CN118324717A - Substituted benzoyl piperazine compound and application thereof in preparation of medicines for resisting chikungunya virus - Google Patents

Abstract

The present invention discloses an application of a substituted benzoylpiperazine compound in preparing an anti-Chikungunya virus drug, wherein the substituted benzoylpiperazine compound has the following general structural formula: R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ are each independently selected from hydrogen, hydroxyl, C1-C10 alkyl, C1-C10 alkoxy, and halogen; X is selected from C or N; and Y is selected from one of the following groups: R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ , and R ₁₅ are each independently selected from hydrogen, hydroxyl, halogen, C1-C10 alkyl, and C1-C10 alkoxy. The substituted benzoylpiperazine compounds of the present invention have good anti-CHIKV effect, and the cell infection rate is less than 50%. The compounds prepared in the embodiments of the present invention all show good inhibitory effect on CHIKV and can be used as anti-Chikungunya virus drugs.

Description

A class of substituted benzoylpiperazine compounds and their application in the preparation of anti-Chikungunya virus drugs

This application is a divisional application of the following original divisional application: the application date is November 24, 2020, the application number is 202210922028.5, and the invention name is "A class of substituted benzoylpiperazine compounds and their use in the preparation of anti-Chikungunya virus drugs"; the original divisional application is a divisional application of the following parent application: the application date is November 24, 2020, the application number is 202011329695.X, and the invention name is "A class of substituted benzoylpiperazine compounds and their use in the preparation of anti-Chikungunya virus drugs". This application is a re-divisional application of the applicant for the original divisional application in accordance with the examination opinion on the unity issue in the first examination opinion notice of the original divisional application.

Technical Field

The invention belongs to the field of medical technology, and in particular relates to a class of substituted benzoylpiperazine compounds and their application in preparing anti-chikungunya virus drugs.

Background technique

Chikungunya virus (CHIKV) is a member of the genus Alphavirus of the family Togaviridae. Humans and non-human primates are the main hosts of CHIKV. Chikungunya virus can be called Chikungunya fever. Chikungunya fever is an acute febrile infectious disease transmitted by mosquito bites. In the past, this virus disease was mainly distributed in tropical and subtropical areas of Africa, South Asia, and Southeast Asia. In recent years, with factors such as global warming and modern transportation, the virus has shown a trend of continuous outbreaks and spread. On November 19, 2009, the first imported case of Chikungunya fever was detected at the Shenzhen Port. After being infected with Chikungunya virus, patients will experience severe pain in muscles and joints, accompanied by fever, nausea, and vomiting. After the acute phase, the joint pain and stiffness of most patients can be completely recovered. Some patients may have persistent joint pain and stiffness for weeks to months, or even more than 3 years. Some patients have sequelae such as impaired joint function, which seriously endangers human health. Currently, there is no approved vaccine or specific antiviral drug for Chikungunya fever, and treatment is mainly symptomatic treatment such as antipyretic and analgesic.

Summary of the invention

The first object of the present invention is to provide a class of substituted benzoylpiperazine compounds.

The second object of the present invention is to provide a substituted benzoylpiperazine compound and its use in preparing an anti-Chikungunya virus drug.

In order to achieve the above object, the technical solution adopted by the present invention is as follows:

The first aspect of the present invention provides a class of substituted benzoylpiperazine compounds or pharmaceutically acceptable salts thereof, the structure of which is one of the following structures:

R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ are each independently selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy, and halogen (fluorine, chlorine, bromine, and iodine);

R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ , and R ₁₅ are each independently selected from hydrogen, hydroxy, halogen, C1-C10 alkyl, and C1-C10 alkoxy;

Or, R ₈ , R ₉ , C and O form a 3- to 7-membered ring (such as 1,3-dioxolane);

R ₁₆ , R ₁₇ , R ₁₈ , R ₁₉ and R ₂₀ are each independently selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy and halogen.

