CN114014866A - 5, 7-dihydrofuro [3,4-d ] pyrimidine compound and preparation method and application thereof - Google Patents
5, 7-dihydrofuro [3,4-d ] pyrimidine compound and preparation method and application thereof Download PDFInfo
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- CN114014866A CN114014866A CN202111319949.4A CN202111319949A CN114014866A CN 114014866 A CN114014866 A CN 114014866A CN 202111319949 A CN202111319949 A CN 202111319949A CN 114014866 A CN114014866 A CN 114014866A
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- Prior art keywords
- dihydrofuro
- compound
- pyrimidine
- boc
- dimethylformamide
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- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- -1 5, 7-dihydrofuro [3,4-d ] pyrimidine compound Chemical class 0.000 title claims description 21
- 150000001875 compounds Chemical class 0.000 claims abstract description 37
- APPUSLHNGZUZJW-UHFFFAOYSA-N 5,7-dihydrofuro[3,4-d]pyrimidine Chemical class C1=NC=C2COCC2=N1 APPUSLHNGZUZJW-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000002259 anti human immunodeficiency virus agent Substances 0.000 claims abstract description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 40
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 34
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- 239000000543 intermediate Substances 0.000 claims description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 19
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 18
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 13
- 239000000047 product Substances 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 239000011734 sodium Substances 0.000 claims description 8
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- 238000003786 synthesis reaction Methods 0.000 claims description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- LZRDHSFPLUWYAX-UHFFFAOYSA-N tert-butyl 4-aminopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(N)CC1 LZRDHSFPLUWYAX-UHFFFAOYSA-N 0.000 claims description 6
- PBYPWLVGLJZCCV-ONEGZZNKSA-N (e)-3-(4-hydroxy-3,5-dimethylphenyl)prop-2-enenitrile Chemical compound CC1=CC(\C=C\C#N)=CC(C)=C1O PBYPWLVGLJZCCV-ONEGZZNKSA-N 0.000 claims description 4
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 4
- 239000007858 starting material Substances 0.000 claims description 4
- CKXZPVPIDOJLLM-UHFFFAOYSA-N tert-butyl n-piperidin-4-ylcarbamate Chemical compound CC(C)(C)OC(=O)NC1CCNCC1 CKXZPVPIDOJLLM-UHFFFAOYSA-N 0.000 claims description 4
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical class BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 claims description 3
- 229940073608 benzyl chloride Drugs 0.000 claims description 3
- 150000005524 benzylchlorides Chemical class 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 2
- WRAAHQVXMZLMQR-UHFFFAOYSA-N 2,4-dichloro-5,7-dihydrofuro[3,4-d]pyrimidine Chemical compound ClC1=NC(Cl)=NC2=C1COC2 WRAAHQVXMZLMQR-UHFFFAOYSA-N 0.000 claims description 2
- 125000006278 bromobenzyl group Chemical group 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 125000004803 chlorobenzyl group Chemical group 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 150000008423 fluorobenzenes Chemical class 0.000 claims description 2
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims 1
- 229940124411 anti-hiv antiviral agent Drugs 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 229940095064 tartrate Drugs 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 22
- 238000002474 experimental method Methods 0.000 abstract description 6
- 238000012216 screening Methods 0.000 abstract description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 32
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- 229960002049 etravirine Drugs 0.000 description 9
- PYGWGZALEOIKDF-UHFFFAOYSA-N etravirine Chemical compound CC1=CC(C#N)=CC(C)=C1OC1=NC(NC=2C=CC(=CC=2)C#N)=NC(N)=C1Br PYGWGZALEOIKDF-UHFFFAOYSA-N 0.000 description 9
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- 229960002814 rilpivirine Drugs 0.000 description 7
- YIBOMRUWOWDFLG-ONEGZZNKSA-N rilpivirine Chemical compound CC1=CC(\C=C\C#N)=CC(C)=C1NC1=CC=NC(NC=2C=CC(=CC=2)C#N)=N1 YIBOMRUWOWDFLG-ONEGZZNKSA-N 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
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- 238000002835 absorbance Methods 0.000 description 4
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- 208000030507 AIDS Diseases 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
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- 229940124321 AIDS medicine Drugs 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
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- 239000000203 mixture Substances 0.000 description 2
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 2
- 229940042402 non-nucleoside reverse transcriptase inhibitor Drugs 0.000 description 2
- 239000002726 nonnucleoside reverse transcriptase inhibitor Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 2
