethyl acetate=1/1) to give tert-butyl (3- (2-thio-4-oxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-1-yl) -2- (2, 2-trifluoroethoxy) propyl) carbamate Cpd-032L (278 mg, white solid), yield: 79%.
MS m/z(ESI):423.0[M+1] + .
Twelfth step
Preparation of 1- (3-amino-2- (2, 2-trifluoroethoxy) propyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
The separated and purified tert-butyl (3- (2-thio-4-oxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-1-yl) -2- (2, 2-trifluoroethoxy) propyl) carbamate Cpd-032L (278 mg,0.7 mmol) was dissolved in ethanol hydrochloride (10 mL), and the mixture was heated to 30℃under nitrogen atmosphere and stirred for 1 hour. After the completion of the reaction, the reaction mixture was concentrated, the resulting crude product was neutralized with saturated aqueous sodium hydrogencarbonate (100 mL), dichloromethane/methanol (10/1, 50 mL) was extracted three times, the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was separated and purified by a silica gel column (dichloromethane/methanol=1/0-10/1) to give 1- (3-amino-2- (2, 2-trifluoroethoxy) propyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-032 (40 mg, white solid), yield: 19%.
MS m/z(ESI):323.0[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.36(s,1H),7.35(d,J=2.7Hz,1H),6.34(d,J=2.7Hz,1H),4.42(dd,J=13.5,5.2Hz,1H),4.25(dd,J=13.4,6.9Hz,1H),4.15-3.97(m,2H),3.63-3.42(m,3H).
Example 33
1- (3- (dimethylamino) -2- (2, 2-trifluoroethoxy) propyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
1- (3-amino-2- (2, 2-trifluoroethoxy) propyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one (hydrochloride) Cpd-032 (40 mg,0.12 mmol), paraformaldehyde (37 mg,1.2 mmol) was dissolved in methanol (3 mL) and saturated aqueous sodium bicarbonate (2 mL) and stirred at room temperature for half an hour. After the completion of the reaction, the reaction mixture was poured into water (100 mL), extracted twice with ethyl acetate (50 mL), and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product which was separated and purified by silica gel column (dichloromethane/methanol=1/0-14/1) to give 1- (3- (dimethylamino) -2- (2, 2-trifluoroethoxy) propyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-033 (25 mg, colorless oil), yield: 53%.
MS m/z(ESI):351.0[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.38(s,1H),12.15(s,1H),7.37(s,1H),6.27(d,J=2.1Hz,1H),4.47(dd,J=13.5,7.3Hz,1H),4.35(dd,J=13.6,6.6Hz,1H),4.06-3.92(m,2H),3.78(dd,J=10.1,6.7Hz,1H),3.66(dd,J=10.1,4.7Hz,1H),3.53-3.40(m,1H),2.32(s,6H).
Example 34
2-thio-1- (2, 2-trifluoro-1- (1H-imidazol-2-yl) ethoxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of 1-trityl-1H-imidazole-2-carbaldehyde
1H-imidazole-2-carbaldehyde Cpd-034A (2.0 g,20.8 mmol) was dissolved in N, N-dimethylformamide (20 mL). And triphenylchloromethane (4.2 g,41.6 mmol) and triethylamine (6.4 g,22.8 mmol) were added thereto. The reaction solution was reacted at room temperature for 3 hours. Water (50 mL) was added to the reaction solution, followed by extraction with ethyl acetate (3X 50 mL). The organic phases were combined, washed with water (3X 100 mL), dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel column (petroleum ether/ethyl acetate=3/2) to give 1-trityl-1H-imidazole-2-carbaldehyde Cpd-034B (2.2 g, yellow solid), yield: 31%.
1 H NMR(400MHz,DMSO-d6)δ9.13(s,1H),7.40-7.35(m,10H),7.08-7.03(m,7H).
Second step
Preparation of 2, 2-trifluoro-1- (1-trityl-1H-imidazol-2-yl) ethan-1-ol
1-trityl-1H-imidazole-2-carbaldehyde Cpd-034B (2.1 g,6.2 mmol) was dissolved in tetrahydrofuran (20 mL), to which was added trimethyl (trifluoromethyl) silane (1.8 g,12.4 mmol) and tetrabutylammonium fluoride (0.8 g,3.1 mmol). The reaction solution was reacted at 25℃for 4 hours. The reaction solution was then concentrated, slurried with dichloromethane/methanol (20/1), filtered, and the cake collected to give 2, 2-trifluoro-1- (1-trityl-1H-imidazol-2-yl) ethan-1-ol Cpd-034C (1.9 g, white solid), yield: 68%.
1 H NMR(400MHz,DMSO-d6)δ7.43-7.32(m,9H),7.13(d,J=7.3Hz,6H),7.03(s,1H),6.83(s,1H),6.42(d,J=3.0Hz,1H),4.31(s,1H).
Third step
Preparation of 2- (1- (2- (tert-butyldimethylsilyloxy) ethoxy) -2, 2-trifluoroethyl) -1-trityl-1H-imidazole
2, 2-trifluoro-1- (1-trityl-1H-imidazol-2-yl) ethan-1-ol Cpd-034C (1.9 g,4.7 mmol) was dissolved in ultra-dry N, N-dimethylformamide (20 mL) and sodium hydrogen (280 mg,7.1 mmol) was added thereto. The reaction solution was stirred for half an hour under nitrogen protection at 0 ℃. (2-Bromoethoxy) (tert-butyl) dimethylsilane (2.2 g,9.4 mmol) was then added to the reaction mixture and the reaction was continued for 16 hours. After the reaction was completed, diluted with water, extracted with ethyl acetate (3×100 mL), the organic phases were combined, washed with water (4×100 mL), dried over anhydrous sodium sulfate and concentrated to give crude 2- (1- (2- (tert-butyldimethylsilyloxy) ethoxy) -2, 2-trifluoroethyl) -1-trityl-1H-imidazole Cpd-034D (2.1 g, yellow solid), yield: 66%.
1 H NMR(400MHz,DMSO-d6)δ7.44-7.37(m,9H),7.13(d,J=7.3Hz,6H),7.06(s,1H),6.89(s,1H),4.26-4.21(m,1H),3.49-3.40(m,2H),3.25-3.20(m,1H),2.85-2.80(m,1H),0.82(s,9H),-0.01(d,J=7.5Hz,6H).
Fourth step
Preparation of 2- (2, 2-trifluoro-1- (1-trityl-1H-imidazol-2-yl) ethoxy) ethan-1-ol
2- (1- (2- (t-Butyldimethylsilanyloxy) ethoxy) -2, 2-trifluoroethyl) -1-trityl-1H-imidazole Cpd-034D (2.1 g,3.7 mmol) was dissolved in tetrahydrofuran (20 mL), and tetrabutylammonium fluoride (970 mg,3.7 mmol) was added thereto and reacted at 25℃for 3 hours. After the reaction, tetrahydrofuran was distilled off. The resulting residue was extracted with ethyl acetate (3×50 mL), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by separation on a silica gel column (petroleum ether/ethyl acetate=3/2) to give 2- (2, 2-trifluoro-1- (1-trityl-1H-imidazol-2-yl) ethoxy) ethan-1-ol Cpd-034E (1.4 g, white solid), yield: 76%.
1 H NMR(400MHz,DMSO-d6)δ7.47-7.37(m,9H),7.13(d,J=7.2Hz,6H),7.05(s,1H),6.88(s,1H),4.63(t,J=5.4Hz,1H),4.28-4.19(m,1H),3.28(s,2H),2.78(dt,J=8.2,3.9Hz,1H).
Fifth step
Preparation of 2- (2, 2-trifluoro-1- (1-trityl-1H-imidazol-2-yl) ethoxy) acetaldehyde
Oxalyl chloride (700 mg,5.5 mmol) was dissolved in dry dichloromethane (10 mL) and dry dimethyl sulfoxide (600 mg,7.7 mmol) dissolved in dichloromethane was added thereto under nitrogen protection at-78 ℃. After stirring for 10 minutes, 2- (2, 2-trifluoro-1- (1-trityl-1H-imidazol-2-yl) ethoxy) ethane-1-ol Cpd-034E (1 g,2.2 mmol) in dichloromethane was added thereto. After the reaction solution was stirred at-78℃for 30 minutes, triethylamine (1.1 g,11 mmol) was added thereto. The reaction solution was stirred and returned to room temperature. After the reaction was completed, the mixture was washed with water, and the organic phase was dried over sodium sulfate and concentrated to give crude 2- (2, 2-trifluoro-1- (1-trityl-1H-imidazol-2-yl) ethoxy) acetaldehyde Cpd-034F (1 g, yellow solid), yield: 91%. The crude product was used directly in the next reaction without further treatment.
Sixth step
Preparation of ethyl 3- ((2- (2, 2-trifluoro-1- (1H-imidazol-2-yl) ethoxy) ethyl) amino) -1H-pyrrole-2-carboxylate
2- (2, 2-trifluoro-1- (1-trityl-1H-imidazol-2-yl) ethoxy) acetaldehyde Cpd-034F (1 g,2.3 mmol) was dissolved in methanol (4 mL) and ethyl 3-amino-1H-pyrrole-2-carboxylate (350 mg,2.3 mmol) and glacial acetic acid (2 drops) were added thereto. The reaction mixture was reacted at 25℃for 1 hour. Sodium cyanoborohydride (430 mg,6.9 mmol) was added to the reaction solution to continue the reaction for 16 hours. After the reaction was completed, methanol was removed by rotary evaporation, and the resulting residue was separated and purified by silica gel column (petroleum ether/ethyl acetate=3/1) to give ethyl 3- ((2- (2, 2-trifluoro-1- (1H-imidazol-2-yl) ethoxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-034G (820 mg, colorless oil), yield: 52%.
MS m/z(ESI):347[M+1] + .
Seventh step
Preparation of ethyl 3- (3- (ethoxycarbonyl) -1- (2, 2-trifluoro-1- (1H-imidazol-2-yl) ethoxy) ethyl) thioureido) -1H-pyrrole-2-carboxylate
3- ((2- (2, 2-trifluoro-1- (1H-imidazol-2-yl) ethoxy) ethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-034G (400 mg,1.15 mmol) was dissolved in dichloromethane (10 mL), and ethyl isothiocyanate (303 mg,2.3 mmol) was added thereto for reaction at 25℃for 2 hours. After the reaction, dichloromethane was distilled off. The resulting residue was extracted with ethyl acetate (3×15 mL), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give crude 3- (3- (ethoxycarbonyl) -1- (2, 2-trifluoro-1- (1H-imidazol-2-yl) ethoxy) ethyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-034H (500 mg, yellow oil), yield: 72%.
MS m/z(ESI):478[M+1] + .
Eighth step
Preparation of 2-thio-1- (2, 2-trifluoro-1- (1H-imidazol-2-yl) ethoxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
3- (3- (ethoxycarbonyl) -1- (2, 2-trifluoro-1- (1H-imidazol-2-yl) ethoxy) ethyl) thioureido) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-034H (500 mg,1.0 mmol) was dissolved in methanol (10 mL), and cesium carbonate (1.4 g,4.2 mmol) was added thereto. The reaction solution was heated to 65℃and reacted for 6 hours. After the reaction was completed, the reaction solution was cooled to room temperature and methanol was removed by rotary evaporation, and the obtained residue was purified crude by silica gel column (dichloromethane/methanol=12/1) and was further purified by preparative plate (dichloromethane/methanol=14/1) to give 2-thio-1- (2, 2-trifluoro-1- (1H-imidazol-2-yl) ethoxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-034 (120 mg, white solid), yield: 30%.
MS m/z(ESI):360[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.40(s,1H),12.35(s,1H),12.21(s,1H),7.34(t,J=2.7Hz,1H),7.22(s,1H),6.96(s,1H),6.29(s,1H),5.38-5.33(m,1H),4.65-4.48(m,2H),3.96-3.74(m,2H).
Example 35
2-thio-1- (2- ((3- (trifluoromethyl) pyrrolidin-3-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of 3-hydroxy-3- (trifluoromethyl) pyrrolidine-1-carboxylic acid tert-butyl ester
3-Oxopyrrolidine-1-carboxylic acid tert-butyl ester Cpd-035A (2.0 g,10.8 mmol), trimethyl (trifluoromethyl) silane (3.1 g,21.6 mmol) and tetrabutylammonium fluoride (1.2 mL,1.1 mmol) were dissolved in dry tetrahydrofuran (15 mL). The reaction was allowed to react overnight at room temperature. To the reaction solution was added a saturated sodium chloride solution (50 mL), followed by extraction with ethyl acetate (2X 50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated and purified by separation (petroleum ether/ethyl acetate=5/1) to give 3-hydroxy-3- (trifluoromethyl) pyrrolidine-1-carboxylic acid tert-butyl ester Cpd-035B (2.5 g, white solid), yield: 90%.
1 H NMR(400MHz,DMSO-d6)δ3.67-3.48(m,4H),3.15(br,1H),2.26-2.17(m,1H),2.02-1.98(m,1H),1.45(s,9H).
Second step
Preparation of tert-butyl 3- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) -3- (trifluoromethyl) pyrrolidine-1-carboxylate
3-hydroxy-3- (trifluoromethyl) pyrrolidine-1-carboxylic acid tert-butyl ester Cpd-035B (1.0 g,2.4 mmol) was dissolved in DMF (5 mL) and cooled to 0deg.C in ice bath. And sodium hydride (212 mg,8.3 mmol) was added thereto and stirred for 30min. (2-Bromoethoxy) (tert-butyl) dimethylsilane (900 mg,2.9 mmol) was added thereto and reacted at 25℃for 12 hours. The reaction mixture was washed with saturated aqueous sodium chloride (50 mL. Times.3). The organic phase was dried over anhydrous sodium sulfate to give 3- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) -3- (trifluoromethyl) pyrrolidine-1-carboxylic acid tert-butyl ester Cpd-035C (1.5 g, yellow oil), yield: 80%. The crude product was used directly in the next step without further purification.
Third step
Preparation of 3- (2-hydroxyethoxy) -3- (trifluoromethyl) pyrrolidine-1-carboxylic acid tert-butyl ester
3- (2- ((tert-Butyldimethylsilyloxy) ethoxy) -3- (trifluoromethyl) pyrrolidine-1-carboxylic acid tert-butyl ester Cpd-035C (1.0 g,3.3 mmol) was dissolved in THF (5 mL) and tetrabutylammonium fluoride (0.33 mL,3.3 mmol) was added thereto. The reaction solution was reacted at 25℃for 30 minutes. After completion of the reaction, tetrahydrofuran was removed by rotary evaporation, ethyl acetate (5 mL) was added to dissolve the tetrahydrofuran, and the resultant mixture was washed with saturated sodium chloride (10 ml×3), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was isolated and purified on silica gel column (petroleum ether/ethyl acetate=1/2) to give 3- (2-hydroxyethoxy) -3- (trifluoromethyl) pyrrolidine-1-carboxylic acid tert-butyl ester Cpd-035D (200 mg, yellow oil), yield: 20%.
1 H NMR(400MHz,CDCl 3 )δ3.73-3.46(m,5H),3.35-3.31(m,1H),2.26-2.08(m,2H),1.66(s,2H),1.45(d,J=3.1Hz,9H).
Fourth step
Preparation of 3- (2-carboxyethoxy) -3- (trifluoromethyl) pyrrolidine-1-carboxylic acid tert-butyl ester
3- (2-hydroxyethoxy) -3- (trifluoromethyl) pyrrolidine-1-carboxylic acid tert-butyl ester Cpd-035D (100 mg,0.3 mmol) was dissolved in dry dichloromethane (2 mL) and cooled to 0deg.C in an ice water bath. To this was added dessmartin reagent (170 mg,0.4 mmol) and the mixture was reacted for 1 hour. The reaction solution was quenched with aqueous sodium thiosulfate (5 mL) and then washed with saturated aqueous sodium bicarbonate (10 mL. Times.3). The organic phase was dried over anhydrous sodium sulfate and evaporated in vacuo to give 3- (2-carbonylethoxy) -3- (trifluoromethyl) pyrrolidine-1-carboxylic acid tert-butyl ester Cpd-035E (80 mg, light brown solid), yield: 88%. The crude product was used directly in the next step without further purification.
Fifth step
Preparation of ethyl 3- ((2- ((1- (1- (tert-butoxycarbonyl) -3- (trifluoromethyl) pyrrolidin-3-yl) oxy) ethyl) amino) ethyl-1H-pyrrole-2-carboxylate
3- (2-Coarbonylethoxy) -3- (trifluoromethyl) pyrrolidine-1-carboxylic acid tert-butyl ester Cpd-035E (80 mg,0.2 mmol) was dissolved in methanol (2 mL) and then ethyl 3-amino-1H-pyrrole-2-carboxylate (26 mg,0.9 mmol) and acetic acid (0.5 mL) were added sequentially. The reaction solution was reacted for 4 hours. Sodium cyanoborohydride (22 mg,0.4 mmol) was added and the reaction was carried out for 1 hour. Methanol was removed by rotary evaporation, dissolved in ethyl acetate (5 mL), washed with saturated brine (10 mL. Times.3), and dried over anhydrous sodium sulfate. Separation and purification on a silica gel column (petroleum ether/ethyl acetate=1/2) gave Cpd-035F (30 mg, oily liquid), yield: 27%.
MS m/z(ESI):436[M+1] + .
Sixth step
Preparation of ethyl 3- (1- (2- (((1- (tert-butoxycarbonyl) -3- (trifluoromethyl) pyrrolidin-3-yl) oxy) ethyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylate
3- ((2- ((1- (1- (tert-butoxycarbonyl) -3- (trifluoromethyl) pyrrolidin-3-yl) oxy) ethyl) amino) ethyl-1H-pyrrole-2-carboxylate Cpd-035F (30 mg,0.07 mmol) was dissolved in DCM (2 mL) and ethyl isothiocyanate (10 mg,0.08 mmol) was added and the reaction mixture reacted at room temperature for 30 min after the end of the reaction was distilled off to give 3- (1- (2- (((1- (tert-butoxycarbonyl) -3- (trifluoromethyl) pyrrolidin-3-yl) oxy) ethyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylate Cpd-035G crude (30 mg, yellow oil) in 77% yield.
MS m/z(ESI):589[M+23] + .
Seventh step
Preparation of 3- (2- (2-thio-4-oxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-1-yl) ethoxy) -3- (trifluoromethyl) pyrrolidine-1-carboxylic acid tert-butyl ester
3- (1- (2- (((1- (tert-Butoxycarbonyl) -3- (trifluoromethyl) pyrrolidin-3-yl) oxy) ethyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-035G (30 mg,0.05 mmol) was dissolved in anhydrous methanol (2 mL) cesium carbonate (60 mg,0.18 mmol) was added and placed in an oil bath at 65℃for 12 hours after the reaction was completed, the reaction mixture was cooled to room temperature and spin-dried to climb a plate (petroleum ether/ethyl acetate=1/2) to give 3- (2- (2-thio-4-oxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-1-yl) ethoxy) -3- (trifluoromethyl) pyrrolidine-1-carboxylic acid tert-butyl ester Cpd-035H (20 mg, yellow oil) in 84% yield.
MS m/z(ESI):471[M+23] + .
Eighth step
Preparation of 2-thio-1- (2- (((3- (trifluoromethyl) pyrrolidin-3-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
3- (2- (2-thio-4-oxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-1-yl) ethoxy) -3- (trifluoromethyl) pyrrolidine-1-carboxylic acid tert-butyl ester Cpd-035H (20 mg,0.04 mmol) was dissolved in methanol (1 mL), then methanol hydrochloride solution (0.2 mL) was added and the reaction was carried out for 2 hours, followed by rotary evaporation to remove methanol. Beating with ethyl acetate gives 2-thio-1- (2- (((3- (trifluoromethyl) pyrrolidin-3-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-035 (15 mg, white solid) in 90% yield.
MS m/z(ESI):332[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.38(s,1H),12.25(s,1H),9.89(s,1H),9.72(s,1H),7.35(s,1H),6.43(s,1H),4.62-4.53(m,2H),4.02(s,2H),3.71-3.59(m,3H),3.26(s,1H),2.33-2.13(m,2H).
Example 36
2-thio-1- (2- (((1-methyl-3- (trifluoromethyl) pyrrolidin-3-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
2-thio-1- (2- (((3- (trifluoromethyl) pyrrolidin-3-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-035 (30 mg,0.09 mmol) was dissolved in methanol (2 mL) and paraformaldehyde (10 mg) and two drops of acetic acid were then added after 2 hours of reaction, sodium cyanoborohydride (20 mg,0.32 mmol) was added and the reaction was completed after 1 hour, methanol was removed by rotary chromatography and 2-thio-1- (2- (((1-methyl-3- (trifluoromethyl) pyrrolidin-3-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-036 (20 mg, white solid) was isolated by column chromatography (DCM/MeOH=10/1), yield 90%.
MS m/z(ESI):363[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.35(s,1H),12.25(s,1H),7.35(s,1H),6.30(s,1H),4.52(t,J=5.2Hz,2H),3.99(dd,J=12.3,5.5Hz,2H),2.69-2.51(m,2H),2.31(t,J=6.7Hz,2H),2.12(s,3H),1.99-1.82(m,2H).
Example 37
2-thio-1- (4, 4-trifluoro-3-hydroxymethylbutyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of ethyl 3-hydroxymethyl-4, 4-trifluorobutyrate
Ethyl 3-hydroxy-4, 4-trifluorobutyrate Cpd-037A (0.5 g,2.7 mmol) was dissolved in acetonitrile (10 mL), and cesium carbonate (1.7 g,5.4 mmol) and methyl iodide (0.8 g,5.4 mmol) were added to the reaction solution. The reaction was stirred at room temperature overnight. After the reaction was completed, cesium carbonate was suction-filtered and then concentrated under reduced pressure to give the compound ethyl 3-hydroxymethyl-4, 4-trifluorobutyrate Cpd-037B (0.56 g, yellow oil), yield: 74%.
1 H NMR(400MHz,DMSO-d6)δ4.34-4.21(m,1H),4.18-4.07(m,2H),3.48(s,3H),2.78(dd,J=16.3,3.5Hz,1H),2.56(dd,J=16.4,9.6Hz,1H),1.21(t,J=7.1Hz,3H).
Second step
Preparation of 3-hydroxymethyl-4, 4-trifluoro-1-butanol
Ethyl 3-hydroxymethyl-4, 4-trifluorobutyrate Cpd-037B (0.5 g,2.8 mmol) was dissolved in 15mL dry tetrahydrofuran, cooled to 0deg.C, followed by slow addition of lithium aluminum hydride (0.1 g,2.8 mmol). The reaction solution was stirred at 0℃for 1 hour. After the reaction was completed, the reaction was quenched by slowly dropping water (0.1 mL) and 15% sodium hydroxide solution (0.1 mL), followed by adding water (0.3 mL) and anhydrous sodium sulfate, stirring at room temperature for 0.5 hours, suction filtration, collection of filtrate and concentration under reduced pressure, and purification of the residue by silica gel column chromatography (petroleum ether/ethyl acetate=3/1) to give compound 3-hydroxymethyl-4, 4-trifluoro-1-butanol Cpd-037C (0.49 g, yellow oil), yield: 73%.
1 H NMR(400MHz,DMSO-d6)δ4.71(t,J=5.1Hz,1H),3.90(ddd,J=9.8,7.1,2.7Hz,1H),3.62-3.40(m,5H),1.78-1.52(m,2H).
Third step
Preparation of 3-hydroxymethyl-4, 4-trifluorobutanal
Oxalyl chloride (150 mg,1.13 mmol) was dissolved in dichloromethane and cooled to-65 ℃, followed by slow addition of dimethyl sulfoxide (80 mg,1.04 mmol). After stirring for 10 minutes, 3-hydroxymethyl-4, 4-trifluoro-1-butanol Cpd-037C (0.15 g,0.94 mmol) was slowly added. After stirring the reaction solution at-65℃for 1 hour, triethylamine (0.5 g,4.7 mmol) was slowly added. After stirring for 10 minutes, slowly warm to room temperature and wash with water (2 mL). The organic phase was separated and collected, and dried over anhydrous sodium sulfate to give a methylene chloride solution of the compound 3-hydroxymethyl-4, 4-trifluorobutyraldehyde Cpd-037D. The solution was used directly in the next reaction without further treatment.
Fourth step
Preparation of 3- ((3-hydroxymethyl-4, 4-trifluorobutyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester
Ethyl 3-amino-1H-pyrrole-2-carboxylate (140 mg,0.9 mmol) was dissolved in methanol (5 mL), followed by the sequential addition of 3-hydroxymethyl-4, 4-trifluorobutyraldehyde Cpd-037D (dichloromethane solution), acetic acid (100 mg,1.7 mmol). After stirring at room temperature for half an hour, sodium cyanoborohydride (60 mg,0.9 mmol) was added. The reaction was stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to give the title compound 3- ((3-hydroxymethyl-4, 4-trifluorobutyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-037E (170 mg, yellow oil), yield: 61%.
1 H NMR(400MHz,DMSO-d6)δ10.78(s,1H),6.77(t,J=2.8Hz,1H),5.65(s,1H),5.39(s,1H),4.18(q,J=7.1Hz,2H),3.97-3.87(m,1H),3.49(s,3H),3.29-3.17(m,2H),1.87(ddd,J=14.5,8.7,5.9Hz,1H),1.70(dd,J=14.8,8.7Hz,1H),1.27(d,J=7.1Hz,3H).
Fifth step
Preparation of 3- (1- (3-hydroxymethyl-4, 4-trifluorobutyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester
3- ((3-hydroxymethyl-4, 4-trifluorobutyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-037E (30 mg,0.1 mmol) was dissolved in dichloromethane (2 mL) followed by ethyl isothiocyanate (14 mg,0.1 mmol). The reaction was stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was separated with a silica gel preparation plate (petroleum ether/ethyl acetate=3/1) to give the title compound, 3- (1- (3-hydroxymethyl-4, 4-trifluorobutyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-037F (28 mg, yellow solid), yield: 61%.
MS m/z(ESI):426[M+1] + .
Sixth step
Preparation of 2-thio-1- (4, 4-trifluoro-3-hydroxymethylbutyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
3- (1- (3-hydroxymethyl-4, 4-trifluorobutyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-037F (28 mg,0.07 mmol) was dissolved in methanol (5 mL) followed by cesium carbonate (100 mg,0.33 mmol). The reaction solution was heated to 65℃and stirred for 8 hours. After the reaction was completed, water (10 mL) and ethyl acetate (10 mL) were added, followed by extraction of the aqueous phase with ethyl acetate (10 ml×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated using a silica gel preparation plate (dichloromethane/methanol=20/1) to give the compound 2-thio-1- (4, 4-trifluoro-3-hydroxymethylbutyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-037 (15 mg, pale yellow solid), yield: 70%.
MS m/z(ESI):308[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.47(s,1H),12.23(s,1H),7.41(d,J=2.4Hz,1H),6.29(d,J=2.5Hz,1H),4.53(s,2H),4.17(s,1H),3.51(s,3H),2.11-1.89(m,2H).
Example 38
1- (4, 4-trifluoro-3- (methylamino) butyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of ethyl 3-amino-4, 4-trifluorobutyrate
Thionyl chloride (1.2 g,10.2 mmol) was added dropwise to absolute ethanol (10 mL) in an ice bath, and after completion of the dropwise addition, 3-amino-4, 4-trifluoro-butyric acid Cpd-038A (0.4 g,2.5 mmol) was added to the reaction solution, followed by heating to 60℃for two hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated, and after the concentration, water (20 mL) was added to quench the residual thionyl chloride thoroughly, followed by lyophilization to give ethyl 3-amino-4, 4-trifluorobutyrate Cpd-038B (500 mg, white solid), yield: 85%.
1 H NMR(400MHz,DMSO-d6)δ9.09(s,3H),4.50(dd,J=14.1,7.0Hz,1H),4.15(q,J=7.1Hz,2H),2.94(d,J=6.3Hz,2H),1.22(t,J=7.1Hz,3H).
Second step
Preparation of ethyl 3- (((tert-butoxy) carbonyl) amino) -4, 4-trifluorobutyrate
Ethyl 3-amino-4, 4-trifluorobutyrate Cpd-038B (200 mg,0.9 mmol) and triethylamine (365 mg,3.6 mmol) were dissolved in ethanol (7 mL) followed by the addition of di-tert-butyl dicarbonate (1.6 g,7.2 mmol) and heated to 60℃with nitrogen and stirred for 2 hours. After the completion of the reaction, the reaction mixture was concentrated, diluted with water (100 mL), extracted with ethyl acetate (50 ml×2), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was separated and purified by a silica gel column (petroleum ether/ethyl acetate=10/1) to give 3- (((tert-butoxy) carbonyl) amino) -4, 4-trifluoro-ethyl butyrate Cpd-038C (263 mg, white solid), yield: 102%.
1 H NMR(400MHz,DMSO-d6)δ7.66(d,J=8.9Hz,1H),4.54(d,J=5.4Hz,1H),4.15-3.99(m,2H),2.77(dd,J=16.2,4.0Hz,1H),2.69-2.57(m,1H),1.18(t,J=7.1Hz,3H).
Third step
Preparation of ethyl 3- (((tert-butoxy) carbonyl) methylamino) -4, 4-trifluorobutyrate
Ethyl 3- (((tert-butoxy) carbonyl) amino) -4, 4-trifluorobutyrate Cpd-038C (160 mg,0.56 mmol) cesium carbonate (284 mg,2.80 mmol) was dissolved in acetonitrile (3 mL) followed by dropwise addition of methyl iodide (239 mg,1.68 mmol) at room temperature and after the addition the reaction mixture was heated at 30℃under nitrogen and stirred for 12 hours. After the reaction was completed, the reaction mixture was filtered through celite, and the crude product obtained by concentrating the filtrate was separated and purified by silica gel column (petroleum ether/ethyl acetate=10/1) to obtain ethyl 3- (((tert-butoxy) carbonyl) amino) -4, 4-trifluorobutyrate Cpd-038D (160 mg, white solid), yield: 95%.
1 H NMR(400MHz,DMSO-d6)δ5.11(s,1H),4.10(s,2H),2.98-2.86(m,2H),2.74(d,J=7.8Hz,3H),1.40(d,J=8.1Hz,9H),1.17(s,3H).
Fourth step
Preparation of tert-butyl N-methyl-N- (1, 1-trifluoro-4-hydroxybutan-2-yl) carbamate
Ethyl 3- (((tert-butoxy) carbonyl) amino) -4, 4-trifluorobutyrate Cpd-038D (120 mg,0.40 mmol) was dissolved in tetrahydrofuran (6 mL) and lithium aluminum tetrahydrofuran solution (1.2 mL,1.2mmol, 1M) was added dropwise under nitrogen in ice bath. After the completion of the dropwise addition, stirring was continued for 10 minutes. After the completion of the reaction, the reaction mixture was diluted with tetrahydrofuran (50 mL), aqueous sodium hydroxide (0.5 mL,2 m) was added dropwise under ice bath, stirred for 10 minutes, then anhydrous sodium sulfate solid was added and stirred for half an hour, after completion of quenching, the reaction mixture was filtered through celite, and the crude product obtained by concentration of the filtrate was separated and purified by silica gel column (petroleum ether/ethyl acetate=2/1) to give tert-butyl N-methyl-N- (1, 1-trifluoro-4-hydroxybutan-2-yl) carbamate Cpd-038E (100 mg, white solid), yield: 97%.
1 H NMR(400MHz,DMSO-d6)δ4.90(s,1H),4.73-4.63(m,1H),3.55-3.40(m,1H),3.31-3.22(m,1H),2.72(d,J=7.8Hz,3H),1.98-1.81(m,1H),1.80-1.70(m,1H),1.40(d,J=10.6Hz,9H).
Fifth step
Preparation of tert-butyl N-methyl-N- (1, 1-trifluoro-4-oxobutan-2-yl) carbamate
Tert-butyl N-methyl-N- (1, 1-trifluoro-4-hydroxybutan-2-yl) carbamate Cpd-038E (100 mg,0.39 mmol) was dissolved in dichloromethane (5 mL) followed by addition of dessert-martin oxidant (330 mg,0.78 mmol) in ice bath and stirring at room temperature under nitrogen for 1 hour. After the reaction was completed, the reaction mixture was filtered through celite, the filtrate was concentrated at room temperature, and the crude product obtained by concentrating the filtrate was purified by separation on a silica gel column (petroleum ether/ethyl acetate=4/1) to give tert-butyl N-methyl-N- (1, 1-trifluoro-4-hydroxybutan-2-yl) carbamate Cpd-038E (100 mg, white solid), yield: 100%.
1 H NMR(400MHz,DMSO-d6)δ9.61(d,J=8.6Hz,1H),5.43-5.11(m,1H),3.25-3.05(m,1H),3.05-2.95(m,1H),2.70(d,J=9.4Hz,3H),1.42(s,9H).
Sixth step
Preparation of ethyl 3- ((3- ((tert-butoxycarbonyl) methylamino) -4, 4-trifluorobutyl) amino) -1H-pyrrole-2-carboxylate
Tert-butyl N-methyl-N- (1, 1-trifluoro-4-hydroxybutan-2-yl) carbamate Cpd-038E (100 mg,0.39 mmol), ethyl 3-amino-1H-pyrrole-2-carboxylate (72 mg,0.47 mmol) and two drops of acetic acid were dissolved in methanol (5 mL) and stirred at room temperature for half an hour, followed by sodium cyanoborohydride (123 mg,1.95 mmol) at room temperature and stirred for 12 hours. After the reaction was completed, the reaction solution was diluted with water (200 mL), extracted with ethyl acetate (100 ml×2), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was separated and purified by a silica gel column (petroleum ether/ethyl acetate=4/1) to give 3- ((3- ((t-butoxycarbonyl) methylamino) -4, 4-trifluorobutyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-038F (93 mg, colorless oil), yield: 60%.
MS m/z(ESI):394[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ10.77(s,1H),6.75(t,J=2.8Hz,1H),5.64(s,1H),5.31(s,1H),4.90-4.72(m,1H),4.19(q,J=7.1Hz,2H),3.22-2.94(m,2H),2.76(d,J=8.6Hz,3H),2.02-1.87(m,2H),1.38(d,J=39.7Hz,9H),1.26(t,J=7.0Hz,3H).
Seventh step
Preparation of ethyl 3- (1- (3- ((tert-butoxycarbonyl) methylamino) -4, 4-trifluorobutyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylate
3- ((3- ((tert-Butoxycarbonyl) methylamino) -4, 4-trifluorobutyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-038F (93 mg,0.24 mmol) and ethoxycarbonyl isothiocyanate (46 mg,0.35 mmol) were dissolved in methanol (5 mL) followed by stirring at room temperature under nitrogen for 1 hour. After the reaction was completed, the reaction solution was concentrated to give crude 3- (1- (3- ((t-butoxycarbonyl) methylamino) -4, 4-trifluorobutyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-038G (130 mg, colorless oil), yield: 104%. The crude product was used directly in the next step without further purification.
MS m/z(ESI):525[M+1] + .
Eighth step
Preparation of tert-butyl (1, 1-trifluoro-4- (4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) butan-2-yl) methylcarbamate
The resulting crude 3- (1- (3- ((tert-butoxycarbonyl) methylamino) -4, 4-trifluorobutyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-038G (130 mg,0.25 mmol) and cesium carbonate (400 mg,1.24 mmol) were dissolved in methanol (5 mL) and then heated to 60℃under nitrogen and stirred for 5 hours. After the completion of the reaction, the reaction mixture was concentrated, quenched with saturated aqueous ammonium chloride (100 mL), extracted with ethyl acetate (50 ml×2), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the concentrated crude product was purified by separation on a silica gel column (petroleum ether/ethyl acetate=1/1) to give (1, 1-trifluoro-4- (4-oxo-2-thio-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) butan-2-yl) methyl carbamic acid tert-butyl ester Cpd-038H (80 mg, white solid), yield: 79%.
MS m/z(ESI):407[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.44(s,1H),12.23(s,1H),7.39(s,1H),6.49(d,J=13.1Hz,1H),5.12-4.84(m,1H),4.56(s,1H),4.18(s,1H),2.86(d,J=15.0Hz,3H),2.25(s,1H),2.08(s,1H),1.41(d,J=19.1Hz,9H).
