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CN-121990997-A - Aza alicyclic ring substituted pyrimidine derivative and preparation method and application thereof

CN121990997ACN 121990997 ACN121990997 ACN 121990997ACN-121990997-A

Abstract

The invention relates to an aza-alicyclic substituted pyrimidine derivative and a preparation method thereof, wherein the aza-alicyclic substituted pyrimidine derivative has a structure shown in a formula I, the aza-alicyclic substituted pyrimidine compound provided by the invention has novel structure, most of the compounds show stronger anti-HIV-1 activity, and the EC 50 value is between 9.40 nM and 238 nM. Among them, the compounds WP-10a (EC 50 =12.6±0.68 nM）、WP-10b（EC 50 =9.40±0.96 nM）、WP-10c（EC 50 =18.3+ -1.6 nM) and WP-10d (EC 50 =26.2+ -6.0 nM) with X-position substituted amino azetidine are especially prominent in activity, and the WP-10b with optimal activity has single digit nanomole antiviral efficacy, which is improved by nearly 30 times compared with the activity of the marketed drug nevirapine (EC 50 =281+ -38.7 nM), and is equivalent to the activity of efavirenz (EC 50 =5.20+ -0.90 nM) and zidovudine (EC 50 =7.50+ -1.8 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
20260508
Application Date
20260130

Claims (7)