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- HGKPAXHJTMHWAH-UHFFFAOYSA-N 1-(bromomethyl)-4-methylsulfonylbenzene Chemical compound CS(=O)(=O)C1=CC=C(CBr)C=C1 HGKPAXHJTMHWAH-UHFFFAOYSA-N 0.000 description 1
- MCHDHQVROPEJJT-UHFFFAOYSA-N 1-(chloromethyl)-4-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=C(CCl)C=C1 MCHDHQVROPEJJT-UHFFFAOYSA-N 0.000 description 1
- OAVCWZUKQIEFGG-UHFFFAOYSA-O 2-(5-methyl-2H-tetrazol-1-ium-1-yl)-1,3-thiazole Chemical compound CC1=NN=N[NH+]1C1=NC=CS1 OAVCWZUKQIEFGG-UHFFFAOYSA-O 0.000 description 1
- AZKSAVLVSZKNRD-UHFFFAOYSA-M 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AZKSAVLVSZKNRD-UHFFFAOYSA-M 0.000 description 1
- PBYPWLVGLJZCCV-UHFFFAOYSA-N 3-(4-hydroxy-3,5-dimethylphenyl)prop-2-enenitrile Chemical compound CC1=CC(C=CC#N)=CC(C)=C1O PBYPWLVGLJZCCV-UHFFFAOYSA-N 0.000 description 1
- ASSMPDZEDVTRKG-UHFFFAOYSA-N 4-(bromomethyl)aniline Chemical compound NC1=CC=C(CBr)C=C1 ASSMPDZEDVTRKG-UHFFFAOYSA-N 0.000 description 1
- QNJHTLTUBNXLFS-UHFFFAOYSA-N 4-(bromomethyl)benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=C(CBr)C=C1 QNJHTLTUBNXLFS-UHFFFAOYSA-N 0.000 description 1
- OVILZFVTUVWJTO-UHFFFAOYSA-N 4-(chloromethyl)benzamide Chemical compound NC(=O)C1=CC=C(CCl)C=C1 OVILZFVTUVWJTO-UHFFFAOYSA-N 0.000 description 1
- VOLRSQPSJGXRNJ-UHFFFAOYSA-N 4-nitrobenzyl bromide Chemical compound [O-][N+](=O)C1=CC=C(CBr)C=C1 VOLRSQPSJGXRNJ-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
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- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
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- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Virology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Tropical Medicine & Parasitology (AREA)
- Medicinal Chemistry (AREA)
- Communicable Diseases (AREA)
- AIDS & HIV (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a 5, 7-dihydrofuro [3,4-d]Pyrimidine compounds and a preparation method and application thereof. The compound has a structure shown in a general formula I or II. The invention also relates to a pharmaceutical composition containing the compound with the structure shown in the formula I or II. The activity screening experiment shows that the compound has good anti-HIV-1 activity, so the invention also provides the application of the compound in preparing anti-AIDS drugs.
Description
Technical Field
The invention belongs to the technical field of organic compound synthesis and medical application, and particularly relates to a 5, 7-dihydrofuro [3,4-d ] pyrimidine compound and a preparation method and application thereof.
Background
AIDS is a clinical syndrome which is infected by human immunodeficiency virus (HIV-1) and causes defects in the defense functions of the human body, thus easily causing opportunistic infection and tumors. At present, about 3800 ten thousand HIV infectors exist in the world, and about 170 ten thousand new infectors exist in each year; in China, the prevalence of AIDS has already entered into a rapid growth period, the number of infected people is over 100 million at present, but most of the anti-AIDS drugs clinically used for free treatment in China are patent overdue imitation drugs, the varieties are few, the toxic and side effects are large, and in long-term clinical application, serious drug resistance is easy to generate, and the clinical requirements of patients cannot be met. Therefore, the development of the original new drug for treating AIDS with independent intellectual property rights based on independent innovation provides the national anti-AIDS drug with safety, effectiveness and low price, and is the important demand facing the national development strategy and the life health of people.
Etravirine (Etravirine, ETR) and Rilpivirine (RPV) are second generation anti-aids marketed drugs approved by the FDA in the united states, both of which are HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). They have high inhibitory activity to HIV-1 wild strains and clinically common single mutant strains, but with the wide clinical application of the mutant strains, a plurality of mutant strains aiming at the wild strains and the clinically common single mutant strains appear at present. For example, the activity of etravirine on the double mutant K103N/Y181C (EC)5045.4nM) and rilpivirine activity against the double mutant F227L/V106A (EC)5081.6nM) were all significantly reduced. In our previous work (J.Med.chem.2019,62,1484-1501), an anti-HIV-1 drug candidate 13c2 was obtained by rational drug design based on targets, which has highly potent antiviral activity against HIV-1 wild strain, common single mutant and double mutant F227L/V106A, but activity against double mutant K103N/Y181C was reduced by about 26-fold compared to wild strain. Therefore, structural modification is urgently needed to find a new generation of anti-AIDS drug candidates with high-efficiency anti-drug resistance.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a 5, 7-dihydrofuro [3,4-d ] pyrimidine compound and a preparation method thereof; the invention also provides application of the 5, 7-dihydrofuro [3,4-d ] pyrimidine compound in preparing anti-HIV drugs.