Ninth step
Preparation of 1- (4, 4-trifluoro-3- (methylamino) butyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Tert-butyl (1, 1-trifluoro-4- (4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) butan-2-yl) methylcarbamate Cpd-038H (80 mg,0.20 mmol) was dissolved in ethanol hydrochloride (5 mL) and heated to 30℃for half an hour under nitrogen. After the reaction was completed, the reaction mixture was concentrated, purified by a C18 reverse column (methanol/water (1%o formic acid) =1/4), washed with aqueous sodium bicarbonate solution, and extracted with ethyl acetate to give 1- (4, 4-trifluoro-3- (methylamino) butyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-038 (27 mg, white solid), yield: 45%.
MS m/z(ESI):307[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.46(s,1H),12.21(s,1H),7.41(s,1H),6.38(s,1H),4.50(t,J=7.5Hz,2H),3.30-3.20(m,1H),2.43(s,3H),2.11-1.99(m,1H),1.89-1.76(m,1H).
Example 39
1- (3- (dimethylamino) -4, 4-trifluorobutyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of 1- (3- (dimethylamino) -4, 4-trifluorobutyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
1- (4, 4-trifluoro-3- (methylamino) butyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-038 (25 mg,0.08 mmol) and paraformaldehyde (12 mg,0.41 mmol) were dissolved in methanol (2 mL) followed by addition of sodium cyanoborohydride (51 mg,0.82 mmol) at room temperature and stirring at room temperature under nitrogen for half an hour. After the completion of the reaction, the reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (50 ml×2), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was separated, purified and concentrated by a C18 reverse phase column (methanol/water (1 millformic acid) =1/4) and washed with aqueous sodium bicarbonate solution, and extracted with ethyl acetate to give 1- (3- (dimethylamino) -4, 4-trifluorobutyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-039 (10 mg, white solid), yield: 38%.
MS m/z(ESI):321[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.44(s,1H),12.22(s,1H),7.41(d,J=2.8Hz,1H),6.33(d,J=2.8Hz,1H),4.68-4.53(m,1H),4.35-4.21(m,1H),3.67-3.55(m,1H),2.45(s,6H),2.18-2.02(m,1H),1.95-1.80(m,1H).
Example 40
1- ((3- (aminomethyl) -4-chlorophenyl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of (5-bromo-2-chlorobenzyl) carbamic acid tert-butyl ester
5-bromo-2-chloro-benzylamine Cpd-040A (0.9 g,4.1 mmol) was dissolved in dichloromethane (50 mL), followed by the addition of di-tert-butyl dicarbonate (1.8 g,8.2 mmol) and triethylamine (1.2 g,12.2 mmol) and stirring at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated, and the obtained crude product was purified by a silica gel column (petroleum ether/ethyl acetate=9/1) to give tert-butyl (5-bromo-2-chlorobenzyl) carbamate Cpd-040B (1.5 g, white solid), yield: 97%.
1 H NMR(400MHz,DMSO-d6)δ7.52-7.35(m,4H),4.18(d,J=5.9Hz,2H),1.41(s,9H).
Second step
Preparation of tert-butyl (2-chloro-5-formylbenzyl) carbamate
Tert-butyl (5-bromo-2-chlorobenzyl) carbamate Cpd-040B (300 mg,0.93 mmol) was dissolved in dimethyl sulfoxide (5 mL), triethylsilane (163 mg,1.40 mmol), N, N-diisopropylethylamine (423 mg,3.27 mmol), and bis (di-tert-butyl- (4-dimethylaminophenyl) phosphine) palladium (II) dichloride (130 mg,0.18 mmol) were then added, and the reaction mixture was heated to 90℃for 2 hours. The reaction solution was cooled to room temperature, ethyl acetate (50 mL) was added, saturated brine was washed once, and the organic phase was dried over anhydrous sodium sulfate and concentrated, and the obtained residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate=5/1) to give tert-butyl (2-chloro-5-formylbenzyl) carbamate Cpd-040C (120 mg, pale yellow solid), yield: 43%.
1 H NMR(400MHz,CDCl 3 )δ9.99(s,1H),7.89(s,1H),7.75(dd,J=8.2,1.7Hz,1H),7.53(d,J=8.2Hz,1H),5.05(s,1H),4.48(s,2H),1.47(s,9H).
Third step
Preparation of 3- ((3- (((tert-butoxycarbonyl) amino) methyl) -4-chlorobenzyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester
Ethyl 3-amino-1H-pyrrole-2-carboxylate (140 mg,0.9 mmol) was dissolved in methanol (15 mL), followed by the sequential addition of tert-butyl (2-chloro-5-formylbenzyl) carbamate Cpd-040C (250 mg,0.9 mmol) and acetic acid (110 mg,1.8 mmol). After stirring at room temperature for half an hour, sodium cyanoborohydride (60 mg,0.9 mmol) was added. The reaction was stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/1) to give compound 3- ((3- (((t-butoxycarbonyl) amino) methyl) -4-chlorobenzyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-040D (238 mg, colorless oil), yield: 60%.
1 H NMR(400MHz,DMSO-d6)δ10.75(s,1H),7.47-7.15(m,4H),6.67(s,1H),5.80(s,1H),5.51(s,1H),4.26(d,J=6.0Hz,2H),4.23-4.08(m,4H),1.38(s,9H),1.26(t,J=7.0Hz,3H).
Fourth step
Preparation of ethyl 3- (1- (3- ((tert-butoxycarbonyl) amino) methyl) -4-chlorobenzyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylate
3- ((3- (((tert-Butoxycarbonyl) amino) methyl) -4-chlorobenzyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-040D (238 mg,0.58 mmol) was dissolved in methanol (3 mL) followed by addition of ethoxycarbonyl isothiocyanate (92 mg,0.70 mmol) at room temperature and stirring under nitrogen for 1 hour. After the reaction was completed, the reaction solution was concentrated to give crude 3- (1- (3- ((t-butoxycarbonyl) amino) methyl) -4-chlorobenzyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-040E (314 mg, colorless oil), yield: 99%.
MS m/z(ESI):539[M+1] + .
Fifth step
Preparation of (2-chloro-5- ((4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) methyl) benzyl) carbamic acid tert-butyl ester
The reaction solution was concentrated to give crude ethyl 3- (1- (3- ((t-butoxycarbonyl) amino) methyl) -4-chlorobenzyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylate Cpd-040E (314 mg,0.58 mmol) which was dissolved in methanol (8 mL), followed by cesium carbonate (1328 mg,4.08 mmol) and heated at 65℃for four hours under nitrogen. After the completion of the reaction, the reaction mixture was concentrated, the residue was dispersed with an aqueous ammonium chloride solution (100 mL), extracted with ethyl acetate (50 ml×2), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the concentrated crude product was slurried with methylene chloride to give tert-butyl (2-chloro-5- ((4-oxo-2-thio-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) methyl) benzyl) carbamate Cpd-040F (100 mg, white solid), yield: 41%.
MS m/z(ESI):365[M-56+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.29(br,1H),7.38(d,J=7.9Hz,2H),7.29(s,2H),7.23(d,J=8.3Hz,1H),6.11(d,J=2.0Hz,1H),5.68(s,2H),4.12(d,J=5.8Hz,2H),1.36(s,9H).
Sixth step
Preparation of 1- ((3- (aminomethyl) -4-chlorophenyl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Tert-butyl (2-chloro-5- ((4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) methyl) benzyl) carbamate Cpd-040F (100 mg,0.23 mmol) was dissolved in ethanol hydrochloride (10 mL) followed by stirring at 30℃for 1 hour. After the reaction, the reaction mixture was concentrated, and the crude product obtained was purified by a C18 reverse column (methanol/water (1%o formic acid) =1/4-3/2), washed with aqueous sodium bicarbonate solution after concentration, and extracted with ethyl acetate to give 1- ((3- (aminomethyl) -4-chlorophenyl) methyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-040 (35 mg, white solid), yield: 46%.
MS m/z(ESI):321[M+1] + .
Example 41
1- (4-chloro-3- ((dimethylamino) methyl) benzyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of 1- (4-chloro-3- ((dimethylamino) methyl) benzyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
1- ((3- (aminomethyl) -4-chlorophenyl) methyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-040 (30 mg,0.08 mmol) and paraformaldehyde (52 mg,0.84 mmol) were dissolved in methanol (3 mL), followed by the addition of sodium cyanoborohydride (42 mg,0.67 mmol) at room temperature and stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was quenched with water (100 mL), extracted with ethyl acetate (50 ml×2), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to give a crude product, which was purified by C18 reverse phase column (methanol/water (1 millformic acid) =1/4-1/1), concentrated and washed with aqueous sodium bicarbonate solution, extracted with ethyl acetate to give 1- (4-chloro-3- ((dimethylamino) methyl) benzyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-041 (10 mg, white solid), yield: 34%.
MS m/z(ESI):349[M+1] + .
Example 42
1- (2- (1- ((methylamino) methyl) cyclopropyloxy) ethyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of methyl 1- (2- ((tert-butyldimethylsilyloxy) ethoxy) cyclopropane-1-carboxylate
Sodium hydrogen (0.9 g,22.4 mmol) was dissolved in N, N-dimethylformamide (20 mL), the reaction was cooled to-40℃and methyl 1-hydroxycyclopropane-1-carboxylate Cpd-042A (2.0 g,17.2 mmol) was added thereto. The reaction solution was stirred at-40℃for 2 hours, and then (2-bromoethoxy) (tert-butyl) dimethylsilane (4.1 g,17.2 mmol) was added thereto. The reaction was allowed to react overnight at room temperature. Water (50 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL. Times.3). The organic phases were combined, washed with water (100 ml×3), dried over anhydrous sodium sulfate and concentrated at low temperature to give crude methyl 1- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) cyclopropane-1-carboxylate Cpd-042B (2.8 g, brown liquid), yield: 53.4%.
1 H NMR(400MHz,DMSO-d6)δ3.88(t,J=5.7Hz,2H),3.64(s,3H),3.52(t,J=5.7Hz,2H),1.21-1.11(m,4H),0.88(s,9H),0.07(s,6H).
Second step
Preparation of (1- (2- ((tert-butyldimethylsilyloxy) ethoxy) cyclopropyl) methanol
Methyl 1- (2- ((tert-butyldimethylsilyloxy) ethoxy) cyclopropane-1-carboxylate Cpd-042B (2.5 g,9.5 mmol) was dissolved in tetrahydrofuran (10 mL), the reaction solution was cooled to 0 ℃ and a 1M suspension of aluminum lithium hydrogen in tetrahydrofuran (20 mL) was slowly added thereto. The reaction solution was reacted at 0 ℃ for 2 hours, then quenched at 0 ℃, filtered, and the filtrate was concentrated to give (1- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) cyclopropyl) methanol Cpd-042C (750 mg, yellow liquid), yield: 28.4%.
1 H NMR(400MHz,DMSO-d6)δ4.61(t,J=5.8Hz,1H),3.61-3.56(m,2H),3.53(dd,J=4.9,3.5Hz,2H),3.48(d,J=5.8Hz,2H),0.85(s,9H),0.62(t,J=5.7Hz,2H),0.51(t,J=5.7Hz,2H),0.01(s,6H).
Third step
Preparation of 1- (2- ((tert-butyldimethylsilyloxy) ethoxy) cyclopropane-1-carbaldehyde
Oxalyl chloride (515 mg,4.0 mmol) was dissolved in dry dichloromethane (5 mL) and dry dimethyl sulfoxide (553mg, 7.1 mmol) dissolved in dichloromethane was added thereto under nitrogen protection at-78deg.C. After stirring for 10 minutes, (1- (2- ((tert-butyldimethylsilyloxy) ethoxy) cyclopropyl) methanol Cpd-042C (500 mg,2.0 mmol) dissolved in dichloromethane was added thereto. After the reaction solution was stirred at-78℃for 30 minutes, triethylamine (1.1 g,11 mmol) was added thereto. The reaction solution was stirred and returned to room temperature. After the reaction was completed, the mixture was washed with water, and the organic phase was dried over sodium sulfate and concentrated to give crude 1- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) cyclopropane-1-carbaldehyde Cpd-042D (470 mg, colorless oil), yield: 85%.
MS m/z(ESI):245[M+1] + .
Fourth step
Preparation of 1- (1- (2- ((tert-butyldimethylsilyloxy) ethoxy) cyclopropyl) -N-methyl methylamine
1- (2- ((tert-Butyldimethylsilyloxy) ethoxy) cyclopropane-1-carbaldehyde Cpd-042D (470 mg,1.9 mmol) was dissolved in methanol (5 mL) and a solution of methylamine in tetrahydrofuran (2.8 mL,5.7 mmol) and glacial acetic acid (2 drops) were added thereto. The reaction mixture was reacted at 25℃for 1 hour, and sodium cyanoborohydride (803 mg,5.7 mmol) was added thereto for further 16 hours. After the reaction, the methanol is removed by rotating to obtain crude 1- (1- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) cyclopropyl) -N-methyl methylamine Cpd-042E which is directly used for the next reaction.
MS m/z(ESI):260[M+1] + .
Fifth step
Preparation of tert-butyl (1- (2- ((tert-butyldimethylsilyloxy) ethoxy) cyclopropyl) methyl) (methyl) carbamate
Crude 1- (1- (2- ((tert-butyldimethylsilyloxy) ethoxy) cyclopropyl) -N-methylmethylamine Cpd-042E (500 mg,1.9 mol) was dissolved in dichloromethane (10 mL) and di-tert-butyl dicarbonate (842 mg,3.9 mmol) and triethylamine (585 mg,5.8 mmol) were added thereto. The reaction solution was reacted at 25 ℃ for 2 hours, then dichloromethane was distilled off, and the obtained residue was separated and purified by silica gel column (petroleum ether/ethyl acetate=9/1) to obtain tert-butyl (1- (2- ((tert-butyldimethylsilyloxy) ethoxy) cyclopropyl) methyl) (methyl) carbamate Cpd-042F (145 mg, colorless oil), yield: 19%.
MS m/z(ESI):360[M+1] + .
Sixth step
Preparation of tert-butyl (1- (2-hydroxyethoxy) cyclopropylmethyl (methyl) carbamate
Tert-butyl (1- (2- ((tert-butyldimethylsilyloxy) ethoxy) cyclopropyl) methyl) (methyl) carbamate Cpd-042F (145 mg,0.4 mmol) was dissolved in tetrahydrofuran (5 mL) and tetrabutylammonium fluoride (211 mg,0.8 mmol) was added thereto. The reaction solution was reacted at 25℃for 2 hours. After the completion of the reaction, tetrahydrofuran was distilled off, and the obtained residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate=8/1) to obtain (tert-butyl 1- (2-hydroxyethoxy) cyclopropylmethyl (methyl) carbamate Cpd-042G (74 mg, colorless oil), yield: 71%.
MS m/z(ESI):268[M+1] + .
Seventh step
Preparation of tert-butyl methyl ((1- (2-oxyethoxy) cyclopropyl) methyl) carbamate
Oxalyl chloride (115 mg,0.9 mmol) was dissolved in dry dichloromethane (4 mL) and dry dimethyl sulfoxide (94 mg,1.2 mmol) dissolved in dichloromethane was added thereto under nitrogen protection at-78deg.C. After stirring for 10 minutes, tert-butyl (1- (2-hydroxyethoxy) cyclopropylmethyl (methyl) carbamate Cpd-042G (74 mg,0.3 mmol) dissolved in methylene chloride was added thereto, triethylamine (182 mg,1.8 mmol) was added thereto after stirring at-78℃for 30 minutes, the reaction mixture was stirred and returned to room temperature, after completion of the reaction, water was washed therein, and the organic phase was dried over sodium sulfate and concentrated to give crude methyl ((1- (2-hydroxyethoxy) cyclopropyl) methyl) carbamic acid tert-butyl ester Cpd-042H (70 mg, brown liquid) in 95% yield.
MS m/z(ESI):244[M+1] + .
Eighth step
Preparation of ethyl 3- ((2- (1- ((tert-butoxycarbonyl) methylamino) methyl) cyclopropane) amino) -1H-pyrrole-2-carboxylate
Crude methyl tert-butyl ((1- (2-oxoethoxy) cyclopropyl) methyl) carbamate Cpd-042H (70 mg,0.8 mmol) was dissolved in methanol (4 mL) and ethyl 3-amino-1H-pyrrole-2-carboxylate (53 mg,0.3 mmol) and glacial acetic acid (2 drops) were added thereto. The reaction mixture was reacted at 25℃for 1 hour. Sodium cyanoborohydride (54 mg,0.9 mmol) was added to the reaction solution to continue the reaction for 16 hours. After the reaction was completed, methanol was removed by rotary evaporation, and the obtained residue was separated and purified by silica gel column (petroleum ether/ethyl acetate=4/1) to give ethyl 3- ((2- (1- ((t-butoxycarbonyl) (methyl) amino) methyl) cyclopropane) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-042I (80 mg, colorless oil), yield: 73%.
MS m/z(ESI):382[M+1] + .
Ninth step
Preparation of ethyl 3- (1- (2- (1- ((tert-butoxycarbonyl) methylamino) methyl) cyclopropyloxy) ethyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylate
3- ((2- (1- ((t-butoxycarbonyl) (methyl) amino) methyl) cyclopropane) ethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-042I (50 mg,0.1 mmol) was dissolved in methylene chloride (4 mL), and ethyl isothiocyanamide (34 mg,0.3 mmol) was added thereto for reaction at 25℃for 2 hours. After the reaction, dichloromethane was distilled off. The resulting residue was extracted with ethyl acetate (3×15 mL), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give crude 3- (1- (2- (1- ((tert-butoxycarbonyl) methylamino) methyl) cyclopropoxy) ethyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-042J (60 mg, yellow oil), yield: 89%.
MS m/z(ESI):513[M+1] + .
Tenth step
Preparation of methyl ((1- (2- (4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) ethoxy) cyclopropyl) methyl) carbamic acid tert-butyl ester
Ethyl 3- (1- (2- (1- ((tert-butoxycarbonyl) (methyl) amino) methyl) cyclopropyloxy) ethyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylate Cpd-042J (80 mg,0.2 mmol) was dissolved in methanol (4 mL), and cesium carbonate (152 mg,0.5 mmol) was added thereto. The reaction solution was heated to 65℃and reacted for 6 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature, methanol was removed by rotary evaporation, and the resulting residue was purified by a preparative plate (dichloromethane/methanol=20/1) to give tert-butyl methyl ((1- (2- (4-oxo-2-thio-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) ethoxy) cyclopropyl) methylcarbamate Cpd-042K (50 mg, colorless oil), yield: 65%.
MS m/z(ESI):395[M+1] + .
Eleventh step
Preparation of 1- (2- (1- ((methylamino) methyl) cyclopropyloxy) ethyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Methyl ((1- (2- (4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) ethoxy) cyclopropyl) methyl tert-butyl carbamate Cpd-042K (50 mg,0.12 mmol) was dissolved in ethanol (2 mL), 3M ethanol hydrochloride solution (2 mL) was added thereto, the reaction mixture was reacted at 25 ℃ for 16 hours, then the acid therein was neutralized with saturated sodium bicarbonate solution, methanol was removed by swirling, the residue was extracted with ethyl acetate (15 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified with C18 column (acetonitrile/water (containing 1 millof formic acid) =4/1) to give 1- (2- (1- ((methylamino) methyl) cyclopropyloxy) ethyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-042 (1.45 mg, light yellow solid, yield, 13.13%).
MS m/z(ESI):295[M+1] + .
1 H NMR(400MHz,MeOD)δ8.53(s,1H),7.30(d,J=2.4Hz,1H),6.27(d,J=2.4Hz,1H),4.61(t,J=5.4Hz,2H),4.02(t,J=5.6Hz,2H),3.20(s,2H),2.73(s,3H),0.81(s,2H),0.70(s,2H).
Example 43
6, 7-dimethyl-2-thioxo-1- (2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of (Z) - (3-cyano-2-en-2-yl) glycine ethyl ester
2-methyl-3-oxobutyronitrile Cpd-043A (900 mg,9.27 mmol) was reacted with ethyl glycinate (1.24 g,12.05 mmol) and triethylamine (1.41 g,13.90 mmol) in ethanol (20 mL) for 8 hours at room temperature. After the completion of the reaction, ethanol was removed by spinning, followed by extraction with ethyl acetate (50 ml×3) and saturated brine (50 mL), and the organic phase was concentrated by drying to give ethyl (Z) - (3-cyano-2-en-2-yl) glycinate Cpd-043B (1.2 g, yellow solid), yield: 58%.
MS m/z(ESI):183.1[M+1] + .
Second step
Preparation of 3-amino-4, 5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester
Ethyl (Z) - (3-cyano-2-en-2-yl) glycinate Cpd-043B (1 g,5.50 mmol) was dissolved in dry ethanol (20 mL), then sodium ethoxide (750 mg,11.00 mmol) was added, the reaction was warmed to 70℃under nitrogen atmosphere for 2 hours, ethanol was removed by rotary evaporation after the reaction was completed, then extracted with ethyl acetate (50 mL. Times.3) and saturated saline (50 mL), the organic phase was concentrated by dryness, and the obtained residue was isolated and purified by silica gel column (petroleum ether/ethyl acetate=4/1) to give 3-amino-4, 5-dimethyl-1H-pyrrole-2-carboxylate Cpd-043C (650 mg, yellow solid), yield: 64%.
MS m/z(ESI):183.1[M+1] + .
Third step
Preparation of ethyl 4, 5-dimethyl-3- ((2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate
Ethyl 3-amino-4, 5-dimethyl-1H-pyrrole-2-carboxylate Cpd-043C (100 mg,0.55 mmol) was dissolved in methanol (10 mL) and then 2- ((1, 1-trifluoropropan-2-yl) oxy) acetaldehyde (86 mg,0.55 mmol) and sodium cyanoborohydride (69 mg,1.10 mmol) were added and reacted at room temperature for 1 hour. After the reaction was completed, methanol was removed by rotary evaporation, and the resulting residue was separated and purified by silica gel column (petroleum ether/ethyl acetate=10/1) to give ethyl 4, 5-dimethyl-3- ((2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-043D (100 mg, yellow solid), yield: 56%.
MS m/z(ESI):323.1[M+1] + .
Fourth step
Preparation of ethyl 3- (3- (ethoxycarbonyl) -1- (2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) thioureido) -4, 5-dimethyl-1H-pyrrole-2-carboxylate
Ethyl 4, 5-dimethyl-3- ((2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-043D (100 mg,0.31 mmol) was dissolved in methanol (15 mL), followed by addition of ethyl isothiocyanamide (49 mg,0.37 mmol), and reacted at room temperature for 1 hour, and after completion of the reaction, the reaction solution was directly used in the next step.
MS m/z(ESI):454.0[M+1] + .
Fifth step
Preparation of 6, 7-dimethyl-2-thioxo-1- (2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Cesium carbonate (303 mg,0.93 mmol) was added to 3- (3- (ethoxycarbonyl) -1- (2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) thioureido) -4, 5-dimethyl-1H-pyrrole-2-carboxylate Cpd-043E (141 mg,0.31 mmol) in methanol (15 mL), stirred for 3 hours at 65 ℃, methanol was removed by rotary evaporation after the reaction was completed, and the resulting residue was isolated and purified by silica gel column (dichloromethane/methanol=50/1) to give 6, 7-dimethyl-2-thio-1- (2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-043 (40 mg, white solid), yield: 52%.
MS m/z(ESI):336.0[M+1] +
1 H NMR(400MHz,DMSO-d6)δ12.16(s,1H),12.09(s,1H),4.72(s,2H),4.20-4.14(m,1H),4.03-3.91(m,2H),2.21(d,J=5.4Hz,6H),1.18(d,J=6.4Hz,3H).
Example 44
7- ((dimethylamino) methyl) -2-thio-1- (2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of 3- ((tert-Butoxycarbonyl) amino) -4-formyl-1H-pyrrole-2-carboxylic acid ethyl ester
3- ((Boc) amino) -4-iodo-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-044A (500 mg,1.32 mmol) was dissolved in DMSO (10 mL), pdA mphos (186 mg,0.26 mmol), triethylsilane (535 mg,4.60 mmol) and N, N-diisopropylethylamine (200 mg,1.97 mmol) were added sequentially and reacted at 90℃for 18 hours under carbon monoxide atmosphere. After the reaction was completed, extracted with ethyl acetate (50 ml×3) and saturated aqueous sodium chloride (50 mL), the organic phase was concentrated by dryness, and the obtained residue was separated and purified by silica gel column (petroleum ether/ethyl acetate=7/3) to give 3- ((tert-butoxycarbonyl) amino) -4-formyl-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-044B (130 mg, pale yellow solid), yield: 36%.
MS m/z(ESI):283.1[M+1] + .
Second step
Preparation of 3- ((tert-Butoxycarbonyl) amino) -4- ((dimethylamino) methyl) -1H-pyrrole-2-carboxylic acid ethyl ester
3- ((Boc) amino) -4-formyl-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-044B (130 mg,0.46 mmol) was dissolved in methanol (10 mL) and then dimethylamine methanol solution (2M, 0.46mL,0.92 mmol) and sodium cyanoborohydride (58 mg,0.92 mmol) were added and reacted at room temperature for 1 hour. After the reaction was completed, methanol was removed by rotary evaporation, and the resulting residue was separated and purified by silica gel column (dichloromethane/methanol=10/1) to give 3- ((tert-butoxycarbonyl) amino) -4- ((dimethylamino) methyl) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-044C (130 mg, colorless oil), yield: 91%.
MS m/z(ESI):312.0[M+1] + .
Third step
Preparation of 3-amino-4- ((dimethylamino) methyl) -1H-pyrrole-2-carboxylic acid ethyl ester hydrochloride
3- ((tert-Butoxycarbonyl) amino) -4- ((dimethylamino) methyl) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-044C (130 mg,0.42 mmol) was dissolved in methanol hydrochloride (4M, 5 mL) and reacted for 2 hours at room temperature. After the reaction was completed, the methanolic hydrochloride solution was removed by rotary evaporation, dissolved in methanol (10 mL), and concentrated by drying to give 3-amino-4- ((dimethylamino) methyl) -1H-pyrrole-2-carboxylic acid ethyl ester hydrochloride Cpd-044D (100 mg, colorless oil), yield: 96%.
MS m/z(ESI):212.1[M+1] + .
Fourth step
Preparation of ethyl 4- ((dimethylamino) methyl) -3- ((2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate
3-amino-4- ((dimethylamino) methyl) -1H-pyrrole-2-carboxylic acid ethyl ester hydrochloride Cpd-044D (100 mg,0.40 mmol) was dissolved in methanol (5 mL) and then 2- ((1, 1-trifluoropropan-2-yl) oxy) acetaldehyde (75 mg,0.48 mmol) and sodium cyanoborohydride (30 mg,0.48 mmol) were added and reacted at room temperature for 1 hour. After the reaction was completed, methanol was removed by rotary evaporation, and the resulting residue was separated and purified by silica gel column (dichloromethane/methanol=10/1) to give ethyl 4- ((dimethylamino) methyl) -3- ((2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-044E (50 mg, colorless oil), yield: 36%.
MS m/z(ESI):352.1[M+1] + .
Fifth step
Preparation of ethyl 4- ((dimethylamino) methyl) -3- (3- (ethoxycarbonyl) -1- (2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) thioureido) -1H-pyrrole-2-carboxylate
4- ((dimethylamino) methyl) -3- ((2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-044E (50 mg,0.14 mmol) was dissolved in methanol (5 mL), then ethyl isothiocyanamide (22 mg,0.17 mmol) was added and reacted at room temperature for 1 hour, after which the reaction solution was directly used in the next step.
MS m/z(ESI):483.1[M+1] + .
Sixth step
Preparation of 7- ((dimethylamino) methyl) -2-thio-1- (2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Cesium carbonate (228 mg,0.70 mmol) was added to methanol (5 mL) of 5- ((dimethylamino) methyl) -3- (3- (ethoxycarbonyl) -1- (2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) thioureido) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-044F (68 mg,0.14 mmol), stirred for 3 hours at 65 ℃, methanol was removed by rotary evaporation after completion of the reaction, and the resulting residue was isolated and purified by silica gel column (dichloromethane/methanol=100/6) to give 7- ((dimethylamino) methyl) -2-thio-1- (2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-044 (4 mg, white solid), yield: 8%.
MS m/z(ESI):365.0[M+1] +
1 H NMR(400MHz,DMSO-d6)δ12.30(s,2H),7.29(d,J=2.0Hz,1H),5.00(s,2H),4.17-4.12(m,1H),4.04-3.93(m,2H),2.13(s,6H),1.17(d,J=6.4Hz,3H).
Example 45
7-methoxy-2-thio-1- (2- (1, 1-trifluoroisopropoxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
(3- ((tert-Butoxycarbonyl) amino) -4- (phenyl-. Lambda. 3 Preparation of ethyl-1H-pyrrole-2-carboxylate
3- ((tert-Butoxycarbonyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-045A (1.00 g,3.93 mmol) was reacted with iodobenzene acetate (1.39 g,4.32 mmol) in trifluoroethanol (15 mL) for 3 hours at room temperature. Reaction completionRemoving trifluoroethanol by post rotary evaporation, pulping the obtained solid by ethyl acetate, and filtering to obtain (3- ((tert-butoxycarbonyl) amino) -4- (phenyl-lambda) 3 -iodikyl) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-045B (1.1 g, white solid), yield: 61%.
Second step
Preparation of 3- ((tert-Butoxycarbonyl) amino) -4-methoxy-1H-pyrrole-2-carboxylic acid ethyl ester
(3- ((tert-Butoxycarbonyl) amino) -4- (phenyl-. Lambda.) amino 3 Ethyl-iodate) -1H-pyrrole-2-carboxylate Cpd-045B (500 mg,1.09 mmol) was dissolved in dry methanol (15 mL), then sodium methoxide (177 mg,3.27 mmol) and copper triflate (197mg, 0.55 mmol) were added and the reaction was carried out under nitrogen atmosphere with microwave heating to 90 ℃ for 1 hour. After the reaction was completed, a saturated aqueous ammonium chloride solution (10 mL) was added to quench, followed by extraction with ethyl acetate (50 ml×3) and saturated brine (50 mL), and the resultant residue was concentrated by organic phase dryness, and after separation and purification with a silica gel column (petroleum ether/ethyl acetate=4/1), 3- ((t-butoxycarbonyl) amino) -4-methoxy-1H-pyrrole-2-carboxylic acid methyl ester Cpd-045C (50 mg, colorless oil), yield: 17%.
MS m/z(ESI):271.1[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ11.24(s,1H),7.90(s,1H),6.62(d,J=3.2Hz,1H),3.69(s,3H),3.62(s,3H),1.39(s,9H).
Third step
Preparation of 3-amino-4-methoxy-1H-pyrrole-2-carboxylic acid ethyl ester hydrochloride
3- ((tert-Butoxycarbonyl) amino) -4-methoxy-1H-pyrrole-2-carboxylic acid methyl ester Cpd-045C (50 mg,0.19 mmol) was dissolved in methanol hydrochloride (4.0M, 5mL,20.00 mmol) and reacted at room temperature for 2 hours. After the reaction, the methanolic hydrochloride solution was removed by rotary evaporation, dissolved in methanol (10 mL), and concentrated by drying to give 3-amino-4-methoxy-1H-pyrrole-2-carboxylic acid methyl ester hydrochloride Cpd-045D (25 mg, colorless oil), yield: 64%.
MS m/z(ESI):171.1[M+1] + .
Fourth step
Preparation of ethyl 5-methoxy-3- ((2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate
Methyl 3-amino-4-methoxy-1H-pyrrole-2-carboxylate hydrochloride Cpd-045D (25 mg,0.12 mmol) was dissolved in methanol (5 mL) and then 2- ((1, 1-trifluoropropan-2-yl) oxy) acetaldehyde (37 mg,0.24 mmol) and sodium cyanoborohydride (15 mg,0.24 mmol) were added and reacted at room temperature for 1 hour. After the reaction was completed, methanol was removed by rotary evaporation, and the resulting residue was separated and purified by silica gel column (petroleum ether/ethyl acetate=4/1) to give methyl 5-methoxy-3- ((2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-045E (20 mg, colorless oil), yield: 54%.
MS m/z(ESI):171.1[M+1] + .
Fifth step
Preparation of ethyl 3- (3- (ethoxycarbonyl) -1- (2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) thioureido) -4-methoxy-1H-pyrrole-2-carboxylate
Methyl 5-methoxy-3- ((2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-045E (20 mg,0.06 mmol) was dissolved in methanol (5 mL), followed by addition of ethyl isothiocyanate (12 mg,0.09 mmol), and reacted at room temperature for 1 hour, and after completion of the reaction, the reaction solution was directly used in the next step.
MS m/z(ESI):442.1[M+1] + .
Sixth step
Preparation of 7-methoxy-2-thio-1- (2- (1, 1-trifluoroisopropoxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Cesium carbonate (98 mg,0.30 mmol) was added to methyl 3- (3- (ethoxycarbonyl) -1- (2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) thioureido) -4-methoxy-1H-pyrrole-2-carboxylate Cpd-045F (26 mg,0.06 mmol) in methanol (5 mL), heated to 65 ℃ and stirred for 3 hours, methanol was removed by rotary evaporation after completion of the reaction, and the residue was isolated and purified by silica gel column (dichloromethane/methanol=50/1) to give 7-methoxy-2-thio-1- (2- (1, 1-trifluoroisopropoxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-045 (6 mg, white solid), yield: 30%.
MS m/z(ESI):338.0[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.23(s,1H),12.03(s,1H),7.21(d,J=3.6Hz,1H),4.73(dd,J=15.2,7.2Hz,2H),4.18-4.11(m,1H),3.91(t,J=6.8Hz,2H),3.77(s,3H),1.20(d,J=6.4Hz,3H).
Example 46
1- (3- (2, 2-trifluoroethoxy) propan-2-yl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of 3- (bis (4-methoxybenzyl) amino) propane-1, 2-diol
3-aminopropane-1, 2-diol Cpd-046A (10.0 g,100 mmol) was dissolved in dry dichloromethane (20 mL), diisopropylethylamine (15.4 g,120 mmol) was added, then PMBCl (18.7 g,120 mmol) was added dropwise and reacted overnight at room temperature after the addition was completed. After the reaction was completed, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and rotary distilled to obtain crude product, which was subjected to column chromatography (petroleum ether/ethyl acetate=4/1) to obtain 3- (bis (4-methoxybenzyl) amino) propane-1, 2-diol Cpd-046B (15 g, colorless oil), yield: 45%.
MS m/z(ESI):331[M+1] + .
Second step
Preparation of 1- (bis (4-methoxybenzyl) amino) -3- ((tert-butyldimethylsilyl) oxy) propan-2-ol
3- (bis (4-methoxybenzyl) amino) propane-1, 2-diol Cpd-046B (2.0 g,6.0 mmol) was dissolved in dry dichloromethane (10 mL) and imidazole (0.5 g,7.3 mmol) was added. Cooled to 0℃in an ice bath, TBSCl (1.1 g,7.3 mmol) was added portionwise. After 1 hour of reaction, the mixture was dried by spin-drying, and the 1- (bis (4-methoxybenzyl) amino) -3- ((tert-butyldimethylsilyl) oxy) propan-2-ol Cpd-046C (2.2 g, colorless liquid) was obtained by column chromatography, yield: 82%.
MS m/z(ESI):446[M+1] + .
Third step
Preparation of 1- (bis (4-methoxybenzyl) amino) -3- ((tert-butyldimethylsilyl) oxy) propan-2-yl acetate
Preparation of 1- (bis (4-methoxybenzyl) amino) -3- ((tert-butyldimethylsilyl) oxy) propan-2-ol Cpd-046C (2.2 g,4.9 mmol) and triethylamine (997 mg,9.9 mmol) were dissolved in dry dichloromethane (5 mL), cooled to 0 ℃, acetic anhydride (604 mg,5.9 mmol) was slowly added, after the addition was completed, the reaction was carried out at 0℃for 1 hour, after the completion of the reaction, the solvent was removed by spinning, and the residue was purified by column chromatography to give 1- (bis (4-methoxybenzyl) amino) -3- ((tert-butyldimethylsilyl) oxy) propan-2-ylacetate Cpd-046D (2.4 g, colorless liquid), yield: 92%.
MS m/z(ESI):488[M+1] + .
Fourth step
Preparation of 1- (bis (4-methoxybenzyl) amino) -3-hydroxypropyl-2-acetate
1- (bis (4-methoxybenzyl) amino) -3- ((tert-butyldimethylsilyloxy) propan-2-yl acetate Cpd-046D (2.4 g,4.5 mmol) was dissolved in tetrahydrofuran (4 mL), TBAF (2 mL) was added and reacted at room temperature for 2.5 hours. After the reaction was completed, 10mL of water was added to quench, extraction was performed with ethyl acetate, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and rotary distilled to obtain crude product, which was purified by column to obtain 1- (bis (4-methoxybenzyl) amino) -3-hydroxypropyl-2-acetate Cpd-046E (1.2 g, colorless oil), yield: 80%.
