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CN-122010902-A - Carbonyl substituted pyrimidine HIV-1 reverse transcriptase inhibitor and preparation method and application thereof

CN122010902ACN 122010902 ACN122010902 ACN 122010902ACN-122010902-A

Abstract

The invention relates to a carbonyl substituted pyrimidine derivative, a preparation method and application thereof, belonging to the technical field of synthesis and medical application of organic compounds. The carbonyl substituted pyrimidine derivative has a structure shown in the formula I, has a novel structure, shows good anti-HIV-1 activity as an HIV-1 inhibitor, and has an EC 50 value range of 4.28 nM-274 nM, which is obviously better than the marketed drug nevirapine (EC 50 =281+ -38.7 nM).

Inventors

  • WANG ZHAO
  • LIU XINYONG
  • ZHAN PENG
  • KANG DONGWEI
  • Sang Zihao

Assignees

  • 山东大学
  • 山东大学苏州研究院

Dates

Publication Date
20260512
Application Date
20260130

Claims (7)

  1. 1. A carbonyl substituted pyrimidine HIV-1 reverse transcriptase inhibitor or a pharmaceutically acceptable salt thereof, which is characterized by having a structure represented by the following general formula I: ; Wherein, the R 1 is H, CH 3 、OH、OCH 3 、OCH 2 CH 3 、NH 2 、NHNH 2 、NHCH 3 , NHOH or NHOCH 3 ; r 2 is halogen atom 、H、CH 3 、OH、CN、NH 2 、NO 2 、NHSO 2 NH 2 、NHSO 2 CH 3 、COOCH 3 、COOH、SO 2 NH 2 、CONH 2 、SO 2 CH 3 or B (OH) 2 , and the substituent is ortho-, meta-, para-monosubstituted or polysubstituted; R 3 is CN, CH 3 , ch=chcn or p-C 4 H 6 -CN.
  2. 2. The carbonyl-substituted pyrimidine HIV-1 reverse transcriptase inhibitor, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein the carbonyl-substituted pyrimidine derivative, or a pharmaceutically acceptable salt thereof, is selected from one of the following: Ethyl 4- (4-cyano-2, 6-dimethylphenoxy) -2- ((1- (4-sulfonylaminobenzyl) piperidin-4-yl) amino) pyrimidine-5-carboxylate (E1); ethyl 2- ((1- (4-carbamoyl-benzyl) piperidin-4-yl) amino) -4- (4-cyano-2, 6-dimethylphenoxy) pyrimidine-5-carboxylate (E2); Ethyl 4- (4-cyano-2, 6-dimethylphenoxy) -2- ((1- (4- (methylsulfonyl) benzyl) piperidin-4-yl) amino) pyrimidine-5-carboxylate (E3); (4- ((4- ((4- (4-cyano-2, 6-dimethylphenoxy) -5- (ethoxycarbonyl) pyrimidin-2-yl) amino) piperidin-1-yl) methyl) phenyl) boronic acid (E4); Methyl 4- (4-cyano-2, 6-dimethylphenoxy) -2- ((1- (4-sulfonylaminobenzyl) piperidin-4-yl) amino) pyrimidine-5-carboxylate (E5); 2- ((1- (4-carbamoyl-benzyl) piperidin-4-yl) amino) -4- (4-cyano-2, 6-dimethylphenoxy) pyrimidine-5-carboxylic acid methyl ester (E6); Methyl 4- (4-cyano-2, 6-dimethylphenoxy) -2- ((1- (4- (methylsulfonyl) benzyl) piperidin-4-yl) amino) pyrimidine-5-carboxylate (E7); (4- ((4- ((4- (4-cyano-2, 6-dimethylphenoxy) -5- (methoxycarbonyl) pyrimidin-2-yl) amino) piperidin-1-yl) methyl) phenyl) boronic acid (E8); 4- (4-cyano-2, 6-dimethylphenoxy) -2- ((1- (4-sulfonylaminobenzyl) piperidin-4-yl) amino) pyrimidine-5-carboxylic acid (E9); 2- ((1- (4-carbamoyl-benzyl) piperidin-4-yl) amino) -4- (4-cyano-2, 6-dimethylphenoxy) pyrimidine-5-carboxylic acid (E10); 4- (4-cyano-2, 6-dimethylphenoxy) -2- ((1- (4- (methylsulfonyl) benzyl) piperidin-4-yl) amino) pyrimidine-5-carboxylic acid (E11); 2- ((1- (4-boranyl) piperidin-4-yl) amino) -4- (4-cyano-2, 6-dimethylphenoxy) pyrimidine-5-carboxylic