The technical scheme of the invention is as follows:
mono, 5, 7-dihydrofuro [3,4-d ] pyrimidines
The 5, 7-dihydrofuro [3,4-d ] pyrimidine compound or the pharmaceutically acceptable salt thereof has a structure shown in the following general formula I or II:
wherein R is: SO (SO)2NH2，SO2CH3，CONH2，NHSO2NH2，NHSO2CH3，NO2，NH2，CF3，OH，COOH，CH2OH，CO2Me，F，Cl，Br，CH3，OCH3(ii) a The substituent is mono-substituted or multi-substituted in ortho, meta and para positions.
According to the invention, the 5, 7-dihydrofuro [3,4-d ] pyrimidine compound is preferably one of the following compounds:
preparation method of di, 5, 7-dihydrofuro [3,4-d ] pyrimidine compound
(1) The preparation method of the 5, 7-dihydrofuro [3,4-d ] pyrimidine compound I comprises the following steps: taking 2, 4-dichloro-5, 7-dihydrofuro [3,4-d ] pyrimidine A as a starting material, and firstly reacting the starting material with (E) -3, 5-dimethyl-4-hydroxyphenylacrylonitrile in an N, N-dimethylformamide solution to generate an intermediate B; then the intermediate B and N-Boc-4-aminopiperidine are subjected to nucleophilic substitution reaction to generate an intermediate C, the intermediate C is subjected to Boc removal protection in trifluoroacetic acid to obtain an intermediate D, and finally the intermediate D and various substituted chlorobenzyl or bromobenzyl are subjected to reaction to generate a target product I.
The synthesis route one is as follows:
reagents and conditions: (i) (E) -3, 5-dimethyl-4-hydroxybenzeneacrylonitrile, N-dimethylformamide, potassium carbonate, 20 ℃; (ii) N-Boc-4-aminopiperidine, N, N-dimethylformamide, potassium carbonate, 100-; (iii) trifluoroacetic acid, dichloromethane, 20 ℃; (iv) substituted benzyl chloride or benzyl bromide, N, N-dimethylformamide and potassium carbonate at 20-40 ℃.
(2) The preparation method of the 5, 7-dihydrofuro [3,4-d ] pyrimidine compound II comprises the following steps: taking para-substituted fluorobenzene A1 as an initial raw material, reacting with 4-Boc-aminopiperidine in dimethyl sulfoxide to obtain an intermediate B1, removing Boc from B1 by trifluoroacetic acid to obtain an intermediate C1, and finally carrying out nucleophilic substitution reaction on the intermediates C1 and B to obtain a target product II.
The second synthetic route is as follows:
reagents and conditions: (i) 4-Boc-aminopiperidine, dimethyl sulfoxide, 120 ℃; (ii) trifluoroacetic acid, dichloromethane, 20 ℃; (iii) the compound B, N, N-dimethylformamide, potassium carbonate, 100-120 ℃;
r is shown as the general formula I or II.
Application of tri, 5, 7-dihydrofuro [3,4-d ] pyrimidine compound
The invention discloses a screening result of anti-HIV-1 activity of 5, 7-dihydrofuro [3,4-d ] pyrimidine compounds and the first application of the compounds as anti-HIV inhibitors. Experimental results prove that the 5, 7-dihydrofuro [3,4-d ] pyrimidine compound can be used for preparing anti-HIV drugs.
anti-HIV-1 activity test and pharmaceutical evaluation of target compound
For 5, 7-dihydrofuro [3,4-d ] synthesized according to the above method]Pyrimidine compoundCell level anti-HIV-1 wild type strain IIIBThe activity of mutants K103N, Y181C, E138K, F227L/V106A and K103N/Y181C were screened, and Etravirine (ETR) and Rilpivirine (RPV) were used as positive controls. Their anti-HIV-1 activity is shown in Table 1, and the pharmacokinetic parameters of Compounds E3 and F2 are shown in Table 2.
As can be seen from Table 1, the 5, 7-dihydrofuro [3,4-d ] pyrimidine compounds of the present invention exhibit very strong activity against HIV-1 wild-type strains and mutant strains. The activity of the compounds E3 and F2 is particularly outstanding, particularly the resistance to double mutant strains F227L/V106A and K103N/Y181C is obviously improved, and the compounds have the activity superior to the ETR of the marketed drug,
as can be seen from table 2, the half-life of E3 in rats was 1.05h, and the bioavailability was 32.1%; the half-life of F2 in rats was 1.47h, and the bioavailability was 16.6%. The results show that the compounds E3 and F2 have good pharmacokinetic properties and can be used and developed as candidate medicines for preparing anti-HIV medicines.
Therefore, the 5, 7-dihydrofuro [3,4-d ] pyrimidine compound can be used as a non-nucleoside HIV-1 inhibitor. In particular to the application of the compound as an HIV-1 inhibitor in preparing anti-AIDS drugs.