Fifth step
Preparation of 1- (bis (4-methoxybenzyl) amino) -3-bromopropane-2-yl acetate
1- (bis (4-methoxybenzyl) amino) -3-hydroxypropyl-2-acetate Cpd-046E (1.2 g,3.2 mmol) was dissolved in dichloromethane (5 mL), cooled to 0℃and carbon tetrabromide (1.6 g,4.8 mmol), triphenylphosphine (1.2 g,4.8 mmol) was added thereto. Then stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was washed once with water (5 mL), and the organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was isolated and purified by silica gel column (petroleum ether/ethyl acetate=5/1) to give 1- (bis (4-methoxybenzyl) amino) -3-bromopropane-2-yl acetate Cpd-046F (800 mg, yellow oil), yield: 56%.
MS m/z(ESI):434[M+1] + .
Sixth step
Preparation of 1- (bis (4-methoxybenzyl) amino) -3- (2, 2-trifluoroethoxy) propan-2-yl acetate
1- (bis (4-methoxybenzyl) amino) -3-bromopropane-2-yl acetate Cpd-046F (800 mg,1.8 mmol) was dissolved in trifluoroethanol (5 mL) followed by the addition of potassium tert-butoxide tetrahydrofuran solution (2 mL). The reaction was warmed to 65 ℃ and stirred overnight. After the reaction was completed, the solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=2/1) to give 1- (bis (4-methoxybenzyl) amino) -3- (2, 2-trifluoroethoxy) propan-2-ylacetate Cpd-046G (600 mg, colorless oil), yield: 71%.
MS m/z(ESI):455[M+1] + .
Seventh step
Preparation of 1- (bis (4-methoxybenzyl) amino) -3- (2, 2-trifluoroethoxy) propanol
1- (bis (4-methoxybenzyl) amino) -3- (2, 2-trifluoroethoxy) propan-2-ylacetate Cpd-046G (800 mg,1.8 mmol) was dissolved in methanol/water=1/1 (4 mL), lithium hydroxide (175 mg,7.3 mmol) was added thereto, and the reaction solution was stirred at room temperature overnight. After the completion of the reaction, methanol was removed by spinning, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated. Purification of the crude product by silica gel column chromatography (petroleum ether/ethyl acetate=2/1) gave 1- (bis (4-methoxybenzyl) amino) -3- (2, 2-trifluoroethoxy) propanol Cpd-046H (400 mg, colorless oil), yield: 73%.
MS m/z(ESI):414[M+1] + .
Eighth step
Preparation of 2-bromo-N, N-bis (4-methoxybenzyl) -3- (2, 2-trifluoroethoxy) propan-1-amine
1- (bis (4-methoxybenzyl) amino) -3- (2, 2-trifluoroethoxy) propanol Cpd-046H (400 mg,1.0 mmol) was dissolved in methylene chloride (3 mL) and cooled to 0℃and then carbon tetrabromide (480 mg,1.5 mmol) and triphenylphosphine (380 mg,1.5 mmol) were added thereto, and the reaction solution was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was washed once with water (5 mL), and the organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=4/1) to give 2-bromo-N, N-bis (4-methoxybenzyl) -3- (2, 2-trifluoroethoxy) propan-1-amine Cpd-046I (250 mg, yellow oil), yield: 54%.
MS m/z(ESI):478[M+1] + .
Ninth step
Preparation of 3- ((1- (bis (4-methoxybenzyl) amino) -3- (2, 2-trifluoromethoxy) propan-2-yl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester
2-bromo-N, N-bis (4-methoxybenzyl) -3- (2, 2-trifluoroethoxy) propan-1-amine Cpd-046I (250 mg,0.5 mmol) was dissolved in acetonitrile (3 mL), ethyl 3-amino-1H-pyrrole-2-carboxylate (80 mg,0.5 mmol) and DIEA (101 mg,0.9 mmol) were added thereto, and the reaction solution was heated to 65℃for reaction overnight. After the reaction was completed, the solvent was removed by rotary evaporation, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give ethyl 3- ((1- (bis (4-methoxybenzyl) amino) -3- (2, 2-trifluoro-oxy) propan-2-yl) amino) -1H-pyrrole-2-carboxylate Cpd-046J (200 mg, colorless oil), yield: 70%.
MS m/z(ESI):550[M+1] + .
Tenth step
Preparation of 3- ((1-amino-3- (2, 2-trifluoromethoxy) propan-2-yl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester
3- ((1- (bis (4-methoxybenzyl) amino) -3- (2, 2-trifluoro-oxy) propan-2-yl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-046J (200 mg,0.4 mmol) was dissolved in methanol (2 mL), palladium hydroxide (98 mg,0.7 mmol) was added thereto, followed by replacement of the internal atmosphere with hydrogen. The reaction solution was heated to 60 ℃ for 2 hours, then cooled to room temperature, the solid was removed by filtration, and the solvent was removed under reduced pressure to give ethyl 3- ((1-amino-3- (2, 2-trifluorooxy) propan-2-yl) amino) -1H-pyrrole-2-carboxylate Cpd-046K (80 mg, colorless oil), yield: 71%.
MS m/z(ESI):310[M+1] + .
Eleventh step
Preparation of ethyl 3- ((1- ((tert-butoxycarbonyl) amino) -3- (2, 2-trifluoroethoxy) propan-2-yl) amino) -1H-pyrrole-2-carboxylate
3- ((1-amino-3- (2, 2-trifluoromethoxy) propan-2-yl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-046K (80 mg,0.3 mmol) was dissolved in dichloromethane (2 mL), and triethylamine (39 mg,0.4 mmol) and di-tert-butyl dicarbonate were added thereto to react (67 mg)0.3 mmol) and reacted at room temperature for 2 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=2/1) to give 3- ((1- ((tert-butoxycarbonyl) amino) -3- (2, 2-trifluoroethoxy) propan-2-yl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-046L (85 mg, colorless oil), yield: 77%. MS m/z (ESI) 410[ M+1 ]] + .
Twelfth step
Preparation of tert-butyl 3- (1- (1- ((tert-butoxycarbonyl) amino) -3- (2, 2-trifluoroethoxy) propan-2-yl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-1-carboxylate-2-carboxylate
3- ((1- ((tert-Butoxycarbonyl) amino) -3- (2, 2-trifluoroethoxy) propan-2-yl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-046L (85 mg,0.2 mmol) was dissolved in dichloromethane (2 mL), cooled to 0℃and ethyl isothiocyanamide (26 mg,0.2 mmol) was then added thereto and stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was washed once with water (5 mL), the organic layer was dried over anhydrous sodium sulfate and concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=2/1) to give 3- (1- (1- ((t-butoxycarbonyl) amino) -3- (2, 2-trifluoroethoxy) propan-2-yl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-1-carboxylic acid tert-butyl ester-2-carboxylic acid ethyl ester Cpd-046M (80 mg, colorless oil), yield: 70%.
MS m/z(ESI):541[M+1] + .
Thirteenth step
Preparation of tert-butyl 2- (4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) -3- (2, 2-trifluoroethoxy) propancarbamate
3- (1- (1- ((tert-Butoxycarbonyl) amino) -3- (2, 2-trifluoroethoxy) propan-2-yl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-1-carboxylic acid tert-butyl ester-2-carboxylic acid ethyl ester Cpd-046M (80 mg,0.14 mmol) was dissolved in methanol (2 mL), cesium carbonate (91 mg,0.28 mmol) was added thereto, and the reaction solution was heated to 65℃for 3 hours. The reaction solution was cooled to room temperature, a saturated aqueous ammonium chloride solution (5 mL) was then added, extraction was performed with ethyl acetate (10 mL. Times.3), and the organic layer was dried over anhydrous sodium sulfate and concentrated. Purification of the crude product by preparative silica gel plate (dichloromethane/methanol=20/1) gave tert-butyl 2- (4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) -3- (2, 2-trifluoroethoxy) propancarbamate Cpd-046N (40 mg, white solid), yield: 68%. MS M/z (ESI): 423 (M-100+1).
Fourteenth step
Preparation of 1- (1-amino-3- (2, 2-trifluoroethoxy) propan-2-yl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Tert-butyl (2- (4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) -3- (2, 2-trifluoroethoxy) propyl) carbamate Cpd-046N (40 mg,0.09 mmol) was dissolved in methanol (1 mL), and a methanol solution (1 mL) of hydrogen chloride was added thereto, and the reaction solution was heated to 60℃for 1 hour. After the reaction solution was cooled to room temperature, the solvent was removed by spin-drying, the crude product was slurried with ethyl acetate, filtered, the cake was washed with aqueous sodium bicarbonate, extracted with ethyl acetate, concentrated and dried to give 1- (1-amino-3- (2, 2-trifluoroethoxy) propan-2-yl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-046 (20 mg, white solid), yield: 66%.
MS m/z(ESI):322[M+1] + .
Example 47
1- (1- (dimethylamino) -3- (2, 2-trifluoroethoxy) propan-2-yl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
1- (1-amino-3- (2, 2-trifluoroethoxy) propan-2-yl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-046 (10 mg,0.03 mmol) was dissolved in methanol (1 mL), to which was added paraformaldehyde (3 mg,0.09 mmol), acetic acid and sodium cyanoborohydride (2 mg,0.09 mmol). The reaction mixture was heated to 65℃and reacted overnight. After the reaction solution was cooled to room temperature, it was concentrated, and the crude product was separated by preparative silica gel plate (dichloromethane/methanol=20/1) to give 1- (1-dimethylamino-3- (2, 2-trifluoroethoxy) propan-2-yl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-047 (8 mg, white solid), yield: 73%.
MS m/z(ESI):351[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.44(s,1H),12.21(s,1H),7.39(s,1H),6.32(s,1H),4.42(s,1H),4.04-3.81(m,4H),2.91(s,2H),1.23(s,6H).
Example 48
1- (((4-cyclopropylmorpholin-2-yl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Morpholin-2-yl methanol preparation
Tert-butyl 2- (hydroxymethyl) morpholine-4-carboxylate Cpd-048A (2 g,9.2 mmol) was dissolved in dichloromethane (20 mL) and then a solution of ethyl acetate hydrochloride (10 mL) was added dropwise at room temperature, stirred at room temperature for 2 hours after the addition, and concentrated directly to give product morpholin-2-yl methanol Cpd-048B (1 g, colorless oily liquid), yield: 100%.
MS m/z(ESI):118[M+1] + .
Second step
Preparation of (4-cyclopropylmorpholin-2-yl) methanol
Morpholin-2-ylmethanol Cpd-048B (1 g,8.53 mmol) was dissolved in methanol (25 mL), and (1-ethoxycyclopropoxy) trimethylsilane (1.48 g,8.53 mmol), acetic acid (2 mL) and sodium cyanoborohydride (1.07 g,17.07 mmol) were added in this order, and the reaction was heated to 50 ℃ and stirred for 5 hours. After the reaction was completed, the solution was cooled to room temperature, the pH was adjusted to be alkaline with 2M aqueous sodium hydroxide solution, methylene chloride (100 mL) was added after spinning-dry, stirring was performed at room temperature for 1 hour, methylene chloride was filtered, dried over anhydrous sodium sulfate, and spun-dry to give the product (4-cyclopropylmorpholin-2-yl) methanol Cpd-048C (800 mg, colorless oil), yield: 54%.
MS m/z(ESI):158[M+1] + .
Third step
Preparation of 4-cyclopropylmorpholine-2-carbaldehyde
Oxalyl chloride (523.85 mg,4.2 mmol) was dissolved in dry dichloromethane (2 mL), the solution was cooled to-70℃under nitrogen protection, dimethyl sulfoxide (650 mg,8.4 mmol) was then slowly added dropwise to dichloromethane (1 mL), the solution was kept stirring at-70℃for 30 min, then (4-cyclopropylmorpholin-2-yl) methanol Cpd-048C (600 mg,3.8 mmol) was slowly added dropwise, the mixed solution was stirred at-70℃for 2 h, then triethylamine (1.2 g,4.2 mmol) was added and stirred for 30 min, the reaction solution was slowly and naturally warmed to 0℃and diluted with dichloromethane (20 mL), and water (10 mL) was added thereto, the separated solution was washed with saturated sodium chloride, and the anhydrous sodium sulfate was dried to obtain a solution of 4-cyclopropylmorpholin-2-carbaldehyde in dichloromethane Cpd-048D (20 mL) which was directly used in the next step without treatment.
Fourth step
3- (((4-Cyclopropylmorpholin-2-yl) methyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester
Ethyl 3-amino-1H-pyrrole-2-carboxylate (664 mg,4.28 mmol) was dissolved in methanol (5 mL), acetic acid (23.37 mg,0.39 mmol) and a dichloromethane solution (20 mL) of 4-cyclopropylmorpholine-2-carbaldehyde Cpd-048D were added sequentially, and stirred at room temperature for 0.5 hours. Sodium cyanoborohydride (293 mg,4.67 mmol) was then added in portions and stirred at room temperature for 16 hours. After the reaction was completed, 20mL of water was added to quench, extraction was performed with ethyl acetate, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and rotary distilled to obtain crude product, which was purified by column to obtain 3- (((4-cyclopropylmorpholin-2-yl) methyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-048E (110 mg, light brown oil), yield: 9.6%.
MS m/z(ESI):294[M+1] + .
Fifth step
Preparation of 3- (1- (((4-cyclopropylmorpholin-2-yl) methyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester
3- (((4-Cyclopropylmorpholin-2-yl) methyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-048E (85 mg,0.28 mmol) was dissolved in dichloromethane (5 mL), cooled to 0℃and ethyl isothiocyanamide (45.6 mg,0.35 mmol) was added thereto, followed by stirring at room temperature for 3 hours. After completion of the reaction, the reaction mixture was washed once with water (20 mL), and the organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was isolated and purified by silica gel column (petroleum ether/ethyl acetate=1/1) to give 3- (1- (((4-cyclopropylmorpholin-2-yl) methyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-048F (90 mg, light brown oil), yield: 73%.
MS m/z(ESI):425[M+1] + .
Sixth step
Preparation of 1- (((4-cyclopropylmorpholin-2-yl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
3- (1- (((4-cyclopropylmorpholin-2-yl) methyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-048F (90 mg,0.2 mmol) was dissolved in methanol (5 mL), sodium methoxide (17 mg,0.3 mmol) was added thereto, the reaction mixture was heated to 90℃for 2 hours, the reaction mixture was cooled to room temperature and was adjusted to pH=4-5 with dilute hydrochloric acid (1M), the solution was dried by spinning to give a crude product, and separation and purification by Prep-HPLC (acetonitrile/water (1 millof formic acid)) gave 1- (((4-cyclopropylmorpholin-2-yl) methyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-048 (18 mg, white solid) in 28% yield.
MS m/z(ESI):307[M+1] + .
1 H NMR(400MHz,CDCl 3 )δ10.49(s,1H),9.56(s,1H),7.21(s,1H),6.27(s,1H),4.79(m,1H),4.14(s,2H),3.81(m,1H),3.52(s,1H),3.10(s,1H),2.82(s,1H),2.42(s,1H),2.25(s,1H),1.69(s,1H),0.49(s,4H).
Example 49
3-methyl-5-thioxy-4- (2- ((1, 1-trifluoro-2-yl) oxy) ethyl) -1,4,5, 6-tetrahydro-7H-pyrazolo [4,3-d ] pyrimidin-7-one
First step
Preparation of 3-methyl-4-nitro-1H-pyrazole-5-carboxylic acid
3-methyl-1H-pyrazole-5-carboxylic acid ethyl ester Cpd-049A (3 g,19.5 mmol) was dissolved in a sulfuric acid/nitric acid (3/1) mixed solution (20 mL) and the reaction stirred at 60℃for 3 hours. After the reaction, the reaction mixture was extracted with methylene chloride (3X 10 mL), and the organic phase was washed with saturated brine, followed by spin-drying the solvent to obtain a crude product. The crude product was isolated and purified by column chromatography (PE/EA) to give 3-methyl-4-nitro-1H-pyrazole-5-carboxylic acid Cpd-049B (3 g, white solid), yield: 81%.
MS m/z(ESI):172.1[M+1] + .
Second step
Preparation of 3-methyl-4-nitro-1H-pyrazole-5-carboxylic acid ethyl ester
3-methyl-4-nitro-1H-pyrazole-5-carboxylic acid Cpd-049B (3 g,17.5 mmol) was dissolved in ethanol (20 mL), thionyl chloride (420 mg,3.5 mmol) was added and the reaction stirred at 70℃for 1 hour. After the completion of the reaction, the reaction mixture was extracted with methylene chloride (10 mL. Times.3), and the organic phase was washed with saturated brine, followed by spin-removal of the solvent to obtain a crude product. The crude product was isolated and purified by column chromatography to give 3-methyl-4-nitro-1H-pyrazole-5-carboxylic acid ethyl ester Cpd-049C (2.5 g, white solid), yield: 65%.
MS m/z(ESI):200.2[M+1] + .
Third step
Preparation of 1- (4-methoxybenzyl) -3-methyl-4-nitro-1H-pyrazole-5-carboxylic acid ethyl ester and 1- (4-methoxybenzyl) -5-methyl-4-nitro-1H-pyrazole-3-carboxylic acid ethyl ester
3-methyl-4-nitro-1H-pyrazole-5-carboxylic acid ethyl ester Cpd-049C (2 g,10.04 mmol) was dissolved in acetonitrile (10 mL), potassium iodide (1.67 g,10.04 mmol) and potassium carbonate (1.39 g,10.04 mmol) were added followed by p-methoxybenzyl chloride (3.15 g,20.08 mmol). The reaction was stirred at 85℃for 2 hours. After the completion of the reaction, the reaction mixture was extracted with methylene chloride (3X 10 mL), and the organic phase was washed with saturated brine, followed by spin-drying of the solvent to obtain a crude product. The crude product was isolated and purified by column chromatography to give a mixture of 1- (4-methoxybenzyl) -3-methyl-4-nitro-1H-pyrazole-5-carboxylic acid ethyl ester Cpd-049D-1 and 1- (4-methoxybenzyl) -5-methyl-4-nitro-1H-pyrazole-3-carboxylic acid ethyl ester Cpd-049D-2 (3 g, orange oily liquid), yield: 84%.
MS m/z(ESI):342.1[M+1] + .
Fourth step
Preparation of 1- (4-methoxybenzyl) -3-methyl-4-amino-1H-pyrazole-5-carboxylic acid ethyl ester and 1- (4-methoxybenzyl) -5-methyl-4-amino-1H-pyrazole-3-carboxylic acid ethyl ester
A mixture (2 g,6.3 mmol) of 1- (4-methoxybenzyl) -3-methyl-4-nitro-1H-pyrazole-5-carboxylic acid ethyl ester Cpd-049D-1 and 1- (4-methoxybenzyl) -5-methyl-4-nitro-1H-pyrazole-3-carboxylic acid ethyl ester Cpd-049D-2 was dissolved in methanol (10 mL) and palladium on carbon catalyst (340 mg,3.1 mmol) was added. The reaction was stirred at room temperature for 2 hours under an atmosphere of hydrogen. After the reaction, the reaction mixture was extracted with methylene chloride (10 mL. Times.3), and the organic phase was washed with saturated brine, followed by spin-drying the solvent to obtain a crude product. The crude product was isolated and purified by column chromatography to give a mixture of 1- (4-methoxybenzyl) -3-methyl-4-amino-1H-pyrazole-5-carboxylic acid ethyl ester Cpd-049E-1 and 1- (4-methoxybenzyl) -5-methyl-4-amino-1H-pyrazole-3-carboxylic acid ethyl ester Cpd-049E-2 (1.6 g, white solid), yield: 79%.
MS m/z(ESI):290.2[M+1] + .
Fifth step
Preparation of ethyl 1- (4-methoxybenzyl) -3-methyl-4- ((2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrazole-5-carboxylate and ethyl 1- (4-methoxybenzyl) -5-methyl-4- ((2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrazole-3-carboxylate
A mixture (500 mg,1.73 mmol) of 1- (4-methoxybenzyl) -3-methyl-4-amino-1H-pyrazole-5-carboxylic acid ethyl ester Cpd-049E-1 and 1- (4-methoxybenzyl) -5-methyl-4-amino-1H-pyrazole-3-carboxylic acid ethyl ester Cpd-049E-2 was dissolved in methanol (5 mL), acetic acid (0.1 mL) was added, and 2- ((1, 1-trifluoropropan-2-yl) oxy) acetaldehyde (217 mg,1.38 mmol) was added and the reaction stirred at room temperature for 30 min. Sodium cyanoborohydride (325 mg,5.18 mmol) was then added and the reaction was stirred at room temperature for 2 hours. After the reaction, the reaction mixture was extracted with methylene chloride (10 mL. Times.3), and the organic phase was washed with saturated brine, followed by spin-drying the solvent to obtain a crude product. The crude product was isolated and purified by column chromatography to give a mixture of ethyl 1- (4-methoxybenzyl) -3-methyl-4- ((2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrazole-5-carboxylate Cpd-049F-1 and 1- (4-methoxybenzyl) -5-methyl-4- ((2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrazole-3-carboxylate Cpd-049F-2 (582 mg, colorless liquid), yield: 71%.
MS m/z(ESI):430.2[M+1] + .
Sixth step
Preparation of ethyl 4- (3- (ethoxycarbonyl) -1- (2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) thioureido) -1- (4-methoxybenzyl) -3-methyl-1H-pyrazole-5-carboxylate and ethyl 4- (3- (ethoxycarbonyl) -1- (2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) thioureido) -1- (4-methoxybenzyl) -5-methyl-1H-pyrazole-3-carboxylate
A mixture (260 mg,0.60 mmol) of ethyl 1- (4-methoxybenzyl) -3-methyl-4- ((2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrazole-5-carboxylate Cpd-049F-1 and ethyl 1- (4-methoxybenzyl) -5-methyl-4- ((2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrazole-3-carboxylate Cpd-049F-2 was dissolved in dichloromethane (5 mL) and ethyl N-thiocarbamate (158 mg,1.2 mmol) was added at 0deg.C. The reaction was stirred at room temperature for 2 hours. After the reaction, the reaction mixture was extracted with methylene chloride (10 mL. Times.3), and the organic phase was washed with saturated brine, followed by spin-drying the solvent to obtain a crude product. The crude product was isolated and purified by column chromatography to give a mixture of 4- (3- (ethoxycarbonyl) -1- (2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) thioureido) -1- (4-methoxybenzyl) -3-methyl-1H-pyrazole-5-carboxylic acid ethyl ester Cpd-049G-1 and 4- (3- (ethoxycarbonyl) -1- (2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) thioureido) -1- (4-methoxybenzyl) -5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester Cpd-049G-2 (200 mg, colorless liquid), yield: 53%.
MS m/z(ESI):561.2[M+1] + .
Seventh step
Preparation of 1- (4-methoxybenzyl) -3-methyl-5-thioxy-4- (2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) -1,4,5, 6-tetrahydro-7H-pyrazolo [4,3-d ] pyrimidin-7-one and 2- (4-methoxybenzyl) -3-methyl-5-thioxy-4- (2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) -2,4,5, 6-tetrahydro-7H-pyrazolo [4,3-d ] pyrimidin-7-one
A mixture (100 mg,0.18 mmol) of 4- (3- (ethoxycarbonyl) -1- (2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) thioureido) -1- (4-methoxybenzyl) -3-methyl-1H-pyrazole-5-carboxylic acid ethyl ester Cpd-049G-1 and 4- (3- (ethoxycarbonyl) -1- (2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) thioureido) -1- (4-methoxybenzyl) -5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester Cpd-049G-2 was dissolved in ethanol (3 mL) and sodium ethoxide (24 mg,0.36 mmol) was added. The reaction was stirred at 100℃for 2 hours under microwave conditions. And after the reaction is finished, spin-drying the solvent to obtain a crude product. The crude product was isolated and purified by column chromatography to give a mixture of 1- (4-methoxybenzyl) -3-methyl-5-thioxo-4- (2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) -1,4,5, 6-tetrahydro-7H-pyrazolo [4,3-d ] pyrimidin-7-one Cpd-049H-1 and 2- (4-methoxybenzyl) -3-methyl-5-thioxo-4- (2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) -2,4,5, 6-tetrahydro-7H-pyrazolo [4,3-d ] pyrimidin-7-one Cpd-049H-2 (60 mg, colorless oily liquid), yield: 68%.
MS m/z(ESI):456.1(M+23).
Eighth step
Preparation of 3-methyl-5-thioxy-4- (2- ((1, 1-trifluoro-2-yl) oxy) ethyl) -1,4,5, 6-tetrahydro-7H-pyrazolo [4,3-d ] pyrimidin-7-one
1- (4-methoxybenzyl) -3-methyl-5-thioxy-4- (2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) -1,4,5, 6-tetrahydro-7H-pyrazolo [4,3-d ]Pyrimidin-7-one Cpd-049H-1 and 2- (4-methoxybenzyl) -3-methyl-5-thioxo-4- (2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) -2,4,5, 6-tetrahydro-7H-pyrazolo [4,3-d]A mixture of pyrimidin-7-one Cpd-049H-2 (60 mg,0.14 mmol) was dissolved in trifluoroacetic acid (5 mL) and the reaction was reacted at 90℃for 2 hours. And after the reaction is finished, spin-drying the solvent to obtain a crude product. The crude product was purified by Prep-HPLC (CAN/H 2 O (formic acid 1%), concentrating, washing with sodium bicarbonate aqueous solution, extracting with ethyl acetate, concentrating, and drying to obtain 3-methyl-5-thioxy-4- (2- ((1, 1-trifluoro-2-yl) oxy) ethyl) -1,4,5, 6-tetrahydro-7H-pyrazole [4,3-d ]]Pyrimidin-7-one Cpd-049 (2 mg, white solid), yield: 7%.
MS m/z(ESI):323.0[M+1] + .
Example 50
1- (2- (1, 1-trifluoroisopropoxy) ethyl) -2-thioxo-7-methyl-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of 3-amino-4-bromo-1H-pyrrole-2-carboxylic acid ethyl ester
3-amino-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-050A (1500 mg,9.74 mmol) was dissolved in tetrahydrofuran (20 mL). NBS (1730 mg,9.74 mmol) was added in portions after cooling to 0℃and stirred at 0℃for 1 hour. After the reaction was completed, it was washed with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by column purification to give 3-amino-4-bromo-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-050B (1200 mg, brown oil), yield: 52.9%.
Second step
Preparation of 1-tert-Butoxycarbonyl-3-bis (tert-butoxycarbonyl) amino-4-bromo-1H-pyrrole-2-carboxylic acid ethyl ester
3-amino-4-bromo-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-050B (1.20 g,5.15 mmol) was dissolved in tetrahydrofuran (20 mL) to which (Boc) was added 2 O (5.61 g,25.75 mmol), DIPEA (3.32 g,25.75 mmol) and DMAP (6278 mg,5.15 mmol) were reacted at 75℃for 16 hours. After the reaction was completed, it was concentrated, and the residue was purified by column to give ethyl 1-tert-butoxycarbonyl-3-bis (tert-butoxycarbonyl) amino-4 bromo-1H-pyrrole-2-carboxylate Cpd-050C (1.5 g, pale yellow solid), yield: 55.5%.
MS m/z(ESI):433,435(M-100+1).
Third step
Preparation of 1-tert-Butoxycarbonyl-3-bis (tert-butoxycarbonyl) amino-4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester
1-Boc-3-bis (t-Butoxycarbonyl) amino-4 bromo-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-050C (500 mg,1.15 mmol) was dissolved in dioxane (10 mL) and methyl boric acid (208 mg,3.46 mmol), pd (amphos) Cl were added sequentially 2 (82 mg,0.11 mmol) and potassium carbonate (800 mg,5.77 mmol), under nitrogen, were heated to 90℃and reacted for 2 hours. After the reaction was completed, 2mL of water was added to quench, extraction was performed with ethyl acetate, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and rotary distilled to obtain crude product, which was purified by column to obtain ethyl 1-tert-butoxycarbonyl-3-bis (tert-butoxycarbonyl) amino-4-methyl-1H-pyrrole-2-carboxylate Cpd-050D (300 mg, pale yellow liquid), yield: 68 .3%。
MS m/z(ESI):369(M-100+1).
Fourth step
Preparation of 3-amino-4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester
1-Boc-3-bis (t-Butoxycarbonyl) amino-4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-050D (300 mg,0.64 mmol) was dissolved in HCl-EtOH (10 mL, 2M) and then stirred at room temperature for 3 hours. After the completion of the reaction, the reaction solution was neutralized with saturated sodium hydrogencarbonate, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated. 3-amino-4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-050E (100 mg, pale yellow solid), yield: 93%.
MS m/z(ESI):169[M+1] + .
Fifth step
Preparation of ethyl 4-methyl-3- (((2- (((1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate)
Ethyl 3-amino-4-methyl-1H-pyrrole-2-carboxylate Cpd-050E (100 mg,0.59 mmol) was dissolved in methanol (5 mL), acetic acid (36 mg,0.59 mmol) and 2- ((1, 1-trifluoropropan-2-yl) oxy) acetaldehyde (102 mg,0.59 mmol) were added sequentially and stirred at room temperature for 1 hour. Sodium cyanoborohydride (37 mg,0.59 mmol) was then added and stirred at room temperature for 16 hours. After the reaction was completed, 5mL of water was added to quench, extraction was performed with ethyl acetate, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and rotary distilled to obtain crude product, which was purified by column to obtain 4-methyl-3- (((2- (((1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-050F (80 mg, colorless oil), yield: 43.7%.
MS m/z(ESI):309[M+1] + .
Sixth step
Preparation of ethyl 3- (3- (ethoxycarbonyl) -1- (2- (((1, 1-trifluoropropan-2-yl) oxy) ethyl) thioureido) -4-methyl-1H-pyrrole-2-carboxylate
4-methyl-3- (((2- (((1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-050F (80 mg,0.26 mmol) was dissolved in dichloromethane (5 mL), cooled to 0℃and ethyl isothiocyanate (41 mg,0.31 mmol) was added thereto, followed by stirring at 0℃for 1 hour after completion of the reaction, the reaction mixture was washed once with water (5 mL), and the organic layer was dried over anhydrous sodium sulfate and concentrated, and the resulting residue was isolated and purified by a silica gel column (petroleum ether/ethyl acetate=3/1) to give 3- (3- (ethoxycarbonyl) -1- (2- (((1, 1-trifluoropropan-2-yl) oxy) ethyl) thioureido) -4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-050G (80 mg, light brown oil) in a yield of 70.2%.
MS m/z(ESI):440[M+1] + .
Seventh step
Preparation of 1- (2- (1, 1-trifluoroisopropoxy) ethyl) -2-thio-7-methyl-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
3- (3- (ethoxycarbonyl) -1- (2- (((1, 1-trifluoropropan-2-yl) oxy) ethyl) thioureido) -4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-050G (80 mg,0.18 mmol) was dissolved in methanol (3 mL) and cesium carbonate (178 mg,0.55 mmol) was added thereto, the reaction solution was heated to 65℃for 6 hours, after the reaction was completed, the reaction solution was cooled to room temperature and quenched with ammonium chloride, ethyl acetate was extracted, and the organic layer was dried over anhydrous sodium sulfate and concentrated.
MS m/z(ESI):322[M+1] + .
1 H NMR(400MHz,CDCl 3 )δ12.24(s,1H),12.13(s,1H),7.17(s,1H),4.70(s,2H),4.18-4.12(m,1H),4.05-3.93(m,2H),2.30(s,3H),1.15(d,J=6.4Hz,3H).
Example 51
1- (2- (2-aminoethoxy) ethyl) -7-methyl-2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of tert-butyl (2- (2-hydroxyethoxy) ethyl) carbamate
2- (2-Aminoethoxy) ethanol Cpd-051A (1.0 g,9.5 mmol) was dissolved in anhydrous dichloromethane (10 mL), cooled to 0deg.C in an ice bath, di-tert-butyl dicarbonate (3.1 g,14.2 mmol) and triethylamine (1.4 g,14.2 mmol) were added and stirred for 2 hours. After the completion of the reaction, 1M diluted hydrochloric acid (30 mL) was added, followed by washing with water three times, and the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to give tert-butyl (2- (2-hydroxyethoxy) ethyl) carbamate Cpd-051B (1.5 g, colorless liquid), yield: 76%.
1 H NMR(400MHz,CDCl 3 )δ3.78-3.70(m,2H),3.61-3.51(m,4H),3.33(t,J=5.1Hz,2H),1.55-1.41(m,9H).
Second step
Preparation of tert-butyl (2- (2-oxoethoxy) ethyl) carbamate
Tert-butyl (2- (2-hydroxyethoxy) ethyl) carbamate Cpd-051B (400 mg,1.8 mmol) was dissolved in dry dichloromethane (2 mL) and dess-Martin oxidant (1.0 g,2.2 mmol) was slowly added. The reaction solution was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was quenched by addition of a saturated sodium thiosulfate solution (30 mL), and the organic phase was washed with a saturated sodium carbonate solution (30 mL. Times.3), dried over anhydrous sodium sulfate, and filtered through celite. Purification by column chromatography (EA/pe=1/1) gave tert-butyl (2- (2-oxoethoxy) ethyl) carbamate Cpd-051C (200 mg, 51%).
Third step
Preparation of ethyl 3- ((2- (2- ((tert-butoxycarbonyl) amino) ethoxy) ethyl) amino) -4-methyl-1H-pyrrole 2-carboxylate
Tert-butyl (2- (2-oxoethoxy) ethyl) carbamate Cpd-051C (50 mg,0.2 mmol), ethyl 3-amino-4-methyl-1H-pyrrole-2-carboxylate (41 mg,0.2 mmol), acetic acid (15 mg,0.2 mmol) and methanol (2 mL) were added to the flask, stirred at room temperature under nitrogen atmosphere for 1 hour, then sodium cyanoborohydride (15 mg,0.2 mmol) was added to the flask, and the reaction was continued for 1 hour. After the completion of the reaction, the reaction mixture was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. Purification by column chromatography (EA/pe=1/1) afforded 3- ((2- (2- ((tert-butoxycarbonyl) amino) ethoxy) ethyl) amino) -4-methyl-1H-pyrrole 2-carboxylic acid ethyl ester Cpd-051D (25 mg, 30%).
Fourth step
Preparation of ethyl 3- (1- (2- (2- (2- ((tert-butoxycarbonyl) amino) ethoxy) ethyl) -3- (ethoxycarbonyl) thiourea) -4-methyl-1H-pyrrole-2-carboxylate
Ethyl 3- ((2- (2- ((tert-butoxycarbonyl) amino) ethoxy) ethyl) amino) -4-methyl-1H-pyrrole 2-carboxylate Cpd-051D (25 mg,0.07 mmol) ethyl isothiocyanate (10 mg,0.07 mmol) was dissolved in dichloromethane (20 mL) and the reaction mixture was reacted at room temperature under nitrogen atmosphere for 1 hour. After the reaction, the reaction mixture was quenched with water, extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give a crude product. The crude product was isolated and purified using a Flash column (petroleum ether/ethyl acetate=85/15) to give 3- (1- (2- (2- (2- ((tert-butoxycarbonyl) amino) ethoxy) ethyl) -3- (ethoxycarbonyl) thiourea) -4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-051E (20 mg, 60%).
MS m/z(ESI):509(M+23).
Fifth step
Preparation of (2- (2- (7-methyl-4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) ethoxy) ethyl) carbamic acid tert-butyl ester
Ethyl 3- (1- (2- (2- (2- ((tert-butoxycarbonyl) amino) ethoxy) ethyl) -3- (ethoxycarbonyl) thiourea) -4-methyl-1H-pyrrole-2-carboxylate Cpd-051E (20 mg,0.04 mmol) was dissolved in methanol (3 mL) and the reaction mixture was reacted overnight at 60 ℃ after the completion of the reaction, the silica gel was prepared and the plates were separated to give tert-butyl (2- (2- (7-methyl-4-oxo-2-thio-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) ethoxy) ethyl) carbamate Cpd-051F (12 mg, 80%).
MS m/z(ESI):369[M+1] + .
