CN115785080B - Uracil parent nucleus compound and preparation method and application thereof - Google Patents
Uracil parent nucleus compound and preparation method and application thereof Download PDFInfo
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- CN115785080B CN115785080B CN202211626949.3A CN202211626949A CN115785080B CN 115785080 B CN115785080 B CN 115785080B CN 202211626949 A CN202211626949 A CN 202211626949A CN 115785080 B CN115785080 B CN 115785080B
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- acid
- uracil
- methyl
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 94
- 238000002360 preparation method Methods 0.000 title claims abstract description 63
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 title claims abstract description 56
- 229940035893 uracil Drugs 0.000 title claims abstract description 25
- 241000711573 Coronaviridae Species 0.000 claims abstract description 22
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 22
- 108091005804 Peptidases Proteins 0.000 claims abstract description 15
- 239000004365 Protease Substances 0.000 claims abstract description 15
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 claims abstract description 15
- 230000000694 effects Effects 0.000 claims abstract description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- YNHVBNGRNNVEMD-UHFFFAOYSA-N 2-(bromomethyl)-5-(trifluoromethyl)furan Chemical compound FC(F)(F)C1=CC=C(CBr)O1 YNHVBNGRNNVEMD-UHFFFAOYSA-N 0.000 claims description 25
- 238000006243 chemical reaction Methods 0.000 claims description 22
- KVSVNRFSKRFPIL-UHFFFAOYSA-N 1-(bromomethyl)-3,5-difluorobenzene Chemical compound FC1=CC(F)=CC(CBr)=C1 KVSVNRFSKRFPIL-UHFFFAOYSA-N 0.000 claims description 21
- 239000003814 drug Substances 0.000 claims description 21
- 229940079593 drug Drugs 0.000 claims description 17
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- 241001678559 COVID-19 virus Species 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 9
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- 238000006443 Buchwald-Hartwig cross coupling reaction Methods 0.000 claims description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 239000012312 sodium hydride Substances 0.000 claims description 6
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 6
- PKUFNWPSFCOSLU-UHFFFAOYSA-N 6-chloro-1h-pyrimidine-2,4-dione Chemical compound ClC1=CC(=O)NC(=O)N1 PKUFNWPSFCOSLU-UHFFFAOYSA-N 0.000 claims description 5
- 238000005804 alkylation reaction Methods 0.000 claims description 5
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 5
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 5
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 3
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 claims description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 3
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 3
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 3
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 235000003704 aspartic acid Nutrition 0.000 claims description 3
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 3
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 3
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 3
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 claims description 3
- 239000001530 fumaric acid Substances 0.000 claims description 3
- 235000013922 glutamic acid Nutrition 0.000 claims description 3
- 239000004220 glutamic acid Substances 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 239000003446 ligand Substances 0.000 claims description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 3
- 239000011976 maleic acid Substances 0.000 claims description 3
- 239000001630 malic acid Substances 0.000 claims description 3
- 235000011090 malic acid Nutrition 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- 229910017604 nitric acid Inorganic materials 0.000 claims description 3
- 235000006408 oxalic acid Nutrition 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims 1
- 201000010099 disease Diseases 0.000 abstract description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 150
- YRZNRFJEBAPCCO-UHFFFAOYSA-N Cn1cc2cc(N)c(Cl)cc2n1 Chemical compound Cn1cc2cc(N)c(Cl)cc2n1 YRZNRFJEBAPCCO-UHFFFAOYSA-N 0.000 description 26
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 24
- 238000005160 1H NMR spectroscopy Methods 0.000 description 24
- 210000004027 cell Anatomy 0.000 description 19
- 229940125674 nirmatrelvir Drugs 0.000 description 18
- 229940125904 compound 1 Drugs 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- -1 bromobenzyl compound Chemical class 0.000 description 13
- 229940126246 S-217622 Drugs 0.000 description 11
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- 102000004169 proteins and genes Human genes 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 8
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 6
- 125000006288 3,5-difluorobenzyl group Chemical group [H]C1=C(F)C([H])=C(C([H])=C1F)C([H])([H])* 0.000 description 5
- 125000000174 L-prolyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C(*)=O 0.000 description 5
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- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
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Classifications
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention provides a uracil parent nucleus compound, a preparation method and application thereof, wherein the uracil parent nucleus compound is a compound with the following structure or pharmaceutically acceptable salt thereof
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to uracil parent nucleus compounds for inhibiting activity of coronavirus 3CL protease, and a preparation method and application thereof.
Background
Since the outbreak of a new crown epidemic in 2019, a continuous COVID-19 (Corona Virus Disease 2019, novel coronavirus infection) pandemic causes a great number of life deaths to the world, has a great influence on global economy and forms a considerable threat to global health safety. To date, various variant strains thereof are continuously emerging, which have a greater transmission capacity. No specific drug against SARS-CoV-2 has been developed at present, and therefore, a drug capable of effectively inhibiting novel coronaviruses is required.
SARS-CoV-2, SARS-CoV and MERS-CoV all belong to the beta-coronavirus, and the 5' -end of the coronavirus genome has two large open reading frames (ORF 1a and ORF1 b) of non-structural proteins, which encode multifunctional proteins involved in transcription and replication of viral RNA, and during the infection of a host by coronavirus, the enzyme-main protease (M pro is also called 3CL pro) necessary for replication of the virus is a class of cysteine hydrolase, which is capable of cleaving multiple protein bodies at multiple sites in the virus, generating multiple active functional proteins. The 3CL pro sequence is critical to the normal function of coronaviruses and is one of the key targets for the development of broad-spectrum anti-coronavirus drugs at present.
The 3CL protease, a key enzyme in the coronavirus, plays an extremely critical role in the replication and transcription of the progeny virus. Recent studies have shown that 3CL pro has been demonstrated to be a drug discovery target for SARS, MERS and SARS-CoV-2 coronavirus. Most functional proteins (nonstructural proteins) of coronaviruses are encoded by the ORF1ab gene, translated into a polyprotein (7096 aa) and cleaved by 3CL pro into a plurality of active proteins such as the viral replication protein RdRp. In addition, the protein may cleave the intracellular protein NEMO thereby inhibiting the activation of the interferon signaling pathway. The protein is an important non-structural protein in coronaviruses, and has similar cleavage site specificity to the 3CL protease of microRNA viruses. The 3CL pro is composed of 306 amino acids, cysteine proteinase (much smaller than S protein) of about 33kDa, can specifically identify 11 cutting sites of non-structural proteins NSP4-NSP16 and cut, so that other non-structural proteins of coronavirus are released, and the non-structural proteins NSP4-NSP16 released by 3CL pro hydrolysis and cutting are carriers of viral genome replication and transcription and are responsible for important life processes of protein post-translational cutting, modification, nucleic acid synthesis and the like. Therefore, inhibition of 3CL pro can effectively inhibit viral infection and replication. However, no good drug for inhibiting 3CL pro exists at present.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention aims to provide uracil parent nucleus compounds, a preparation method and application thereof, wherein the compounds have the effect of inhibiting the activity of coronavirus 3CL protease and can be used for treating related diseases caused by coronaviruses.