Preferably, the substituted benzoylpiperazine compound is one of the following structures:

The second aspect of the present invention provides a use of a substituted benzoylpiperazine compound or a pharmaceutically acceptable salt thereof in the preparation of an anti-Chikungunya virus drug, wherein the substituted benzoylpiperazine compound has the following general structural formula:

R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ are each independently selected from hydrogen, hydroxy, C1-C10 alkyl, C1-C10 alkoxy, and halogen;

X is selected from C or N;

Y is selected from one of the following groups:

R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ , and R ₁₅ are each independently selected from hydrogen, hydroxy, halogen, C1-C10 alkyl, and C1-C10 alkoxy;

Or, R ₈ , R ₉ , C and O form a 3- to 7-membered ring (such as 1,3-dioxolane);

R ₁₆ , R ₁₇ , R ₁₈ , R ₁₉ and R ₂₀ are each independently selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy and halogen.

Preferably, the substituted benzoylpiperazine compound is one of the following structures:

R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ are each independently selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy, and halogen;

R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ , and R ₁₅ are each independently selected from hydrogen, hydroxy, halogen, C1-C10 alkyl, and C1-C10 alkoxy;

Or, R ₈ , R ₉ , C and O form a 3- to 7-membered ring (such as 1,3-dioxolane);

R ₁₆ , R ₁₇ , R ₁₈ , R ₁₉ and R ₂₀ are each independently selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy and halogen.

Most preferably, the substituted benzoylpiperazine compound is one of the following structures:

Due to the adoption of the above technical solution, the present invention has the following advantages and beneficial effects:

The substituted benzoylpiperazine compounds of the present invention have good anti-CHIKV effect, and the infection rate is less than 50%. The compounds prepared in the embodiments of the present invention all show good CHIKV inhibition effect and can be used as anti-Chikungunya virus drugs.

Detailed ways

In order to explain the present invention more clearly, the present invention is further described below in conjunction with preferred embodiments. It should be understood by those skilled in the art that the following specific description is illustrative rather than restrictive, and should not be used to limit the scope of protection of the present invention.

The materials used in the embodiments of the present invention are as follows: Bruker Spectmspin AC-P300 (Bruker, Switzerland); AC-P600 nuclear magnetic resonance instrument (Bruker, Switzerland); Agilent 6120 LC-MS mass spectrometer (Agilent, USA); silica gel plate GF254 (Yantai Huanghai Chemical, China); dark box UV analyzer (ZF-20D model); rotary evaporator (Buchi Rotavapor R-3 model); SHB-III circulating multi-purpose vacuum pump; vacuum drying oven (DZF-6021 model); ultrasonic cleaner (KQ-500E model); the reagents (analytical grade) and raw materials used in the experiment were purchased from Anage Reagent Co., Ltd., Bailingwei Technology Co., Ltd., Bid Pharmaceutical Technology Co., Ltd., Exploration Platform, etc.

Example 1

Preparation of compound 1B-1:

3,4,5-Trimethoxybenzoic acid (Compound 1) (100.0 mg, 0.5 mmol) was placed in a 100 ml round-bottom flask, DCM (10.0 ml, dichloromethane) was added to dissolve it, and then 1-(2-chlorophenyl)piperazine (120.0 mg, 0.6 mmol), DCC (124.0 mg, 0.6 mmol, N,N'-dicyclohexylcarboximide), DMAP (244.0 mg, 2.0 mmol) were added in sequence, and stirred at room temperature for 6 h. It was observed that the solution changed from clear to turbid, and TLC detection (DCM: MeOH = 10: 1) was performed until the reaction was completed. Filter, evaporate the filtrate under reduced pressure, and recrystallize with 95% EtOH to obtain Compound 1A-1 (111.0 mg, yield: 56%).