Sixth step
Preparation of 1- (2- (2-aminoethoxy) ethyl) -7-methyl-2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Tert-butyl (2- (2- (7-methyl-4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) ethoxy) ethyl) carbamate Cpd-051F (12 mg,0.03 mmol) was dissolved in methanol (1 mL), and a solution of hydrogen chloride in 1, 4-dioxane (1 mL) was added dropwise to the solution and reacted for 1 hour. After the reaction, the mixture was slurried with ethyl acetate, filtered, and the cake was washed with aqueous sodium hydrogencarbonate, extracted with ethyl acetate, concentrated and dried to give 1- (2- (2-aminoethoxy) ethyl) -7-methyl-2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-051 (5 mg, 58%).
MS m/z(ESI):269[M+1] + .
Example 52
7-methyl-1- ((4-methyl-1, 4-oxazepan-7-yl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of 2-hydroxy-4- ((4-methoxybenzyl) amino) butanoic acid
Sodium hydroxide (0.7 g,18.0 mmol) was added to water (20 mL), after which 4-amino-2-hydroxybutyric acid Cpd-052A (2.0 g,16.8 mmol) was added in portions followed by p-methoxybenzaldehyde (2.4 g,18.0 mmol), and stirred at room temperature for half an hour, followed by adding sodium borohydride (0.6 g,16.8 mmol) in portions under ice bath, and after the addition was completed, stirred overnight, the temperature was naturally raised to room temperature. After the completion of the reaction, diluted with water (20 mL), extracted with ethyl acetate (20 mL), the aqueous phase was acidified with concentrated hydrochloric acid to a pH equal to 3, the reaction solution was not precipitated, and the aqueous phase was passed through a C18 reverse column (methanol/water (1 millformic acid) =1/4) to give 2-hydroxy-4- ((4-methoxybenzyl) amino) butyric acid Cpd-052B (2.0 g, white solid), yield: 50%.
MS m/z(ESI):240[M+1] + .
Second step
Preparation of ethyl 2-hydroxy-4- ((4-methoxybenzyl) amino) butyrate
Thionyl chloride (2.0 g,16.8 mmol) was added dropwise to absolute ethanol (20 mL) under ice bath followed by ethyl 2-hydroxy-4- ((4-methoxybenzyl) amino) butyrate Cpd-052B (2.0 g,8.4 mmol), followed by removal of the ice bath and stirring at room temperature under nitrogen for one hour. After the reaction was completed, it was concentrated at room temperature, quenched with ice-water sodium bicarbonate (100 mL), extracted with ethyl acetate (50 ml×2), and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated at room temperature to give ethyl 2-hydroxy-4- ((4-methoxybenzyl) amino) butyrate Cpd-052C (2.2 g, colorless oil), yield: 98%.
MS m/z(ESI):268[M+1] + .
Third step
Preparation of ethyl 4- (2-chloro-N- (4-methoxybenzyl) acetamide) -2-hydroxybutyrate
Ethyl 2-hydroxy-4- ((4-methoxybenzyl) amino) butyrate Cpd-052C (2.2 g,8.2 mmol) and N, N-diisopropylethylamine (2.1 g,16.4 mmol) were dissolved in dichloromethane (30 mL), chloroacetyl chloride (1.1 g,9.8 mmol) was added dropwise under nitrogen in an ice bath, and stirred for half an hour. After the reaction was completed, the reaction mixture was quenched by pouring it into ice water (100 mL), extracted with dichloromethane (50 ml×2), and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product, which was purified by separation with silica gel column (petroleum ether/ethyl acetate=1/1) to give ethyl 4- (2-chloro-N- (4-methoxybenzyl) acetamide) -2-hydroxybutyrate Cpd-052D (2.0 g, white solid), yield: 69%.
MS m/z(ESI):344[M+1] + .
Fourth step
Preparation of 4- (4-methoxybenzyl) -3-oxo-1, 4-oxazacyclopentane-7-carboxylic acid ethyl ester
Ethyl 4- (2-chloro-N- (4-methoxybenzyl) acetamide) -2-hydroxybutyrate Cpd-052D (2.0 g,5.8 mmol) was dissolved in anhydrous N, N-dimethylformamide (25 mL), sodium hydrogen (0.3 g,12.5 mmol) was added under ice bath, and the ice bath was removed under nitrogen and stirred for 1 hour. After the completion of the reaction, the reaction mixture was poured into an aqueous solution of ice saturated ammonium chloride (200 mL), extracted with ethyl acetate (100 ml×2), and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was separated and purified by a silica gel column (petroleum ether/ethyl acetate=1/1) to give 4- (4-methoxybenzyl) -3-oxo-1, 4-oxazalane-7-carboxylic acid ethyl ester Cpd-052E (1.0 g, white solid), yield: 58%.
MS m/z(ESI):308[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ7.18(d,J=8.6Hz,2H),6.89(d,J=8.6Hz,2H),4.44(s,2H),4.36-4.27(m,3H),4.11(q,J=7.1Hz,2H),3.73(s,3H),3.50(dd,J=14.2,9.8Hz,1H),3.36(d,J=7.5Hz,1H),2.16-2.06(m,1H),1.85(dt,J=13.4,9.9Hz,1H),1.22-1.16(m,3H).
Fifth step
Preparation of (4- (4-methoxybenzyl) -1, 4-oxazol-7-yl) methanol
Ethyl 4- (4-methoxybenzyl) -3-oxo-1, 4-oxazalane-7-carboxylate Cpd-052E (1.0 g,3.3 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and a tetrahydrofuran suspension (5.0 mL,5.0mmol, 1M) of lithium aluminum hydride was added dropwise under an ice bath under nitrogen, followed by heating to 60℃for reaction for 1.5 hours. After the completion of the reaction, tetrahydrofuran (100 mL) was added to dilute the reaction solution, and aqueous sodium hydroxide (0.6 mL,2 m) was added dropwise under ice bath to quench the reaction, followed by drying over anhydrous sodium sulfate, filtration through celite, and concentration of the filtrate to give crude (4- (4-methoxybenzyl) -1, 4-oxazol-7-yl) methanol Cpd-052F (0.6 g, colorless oil), yield: 70%. The crude product was used directly in the next reaction without further purification.
MS m/z(ESI):252[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ7.21(d,J=8.6Hz,2H),6.92-6.82(m,2H),4.55(t,J=5.7Hz,1H),3.78-3.70(m,4H),3.69-3.58(m,1H),3.55-3.45(m,3H),3.39-3.33(m,1H),3.25-3.17(m,1H),2.64-2.51(m,4H),1.826-1.78(m,1H),1.67-1.55(m,1H).
Sixth step
Preparation of 7- (hydroxymethyl) -1, 4-oxazapent-4-carboxylic acid tert-butyl ester
(4- (4-methoxybenzyl) -1, 4-oxazol-7-yl) methanol Cpd-052F (300 mg,1.2 mmol) and palladium hydroxide (84 mg,0.6 mmol) were dissolved in ethanol (10 mL), the reaction was heated at 60℃for 1 hour after the hydrogen balloon was replaced three times, the reaction solution was cooled to room temperature after the completion of the reaction, and then di-t-butyl dicarbonate (521 mg,2.4 mmol) was added thereto and stirred at room temperature for one hour. After the reaction was completed, the reaction mixture was filtered through celite, the residue was washed with methanol, and the combined organic phases were concentrated to give crude product, which was purified by separation on a silica gel column (petroleum ether/ethyl acetate=1/1) to give 7- (hydroxymethyl) -1, 4-oxazacyclo-pentane-4-carboxylic acid tert-butyl ester Cpd-052G (191 mg, colorless oil), yield: 69%.
MS m/z(ESI):132[M-100+1] + .
Seventh step
Preparation of 7-formyl-1, 4-oxetane-4-carboxylic acid tert-butyl ester
7- (hydroxymethyl) -1, 4-oxazapenta-4-carboxylic acid tert-butyl ester Cpd-052G (191 mg,0.83 mmol) was dissolved in dichloromethane (5 mL) and dessert-martin oxidant (420 mg,0.99 mmol) was added portionwise under ice-bath followed by removal of ice-bath nitrogen blanket and stirring for half an hour. After the reaction was completed, the reaction cloudy solution was filtered with celite, the filter residue was washed with dichloromethane, and the combined organic phases were concentrated, and the obtained crude product was purified by separation on a silica gel column (petroleum ether/ethyl acetate=2/1) to obtain 7-formyl-1, 4-oxetane-4-carboxylic acid tert-butyl ester Cpd-052H (170 mg, colorless oil), yield: 90%.
Eighth step
Preparation of 7- (((2- (ethoxycarbonyl) -4-methyl-1H-pyrrol-3-yl) amino) methyl) -1, 4-oxazapenta-4-carboxylic acid tert-butyl ester
7-formyl-1, 4-oxetane-4-carboxylic acid tert-butyl ester Cpd-052H (136 mg,0.59 mmol) and 3-amino-4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (100 mg,0.59 mmol) were dissolved in methanol (5 mL), one drop of acetic acid was added dropwise, stirred at room temperature for half an hour, followed by sodium cyanoborohydride (150 mg,2.38 mmol) and stirred at room temperature for half an hour. After the reaction was completed, the reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (50 ml×2), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was purified by separation on a silica gel column (petroleum ether/ethyl acetate=4/1) to give 7- (((2- (ethoxycarbonyl) -4-methyl-1H-pyrrol-3-yl) amino) methyl) -1, 4-oxazapentan-4-carboxylic acid tert-butyl ester Cpd-052I (120 mg, colorless oil), yield: 53%.
MS m/z(ESI):382[M+1] + .
Ninth step
Preparation of 7- ((3- (ethoxycarbonyl) -1- (2- (ethoxycarbonyl) -4-methyl-1H-pyrrol-3-yl) thiourea) methyl) -1, 4-oxazacyclo-4-carboxylic acid tert-butyl ester
7- (((2- (ethoxycarbonyl) -4-methyl-1H-pyrrol-3-yl) amino) methyl) -1, 4-oxazacyclopenta-4-carboxylic acid tert-butyl ester Cpd-052I (120 mg,0.31 mmol) was dissolved in dichloromethane (3 mL), then ethoxycarbonyl isothiocyanate (62 mg,0.47 mmol) was added at room temperature and stirred for one hour. After the reaction was completed, the reaction solution was concentrated to give crude 7- ((3- (ethoxycarbonyl) -1- (2- (ethoxycarbonyl) -4-methyl-1H-pyrrol-3-yl) thiourea) methyl) -1, 4-oxazacyclo-4-carboxylic acid tert-butyl ester Cpd-052J (170 mg, colorless oil), yield: 105%. The crude product was used directly in the next reaction without further purification.
MS m/z(ESI):513[M+1] + .
Tenth step
Preparation of 7- ((7-methyl-4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) methyl) -1, 4-oxazapentan-4-carboxylic acid tert-butyl ester
7- ((3- (ethoxycarbonyl) -1- (2- (ethoxycarbonyl) -4-methyl-1H-pyrrol-3-yl) thiourea) methyl) -1, 4-oxazacyclo-4-carboxylic acid tert-butyl ester Cpd-052J (160 mg,0.31 mmol) and cesium carbonate (508 mg,1.56 mmol) were dissolved in methanol (5 mL) and then heated to 60℃and stirred for 6 hours. After completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL. Times.2). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=1/1) to give 7- ((7-methyl-4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) methyl) -1, 4-oxazapentan-4-carboxylic acid tert-butyl ester Cpd-052K (70 mg, white solid), yield: 57%.
MS m/z(ESI):395[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.18(s,1H),12.07(s,1H),7.13(s,1H),4.71(s,1H),4.14(s,2H),3.73(d,J=8.7Hz,1H),3.57-3.38(m,3H),3.23(d,J=32.4Hz,2H),2.29(s,3H),1.93(s,1H),1.63(s,1H),1.39(d,J=9.6Hz,9H).
Eleventh step
Preparation of 7-methyl-1- ((1, 4-oxazepan-7-yl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
7- ((7-methyl-4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) methyl) -1, 4-oxazacyclo-pentane-4-carboxylic acid tert-butyl ester Cpd-052K (60 mg,0.15 mmol) was dissolved in methanol hydrochloride (5 mL, 3M), heated to 30℃and stirred for half an hour. After the reaction was completed, the reaction mixture was concentrated to give crude 7-methyl-1- ((1, 4-oxazepan-7-yl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-052L (50 mg, white solid), yield: 111%. The crude product was used directly in the next reaction without further purification.
MS m/z(ESI):295[M+1] + .
Twelfth step
Preparation of 7-methyl-1- ((4-methyl-1, 4-oxazepan-7-yl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
7-methyl-1- ((1, 4-oxazacyclo-7-yl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-052L (50 mg,0.15 mmol) paraformaldehyde (14 mg,0.45 mmol) was dissolved in methanol (3 mL) and saturated aqueous sodium bicarbonate (2 mL), followed by addition of sodium cyanoborohydride (47 mg,0.75 mmol) and stirred at room temperature for half an hour. After the reaction was completed, the reaction mixture was poured into a solution of water (100 mL), extracted with ethyl acetate (50 ml×2), and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product which was sent to pre-HPLC to give 7-methyl-1- ((4-methyl-1, 4-oxazepin-7-yl) methyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one formate Cpd-052 (3 mg, white solid), yield: 6.4%.
MS m/z(ESI):309[M+1] + .
1 H NMR(400MHz,MeOD)δ8.48(s,1H),7.11(s,1H),4.48(s,2H),3.98(d,J=14.1Hz,1H),3.70(d,J=14.1Hz,1H),3.47-3.39(m,1H),3.25(d,J=10.5Hz,3H),2.84(s,3H),2.39(s,3H),2.33-2.01(m,3H).
Example 53
7-methyl-1- ((4-methyl-1, 4-oxazepan-2-yl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of 1, 4-oxaheptane-4-carboxylic acid tert-butyl ester-2-carbaldehyde
Oxalyl chloride (90 mg,0.7 mmol) was dissolved in dry dichloromethane (5 mL). Cooling to-65 ℃, then slowly adding a dichloromethane (1 mL) solution of dimethyl sulfoxide (110 mg,1.4 mmol), controlling the temperature to be lower than-60 ℃, stirring for 30 minutes at-65 ℃ after the addition is finished, then dropwise adding a dichloromethane (1 mL) solution of 1, 4-oxaheptane-4-tert-butyl formate-2-hydroxymethyl Cpd-053A (150 mg,0.6 mmol), and preserving the temperature for 2 hours after the addition is finished. Triethylamine (195 mg,1.9 mmol) was then added dropwise, after the addition was completed, the temperature was slowly raised to 0℃and water (10 mL) was added thereto, and the solution was separated, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate to give a dichloromethane solution (7 mL) containing tert-butyl 1, 4-oxaheptane-4-carboxylate-2-carbaldehyde Cpd-053B, and the next step was carried out without treatment.
Second step
Preparation of 2- (1, 4-oxaheptane-4-carboxylic acid tert-butyl ester-methylamino) -1H-pyrrole-2-carboxylic acid ethyl ester
Ethyl 3-amino-4-methyl-1H-pyrrole-2-carboxylate (100 mg,0.6 mmol) was dissolved in methanol (10 mL), acetic acid (36 mg,0.6 mmol) and a dichloromethane solution (7 mL) of tert-butyl 1, 4-oxaheptane-4-carboxylate-2-formaldehyde Cpd-053B were added sequentially, and stirred at room temperature for 0.5 hours. Sodium cyanoborohydride (41 mg,0.6 mmol) was then added in portions and stirred at room temperature for 16 hours. After the reaction was completed, quenched by addition of water (5 mL), extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated in vacuo to give crude product, which was purified by column chromatography to give ethyl 2- (1, 4-oxaheptane-4-carboxylate-methylamino) -1H-pyrrole-2-carboxylate Cpd-053C (100 mg, light brown oil), yield: 40%.
Third step
Preparation of tert-butyl 2- ((3- (ethoxycarbonyl) -1- (2- (ethoxycarbonyl) -4-methyl-1H-pyrrol-3-yl) thiourea) methyl) -1, 4-oxazacyclo-4-carboxylate
2- (1, 4-oxaheptane-4-carboxylic acid tert-butyl ester-methylamino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-053C (100 mg,0.2 mmol) was dissolved in dichloromethane (10 mL), cooled to 0℃and ethyl isothiocyanamide (39 mg,0.3 mmol) was added thereto, followed by stirring at room temperature for 3 hours. After completion of the reaction, the reaction mixture was washed once with water (5 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated. The resulting residue was isolated and purified by silica gel column (ethyl acetate/petroleum ether=1/3) to give tert-butyl 2- ((3- (ethoxycarbonyl) -1- (2- (ethoxycarbonyl) -4-methyl-1H-pyrrol-3-yl) thiourea) methyl) -1, 4-oxazacyclo-4-carboxylate Cpd-053D (100 mg, light brown oil), yield: 74%.
MS m/z(ESI):513[M+1] + .
Fourth step
Preparation of tert-butyl 2- ((7-methyl-4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) methyl) -1, 4-oxazapentan-4-carboxylate
2- ((3- (ethoxycarbonyl) -1- (2- (ethoxycarbonyl) -4-methyl-1H-pyrrol-3-yl) thiourea) methyl) -1, 4-oxazacyclo-4-carboxylic acid tert-butyl ester Cpd-053D (100 mg,0.2 mmol) was dissolved in methanol (2 mL), cesium carbonate (195 mg,0.6 mmol) was added thereto, and the reaction solution was heated to 65℃for 3 hours. The reaction solution was cooled to room temperature, a saturated aqueous ammonium chloride solution (5 mL) was added, extraction was performed with ethyl acetate (10 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was isolated by preparative silica gel plate to give tert-butyl 2- ((7-methyl-4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) methyl) -1, 4-oxazapentan-4-carboxylate Cpd-053E (50 mg, white solid), yield: 77%.
Fifth step
Preparation of 1- ((1, 4-oxazacyclo-2-yl) methyl) -7-methyl-2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
2- ((7-methyl-4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) methyl) -1, 4-oxazacyclo-penta-4-carboxylic acid tert-butyl ester Cpd-053E (50 mg,0.1 mmol) was dissolved in methanol hydrochloride (2 mL), stirred at room temperature for 2 hours, neutralized with aqueous sodium bicarbonate after completion of the reaction, extracted with ethyl acetate, and concentrated to give 1- ((1, 4-oxazacyclo-2-yl) methyl) -7-methyl-2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-053F (20 mg, white solid), yield: 54%.
MS m/z(ESI):295[M+1] + .
Sixth step
Preparation of 7-methyl-1- ((4-methyl-1, 4-oxazepan-2-yl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
1- ((1, 4-oxazacyclo-2-yl) methyl) -7-methyl-2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-053F (20 mg,0.07 mmol) was dissolved in methanol (2 mL), paraformaldehyde (9 mg,0.1 mmol) and sodium cyanoborohydride (7 mg,0.1 mmol) were added, the reaction mixture was stirred at room temperature for 3 hours, after completion of the reaction, concentrated, and the residue was isolated by preparative separation to give 7-methyl-1- ((4-methyl-1, 4-oxazacyclo-2-yl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-053 (6 mg, white solid), yield: 28%.
MS m/z(ESI):309[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.16(s,1H),12.07(s,1H),7.13(d,J=2.8Hz,1H),4.70(s,1H),4.35-4.25(m,2H),3.70-3.65(m,1H),3.50-3.45(m,1H),2.85-2.75(m,1H),2.66-2.61(m,1H),2.34-2.26(m,8H),1.85-1.65(m,2H).
Example 54
2-thio-1- (2- ((1, 1-trifluoro-2-methyl-3- (methylamino) propan-2-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of 1, 1-trifluoro-2-methyl-3-nitropropan-2-ol
Cetyl trimethylammonium chloride (1.7 g,5.8 mmol), lithium hydroxide (0.1 g,4.5 mmol), anhydrous magnesium sulfate (1.1 g,8.9 mmol) were dissolved in water (15 mL), nitromethane Cpd-054A (2.7 g,44.6 mmol) and 1, 1-trifluoroacetone (5.0 g,44.6 mmol) were added, the reaction solution was stirred at room temperature for 16 hours, after completion of the reaction, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether/ethyl acetate=4/1) to give 1, 1-trifluoro-2-methyl-3-nitropropan-2-ol Cpd-054B (7.0 g, colorless liquid), yield: 91%.
1 H NMR(400MHz,DMSO-d6)δ6.96(s,1H),4.85-4.73(m,2H),1.48(s,3H).
Second step
Preparation of 3-amino-1, 1-trifluoro-2-methylpropan-2-ol
1, 1-trifluoro-2-methyl-3-nitropropan-2-ol Cpd-054B (7.0 g,49 mmol) was dissolved in methanol (100 mL) and Pd (OH) was added 2 and/C (500 mg), stirring at room temperature under hydrogen atmosphere for 1 hour. After the reaction was completed, the mixture was filtered through celite, and the filtrate was dried by spin to give 3-amino-1, 1-trifluoro-2-methylpropan-2-ol Cpd-054C (5.0 g, colorless liquid), yield: 88%. The crude product was used directly in the next reaction without further purification.
1 H NMR(400MHz,DMSO-d6)δ3.17(s,1H),2.71-2.49(m,2H),1.21(s,3H).
Third step
Preparation of 1, 1-trifluoro-3- ((4-methoxybenzyl) methylamino) -2-methylpropan-2-ol
3-amino-1, 1-trifluoro-2-methylpropan-2-ol Cpd-054C (2.2 g,15.5 mmol) and 4-methoxybenzaldehyde (2.1 g,15.5 mmol) were dissolved in methanol (50 mL), a catalytic amount of acetic acid was added, stirred at room temperature for 0.5 hours, then sodium cyanoborohydride (2.9 g,46.5 mmol) was added, stirred at room temperature for 0.5 hours, paraformaldehyde (0.9 g,31.0 mmol) was added, and stirred at room temperature for 0.5 hours. After the reaction was completed, water was added to quench, ethyl acetate was used to extract, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give 1, 1-trifluoro-3- ((4-methoxybenzyl) methylamino) -2-methylpropan-2-ol Cpd-054D (2.9 g, colorless liquid), yield: 67%.
1 H NMR(400MHz,MeOD)δ7.25(d,J=8.6Hz,2H),6.88(d,J=8.6Hz,2H),3.79(s,3H),3.57(dd,J=106.0,12.9Hz,2H),2.62(s,2H),2.32(s,3H),1.33(s,3H).
Fourth step
Preparation of ethyl 2- ((1, 1-trifluoro-3- ((4-methoxybenzyl) methylamino) -2-methylpropan-2-yl) oxy) acetate
1, 1-trifluoro-3- ((4-methoxybenzyl) methylamino) -2-methylpropan-2-ol Cpd-054D (1000 mg,3.6 mmol) was dissolved in N, N-dimethylformamide (10 mL), cooled to 0℃and sodium hydrogen (173 mg,4.3 mmol) was added in portions, after which time stirring was carried out at room temperature for 1 hour, and then ethyl 2-bromoacetate (663 mg,4.0 mmol) was slowly added and the reaction stirred at room temperature for 16 hours. After the reaction was completed, water was added to quench, ethyl acetate was extracted, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give ethyl 2- ((1, 1-trifluoro-3- ((4-methoxybenzyl) methylamino) -2-methylpropan-2-yl) oxy) acetate Cpd-054E (800 mg, colorless liquid), yield: 61%.
MS m/z(ESI):364[M+1] + .
Fifth step
Preparation of 2- ((1, 1-trifluoro-3- ((4-methoxybenzyl) methylamino) -2-methylpropan-2-yl) oxy) ethan-1-ol
Ethyl 2- ((1, 1-trifluoro-3- ((4-methoxybenzyl) methylamino) -2-methylpropan-2-yl) oxy) acetate Cpd-054E (100 mg,0.3 mmol) was dissolved in tetrahydrofuran (5 mL), cooled to 0 ℃, lithium aluminum hydride (0.3mL,0.3mmol,1.0M in THF) was slowly added, then reacted for 1 hour at 0 ℃, after the reaction was completed, quenched with water, filtered, and the filtrate was dried over anhydrous sodium sulfate and concentrated to give 2- ((1, 1-trifluoro-3- ((4-methoxybenzyl) methylamino) -2-methylpropan-2-yl) oxy) ethane-1-ol Cpd-054F (60 mg, colorless liquid), yield: 68%.
MS m/z(ESI):322[M+1] + .
Sixth step
Preparation of 2- ((1, 1-trifluoro-3- ((4-methoxybenzyl) methylamino) -2-methylpropan-2-yl) oxy) acetaldehyde
Oxalyl chloride (44 mg,0.34 mmol) was dissolved in dichloromethane (5 mL), cooled to-65 ℃, dimethyl sulfoxide (53 mg,0.68 mmol) was slowly added, the reaction was incubated for 0.5 h, a solution of 2- ((1, 1-trifluoro-3- ((4-methoxybenzyl) methylamino) -2-methylpropan-2-yl) oxy) ethan-1-ol Cpd-054F (100 mg,0.31 mmol) in dichloromethane (0.5 mL) was added, the reaction was incubated for 1 h, and then triethylamine (94 mg,0.93 mmol) was added and the temperature was naturally raised to 0 ℃. After the reaction, water quenching and dichloromethane extraction are carried out, and the organic phase is dried by anhydrous sodium sulfate to obtain a dichloromethane solution of 2- ((1, 1-trifluoro-3- ((4-methoxybenzyl) methylamino) -2-methylpropan-2-yl) oxy) acetaldehyde Cpd-054G. The solution was used directly in the next reaction without further purification.
Seventh step
Preparation of ethyl 3- ((2- ((1, 1-trifluoro-3- ((4-methoxybenzyl) methylamino) -2-methylpropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate
A solution of 2- ((1, 1-trifluoro-3- ((4-methoxybenzyl) methylamino) -2-methylpropan-2-yloxy) acetaldehyde Cpd-054G (0.31 mmol) in methylene chloride was dissolved in methanol (5 mL), ethyl 3-amino-1H-pyrrole-2-carboxylate (48 mg,0.31 mmol) and acetic acid (18.6 mg,0.31 mmol) were added in this order, the reaction mixture was stirred at room temperature for 1 hour, then sodium cyanoborohydride (21 mg,0.31 mmol) was added and stirred at room temperature for 16 hours. After the reaction was completed, quenched with water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether/ethyl acetate=3/1) to give 3- ((2- ((1, 1-trifluoro-3- ((4-methoxybenzyl) methylamino) -2-methylpropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-054H (100 mg, colorless liquid), yield: 70%.
MS m/z(ESI):458[M+1] + .
Eighth step
Preparation of ethyl 3- ((2- ((1, 1-trifluoro-2-methyl-3- (methylamino) propan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate
3- ((2- ((1, 1-trifluoro-3- ((4-methoxybenzyl) methylamino) -2-methylpropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-054H (100 mg,0.22 mmol) was dissolved in isopropanol (5 mL), palladium hydroxide on carbon (10 mg) was added and stirred under hydrogen atmosphere at 50℃for 16 hours. After the reaction was completed, celite was filtered and the filtrate was dried to give 3- ((2- ((1, 1-trifluoro-2-methyl-3- (methylamino) propan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-054I (70 mg, colorless liquid), yield: 95%.
MS m/z(ESI):338[M+1] + .
Ninth step
Preparation of ethyl 3- ((2- ((3- ((tert-butoxycarbonyl) methylamino) -1, 1-trifluoro-2-methylpropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate
3- ((2- ((1, 1-trifluoro-2-methyl-3- (methylamino) propan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-054I (70 mg,0.2 mmol) was dissolved in dichloromethane (10 mL), di-tert-butyl dicarbonate (44 mg,0.2 mmol) was added, stirred at room temperature for 1 hour, after completion of the reaction, concentrated to give 3- ((2- ((3- ((tert-butoxycarbonyl) methylamino) -1, 1-trifluoro-2-methylpropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-054J (80 mg, colorless liquid), yield: 88%.
MS m/z(ESI):438[M+1] + .
Tenth step
Preparation of ethyl 3- (1- (2- ((3- ((tert-butoxycarbonyl) methylamino) -1, 1-trifluoro-2-methylpropan-2-yl) oxy) ethyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylate
3- ((2- ((3- ((tert-Butoxycarbonyl) methylamino) -1, 1-trifluoro-2-methylpropan-2-yloxy) ethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-054J (80 mg,0.18 mmol) was dissolved in dichloromethane (5 mL), ethyl isothiocyanate (29 mg,0.22 mmol) was added, stirred at room temperature for 1 hour, after the end of the reaction, concentrated to give 3- (1- (2- ((3- ((tert-butoxycarbonyl) methylamino) -1, 1-trifluoro-2-methylpropan-2-yl) oxy) ethyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-054K (80 mg, pale brown liquid), yield: 77%.
MS m/z(ESI):569[M+1] + .
Preparation of tert-butyl (3, 3-trifluoro-2-methyl-2- (2- (4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) ethoxy) propyl) methylcarbamate in the eleventh step
3- (1- (2- ((3- ((tert-butoxycarbonyl) methylamino) -1, 1-trifluoro-2-methylpropan-2-yl) oxy) ethyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-054K (80 mg,0.14 mmol) was dissolved in methanol (5 mL), cesium carbonate (137 mg,0.42 mmol) was added, the reaction mixture was stirred at 60 ℃ for 3 hours, after completion of the reaction, washed with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by column chromatography (dichloromethane/methanol=10/1) to give (3, 3-trifluoro-2-methyl-2- (2- (4-oxo-2-thio-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) ethoxy) propyl) methyl tert-butyl carbamate Cpd-054L (30 mg, white solid), yield: 63%.
MS m/z(ESI):451[M+1] + .
Twelfth step
Preparation of 1- (2- (((1, 1-trifluoro-2-methyl-3- (methylamino) propan-2-yl) oxy) ethyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Tert-butyl (3, 3-trifluoro-2-methyl-2- (2- (4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) ethoxy) propyl) methylcarbamate Cpd-054L (30 mg,0.07 mmol) was dissolved in methanol hydrochloride (2 mL, 4M) and stirred at room temperature for 2 hours. After the reaction was completed, neutralized with aqueous sodium bicarbonate, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the preparation plate (dichloromethane/methanol=10/1) was separated to give 1- (2- ((1, 1-trifluoro-2-methyl-3- (methylamino) propan-2-yl) oxy) ethyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-054 (10 mg, white solid), yield: 43%.
MS m/z(ESI):351[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.37(s,1H),7.36(d,J=2.8Hz,1H),6.30(d,J=2.8Hz,1H),4.55-4.51(m,2H),3.99-3.90(m,2H),2.69-2.54(m,2H),2.19(s,3H),1.23(s,3H).
Example 55
1- (2- ((3- (dimethylamino) -1, 1-trifluoro-2-methylpropan-2-yl) oxy) ethyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
2-thio-1- (2- ((1, 1-trifluoro-2-methyl-3- (methylamino) propan-2-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-054 (40 mg,0.1 mmol) was dissolved in methanol (5 mL), paraformaldehyde (18 mg,0.2 mmol) and sodium cyanoborohydride (12 mg,0.2 mmol) were added, the reaction mixture was stirred at room temperature for 16 hours, after the end of the reaction, concentrated, and the preparation plate was isolated (dichloromethane/methanol=10/1) to give 1- (2- ((3- (dimethylamino) -1, 1-trifluoro-2-methylpropan-2-yl) oxy) ethyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-055 (2 mg, white solid), yield: 5%.
MS m/z(ESI):365[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.32(s,1H),12.19(s,1H),7.35(d,J=2.8Hz,1H),6.23(t,J=2.8Hz,1H),4.54-4.50(m,2H),4.00-3.91(m,2H),2.41-2.31(m,2H),2.10(s,6H),1.29(s,3H).
Example 56
2-thio-1- (2- (1- (1- (trifluoromethyl) cyclobutoxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of 1- (trifluoromethyl) cyclobutan-1-ol
Cyclobutanone Cpd-056A (4 g,57.1 mmol) was dissolved in tetrahydrofuran (50 mL), then trimethyl (trifluoromethyl) silane (9.74 g,68.5 mmol) was added, then a tetrahydrofuran solution of tetrabutylammonium fluoride (0.5 mL,1 m) was slowly added dropwise at a temperature of 0 ℃, after the addition was completed, stirring was carried out at room temperature for 2 hours, after the completion of the reaction, ethyl acetate was added for dilution, washed twice with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and concentrated by filtration to give product 1- (trifluoromethyl) cyclobutan-1-ol Cpd-056B (1.7 g, brown liquid), yield: 21%.
Second step
Preparation of ethyl 2- (1- (trifluoromethyl) cyclobutoxy) acetate
1- (trifluoromethyl) cyclobutan-1-ol Cpd-056B (1.2 g,8.6 mmol) was dissolved in tetrahydrofuran (20 mL) and then sodium hydrogen (0.3 g,12.9 mmol) was added in portions at zero degrees, the reaction was allowed to warm to room temperature and stirred for 30 minutes, then ethyl bromoacetate (2.15 g,12.9 mmol) was slowly added dropwise and the solution stirred at room temperature for 2 hours. After the reaction was completed, water was added to conduct extraction, ethyl acetate was used for extraction, the organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate and spin-dried to obtain a crude product, and the obtained crude product was separated and purified by a silica gel column (petroleum ether/ethyl acetate=2/1) to obtain the product, ethyl 2- (1- (trifluoromethyl) cyclobutoxy) acetate Cpd-056C (500 mg, colorless oil), yield: 26%.
MS m/z(ESI):227[M+1] + .
Third step
Preparation of 2- (1- (trifluoromethyl) cyclobutoxy) ethan-1-ol
Ethyl 2- (1- (trifluoromethyl) cyclobutoxy) acetate Cpd-056C (500 mg,2.21 mmol) was dissolved in tetrahydrofuran (10 mL), then a solution of lithium borohydride in tetrahydrofuran (1 m,0.5 mL) was slowly added dropwise at zero degrees, the reaction was allowed to warm to room temperature and stirred for 16 hours, after the completion of the reaction, it was extracted with methanol, diluted with water, extracted with ethyl acetate, the organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to give crude product, which was isolated and purified by silica gel column (petroleum ether/ethyl acetate=1/1) to give Cpd-056D (200 mg, colorless oily liquid) as product, yield: 53%.
Fourth step
Preparation of 2- (1- (trifluoromethyl) cyclobutoxy) acetaldehyde
Oxalyl chloride (75.81 mg,0.59 mmol) was dissolved in dry dichloromethane (2 mL), the solution was cooled to-70℃under nitrogen protection, dimethyl sulfoxide (93 mg,1.2 mmol) was then slowly added dropwise to dichloromethane (1 mL), the solution was kept stirring at-70℃for 30 minutes, then 2- (1- (trifluoromethyl) cyclobutoxy) ethane-1-ol Cpd-056D (100 mg,0.54 mmol) was slowly added dropwise, the mixed solution was stirred at-70℃for 2 hours, then triethylamine (164.84 mg,1.63 mmol) was added and stirred for 30 minutes, the reaction solution was slowly warmed naturally to room temperature, dichloromethane (20 mL) was added thereto for dilution, water (10 mL) was added, the separated solution was washed with saturated sodium chloride, and 20mL of a solution of dichloromethane Cpd-056E containing 2- (1- (trifluoromethyl) cyclobutoxy) acetaldehyde was obtained after drying over anhydrous sodium sulfate.
Fifth step
Preparation of ethyl 3- ((2- (1- (trifluoromethyl) cyclobutoxy) ethyl) amino) -1H-pyrrole-2-carboxylate
Ethyl 3-amino-1H-pyrrole-2-carboxylate (100 mg,0.55 mmol) was dissolved in methanol (5 mL), followed by addition of acetic acid (10 mg,0.16 mmol) and a dichloromethane solution (20 mL) of 2- (1- (trifluoromethyl) cyclobutoxy) acetaldehyde Cpd-056E, followed by stirring at room temperature for 0.5 hours. Sodium cyanoborohydride (103.50 mg,1.65 mmol) was then added and stirred at room temperature for 16 hours. After the reaction was completed, 20mL of water was added to quench, extraction was performed with ethyl acetate, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and rotary distilled to obtain crude product, which was purified by column to obtain 3- ((2- (1- (trifluoromethyl) cyclobutoxy) ethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-056F (40 mg, light brown oil), yield: 23%.
MS m/z(ESI):227[M+1] + .
Sixth step
Preparation of ethyl 3- (3- (ethoxycarbonyl) -1- (2- (1- (trifluoromethyl) cyclobutoxy) ethyl) thioureido) -1H-pyrrole-2-carboxylate
3- ((2- (1- (trifluoromethyl) cyclobutoxy) ethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-056F (40 mg,0.125 mmol) was dissolved in dichloromethane (3 mL), cooled to 0℃and ethyl isothiocyanamide (19.66 mg,0.15 mmol) was added thereto, followed by stirring at room temperature for 3 hours. After completion of the reaction, the reaction mixture was washed once with water (20 mL), and the organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was isolated and purified by silica gel column (petroleum ether/ethyl acetate=1/1) to give ethyl 3- (3- (ethoxycarbonyl) -1- (2- (1- (trifluoromethyl) cyclobutoxy) ethyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-056G (88 mg, light brown oil), yield: 88%.