  1. 1. An aza-alicyclic substituted pyrimidine derivative has a structure shown in the following formula I: ; Wherein, the X is an aza-aliphatic ring, including piperazine ring, aminopiperidine ring, aminoazetidine, aminoazabicyclooctane, aza-spiro ring, or homopiperazine ring; R 1 is Boc、H、CH 3 、SO 2 NH 2 、SO 2 CH 3 、SO 2 CH 2 CH 3 、SO 2 N(CH 3 ) 2 、SO 2 CH(CH 3 ) 2 、CONH 2 、COCH 3 、COCH 2 CH 3 、CON(CH 3 ) 2 or COCH (CH 3 ) 2 ; R 2 is CN, CH 3 , ch=chcn, or substituted phenyl.
  2. 2. The aza-alicyclic substituted pyrimidine derivative according to claim 1, wherein: the aza-alicyclic substituted pyrimidine derivative is selected from one of the following: 4- ((2- ((4-cyanophenyl) amino) -6- (piperazin-1-yl) pyrimidin-4-yl) oxy) -3, 5-dimethylbenzonitrile (WP-4 a); 4- ((2- ((4-cyanophenyl) amino) -6- (4- (methylsulfonyl) piperazin-1-yl) pyrimidin-4-yl) oxy) -3, 5-dimethylbenzonitrile (WP-4 b); 4- ((2- ((4-cyanophenyl) amino) -6- (4- (ethylsulfonyl) piperazin-1-yl) pyrimidin-4-yl) oxy) -3, 5-dimethylbenzonitrile (WP-4 c); 4- (6- (4-cyano-2, 6-dimethylphenoxy) -2- ((4-cyanophenyl) amino) pyrimidin-4-yl) -N, N-dimethylpiperazine-1-sulfonamide (WP-4 d); 4- ((6- (4-aminopiperidin-1-yl) -2- ((4-cyanophenyl) amino) pyrimidin-4-yl) oxy) -3, 5-dimethylbenzonitrile (WP-6 a); N- (1- (6- (4-cyano-2, 6-dimethylphenoxy) -2- ((4-cyanophenyl) amino) pyrimidin-4-yl) piperidin-4-yl) methanesulfonamide (WP-6 b); N- (1- (6- (4-cyano-2, 6-dimethylphenoxy) -2- ((4-cyanophenyl) amino) pyrimidin-4-yl) piperidin-4-yl) ethanesulfonamide (WP-6 c); N- (1- (6- (4-cyano-2, 6-dimethylphenoxy) -2- ((4-cyanophenyl) amino) pyrimidin-4-yl) piperidin-4-yl) -N, N-dimethyl sulfonamide (WP-6 d); 4- ((2- ((4-cyanophenyl) amino) -6- (piperidin-4-ylamino) pyrimidin-4-yl) oxy) -3, 5-dimethylbenzonitrile (WP-8 a); 4- ((2- ((4-cyanophenyl) amino) -6- ((1- (methylsulfonyl) piperidin-4-yl) amino) pyrimidin-4-yl) oxy) -3, 5-dimethylbenzonitrile (WP-8 b); 4- ((2- ((4-cyanophenyl) amino) -6- ((1- (ethylsulfonyl) piperidin-4-yl) amino) pyrimidin-4-yl) oxy) -3, 5-dimethylbenzonitrile (WP-8 c); 4- ((6- (4-cyano-2, 6-dimethylphenoxy) -2- ((4-cyanophenyl) amino) pyrimidin-4-yl) amino) -N, N-dimethylpiperidine-1-sulfonamide (WP-8 d); 4- ((6- (3-aminoazetidin-1-yl) -2- ((4-cyanophenyl) amino) pyrimidin-4-yl) oxy) -3, 5-dimethylbenzonitrile (WP-10 a); N- (1- (6- (4-cyano-2, 6-dimethylphenoxy) -2- ((4-cyanophenyl) amino) pyrimidin-4-yl) azetidin-3-yl) methanesulfonamide (WP-10 b); N- (1- (6- (4-cyano-2, 6-dimethylphenoxy) -2- ((4-cyanophenyl) amino) pyrimidin-4-yl) azetidin-3-yl) ethanesulfonamide (WP-10 c); N- (1- (6- (4-cyano-2, 6-dimethylphenoxy) -2- ((4-cyanophenyl) amino) pyrimidin-4-yl) azetidin-3-yl) -N, N-dimethyl sulfonamide (WP-10 d); 4- ((6- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- ((4-cyanophenyl) amino) pyrimidin-4-yl) oxy) -3, 5-dimethylbenzonitrile (WP-14 a); 4- ((2- ((4-cyanophenyl) amino) -6- ((1 r,5 s) -8- (methylsulfonyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) pyrimidin-4-yl) oxy) -3, 5-dimethylbenzonitrile (WP-14 b); 4- ((2- ((4-cyanophenyl) amino) -6- ((1 r,5 s) -8- (ethylsulfonyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) pyrimidin-4-yl) oxy) -3, 