The invention is realized by the following technical scheme:
A uracil parent nucleus compound which is a compound of formula I or a pharmaceutically acceptable salt thereof, or a solvent compound, enantiomer, diastereomer or tautomer of the compound of formula I or the pharmaceutically acceptable salt thereof;
Wherein R 1 is at least one of a hydrogen atom, a methyl group, a tert-butyl group, a methoxy group, a difluoromethyl group, a trifluoromethyl group, a trifluoromethoxy group, a nitro group, a cyano group, a halogen atom, a phenyl group and an aromatic heterocyclic group;
R 2 is
One of the following;
R 3 is One of them.
Preferably, the compound of formula I is one of the following structures:
Preferably, the pharmaceutically acceptable salt is a salt formed by uracil parent nucleus compound and hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, fumaric acid, maleic acid, oxalic acid, malonic acid, succinic acid, citric acid, malic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, glutamic acid or aspartic acid.
The preparation method of the uracil parent nucleus compound comprises the following steps:
(1) 6-chlorouracil is used as a raw material and is subjected to alkylation reaction with a bromobenzyl compound to obtain a compound a;
(2) Under the reaction condition of sodium hydride, the compound a reacts with aromatic heterocyclic chloride or aromatic heterocyclic bromide to obtain a compound b;
(3) Carrying out Buchwald-Hartwig amination reaction on the compound b and aromatic heterocyclic amine to generate a compound shown in a formula I;
Preferably, in the step (1), the alkylation reaction is performed under the conditions of potassium carbonate and heating reflux by taking acetonitrile as a solvent; in the step (2), the reaction is carried out at room temperature by taking N, N-dimethylformamide as a solvent.
Preferably, in the step (3), the Buchwald-Hartwig amination reaction is carried out in the presence of palladium acetate, ligand bis-diphenylphosphine and alkali cesium carbonate serving as catalysts by taking 1, 4-dioxane as a solvent.
The uracil parent nucleus compound is applied to the preparation of medicines for inhibiting the activity of coronavirus 3CL protease.
Preferably, the coronavirus 3CL protease is SARS-CoV-2 3CL protease.
The uracil parent nucleus compound is applied to the preparation of anti-coronavirus drugs.
Preferably, the coronavirus is the novel coronavirus SARS-CoV-2.
Compared with the prior art, the invention has the following beneficial effects:
The invention provides a uracil parent nucleus compound which can effectively inhibit SARS-CoV-23CL pro activity. The test result of the 3CL pro inhibition activity shows that the compound synthesized by the invention has stronger inhibition effect on 3CL pro, and preferably, the IC 50 values of the compounds 1, 5, 11, 17 and 23 on 3CL pro are all below 200nM, wherein the inhibition activity of the compound 1 is optimal; the cytotoxicity test result shows that the inhibition rate of the compound 1 on HepG2 cells and HEK293 cells is lower than PF-07321332 and S-217622 at any concentration, the toxicity on A549 cells is better than PF-07321332 and S-217622 at low concentration, and the in vivo pharmacokinetics study result of rats shows that the compound 1 is well absorbed and has long exposure duration in the systemic circulation and is obviously better than PF-07321332. The compound can be used for preparing SARS-CoV-23CL pro inhibitor, blocking the replication and transcription of SARS-CoV-2 virus in patients, and can be used as anti-coronavirus medicine for development and application.
The preparation method of the uracil parent nucleus compound has the advantages of simple operation, low requirement on reaction equipment, simple and easily obtained raw materials, less pollution and suitability for industrial production.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of compound 1 of the present invention in deuterated DMSO;
FIG. 2 is a nuclear magnetic resonance spectrum of compound 1 of the present invention in deuterated DMSO;
FIG. 3 is the inhibitory effect of Compound 1 on 3CL pro of the present invention;
FIG. 4 is an inhibition of 3CL pro by Compound 11 of the present invention;
FIG. 5 is the inhibitory effect of compound 23 of the present invention on 3CL pro;
FIG. 6 shows the survival of PF-07321332, S-217622 and Compound 1 on A549 cells at various concentrations;
FIG. 7 is the survival of HEK2932 cells with PF-07321332, S-217622 and Compound 1 at various concentrations;
FIG. 8 shows the survival of PF-07321332, S-217622 and Compound 1 on HepG2 cells at various concentrations.
Detailed Description
For a further understanding of the present invention, the present invention is described below in conjunction with the following examples, which are provided to further illustrate the features and advantages of the present invention and are not intended to limit the claims of the present invention.
The uracil parent nucleus compound disclosed by the invention is a compound shown in a formula I or pharmaceutically acceptable salt thereof, and a solvent compound, enantiomer, diastereoisomer, tautomer or mixture of any proportion of the compound shown in the formula I or pharmaceutically acceptable salt thereof, including a racemic mixture.
The structural formula of the compound shown in the formula I is as follows:
Wherein R 1 is independently selected from the group consisting of a hydrogen atom, a methyl group, a tert-butyl group, a methoxy group, a difluoromethyl group, a trifluoromethyl group, a trifluoromethoxy group, a nitro group, a cyano group, a halogen atom, a phenyl group and an aromatic heterocyclic group, and the number of substitution is 1 to 4; the term "halogen" means fluorine, chlorine, bromine or iodine;
R 2 is independently selected from:
One of the above aromatic heterofive membered rings;
R 3 is independently selected from:
one of the above aromatic heterocycles.
The pharmaceutically acceptable salt is a salt formed by uracil parent nucleus compound for inhibiting activity of coronavirus 3CL protease and hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, fumaric acid, maleic acid, oxalic acid, malonic acid, succinic acid, citric acid, malic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, glutamic acid or aspartic acid.
The preparation method of uracil parent nucleus compound for inhibiting the activity of coronavirus 3CL protease provided by the invention comprises the following steps:
(1) 6-chlorouracil is used as a raw material and is subjected to alkylation reaction with a bromobenzyl compound to obtain a compound a;
Wherein, the mol ratio of the 6-chlorouracil to the bromobenzyl compound is 1:1.1; the solvent used in the synthesis process of the compound a is acetonitrile, and the acetonitrile reacts under the conditions of potassium carbonate and heating reflux;
(2) The compound a prepared in the step (1) is connected with aromatic heterocyclic chloride or aromatic heterocyclic bromide under the reaction condition of sodium hydride to obtain a corresponding compound b;
Wherein, the solvent used in the synthesis process of the compound b is N, N-dimethylformamide, and the alkylating reagent used in the reaction is sodium hydride; the molar ratio of the compound a to the aromatic heterocyclic chloride or aromatic heterocyclic bromide is 1:1.5; the molar ratio of compound a to sodium hydride is 1:3, a step of; carrying out the reaction at room temperature;
(3) Carrying out Buchwald-Hartwig amination reaction on the compound b prepared in the step (2) and aromatic amine to obtain a corresponding compound shown in a formula I;
Wherein the solvent in the Buchwald-Hartwig amination reaction is 1, 4-dioxane, the catalyst is palladium acetate, the ligand is bis (diphenylphosphine), and the alkali is cesium carbonate. The molar ratio of the compound b to the aromatic hetero amine, palladium acetate, bis-diphenylphosphine and cesium carbonate is 1:1.5:0.1:0.15:1.5, the reaction temperature is 100 ℃.