MS m/z(ESI):452[M+1] + .
Seventh step
Preparation of 2-thio-1- (2- (1- (1- (trifluoromethyl) cyclobutoxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
3- (3- (ethoxycarbonyl) -1- (2- (1- (trifluoromethyl) cyclobutoxy) ethyl) thioureido) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-056G (50 mg,0.11 mmol) was dissolved in methanol (3 mL), sodium methoxide (12 mg,0.22 mmol) was added thereto, and the reaction solution was heated to 90℃for 2 hours. The reaction solution was cooled to room temperature and adjusted to ph=4-5 with dilute hydrochloric acid (1M), the solution was dried by spin to give crude product, which was isolated and purified by Prep-HPLC (acetonitrile/water (formic acid 1 mill)) to give 2-thio-1- (2- (1- (1- (trifluoromethyl) cyclobutoxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-056 (10 mg, white solid) in 27% yield.
MS m/z(ESI):334[M+1] + .
1 H NMR(400MHz,CDCl 3 )δ10.12(s,1H),9.47(s,1H),7.23(s,1H),6.29(s,1H),4.66-4.53(m,2H),4.08-3.94(m,,2H),2.35-2.19(m,2H),2.12-1.99(m,2H),1.80-1.69(m,2H).
Example 57
2-thio-1- (2- ((3- (trifluoromethyl) azetidin-3-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of 3-hydroxy-3- (trifluoromethyl) azetidine-1-carboxylic acid tert-butyl ester
3-Oxoazaaniline-1-carboxylic acid tert-butyl ester Cpd-057A (2.0 g,11.7 mmol), trifluoromethyl trimethylsilane (3.3 g,23.4 mmol) and tetrabutylammonium fluoride (3.0 g,11.7 mmol) were dissolved in dry tetrahydrofuran (50 mL). The reaction was allowed to react overnight at room temperature. To the reaction mixture was added saturated brine (50 mL), followed by extraction with ethyl acetate (50 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated and purified by separation (petroleum ether/ethyl acetate=5/1) to give 3-hydroxy-3- (trifluoromethyl) azetidine-1-carboxylic acid tert-butyl ester Cpd-057B (1.8 g, yellow liquid), yield: 64%.
1 H NMR(400MHz,DMSO-d6)δ7.37(s,1H),4.08-3.97(m,2H),3.85(d,J=9.6Hz,2H),1.39(s,9H).
Second step
Preparation of tert-butyl 3- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) -3- (trifluoromethyl) azetidine-1-carboxylate
3-hydroxy-3- (trifluoromethyl) azetidine-1-carboxylic acid tert-butyl ester Cpd-057B (1.8 g,7.5 mmol) was dissolved in N, N-dimethylformamide (5 mL), cooled to 0℃in an ice bath, then sodium hydride (268 mg,11.2 mmol) was added thereto, and after stirring for 30 minutes (2-bromoethoxy) (tert-butyl) dimethylsilane (2.7 g,11.2 mmol) was added. The reaction mixture was reacted at 25℃for 12 hours. The reaction solution was washed with saturated brine (50 ml×3), and the organic phase was dried over anhydrous sodium sulfate to give 3- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) -3- (trifluoromethyl) azetidine-1-carboxylic acid tert-butyl ester Cpd-057C (1.5 g, yellow liquid), yield: 50%. The crude product was used directly in the next step without further purification.
MS m/z(ESI):344[M-56+1] + .
Third step
Preparation of tert-butyl 3- (2-hydroxyethoxy) -3- (trifluoromethyl) azetidine-1-carboxylate
3- (2- ((tert-Butyldimethylsilyloxy) ethoxy) -3- (trifluoromethyl) azetidine-1-carboxylic acid tert-butyl ester Cpd-057C (1.5 g,3.8 mmol) was dissolved in tetrahydrofuran (5 mL) and tetrabutylammonium fluoride (3.8 mL,3.8mmol, 1M) was added thereto. The reaction solution was reacted at 25℃for two hours. After completion of the reaction, tetrahydrofuran was removed by rotary evaporation, ethyl acetate (5 mL) was added thereto for dissolution, and the resultant mixture was washed with saturated brine (10 ml×3), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was separated and purified by silica gel column (petroleum ether/ethyl acetate=1/2) to give 3- (2-hydroxyethoxy) -3- (trifluoromethyl) azetidine-1-carboxylic acid tert-butyl ester Cpd-057D (500 mg, yellow liquid), yield: 46%.
Fourth step
Preparation of tert-butyl 3- (2-oxyethoxy) -3- (trifluoromethyl) azetidine-1-carboxylate
Oxalyl chloride (333 mg,2.6 mmol) was dissolved in dry dichloromethane (3 mL), dimethyl sulfoxide (409 mg,5.2 mmol) was added and cooled to-60℃under nitrogen. 3- (2-hydroxyethoxy) -3- (trifluoromethyl) azetidine-1-carboxylic acid tert-butyl ester Cpd-057D (500 mg,1.8 mmol) was dissolved in dry dichloromethane (2 mL) and added to the reaction system for 30 minutes. Triethylamine (795 mg,7.9 mmol) was added thereto and stirred for 10 minutes. The reaction mixture was washed with saturated brine (10 mL. Times.3). The organic phase was dried over anhydrous sodium sulfate and evaporated to give 3- (2-oxoethoxy) -3- (trifluoromethyl) azetidine-1-carboxylic acid tert-butyl ester Cpd-057E (200 mg, yellow liquid), yield: 40%. The crude product was used directly in the next step without further purification.
Fifth step
Preparation of ethyl 3- ((2- ((1- (tert-butoxycarbonyl) -3- (trifluoromethyl) azetidin-3-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate
3- (2-Oxoethoxy) -3- (trifluoromethyl) azetidine-1-carboxylic acid tert-butyl ester Cpd-057E (200 mg,0.7 mmol) was dissolved in methanol (5 mL) and 3-amino-1H-pyrrole-2-carboxylic acid ethyl ester (109 mg,0.7 mmol) and acetic acid (0.5 mL) were added sequentially. After the reaction solution was stirred for 1 hour, sodium cyanoborohydride (88 mg,1.4 mmol) was added thereto, and stirring was continued for 4 hours. After the reaction was completed, methanol was removed by rotary evaporation, dissolved with ethyl acetate (5 mL), washed with saturated brine (10 ml×3), dried over anhydrous sodium sulfate and concentrated, and the obtained crude product was isolated and purified by silica gel column (petroleum ether/ethyl acetate=1/2) to give 3- ((2- ((1- (t-butoxycarbonyl) -3- (trifluoromethyl) azetidin-3-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-057F (150 mg, yellow liquid), yield: 50%.
MS m/z(ESI):422[M+1] + .
Sixth step
3- (1- (2- ((1- (tert-Butoxycarbonyl) -3- (trifluoromethyl) azetidin-3-yl) oxy) ethyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester
Preparation of esters
3- ((2- ((1- (tert-Butoxycarbonyl) -3- (trifluoromethyl) azetidin-3-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-057F (150 mg,0.35 mmol) was dissolved in dichloromethane (2 mL), and ethoxycarbonyl isothiocyanate (46 mg,0.35 mmol) was added and the reaction solution reacted at room temperature for 30 minutes. After the reaction was completed, it was distilled off to give crude 3- (1- (2- ((1- (t-butoxycarbonyl) -3- (trifluoromethyl) azetidin-3-yl) oxy) ethyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-057G (120 mg, yellow oil), yield: 62%. The crude product was used directly in the next reaction without further purification.
MS m/z(ESI):553[M+1] + .
Seventh step
Preparation of 3- (2- (4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) ethoxy) -3- (trifluoromethyl) azetidine-1-carboxylic acid tert-butyl ester
3- (1- (2- ((1- (tert-Butoxycarbonyl) -3- (trifluoromethyl) azetidin-3-yl) oxy) ethyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-057G (120 mg,0.21 mmol) was dissolved in anhydrous methanol (5 mL), cesium carbonate (136 mg,0.42 mmol) was added and the reaction warmed to 65℃and stirred for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, dried by spin, and the plate was climbed (petroleum ether/ethyl acetate=1/2) to give tert-butyl 3- (2- (4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) ethoxy) -3- (trifluoromethyl) azetidine-1-carboxylate Cpd-057H (60 mg, yellow solid), yield: 66%.
MS m/z(ESI):379[M-56+1] + .
Eighth step
Preparation of 2-thio-1- (2- ((3- (trifluoromethyl) azetidin-3-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
The resulting tert-butyl 3- (2- (4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) ethoxy) -3- (trifluoromethyl) azetidine-1-carboxylate Cpd-057H (60 mg,0.14 mmol) was dissolved in methanol (2 mL) and then added to a methanolic hydrochloride solution (1 mL). The reaction solution was stirred at room temperature for 2 hours, then methanol was removed by rotary evaporation, the residue was slurried with ethyl acetate, filtered, the cake was washed with aqueous sodium bicarbonate, extracted with ethyl acetate, concentrated and dried to give 2-thio-1- (2- ((3- (trifluoromethyl) azetidin-3-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-057 (30 mg, white solid), yield: 64%.
MS m/z(ESI):335[M+1] + .
Example 58
1- (2- ((1-methyl-3- (trifluoromethyl) azetidin-3-yl) oxy) ethyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of 1- (2- ((1-methyl-3- (trifluoromethyl) azetidin-3-yl) oxy) ethyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
2-thio-1- (2- ((3- (trifluoromethyl) azetidin-3-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-057 (15 mg,0.04 mmol) was dissolved in methanol (2 mL), paraformaldehyde (2 mg) and two drops of acetic acid were added. The reaction solution was stirred at room temperature for 1 hour, followed by addition of sodium cyanoborohydride (20 mg,0.32 mmol) and stirring was continued for 2 hours. After the reaction was completed, methanol was removed by rotary evaporation, and the residue was separated and purified by column chromatography (dichloromethane/methanol=10/1) to give 1- (2- ((1-methyl-3- (trifluoromethyl) azetidin-3-yl) oxy) ethyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-058 (10 mg, white solid), yield: 71%.
MS m/z(ESI):349[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.30(br,2H),7.37(d,J=2.8Hz,1H),6.34(d,J=2.8Hz,1H),4.57(t,J=5.2Hz,2H),4.00(t,J=5.1Hz,2H),3.41(d,J=9.6Hz,2H),2.86(d,J=9.1Hz,2H),2.06(s,3H).
Example 59
1- (2- ((1-methylpyrrolidin-3-yl) oxy) ethyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of 3-hydroxy-3-methylpyrrolidine-1-carboxylic acid tert-butyl ester
3-Oxopyrrolidine-1-carboxylic acid tert-butyl ester Cpd-059A (5.0 g,27.0 mmol) was dissolved in dry diethyl ether (100 mL), cooled to 0deg.C, and methyl magnesium bromide (6.4 g,5.4 mmol) was added dropwise thereto for reaction at room temperature for 1 hour. After the reaction was completed, it was quenched with saturated aqueous ammonium chloride (50 mL), extracted with ethyl acetate (3×50 mL), and the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and rotary distilled to give 3-hydroxy-3-methylpyrrolidine-1-carboxylic acid tert-butyl ester Cpd-059B (5.0 g, light brown oil), yield: 83%.
1 H NMR(400MHz,DMSO-d6)δ4.71(s,1H),3.32-3.26(m,2H),3.16(d,J=10.9Hz,1H),3.04(t,J=11.4Hz,1H),1.72(t,J=9.4Hz,2H),1.39(s,9H),1.24(d,J=2.5Hz,3H).
Second step
Preparation of 3- (2- (t-butyldimethylsilyloxy) ethoxy) -3-methylpyrrolidine-1-carboxylic acid tert-butyl ester
3-hydroxy-3-methylpyrrolidine-1-carboxylic acid tert-butyl ester Cpd-059B (5.0 g,24.8 mmol) was dissolved in anhydrous N, N-dimethylformamide (50 mL), cooled to 0℃sodium hydrogen (1.2 g,3.8 mmol) was carefully added, reacted at room temperature for 10 min, (2-bromoethoxy) (tert-butyl) dimethylsilane (8.9 g,37.2 mmol) was added, then the reaction was continued at room temperature for 2 h, after completion of the reaction quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate (100 mL. Times.3), the organic phase was concentrated by dryness, and the resulting residue was isolated and purified using a silica gel column (petroleum ether/ethyl acetate=10/1) to give 3- (2- (tert-butyldimethylsilyloxy) ethoxy) -3-methylpyrrolidine-1-carboxylic acid tert-butyl ester Cpd-059C (700 mg, colorless oil), yield: 7%.
1 H NMR(400MHz,CDCl3)δ3.70(t,J=5.6Hz,2H),3.50-3.36(m,5H),3.12(d,J=11.5Hz,1H),2.08-2.03(m,1H),1.73-1.68(m,1H),1.45(s,9H),1.29(s,2H),0.89(s,9H),0.06(s,6H).
Third step
Preparation of 3- (2-hydroxyethoxy) -3-methylpyrrolidine-1-carboxylic acid tert-butyl ester
3- (2- (t-Butyldimethylsilanyloxy) ethoxy) -3-methylpyrrolidine-1-carboxylic acid tert-butyl Cpd-059C (700 mg,1.9 mmol) was dissolved in tetrahydrofuran (10 mL), then tetrabutylammonium fluoride in tetrahydrofuran (1M, 6mL,6 mmol) was added, the reaction was allowed to react at room temperature for 2 hours, after completion of the reaction, quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate (50 mL. Times.3), and the organic phase was concentrated by dryness, and the obtained residue was isolated and purified by silica gel column (petroleum ether/ethyl acetate=4/1) to give 3- (2-hydroxyethoxy) -3-methylpyrrolidine-1-carboxylic acid tert-butyl Cpd-059D (300 mg, yellow oil), yield: 60%.
1 H NMR(400MHz,DMSO-d6)δ4.52(s,1H),3.43(s,2H),3.37-3.24(m,5H),3.05(t,J=10.6Hz,1H),2.01-1.98(m,1H),1.68(tt,J=13.2,9.1Hz,1H),1.39(s,9H),1.25(s,3H).
Fourth step
Preparation of 3-methyl-3- (2-carbonylethoxy) pyrrolidine-1-carboxylic acid tert-butyl ester
Oxalyl chloride (414 mg,3.3 mmol) was dissolved in dry dichloromethane (10 mL) and dry dimethyl sulfoxide (510 mg,6.5 mmol) dissolved in dichloromethane was added thereto under nitrogen protection at-55deg.C. After stirring for 10 minutes, 3- (2-hydroxyethoxy) -3-methylpyrrolidine-1-carboxylic acid tert-butyl ester Cpd-059D (200 mg,0.8 mmol) in dichloromethane was added thereto. After the reaction solution was stirred at-55℃for 30 minutes, triethylamine (660 mg,6.5 mmol) was added thereto. The reaction solution was stirred and returned to room temperature. After the reaction was completed, the mixture was washed with water, and the organic phase was dried over sodium sulfate and concentrated to give crude 3-methyl-3- (2-carbonylethoxy) pyrrolidine-1-carboxylic acid tert-butyl ester Cpd-059E (200 mg, yellow oil). The crude product is directly used for the next reaction without further treatment.
Fifth step
Preparation of ethyl 3- ((2- ((1- (tert-butoxycarbonyl) -3-methylpyrrolidin-3-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate
3-methyl-3- (2-carboethoxy) pyrrolidine-1-carboxylic acid tert-butyl ester Cpd-059E (200 mg,0.8 mmol) was dissolved in methanol (4 mL) and ethyl 3-amino-1H-pyrrole-2-carboxylate (139 mg,0.9 mmol) and glacial acetic acid (1 drop) were added thereto. The reaction mixture was reacted at 25℃for 1 hour. Sodium cyanoborohydride (210 mg,3.3 mmol) was added to the reaction solution to continue the reaction for 16 hours. After the reaction was completed, methanol was removed by rotary evaporation, and the resulting residue was separated and purified by silica gel column (petroleum ether/ethyl acetate=1/1) to give ethyl 3- ((2- ((1- (t-butoxycarbonyl) -3-methylpyrrolidin-3-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-059F (65 mg, yellow oil), yield: 9%.
MS m/z(ESI):382[M+1] + .
Sixth step
Preparation of ethyl 3- (1- (2- ((1- (tert-butoxycarbonyl) -3-methylpyrrolidin-3-yl) oxy) ethyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylate
Ethyl 3- ((2- ((1- (tert-butoxycarbonyl) -3-methylpyrrolidin-3-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate 108F (65 mg,0.2 mmol) was dissolved in dichloromethane (2 mL), and ethyl isothiocyanate (46 mg,0.4 mmol) was added thereto for reaction at 25℃for 2 hours. After the reaction, dichloromethane was distilled off. The resulting residue was extracted with ethyl acetate (15 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give crude 3- (1- (2- ((1- (tert-butoxycarbonyl) -3-methylpyrrolidin-3-yl) oxy) ethyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylate preparation Cpd-059G (80 mg, yellow oil), yield: 73%.
MS m/z(ESI):513[M+1] + .
Seventh step
Preparation of 3-methyl-3- (2- (4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) ethoxy) pyrrolidine-1-carboxylic acid tert-butyl ester
Preparation of ethyl 3- (1- (2- ((1- (tert-butoxycarbonyl) -3-methylpyrrolidin-3-yl) oxy) ethyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylate Cpd-059G (80 mg,0.2 mmol) was dissolved in methanol (2 mL) and cesium carbonate (102 mg,0.3 mmol) was added thereto. The reaction solution was heated to 65℃and reacted for 6 hours. After the completion of the reaction, methylene chloride (10 mL) was added, followed by washing with water (5 mL) and saturated brine (5 mL), drying over anhydrous sodium sulfate, and concentrating to obtain tert-butyl 3-methyl-3- (2- (4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) ethoxy) pyrrolidine-1-carboxylate Cpd-059H (70 mg, yellow oil), yield: 90%.
MS m/z(ESI):395[M+1] + .
Eighth step
Preparation of 1- (2- ((3-methylpyrrolidin-3-yl) oxy) ethyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
3-methyl-3- (2- (4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) ethoxy) pyrrolidine-1-carboxylic acid tert-butyl ester Cpd-059H (70 mg,0.2 mmol) was dissolved in methanol (1 mL), and 4N methanolic hydrochloride solution (1 mL) was added thereto and reacted at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated and neutralized with aqueous sodium bicarbonate, then extracted with ethyl acetate, and the organic phase was concentrated, and the residue was purified by reverse phase preparative column to give 1- (2- ((3-methylpyrrolidin-3-yl) oxy) ethyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-059 (32 mg, white solid), yield: 40%.
MS m/z(ESI):295[M+1] + 。
1 H NMR(400MHz,MeOD)δ8.53(s,1H),7.31(s,1H),6.32(s,1H),4.69-4.59(m,2H),3.90(d,J=4.4Hz,2H),3.39-3.34(m,1H),2.99(d,J=12.2Hz,1H),2.20(dd,J=13.3,6.8Hz,1H),1.83(dd,J=23.6,10.1Hz,1H),1.32(s,3H).
Example 60
1- (2- ((1, 3-dimethylpyrrolidin-3-yl) oxy) ethyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
1- (2- ((3-methylpyrrolidin-3-yl) oxy) ethyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-059 (30 mg,0.09 mmol) was dissolved in methanol (2 mL) and saturated sodium bicarbonate (0.5 mL), paraformaldehyde (6 mg,0.18 mmol) was added and reacted at room temperature for 1 hour. Sodium cyanoborohydride (6 mg,0.18 mmol) was added and the reaction was carried out at room temperature for 16 hours. The reaction solution was purified by reverse phase preparative column to give 1- (2- ((1, 3-dimethylpyrrolidin-3-yl) oxy) ethyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-060 (2.17 mg, white solid), yield: 7%.
MS m/z(ESI):309[M+1] + .
1 H NMR(400MHz,MeOD)δ7.32(d,J=2.4Hz,1H),6.33(d,J=2.5Hz,1H),4.65(dd,J=9.4,4.9Hz,2H),3.92(dd,J=10.1,5.1Hz,2H),3.13(s,2H),2.82(s,3H),2.23(s,1H),1.97(s,1H),1.33(s,3H).
Example 61
2-thio-1- (2- ((1- (trifluoromethyl) cyclopentyl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrole [3,2-d ] pyrimidin-4-one
First step
Preparation of 1- (trifluoromethyl) cyclopentan-1-ol
Cyclopentanone Cpd-061A (2.0 g,23.8 mmol), trifluoromethyl trimethylsilane (5.1 g,35.7 mmol) and tetrabutylammonium fluoride (6.2 g,23.8 mmol) were dissolved in dry tetrahydrofuran (50 mL). The reaction was allowed to react overnight at room temperature. To the reaction mixture was added saturated brine (50 mL), followed by extraction with ethyl acetate (50 mL. Times.2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated and purified by separation (petroleum ether/ethyl acetate=5/1) to give 1- (trifluoromethyl) cyclopentan-1-ol Cpd-061B (1.5 g, white solid), yield: 42%.
Second step
Preparation of ethyl 2- ((1- (trifluoromethyl) cyclopentyl) oxy) acetate
1- (trifluoromethyl) cyclopentan-1-ol Cpd-061B (1.5 g,9.7 mmol) was dissolved in N, N-dimethylformamide (5 mL), the reaction was cooled to 0deg.C in an ice bath, sodium hydride (350 mg,14.6 mmol) was added thereto and stirred for 30 min, followed by ethyl bromoacetate (1.8 g,10.7 mmol). The reaction mixture was reacted at 25℃for 12 hours. After the completion of the reaction, the reaction mixture was washed with saturated brine (50 mL. Times.5). The organic phase was dried over anhydrous sodium sulfate, concentrated and purified by silica gel column (petroleum ether/ethyl acetate=8/1) to give ethyl 2- ((1- (trifluoromethyl) cyclopentyl) oxy) acetate Cpd-061C (1.1 g, yellow liquid), yield: 47%. The crude product was used directly in the next step without further purification.
Third step
Preparation of 2- ((1- (trifluoromethyl) cyclopentyl) oxy) ethane-1-ol
Ethyl 2- ((1- (trifluoromethyl) cyclopentyl) oxy) acetate Cpd-061C (500 mg,2.1 mmol) was dissolved in tetrahydrofuran (5 mL) and a suspension of lithium aluminum hydride in tetrahydrofuran (4.2 mL,4.2mmol, 1M) was added thereto, and the reaction was stirred at 25℃for 30 minutes. After the reaction was completed, 15% aqueous sodium hydroxide solution (2 mL) was added and stirred for 10 minutes, a white solid was precipitated, the pH was adjusted to 7 with dilute hydrochloric acid, a small amount of anhydrous sodium sulfate was added, stirred for 10 minutes, suction filtration was performed, and the filtrate was dried by spin to give crude 2- ((1- (trifluoromethyl) cyclopentyl) oxy) ethane-1-ol Cpd-061D (200 mg, colorless liquid), yield: 49%. The crude product was used directly in the next step without further purification.
Fourth step
Preparation of 2- ((1- (trifluoromethyl) cyclopentyl) oxy) acetaldehyde
Oxalyl chloride (192 mg,1.5 mmol) was dissolved in dry dichloromethane (4 mL), cooled to-60℃under nitrogen, dimethyl sulfoxide (236 mg,3.0 mmol) was added and stirred for 15 min. 2- ((1- (trifluoromethyl) cyclopentyl) oxy) ethane-1-ol Cpd-061D (200 mg,1.0 mmol) was dissolved in dry dichloromethane (1 mL) and added dropwise to the reaction system, the temperature was controlled no more than-55deg.C throughout the reaction for 30 minutes. Triethylamine (459 mg,4.5 mmol) was added thereto and stirred for 10 minutes. After the reaction was completed, the organic phase was dried over anhydrous sodium sulfate and distilled off to give 2- ((1- (trifluoromethyl) cyclopentyl) oxy) acetaldehyde Cpd-061E (150 mg, colorless liquid), yield: 75%. The crude product was used directly in the next step without further purification.
Fifth step
Preparation of 3- ((2- ((1- (trifluoromethyl) cyclopentyl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester
2- ((1- (trifluoromethyl) cyclopentyl) oxy) acetaldehyde Cpd-061E (150 mg,0.76 mmol) was dissolved in methanol (2 mL) followed by the sequential addition of 3-amino-1H-pyrrole-2-carboxylic acid ethyl ester (117 mg,0.76 mmol) and acetic acid (0.5 mL). The reaction solution was stirred at room temperature for 4 hours, followed by addition of sodium cyanoborohydride (94 mg,1.52 mmol) and stirring was continued for 1 hour. After the reaction was completed, methanol was removed by rotary evaporation, the residue was dissolved with ethyl acetate (5 mL), saturated brine (10 ml×3), dried over anhydrous sodium sulfate and dried by rotary evaporation, and the crude product was separated and purified by silica gel column (petroleum ether/ethyl acetate=2/1) to give 3- ((2- ((1- (trifluoromethyl) cyclopentyl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-061F (90 mg, yellow liquid), yield: 35%.
Sixth step
Preparation of ethyl 3- (3- (ethoxycarbonyl) -1- (2- ((1- (trifluoromethyl) cyclopentyl) oxy) ethyl) thioureido) -1H-pyrrole-2-carboxylate
3- ((2- ((1- (trifluoromethyl) cyclopentyl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-061F (90 mg,0.27 mmol) was dissolved in dichloromethane (4 mL), and ethoxycarbonyl isothiocyanate (42 mg,0.32 mmol) was added and the reaction solution reacted at room temperature for 30 minutes. After the reaction, rotary evaporation gave crude 3- (3- (ethoxycarbonyl) -1- (2- ((1- (trifluoromethyl) cyclopentyl) oxy) ethyl) thioureido) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-061G (80 mg, yellow liquid), yield: 64%. The crude product was used directly in the next step without further treatment.
MS m/z(ESI):466[M+1] + .
Seventh step
Preparation of 2-thio-1- (2- ((1- (trifluoromethyl) cyclopentyl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
3- (3- (ethoxycarbonyl) -1- (2- ((1- (trifluoromethyl) cyclopentyl) oxy) ethyl) thioureido) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-061G (80 mg,0.17 mmol) was dissolved in anhydrous methanol (4 mL) followed by cesium carbonate (112 mg,0.34 mmol). The reaction was warmed to 65 ℃ and stirred for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature and dried by spin-drying, and the crude product was purified over a large plate (petroleum ether/ethyl acetate=1/2) to give 2-thio-1- (2- ((1- (trifluoromethyl) cyclopentyl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-061 (50 mg, yellow oil), yield: 84%.
MS m/z(ESI):348[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.31(s,1H),12.24(s,1H),7.35(d,J=2.9Hz,1H),6.28(d,J=2.9Hz,1H),4.51(t,J=5.5Hz,2H),3.93(t,J=5.3Hz,2H),1.72(t,J=6.3Hz,4H),1.59-1.46(m,2H),1.40-1.30(m,2H).
Example 62
2-thio-1- (2- ((1- (trifluoromethyl) cyclohexyl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of 1- (trifluoromethyl) cyclohexanol
Cyclohexanone Cpd-062A (2.0 g,20 mmol) was dissolved in tetrahydrofuran (20 mL) and (trifluoromethyl) trimethylsilane (5.8 g,40 mmol) and tetrabutylammonium fluoride (2.6 g,10 mmol) were added at 0deg.C. The reaction solution was stirred at room temperature for 2 hours. After the completion of the spot plate monitoring reaction, water quenching was added, ethyl acetate extraction was performed, the organic phase was dried over saturated brine, anhydrous sodium sulfate and spin-dried, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate=4/1) to give 1- (trifluoromethyl) cyclohexanol Cpd-062B (675 mg, colorless oil), yield: 18%.
1 H NMR(400MHz,DMSO-d6)δ5.58(s,1H),1.66-1.27(m,10H).
Second step
Preparation of ethyl 2- ((1- (trifluoromethyl) cyclohexyl) oxy) acetate
1- (trifluoromethyl) cyclohexanol Cpd-062B (500 mg,2.9 mmol) was dissolved in dry N, N-dimethylformamide (10 mL), sodium hydrogen (143 mg,3.5 mmol) was added in portions at 0deg.C, reacted at room temperature for 1 hour, then ethyl bromoacetate (520 mg,3.1 mmol) was added slowly at 0deg.C, and stirred at room temperature for 4 hours. The reaction was monitored by spotting, quenching with water, extraction with ethyl acetate, washing the organic phase with water, saturated brine, drying over anhydrous sodium sulfate, and spin-drying, and purifying the crude product by column chromatography (petroleum ether/ethyl acetate=10/1) to give 2- ((1- (trifluoromethyl) cyclohexyl) oxy) ethyl acetate Cpd-062C (370 mg, colorless oil), yield: 49%.
1 H NMR(400MHz,CDCl 3 )δ4.23(q,J=7.2Hz,2H),4.18(s,2H),2.04-1.98(m,2H),1.75-1.48(m,8H),1.31(t,J=7.2Hz,3H).
Third step
Preparation of 2- ((1- (trifluoromethyl) cyclohexyl) oxy) ethane-1-ol
Ethyl 2- ((1- (trifluoromethyl) cyclohexyl) oxy) acetate Cpd-062C (370 mg,1.4 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to 0℃and a suspension of lithium aluminum hydride in tetrahydrofuran (1.4 mL,1.4mmol, 1M) was slowly added dropwise thereto and stirred at room temperature for 1 hour. After the reaction was completed, water (0.5 mL) was added, quenched with aqueous sodium hydroxide (0.5 mL), stirred at room temperature for 15 minutes, dried over anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried to give crude 2- ((1- (trifluoromethyl) cyclohexyl) oxy) ethane-1-ol Cpd-062D (250 mg, colorless oil), yield: 81%. The product was used directly in the next step without further treatment.
Fourth step
Preparation of 2- ((1- (trifluoromethyl) cyclohexyl) oxy) acetaldehyde
Oxalyl chloride (76 mg,0.6 mmol) was dissolved in dry dichloromethane (5 mL). Cooling to-65deg.C, slowly adding dimethyl sulfoxide (78 mg,1.0 mmol) in dichloromethane (0.5 mL), controlling temperature below-60deg.C, and stirring at-65deg.C for 30 min. A solution of 2- ((1- (trifluoromethyl) cyclohexyl) oxy) ethan-1-ol Cpd-062D (100 mg,0.5 mmol) in dichloromethane (0.5 mL) was added and maintained at-65℃for 2 hours. Finally, triethylamine (151 mg,1.5 mmol) was added thereto and the temperature was slowly raised to 0℃naturally, and water (10 mL) was added thereto, and the organic phase was separated, washed with saturated brine and dried over anhydrous sodium sulfate to obtain 6mL of a methylene chloride solution containing 2- ((1- (trifluoromethyl) cyclohexyl) oxy) acetaldehyde Cpd-062E. The solution was used directly in the next step without further purification.
Fifth step
Preparation of 3- ((2- ((1- (trifluoromethyl) cyclohexyl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester
Ethyl 3-amino-1H-pyrrole-2-carboxylate (77 mg,0.5 mmol) was dissolved in methanol (10 mL), acetic acid (30 mg,0.5 mmol) and a dichloromethane solution (6 mL,0.5 mmol) of 2- ((1- (trifluoromethyl) cyclohexyl) oxy) acetaldehyde Cpd-062E were added sequentially, and stirred at room temperature for 0.5 hours. Sodium cyanoborohydride (31 mg,0.5 mmol) was added in portions and stirred at room temperature for 16 hours. After the reaction was completed, quenched with water (5 mL), extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated in vacuo to give a crude product, which was purified by column chromatography (petroleum ether/ethyl acetate=3/1) to give 3- ((2- ((1- (trifluoromethyl) cyclohexyl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-062F (80 mg, light brown oil), yield: 46%.
MS m/z(ESI):349[M+1] + .
Sixth step
Preparation of ethyl 3- (3- (ethoxycarbonyl) -1- (2- ((1- (trifluoromethyl) cyclohexyl) oxy) ethyl) thioureido) -1H-pyrrole-2-carboxylate
3- ((2- ((1- (trifluoromethyl) cyclohexyl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-062F (80 mg,0.2 mmol) was dissolved in dichloromethane (10 mL), cooled to 0℃and ethyl isothiocyanato (39 mg,0.3 mmol) was added thereto and stirred at room temperature for 1 hour. After the completion of the reaction, the reaction mixture was washed once with water (5 mL), the organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was separated and purified by silica gel column (petroleum ether/ethyl acetate=3/1) to give 3- (3- (ethoxycarbonyl) -1- (2- ((1- (trifluoromethyl) cyclohexyl) oxy) ethyl) thioureido) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-062G (85 mg, light brown oil), yield: 77%.
Seventh step
Preparation of 2-thio-1- (2- ((1- (trifluoromethyl) cyclohexyl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
3- (3- (ethoxycarbonyl) -1- (2- ((1- (trifluoromethyl) cyclohexyl) oxy) ethyl) thioureido) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-062G (50 mg,0.1 mmol) was dissolved in methanol (2 mL), cesium carbonate (98 mg,0.3 mmol) was added thereto, and the reaction mixture was heated to 65℃for 3 hours. The reaction solution was cooled to room temperature, a saturated aqueous ammonium chloride solution (5 mL) was added, extraction was performed with ethyl acetate (10 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was isolated by preparative silica gel plate to give 2-thio-1- (2- ((1- (trifluoromethyl) cyclohexyl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-062 (10 mg, white solid), yield: 26%.
MS m/z(ESI):362[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.32(s,1H),12.22(s,1H),7.35(d,J=2.8Hz,1H),6.29(t,J=2.8Hz,1H),4.57(t,J=5.2Hz,2H),3.95(t,J=5.2Hz,2H),1.76(d,J=12.8Hz,2H),1.45-1.30(m,5H),1.15-1.00(m,3H).
Example 63
2-thio-1- (2- ((3- (trifluoromethyl) tetrahydrofuran-3-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of 3- (trifluoromethyl) tetrahydrofuran-3-ol
Dihydro-3 (2H) -furanone Cpd-063A (2.0 g,23.2 mmol), trifluoromethyl trimethylsilane (6.6 g,46.5 mmol) and tetrabutylammonium fluoride (12.1 g,46.5 mmol) were dissolved in dry tetrahydrofuran (20 mL). The reaction was allowed to react overnight at room temperature. To the reaction solution was added saturated brine (50 mL), followed by extraction with ethyl acetate (50 ml×2), and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by separation (petroleum ether/ethyl acetate=5/1) to give 3- (trifluoromethyl) tetrahydrofuran-3-ol Cpd-063 (800 mg, white solid), yield: 20%.
1 H NMR(400MHz,DMSO-d6)δ6.41(s,1H),3.94-3.81(m,3H),3.63(d,J=9.9Hz,1H),2.05-1.90(m,2H).
Second step
Preparation of ethyl 2- ((3- (trifluoromethyl) tetrahydrofuran-3-yl) oxy) acetate
3- (trifluoromethyl) tetrahydrofuran-3-ol Cpd-063B (800 mg,5.1 mmol) was dissolved in N, N-dimethylformamide (5 mL), cooled to 0℃and then sodium hydride (185 mg,7.7 mmol) was added thereto and stirred for 30 minutes. Ethyl bromoacetate (1.1 g,5.6 mmol) was added to the reaction, and the reaction mixture was stirred at 25℃for 12 hours. After the reaction was completed, the reaction solution was washed with saturated brine (50 ml×5), the organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was separated and purified by a silica gel column (petroleum ether/ethyl acetate=8/1) to give ethyl 2- ((3- (trifluoromethyl) tetrahydrofuran-3-yl) oxy) acetate Cpd-063C (600 mg, yellow liquid), yield: 48%.
Third step
Preparation of 2- ((3- (trifluoromethyl) tetrahydrofuran-3-yl) oxy) ethan-1-ol
Ethyl 2- ((3- (trifluoromethyl) tetrahydrofuran-3-yl) oxy) acetate Cpd-063C (600 mg,2.5 mmol) was dissolved in tetrahydrofuran (5 mL) and a suspension of lithium aluminum hydride in tetrahydrofuran (5.0 mL,5.0mmol, 1M) was added thereto. The reaction solution was reacted at 25℃for 30 minutes. After the reaction, 15% aqueous sodium hydroxide (2 mL) was added and stirred for 10 minutes, the pH was adjusted to 7 with dilute hydrochloric acid, a small amount of anhydrous sodium sulfate was added, stirred for 10 minutes, and suction filtration was performed. The filtrate was dried to give crude 2- ((3- (trifluoromethyl) tetrahydrofuran-3-yl) oxy) ethan-1-ol Cpd-063D (180 mg, yellow liquid), yield: 36%. The crude product was used directly in the next step without further purification.