5-dimethylbenzonitrile (WP-14 c); (1 r,5 s) -3- (6- (4-cyano-2, 6-dimethylphenoxy) -2- ((4-cyanophenyl) amino) pyrimidin-4-yl) -N, N-dimethyl-3, 8-diazabicyclo [3.2.1] octane-8-sulfonamide (WP-14 d); 4- ((2- ((4-cyanophenyl) amino) -6- (1, 4-diazepan-1-yl) pyrimidin-4-yl) oxy) -3, 5-dimethylbenzonitrile (WP-16 a); 4- ((2- ((4-cyanophenyl) amino) -6- (4- (methylsulfonyl) -1, 4-diazepan-1-yl) pyrimidin-4-yl) oxy) -3, 5-dimethylbenzonitrile (WP-16 b); 4- ((2- ((4-cyanophenyl) amino) -6- (4- (ethylsulfonyl) -1, 4-diazepan-1-yl) pyrimidin-4-yl) oxy) -3, 5-dimethylbenzonitrile (WP-16 c); 4- (6- (4-cyano-2, 6-dimethylphenoxy) -2- ((4-cyanophenyl) amino) pyrimidin-4-yl) -N, N-dimethyl-1, 4-diazacycloheptane-1-sulfonamide (WP-16 d).
  3. 3. The process for preparing an aza-alicyclic substituted pyrimidine derivative according to claim 1, comprising the steps of: 1) Taking 2,4, 6-trichloropyrimidine 1 as a starting material, and carrying out nucleophilic substitution reaction with 4-hydroxy-3, 5-dimethylbenzonitrile in a1, 4-dioxane solution to prepare an intermediate 2; 2) Intermediate 2 reacts with p-aminobenzonitrile under the alkaline condition of potassium tert-butoxide to obtain intermediate 3, N-dimethylformamide is taken as a solvent, intermediate 3 reacts with piperazine-1-carboxylic acid tert-butyl ester or piperidine-4-carbamic acid tert-butyl ester or 4-aminopiperidine-1-carboxylic acid tert-butyl ester or azetidine-3-carbamic acid tert-butyl ester or (1R, 5S) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester or 1, 4-diazacycloheptane-1-carboxylic acid tert-butyl ester under the high-temperature alkaline condition to obtain key intermediate 4a-f through nucleophilic substitution reaction, and then intermediate 4a-f removes Boc protecting groups in dichloromethane solution through trifluoroacetic acid to generate intermediate 5a-f; 3) The intermediates 5a-f respectively carry out acylation reaction with various substituted sulfonyl chlorides or acyl chlorides under the alkaline condition of triethylamine to obtain a target compound I; The synthetic route is as follows: ; Reagents and conditions of (i) 4-hydroxy-3, 5-dimethylbenzonitrile, N, N-diisopropylethylamine, 1, 4-dioxane, 65 ℃, (ii) p-aminobenzonitrile, potassium tert-butoxide, N-methylpyrrolidone, 0 ℃ to room temperature, (iii) aminoazaalicyclic ring, potassium carbonate, N, N-dimethylformamide, 120 ℃, (iv) trifluoroacetic acid, dichloromethane, room temperature, (v) substituted sulfonyl chloride or acyl chloride, triethylamine, dichloromethane, 0 ℃ to room temperature.
  4. 4. Use of an aza-alicyclic substituted pyrimidine derivative as claimed in claim 1 as an HIV-1 inhibitor.
  5. 5. The use of an aza-alicyclic substituted pyrimidine derivative as defined in claim 1 for the preparation of an anti-aids drug.
  6. 6. The use of an aza-alicyclic substituted pyrimidine derivative as claimed in claim 1 as non-nucleoside NNRTIs for the preparation of anti-hiv drugs.
  7. 7. An anti-HIV-1 pharmaceutical composition comprising an aza-alicyclic substituted pyrimidine derivative according to claim 1, a pharmaceutically acceptable salt thereof, and a pharmaceutical excipient.