1. Specific examples of the Synthesis of Compounds of formula I
Representative compounds of the present invention of formula I are shown below:
examples of the synthesis of the above compounds are given below.
Example 1
Compound 1: preparation of 6- (6-chloro-2-methyl-2H-indazol-5-yl) amino) -1- (3, 5-difluorobenzyl) -3- (5-trifluoromethyl) furan-2-yl) methylpyrimidine-2, 4 (1H, 3H) -dione
(1) Preparation of Compound a1
6-Chlorouracil (146.53 mg,1.0 mmol), 3, 5-difluorobromobenzyl (227.7 mg,1.1 mmol) and potassium carbonate (165.8 mg,1.2 mmol) were placed in a reactor, 20ml acetonitrile was added to dissolve the reaction, heated to reflux for 3h, and monitored by TLC. After the reaction, the reaction solvent was concentrated under reduced pressure, the obtained solid was washed with saturated aqueous sodium chloride solution, extracted with ethyl acetate, and the organic phase was collected, separated and purified by column chromatography (petroleum ether: ethyl acetate (V: V) =1:1 as mobile phase), and dried to give compound a 1.241 mg, yield 88.56%.
(2) Preparation of Compound b1
A1 (272.6 mg,1 mmol) obtained in the above step was reacted with sodium hydride (72 mg,3 mmol) in 20mL of N, N-dimethylformamide for 30min in an ice-bath, after which 2- (bromomethyl) -5- (trifluoromethyl) furan (343.5 mg,1.5 mmol) was added to the reaction solution for 5h, followed by TLC monitoring. After the reaction, the reaction solution was extracted with saturated aqueous sodium chloride solution and ethyl acetate, and the organic phase was collected, separated and purified by column chromatography (petroleum ether: ethyl acetate (V: V) =3:2 as mobile phase), and dried to give compound b1 191.9mg, yield 45.63%.
(3) Preparation of Compound 1
Compound b1 (420.7 mg,1 mmol), 6-chloro-2-methyl-2H-indazol-5-amine (272.4 mg,1.5 mmol), palladium acetate (22.4 mg,0.1 mmol), bis-diphenylphosphine (86.8 mg,0.15 mmol) and cesium carbonate (488.7 mg,1.5 mmol) were placed in a reactor, 30mL of solvent 1, 4-dioxane was added, and the reaction was monitored by tlc for 3H. After the reaction, the obtained reaction solution was washed with saturated aqueous sodium chloride solution, extracted with ethyl acetate, and the organic phase was collected, separated and purified by column chromatography (dichloromethane: methanol (V) =20:1 as mobile phase), and dried to obtain compound 1.184.1 mg, with a yield of 25.98%. The nuclear magnetic hydrogen spectrum of compound 1 in deuterated DMSO is shown in fig. 1, and the nuclear magnetic carbon spectrum in deuterated DMSO is shown in fig. 2.
1H NMR(400MHz,DMSO)δ8.11(s,1H),7.67(s,1H),7.17(d,J＝8.2Hz,3H),7.13(s,1H),7.09–7.03(m,1H),7.01(d,J＝2.1Hz,1H),6.33(s,1H),5.34(s,2H),4.99(s,2H),3.98–3.90(m,1H),3.25(d,J＝2.3Hz,3H).
13C NMR(151MHz,DMSO)δ161.85,161.76,160.12,157.61,154.78,153.45,145.48,144.15,130.80,123.07,122.27,116.58,114.41,110.91,110.75,110.52,108.14,101.96,100.06,69.24,43.68,40.56,36.24.
Example 2
Compound 2: preparation of 3- (1-methyl-1H-1, 2, 4-triazol-5-yl) methyl) -6- (2-methyl-2H-tetrazol-5-yl) amino) -1- (4-nitrobenzyl) pyrimidine-2, 4 (1H, 3H) -dione
Preparation method referring to example 1, only 3, 5-difluorobenzyl bromide was replaced with p-nitrobenzyl bromide, 2- (bromomethyl) -5- (trifluoromethyl) furan was replaced with 5-chloromethyl-1-methyl-1H-1, 2, 4-triazole, 6-chloro-2-methyl-2H-indazol-5-amine was replaced with 2-methyl-2H-tetraazacyclo-5-amine. Yield of compound 2 obtained: 23.84%.
1H NMR(400MHz,DMSO)δ9.21(s,1H),8.05(s,1H),7.87(d,J＝8.3Hz,2H),7.33(s,1H),7.05(m,1H),5.93(d,J＝2.4Hz,1H),5.25(s,1H),4.86(s,2H),4.74(s,2H),4.13(s,1H),3.87(m,1H),3.55(d,J＝2.2Hz,3H).
13C NMR(151MHz,DMSO)δ162.65,161.38,160.38,156.68,153.45,146.75,143.86,127.57,124.52,116.58,71.57,68.57,49.57,43.87,35.58.
Example 3
Compound 3: preparation of 6- (1, 2, 3-thiadiazol-4-yl) amino) -1- (4-chlorobenzyl) -3- (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl) pyrimidine-2, 4 (1H, 3H) -dione
Preparation method referring to example 1, only 3, 5-difluorobenzyl bromide was replaced with p-chlorobenzyl bromide, 2- (bromomethyl) -5- (trifluoromethyl) furan was replaced with 3-chloromethyl-1-methyl-1H-1, 2, 4-triazole, and 6-chloro-2-methyl-2H-indazol-5-amine was replaced with 1,2, 3-thiadiazol-5-amine. Yield of the resulting compound 3: 28.14%.
1H NMR(400MHz,DMSO)δ8.92(s,1H),8.19(s,1H),7.52(d,J＝8.4Hz,2H),7.24(s,1H),7.11(m,1H),6.83(d,J＝2.5Hz,1H),6.75(s,1H),4.66(s,2H),4.49(s,2H),3.78(d,J＝2.2Hz,3H).
13C NMR(151MHz,DMSO)δ163.58,162.56,158.64,151.38,148.13,145.67,143.73,137.57,133.12,130.86,129.03,75.53,48.78,43.17,37.37.
Example 4
Compound 4: preparation of 4- (3- (5-methyl-1, 2, 4-oxadiazol-3-yl) methyl) -2, 4-dioxo-6- (quinolin-6-ylamino) -3, 4-dihydropyrimidin-1 (2H) ylmethyl) benzonitrile
Preparation method referring to example 1, only 3, 5-difluorobenzyl bromide was replaced with p-cyanobenzyl bromide, 2- (bromomethyl) -5- (trifluoromethyl) furan was replaced with 3-chloromethyl-5-methyl-1, 2, 4-oxadiazole, 6-chloro-2-methyl-2H-indazol-5-amine was replaced with quinolin-6-amine. Yield of the resulting compound 4: 26.25%.
1H NMR(400MHz,DMSO)δ9.32(s,1H),8.73–8.65(s,2H),7.86(s,1H),7.45(s,1H),7.23(d,J＝8.1Hz,3H),7.04(s,1H),6.98–6.89(m,1H),6.67(d,J＝1.9Hz,1H),5.56(s,2H),4.52(s,2H),4.19(m,1H),2.89(d,J＝2.3Hz,3H).