An anti-HIV-1 pharmaceutical composition comprising a 5, 7-dihydrofuro [3,4-d ] pyrimidine compound of the invention and one or more pharmaceutically acceptable carriers or excipients.
The invention provides a 5, 7-dihydrofuro [3,4-d ] pyrimidine compound with a brand-new structure, a preparation method thereof, an anti-HIV-1 activity screening result thereof and a first application thereof in the field of antivirus. Experiments prove that the 5, 7-dihydrofuro [3,4-d ] pyrimidine compound can be used as an HIV-1 non-nucleoside reverse transcriptase inhibitor and has high application value. In particular to the application of the compound as an HIV-1 inhibitor in preparing anti-AIDS drugs.
Detailed Description
The present invention will be understood by reference to the following examples, in which all the numbers of the objective compounds are the same as those in Table 1, but the contents of the present invention are not limited thereto.
Scheme 1:
reagents and conditions: (i) (E) -3, 5-dimethyl-4-hydroxybenzeneacrylonitrile, N-dimethylformamide, potassium carbonate, 20 ℃; (ii) N-Boc-4-aminopiperidine, N-dimethylformamide, potassium carbonate, 120 ℃; (iii) trifluoroacetic acid, dichloromethane, 20 ℃; (iv) substituted benzyl chloride or benzyl bromide, N, N-dimethylformamide and potassium carbonate at 20-40 ℃.
Scheme 2:
reagents and conditions: (i) (E) -3, 5-dimethyl-4-hydroxybenzeneacrylonitrile, N-dimethylformamide, potassium carbonate, 20 ℃; (ii) c1, N-dimethylformamide, potassium carbonate, 120 ℃.
EXAMPLE 1 Synthesis of 2- (piperidin-4-amine) -4- (2, 6-dimethyl-4-cyanovinylphenoxy) 5, 7-dihydrofuro [3,4-D ] pyrimidine (D)
2, 4-dichloro-5, 7-dihydrofuro [3,4-d ]]Pyrimidine (A,1.72g,10mmol), 4-hydroxy-3, 5-dimethylbenzeneacrylonitrile (1.73g,10mmol) and potassium carbonate (1.70g,12mmol) were added to 30mL of N, N-Dimethylformamide (DMF) and stirred at room temperature for 5 h. Then, 25mL of ice water was slowly added to the reaction solution, filtered and dried to obtain a white solid, i.e., Compound B. ESI-MS: M/z 328.3[ M +1 ]]+,350.4[M+Na]+.C17H14ClN3O2(327.08).
Compound B (3.2g,10mmol), N-Boc-4-aminopiperidine (2.4g,12mmol) is reacted with potassium carbonate (2.8g,20mmol) in 50mL DMF at 120 ℃ for 6 h. After the reaction was cooled, the reaction solution was slowly poured into 200mL of water to form a large amount of white solid. Filtering and drying to obtain a crude product C, and directly putting the compound C into the next step without purification.
C (0.49g,1.0mmol) was weighed out and dissolved in 4mL of dichloromethane, and trifluoroethyl ether was added to the reaction solutionAcid (0.74mL,10mmol) was reacted at room temperature for 5 h. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture to adjust the pH to 9. Then, the mixture was extracted with dichloromethane, washed with saturated sodium chloride solution and water, and the organic layer was dried over anhydrous sodium sulfate. Finally, the intermediate D is obtained by column chromatography separation, and the yield is 66%. ESI-MS of M/z 392.4[ M +1 ]]+,C22H25N5O2(391.20).
EXAMPLE 2 Synthesis of Compound of interest E
Compound D (0.39g,1.0mmol), potassium carbonate (0.28g,2.0mmol) and substituted benzyl (1.2mmol) were added to 10mL DMF and stirred at room temperature for 3-8h (TLC detection). Adding 40mL of water into the reaction solution, extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, and finally separating by flash column chromatography to obtain the target compound E.
The target compound E1-6 was prepared from different substituted benzyl groups and intermediate D by the methods described above, and the results were as follows:
the procedure was as above except that D and 4-bromomethylbenzenesulfonamide were used, the product was E1, white solid, yield: 84 percent.
1H NMR(400MHz,DMSO-d6)δ7.78(d,J＝7.8Hz,2H),7.60(d,J＝16.4Hz,1H,ArCH＝),7.48-7.45(m,4H),7.37-7.24(m,2H),7.08(s,1H,NH),6.41(d,J＝16.7Hz,1H,＝CHCN),4.92(s,2H,O-CH2),4.76(s,2H,O-CH2),3.78-3.37(m,3H),2.92-2.56(m,2H),2.08(s,6H),1.88-1.13(m,6H).13C NMR(100MHz,DMSO-d6)δ163.0,162.9,150.5,148.5,143.1,131.7,131.6,129.4,128.9,128.3,126.9,126.0,119.3,96.6,69.4,61.9,52.6,31.6,16.5.ESI-MS:m/z 561.3[M+1]+,583.4[M+Na]+
The procedure was as above except D and 4- (methylsulfonyl) benzyl bromide were used, the product was E2, white solid, yield: 82 percent.