Compound 1A-1 (100.0 mg, 0.3 mmol) was placed in a 100 ml round-bottom three-necked flask, anhydrous DCM (10.0 ml) was added under the protection of anhydrous oxygen-free argon, and a DCM solution of BBr ₃ (6.0 ml, 3.0 mmol) was added dropwise at a constant rate of two drops per second at a temperature of -30°C. After the addition, the reaction apparatus was moved to room temperature and stirred overnight, and TLC was detected (DCM: MeOH = 10: 1). After the reaction was completed, 100.0 ml of water was added for quenching, and the mixture was stirred at room temperature for 1 h. Then, whether solid precipitation was observed, if solid precipitation was observed, the mixture was filtered, and the filter cake was placed in an oven for drying; if no solid precipitation was observed, EA was extracted three times, the organic phases were combined, dried over anhydrous sodium sulfate, the organic phases were evaporated to dryness, and recrystallized from DCM or EtOH to obtain compound 1B-1.

Example 2

Preparation of compound 1B-2:

1-(3-chlorophenyl)piperazine (120.0 mg, 0.6 mmol) was used to replace 1-(2-chlorophenyl)piperazine used in Example 1, and the rest was referred to Example 1 to obtain compound 1A-2 (123.0 mg, yield: 61%). The preparation of compound 1B-2 was referred to the preparation of compound 1B-1 in Example 1.

Example 3

1-(2,3-dichlorophenyl)piperazine (140.0 mg, 0.6 mmol) was used to replace the 1-(2-chlorophenyl)piperazine used in Example 1, and the rest was referred to Example 1 to obtain compound 1A-3 (107.0 mg, yield: 58%). The preparation of compound 1B-3 was referred to the preparation of compound 1B-1 in Example 1.

Example 4

3,4,5-Trimethoxybenzoic acid (Compound 1) (100.0 mg, 0.5 mmol) was placed in a 100 ml round-bottom flask, DMF (10.0 ml) was added to dissolve it, and then 4,4'-difluorobenzhydrylpiperazine (173.0 mg, 0.6 mmol), PyBOP (312.2 mg, 0.6 mmol), and DIEA (1.0 ml, 2.0 mmol) were added in sequence. After the addition was completed, the mixture was stirred at room temperature for 4 h, and TLC was performed (DCM: MeOH = 10: 1). When the reaction was completed, 100.0 ml of water was added for quenching, and the mixture was stirred at room temperature for 1 h to observe whether solids were precipitated. If solids were precipitated, the mixture was filtered, and the filter cake was dried in an oven. Compound 1A-4 (118.0 mg, yield: 60%) was obtained after recrystallization with 95% EtOH.

The preparation of compound 1B-4 refers to the preparation of compound 1B-1 in Example 1.

Example 5

3,4,5-trimethoxybenzoic acid (Compound 1) (100.0 mg, 0.5 mmol), N-Boc-piperazine (150.0 mg, 0.6 mmol), PyBOP (312.2 mg, 0.6 mmol), and then DIEA (1.0 ml, 2.0 mmol) were added. After the addition was completed, the mixture was stirred at room temperature for 4 h, and TLC was detected (DCM: MeOH = 10: 1). After the reaction was completed, 100.0 ml of water was added for quenching, and the mixture was stirred at room temperature for 1 h, filtered, and the filter cake was recrystallized from 95% EtOH to obtain intermediate a. The product was weighed and dissolved in hydrochloric acid-ethyl acetate solution at an equivalent ratio of 1:3, stirred at room temperature, and detected by TLC (DCM: MeOH = 10: 1). After the reaction was completed, the mixture was filtered and recrystallized from 95% EtOH to obtain intermediate b.

Intermediate b (140.0 mg, 0.5 mmol), 2,3-dichlorobenzoic acid (115.0 mg, 0.6 mmol), PyBOP (312.2 mg, 0.6 mmol) and DIEA (1.0 ml, 2.0 mmol) were used in the same manner as compound 1A-4 to obtain compound 1A-5 121.0 mg (yield: 59%).

The preparation of compound 1B-5 refers to the preparation of compound 1B-1 in Example 1.

Example 6

3,4-dichlorobenzoic acid (115.0 mg, 0.6 mmol) was used to replace the 2,3-dichlorobenzoic acid used in Example 5, and the rest was referred to Example 5 to obtain compound 1A-6 (115.0 mg, yield: 58%). The preparation of compound 1B-6 was referred to the preparation of compound 1B-1 in Example 1.