13C NMR(151MHz,DMSO)δ178.38,163.52,159.93,157.56,152.95,145.34,143.65,141.67,138.03,135.67,132.64,130.75,128.57,126.76,120.57,117.58,115.51,111.34,109.25,70.59,48.31,40.86,20.64.
Example 5
Compound 5:6- (1H-pyrazolo [3,4-d ] pyrimidin-4-yl) amino) -3- (2-bromothiazol-5-yl) methyl) -1-)
Preparation of (4-trifluoromethylbenzyl) pyrimidine-2, 4 (1H, 3H) -dione
Preparation method referring to example 1, only 3, 5-difluorobenzyl bromide was replaced with 4-trifluoromethyl benzyl bromide, 2- (bromomethyl) -5- (trifluoromethyl) furan was replaced with 2-bromo-5-chloromethylthiazole, 6-chloro-2-methyl-2H-indazol-5-amine was replaced with 1H-pyrazolo [3,4-d ] pyrimidin-4-amine. Yield of the resulting compound 5: 24.65%.
1H NMR(400MHz,DMSO)δ11.82(s,1H),8.41(s,1H),7.52(d,J＝8.2Hz,2H),7.41(s,1H),7.08(m,1H),6.63(d,J＝2.2Hz,1H),6.45(s,1H),4.94(s,2H),4.41(s,2H),4.25–3.78(d,J＝2.2Hz,2H).
13C NMR(151MHz,DMSO)δ163.35,161.17,155.61,152.78,153.21,142.75,140.75,139.73,137.47,133.25,130.28,129.43,127.36,125.16,123.63,98.23,75.02,48.36,43.85.
Example 6
Compound 6: preparation of 1- (4-methoxybenzyl) -3- (3-methyl-1, 2, 4-oxadiazol-5-yl) methyl) -6-oxazol-2-amidopyrimidine-2, 4 (1H, 3H) -dione
Preparation method referring to example 1, only 3, 5-difluorobenzyl bromide was replaced with p-methoxybenzyl bromide, 2- (bromomethyl) -5- (trifluoromethyl) furan was replaced with 5-chloromethyl-3-methyl-1, 2, 4-oxadiazole, 6-chloro-2-methyl-2H-indazol-5-amine was replaced with oxazol-2-amine. Yield of the resulting compound 6: 26.73%.
1H NMR(400MHz,DMSO)δ8.72(s,1H),7.56(s,1H),7.31(d,J＝8.3Hz,2H),7.22(s,1H),7.01(m,1H),6.77(d,J＝2.4Hz,1H),6.35(s,1H),4.73(s,2H),4.42(s,2H),3.81(d,J＝2.2Hz,3H),2.26(d,J＝1.9Hz,3H).
13C NMR(151MHz,DMSO)δ163.13,162.75,159.47,157.36,152.25,151.62,137.35,132.57,129.74,127.31,121.30,113.81,78.56,55.73,48.53,43.47,21.36.
Example 7
Compound 7: preparation of 1- (4-methoxybenzyl) -3- (3-methyl-1, 2, 4-oxadiazol-5-yl) methyl) -6-oxazol-2-amidopyrimidine-2, 4 (1H, 3H) -dione
Preparation method referring to example 1, only 3, 5-difluorobenzyl bromide was replaced with p-fluorobenzyl bromide, 2- (bromomethyl) -5- (trifluoromethyl) furan was replaced with 4-chloromethyl-1-methylpyrazole, 6-chloro-2-methyl-2H-indazol-5-amine was replaced with 4- (4-aminophenyl) morpholin-3-one. Yield of the resulting compound 7: 28.16%.
1H NMR(400MHz,DMSO)δ9.15(s,1H),7.87–7.65(s,2H),7.47(s,1H),,7.32(s,1H),7.25–7.12(s,3H),7.03(d,J＝8.2Hz,3H),6.95(s,1H),6.81–6.68(m,3H),6.56(d,J＝1.9Hz,2H),5.23(s,2H),4.73(s,2H),4.21(m,1H),3.74(d,J＝2.2Hz,3H).
13C NMR(151MHz,DMSO)δ163.74,162.96,161.58,157.45,154.78,153.36,145.34,142.85,136.88,133.67,132.69,126.62,124.56,119.11,115.95,112.37,111.23,110.07,75.35,68.47,55.36,44.38,41.76,37.57.
Example 8
Compound 8: preparation of 3- (2-chlorothiazol-5-yl) methyl-6-pyrimidin-4-amino-1- (2, 4, 5-trifluorobenzyl) pyrimidine-2, 4 (1H, 3H) -dione
Preparation method referring to example 1, only 3, 5-difluorobenzyl bromide was replaced with 3,4, 5-trifluorobenzyl bromide, 2- (bromomethyl) -5- (trifluoromethyl) furan was replaced with 2-bromo-5- (chloromethyl) thiazole, and 6-chloro-2-methyl-2H-indazol-5-amine was replaced with pyrimidin-4-amine. Yield of compound 8 obtained: 24.38%.
1H NMR(400MHz,DMSO)δ8.85(s,1H),8.31(s,1H),7.47(d,J＝8.1Hz,2H),7.24(s,1H),7.11(m,1H),6.44(d,J＝2.2Hz,1H),4.64(s,2H),4.40(s,1H),4.23–3.94(d,J＝2.1Hz,2H).
13C NMR(151MHz,DMSO)δ163.57,162.68,159.58,157.48,155.81,152.68,150.63,149.86,147.35,143.65,139.68,138.68,127.85,120.68,109.31,75.34,48.78,43.56.
Example 9
Compound 9: preparation of 6- (1, 2, 4-triazin-3-yl) amino-1- (4-tert-butyl) benzyl) -3- (thiazol-4-ylmethyl) pyrimidine-2, 4 (1H, 3H) -dione
Preparation method referring to example 1, only 3, 5-difluoro benzyl bromide to p-tert-butyl benzyl bromide, 2- (bromomethyl) -5- (trifluoromethyl) furan to 4- (chloromethyl) thiazole, 6-chloro-2-methyl-2H-indazol-5-amine to 1,2, 4-three triazine-3-amine. Yield of the resulting compound 9: 25.93%.
1H NMR(400MHz,DMSO)δ9.12(s,1H),9.04(s,1H),8.64(s,1H),7.78(d,J＝7.9Hz,2H),7.54(s,1H),7.37(m,2H),6.82(d,J＝2.1Hz,1H),4.93(s,2H),4.32(s,1H),4.23(d,J＝2.1Hz,2H),1.87(s,9H).
13C NMR(151MHz,DMSO)δ163.58,162.16,161.87,157.86,155.47,153.45,149.57,143.65,138.35,135.65,127.85,125.47,121.57,108.47,75.61,48.58,43.56,35.25,31.15.
Example 10
Compound 10: preparation of 6- (4H-1, 2, 4-triazol-4-yl) amino) -1- (4-bromobenzyl) -3- (5-trifluoromethylfuran-2-yl) methylpyrimidine-2, 4 (1H, 3H) -dione
Preparation method referring to example 1, only 3, 5-difluorobenzyl bromide was replaced with p-bromobenzyl bromide, 2- (bromomethyl) -5- (trifluoromethyl) furan was replaced with 2- (bromomethyl) -5- (trifluoromethyl) furan, and 6-chloro-2-methyl-2H-indazol-5-amine was replaced with 4H-1,2, 4-triazol-4-amine. Yield of the resulting compound 10: 26.77%.