1H NMR(400MHz,DMSO-d6)δ7.90-7.86(m,2H),7.60-7.58(m,1H,ArCH＝),7.54(d,J＝7.8Hz,2H),7.44(s,2H,C3,C5-Ph-H),7.31-6.99(m,1H),6.40(d,J＝16.6Hz,1H,＝CHCN),5.00-4.87(m,2H,O-CH2),4.76(s,2H,O-CH2),3.63-3.39(m,3H),3.20(s,3H,SO2CH3),2.85-2.56(m,2H),2.08(s,6H),1.83-1.07(m,6H).13C NMR(100MHz,DMSO-d6)δ163.0,162.9,150.5,149.2,148.5,145.4,139.8,139.5,131.7,131.6,129.7,128.5,127.3,119.4,96.6,72.4,69.5,62.6,61.8,52.6,44.1,31.6,16.5.ESI-MS:m/z 560.2[M+1]+,582.8[M+Na]+.C30H33N5O4S(559.23).
The procedure was as above except D and 4-chloromethylbenzamide were used and the product was E3, white solid, yield: 74 percent.
1H NMR(400MHz,DMSO-d6)δ7.79(d,J＝8.0Hz,2H),7.60(d,J＝16.3Hz,1H,ArCH＝),7.54-7.45(m,2H),7.44(m,2H,C3,C5-Ph-H),7.37-7.24(m,2H),7.07(s,1H,NH),6.40(d,J＝16.4Hz,1H,＝CHCN),4.94-4.92(m,2H,O-CH2),4.76(s,2H,O-CH2),3.65-3.37(m,3H),2.90-2.61(m,2H),2.08(s,6H),1.88-1.09(m,6H).13C NMR(100MHz,DMSO-d6)δ163.0,162.8,150.5,148.5,143.1,139.5,131.8,129.4,128.9,128.5,127.0,126.3,119.3,96.6,72.5,69.4,61.7,52.6,31.6,16.5.ESI-MS:m/z 525.3[M+1]+,547.5[M+Na]+.C30H32N6O3(524.25).
The procedure is as above except that D and p-nitrobenzyl bromide are used, product E4, white solid, yield: 88 percent.
1H NMR(400MHz,DMSO-d6)δ8.19(d,J＝8.3Hz,2H,C3,C5-Ph’-H),7.61-7.54(m,3H),7.44(s,2H,C3,C5-Ph-H),7.36-7.00(m,1H),6.40(d,J＝16.6Hz,1H,＝CHCN),4.90(s,2H,O-CH2),4.76(s,2H,O-CH2),3.64-3.44(m,3H),2.87-2.58(m,2H),2.07(s,6H),1.87-1.16(m,6H).13C NMR(100MHz,DMSO-d6)δ163.1,162.9,150.5,148.5,147.5,146.9,131.7,131.6,130.0,128.5,123.8,119.3,96.6,72.3,69.5,61.6,52.6,31.6,29.0,26.8,16.5.ESI-MS:m/z 527.5[M+1]+.C29H30N6O4(526.23).
The procedure was as above except D and p-aminobenzyl bromide were used, the product was E5, white solid, yield: 51 percent.
1H NMR(400MHz,DMSO-d6)δ7.66-7.55(m,2H),7.45(s,2H,C3,C5-Ph-H),7.08-7.05(m,1H),6.54(d,J＝7.0Hz,2H),6.42(d,J＝16.7Hz,1H,＝CHCN),5.89(s,1H,NH),5.28(s,2H,NH2),4.92(s,2H,O-CH2),4.77(s,2H,O-CH2),4.09-3.60(m,3H),2.87-2.70(m,2H),2.08(s,6H),1.90-1.04(m,6H).13C NMR(100MHz,DMSO-d6)δ163.0,162.7,150.4,148.5,131.7,128.5,123.7,119.3,118.3,113.9,96.7,95.6,72.4,69.5,29.5,16.6.ESI-MS:m/z 497.5[M+1]+,519.7[M+Na]+.C29H32N6O2(496.26).
The procedure was as above except D and p-trifluoromethylbenzyl chloride were used, the product was E6, white solid, yield: 77 percent.