Example 7

3,4,5-trifluorobenzoic acid (110.0 mg, 0.6 mmol) was used to replace the 2,3-dichlorobenzoic acid used in Example 5, and the rest was referred to Example 5 to obtain compound 1A-7 (120.0 mg, yield: 65%). The preparation of compound 1B-7 was referred to the preparation of compound 1B-1 in Example 1.

Example 8

Trans-cinnamic acid (100.0 mg, 0.6 mmol) was used to replace the 2,3-dichlorobenzoic acid used in Example 5, and the rest was referred to Example 5 to obtain compound 1A-8 (116.0 mg, yield: 59%). The preparation of compound 1B-8 was referred to the preparation of compound 1B-1 in Example 1.

Embodiment 9

Phenoxyacetic acid (100.0 mg, 0.6 mmol) was used to replace the 2,3-dichlorobenzoic acid used in Example 5, and the rest was referred to Example 5 to obtain compound 1A-9 (130.0 mg, yield: 75%). The preparation of compound 1B-9 was referred to the preparation of compound 1B-1 in Example 1.

Example 10

2,4-dichlorophenoxyacetic acid (135.0 mg, 0.6 mmol) was used to replace the 2,3-dichlorobenzoic acid used in Example 5, and the rest was referred to Example 5 to obtain compound 1A-10 (109.0 mg, yield: 58%). The preparation of compound 1B-10 was referred to the preparation of compound 1B-1 in Example 1.

Embodiment 11

Compound c (163.0 mg, 0.6 mmol) was placed in a 100 ml round-bottom flask, DMF (10.0 ml) was added to dissolve it, and then 3,4,5-trimethoxybenzoic acid (compound 1) (100.0 mg, 0.5 mmol), PyBOP (312.2 mg, 0.6 mmol), and DIEA (1.0 ml, 2.0 mmol) were added in sequence. After the addition was completed, the mixture was stirred at room temperature for 2 h, and TLC was performed (DCM: MeOH = 10: 1). After the reaction was completed, 100.0 ml of water was added for quenching, and the mixture was stirred at room temperature for 1 h to observe whether solids were precipitated. If solids were precipitated, the mixture was filtered, and the filter cake was dried in an oven. 1A-11 (138.0 mg, yield: 78%) was obtained after recrystallization with 95% EtOH.

Preparation of Compound 1B-11 Refer to the preparation of Compound 1B-1 in Example 1.

Example 12

2,3,4-Trimethoxybenzoic acid (Compound 4) (100.0 mg, 0.5 mmol), 1-(2-chlorophenyl)piperazine (120.0 mg, 0.6 mmol), DCC (124.0 mg, 0.6 mmol), DMAP (244.0 mg, 2.0 mmol), the method was the same as 1A-1 in Example 1, to obtain compound 1C-1 (102.0 mg, yield: 48%).

Compound 1C-1 (100.0 mg, 0.3 mmol), BBr ₃ DCM solution (6.0 ml, 3.0 mmol), the method is the same as compound 1B-1 in Example 1, to obtain compound 1D-1.

Embodiment 13

1-(3-chlorophenyl)piperazine (120.0 mg, 0.6 mmol) was used instead of 1-(2-chlorophenyl)piperazine used in Example 12. The rest was carried out as per Example 12 to obtain compound 1C-2 (110.0 mg, yield: 54%).

The preparation of compound 1D-2 was carried out according to the preparation of compound 1D-1 in Example 12.

Embodiment 14

1-(2,3-dichlorophenyl)piperazine (140.0 mg, 0.6 mmol) was used instead of 1-(2-chlorophenyl)piperazine used in Example 12. The rest was referred to Example 12 to obtain compound 1C-3 (109.0 mg, yield: 50%).

The preparation of compound 1D-3 was carried out according to the preparation of compound 1D-1 in Example 12.