1H NMR(400MHz,DMSO)δ8.29(s,1H),8.12(s,1H),7.73(d,J＝8.1Hz,2H),7.28(s,1H),6.63(d,J＝2.2Hz,1H),6.25(s,1H),4.53(s,2H),4.32(s,2H),4.15(d,J＝2.3Hz,2H),1.69(s,1H).
13C NMR(151MHz,DMSO)δ163.34,161.57,159.47,153.57,152.67,149.65,147.68,135.57,132.86,129.87,123.08,121.57,120.38,105.85,78.58,47.58,41.38.
Example 11
Compound 11: preparation of 1- (1, 1' -biphenyl ] -4-ylmethyl) -6- (6-chloro-2-methyl-2H-indazol-5-yl) amino) -3- (1-methyl-1H-1, 2, 4-triazol-5-yl) methyl) pyrimidine-2, 4 (1H, 3H) -dione
Preparation method referring to example 1, only 3, 5-difluorobenzyl was replaced with 4-bromobiphenyl, 2- (bromomethyl) -5- (trifluoromethyl) furan with 5- (chloromethyl) -1-methyl-1H-1, 2, 4-triazole, 6-chloro-2-methyl-2H-indazol-5-amine with 6-chloro-2-methyl-2H-indazol-5-amine. Yield of the resulting compound 11: 22.85%.
1H NMR(400MHz,DMSO)δ9.05(s,1H),7.97(s,1H),7.71(s,2H),7.73(d,J＝8.2Hz,3H),7.39–7.23(s,3H),7.05(d,J＝8.1Hz,3H),6.87(d,J＝1.9Hz,2H),4.93(s,1H),4.72(s,2H),4.32(m,1H),,3.87(s,3H)3.68(d,J＝2.2Hz,3H).
13C NMR(151MHz,DMSO)δ163.56,162.63,159.85,153.71,144.36,143.85,142.85,139.44,138.38,137.89,135.89,129.58,128.61,126.37,125.68,123.63,119.14,118.23,112.36,103.47,75.25,48.34,43.25,40.74,36.37.
Example 12
Compound 12: preparation of 1- (3, 5-dimethylbenzyl) -3- (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl) -6- (2-methyl-2H-tetrazol-5-yl) aminopyrimidin-2, 4 (1H, 3H) -dione
Preparation method referring to example 1, only 3, 5-difluorobenzyl bromide was replaced with 3, 5-dimethylbenzyl bromide, 2- (bromomethyl) -5- (trifluoromethyl) furan was replaced with 5- (chloromethyl) -1-methyl-1H-1, 2, 4-triazole, 6-chloro-2-methyl-2H-indazol-5-amine was replaced with 2-methyl-2H-tetrazol-5-amine. Yield of the resulting compound 12: 23.52%.
1H NMR(400MHz,DMSO)δ8.73(s,1H),8.53(s,1H),8.36(s,1H),7.25(d,J＝8.3Hz,2H),7.12(s,1H),7.03(m,1H),6.97(d,J＝2.3Hz,1H),6.57(s,1H),4.37(s,2H),4.19(s,2H),3.35(d,J＝2.1Hz,3H),2.27(s,6H).
13C NMR(151MHz,DMSO)δ163.48,162.34,157.74,152.86,147.25,142.12,139.85,127.58,125.87,113.81,78.41,55.13,48.73,43.47,38.25,22.58.
Example 13
Compound 13: preparation of 6- (1, 2, 3-thiadiazol-5-yl) amino) -3- (2-bromothiazol-5-yl) methyl) -1- (3, 5-dimethoxybenzyl) pyrimidine-2, 4 (1H, 3H) -dione
Preparation method referring to example 1, only 3, 5-difluorobenzyl bromide was replaced with 3, 5-dimethoxybenzyl bromide, 2- (bromomethyl) -5- (trifluoromethyl) furan was replaced with 5- (bromomethyl) -2-chlorothiazole, and 6-chloro-2-methyl-2H-indazol-5-amine was replaced with 1,2, 3-thiadiazol-5-amine. Yield of compound 13 obtained: 26.15%.
1H NMR(400MHz,DMSO)δ9.47(s,1H),8.15(s,1H),6.74(s,1H),6.72–6.63(d,2H),6.31(s,1H),4.96(s,2H),4.89(s,1H),4.48(s,2H),3.81(m,6H).
13C NMR(151MHz,DMSO)δ163.35,162.57,159.58,152.85,145.65,142.45,139.58,137.68,122.68,116.26,103.41,98.85,75.52,56.89,48.65,45.56.
Example 14
Compound 14: preparation of 1- (3, 5-difluorobenzyl) -3- (1-methyl-1H-pyrazol-4-yl) methyl) -6- (3-methyl-4-methyleneaminophenyl) aminopyrimidine-2, 4 (1H, 3H) -dione
Preparation method referring to example 1, only 3, 5-difluorobenzyl bromide was replaced with 3, 5-dimethoxybenzyl bromide, 2- (bromomethyl) -5- (trifluoromethyl) furan was replaced with 4- (chloromethyl) -1-methyl-1H-pyrazole, and 6-chloro-2-methyl-2H-indazol-5-amine was replaced with quinolin-6-amine. Yield of the resulting compound 14: 24.35%.
1H NMR(400MHz,DMSO)δ10.72(s,1H),8.72(s,1H),8.55(s,1H),8.33(s,1H),7.52–7.31(m,4H),6.71–6.60(m,4H),4.99(s,1H),4.46(m,4H),3.92(m,3H).
13C NMR(151MHz,DMSO)δ164.52,162.58,160.58,158.85,153.85,145.58,144.58,142.58,138.20,133.85,132.81,126.58,124.01,121.78,118.55,112.65,111.58,103.52,101.52,73.25,43.57,40.37,36.57.
Example 15
Compound 15: preparation of 1- (3, 5-difluorobenzyl) -3- (1-methyl-1H-pyrazol-4-yl) methyl) -6- (3-methyl-4-methyleneaminophenyl) aminopyrimidine-2, 4 (1H, 3H) -dione
Preparation method referring to example 1, only 3, 5-difluorobenzyl bromide was replaced with p-nitrobenzyl bromide, 2- (bromomethyl) -5-
The (trifluoromethyl) furan is replaced by 5- (chloromethyl) -3-methyl-1, 2, 4-oxadiazole and the 6-chloro-2-methyl-2H-indazol-5-amine is replaced by 1H-pyrazolo [3,4-d ] pyrimidine-4-amine. Yield of compound 15 obtained: 21.17%.
1H NMR(400MHz,DMSO)δ13.25(s,1H),9.52(s,1H),8.29(m,2H),8.27(s,1H),7.91(m,2H),7.52(s,1H),4.93(s,1H),4.47(m,2H),4.32(m,2H),2.31(m,3H).