acid (E12); 4- (4-cyano-2, 6-dimethylphenoxy) -N-methoxy-2- ((1- (4-sulfonylaminobenzyl) piperidin-4-yl) amino) pyrimidine-5-carboxamide (E13); 2- ((1- (4-carbamoyl-benzyl) piperidin-4-yl) amino) -4- (4-cyano-2, 6-dimethylphenoxy) -N-methoxypyrimidine-5-carboxamide (E14); 4- (4-cyano-2, 6-dimethylphenoxy) -N-methoxy-2- ((1- (4- (methylsulfonyl) benzyl) piperidin-4-yl) amino) pyrimidine-5-carboxamide (E15); (4- ((4- ((4- (4-cyano-2, 6-dimethylphenoxy) -5- (methoxycarbamoyl) pyrimidin-2-yl) amino) piperidin-1-yl) methyl) phenyl) boronic acid (E16).
  3. 3. The process for preparing a carbonyl-substituted pyrimidine HIV-1 reverse transcriptase inhibitor, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, comprising the steps of: 1) Taking 2, 4-dichloropyrimidine-5-ethyl formate A1 or 2, 4-dichloropyrimidine-5-methyl formate A2 as a starting material, and carrying out nucleophilic substitution reaction with 4-hydroxy-3, 5-dimethylbenzonitrile in N, N-dimethylformamide solution to obtain an intermediate B1 or B2; 2) Intermediate B1 or B2 and 4-aminopiperidine-1-tert-butyl formate are subjected to nucleophilic substitution reaction to obtain intermediate C1 or C2, and a Boc protecting group is removed by trifluoroacetic acid to generate a key intermediate D1 or D2; 3) The intermediate D1 or D2 respectively reacts with substituted bromobenzyl or chlorobenzyl to obtain target compounds E1-E4 or E5-E8, the compounds E1-E4 undergo ester hydrolysis reaction under the action of lithium hydroxide hydrate in a mixed solution of methanol and water to obtain target compounds E9-E12, and simultaneously, the compounds E9-E12 undergo amide condensation reaction with O-methylhydroxylamine hydrochloride under the action of a condensing agent 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate to obtain target compounds E13-E16; The synthetic route is as follows: ; reagents and conditions (i) 4-hydroxy-3, 5-dimethylbenzonitrile, potassium carbonate, N, N-dimethylformamide, room temperature, (ii) t-butyl 4-aminopiperidine-1-carboxylate, potassium carbonate, N, N-dimethylformamide, 120 ℃, (iii) trifluoroacetic acid, dichloromethane, room temperature, (iv) substituted bromobenzyl or chlorobenzyl, potassium carbonate, N, N-dimethylformamide, room temperature; ; Reagents and conditions (i) lithium hydroxide hydrate, methanol: water=1:1V/V, room temperature, (ii) O-methyl hydroxylamine hydrochloride, 2- (7-azabenzotriazol) -N, N' -tetramethylurea hexafluorophosphate, N-diisopropylethylamine, N-dimethylformamide, 0 ℃ to room temperature.
  4. 4. Use of a carbonyl-substituted pyrimidine HIV-1 reverse transcriptase inhibitor, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, as an HIV-1 inhibitor.
  5. 5. The use of a carbonyl-substituted pyrimidine HIV-1 reverse transcriptase inhibitor, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, for the preparation of an anti-aids drug.
  6. 6. The use of a carbonyl-substituted pyrimidine HIV-1 reverse transcriptase inhibitor of claim 1, or a pharmaceutically acceptable salt thereof, as non-nucleoside NNRTIs for the manufacture of an anti-HIV medicament.
  7. 7. An anti-HIV-1 pharmaceutical composition comprising the carbonyl-substituted pyrimidine HIV-1 reverse transcriptase inhibitor of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.