1H NMR(400MHz,DMSO-d6)δ7.67(d,J＝7.8Hz,2H,C3,C5-Ph’-H),7.64-7.55(m,1H),7.49(d,J＝7.9Hz,2H,C2,C6-Ph’-H),7.44(s,2H,C3,C5-Ph-H),7.24-7.08(m,1H),6.40(d,J＝16.7Hz,1H,＝CHCN),4.90(s,2H,O-CH2),4.76(s,2H,O-CH2),3.57-3.39(m,2H),2.82-2.56(m,3H),2.07(s,6H),1.93-1.13(m,6H).13C NMR(100MHz,DMSO-d6)δ163.0,162.9,150.5,144.2,131.7,131.6,129.7,128.5,126.1,125.5,125.4,123.4,119.3,96.7,69.4,61.9,52.6,31.5,29.0,16.5.
EXAMPLE 3 Synthesis of Compound F
Compound D (0.39g,1.0mmol), potassium carbonate (0.28g,2.0mmol) and compound C1(1.2mmol) were added to 10mL DMF and reacted at 120 ℃ for 6 h. After the reaction is cooled, the reaction solution is slowly poured into 50mL of water, then ethyl acetate is used for extraction, the organic phase is dried by anhydrous sodium sulfate, and finally the target compound F1-2 is obtained by flash column chromatography separation.
The procedure was as above except that D and N- (4- (4-aminopiperidin-1-yl) phenyl) sulfamide were used, the product was F1, white solid, yield: 29 percent.
1H NMR(400MHz,DMSO-d6)δ9.67(s,1H,NH),7.68(d,J＝16.4Hz,1H,ArCH＝),7.52(s,2H,C3,C5-Ph-H),7.48-7.45(m,2H),7.25(d,J＝8.1Hz,2H,C3,C5-Ph’-H),6.90(d,J＝8.1Hz,2H,C2,C6-Ph’-H),6.51(d,J＝16.7Hz,1H,＝CHCN),5.04(s,2H,O-CH2),4.90(s,2H,O-CH2),3.39(s,2H,Ph-CH2),3.09(t,J＝4.8Hz,4H,C3,C5-piperazine-H),2.39(t,J＝4.8Hz,4H,C2,C6-piperazine-H),2.10(s,6H).13C NMR(100MHz,DMSO-d6)δ173.9,162.8,160.6,152.2,150.5,139.5,131.9,131.8,130.8,129.1,128.6,119.4,118.6,104.5,96.8,72.2,69.5,61.5,52.1,45.9,16.5.ESI-MS:m/z 562.2[M+1]+,584.5[M+Na]+.C28H31N7O4S(561.22).
The procedure was as above except that D and N- (4- (4-aminopiperidin-1-yl) phenyl) methanesulfonamide were used, the product was F2, white solid, yield: 79 percent.
1H NMR(400MHz,DMSO-d6)δ9.69(s,1H,NH),7.69(d,J＝16.7Hz,1H,ArCH＝),7.54(s,2H,C3,C5-Ph-H),7.25(d,J＝7.7Hz,2H,C3,C5-Ph’-H),6.91(d,J＝8.1Hz,2H,C2,C6-Ph’-H),6.50(d,J＝16.7Hz,1H,＝CHCN),5.06(s,2H,O-CH2),4.88(s,2H,O-CH2),3.37(s,2H,Ph-CH2),3.09(t,J＝4.9Hz,4H,C3,C5-piperazine-H),2.88(s,3H,SO2CH3),2.39(t,J＝4.8Hz,4H,C2,C6-piperazine-H),2.10(s,6H).13C NMR(100MHz,DMSO-d6)δ173.9,162.8,160.6,152.2,150.5,139.5,131.9,131.8,130.8,129.1,128.6,119.4,118.6,104.5,96.8,72.2,69.5,61.5,52.1,45.9,34.1,16.5.ESI-MS:m/z 561.4[M+1]+,583.6[M+Na]+.C29H32N6O4S(560.22).
Example 4: in vitro anti-HIV Activity test experiment of target Compounds
Principle of testing
The compound in vitro anti-HIV activity screening adopts an MTT method. MTT is known collectively as 3- (4, 5-dimethyl-2-thiazolyl) -2, 5-diphenyltetrazolium bromide (trade name: thiazole blue), and can be used to detect the survival and growth of cells. The detection principle is as follows: MTT can be combined with succinate dehydrogenase in living cells and reduced to blue-violet crystal formazan which is insoluble in water, and the MTT is deposited in the cells, but dead cells do not have the function. Formazan in cells can be dissolved by dimethyl sulfoxide, and the number of living cells can be indirectly reflected by detecting the absorbance (A) value at 590nm by using an enzyme labeling instrument. Within a certain range of cell number, MTT crystals are formed in an amount proportional to the cell number.