13C NMR(151MHz,DMSO)δ163.58,162.36,157.74,155.36,152.86,147.25,142.12,139.85,127.58,125.87,113.81,78.41,55.13,48.73,43.47,38.25,22.58.
Example 16
Compound 16: preparation of 1-chlorobenzyl-3- (2-methylthiazol-5-yl) methyl-6-oxazol-2-aminopyrimidine-2, 4-dione
Preparation method referring to example 1, only 3, 5-difluorobenzyl bromide was replaced with p-chlorobenzyl bromide, 2- (bromomethyl) -5- (trifluoromethyl) furan was replaced with 5- (bromomethyl) -2-chlorothiazole, and 6-chloro-2-methyl-2H-indazol-5-amine was replaced with oxazol-2-amine. Yield of compound 16 obtained: 25.31%.
1H NMR(400MHz,DMSO)δ9.55(s,1H),7.61(s,1H),7.28(m,4H),7.17(s,1H),6.87(m,1H),4.92(s,1H),4.47(m,2H),4.41(m,2H),2.58(m,3H).
13C NMR(151MHz,DMSO)δ165.47,163.08,162.74,153.42,152.34,141.34,139.24,138.34,136.57,134.27,132.85,129.57,127.57,77.55,46.98,45.55,20.43.
Example 17
Compound 17: preparation of 4- (3- (5-methyl-1, 2, 4-oxadiazol-3-yl) methyl) -2, 4-dioxo-6- (4- (3-oxomorpholinyl) phenyl) amino) -3, 4-dihydropyrimidin-1 (2H) ylmethyl) benzonitrile
Preparation method referring to example 1, only 3, 5-difluorobenzyl bromide was replaced with p-cyanobenzyl bromide, 2- (bromomethyl) -5- (trifluoromethyl) furan was replaced with 3- (chloromethyl) -5-methyl-1, 2, 4-oxadiazole, 6-chloro-2-methyl-2H-indazol-5-amine was replaced with 4- (4-aminophenyl) morpholin-3-one. Yield of the resulting compound 17: 23.85%.
1H NMR(400MHz,DMSO)δ10.15(s,1H),7.71(m,2H),7.48(m,2H),6.69(m,2H),6.62(m,2H),4.91(s,1H),4.45(m,2H),4.41(m,2H),4.38(m,2H),3.57–3.49(m,4H),2.64(m,3H).
13C NMR(151MHz,DMSO)δ173.28,165.85,163.35,161.58,159.21,153.34,148.35,142.34,135.67,133.36,131.39,129.68,128.39,125.36,119.37,117.34,111.58,107.03,75.36,66.25,54.89,48.37,43.12,15.38.
Example 18
Compound 18: preparation of 6-pyrimidin-4-ylamino-3-thiazol-5-ylmethyl-1- (4-trifluoromethylbenzyl) pyrimidine-2, 4 (1H, 3H) -dione
Preparation method referring to example 1, only 3, 5-difluorobenzyl bromide was replaced with p-trifluoromethyl benzyl bromide, 2- (bromomethyl) -5- (trifluoromethyl) furan was replaced with 4- (chloromethyl) thiazole, 6-chloro-2-methyl-2H-indazol-5-amine was replaced with pyrimidin-4-amine. Yield of the resulting compound 18: 24.64%.
1H NMR(400MHz,DMSO)δ9.45(s,1H),8.99(s,1H),8.41–8.35(m,2H),7.58(m,2H),7.19(m,2H),6.92(s,1H),6.41(s,1H),4.95(s,1H),4.47(m,2H),4.41(m,2H).
13C NMR(151MHz,DMSO)δ163.47,161.15,159.37,158.12,155.34,152.38,142.37,139.47,134.31,133.25,130.83,129.54,126.61,125.38,105.59,75.02,48.36,43.85.
Example 19
Compound 19: preparation of 6- (1, 2, 4-triazin-3-yl) amino) -1- (4-methoxybenzyl) -3- (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl) pyrimidine-2, 4 (1H, 3H) -dione
Preparation method referring to example 1, only 3, 5-difluoro-benzyl-to-methoxy-benzyl bromide, 2- (bromomethyl) -5- (trifluoromethyl) -furan to 3- (chloromethyl) -1-methyl-1H-1, 2, 4-triazole, 6-chloro-2-methyl-2H-indazol-5-amine to 1,2, 4-triazine-3-amine. Yield of compound 19 obtained: 27.56%.
1H NMR(400MHz,DMSO)δ9.41(s,1H),9.09(s,1H),8.71–8.65(m,2H),7.17(m,2H),7.01(m,2H),4.97(s,1H),4.45(m,2H),4.41(m,2H),3.80(m,3H),3.77(m,3H).
13C NMR(151MHz,DMSO)δ163.45,162.21,161.58,158.34,152.87,148.53,147.28,142.51,139.34,131.22,129.76,115.38,78.35,55.37,48.38,43.76,38.38.
Example 20
Compound 20: preparation of 6- (4H-1, 2, 4-triazol-4-yl) amino) -1- (4-fluorobenzyl) -3- (5-methyl-1, 2, 4-oxadiazol-3-yl) methyl) pyrimidine-2, 4 (1H, 3H) -dione
Preparation method referring to example 1, only 3, 5-difluorobenzyl bromide was replaced with p-fluorobenzyl bromide, 2- (bromomethyl) -5- (trifluoromethyl) furan was replaced with 3- (chloromethyl) -5-methyl-1, 2, 4-oxadiazole, 6-chloro-2-methyl-2H-indazol-5-amine was replaced with 4H-1,2, 4-triazol-4-amine. Yield of the resulting compound 20: 24.28%.
1H NMR(400MHz,DMSO)δ8.28(m,2H),7.27(m,2H),7.04(m,2H),4.49(m,2H),4.41(m,2H),4.19(s,1H),3.67(m,3H),1.51(s,1H).
13C NMR(151MHz,DMSO)δ172.54,163.86,162.15,161.34,159.28,156.36,143.28,132.58,129.55,126.87,111.17,78.88,49.14,43.31,17.76.
Example 21
Compound 21: preparation of 3- (2-bromothiazol-5-yl) methyl-1- (4-tert-butyl) benzyl) -6-oxazol-2-amino) pyrimidine-2, 4 (1H, 3H) -dione
Preparation method referring to example 1, only 3, 5-difluorobenzyl bromide was replaced with p-tert-butylbenzyl bromide, 2- (bromomethyl) -5- (trifluoromethyl) furan was replaced with 2-bromo-5- (chloromethyl) thiazole, 6-chloro-2-methyl-2H-indazol-5-amine was replaced with oxazol-2-amine. Yield of compound 21 obtained: 21.17%.
1H NMR(400MHz,DMSO)δ9.45(s,1H),7.62(s,1H),7.31(m,2H),7.19–7.11(m,3H),6.77(s,1H),4.99(s,1H),4.46(m,2H),4.39(m,2H),1.34(m,9H).
13C NMR(151MHz,DMSO)δ164.83,162.53,152.34,151.48,149.36,141.85,139.65,138.64,137.62,135.07,127.38,125.24,121.36,105.86,75.23,48.12,43.31,35.39,32.98.