Fourth step
Preparation of 2- ((3- (trifluoromethyl) tetrahydrofuran-3-yl) oxy) acetaldehyde
Oxalyl chloride (170 mg,1.4 mmol) was dissolved in dry dichloromethane (4 mL), cooled to-60℃under nitrogen, dimethyl sulfoxide (210 mg,2.7 mmol) was added, and stirred for 15 minutes. 2- ((3- (trifluoromethyl) tetrahydrofuran-3-yl) oxy) ethan-1-ol Cpd-063D (180 mg,0.9 mmol) was dissolved in dry dichloromethane (1 mL) and added dropwise to the reaction system at a temperature no greater than-55deg.C throughout. After the reaction was carried out for 30 minutes, triethylamine (169 mg,4.1 mmol) was added to the reaction solution, and stirring was continued for 10 minutes. After the reaction was completed, the reaction solution was washed with saturated brine (10 ml×3), and the organic phase was dried over anhydrous sodium sulfate and spin-dried to give 2- ((3- (trifluoromethyl) tetrahydrofuran-3-yl) oxy) acetaldehyde Cpd-063E (150 mg, white liquid), yield: 84%. The crude product was used directly in the next step without further purification.
Fifth step
Preparation of ethyl 3- ((2- ((3- (trifluoromethyl) tetrahydrofuran-3-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate
2- ((3- (trifluoromethyl) tetrahydrofuran-3-yl) oxy) acetaldehyde Cpd-063E (150 mg,0.75 mmol) was dissolved in methanol (2 mL) followed by the sequential addition of ethyl 3-amino-1H-pyrrole-2-carboxylate (115 mg,0.76 mmol) and acetic acid (0.5 mL). After the reaction mixture was reacted for 4 hours, sodium cyanoborohydride (93 mg,1.47 mmol) was added thereto, and the reaction was continued for 1 hour. After the reaction was completed, methanol was removed by rotary evaporation, the residue was dissolved with ethyl acetate (5 mL), saturated brine (10 ml×3), and the organic phase was dried over anhydrous sodium sulfate, and the obtained crude product was separated and purified by silica gel column (petroleum ether/ethyl acetate=2/1) to give 3- ((2- ((3- (trifluoromethyl) tetrahydrofuran-3-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-063F (60 mg, yellow liquid), yield: 24%.
Sixth step
Preparation of ethyl 3- (3- (ethoxycarbonyl) -1- (2- ((3- (trifluoromethyl) tetrahydrofuran-3-yl) oxy) ethyl) thioureido) -1H-pyrrole-2-carboxylate
3- ((2- ((3- (trifluoromethyl) tetrahydrofuran-3-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-063F (60 mg,0.17 mmol) was dissolved in dichloromethane (3 mL), and ethoxycarbonyl isothiocyanate (30 mg,0.21 mmol) was added and the reaction mixture was reacted at room temperature for 30 minutes. After the reaction was completed, the crude 3- (3- (ethoxycarbonyl) -1- (2- ((3- (trifluoromethyl) tetrahydrofuran-3-yl) oxy) ethyl) thioureido) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-063G (60 mg, yellow liquid) was obtained by rotary evaporation, yield: 75%. The crude product was used directly in the next step without further purification.
MS m/z(ESI):468[M+1] + .
Seventh step
Preparation of 2-thio-1- (2- ((3- (trifluoromethyl) tetrahydrofuran-3-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
3- (3- (ethoxycarbonyl) -1- (2- ((3- (trifluoromethyl) tetrahydrofuran-3-yl) oxy) ethyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-063G (60 mg,0.13 mmol) was dissolved in anhydrous methanol (2 mL). Cesium carbonate (85 mg,0.26 mmol) was added. The reaction was warmed to 65℃and allowed to react for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature and dried by spin-drying, and the crude product was purified over a large plate (petroleum ether/ethyl acetate=1/2) to give 2-thio-1- (2- ((3- (trifluoromethyl) tetrahydrofuran-3-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-063 (40 mg, white solid), yield: 88%.
MS m/z(ESI):350[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.35(s,1H),12.24(s,1H),7.35(d,J=2.7Hz,1H),6.30(d,J=2.8Hz,1H),4.54(t,J=5.6Hz,2H),4.05-3.93(m,2H),3.79(d,J=10.6Hz,1H),3.77-3.68(m,2H),3.61(q,J=7.6Hz,1H),2.11-2.04(m,2H).
Example 64
1- (2, 2-difluorocyclopropyloxy) ethyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of 2- (ethyleneoxy) ethyl benzoate
2- (ethyleneoxy) ethan-1-ol Cpd-064A (5 g,57 mmol) was dissolved in dichloromethane (250 mL) and triethylamine (20 mL,142 mmol) was added. Benzoyl chloride (10 mL,85 mmol) was added dropwise at room temperature. The reaction solution was reacted at room temperature for 6 hours. The reaction mixture was cooled to 0℃and 1M hydrochloric acid (50 mL) was added thereto, followed by extraction with methylene chloride (200 mL. Times.3). The organic phases were combined and washed with saturated sodium bicarbonate (75 mL) and saturated brine (75 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was separated and purified by silica gel column (petroleum ether/ethyl acetate=10/1) to give benzoic acid (2- (ethyleneoxy) ethyl) ester Cpd-064B (7.0 g, colorless oil), yield: 64%.
1 H NMR(400MHz,CDCl 3 )δ8.07(d,J=7.2Hz,2H),7.56(t,J=7.4Hz,1H),7.44(t,J=7.7Hz,2H),6.52(dd,J=14.3,6.8Hz,1H),4.57-4.55(m,2H),4.24(dd,J=14.3,2.2Hz,1H),4.07(dd,J=6.8,2.3Hz,1H),4.04-4.01(m,2H).
Second step
Preparation of 2- (2, 2-difluorocyclopropyloxy) ethyl benzoate
(2- (ethyleneoxy) ethyl) benzoate Cpd-064B (1.0 g,5.2 mmol) tetrahydrofuran (10 mL) was added thereto (trifluoromethyl) trimethylsilane (1.5 g,10.4 mmol) and sodium iodide (1.6 g,10.4 mmol) and the reaction solution was stirred under nitrogen at 65℃for 4 hours. Then, water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL. Times.3), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was isolated and purified by silica gel column (petroleum ether/ethyl acetate=10/1) to give 2- (2, 2-difluorocyclopropyloxy) ethyl benzoate Cpd-064C (1.2 g, colorless oil), yield: 94%.
1 H NMR(400MHz,DMSO-d6)δ8.06(d,J=7.1Hz,2H),7.57(t,J=7.4Hz,1H),7.45(t,J=7.7Hz,2H),4.51-4.49(m,2H),3.94(t,J=4.6Hz,2H),3.76-3.70(m,1H),1.59-1.42(m,2H).
Third step
Preparation of 2- (2, 2-difluorocyclopropyloxy) ethane-1-ol
2- (2, 2-Difluorocyclopropoxy) ethyl benzoate Cpd-064C (1.0 g,4.1 mmol) was dissolved in methanol (10 mL), and 2N sodium hydroxide solution (10 mL) was added and the reaction solution was stirred at room temperature for 2 hours. Water (10 mL) was added for dilution, ethyl acetate (20 mL. Times.3) was extracted, dried over anhydrous sodium sulfate and concentrated to give 2- (2, 2-difluorocyclopropoxy) ethane-1-ol Cpd-064D (380 mg, colorless oil), yield: 61%.
1 H NMR(400MHz,DMSO-d6)δ4.72(s,1H),3.92-3.79(m,1H),3.60-3.46(m,4H),1.66(dtd,J=15.6,9.0,6.7Hz,1H),1.49(ddt,J=17.1,9.4,4.9Hz,1H).
Fourth step
Preparation of 2- (2, 2-difluorocyclopropyloxy) acetaldehyde
Oxalyl chloride (1.40 g,11.0 mmol) was dissolved in dry dichloromethane (10 mL) and dry dimethyl sulfoxide (1.72 g,22.0 mmol) dissolved in dichloromethane was added thereto under nitrogen protection at-55deg.C. After stirring for 10 minutes, 2- (2, 2-difluorocyclopropyloxy) ethane-1-ol Cpd-064D (380 mg,2.8 mmol) in methylene chloride was added thereto. After the reaction solution was stirred at-55℃for 30 minutes, triethylamine (2.23 g,22.0 mmol) was added thereto. The reaction mixture was stirred and brought to room temperature, washed with water, dried over sodium sulfate and concentrated to give crude 2- (2, 2-difluorocyclopropyloxy) acetaldehyde Cpd-064E (380 mg, yellow oil). The crude product is directly used for the next reaction without further treatment.
Fifth step
Preparation of 3- ((2- (2, 2-difluorocyclopropyloxy) ethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester
2- (2, 2-Difluorocyclopropoxy) acetaldehyde Cpd-064E (380 mg,2.80 mmol) was dissolved in methanol (4 mL) and 3-amino-1H-pyrrole-2-carboxylic acid ethyl ester (473 mg,3.07 mmol) and glacial acetic acid (2 drops) were added thereto. The reaction mixture was reacted at 25℃for 1 hour. Sodium cyanoborohydride (210 mg,3.35 mmol) was added to the reaction solution to continue the reaction for 16 hours. After the reaction was completed, methanol was removed by rotary evaporation, and the obtained residue was separated and purified by silica gel column (petroleum ether/ethyl acetate=1/1) to give 3- ((2- (2, 2-difluorocyclopropyloxy) ethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-064F (80 mg, yellow oil), yield: 9%.
MS m/z(ESI):275[M+1] + .
Sixth step
Preparation of 3- (1- (2, 2-difluorocyclopropyloxy) ethyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester
3- ((2- (2, 2-difluorocyclopropyloxy) ethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-064F (80 mg,0.29 mmol) was dissolved in dichloromethane (2 mL), and ethyl isothiocyanato (46 mg,0.35 mmol) was added thereto for reaction at 25℃for 2 hours. After the reaction, dichloromethane was distilled off. The resulting residue was extracted with ethyl acetate (15 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give crude 3- (1- (2, 2-difluorocyclopropyloxy) ethyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-064G (60 mg, yellow oil), yield: 100%.
MS m/z(ESI):406[M+1] + .
Seventh step
Preparation of 1- (2, 2-difluorocyclopropyloxy) ethyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
3- (1- (2, 2-difluorocyclopropyloxy) ethyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-064G (60 mg,0.15 mmol) was dissolved in methanol (2 mL), and cesium carbonate (96 mg,0.30 mmol) was added thereto. The reaction solution was heated to 65℃and reacted for 6 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and methanol was removed by rotary evaporation, and the resulting residue was purified in reverse phase to give 1- (2, 2-difluorocyclopropyloxy) ethyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-064 (6 mg, white solid), yield: 14%.
MS m/z(ESI):288[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.34(br,2H),8.48(s,1H),7.36(d,J=2.4Hz,1H),6.29(d,J=2.3Hz,1H),4.58(d,J=5.4Hz,2H),3.93(t,J=5.8Hz,3H),1.67(td,J=15.8,8.6Hz,1H),1.53-1.36(m,1H).
Example 65
1- (4-chloro-3- (difluoromethoxy) benzyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of 4-bromo-1-chloro-2- (difluoromethoxy) benzene
5-bromo-2-chlorophenol Cpd-065A (500 mg,2.41 mmol), sodium 2-chloro-2, 2-difluoroacetate (730 mg,4.82 mmol), cesium carbonate (1178 mg,3.61 mmol) and water (87 mg,4.82 mmol) were dissolved in N, N-dimethylformamide (5 mL), and heated at 100℃for 12 hours. After the reaction was completed, the reaction solution was diluted with 100mL of water, extracted twice with ethyl acetate (50 mL), the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was separated and purified by a silica gel column (petroleum ether/ethyl acetate=10/1) to give 4-bromo-1-chloro-2- (difluoromethoxy) benzene Cpd-065B (500 mg, colorless oil), yield: 80%.
1 H NMR(400MHz,DMSO-d6)δ7.64(d,J=1.7Hz,1H),7.58(d,J=8.6Hz,1H),7.50(dd,J=8.6,2.1Hz,1H),7.37(t,J=72.9Hz,1H).
Second step
Preparation of 4-chloro-3- (difluoromethoxy) benzaldehyde
4-bromo-1-chloro-2- (difluoromethoxy) benzene Cpd-065B (250 mg,0.97 mmol), dichlorodi-tert-butyl- (4-dimethylaminophenyl) palladium (II) (137 mg,0.19 mmol), triethylsilane (399mg, 3.40 mmol), N, N-diisopropylethylamine (188 mg,1.46 mmol) were dissolved in dimethyl sulfoxide (5 mL) and then heated at 90℃for 2 hours after three carbon monoxide balloon ventilation. After the completion of the reaction, the reaction mixture was diluted with 100mL of water, 100mL of ethyl acetate, filtered through celite, and the mixture was extracted and separated, and the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the concentrated crude product was purified by separation on a silica gel column (petroleum ether/ethyl acetate=10/1) to give 4-chloro-3- (difluoromethoxy) benzaldehyde Cpd-065C (170 mg, colorless oil), yield: 84%.
1 H NMR(400MHz,DMSO-d6)δ10.01(s,1H),7.98-7.75(m,3H),7.44(t,J=72.8Hz,1H).
Third step
Preparation of 3- ((4-chloro-3- (difluoromethoxy) benzyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester
4-chloro-3- (difluoromethoxy) benzaldehyde Cpd-065C (170 mg,0.82 mmol), ethyl 3-amino-1H-pyrrole-2-carboxylate (127 mg,0.82 mmol) and two drops of acetic acid were dissolved in methanol (5 mL) and stirred at room temperature for half an hour, followed by addition of sodium cyanoborohydride (319 mg,4.11 mmol) and stirring continued for half an hour. After the reaction was completed, the reaction solution was diluted with 100mL of water, 100mL of ethyl acetate was extracted, the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was separated and purified by a silica gel column (petroleum ether/ethyl acetate=4/1) to obtain 3- ((4-chloro-3- (difluoromethoxy) benzyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-065D (100 mg, colorless oil), yield: 35%.
1 H NMR(400MHz,DMSO-d6)δ10.78(s,1H),7.52(d,J=8.2Hz,1H),7.34(s,1H),7.24(t,J=73.2Hz,1H),7.23(s,1H),6.69(t,J=3.0Hz,1H),5.90(s,1H),5.54(t,J=2.4Hz,1H),4.31(d,J=6.4Hz,2H),4.20(q,J=7.1Hz,2H),1.27(t,J=7.1Hz,3H).
Fourth step
Preparation of ethyl 3- ((4-chloro-3- (difluoromethoxy) benzyl) ((((ethoxycarbonyl) amino) methylsulfonyl) amino) -1H-pyrrole-2-carboxylate
3- ((4-chloro-3- (difluoromethoxy) benzyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-065D (100 mg,0.29 mmol) was dissolved in dichloromethane (3 mL) followed by ethyl isothiocyanato (76 mg,0.58 mmol) and stirred at room temperature for half an hour. After the reaction was completed, the mixture was concentrated to give crude 3- ((4-chloro-3- (difluoromethoxy) benzyl) ((((ethoxycarbonyl) amino) methylsulfonyl)) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-065E (150 mg, colorless oil) which was used directly in the next step.
MS m/z(ESI):476[M+1] + .
Fifth step
Preparation of 1- (4-chloro-3- (difluoromethoxy) benzyl) -2-thio-3H, 5H-pyrrolo [3,2-d ] pyrimidin-4-one
3- ((4-chloro-3- (difluoromethoxy) benzyl) ((((ethoxycarbonyl) amino) methylsulfonyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-065E (150 mg,0.31 mmol) was dissolved in methanol (5 mL), cesium carbonate (513 mg,1.58 mmol) was added and heated at 60℃for 8 hours. After the completion of the reaction, the reaction mixture was concentrated, quenched with saturated aqueous ammonium chloride (100 mL), extracted twice with ethyl acetate (50 mL), the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the concentrated crude product was slurried with methanol to give 1- (4-chloro-3- (difluoromethoxy) benzyl) -2-thio-3 h,5 h-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-065 (40 mg, white solid), yield: 34%.
MS m/z(ESI):358[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.47(s,1H),12.37(s,1H),7.54(d,J=8.3Hz,1H),7.45(s,1H),7.32(d,J=2.3Hz,1H),7.24(t,J=73.2Hz,1H),7.17(d,J=8.3Hz,1H),6.19(d,J=2.7Hz,1H),5.71(s,2H).
Example 66
1- (4-chloro-3- ((methylamino) methyl) benzyl) -7-methyl-2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of (5-bromo-2-chlorobenzyl) carbamic acid tert-butyl ester
To a solution of (5-bromo-2-chlorophenyl) methylamine Cpd-066A (500 mg,2.27 mmol) in methylene chloride (10 mL) was added di-tert-butyl dicarbonate (594 mg,2.72 mmol) and triethylamine (459 mg,4.54 mmol). The reaction solution was stirred at 25℃for 3 hours. The reaction solution was cooled to room temperature, and the solvent was removed by rotary evaporation. After isolation and purification by flash column chromatography (petroleum ether/ethyl acetate=10/1), tert-butyl (5-bromo-2-chlorobenzyl) carbamate Cpd-066B (640 mg, white solid) was obtained, yield: 88%.
MS m/z(ESI):264(M-56+1).
Second step
Preparation of (5-bromo-2-chlorobenzyl) methyl carbamic acid tert-butyl ester
To a solution of tert-butyl (5-bromo-2-chlorobenzyl) carbamate Cpd-066B (50 mg,0.16 mmol) in DMF (1 mL) was added sodium hydrogen (7 mg,0.19mmol, 60%) and the reaction solution was stirred at 25 ℃ for 1 hour. Methyl iodide (27 mg,0.19 mmol) was then added to the solution, and the reaction solution was stirred overnight at 25 ℃. Then quenched with water (10 mL) and the residue extracted with ethyl acetate (15 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give tert-butyl (5-bromo-2-chlorobenzyl) methylcarbamate Cpd-066C (27 mg, white solid), yield: 52%.
MS m/z(ESI):278(M-56+1).
Third step
Preparation of (2-chloro-5-formylbenzyl) methyl carbamic acid tert-butyl ester
Tert-butyl (5-bromo-2-chlorobenzyl) methylcarbamate Cpd-066C (800 mg,2.34 mmol), pd (Amphos) Cl in a carbon monoxide atmosphere 2 (338 mg,0.48 mmol), triethylsilane (973 mg,8.37 mmol), DIPEA (463 mg,3.58 mmol) in DMSO (8 mL) were reacted at 90 ℃. Then quenched with water (10 mL) and the residue extracted with ethyl acetate (15 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated. Crude product was isolated and purified by flash column chromatography (petroleum ether/ethyl acetate=10/1) to give tert-butyl (2-chloro-5-formylbenzyl) methylcarbamate Cpd-066D (72 mg, white solid), yield: 52%.
MS m/z(ESI):228[M-56+1].
Fourth step
Preparation of 3- (3- (((tert-butoxycarbonyl) methylamino) methyl) -4-chlorobenzyl) amino) -4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester
Tert-butyl (2-chloro-5-formylbenzyl) methylcarbamate Cpd-066D (80 mg,0.28 mmol), ethyl 3-amino-4-methyl-1H-pyrrole-2-carboxylate (47 mg,0.28 mmol) in methanol (3 mL) was added acetic acid (17 mg,0.28 mmol), the mixture stirred for 1 hour, then sodium cyanoborohydride (18 mg,0.28 mmol) was added and the mixture stirred overnight. After the reaction was completed, the crude product was purified by preparative TLC (petroleum ether/ethyl acetate=5/1) to give 3- ((3- (((tert-butoxycarbonyl) methylamino) methyl) -4-chlorobenzyl) amino) -4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-066E (100 mg, colorless oil), yield: 82%.
MS m/z(ESI):436[M+1] + .
Fifth step
Preparation of ethyl 3- (1- (3- (((tert-butoxycarbonyl) methylamino) methyl) -4-chlorobenzyl) -3- (ethoxycarbonyl) thiourea) -4-methyl-1H-pyrrole-2-carboxylate
3- ((3- (((t-Butoxycarbonyl) methylamino) methyl) -4-chlorobenzyl) amino) -4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-066E (40 mg,0.09 mmol) was dissolved in dichloromethane (2 mL), ethyl isothiocyanato (14 mg,0.11 mmol) was added thereto under ice bath, and then stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was washed once with water (2 mL), and the organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was isolated and purified by preparative TLC (petroleum ether/ethyl acetate=3/1) to give ethyl 3- (1- (3- (((tert-butoxycarbonyl) methylamino) methyl) -4-chlorobenzyl) -3- (ethoxycarbonyl) thiourea) -4-methyl-1H-pyrrole-2-carboxylate Cpd-066F (50 mg, colorless oil), yield: 96%.
MS m/z(ESI):567[M+1] + .
Sixth step
Preparation of (2-chloro-5- ((7-methyl-4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) methyl) benzyl) methyl carbamic acid tert-butyl ester
To a solution of 3- (1- (3- (((tert-butoxycarbonyl) methylamino) methyl) -4-chlorobenzyl) -3- (ethoxycarbonyl) thiourea) -4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-066F (100 mg,0.18 mmol) in methanol (5 mL) was added cesium carbonate (172 mg,0.53 mmol) and the mixture was stirred at 60℃for 5 hours. After the completion of the reaction, the reaction solution was cooled to room temperature and quenched with water (5 mL), extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by preparative TLC (dichloromethane/methanol=20/1) to give tert-butyl (2-chloro-5- ((7-methyl-4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) methyl) benzyl) methylcarbamate Cpd-066G (70 mg, white solid), yield: 88%.
MS m/z(ESI):449[M+1] + .
Seventh step
Preparation of 1- (4-chloro-3- ((methylamino) methyl) benzyl) -7-methyl-2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
A solution of tert-butyl (2-chloro-5- ((7-methyl-4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) methyl) benzyl) methylcarbamate Cpd-066G (55 mg,0.12 mmol) in HCl in MeOH (4M, 2 mL) was stirred at 25℃for 12 hours. After the completion of the reaction, the reaction mixture was neutralized by adding saturated sodium hydrogencarbonate, extracted with a mixed solution (10/1) of methylene chloride and methanol, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by preparative TLC (dichloromethane/methanol=10/1) to give 1- (4-chloro-3- ((methylamino) methyl) benzyl) -7-methyl-2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-066 (12 mg, white solid), yield: 25%.
MS m/z(ESI):294[M+1] + .
HNMR: 1 H NMR(400MHz,DMSO-d6)δ12.21(br,1H),7.36(d,J=8.2Hz,1H),7.30(s,1H),7.12(s,1H),6.92(d,J=7.6Hz,1H),3.68(s,2H),2.23(s,3H),1.95(s,3H).
Example 67
1- (4-chloro-3- (methylamino) benzyl) -7-methyl-2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of (5-bromo-2-chlorophenyl) carbamic acid tert-butyl ester
5-bromo-2-chloroaniline Cpd-067A (2.0 g,9.7 mmol), di-tert-butyl dicarbonate (2.5 g,11.6 mmol), triethylamine (2.9 g,29.1 mmol) and 4-dimethylaminopyridine (1.2 g,9.7 mmol) were dissolved in dichloromethane (20 mL) and stirred at room temperature for two days. After the reaction was completed, the reaction solution was diluted with water (100 mL), dichloromethane (50 ml×2) was extracted, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was separated and purified by a silica gel column (petroleum ether/ethyl acetate=10/1) to obtain tert-butyl (5-bromo-2-chlorophenyl) carbamate Cpd-067B (2.9 g, white solid), yield: 98%.
1 H NMR(400MHz,CDCl 3 )δ8.41(d,J=1.8Hz,1H),7.18(d,J=8.5Hz,1H),7.08(dd,J=8.5,2.3Hz,1H),6.99(s,1H),1.54(s,9H).
Second step
Preparation of N- (5-bromo-2-chlorophenyl) -N-methylcarbamic acid tert-butyl ester
Tert-butyl (5-bromo-2-chlorophenyl) carbamate Cpd-067B (2.9 g,9.5 mmol) was dissolved in N, N-dimethylformamide (30 mL), sodium hydrogen (0.46 g,11.3 mmol) was added under ice-bath, and stirred under nitrogen for half an hour. Methyl iodide (1.75 g,12.3 mmol) was then added and stirring was continued for ten minutes in an ice bath after addition. After the reaction was completed, the reaction mixture was poured into an aqueous solution of ammonium chloride (200 mL) ice to quench, ethyl acetate (100 ml×2) was extracted, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was separated and purified by a silica gel column (petroleum ether/ethyl acetate=10/1) to obtain tert-butyl N- (5-bromo-2-chlorophenyl) -N-methylcarbamate Cpd-067C (3.0 g, white solid), yield: 99%.
MS m/z(ESI):266[M-56+1] + .
Third step
Preparation of N- (2-chloro-5-formylphenyl) -N-methylcarbamic acid tert-butyl ester
Tert-butyl N- (5-bromo-2-chlorophenyl) -N-methylcarbamate Cpd-067C (1.0 g,3.1 mmol), dichlorodi-tert-butyl- (4-dimethylaminophenyl) palladium (II) (0.2 g,0.31 mmol), triethylsilane (1.1 g,9.3 mmol) and N, N-diisopropylethylamine (0.6 g,4.6 mmol) were dissolved in anhydrous dimethyl sulfoxide (40 mL), and after the carbon monoxide balloon was replaced with gas four times, heated to 90℃and stirred for 12 hours. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (200 mL) and water (300 mL), celite was filtered, the aqueous phase was extracted with ethyl acetate (100 ml×2) after separating the filtrate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was separated and purified by a silica gel column (petroleum ether/ethyl acetate=10/1) to give N- (2-chloro-5-formylphenyl) -N-methylcarbamic acid tert-butyl ester Cpd-067D (0.5 g, colorless oil), yield: 61%.
1 H NMR(400MHz,DMSO-d6)δ9.99(s,1H),7.95(d,J=1.6Hz,1H),7.86(d,J=8.3Hz,1H),7.79(d,J=8.2Hz,1H),3.11(s,3H),1.52-1.25(m,9H).
Fourth step
Preparation of 3- ((3- ((tert-butoxycarbonyl) methylamino) -4-chlorobenzyl) amino) -4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester
Tert-butyl N- (2-chloro-5-formylphenyl) -N-methylcarbamate Cpd-067D (150 mg,0.56 mmol), ethyl 3-amino-4-methyl-1H-pyrrole-2-carboxylate (93 mg,0.56 mmol) and two drops of acetic acid were dissolved in methanol (3 mL), stirred at room temperature for half an hour, followed by addition of sodium cyanoborohydride (175 mg,2.78 mmol) and stirring at room temperature for a further 1 hour. After the reaction was completed, the reaction solution was diluted with water (100 mL), ethyl acetate (50 ml×2), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was separated and purified by silica gel column (petroleum ether/ethyl acetate=4/1) to give 3- ((3- ((t-butoxycarbonyl) methylamino) -4-chlorobenzyl) amino) -4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-067E (110 mg, colorless oil), yield: 47%.
MS m/z(ESI):422[M+1] + .
Fifth step
Preparation of 3- (1- (3- ((tert-butoxycarbonyl) methylamino) -4-chlorobenzyl) -3- (ethoxycarbonyl) thiourea) -4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester
3- ((3- ((tert-Butoxycarbonyl) methylamino) -4-chlorobenzyl) amino) -4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-067E (116 mg,0.27 mmol) and ethoxycarbonyl isothiocyanate (54 mg,0.41 mmol) were dissolved in dichloromethane (3 mL) and stirred at room temperature for half an hour. After the reaction was completed, the reaction solution was concentrated, and the obtained crude product was purified by silica gel column (petroleum ether/ethyl acetate=1/1) to give ethyl 3- (1- (3- ((t-butoxycarbonyl) methylamino) -4-chlorobenzyl) -3- (ethoxycarbonyl) thiourea) -4-methyl-1H-pyrrole-2-carboxylate Cpd-067F (133 mg, colorless oil), yield: 87%.
MS m/z(ESI):553[M+1] + .
Preparation of tert-butyl (2-chloro-5- ((7-methyl-4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) methyl) phenyl) methylcarbamate
3- (1- (3- ((tert-Butoxycarbonyl) methylamino) -4-chlorobenzyl) -3- (ethoxycarbonyl) thiourea) -4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-067F (130 mg,0.23 mmol) and cesium carbonate (383 mg,1.18 mmol) were dissolved in methanol (5 mL) followed by heating to 65℃under nitrogen and stirring for 5 hours. After the reaction was completed, the reaction mixture was concentrated, saturated aqueous ammonium chloride (50 mL) was dispersed, ethyl acetate (30 ml×2) was extracted, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the concentrated crude product was separated and purified by a silica gel column (petroleum ether/ethyl acetate=1/1) to give tert-butyl (2-chloro-5- ((7-methyl-4-oxo-2-thio-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) methyl) phenyl) methylcarbamate Cpd-067G (55 mg, white solid), yield: 54%.
MS m/z(ESI):379[M-56+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.38(s,1H),12.23(s,1H),7.48(d,J=8.3Hz,1H),7.40-6.78(m,3H),3.02(s,3H),1.94(s,3H),1.45(s,2H),1.28-1.04(m,9H).
Seventh step
Preparation of 1- (4-chloro-3- (methylamino) benzyl) -7-methyl-2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Tert-butyl (2-chloro-5- ((7-methyl-4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) methyl) phenyl) methylcarbamate Cpd-067G (25 mg,0.057 mmol) was dissolved in methanol hydrochloride (5 mL), heated to 30℃and stirred for half an hour. After the reaction was completed, the reaction mixture was concentrated, washed with aqueous sodium hydrogencarbonate, extracted with ethyl acetate, concentrated and dried to give 1- (4-chloro-3- (methylamino) benzyl) -7-methyl-2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-067 (18 mg, white solid), yield: 69%.
MS m/z(ESI):335[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.31(s,1H),12.20(s,1H),7.13(s,2H),6.44(s,1H),6.15(s,1H),5.26(br,2H),2.68(s,3H),1.99(s,3H).
Example 68
7-methyl-2-thioxo-1- (2- ((1, 1-trifluorobutan-2-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of ethyl 2- ((1, 1-trifluorobutan-2-yl) oxy) acetate
1, 1-trifluorobutan-2-ol Cpd-068A (400 mg,3.1 mmol) was dissolved in N, N-dimethylformamide (10 mL), sodium hydrogen (186 mg,4.6 mmol) was added under ice-bath and stirred for half an hour under nitrogen, followed by dropwise addition of ethyl bromoacetate (776 mg,4.6 mmol) under ice-bath and stirring continued for half an hour. After the reaction was completed, the reaction solution was poured into an aqueous glacial ammonium chloride solution (100 mL) to quench, ethyl acetate (50 ml×2) was extracted, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated at room temperature to give a crude product which was concentrated at room temperature using a silica gel column (petroleum ether/ethyl acetate=10/1) to give ethyl 2- ((1, 1-trifluorobutan-2-yl) oxy) acetate Cpd-068B (500 mg, colorless oil), yield: 75%.
1 H NMR(400MHz,DMSO-d6)δ4.39-4.27(m,2H),4.13(q,J=7.1Hz,2H),4.09-4.01(m,1H),1.75-1.56(m,2H),1.20(dd,J=9.5,4.7Hz,3H),1.00(t,J=7.4Hz,3H).
Second step
Preparation of 2- ((1, 1-trifluorobutan-2-yl) oxy) ethan-1-ol
Ethyl 2- ((1, 1-trifluorobutan-2-yl) oxy) acetate Cpd-068B (500 mg,2.3 mmol) was dissolved in tetrahydrofuran (5 mL), and a suspension of lithium aluminum tetrahydropalmide in tetrahydrofuran (3.0 mL,3.0mmol, 1M) was added dropwise under ice bath, and stirring was continued for half an hour after the completion of the addition. After the reaction was completed, the reaction solution was diluted with tetrahydrofuran (50 mL), aqueous sodium hydroxide solution (0.3 mL,2 m) was added dropwise under ice bath, stirred for ten minutes, followed by drying over anhydrous sodium sulfate, filtration through celite, and concentration of the filtrate to give 2- ((1, 1-trifluorobutan-2-yl) oxy) ethan-1-ol Cpd-068C (360 mg, colorless oil), yield: 89%.
1 H NMR(400MHz,DMSO-d6)δ4.67(t,J=5.3Hz,1H),3.95-3.84(m,1H),3.75-3.65(m,1H),3.65-3.55(m,1H),3.51(q,J=5.2Hz,2H),1.69-1.58(m,1H),1.57-1.46(m,1H),0.98(t,J=7.4Hz,3H).
Third step
Preparation of 2- ((1, 1-trifluorobutan-2-yl) oxy) acetaldehyde
Oxalyl chloride (220 mg,1.7 mmol) was dissolved in dichloromethane (7 mL) with anhydrous sodium sulfate (50 mg) under nitrogen and a solution of anhydrous dimethyl sulfoxide (203 mg,2.6 mmol) diluted with dichloromethane (1 mL) was added dropwise at-60 ℃. After 5 minutes, a solution of 2- ((1, 1-trifluorobutan-2-yl) oxy) ethan-1-ol Cpd-068C (150 mg,0.9 mmol) in dichloromethane (2 mL) was dropwise added at no more than-55deg.C. The mixture was stirred at the same temperature for half an hour, and then triethylamine (526 mg,5.2 mmol) was added dropwise at a temperature of not higher than-55℃and, after the completion of the addition, the mixture was stirred at room temperature for 10 minutes. After the reaction was completed, the reaction mixture was poured into water (100 mL), extracted with dichloromethane (50 ml×2), and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude 2- ((1, 1-trifluorobutan-2-yl) oxy) acetaldehyde Cpd-068D (180 mg, colorless oil), yield: 121%. The crude product was used directly in the next reaction without further purification.
Fourth step
Preparation of ethyl 4-methyl-3- ((2- ((1, 1-trifluorobutan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate
Ethyl 3-amino-4-methyl-1H-pyrrole-2-carboxylate (100 mg,0.59 mmol) and 2- ((1, 1-trifluorobutan-2-yl) oxy) acetaldehyde Cpd-068D (132 mg,0.77 mmol) were dissolved in methanol (10 mL), and two drops of glacial acetic acid were added dropwise under nitrogen and stirred at room temperature for half an hour, followed by sodium cyanoborohydride (112 mg,1.78 mmol) and stirred at room temperature for half an hour. After the reaction was completed, the reaction mixture was poured into water (100 mL), extracted with ethyl acetate (50 ml×2), and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude product, which was separated and purified by silica gel column (petroleum ether/ethyl acetate=4/1) to give 4-methyl-3- ((2- ((1, 1-trifluorobutan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-068E (100 mg, colorless oil), yield: 52%.
MS m/z(ESI):323[M+1] + .
Fifth step
Preparation of ethyl 3- (3- (ethoxycarbonyl) -1- (2- ((1, 1-trifluorobutan-2-yl) oxy) ethyl) thioureido) -4-methyl-1H-pyrrole-2-carboxylate
4-methyl-3- ((2- ((1, 1-trifluorobutan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-068E (80 mg,0.25 mmol) was dissolved in dichloromethane (3 mL) followed by dropwise addition of ethoxycarbonyl isothiocyanate (65 mg,0.50 mmol) at room temperature and stirring at room temperature for half an hour. After the reaction was completed, the mixture was concentrated to give crude 3- (3- (ethoxycarbonyl) -1- (2- ((1, 1-trifluorobutan-2-yl) oxy) ethyl) thioureido) -4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-068F (160 mg, colorless oil), yield: 142%. The crude product was used directly in the next step without further purification.
MS m/z(ESI):454[M+1] + .
Sixth step
Preparation of 7-methyl-2-thioxo-1- (2- ((1, 1-trifluorobutan-2-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
3- (3- (ethoxycarbonyl) -1- (2- ((1, 1-trifluorobutan-2-yl) oxy) ethyl) thioureido) -4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-068F (160 mg,0.35 mmol) was dissolved in methanol (7 mL), cesium carbonate (344 mg,1.06 mmol) was added and heated to 65℃under nitrogen and stirred for 4 hours. After the completion of the reaction, the reaction mixture was poured into a dilute aqueous hydrochloric acid solution (100 mL,1 m), extracted with ethyl acetate (50 ml×2), and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product which was subjected to HPLC to prepare 7-methyl-2-thioxo-1- (2- ((1, 1-trifluorobutan-2-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-068 (23 mg, white solid), yield: 19%.