Because the HIV-infected MT-4 cells can be diseased within a certain period of time (5-7 days), a solution of a compound to be detected with a proper concentration is added into the suspension of the HIV-infected MT-4 cells, and after a period of culture (5-7 days), the activity of the MT-4 cells is measured by an MTT (methyl thiazolyl tetrazolium) analysis method, so that the concentration of a drug (EC) for protecting 50% of the cells from cytopathic diseases is obtained (the concentration of the drug is the same as that of the drug (EC)50) The anti-HIV activity of the target compound can be obtained.
Test materials and methods
(1)HIV-1(IIIB) Various HIV-1 resistant strains: supplied by the institute Rega research institute of medical institute, Washington, Belgium.
(2) MT-4 cells: supplied by Rega research institute of medical institute, luwen university, belgium.
(3) MTT: purchased from Sigma, usa.
(4) Sample treatment: the samples were dissolved in DMSO to appropriate concentrations and diluted 5-fold with double distilled water, 5 dilutions each.
(5) Positive control drug: etravirine (ETR) and Rilpivirine (RPV).
(6) The test method comprises the following steps: diluting the sample, adding into suspension of HIV-infected MT-4 cell, determining cell activity by MTT colorimetric method after a period of time, recording absorbance (A) value at 590nm in microplate reader, and calculating EC50。
(7) MTT colorimetric method: after adding the sample solution for incubation for a period of time, 20. mu.L of MTT solution (5mg/mL) was added to each well, and after incubation for several hours, the staining solution was discarded, 150. mu.L of DMSO was added to each well, mixed well, and the absorbance (A) at 590nm was measured in a microplate reader.
Experimental methods
50 μ L of 1X 10-containing solution was added to a 96-well cell culture plate4Adding 20 μ L of MT-4 cell suspension (containing 100 times of CCID per ml) infected with HIV-1 into MT-4 cell culture solution50) Then, test compound solutions or positive control drugs with different concentrations are added, and 3 multiple wells are designed for each concentration. Cells were then incubated at 5% CO2The cells were incubated at 37 ℃ for 5 days in an atmosphere, 20. mu.L (5mg/mL) of MTT solution was added to each well, and incubation was continued for 2 hoursThen, DMSO was added, the absorbance of the reaction solution at 540nm was measured using a microplate reader, and the cell proliferation rate P% was calculated for the compounds at different concentrations. Both blank and positive drug controls were set up to calculate the concentration of compound required to protect 50% of the cells from HIV-induced cytopathic Effects (EC)50)。
Synthesis of partial 5, 7-dihydrofuro [3,4-d ] according to the above Experimental method]Cellular anti-HIV-1 wild-type strain III of pyrimidine compoundsBThe single mutants K103N, Y181C and E138K, the double mutants F227L/V106A and K103N/Y181C were screened for activity, and the results of the activity are shown in Table 1.
anti-HIV-1 Activity of 5, 7-dihydrofuro [3,4-d ] pyrimidines and Positive drugs in part 1
Note:aEC50(ii) a concentration of a compound that protects 50% of MT-4 cells infected with HIV-1 from cytopathic effects;
example 5: pharmacokinetic evaluation of Compounds E3 and F2
Test material
The kit comprises a compound to be detected, chromatographic methanol, heparin purchase, purified water, an Eppendorf 5415D type centrifuge, an Agilent 1200LC/MSD liquid chromatography mass spectrometer, a pipette gun (IKA), a rat gavage needle and a healthy male SD rat.
Experimental methods
12 male SD rats were randomly divided into 4 groups of 3 rats each. Fasting was performed for 12h before administration, and water was freely available. The single oral dose of E3 and F2 was 10mg/kg, and was formulated as a dosing formulation with 70% PEG400 and 30% saline prior to administration. After the gavage, blood is collected for about 0.2mL in 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h and 12h through the clavicle venous sinus, the blood sample is placed in a heparinized centrifuge tube, after 2200g of the blood sample is centrifuged for 15min, a supernatant blood plasma sample is taken and stored at the temperature of minus 20 ℃ for later use. The test dose of tail vein injection is 2mg/kg, after injection, the blood is collected by 0.2mL through the clavicle venous sinus after 2min, 5min, 15min, 30min, 1h, 2h, 4h and 8h respectively, and the blood sample treatment is the same as the previous treatment.
The determination of the E3 and F2 concentrations in plasma samples was performed using LC-MS analysis. Fitting analysis of the measured plasma pharmaco-chronologic data using a non-compartmental model of the DAS 2.0 pharmacokinetic program, calculating the principal pharmacokinetic parameter Cmax、AUC、Tmax、T1/2CL, and drawing the average blood concentration-time curve.
The bioavailability was calculated according to the following formula:
F(％)＝[AUC(po)×Div]/[AUC(iv)×Dpo]×100％
AUC: area under the curve; d: dosage to be administered
TABLE 2 pharmacokinetic parameters of Compounds E3 and F2
Claims (6)
1, 5, 7-dihydrofuro [3,4-d ] pyrimidine compounds or pharmaceutically acceptable salts thereof have a structure shown in the following general formula I or II:
wherein R is: SO (SO)2NH2，SO2CH3，CONH2，NHSO2NH2，NHSO2CH3，NO2，NH2，CF3，OH，COOH，CH2OH，CO2Me，F，Cl，Br，CH3，OCH3(ii) a The substituent is mono-substituted or multi-substituted in ortho, meta and para positions.