Example 22
Compound 22: preparation of 6- (1, 2, 3-thiadiazol-5-yl) amino) -1- (4-bromobenzyl) -3- (1-methyl-1H-pyrazol-4-yl) methylpyrimidine-2, 4 (1H, 3H) -dione
Preparation method referring to example 1, only 3, 5-difluorobenzyl bromide was replaced with p-bromobenzyl bromide, 2- (bromomethyl) -5- (trifluoromethyl) furan was replaced with 4- (chloromethyl) -1-methyl-1H-pyrazole, and 6-chloro-2-methyl-2H-indazol-5-amine was replaced with 1,2, 3-thiadiazol-5-amine. Yield of the resulting compound 22: 22.24%.
1H NMR(400MHz,DMSO)δ9.51(s,1H),8.16(s,1H),7.83(m,2H),7.47(s,1H),7.38(s,1H),7.22(m,2H),4.97(s,1H),4.49(m,4H),3.92(m,3H).
13C NMR(151MHz,DMSO)δ163.56,162.52,153.87,139.54,138.86,137.37,132.37,129.34,128.45,126.26,124.14,122.66,75.45,48.14,41.34,38.58.
Example 23
Compound 23: preparation of 1- (1, 1' -biphenyl ] -4-ylmethyl) -6- (6-chloro-2-methyl-2H-indazol-5-yl) amino) -3- (3-methyl-1, 2, 4-oxadiazol-5-yl) methyl) pyrimidine-2, 4 (1H, 3H) -dione
Preparation method referring to example 1, only 3, 5-difluorobenzyl was replaced with 4-bromobiphenyl, 2- (bromomethyl) -5- (trifluoromethyl) furan with 5- (chloromethyl) -3-methyl-1, 2, 4-oxadiazole, 6-chloro-2-methyl-2H-indazol-5-amine with 6-chloro-2-methyl-2H-indazol-5-amine. Yield of the resulting compound 23: 24.53%.
1H NMR(400MHz,DMSO)δ10.32(s,1H),8.02(s,1H),7.74(m,2H),7.51 -7.40(m,8H),7.15(s,1H),4.97(s,1H),4.91(m,2H),4.39(m,2H),3.95(m,3H),2.35(m,3H).
13C NMR(151MHz,DMSO)δ163.32,162.45,159.56,158.65,151.36,143.56,141.72,139.86,138.92,137.54,135.15,129.58,128.22,126.35,125.74,123.42,117.94,118.56,112.14,103.56,75.36,48.46,43.85,40.04,16.03.
Example 24
Compound 24: preparation of 1- (3, 5-dimethylbenzyl) -6-oxazol-2-ylamino) -3- (thiazol-4-ylmethyl) pyrimidine-2, 4 (1H, 3H) -dione
Preparation method referring to example 1, only 3, 5-difluorobenzyl bromide was replaced with 3, 5-dimethoxybenzyl bromide, 2- (bromomethyl) -5- (trifluoromethyl) furan was replaced with 4- (chloromethyl) thiazole, and 6-chloro-2-methyl-2H-indazol-5-amine was replaced with oxazol-2-amine. Yield of the resulting compound 24: 25.61%.
1H NMR(400MHz,DMSO)δ9.54(s,1H),9.06(s,1H),7.66(s,1H),7.32(s,1H),7.17(s,1H),7.08(m,2H),6.95(s,1H),4.96(s,1H),4.49(m,2H),4.43(m,2H),2.17(m,6H).
13C NMR(151MHz,DMSO)δ163.36,162.87,157.56,156.38,153.14,152.89,151.78,149.35,142.37,137.56,129.47,126.58,124.53,75.26,48.23,45.17,23.68.
2. Biological Activity assay
(1) 3CL pro inhibition Activity test
The compounds were tested for their inhibitory activity against SARS-CoV-2 3CL pro using fluorescence resonance energy transfer technology.
The above-mentioned compound was dissolved in DMSO to a solution having a certain concentration gradient, 5. Mu.L of the above-mentioned solution and 91. Mu. LASSAY REAGENT (Assay Buffer:2019-nCoV M pro/3CLpro =90:1, available from Shanghai Biyun biotechnology Co., ltd.) were sequentially added to a black 96-well plate, mixed well, incubated at 37℃for 10 minutes in the absence of light, and then 4. Mu.L of the Substrate (100. Mu.M Dabcyl-KTSAVLQSGFRKME-Edans, available from Shanghai Biyun biotechnology Co., ltd.) were added to each well, and mixed well. After incubation at 37℃for 5min in the absence of light, the signal was stable, and fluorescence measurement was performed by a multifunctional microplate reader (Varioskan Flash) within 5-30min, with excitation wavelength of 340nm and emission wavelength of 490nm, and the inhibition rate of the sample was calculated. ASSAY REAGENT containing no compound is used as 100% enzyme activity control, assay Buffer containing no SARS-CoV-2M pro/3CLpro is used as blank control, S-216722 (Shandong Xuan Shuo medical science and technology Co., ltd.) and PF-07321332 (Jinan Jianfeng chemical Co., ltd.) are used as positive control, and the rest treatment methods are the same. Non-linear regression analysis using GRAPHPAD PRISM software calculated the IC 50 values for the samples (inventive synthetic compounds 1-24).
The results of the experiments are shown in tables 1 and 2 (in Table 1, IC 50 is in column, A: IC 50＜200nM,B：IC50＝200-500nM,C：IC50＝500-1000nM,D：IC50 > 1000 nM), the compounds of the examples all have inhibitory activity on 3CL pro, wherein the compounds 1,5, 11, 17 and 23 have strong inhibitory effect on 3CL pro, and the IC 50 values are below 200 nM.
TABLE 1 inhibitory Activity of Compounds 1-24 against 3CL pro
| Numbering of compounds | IC50(nM) |
| 1 | A |
| 2 | C |
| 3 | B |
| 4 | C |
| 5 | A |
| 6 | B |
| 7 | C |
| 8 | C |
| 9 | D |
| 10 | C |
| 11 | A |
| 12 | B |
| 13 | B |
| 14 | C |
| 15 | B |
| 16 | B |
| 17 | A |
| 18 | C |
| 19 | B |
| 20 | D |
| 21 | B |
| 22 | C |
| 23 | A |
| 24 | D |
TABLE 2 inhibitory Activity of Compounds 1, 11, 23, S-217622 and PF-07321332 on 3CL pro
The data in tables 1-2 show that compounds 1-24 all have varying degrees of inhibition on 3CL pro. The IC 50 values of the compounds 1, 5, 11, 17 and 23 on the 3CL pro are less than 200nM, which shows that the uracil parent compound has inhibitory activity on the coronavirus 3CL pro. The three compounds 1, 11 and 23 with the best inhibitory activity have the inhibitory effect on 3CL pro respectively shown in FIGS. 3-5, wherein the inhibitory effect of the compound 1 is superior to that of the compounds 11 and 23, and can be developed and applied as anti-coronavirus drugs.