Description

Carbonyl substituted pyrimidine HIV-1 reverse transcriptase inhibitor and preparation method and application thereof Technical Field The invention relates to a carbonyl substituted pyrimidine HIV-1 reverse transcriptase inhibitor, a preparation method and application thereof, belonging to the technical field of synthesis and medical application of organic compounds. Background AIDS (acquired immunodeficiency syndrome) is a major infectious disease caused mainly by infection with human immunodeficiency virus type 1 (HIV-1). HIV-1 Reverse Transcriptase (RT) is an asymmetric heterodimer consisting of p66 subunit and p51 subunit formed by transcription and translation of pol gene in HIV-1 genome, and its core function is to catalyze synthesis of double-stranded viral DNA by using single-stranded viral RNA as template, which is a key step in HIV-1 replication cycle. As a key enzyme of HIV-1 replication cycle, reverse transcriptase has the obvious advantages of clear three-dimensional crystal structure analysis, no existence of homologous enzyme in human body and the like, and has become a preferable target for the research and development of anti-AIDS drugs. The non-nucleoside reverse transcriptase inhibitors (NNRTIs) aiming at the target have the advantages of high efficiency, low toxicity and high selectivity. The inhibitor can obtain an active form without phosphorylation in cells, so that the activity of the inhibitor is not influenced by the phosphorylation conversion rate, the conversion speed and the stability after conversion, and meanwhile, the inhibitor can be combined with extracellular (such as in blood plasma) reverse transcriptase to reduce the activity of free viruses, thereby further weakening the infectivity of the viruses. In addition, NNRTIs have the characteristics of various structures, synergistic effect with other drugs and the like, and the advantages make the NNRTIs an indispensable component in antiretroviral therapy. Currently, 6 non-nucleoside reverse transcriptase inhibitors (NNRTIs) have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of HIV-1 infection, and 3 NNRTIs are marketed in other countries and regions. However, after years of clinical application, various drugs gradually expose the problems of drug resistance, toxic and side effects, poor pharmacokinetic properties and the like. Therefore, the development of new generation NNRTIs with high-efficiency drug resistance and good safety is still very important, and the early development of novel high-efficiency low-toxicity anti-AIDS drugs with independent intellectual property rights in China has great significance for clinical treatment. Disclosure of Invention The invention relates to a carbonyl substituted pyrimidine HIV-1 reverse transcriptase inhibitor, a preparation method and application thereof, aiming at the defects of the prior art. The invention is realized by the following technical scheme: The first object of the present invention is to provide a carbonyl-substituted pyrimidine HIV-1 reverse transcriptase inhibitor or a pharmaceutically acceptable salt thereof. A carbonyl-substituted pyrimidine HIV-1 reverse transcriptase inhibitor, or a pharmaceutically acceptable salt thereof, the carbonyl-substituted pyrimidine HIV-1 reverse transcriptase inhibitor having the structure shown in formula I below: Wherein, the R 1 is H, CH 3、OH、OCH3、OCH2CH3、NH2、NHNH2、NHCH3, NHOH or NHOCH 3; r 2 is halogen atom 、H、CH3、OH、CN、NH2、NO2、NHSO2NH2、NHSO2CH3、COOCH3、COOH、SO2NH2、CONH2、SO2CH3 or B (OH) 2, and the substituent is ortho-, meta-, para-monosubstituted or polysubstituted; R 3 is CN, CH 3, ch=chcn or p-C 4H6 -CN. Preferably, according to the present invention, the carbonyl-substituted pyrimidine HIV-1 reverse transcriptase inhibitor or a pharmaceutically acceptable salt thereof is selected from one of the following: Ethyl 4- (4-cyano-2, 6-dimethylphenoxy) -2- ((1- (4-sulfonylaminobenzyl) piperidin-4-yl) amino) pyrimidine-5-carboxylate (E1); ethyl 2- ((1- (4-carbamoyl-benzyl) piperidin-4-yl) amino) -4- (4-cyano-2, 6-dimethylphenoxy) pyrimidine-5-carboxylate (E2); Ethyl 4- (4-cyano-2, 6-dimethylphenoxy) -2- ((1- (4- (methylsulfonyl) benzyl) piperidin-4-yl) amino) pyrimidine-5-carboxylate (E3); (4- ((4- ((4- (4-cyano-2, 6-dimethylphenoxy) -5- (ethoxycarbonyl) pyrimidin-2-yl) amino) piperidin-1-yl) methyl) phenyl) boronic acid (E4); Methyl 4- (4-cyano-2, 6-dimethylphenoxy) -2- ((1- (4-sulfonylaminobenzyl) piperidin-4-yl) amino) pyrimidine-5-carboxylate (E5); 2- ((1- (4-carbamoyl-benzyl) piperidin-4-yl) amino) -4- (4-cyano-2, 6-dimethylphenoxy) pyrimidine-5-carboxylic acid methyl ester (E6); Methyl 4- (4-cyano-2, 6-dimethylphenoxy) -2- ((1- (4- (methylsulfonyl) benzyl) piperidin-4-yl) amino) pyrimidine-5-carboxylate (E7); (4- ((4- ((4- (4-cyano-2, 6-dimethylphenoxy) -5- (methoxycarbonyl) pyrimidin-2-yl) amino) piperidin-1-yl) methyl) phenyl) boronic acid (E8); 4- (4-cyano-2, 6-dimethylphenoxy) -2- ((1- (4-sul