MS m/z(ESI):336[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.22(s,1H),12.11(s,1H),7.17(s,1H),4.73(s,2H),4.11-3.99(m,2H),3.98-3.83(m,1H),2.31(s,3H),1.64-1.51(m,1H),1.47-1.33(m,1H),0.81(t,J=7.4Hz,3H).
Example 69
7-methyl-2-thioxo-1- (2- ((1, 1-trifluoropentan-2-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of 1, 1-trifluoropentan-2-ol
Butyraldehyde Cpd-069A (1.0 g,13.9 mmol) and trifluoromethyl trimethylsilane (3.9 g,27.8 mmol) were dissolved in anhydrous tetrahydrofuran (10 mL), then tetrabutylammonium fluoride tetrahydrofuran solution (20.9 mL,20.9mmol,1 m) was added dropwise under nitrogen protection under ice bath, and after the addition was completed, stirring was resumed at room temperature for two hours. After the reaction was completed, the reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (50 ml×2), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated at room temperature to give crude 1, 1-trifluoropentan-2-ol Cpd-069B (1.6 g, colorless oil), yield: 81%. The crude product was used directly in the next step without further purification.
1 H NMR(400MHz,DMSO-d6)δ6.03(d,J=6.8Hz,1H),3.93-3.81(m,1H),1.52-1.30(m,4H),0.93-0.85(m,3H).
Second step
Preparation of ethyl 2- ((1, 1-trifluoropentan-2-yl) oxy) acetate
1, 1-trifluoropentan-2-ol Cpd-069B (1.6 g,11.2 mmol) was dissolved in N, N-dimethylformamide (30 mL), sodium hydrogen (0.9 g,22.4 mol) was added under ice bath, stirred for half an hour under nitrogen protection, then ethyl bromoacetate (1.9 g,11.2 mmol) was added dropwise under ice bath, and the mixture was returned to room temperature and stirred for two hours. After the reaction was completed, the reaction mixture was poured into an aqueous glacial ammonium chloride solution (300 mL) and quenched, ethyl acetate (100 ml×2) was extracted, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated at room temperature, and the resulting crude product was purified by silica gel column (petroleum ether/ethyl acetate=10/1) to give ethyl 2- ((1, 1-trifluoropentan-2-yl) oxy) acetate Cpd-069C (1.3 g, colorless oil), yield: 51%.
1 H NMR(400MHz,DMSO-d6)δ4.39-4.27(m,2H),4.21-4.05(m,3H),1.64-1.36(m,4H),1.20(dd,J=9.0,5.2Hz,3H),0.94-0.86(m,3H).
Third step
Preparation of 2- ((1, 1-trifluoropentan-2-yl) oxy) ethan-1-ol
Ethyl 2- ((1, 1-trifluoropentan-2-yl) oxy) acetate Cpd-069C (1.3 g,5.7 mmol) was dissolved in tetrahydrofuran (20 mL), and a suspension of lithium aluminum tetrahydroide in tetrahydrofuran (8.6 mL,8.6mmol, 1M) was added dropwise under ice bath, and stirring was continued for half an hour after completion of the addition. After the reaction was completed, the reaction solution was diluted with tetrahydrofuran (50 mL), aqueous sodium hydroxide solution (0.6 mL,2 m) was added dropwise under ice bath, stirred for ten minutes, followed by drying over anhydrous sodium sulfate, filtration through celite, and concentration of the filtrate to give crude product was purified by silica gel column (petroleum ether/ethyl acetate=4/1) to give 2- ((1, 1-trifluoropentan-2-yl) oxy) ethane-1-ol Cpd-069D (0.7 g, colorless oil), yield: 65%.
1 H NMR(400MHz,DMSO-d6)δ4.66(t,J=5.4Hz,1H),3.99-3.92(m,1H),3.77-3.66(m,1H),3.62-3.54(m,1H),3.50(q,J=5.2Hz,2H),1.55-1.37(m,4H),0.91(t,J=6.9Hz,3H).
Fourth step
Preparation of 2- ((1, 1-trifluoropentan-2-yl) oxy) acetaldehyde
Oxalyl chloride (203 mg,1.6 mmol) was dissolved in dichloromethane (10 mL) with anhydrous sodium sulfate (50 mg) under nitrogen and a solution of anhydrous dimethyl sulfoxide (167 mg,2.1 mmol) diluted with dichloromethane (1 mL) was added dropwise at-60 ℃. After 5 minutes, a solution of 2- ((1, 1-trifluoropentan-2-yl) oxy) ethan-1-ol Cpd-069D (200 mg,1.1 mmol) in dichloromethane (3 mL) was maintained at no more than-55deg.C. The mixture was stirred at the same temperature for half an hour, and then triethylamine (432 mg,4.3 mmol) was added dropwise at a temperature of not higher than-55℃and, after the completion of the addition, the mixture was stirred at room temperature for 10 minutes. After the reaction was completed, the reaction mixture was poured into a solution of water (100 mL), extracted with dichloromethane (50 ml×2), and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude 2- ((1, 1-trifluoropentan-2-yl) oxy) acetaldehyde Cpd-069E (220 mg, colorless oil), yield: 111%. The crude product was used directly in the next reaction without further purification.
Fifth step
Preparation of ethyl 4-methyl-3- ((2- ((1, 1-trifluoropentan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate
Ethyl 3-amino-4-methyl-1H-pyrrole-2-carboxylate (100 mg,0.59 mmol) and 2- ((1, 1-trifluoropentan-2-yl) oxy) acetaldehyde Cpd-069E (220 mg,1.10 mmol) were dissolved in methanol (5 mL), and two drops of glacial acetic acid were added dropwise under nitrogen and stirred at room temperature for half an hour, followed by sodium cyanoborohydride (187 mg,2.97 mmol) and stirred at room temperature for half an hour. After the reaction was completed, the reaction mixture was poured into a solution of water (100 mL), extracted with ethyl acetate (50 ml×2), and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product, which was separated and purified by silica gel column (petroleum ether/ethyl acetate=4/1) to give 4-methyl-3- ((2- ((1, 1-trifluoropentan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-069F (130 mg, colorless oil), yield: 65%.
MS m/z(ESI):337[M+1] + .
Sixth step
Preparation of ethyl 3- (3- (ethoxycarbonyl) -1- (2- ((1, 1-trifluoropentan-2-yl) oxy) ethyl) thioureido) -4-methyl-1H-pyrrole-2-carboxylate
4-methyl-3- ((2- ((1, 1-trifluoropentan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-069F (130 mg,0.39 mmol) was dissolved in dichloromethane (5 mL) followed by dropwise ethoxycarbonyl isothiocyanate (76 mg,0.58 mmol) at room temperature and stirred at room temperature for half an hour. After the reaction was completed, the mixture was concentrated to give crude 3- (3- (ethoxycarbonyl) -1- (2- ((1, 1-trifluoropentan-2-yl) oxy) ethyl) thioureido) -4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-069G (180 mg, colorless oil), yield: 99%. The crude product was used directly in the next step without further purification.
MS m/z(ESI):468[M+1] + .
Seventh step
Preparation of 7-methyl-2-thioxo-1- (2- ((1, 1-trifluoropentan-2-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
3- (3- (ethoxycarbonyl) -1- (2- ((1, 1-trifluoropentan-2-yl) oxy) ethyl) thioureido) -4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-069G (180 mg,0.38 mmol) was dissolved in methanol (10 mL), cesium carbonate (375 mg,1.15 mmol) was added and heated to 65℃under nitrogen and stirred for 4 hours. After the completion of the reaction, the reaction mixture was poured into an aqueous ammonium chloride solution (100 mL), extracted with ethyl acetate (50 ml×2), and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product which was subjected to HPLC to prepare 7-methyl-2-thio-1- (2- ((1, 1-trifluoropentan-2-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-069 (6 mg, white solid), yield: 4%.
MS m/z(ESI):350[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.15(s,2H),7.17(s,1H),4.72(s,2H),4.12-3.92(m,3H),2.30(s,3H),1.48-1.32(m,2H),1.26-1.16(m,2H),0.77(t,J=7.3Hz,3H).
Example 70
1- (4-chloro-3- (fluoromethoxy) benzyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of 4-chloro-3- (fluoromethoxy) benzaldehyde
4-chloro-3-hydroxybenzaldehyde Cpd-070A (500 mg,3.19 mmol) was dissolved in acetonitrile (10 mL), then potassium carbonate (1.324 g,9.58 mmol) and fluoroiodomethane (612.88 mg,3.83 mmol) were added in this order, stirred at room temperature for 4 hours after the addition was completed, water (20 mL) was added to extract it, ethyl acetate was used for extraction, the organic phase was washed twice with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and spin-dried to give a crude product, which was isolated and purified by a silica gel column (petroleum ether/ethyl acetate=2/1) to give 4-chloro-3- (fluoromethoxy) benzaldehyde Cpd-070B (0.5 g, white solid), yield: 83%.
1 H NMR(400MHz,CDCl 3 )δ9.97(s,1H),7.70(s,1H),7.63–7.54(m,2H),5.89(s,1H),5.76(s,1H).
Second step
Preparation of 3- ((4-chloro-3- (fluoromethoxy) benzyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester
4-chloro-3- (fluoromethoxy) benzaldehyde Cpd-070B (200 mg,1.06 mmol) was dissolved in methanol (10 mL), then ethyl 3-amino-1H-pyrrole-2-carboxylate (179.84 mg,1.1665 mmol) and acetic acid (6.37 mg,0.1060 mmol) were added sequentially, the reaction was stirred at room temperature for 30 minutes, then sodium cyanoborohydride (133.28 mg,2.12 mmol) was added and the solution was stirred at room temperature for 16 hours. After the reaction, water was added to conduct extraction, methylene chloride was used for extraction, the organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate and spin-dried to obtain a crude product, which was separated and purified by a silica gel column (petroleum ether/ethyl acetate=2/1) to obtain the product 3- ((4-chloro-3- (fluoromethoxy) benzyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-070C (250 mg, yellow oil) in a yield of 72%.
MS m/z(ESI):327(M+1).
Third step
Preparation of 3- (1- (4-chloro-3- (fluoromethoxy) benzyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester
3- ((4-chloro-3- (fluoromethoxy) benzyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-070C (250 mg,0.765 mmol) was dissolved in dichloromethane (20 mL), cooled to 0℃and ethyl isothiocyanamide (120.41 mg,0.9181 mmol) was added thereto, followed by stirring at 0℃for 3 hours. After completion of the reaction, the reaction mixture was washed once with water (20 mL), and the organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was separated and purified by silica gel column (petroleum ether/ethyl acetate=1/1) to give ethyl 3- (1- (4-chloro-3- (fluoromethoxy) benzyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylate Cpd-070D (300 mg, yellow oil) in 86% yield.
MS m/z(ESI):458(M+1).
Fourth step
Preparation of 1- (4-chloro-3- (fluoromethoxy) benzyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
3- (1- (4-chloro-3- (fluoromethoxy) benzyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-070D (200 mg,0.44 mmol) was dissolved in methanol (10 mL), cesium carbonate (426.95 mg,1.31 mmol) was added thereto, and the reaction solution was heated to 90℃for 16 hours. After the completion of the reaction, the reaction solution was cooled to room temperature, and then the solution was spin-dried to give a crude product, which was isolated and purified by Prep-HPLC (acetonitrile/water (0.1% formic acid)) to give 1- (4-chloro-3- (fluoromethoxy) benzyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-070 (133.69 mg, white solid) in 86% yield.
MS m/z(ESI):340(M+1).
1 H NMR(400MHz,CDCl 3 )δ12.41(s,2H),7.44(d,J=8.4Hz,2H),7.32(d,J=2.8Hz,1H),7.01(d,J=8.2Hz,1H),6.18(d,J=2.8Hz,1H),5.96(s,1H),5.82(s,1H),5.71(s,2H).
Example 71
1- (4-chloro-3- (trifluoromethoxy) benzyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of 3- ((4-chloro-3- (trifluoromethoxy) benzyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester
4-chloro-3- (trifluoromethoxy) benzaldehyde Cpd-071A (300 mg,1.34 mmol) was dissolved in methanol (20 mL), 3-amino-1H-pyrrole-2-carboxylic acid ethyl ester (247 mg,1.60 mmol) and acetic acid (1 drop) were added, and the reaction was stirred at room temperature for 1 hour. To the solution was added sodium cyanoborohydride (252 mg,4.01 mmol) and the reaction was stirred at room temperature for 1 hour. After the reaction, the reaction mixture was extracted with dichloromethane (3×10 ml), and the organic phase was washed with saturated brine, followed by spin-drying the solvent to obtain a crude product. The crude product was isolated and purified by column chromatography (petroleum ether/ethyl acetate) to give 3- ((4-chloro-3- (trifluoromethoxy) benzyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-071B (450 mg, white solid), yield: 93%.
MS m/z(ESI)363.1(M+1).
Second step
Preparation of 3- (1- (4-chloro-3- (trifluoromethoxy) benzyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester
3- ((4-chloro-3- (trifluoromethoxy) benzyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-071B (450 mg,1.24 mmol) was dissolved in dichloromethane (5 mL) and ethoxycarbonyl isothiocyanate (178 mg,1.36 mmol) was added. After the reaction, the reaction mixture was extracted with dichloromethane (10×3 ml), and the organic phase was washed with saturated brine, followed by spin-drying the solvent to obtain a crude product. The crude product was isolated and purified by column chromatography (petroleum ether/ethyl acetate) to give ethyl 3- (1- (4-chloro-3- (trifluoromethoxy) benzyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-071C (359 mg, white solid), yield: 53%.
MS m/z(ESI)494.0(M+1).
Third step
Preparation of 1- (4-chloro-3- (trifluoromethoxy) benzyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
3- (1- (4-chloro-3- (trifluoromethoxy) benzyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-071C (330 mg,0.69 mmol) was dissolved in methanol (5 mL) and cesium carbonate (653 mg,2.00 mmol) was added and the reaction stirred at 80℃for 4 hours. After the reaction, the reaction mixture was extracted with dichloromethane (3×10 ml), and the organic phase was washed with saturated brine, followed by spin-drying the solvent to obtain a crude product. The crude product was purified by Prep-HPLC (CAN/H 2 O (0.1% FA)) to obtain 1- (4-chloro-3- (trifluoromethoxy) benzyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3, 2-d)]Pyrimidin-4-one Cpd-071 (9.63 mg, white solid), yield: 4%.
MS m/z(ESI):376.0(M+1).
1 H NMR(400MHz,DMSO-d6)δ12.10(br,1H),7.62(d,J=8.4Hz,2H),7.35(d,J=8.4Hz,1H),7.15(s,1H),6.05(s,1H),5.75(s,2H).
19 F NMR(376MHz,DMSO-d6)δ-56.92.
Example 72
1- (4-chloro-3- (1-hydroxyethyl) benzyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of 2-bromo-1-chloro-4- (dimethoxymethyl) benzene
3-bromo-4-chlorobenzaldehyde Cpd-072A (4 g,18.2 mmol), trimethyl orthoformate (9.66 g,91 mmol) and p-toluenesulfonic acid (0.63 g,0.4 mmol) were dissolved in methanol (50 mL) and reacted at 70℃for 16h. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (ethyl acetate/petroleum ether=12/88) to give 2-bromo-1-chloro-4- (dimethoxymethyl) benzene Cpd-072B (3.1 g, colorless oily liquid), yield: 64%.
1 H NMR(400MHz,CDCl 3 )δ7.73(d,J=2.0Hz,1H),7.44(d,J=8.4Hz,1H),7.32(dd,J=8.4,2.0Hz,1H),5.35(s,1H),3.31(s,6H).
Second step
Preparation of 2-chloro-5- (dimethoxymethyl) benzaldehyde
2-bromo-1-chloro-4- (dimethoxymethyl) benzene Cpd-072B (500 mg,1.9 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), n-butyllithium (0.92mL,2.3mmol,2.5M in hexane) was slowly added dropwise at-70℃and reacted at-70℃for 1 hour after the completion of the addition. Anhydrous N, N-dimethylformamide (165 mg,2.3 mmol) was slowly added dropwise at-70℃and slowly warmed to room temperature after completion of the addition. The reaction solution was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate under reduced pressure, purification of the resulting residue by column chromatography (ethyl acetate/petroleum ether=13/87) gave 2-chloro-5- (dimethoxymethyl) benzaldehyde Cpd-072C (250 mg, colorless oily liquid), yield: 62%.
1 H NMR(400MHz,CDCl 3 )δ10.49(s,1H),8.02(d,J=2.2Hz,1H),7.64(dd,J=8.2,2.2Hz,1H),7.47(d,J=8.2Hz,1H),5.41(s,1H),3.32(s,6H).
Third step
Preparation of 1- (2-chloro-5- (dimethoxymethyl) phenyl) ethan-1-ol
2-chloro-5- (dimethoxymethyl) benzaldehyde Cpd-072C (250 mg,1.2 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), and methyl magnesium bromide (208mg,1.7mmol,3M in Et) was slowly added dropwise at 0deg.C 2 O), after the dripping is finished, reacting for 2 hours at room temperature. The reaction solution was poured into a precooled saturated ammonium chloride solution, extracted with ethyl acetate, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate under reduced pressure, and purification of the resulting residue by column chromatography (ethyl acetate/petroleum ether=3/7) gave 1- (2-chloro-5- (dimethoxymethyl) phenyl) ethan-1-ol Cpd-072D (170 mg, colorless oily liquid), yield: 63%.
1 H NMR(400MHz,DMSO-d 6 )δ7.66(d,J=2.2Hz,1H),7.37(d,J=8.2Hz,1H),7.24(dd,J=8.2,2.2Hz,1H),5.41(d,J=4.4Hz,1H),5.40(s,1H),5.02(dd,J=6.4,4.4Hz,1H),3.25(s,6H),1.30(d,J=6.4Hz,3H).
Fourth step
Preparation of 4-chloro-3- (1-hydroxyethyl) benzaldehyde
1- (2-chloro-5- (dimethoxymethyl) phenyl) ethan-1-ol Cpd-072D (150 mg,0.7 mmol) was dissolved in a tetrahydrofuran/concentrated hydrochloric acid=2/1 (6 mL) mixture and reacted at room temperature for 1h. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with saturated sodium bicarbonate solution and sodium chloride solution, and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure gave 4-chloro-3- (1-hydroxyethyl) benzaldehyde Cpd-072E (110 mg, orange-red liquid), yield: 92%.
MS m/z(ESI):185.0(M+1).
Fifth step
Preparation of ethyl 3- ((4-chloro-3- (1-hydroxyethyl) benzyl) amino) -1H-pyrrole-2-carboxylate
4-chloro-3- (1-hydroxyethyl) benzaldehyde Cpd-072E (100 mg,0.5 mmol), ethyl 3-amino-1H-pyrrole-2-carboxylate (100 mg,0.7 mmol), catalytic amounts of acetic acid and molecular sieves were dissolved in 1, 2-dichloroethane (10 mL) and reacted at room temperature for 1H. Sodium triacetoxyborohydride (345 mg,1.6 mmol) was then added and reacted at room temperature for 16 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (ethyl acetate/petroleum ether=3/7) to give ethyl 3- ((4-chloro-3- (1-hydroxyethyl) benzyl) amino) -1H-pyrrole-2-carboxylate Cpd-072F (130 mg, pale yellow oily liquid), yield: 74%.
MS m/z(ESI):323.2(M+1).
Sixth step
Preparation of ethyl 3- (1- (4-chloro-3- (1-hydroxyethyl) benzyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylate
Compound Cpd-072F (100 mg,0.3 mmol) was dissolved in dichloromethane (5 mL) and ethyl isothiocyanamide (122 mg,0.9 mmol) was added and reacted at room temperature for 1h. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (ethyl acetate/petroleum ether=3/7 followed by methanol/dichloromethane=2.5/97.5) to give ethyl 3- (1- (4-chloro-3- (1-hydroxyethyl) benzyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylate Cpd-072G (130 mg, pale yellow oily liquid), yield: 92%.
MS m/z(ESI):454.1(M+1).
Seventh step
Preparation of 1- (4-chloro-3- (1-hydroxyethyl) benzyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Ethyl 3- (1- (4-chloro-3- (1-hydroxyethyl) benzyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylate Cpd-072G (100 mg,0.2 mmol) was dissolved in methanol (5 mL), sodium methoxide (36 mg,0.7 mmol) was added and reacted at 70 ℃ for 4H. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by prep-HPLC (acetonitrile/water (0.1% formic acid) =44/56) to give 1- (4-chloro-3- (1-hydroxyethyl) benzyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-072 (42.83 mg, white solid), yield: 58%.
MS m/z(ESI):336.0(M+1).
1 H NMR(400MHz,DMSO-d 6 )δ12.46(s,1H),12.34(s,1H),7.63(d,J=2.2Hz,1H),7.34–7.29(m,2H),7.14(dd,J=8.2,2.2Hz,1H),6.13(d,J=2.8Hz,1H),5.77-5.64(m,2H),5.36(d,J=4.0Hz,1H),5.01–4.93(m,1H),1.26(d,J=6.4Hz,3H).
Example 73
1- (4-chloro-3- (2, 2-trifluoroethoxy) benzyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of 4-chloro-3- (2, 2-trifluoroethoxy) benzaldehyde
4-chloro-3-hydroxybenzaldehyde Cpd-073A (300 mg,1.92 mmol) was dissolved in DMF (10 mL) and 2, 2-trifluoroethyl triflate (447 mg,1.91 mmol) and cesium carbonate (936 mg,2.87 mmol) were added. The reaction was stirred at 60℃for 16 hours. After the reaction, the reaction mixture was extracted with methylene chloride (3×10 ml), the organic phase was washed with saturated brine, and the solvent was dried to give a crude product, which was purified by column chromatography (petroleum ether/ethyl acetate) to give 4-chloro-3- (2, 2-trifluoroethoxy) benzaldehyde Cpd-073B (450 mg, pale yellow oily liquid), yield: 99%.
1 H NMR(400MHz,DMSO-d6)δ9.95(s,1H),7.75–7.70(m,2H),7.61(d,J=8.0Hz,1H),4.98(q,J=8.8Hz,2H).
Second step
Preparation of 3- ((4-chloro-3- (2, 2-trifluoroethoxy) benzyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester
4-chloro-3- (2, 2-trifluoroethoxy) benzaldehyde Cpd-073B (300 mg,1.25 mmol) was dissolved in methanol (20 mL), ethyl 3-amino-1H-pyrrole-2-carboxylate (290 mg,1.88 mmol) and acetic acid (1 drop) were added, and the reaction was stirred at room temperature for 1 hour. To the solution was added sodium cyanoborohydride (236 mg,3.76 mmol), and the reaction was stirred at room temperature for 1 hour. After the reaction, the reaction mixture was extracted with dichloromethane (3×10ml), the organic phase was washed with saturated brine, and the solvent was dried to give a crude product, which was purified by column chromatography (petroleum ether/ethyl acetate) to give 3- ((4-chloro-3- (2, 2-trifluoroethoxy) benzyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-073C (276 mg, white solid), yield: 59%.
1 H NMR(400MHz,DMSO-d6)δ10.77(s,1H),7.40(d,J=8.0Hz,1H),7.29(d,J=1.2Hz,1H),7.03(dd,J=8.0,1.2Hz,1H),6.70(t,J=3.2Hz,1H),5.84(s,1H),5.57(t,J=2.4Hz,1H),4.83(q,J=8.8Hz,2H),4.27(d,J=6.4Hz,2H),4.20(q,J=7.2Hz,2H),1.17(t,J=7.2Hz,3H).
Third step
Preparation of ethyl 3- (1- (4-chloro-3- (2, 2-trifluoroethoxy) benzyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylate
3- ((4-chloro-3- (2, 2-trifluoroethoxy) benzyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-073C (250 mg,0.66 mmol) was dissolved in dichloromethane (5 mL) and ethoxycarbonyl isothiocyanate (87 mg,0.66 mmol) was added and the reaction stirred at room temperature for 2 hours. After the reaction, the reaction mixture was extracted with dichloromethane (10 ml x 3), the organic phase was washed with saturated brine, and the solvent was dried by spin-drying to give a crude product, which was purified by column chromatography (petroleum ether/ethyl acetate) to give 3- (1- (4-chloro-3- (2, 2-trifluoroethoxy) benzyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-073D (232 mg, white solid), yield: 69%.
1 H NMR(400MHz,DMSO-d6)δ11.97(s,1H),9.50(s,1H),7.39(d,J=8.0Hz,1H),7.24(s,1H),7.06(d,J=8.0Hz,1H),6.90(t,J=3.2Hz,1H),6.02(t,J=2.4Hz,1H),5.74(d,J=15.6Hz,1H),5.04(d,J=14.8Hz,1H),4.75(dt,J=13.2,6.8Hz,2H),4.29–4.11(m,2H),3.94(d,J=7.2Hz,2H),1.27(t,J=7.2Hz,3H),1.08(t,J=7.2Hz,3H).
Fourth step
Preparation of 1- (4-chloro-3- (2, 2-trifluoroethoxy) benzyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
3- (1- (4-chloro-3- (2, 2-trifluoroethoxy) benzyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-073D (200 mg,0.39 mmol) was dissolved in methanol (5 mL), cesium carbonate (256 mg,0.78 mmol) was added and the reaction stirred at 80℃for 4 hours. After the reaction, the reaction mixture was extracted with dichloromethane (3X 10 mL), the organic phase was washed with saturated brine, and the solvent was dried to give a crude product by Prep-HPLC (CAN/H 2 O (0.1% FA)) to obtain 1- (4-chloro-3- (2, 2-trifluoroethoxy) benzyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3, 2-d)]Pyrimidin-4-one Cpd-073 (13.39 mg, white solid), yield: 9%.
MS m/z(ESI):390.1(M+1).
1 H NMR(400MHz,DMSO-d6)δ11.81(br,1H),7.42(s,1H),7.36(d,J=8.0Hz,1H),7.05(s,1H),6.93(d,J=1.6Hz,1H),5.95(s,1H),5.71(s,2H),4.84(q,J=8.0Hz,2H).
19 F NMR(376MHz,DMSO-d6)δ-72.70.
Example 74
1- (4-chloro-3- (difluoromethoxy) benzyl) -2-thio-6-phenyl-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of 3- (4-toluenesulfonyloxy) -3-phenylprop-2-enenitrile
3-oxo-3-phenylpropionitrile Cpd-074A (5.0 g,34 mmol) and p-toluenesulfonyl chloride (7.9 g,41 mmol) were dissolved in dichloromethane (100 mL) and triethylamine (5.2 g,52 mmol) was added dropwise under nitrogen at 0deg.C. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was diluted with water (200 mL), dichloromethane (100 ml×2) was extracted, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated at room temperature to give a crude product, which was purified by a silica gel column (petroleum ether/ethyl acetate=4/1), and the purified crude product was recrystallized from a mixed solvent (petroleum ether/ethyl acetate=4/1) to give 3- (4-tosyloxy) -3-phenylprop-2-enenitrile Cpd-074B (3.0 g, yellow solid), yield: 29%.
1 H NMR(400MHz,DMSO-d6)δ7.80(d,J=8.4Hz,2H),7.56-7.36(m,7H),6.61(s,1H),2.41(s,3H).
Second step
Preparation of 3-amino-5-phenyl-1H-pyrrole-2-carboxylic acid ethyl ester
3- (4-tosyloxy) -3-phenylpropan-2-enenitrile Cpd-074B (3.0 g,10 mmol) and diethyl 2-aminomalonate hydrochloride (2.54 g,12 mmol) were dissolved in a mixed solvent of absolute ethanol (40 mL) and absolute tetrahydrofuran (20 mL), and the mixed solution was dropped into an ethanol solution of sodium ethoxide (23.5 mL,47mmol, 2M) at 0℃under nitrogen. After the addition was completed, the ice bath was removed and the room temperature was restored to the room temperature and stirring was continued for 2 hours. After the reaction was completed, the reaction solution was poured into an aqueous solution of glacial ammonium chloride (200 mL) and quenched, ethyl acetate (100 ml×2) was extracted, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated at room temperature, and the obtained crude product was purified by a silica gel column (petroleum ether/ethyl acetate=4/1), and the obtained solid was recrystallized from a petroleum ether-ethyl acetate mixed solvent to give 3-amino-5-phenyl-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-074C (1.0 g, brown yellow solid), yield: 32%.
MS m/z(ESI):231[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ10.74(s,1H),7.80-7.69(m,2H),7.36(t,J=7.6Hz,2H),7.26(t,J=7.3Hz,1H),6.00(d,J=2.8Hz,1H),5.10(s,2H),4.23(q,J=7.1Hz,2H),1.30(t,J=7.1Hz,3H).
Third step
Preparation of 3- ((4-chloro-3- (difluoromethoxy) benzyl) amino) -5-phenyl-1H-pyrrole-2-carboxylic acid ethyl ester
Ethyl 3-amino-5-phenyl-1H-pyrrole-2-carboxylate Cpd-074C (120 mg,0.52 mmol), 4-chloro-3- (difluoromethoxy) benzaldehyde (129 mg,0.62 mmol) was dissolved in a mixed solvent of methanol (5 mL) and tetrahydrofuran (5 mL), two drops of glacial acetic acid were added dropwise under nitrogen protection, and stirring was carried out at room temperature for half an hour. Sodium cyanoborohydride (164 mg,2.61 mmol) was added and stirring was continued for half an hour at room temperature. After the reaction was completed, the reaction mixture was poured into water (100 mL), extracted with ethyl acetate (50 ml×2), the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 3- ((4-chloro-3- (difluoromethoxy) benzyl) amino) -5-phenyl-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-074D (130 mg, white solid) after separation and purification of the crude product with a silica gel column (petroleum ether/ethyl acetate=4/1), yield: 59%.
MS m/z(ESI):421[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ10.97(s,1H),7.79-7.69(m,2H),7.54(d,J=8.2Hz,1H),7.44-7.20(m,6H),6.12(dd,J=7.1,2.7Hz,1H),6.01(s,1H),4.38(d,J=6.5Hz,2H),4.26(q,J=7.1Hz,2H),1.31(t,J=7.1Hz,3H).
Fourth step
Preparation of 3- (1- (4-chloro-3- (difluoromethoxy) benzyl) -3- (ethoxycarbonyl) thiourea) -5-phenyl-1H-pyrrole-2-carboxylic acid ethyl ester
3- ((4-chloro-3- (difluoromethoxy) benzyl) amino) -5-phenyl-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-074D (110 mg,0.26 mmol) was dissolved in dichloromethane (5 mL) followed by dropwise addition of ethoxycarbonyl isothiocyanate (51 mg,0.39 mmol) and stirring at room temperature for half an hour. After the reaction, the mixture was concentrated to give crude 3- (1- (4-chloro-3- (difluoromethoxy) benzyl) -3- (ethoxycarbonyl) thiourea) -5-phenyl-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-074E (150 mg, colorless oil), yield: 103%. The crude product was used directly in the next step without further purification.
MS m/z(ESI):552[M+1] + .
Fifth step
Preparation of 1- (4-chloro-3- (difluoromethoxy) benzyl) -2-thio-6-phenyl-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
3- (1- (4-chloro-3- (difluoromethoxy) benzyl) -3- (ethoxycarbonyl) thiourea) -5-phenyl-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-074E (150 mg,0.27 mmol) was dissolved in methanol (5 mL), cesium carbonate (266 mg,0.81 mmol) was added, and the mixture was heated to 65℃under nitrogen and stirred for 8 hours. After the completion of the reaction, the reaction mixture was poured into a dilute aqueous hydrochloric acid solution (100 mL,1 m), extracted with ethyl acetate (50 ml×2), and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 1- (4-chloro-3- (difluoromethoxy) benzyl) -2-thio-6-phenyl-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-074 (3 mg, white solid) by HPLC, yield: 3%.
MS m/z(ESI):434[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.80(s,1H),12.42(s,1H),7.86(d,J=7.4Hz,2H),7.61-7.49(m,2H),7.48-6.72(m,6H),5.73(s,2H).
Example 75
1- (2- (1- (trifluoromethyl) -3-oxetano) ethyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of 3- (trifluoromethyl) -1-oxetan-3-ol
3-oxetanone Cpd-086A (10.0 g,0.14 mol) and trifluoromethyl trimethylsilane (20.7 g,0.15 mmol) were dissolved in anhydrous tetrahydrofuran (200 mL), followed by dropwise addition of tetrabutylammonium fluoride tetrahydrofuran solution (150 mL,0.15mol, 1M) under nitrogen under ice bath, and stirring was continued for two hours at room temperature after completion of the dropwise addition. After the reaction was completed, the reaction solution was diluted with water (400 mL), extracted with ethyl acetate (100 ml×2), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated at room temperature to give crude 3- (trifluoromethyl) -1-oxetan-3-ol Cpd-086B (19.0 g, colorless oil), yield: 96%. The crude product was used directly in the next step without further purification.
Second step
Preparation of ethyl 2- (1- (trifluoromethyl) -3-oxetanyl) acetate
3- (trifluoromethyl) -1-oxetan-3-ol Cpd-086B (19.7 g,0.14 mol) was dissolved in N, N-dimethylformamide (200 mL), sodium hydrogen (6.6 g,0.17 mol) was added under ice bath, stirred under nitrogen for half an hour, then ethyl bromoacetate (25.3 g,0.15 mol) was added dropwise under ice bath, and stirring was continued for two hours at room temperature. After the reaction was completed, the reaction solution was poured into an aqueous glacial ammonium chloride solution (500 mL) and quenched, ethyl acetate (200 ml×2) was extracted, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated at room temperature, and the obtained crude product was purified by silica gel column (petroleum ether/ethyl acetate=4/1) to give ethyl 2- (1- (trifluoromethyl) -3-oxetoxy) acetate Cpd-086C (11.4 g, colorless oil), yield: 36%.
1 H NMR(400MHz,DMSO-d6)δ4.80(dd,J=9.5,1.5Hz,2H),4.63(d,J=9.3Hz,2H),4.47(s,2H),4.16(q,J=7.1Hz,2H),1.21(t,J=7.1Hz,2H).
Third step
Preparation of 2- (1- (trifluoromethyl) -3-oxocyclobutoxy) ethan-1-ol
Ethyl 2- (1- (trifluoromethyl) -3-oxetanyl) acetate Cpd-086C (6.0 g,26.2 mmol) was dissolved in ethanol (70 mL) and sodium borohydride (3.0 g,78.6 mmol) was added slowly. The reaction solution was heated to 40℃and stirred for one hour. After the reaction was completed, the reaction solution was poured into an aqueous solution of glacial ammonium chloride (300 mL) and quenched, ethyl acetate (100 ml×2) was extracted, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated at room temperature, and the resulting crude product was purified by silica gel column (petroleum ether/ethyl acetate=2/1) to give 2- (1- (trifluoromethyl) -3-oxocyclobutoxy) ethane-1-ol Cpd-086D (4.0 g, colorless oil), yield: 82%.
1 H NMR(400MHz,DMSO-d6)δ4.82(t,J=5.5Hz,1H),4.78(d,J=7.6Hz,2H),4.64(d,J=8.6Hz,2H),3.67(t,J=4.9Hz,2H),3.55(dd,J=10.2,5.1Hz,2H).
Fourth step
Preparation of 2- (1- (trifluoromethyl) -3-oxetanyl) acetaldehyde
Oxalyl chloride (4.2 g,32.9 mmol) was dissolved in dichloromethane (100 mL) with anhydrous sodium sulfate (1000 mg) under nitrogen and a solution of anhydrous dimethyl sulfoxide (5.1 g,65.7 mmol) in dichloromethane (20 mL) was added dropwise at-60 ℃. After 5 minutes, a solution of 2- (1- (trifluoromethyl) -3-oxocyclobutoxy) ethan-1-ol Cpd-086D (5.6 g,29.9 mmol) in dichloromethane (10 mL) was added dropwise at no more than-60 ℃. The mixture was stirred at the same temperature for half an hour, and then triethylamine (12.1 g,119.6 mmol) was added dropwise at 60℃or not, and the mixture was stirred at the same temperature for half an hour after completion of the addition, and then stirred at room temperature for 10 minutes by naturally heating. After the completion of the reaction, the reaction mixture was poured into water (300 mL), extracted with dichloromethane (100 ml×2), and the combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude 2- (1- (trifluoromethyl) -3-oxetoxy) acetaldehyde Cpd-086E (5.0 g, colorless oil), yield: 90%. The crude product was used directly in the next reaction without further purification.