(2) Cytotoxicity test
Compounds 1, 11, 23 were evaluated for cytotoxicity in vitro using the MTT method. HepG2, HEK293 and A549 cells in the logarithmic growth phase are taken, are digested by trypsin to prepare cell suspension, the cell density is adjusted to be 5 multiplied by 10 4/mL, 180 mu L of each hole is inoculated into a sterile 96-hole cell culture plate, and the cell suspension is placed in a constant-temperature incubator with 5% CO 2 at 37 ℃ for culturing for 24 hours. After the cells are attached to the bottom of the pore plate, 20 mu L of liquid medicine with concentration gradient is added into each pore, 6 compound pores are arranged in parallel, and a zeroing group (without cells and medicines) and a control group (without medicines) are arranged at the same time. After incubation in a constant temperature incubator at 37℃with 5% CO 2 for 24 hours, 20. Mu.L of MTT solution was added per well for further incubation for 4 hours. After the culture is finished, the culture solution in the holes is gently sucked, 100 mu L of DMSO is added into each hole, the mixture is placed on a shaking table to shake for 10min at a low speed, after the crystals are fully dissolved, the light absorption value of each hole is measured at an OD 490 nm position of an ELISA (enzyme-linked immunosorbent assay) instrument, and the cell survival rate is calculated. The results are shown in tables 3-5, and FIGS. 6-8.
TABLE 3 cytotoxicity of test agents to A549
TABLE 4 toxicity of test drugs to HEK293 cells
TABLE 5 cytotoxicity of test drugs against HepG2
Tables 3-5 show the inhibition rates of PF-07321332, S-217622, representative compounds 1, 11 and 23 on A549 cells, HEK293 and HepG2 cells, respectively, and from the above data and FIGS. 6-8, it was found that the inhibition rates of compound 1 on HepG2 cells and HEK293 cells were slightly lower than PF-07321332 and S-217622 at any concentration, toxicity to A549 cells was better than PF-07321332 and S-217622 at low concentrations, the toxicity of compound 11 and compound 23 on the three tested cells was slightly higher than PF-07321332 and S-217622 at 400nM and 200nM, but the survival rates of HEK293 and HepG2 cells were both higher than PF-07321332 and S-217622 at 12.5nM and lower than compound 1. In view of the above data, the tested compound 1 has good inhibitory activity on 3CL protease and low toxicity, and can be further studied.
(3) In vivo pharmacokinetic studies in rats
① The preparation for administration is prepared: weighing about 6mg of each compound respectively, calculating the total volume according to 0.5mg/mL, adding DMA with the total volume of 5% to completely dissolve the compound, and adding 10% solution with the total volume of 95% to be uniformly mixed before administration.
② Test group and dosing: SD rats were randomly divided into two groups (n=6), and each half of the animals and females were administered 3mg/kg by gavage (drug concentration 0.5mg/mL, drug dose 0.6mL/100 g).
③ Animal test observations and recordings: the animals were observed twice daily for general status and appearance during the test, and possible abnormalities were recorded. On the day of administration, the general state, behavior, activity, excretion, respiration and other abnormal symptoms of the experimental animals were observed before and after each administration and blood sampling, and the abnormal symptoms occurring during the whole test were recorded in the original records.
④ Biological sample collection and processing: blood samples were collected 5, 15, 30min, 1,2, 4, 6, 8, 10 and 24h after dosing into K 2 EDTA anticoagulant tubes and buffered on ice until centrifugation. Centrifuging to obtain blood plasma (at 2-8deg.C for 5min at 8000 rpm) within 60min, centrifuging, adding into 1.5mL centrifuge tube, temporarily storing at-15deg.C, transferring with wet ice box, and storing at-65deg.C until LC-MS/MS detection. The blood sampling time was within 1 hour (including 1 hour), the blood sampling time was considered to be within ±1 minute as an acceptable range, and the blood sampling time after 1 hour was not more than 5% of the standard time was acceptable, and was not considered to be a deviation.
The experimental results are shown in Table 6.
TABLE 6 pharmacokinetic parameters of test drug in plasma after gavage administration of test drug in rats
| Pharmacokinetic parameters | 1 | PF-07321332 |
| t1/2(h) | 3.239 | 0.688 |
| Tmax(h) | 1 | 0.25 |
| Cmax(ng/mL) | 6358 | 1423 |
| AUClast(h×ng/mL) | 35981 | 624.2 |
| AUCinf(h×ng/mL) | 36144 | 637.5 |
| Vz_F_obs(mL/kg) | 340.7 | 1496.7 |
| Cl_F_obs(mL/h/kg) | 112.5 | 2850.3 |
| MRTlast(h) | 4.539 | 0.194 |
| F(％) | 96.83 | 38.92 |
PF-07321332 is a polypeptide derivative, the structure of the PF-07321332 contains a plurality of amide bonds, the bioavailability is low (38.92%) and the blood concentration is fast to decrease due to the influence of the first pass effect, and the in vivo half-life of rats is only 0.69h after oral administration, so that the PF-07321332 must be combined with a CYP3A4 inhibitor and the blood concentration can be maintained after taking the drugs for a plurality of times every day. The in vivo experiments of rats show that the compound 1 has the characteristics of complete absorption, good absorption, long exposure duration in the systemic circulation and the like, has the bioavailability of 96.83 percent, has the in vivo half-life of 3.24 hours (which is obviously superior to PF-07321332), and is an ideal oral medicament.
Claims (9)
1. A uracil parent nucleus compound, which is characterized by being a compound of formula 1 or pharmaceutically acceptable salt thereof;
2. the uracil parent nucleus compound according to claim 1, wherein the pharmaceutically acceptable salt is a salt of uracil parent nucleus compound with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, fumaric acid, maleic acid, oxalic acid, malonic acid, succinic acid, citric acid, malic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, glutamic acid or aspartic acid.
3. The method for preparing uracil parent nucleus compound according to any one of claims 1-2, characterized by comprising the steps of:
(1) 6-chlorouracil is used as a raw material and is subjected to alkylation reaction with 3, 5-difluorobenzyl bromide to obtain a compound a1; the alkylation reaction takes acetonitrile as a solvent and is carried out under the conditions of potassium carbonate and heating reflux;
(2) Reacting the compound a1 with 2- (bromomethyl) -5- (trifluoromethyl) furan under the condition of sodium hydride reaction to obtain a compound b1;
(3) Buchwald-Hartwig amination of compound b1 with 66-chloro-2-methyl-2H-indazol-5-amine to produce a compound of formula 1;
4. the method for producing uracil parent nucleus according to claim 3, wherein in step (2), the reaction is carried out at room temperature using N, N-dimethylformamide as a solvent.
5. The method for preparing uracil parent nucleus according to claim 3, wherein in step (3), the Buchwald-Hartwig amination reaction is carried out in the presence of palladium acetate, ligand bis-diphenylphosphine and alkali cesium carbonate serving as catalysts by using 1, 4-dioxane as a solvent.
6. Use of a uracil parent nucleus compound according to any of claims 1-2 for the preparation of a medicament for inhibiting coronavirus 3CL protease activity.
7. The use according to claim 6, wherein the coronavirus 3CL protease is SARS-CoV-2 3CL protease.
8. Use of uracil parent nucleus compounds according to any of claims 1-2 for the preparation of anti-coronavirus drugs.
9. The use according to claim 8, wherein the coronavirus is the novel coronavirus SARS-CoV-2.
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