2. A 5, 7-dihydrofuro [3,4-d ] pyrimidine compound as claimed in claim 1 wherein the pharmaceutically acceptable salt of the compound is sodium, hydrochloride, sulfate, tartrate or citrate.
3. A 5, 7-dihydrofuro [3,4-d ] pyrimidine compound according to claim 1, characterized by being one of the following:
4. a process for the preparation of 5, 7-dihydrofuro [3,4-d ] pyrimidines as claimed in claim 1, characterised in that the steps of I or II are:
(1) the preparation method of the 5, 7-dihydrofuro [3,4-d ] pyrimidine compound I comprises the following steps: taking 2, 4-dichloro-5, 7-dihydrofuro [3,4-d ] pyrimidine A as a starting material, and firstly reacting the starting material with (E) -3, 5-dimethyl-4-hydroxyphenylacrylonitrile in an N, N-dimethylformamide solution to generate an intermediate B; then the intermediate B and N-Boc-4-aminopiperidine are subjected to nucleophilic substitution reaction to generate an intermediate C, the intermediate C is subjected to Boc removal protection in trifluoroacetic acid to obtain an intermediate D, and finally the intermediate D and various substituted chlorobenzyl or bromobenzyl are subjected to reaction to generate a target product I;
the synthesis route one is as follows:
reagents and conditions: (i) (E) -3, 5-dimethyl-4-hydroxybenzeneacrylonitrile, N-dimethylformamide, potassium carbonate, 20 ℃; (ii) N-Boc-4-aminopiperidine, N, N-dimethylformamide, potassium carbonate, 100-; (iii) trifluoroacetic acid, dichloromethane, 20 ℃; (iv) substituted benzyl chloride or benzyl bromide, N, N-dimethylformamide and potassium carbonate, wherein the temperature is 20-40 ℃;
(2) the preparation method of the 5, 7-dihydrofuro [3,4-d ] pyrimidine compound II comprises the following steps: taking para-substituted fluorobenzene A1 as an initial raw material, reacting with 4-Boc-aminopiperidine in dimethyl sulfoxide to obtain an intermediate B1, removing Boc from B1 by trifluoroacetic acid to obtain an intermediate C1, and finally carrying out nucleophilic substitution reaction on the intermediates C1 and B to obtain a target product II;
the second synthetic route is as follows:
reagents and conditions: (i) 4-Boc-aminopiperidine, dimethyl sulfoxide, 120 ℃; (ii) trifluoroacetic acid, dichloromethane, 20 ℃; (iii) the compound B, N, N-dimethylformamide, potassium carbonate, 100-120 ℃;
r is represented by the general formula I or II of claim 1.
5. Use of a 5, 7-dihydrofuro [3,4-d ] pyrimidine as claimed in any one of claims 1 to 3 in the manufacture of a medicament for the treatment of an anti-HIV agent.
6. A pharmaceutical composition comprising a 5, 7-dihydrofuro [3,4-d ] pyrimidine compound as claimed in any one of claims 1 to 3 and one or more pharmaceutically acceptable carriers or excipients.
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| CN115028642A (en) * | 2022-07-01 | 2022-09-09 | 山东大学 | Diaryl dihydrofuro [3,4-d ] pyrimidine HIV-1 reverse transcriptase inhibitor and preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106117242A (en) * | 2016-06-27 | 2016-11-16 | 山东大学 | Tetrahydric thiapyran miazines derivative and preparation method and application |
| CN108218890A (en) * | 2018-04-12 | 2018-06-29 | 山东大学 | A kind of five yuan of non-aromatic ring miazines HIV-1 reverse transcriptase inhibitor and its preparation method and application |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106117242A (en) * | 2016-06-27 | 2016-11-16 | 山东大学 | Tetrahydric thiapyran miazines derivative and preparation method and application |
| CN108218890A (en) * | 2018-04-12 | 2018-06-29 | 山东大学 | A kind of five yuan of non-aromatic ring miazines HIV-1 reverse transcriptase inhibitor and its preparation method and application |
Non-Patent Citations (1)
| Title |
|---|
| D. FENG等: "Boronic acid-containing diarylpyrimidine derivatives as novel HIV-1 NNRTIs: Design, synthesis and biological evaluation" * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115028642A (en) * | 2022-07-01 | 2022-09-09 | 山东大学 | Diaryl dihydrofuro [3,4-d ] pyrimidine HIV-1 reverse transcriptase inhibitor and preparation method and application thereof |
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