Fifth step
Preparation of 3- ((2- (1- (trifluoromethyl) -3-oxetanyl) ethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester
Ethyl 3-amino-4-methyl-1H-pyrrole-2-carboxylate (4.2 g,27.0 mmol) and 2- (1- (trifluoromethyl) -3-oxetanyl) acetaldehyde Cpd-086E (5.0 g,27.0 mmol) were dissolved in methanol (70 mL), tetraisopropyl titanate (10.0 g,35.1 mmol) was added, heated to 40℃under nitrogen and stirred for half an hour, followed by sodium cyanoborohydride (11.4 g,54.0 mmol) at room temperature. After the reaction was completed, the reaction solution was diluted with dichloromethane (300 mL), water (20 mL) was added dropwise with stirring until no more solid precipitated, the solid-liquid mixture was filtered with celite, the mixed solvent (DCM/meoh=10/1, 200 mL) was washed with filter residue, the combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product after separation and purification with a silica gel column (petroleum ether/ethyl acetate=2/1) to give 3- ((2- (1- (trifluoromethyl) -3-oxethyl) ethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-086F (5.0 g, colorless oil), yield: 57%.
MS m/z(ESI):323[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ10.79(s,1H),6.77(t,J=3.0Hz,1H),5.71(t,J=2.6Hz,1H),5.44(s,1H),4.67(dd,J=30.6,8.2Hz,4H),4.18(q,J=7.1Hz,2H),3.79(t,J=5.3Hz,2H),3.30(d,J=6.2Hz,2H),1.25(dd,J=8.5,5.7Hz,3H).
Sixth step
Preparation of ethyl 3- (1- (2- (1- (trifluoromethyl) oxocyclobutoxy) ethyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylate
3- ((2- (1- (trifluoromethyl) -3-oxetanyl) ethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-086F (5.0 g,15.5 mmol) was dissolved in acetonitrile (70 mL) followed by dropwise addition of ethoxycarbonyl isothiocyanate (4.1 g,31 mmol) at room temperature and stirring at room temperature for half an hour. After the reaction was completed, the crude product was concentrated to give 3- (1- (2- (1- (trifluoromethyl) oxy-cyclobutoxy) ethyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-086G (6.7G, colorless oil) which was purified by silica gel column (petroleum ether/ethyl acetate=2/1), yield: 95%.
MS m/z(ESI):454[M+1] + .
1 H NMR(400MHz,DMSO-d 6 )δ11.99(s,1H),9.32(s,1H),6.99(t,J=3.1Hz,1H),6.15(t,J=2.6Hz,1H),4.72-4.58(m,4H),4.42(s,1H),4.27-4.05(m,4H),3.98-3.81(m,3H),1.25(t,J=7.1Hz,3H),1.07(t,J=7.1Hz,3H).
Seventh step
Preparation of 1- (2- (1- (trifluoromethyl) -3-oxetano) ethyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
3- (1- (2- (1- (trifluoromethyl) oxocyclobutoxy) ethyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-086G (6.7G, 14.8 mmol) was dissolved in methanol (100 mL), cesium carbonate (14.5G, 44.4 mmol) was added, and heated to 65℃under nitrogen and stirred for 8 hours. After the reaction was completed, the reaction mixture was poured into a dilute aqueous hydrochloric acid solution (1 mol/L,200 mL), extracted with ethyl acetate (100 ml×2), and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was slurried with a mixed solvent (dichloromethane/methanol=10/1, 100 mL) to give 1- (2- (1- (trifluoromethyl) -3-oxetano) ethyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-086 (3.1 g, white solid), yield: 62%.
MS m/z(ESI):336[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.38(s,1H),12.27(s,1H),7.36(t,J=3.0Hz,1H),6.40-6.31(m,1H),4.63(t,J=5.7Hz,2H),4.60(s,4H),4.09(t,J=5.6Hz,2H).
Example 76
1- (3- (difluoromethoxy) -4-fluorobenzyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of 3- (difluoromethoxy) -4-fluorobenzaldehyde
4-bromo-1-fluoro-2- (difluoromethoxy) benzene Cpd-087A (1.0 g,4.1 mmol), di-tert-butyl (4-dimethylaminophenyl) palladium (II) dichloride (290 mg,0.4 mmol), triethylsilane (1.2 g,10.3 mmol) and N, N-diisopropylethylamine (1.3 g,10.3 mmol) were dissolved in dimethyl sulfoxide (40 mL) and then heated at 90℃for 1 hour under carbon monoxide atmosphere. After the completion of the reaction, the reaction mixture was diluted with water (100 mL) and ethyl acetate (200 mL), filtered through celite, and the separated organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was separated and purified by a silica gel column (petroleum ether/ethyl acetate=4/1) to give 3- (difluoromethoxy) -4-fluorobenzaldehyde Cpd-087B (300 mg, yellow oily substance) in 34% yield.
1 H NMR(400MHz,CDCl 3 )δ9.95(s,1H),7.79-7.76(m,2H),7.35(dd,J=9.4,8.5Hz,1H),6.62(t,J=72.5Hz,1H).
Second step
Preparation of 3- ((3- (difluoromethoxy) -4-fluorobenzyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester
3- (difluoromethoxy) -4-fluorobenzaldehyde Cpd-087B (280 mg,1.5 mmol), ethyl 3-amino-1H-pyrrole-2-carboxylate (227 mg,1.5 mmol) and two drops of acetic acid were dissolved in methanol (5 mL) and stirred at room temperature for half an hour, followed by addition of sodium cyanoborohydride (185 mg,3.0 mmol) and stirring continued for half an hour. After the reaction was completed, the reaction solution was diluted with water (10 mL), extracted with ethyl acetate (100 mL), the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was separated and purified by silica gel column (petroleum ether/ethyl acetate=4/1) to give 3- ((3- (difluoromethoxy) -4-fluorobenzyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-087C (300 mg, colorless oil), yield: 60%.
MS m/z(ESI):329[M+1] + .
Third step
Preparation of 3- (1- (3- (difluoromethoxy) -4-fluorobenzyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester
3- ((3- (difluoromethoxy) -4-fluorobenzyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-087C (290 mg,0.88 mmol) was dissolved in acetonitrile (3 mL) followed by ethoxycarbonyl isothiocyanate (139 mg,1.06 mmol) and stirred at room temperature for half an hour. After the reaction, the crude product was concentrated to give ethyl 3- (1- (3- (difluoromethoxy) -4-fluorobenzyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylate Cpd-087D (300 mg, colorless oil) after separation and purification on silica gel column (petroleum ether/ethyl acetate=2/1), yield: 74%
MS m/z(ESI):460[M+1] + .
Fourth step
Preparation of 1- (3- (difluoromethoxy) -4-fluorobenzyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
3- (1- (3- (difluoromethoxy) -4-fluorobenzyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-087D (160 mg,0.35 mmol) was dissolved in methanol (5 mL), cesium carbonate (227 mg,0.70 mmol) was added, and heated at 65℃for 8 hours. After the reaction was completed, the reaction solution was cooled to room temperature, water (10 mL) was added thereto and stirred for half an hour, and filtration and cake freeze-drying were carried out to give 1- (3- (difluoromethoxy) -4-fluorobenzyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-087 (105 mg, white solid) in a yield of 87%.
MS m/z(ESI):342[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.39(s,2H),7.46(d,J=7.6Hz,1H),7.39-7.21(m,4H),6.19(d,J=2.8Hz,1H),5.69(s,2H).
Example 77
1- ((1- (2, 2-difluoroethyl) -1H-pyrazol-3-yl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of ethyl 1- (2, 2-difluoroethyl) -1H-pyrazole-3-carboxylate
1H-pyrazole-3-carboxylic acid ethyl ester Cpd-088A (2 g,14 mmol) was dissolved in DMF (20 mL), 1-difluoro-2-iodoethane (5.5 g,28 mmol), potassium carbonate (2.1 g,15.4 mmol) and potassium iodide (4.6 g,28 mmol) were added sequentially, the reaction was heated to 100deg.C in a sealed pot for 18 hours, after the reaction was completed, water (50 mL), ethyl acetate was extracted (2X 100 mL), the organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=3/1) to give 1- (2, 2-difluoroethyl) -1H-pyrazole-3-carboxylic acid ethyl ester Cpd-088B (1.2 g, colorless oil), yield: 47%.
1 H NMR(400MHz,DMSO)δ7.91(d,J=2.4Hz,1H),6.80(d,J=2.4Hz,1H),6.42-6.26(m,1H),4.78-4.70(m,2H),4.27(q,J=7.2Hz,2H),1.28(t,J=7.2Hz,3H).
Second step
Preparation of (1- (2, 2-difluoroethyl) -1H-pyrazol-3-yl) methanol
1- (2, 2-difluoroethyl) -1H-pyrazole-3-carboxylic acid ethyl ester Cpd-088B (500 mg,2.45 mmol) was dissolved in tetrahydrofuran (10 mL), lithium aluminum hydride (2.4 mL,2.45mmol, 1M) was added at 0deg.C, and the reaction solution was stirred at 0deg.C for 1 hour. After the reaction, water was added to conduct extraction, filtration and concentration of the filtrate after drying gave (1- (2, 2-difluoroethyl) -1H-pyrazol-3-yl) methanol Cpd-088C (350 mg, colorless liquid), yield: 88%.
MS m/z(ESI):163(M+1)
Third step
Preparation of 1- (2, 2-difluoroethyl) -1H-pyrazole-3-carbaldehyde
(1- (2, 2-difluoroethyl) -1H-pyrazol-3-yl) methanol Cpd-088C (350 mg,2.16 mmol) was dissolved in methylene chloride (5 mL), and dess-Martin oxidant (1.1 g,2.60 mmol) was added to the solution to react at room temperature for 1 hour, and after completion of the reaction, the solution was filtered and the filtrate was washed with aqueous sodium hydrogencarbonate solution. The organic phase was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel column (petroleum ether/ethyl acetate=10/1) to give 1- (2, 2-difluoroethyl) -1H-pyrazole-3-carbaldehyde Cpd-088D (300 mg, colorless liquid), yield: 87%.
MS m/z(ESI):161(M+1)
Fourth step
Preparation of 3- ((1- (2, 2-difluoroethyl) -1H-pyrazol-3-yl) methyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester
1- (2, 2-difluoroethyl) -1H-pyrazole-3-carbaldehyde Cpd-088D (300 mg,1.87 mmol) was dissolved in methanol (5 mL), and 3-amino-1H-pyrrole-2-carboxylic acid ethyl ester (289 mg,1.87 mmol) and acetic acid (112 mg,1.87 mmol) were added. The reaction solution was stirred at 25℃for 30 minutes, sodium cyanoborohydride (117 mg,1.87 mmol) was added, and stirring was continued at 25℃for 16 hours. After completion of the reaction, the reaction was quenched with water (10 mL) and extracted with ethyl acetate (2X 30 mL). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated. The resulting residue was isolated and purified by silica gel column (petroleum ether/ethyl acetate=3/1) to give ethyl 3- ((1- (2, 2-difluoroethyl) -1H-pyrazol-3-yl) methyl) amino) -1H-pyrrole-2-carboxylate Cpd-088E (500 mg, pale yellow solid), yield: 90%.
MS m/z(ESI):299(M+1)。
Fifth step
Preparation of 3- (1- ((1- (2, 2-difluoroethyl) -1H-pyrazol-3-yl) methyl) -3- (ethoxycarbonyl) thiourea-1H-pyrrole-2-carboxylic acid ethyl ester
3- ((1- (2, 2-difluoroethyl) -1H-pyrazol-3-yl) methyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-088E (500 mg,1.67 mmol) was dissolved in dichloromethane (10 mL). Ethyl isothiocyanamide (220 mg,1.67 mmol) was added. The reaction mixture was reacted at 25℃for 2 hours. After the completion of the reaction, the residue was distilled to dryness, and the obtained residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate=1/1) to give 3- (1- ((1- (2, 2-difluoroethyl) -1H-pyrazol-3-yl) methyl) -3- (ethoxycarbonyl) thiourea-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-088F (500 mg, yellow solid) in 69% yield.
MS m/z(ESI):430(M+1)。
Sixth step
Preparation of 1- ((1- (2, 2-difluoroethyl) -1H-pyrazol-3-yl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
3- (1- ((1- (2, 2-difluoroethyl) -1H-pyrazol-3-yl) methyl) -3- (ethoxycarbonyl) thiourea-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-088F (500 mg,1.16 mmol) and cesium carbonate (1140 mg,3.5 mmol) were dissolved in methanol (10 mL) and reacted for 6 hours at 60 ℃, after completion of the reaction, 1/3 methanol was concentrated and removed, the concentrate was slowly added to an aqueous ammonium chloride solution (20 mL), the solid was precipitated, filtered, washed with water, and the cake was slurried with methylene chloride/methanol=20/1 (10 mL) to remove impurities, and dried to give 1- ((1- (2, 2-difluoroethyl) -1H-pyrazol-3-yl) methyl) -2-thioxy-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-088 (200 mg, white solid) in 55% yield.
MS m/z(ESI):312(M+1)
1 H NMR(400MHz,DMSO)δ12.27(s,2H),7.68(d,J=2.4Hz,1H),7.31(d,J=2.8Hz,1H),6.30-6.15(m,3H),5.63(s,2H),4.61-4.53(m,2H).
Example 78
1- ((1- (2, 2-difluoroethyl) -1H-pyrazol-5-yl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of 1- (2, 2-difluoroethyl) -1H-pyrazole-5-carboxylic acid ethyl ester
1H-pyrazole-3-carboxylic acid ethyl ester Cpd-089A (2 g,14 mmol) was dissolved in DMF (20 mL), 1-difluoro-2-iodoethane (5.5 g,28 mmol), potassium carbonate (2.1 g,15.4 mmol) and potassium iodide (4.6 g,28 mmol) were added sequentially, the reaction was heated to 100deg.C in a sealed pot for 18 hours, after the reaction was completed, water (50 mL), ethyl acetate was extracted (2X 100 mL), the organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=10/1) to give 1- (2, 2-difluoroethyl) -1H-pyrazole-5-carboxylic acid ethyl ester Cpd-089B (1.1 g, colorless oil), yield: 43%.
1 H NMR(400MHz,DMSO)δ7.67(d,J=2.0Hz,1H),6.96(d,J=2.0Hz,1H),6.53-6.23(m,1H),5.02-4.94(m,2H),4.31(q,J=7.2Hz,2H),1.31(t,J=7.2Hz,3H).
Second step
Preparation of (1- (2, 2-difluoroethyl) -1H-pyrazol-5-yl) methanol
1- (2, 2-difluoroethyl) -1H-pyrazole-5-carboxylic acid ethyl ester Cpd-089B (500 mg,2.45 mmol) was dissolved in tetrahydrofuran (10 mL), lithium aluminum hydride (2.4 mL,2.45mmol, 1M) was added at 0deg.C, and the reaction mixture was stirred at 0deg.C for 1 hour. After the reaction, water was added to conduct extraction, filtration and concentration of the filtrate after drying gave (1- (2, 2-difluoroethyl) -1H-pyrazol-5-yl) methanol Cpd-089C (380 mg, colorless liquid), yield: 96%.
MS m/z(ESI):163(M+1)
Third step
Preparation of 1- (2, 2-difluoroethyl) -1H-pyrazole-5-carbaldehyde
(1- (2, 2-difluoroethyl) -1H-pyrazol-5-yl) methanol Cpd-089C (380 mg,2.34 mmol) was dissolved in methylene chloride (5 mL), and dess-Martin oxidant (1.2 g,2.81 mmol) was added to the solution to react at room temperature for 1 hour, and after completion of the reaction, the solution was filtered and the filtrate was washed with aqueous sodium hydrogencarbonate solution. The organic phase was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel column (petroleum ether/ethyl acetate=10/1) to give 1- (2, 2-difluoroethyl) -1H-pyrazole-5-carbaldehyde Cpd-089D (350 mg, colorless liquid), yield: 92%.
1 H NMR(400MHz,DMSO)δ9.92(s,1H),7.75(d,J=2.0Hz,1H),7.18(d,J=2.4Hz,1H),6.50-6.23(m,1H),5.03-4.95(m,2H).
Fourth step
Preparation of 3- ((1- (2, 2-difluoroethyl) -1H-pyrazol-5-yl) methyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester
1- (2, 2-difluoroethyl) -1H-pyrazole-5-carbaldehyde Cpd-089D (350 mg,2.2 mmol) was dissolved in methanol (5 mL), and 3-amino-1H-pyrrole-2-carboxylic acid ethyl ester (337 mg,2.2 mmol) and acetic acid (132 mg,2.2 mmol) were added. The reaction mixture was stirred at 25℃for 30 minutes, sodium cyanoborohydride (138 mg,2.2 mmol) was added, and stirring was continued at 25℃for 16 hours. After the reaction was completed, the reaction was quenched with water (10 mL) and then extracted with ethyl acetate (2X 30 mL). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated. The resulting residue was isolated and purified by silica gel column (petroleum ether/ethyl acetate=3/1) to give ethyl 3- ((1- (2, 2-difluoroethyl) -1H-pyrazol-5-yl) methyl) amino) -1H-pyrrole-2-carboxylate Cpd-089E (500 mg, pale yellow solid), yield: 77%.
MS m/z(ESI):299(M+1)。
Fifth step
Preparation of 3- (1- ((1- (2, 2-difluoroethyl) -1H-pyrazol-5-yl) methyl) -3- (ethoxycarbonyl) thiourea-1H-pyrrole-2-carboxylic acid ethyl ester
3- ((1- (2, 2-difluoroethyl) -1H-pyrazol-5-yl) methyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-089E (500 mg,1.67 mmol) was dissolved in dichloromethane (10 mL). Ethyl isothiocyanamide (220 mg,1.67 mmol) was added. The reaction mixture was reacted at 25℃for 2 hours. After the completion of the reaction, the residue was distilled to dryness, and the obtained residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate=1/1) to give 3- (1- ((1- (2, 2-difluoroethyl) -1H-pyrazol-5-yl) methyl) -3- (ethoxycarbonyl) thiourea-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-089F (500 mg, yellow solid) in 69% yield.
MS m/z(ESI):430(M+1)
Sixth step
Preparation of 1- ((1- (2, 2-difluoroethyl) -1H-pyrazol-5-yl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
3- (1- ((1- (2, 2-difluoroethyl) -1H-pyrazol-5-yl) methyl) -3- (ethoxycarbonyl) thiourea-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-089F (500 mg,1.16 mmol) and cesium carbonate (1140 mg,3.5 mmol) were dissolved in methanol (10 mL) and reacted for 6 hours at 60 ℃, after completion of the reaction, 1/3 methanol was concentrated and removed, the concentrate was slowly added to an aqueous ammonium chloride solution (20 mL), the solid was precipitated, filtered, washed with water, and the filter cake was slurried with methylene chloride/methanol=20/1 (10 mL) to remove impurities, and dried to give 1- ((1- (2, 2-difluoroethyl) -1H-pyrazol-5-yl) methyl) -2-thioxy-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-089 (250 mg, white solid) in 69% yield.
MS m/z(ESI):312(M+1)。
1 H NMR(400MHz,DMSO)δ12.42(s,2H),7.40(d,J=1.6Hz,1H),7.35(d,J=2.8Hz,1H),6.54-6.26(m,1H),6.18(d,J=2.8Hz,1H),5.93(d,J=2.0Hz,1H),5.75(s,2H),4.88-4.79(m,2H).
Example 79
1- ((1- (2, 2-difluoroethyl) -1H-imidazol-5-yl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
First step
Preparation of 1- (2, 2-difluoroethyl) -1H-imidazole-5-carbaldehyde
1H-imidazole-5-carbaldehyde Cpd-093A (1.0 g,10.4 mmol) was dissolved in N, N-dimethylformamide (10 mL), sodium hydrogen (1.7 g,12.5 mmol) was added under ice-bath, stirred under nitrogen for half an hour, followed by dropwise addition of 1, 1-difluoro-2-iodoethane (2.6 g,12.5 mmol) and stirring at 40℃for 6 hours. The reaction solution was quenched with ammonium chloride (100 mL), extracted with ethyl acetate (50 ml×2), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was purified by separation over a silica gel column (petroleum ether/ethyl acetate=2/1) to give 1- (2, 2-difluoroethyl) -1H-imidazole-5-carbaldehyde Cpd-093B (360 mg, colorless oil), yield: 21%.
MS m/z(ESI):161(M+1)。
1 H NMR(400MHz,DMSO-d6)δ9.76(d,J=0.8Hz,1H),8.10(s,1H),7.96(d,J=0.7Hz,1H),6.33(tt,J=55.0,3.5Hz,1H),4.84(td,J=15.3,3.5Hz,2H).
Second step
Preparation of 3- (((1- (2, 2-difluoroethyl) -1H-imidazol-5-yl) methyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester
1- (2, 2-difluoroethyl) -1H-imidazole-5-carbaldehyde Cpd-093B (300 mg,1.87 mmol) and ethyl 3-amino-1H-pyrrole-2-carboxylate (289 mg,1.87 mmol) were dissolved in 1, 2-dichloroethane (3 mL), glacial acetic acid (56 mg,0.93 mmol) was added dropwise and stirred at room temperature under nitrogen for half an hour, followed by sodium borohydride acetate (1.19 g,5.62 mmol) and stirred at room temperature for 2 hours. The reaction solution was quenched with water (100 mL), extracted with dichloromethane (50 ml×2), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was purified by separation over a silica gel column (petroleum ether/ethyl acetate=2/1) to give 3- (((1- (2, 2-difluoroethyl) -1H-imidazol-5-yl) methyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester preparation Cpd-093C (360 mg, colorless oil), yield: 66%.
MS m/z(ESI):299(M+1)。
1 H NMR(400MHz,DMSO-d6)δ10.82(s,1H),7.61(s,1H),6.87(s,1H),6.75(t,J=3.0Hz,1H),6.29(tt,J=55.2,3.5Hz,1H),5.54(s,1H),4.54(td,J=15.7,3.4Hz,2H),4.29(d,J=5.9Hz,2H),4.18(q,J=7.1Hz,2H),1.25(t,J=7.1Hz,3H).
Third step
Preparation of ethyl 3- (1- ((1- (2, 2-difluoroethyl) -1H-imidazol-5-yl) methyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylate
Ethyl 3- (((1- (2, 2-difluoroethyl) -1H-imidazol-5-yl) methyl) amino) -1H-pyrrole-2-carboxylate Cpd-093C (350 mg,1.17 mmol) was dissolved in dichloromethane (8 mL) followed by dropwise addition of ethoxycarbonyl isothiocyanate (308 mg,2.34 mmol) at room temperature, stirred for half an hour under nitrogen protection, after completion of the reaction concentrated at room temperature to give crude 3- (1- ((1- (2, 2-difluoroethyl) -1H-imidazol-5-yl) methyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylate Cpd-093D (430 mg, black oil), yield: 128%.
MS m/z(ESI):430(M+1)。
Fourth step
Preparation of 1- ((1- (2, 2-difluoroethyl) -1H-imidazol-5-yl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
3- (1- ((1- (2, 2-difluoroethyl) -1H-imidazol-5-yl) methyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-093D (500 mg,1.16 mmol) was dissolved with cesium carbonate (1.13 g,3.49 mmol) in methanol (7 mL) followed by heating to 65 ℃ under nitrogen protection for 6 hours, the reaction was concentrated, the crude was quenched with ammonium chloride (100 mL) and the precipitated solid filtered and the crude was prepared in reverse phase with C18 (acetonitrile/water=0% -10%,0.1% fa) to give 1- ((1- (2, 2-difluoroethyl) -1H-imidazol-5-yl) methyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrole [3,2-D ] pyrimidin-4-one Cpd-093 (40 mg, white solid), yield: 11%.
MS m/z(ESI):312(M+1)。
1 H NMR(400MHz,DMSO-d6)δ12.46(s,1H),12.32(s,1H),7.64(s,1H),7.35(d,J=2.8Hz,1H),6.70(s,1H),6.52-6.21(m,2H),5.68(s,2H),4.77(dd,J=16.0,13.3Hz,2H).
Example 80
2-thio-1- ((1- (2, 2-trifluoroethyl) -1H-pyrazol-5-yl) methyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
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First step
Preparation of 1- (2, 2-trifluoroethyl) -1H-pyrazole-5-carboxylic acid ethyl ester
1H-pyrazole-5-carboxylic acid ethyl ester Cpd-098A (2.0 g,14.3 mmol) was dissolved in N, N-dimethylformamide (15 mL), to which were added 1, 1-trifluoro-2-iodoethane (6.1 g,28.6 mmol) and potassium carbonate (3.9 g,28.6 mmol). The reaction mixture was subjected to tube-sealing reaction at 100℃for 16 hours. After the reaction was completed, water (50 mL) was added to dilute and then extracted with ethyl acetate (50 ml×3), the organic phases were combined, washed with water (30 ml×5), dried over anhydrous sodium sulfate and concentrated, and the resulting crude product was separated and purified by a silica gel column (petroleum ether/ethyl acetate=9/1) to give 1- (2, 2-trifluoroethyl) -1H-pyrazole-5-carboxylic acid ethyl ester Cpd-098B (540 mg, colorless liquid), yield: 17%.
MS m/z(ESI):223(M+1)。
Second step
Preparation of (1- (2, 2-trifluoroethyl) -1H-pyrazol-5-yl) methanol
1- (2, 2-trifluoroethyl) -1H-pyrazole-5-carboxylic acid ethyl ester Cpd-098B (500 mg,2.2 mmol) was dissolved in tetrahydrofuran (8 mL), and an aluminum lithium hydrogen tetrahydrofuran solution (3.3 mL,3.3mmol, 1M) was slowly added thereto. The reaction solution was reacted at 0℃for 1 hour. After the completion of the reaction, sodium hydroxide solution (2 ml,1 m) was added and then filtered, and the filtrate was concentrated to give crude (1- (2, 2-trifluoroethyl) -1H-pyrazol-5-yl) methanol Cpd-098C (300 mg, colorless liquid), yield: 73%.
MS m/z(ESI):181(M+1)。
Third step
Preparation of 1- (2, 2-trifluoroethyl) -1H-pyrazole-5-carbaldehyde
(1- (2, 2-trifluoroethyl) -1H-pyrazol-5-yl) methanol Cpd-098C (300 mg,1.6 mmol) was dissolved in methylene chloride (5 mL) and dess-martin oxidant (1.1 g,2.4 mmol) was added thereto. The reaction mixture was reacted at 0℃for 1 hour. After completion of the reaction, filtration, concentration of the filtrate, and purification of the resulting residue by silica gel column (petroleum ether/ethyl acetate=9/1) gave 1- (2, 2-trifluoroethyl) -1H-pyrazole-5-carbaldehyde Cpd-098D (50 mg, pale yellow solid), yield: 17%.
MS m/z(ESI):179(M+1)。
Fourth step
Preparation of 3- (((1- (2, 2-trifluoroethyl) -1H-pyrazol-5-yl) methyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester
1- (2, 2-trifluoroethyl) -1H-pyrazole-5-carbaldehyde Cpd-098D (50 mg,0.31 mmol) was dissolved in methanol (3 mL) and ethyl 3-amino-1H-pyrrole-2-carboxylate (47 mg,0.31 mmol) and two drops of glacial acetic acid were added thereto. The reaction mixture was reacted at 25℃for 1 hour. Sodium cyanoborohydride (30 mg,0.46 mmol) was added to the reaction solution to continue the reaction for 16 hours. After the reaction was completed, methanol was removed by rotary evaporation, the resulting residue was extracted with ethyl acetate (15 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give a crude product which was purified by separation on a silica gel column (petroleum ether/ethyl acetate=9/1) to give ethyl 3- (((1- (2, 2-trifluoroethyl) -1H-pyrazol-5-yl) methyl) amino) -1H-pyrrole-2-carboxylate Cpd-098E (60 mg, pale yellow solid), yield: 48%.
MS m/z(ESI):317(M+1)。
Fifth step
Preparation of ethyl 3- (3- (ethoxycarbonyl) -1- ((1- (2, 2-trifluoroethyl) -1H-pyrazol-5-yl) methyl) thiourea) -1H-pyrrole-2-carboxylate
3- (((1- (2, 2-trifluoroethyl) -1H-pyrazol-5-yl) methyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-098E (60 mg,0.19 mmol) was dissolved in methylene chloride (3 mL), and ethoxycarbonyl isothiocyanate (30 mg,0.23 mmol) was added thereto and reacted at 25℃for 2 hours. After the reaction, dichloromethane was distilled off. The resulting crude product was purified by separation on a silica gel column (petroleum ether/ethyl acetate=3/2) to give ethyl 3- (3- (ethoxycarbonyl) -1- ((1- (2, 2-trifluoroethyl) -1H-pyrazol-5-yl) methyl) thiourea) -1H-pyrrole-2-carboxylate Cpd-098F (50 mg, white solid), yield: 58%.
MS m/z(ESI):448(M+1)。
Sixth step
Preparation of 2-thio-1- ((1- (2, 2-trifluoroethyl) -1H-pyrazol-5-yl) methyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one 3- (3- (ethoxycarbonyl) -1- ((1- (2, 2-trifluoroethyl) -1H-pyrazol-5-yl) methyl) thioureido) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-098F (48 mg,0.11 mmol) was dissolved in methanol (3 mL), and cesium carbonate (69 mg,0.21 mmol) was added thereto. The reaction solution was heated to 65℃and reacted for 6 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature, methanol was removed by rotary evaporation, and saturated ammonium chloride (10 mL) was added to the obtained residue, followed by filtration to precipitate a solid, and the cake was collected and dried. Dichloromethane (3 mL) was then added and stirred for 30 min before filtration, and the filter cake was collected and dried to give 2-thio-1- ((1- (2, 2-trifluoroethyl) -1H-pyrazol-5-yl) methyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-098 (19 mg, white solid), yield: 51%.
MS m/z(ESI):330(M+1)。
1 H NMR(400MHz,DMSO-d6)δ12.41(br,2H),7.46(d,J=1.8Hz,1H),7.35(d,J=2.8Hz,1H),6.17(d,J=2.8Hz,1H),5.99(d,J=1.6Hz,1H),5.78(s,2H),5.34(d,J=9.1Hz,2H).
Biological evaluation
Test example 1 measurement of the Activity of the Compound of the present invention against human MPO
The method is used to determine the inhibitory activity of the compounds of the invention on MPO of human origin.
Experimental procedure
1. Compounds were dissolved in DMSO and subjected to triple dilution;
2. 8uLMPO enzyme was added to 384 well plates and 50-fold dilution was performed;
3. adding 48uL of DMSO solution of the compound to the enzyme, and incubating at 30deg.C for 30 min;
4. adding Ample×Red and hydrogen peroxide, and incubating at 30deg.C for 30 min;
5. plate reading with a microplate reader: e×:530nm, em: 560 nm.
The compound of the present invention was tested for a humanized MPO inhibitor by the above experiment, and IC thus tested 50 The values are shown in Table 1.
TABLE 1 IC of the Compounds of the invention against human MPO inhibitors 50 Value of
Conclusion of experiment: the data show that the compound has obvious inhibition effect on human MPO, and the activity of the compound is obviously superior to that of a positive control medicine BHV3241.
Test example 2, mouse pharmacokinetic experiments of candidate Compounds
The method is used to determine the mouse pharmacokinetics of the compounds of the invention.
The experimental steps are as follows:
1. animals: CD-1 mice
2. Sex and number: 3 androstane/group, 2 group/compound
3. The preparation for administration is prepared: 5% DMSO+10% Solutol+85% Saline. The test compound is ground by dry powder, then a proper amount of test compound (converted purity and salt coefficient) is weighed, 5% DMSO+10% Solutol+85% Saline prepared by the prescription amount is added, and the mixture is stirred to obtain transparent and uniform solution.
4. Mouse dietary status: the dosing was followed by an overnight fast and feed was resumed 4 hours after dosing. And (5) drinking water freely.
5. Administration: 3mg/kg; po.15mg/kg
6. Sampling time points are 5min, 15min, 30min, 1h, 2h, 4h, 8h and 24h after administration. About 30. Mu.L of blood sample was collected at each time point and placed in EDTA-K-containing condition 2 The anticoagulation tube of the anticoagulant is centrifuged within 30 minutes to obtain plasma. The whole blood sample was placed on wet ice prior to centrifugation. All collected plasma samples were stored on dry ice or at no higher than-70 ℃ until assayed.
The pharmacokinetics of the compounds of the present invention were determined by the above experiments and the data obtained are shown in Table 2.
TABLE 2 mouse pharmacokinetics of some of the compounds of the invention
Conclusion of experiment: the above data show that the compound of the invention has significantly better pharmacokinetics than the positive compound BHV3241.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (11)
1. A compound of formula I-4 or a pharmaceutically acceptable salt thereof:
Wherein:
m is 0 or 1;
each R a The same or different, independently of one another, from hydrogen, C 1-3 Alkyl, C 1-3 An alkyl oxy group;
r is selected from
M is O;
R 1 and R is 2 The same or different, independently of one another, from hydrogen, C 1-3 An alkyl group;
R 3 and R is 4 The same or different, independently of one another, from hydrogen, C 1-3 Alkyl, C 1-3 Alkyloxy, C 1-3 Alkylamino, (C) 1-3 Alkyl group 2 Amino, amino-C 1-3 Alkyl, said C 1-3 Alkyl, C 1-3 Alkyloxy, C 1-3 Alkylamino, (C) 1-3 Alkyl group 2 Amino, amino-C 1-3 Alkyl, optionally further cyano, C 1-3 Alkyl, C 1-3 One or more substituents in the alkyloxy group;
alternatively, R 3 And R is 4 Ligating to form C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, said C 3-8 Cycloalkyl and 3-8 membered heterocyclyl, optionally further substituted with C 1-3 Alkyl substitution;
g is selected from optionally one R b1 Substituted
Each R b1 Identical or different, independently of one another, from C 1-3 A haloalkyl group.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula II:
wherein:
represents a double bond;
m is O;
R 1 and R is 2 The same or different, independently of one another, from hydrogen, C 1-3 An alkyl group;
R 3 and R is 4 The same or different, independently of one another, from hydrogen, C 1-3 Alkyl, amino-C 1-3 Alkyl, said amino-C 1-3 Alkyl, optionally further covered by C 1-3 Alkyl substituted;
alternatively, R 3 And R is 4 Ligating to form C 3-6 Cycloalkyl or 3-6 membered heterocyclyl, said C 3-6 Cycloalkyl and 3-6 membered heterocyclyl, optionally further substituted with C 1-3 Alkyl substitution;
e is CH; m and R a Having the definition of claim 1.
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula IV:
wherein G is selected from the group consisting of b1 SubstitutedEach R b1 Identical or different, independently of one another, from C 1-3 A haloalkyl group; r is R a And m has the definition as defined in claim 1.
4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of:
5. a compound as described below or a pharmaceutically acceptable salt thereof:
6. a process for the preparation of a compound according to any one of claims 1 to 5, comprising the steps of:
reacting the compound 1 under the action of alkali to obtain a compound shown as a formula I-4;
wherein R has the definition as defined in any one of claims 1 to 5; r is R 0 Identical or different, independently of one another, from C 1-3 An alkyl group;
and/or the base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide.
7. A pharmaceutical composition comprising a therapeutically effective amount of at least one of the compounds of any one of claims 1-5 or a pharmaceutically acceptable salt thereof.
8. Use of a compound according to any one of claims 1 to 5, or at least one of its pharmaceutically acceptable salts, and a pharmaceutical composition according to claim 7, for the manufacture of a medicament for the treatment of a myeloperoxidase-related disease.
9. The use according to claim 8, characterized in that it is in the preparation of a medicament for MPO inhibitors.
10. Use of at least one of the compounds of any one of claims 1-5 or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition of claim 7 for the manufacture of a medicament for the treatment of neurodegenerative diseases, stroke, epilepsy, depression, traumatic brain injury, cardiovascular diseases, novel coronavirus-related disorders.
11. The use according to claim 10, wherein the neurodegenerative disease is selected from dementia, parkinson's disease, multiple sclerosis, huntington's disease, amyotrophic lateral sclerosis, multiple system atrophy, aphasia; the cardiovascular disease is selected from heart failure, atrial fibrillation, atherosclerosis, thrombosis, acute coronary syndrome, pulmonary hypertension, and diabetes.
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