Description

Aza alicyclic ring substituted pyrimidine derivative and preparation method and application thereof Technical Field The invention relates to an aza-alicyclic substituted pyrimidine derivative, and a preparation method and application thereof, belonging to the technical field of organic compound synthesis and medical application. Background AIDS (AIDS) is a major infectious disease caused mainly by infection with human immunodeficiency virus type 1 (HIV-1). Reverse Transcriptase (RT) in HIV-1 life cycle is a preferred target for anti-AIDS drug development due to its clear mechanism of action and rich structural biological information. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) aiming at the target become a research hot spot in the field of anti-AIDS drug research in recent years by virtue of the advantages of high efficiency, low toxicity and the like. Although 9 NNRTIs are available in the united states, china, europe, russia and other areas, a plurality of medicines are clinically used for years, and the problems of poor drug resistance, toxic and side effects, poor pharmacokinetic properties and the like are gradually exposed. Therefore, the development of new generation NNRTIs with high-efficiency drug resistance activity 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. Disclosure of Invention Aiming at the defects of the prior art, the invention provides an aza-alicyclic substituted pyrimidine derivative and a preparation method thereof. The technical scheme of the invention is as follows: the first object of the invention is to provide an aza-alicyclic substituted pyrimidine derivative. An aza-alicyclic substituted pyrimidine derivative has a structure shown in the following formula I: Wherein, the X is an aza-aliphatic ring, including piperazine ring, aminopiperidine ring, aminoazetidine, aminoazabicyclooctane, aza-spiro ring, or homopiperazine ring; R 1 is Boc、H、CH3、SO2NH2、SO2CH3、SO2CH2CH3、SO2N(CH3)2、SO2CH(CH3)2、CONH2、COCH3、COCH2CH3、CON(CH3)2 or COCH (CH 3)2; R 2 is CN, CH 3, ch=chcn, or substituted phenyl. According to a preferred embodiment of the present invention, the azaalicyclic pyrimidine derivative is selected from one of the following: 4- ((2- ((4-cyanophenyl) amino) -6- (piperazin-1-yl) pyrimidin-4-yl) oxy) -3, 5-dimethylbenzonitrile (WP-4 a); 4- ((2- ((4-cyanophenyl) amino) -6- (4- (methylsulfonyl) piperazin-1-yl) pyrimidin-4-yl) oxy) -3, 5-dimethylbenzonitrile (WP-4 b); 4- ((2- ((4-cyanophenyl) amino) -6- (4- (ethylsulfonyl) piperazin-1-yl) pyrimidin-4-yl) oxy) -3, 5-dimethylbenzonitrile (WP-4 c); 4- (6- (4-cyano-2, 6-dimethylphenoxy) -2- ((4-cyanophenyl) amino) pyrimidin-4-yl) -N, N-dimethylpiperazine-1-sulfonamide (WP-4 d); 4- ((6- (4-aminopiperidin-1-yl) -2- ((4-cyanophenyl) amino) pyrimidin-4-yl) oxy) -3, 5-dimethylbenzonitrile (WP-6 a); N- (1- (6- (4-cyano-2, 6-dimethylphenoxy) -2- ((4-cyanophenyl) amino) pyrimidin-4-yl) piperidin-4-yl) methanesulfonamide (WP-6 b); N- (1- (6- (4-cyano-2, 6-dimethylphenoxy) -2- ((4-cyanophenyl) amino) pyrimidin-4-yl) piperidin-4-yl) ethanesulfonamide (WP-6 c); N- (1- (6- (4-cyano-2, 6-dimethylphenoxy) -2- ((4-cyanophenyl) amino) pyrimidin-4-yl) piperidin-4-yl) -N, N-dimethyl sulfonamide (WP-6 d); 4- ((2- ((4-cyanophenyl) amino) -6- (piperidin-4-ylamino) pyrimidin-4-yl) oxy) -3, 5-dimethylbenzonitrile (WP-8 a); 4- ((2- ((4-cyanophenyl) amino) -6- ((1- (methylsulfonyl) piperidin-4-yl) amino) pyrimidin-4-yl) oxy) -3, 5-dimethylbenzonitrile (WP-8 b); 4- ((2- ((4-cyanophenyl) amino) -6- ((1- (ethylsulfonyl) piperidin-4-yl) amino) pyrimidin-4-yl) oxy) -3, 5-dimethylbenzonitrile (WP-8 c); 4- ((6- (4-cyano-2, 6-dimethylphenoxy) -2- ((4-cyanophenyl) amino) pyrimidin-4-yl) amino) -N, N-dimethylpiperidine-1-sulfonamide (WP-8 d); 4- ((6- (3-aminoazetidin-1-yl) -2- ((4-cyanophenyl) amino) pyrimidin-4-yl) oxy) -3, 5-dimethylbenzonitrile (WP-10 a); N- (1- (6- (4-cyano-2, 6-dimethylphenoxy) -2- ((4-cyanophenyl) amino) pyrimidin-4-yl) azetidin-3-yl) methanesulfonamide (WP-10 b); N- (1- (6- (4-cyano-2, 6-dimethylphenoxy) -2- ((4-cyanophenyl) amino) pyrimidin-4-yl) azetidin-3-yl) ethanesulfonamide (WP-10 c); N- (1- (6- (4-cyano-2, 6-dimethylphenoxy) -2- ((4-cyanophenyl) amino) pyrimidin-4-yl) azetidin-3-yl) -N, N-dimethyl sulfonamide (WP-10 d); 4- ((6- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- ((4-cyanophenyl) amino) pyrimidin-4-yl) oxy) -3, 5-dimethylbenzonitrile (WP-14 a); 4- ((2- ((4-cyanophenyl) amino) -6- ((1 r,5 s) -8- (methylsulfonyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) pyrimidin-4-yl) oxy) -3, 5-dimethylbenzonitrile (WP-14 b); 4- ((2- ((4-cyanophenyl) amino) -6- ((1 r,5 s) -8- (ethylsulfonyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) pyrimidin-4-yl) oxy) -3, 5-dimethylbenzonitrile (WP-14 c); (1 r,5 s) -3- (6- (4-cyano-2, 6-dimethylphenoxy) -2- ((4-cyanophenyl) amino) pyrimidin-4-yl) -N, N-dimet