Embodiment 15

2,3,4-Trimethoxybenzoic acid (Compound 4) (100.0 mg, 0.5 mmol), 4,4'-difluorobenzhydrylpiperazine (173.0 mg, 0.6 mmol), PyBOP (312.2 mg, 0.6 mmol), DIEA (1.0 ml, 2.0 mmol), the method is the same as 1A-4 in Example 4, to obtain compound 1C-4 (117.0 mg, yield: 58%).

The preparation of compound 1D-4 was carried out according to the preparation of compound 1D-1 in Example 12.

Example 16

Take 2,3,4-trimethoxybenzoic acid (Compound 4) (100.0 mg, 0.5 mmol), N-Boc-piperazine (150.0 mg, 0.6 mmol), PyBOP (312.2 mg, 0.6 mmol), DIEA (1.0 ml, 2.0 mmol), and use the same method as that of Intermediate b in Example 5 to obtain Intermediate e.

Weigh intermediate e (140.0 mg, 0.5 mmol), 2,3-dichlorobenzoic acid (115.0 mg, 0.6 mmol), PyBOP (312.2 mg, 0.6 mmol), DIEA (1.0 ml, 2.0 mmol), and use the same method as 1A-4 in Example 4 to obtain 1C-5 (135.0 mg, yield: 79%).

The preparation of compound 1D-5 was carried out according to the preparation of compound 1D-1 in Example 12.

Embodiment 17

3,4-dichlorobenzoic acid (115.0 mg, 0.6 mmol) was used instead of 2,3-dichlorobenzoic acid used in Example 16. The rest was referred to Example 16 to obtain compound 1C-6 (124.0 mg, yield: 68%).

The preparation of compound 1D-6 was carried out according to the preparation of compound 1D-1 in Example 12.

Embodiment 18

3,4,5-trifluorobenzoic acid (110.0 mg, 0.6 mmol) was used instead of 2,3-dichlorobenzoic acid used in Example 16. The rest was referred to Example 16 to obtain compound 1C-7 (132.0 mg, yield: 70%).

The preparation of compound 1D-7 was carried out according to the preparation of compound 1D-1 in Example 12.

Embodiment 19

Trans-cinnamic acid (100.0 mg, 0.6 mmol) was used instead of 2,3-dichlorobenzoic acid used in Example 16. The rest was made by referring to Example 16 to obtain compound 1C-8 (130.0 mg, yield: 78%).

The preparation of compound 1D-8 was carried out according to the preparation of compound 1D-1 in Example 12.

Embodiment 20

Phenoxyacetic acid (100.0 mg, 0.6 mmol) was used instead of 2,3-dichlorobenzoic acid used in Example 16. The rest was carried out as described in Example 16 to obtain compound 1C-9 (139.0 mg, yield: 75%).

The preparation of compound 1D-9 refers to the preparation of compound 1D-1 in Example 12.

Embodiment 21

2,4-dichlorophenoxyacetic acid (135.0 mg, 0.6 mmol) was used instead of 2,3-dichlorobenzoic acid used in Example 16. The rest was referred to Example 16 to obtain compound 1C-10 (125.0 mg, yield: 70%).

The preparation of compound 1D-10 refers to the preparation of compound 1D-1 in Example 12.

Example 22

Weigh intermediate c (163.0 mg, 0.6 mmol), 2,3,4-trimethoxybenzoic acid (compound 4) (100.0 mg, 0.5 mmol), PyBOP (312.2 mg, 0.6 mmol), DIEA (1.0 ml, 2.0 mmol), and use the same method as compound 1A-4 to obtain 1C-11 (134.0 mg, yield: 70%).

The preparation of compound 1D-11 refers to the preparation of compound 1D-1 in Example 12.

Embodiment 23

3,4-Dimethoxybenzoic acid (Compound 5) (100.0 mg, 0.5 mmol), 1-(2-chlorophenyl)piperazine (120.0 mg, 0.6 mmol), PyBOP (312.2 mg, 0.6 mmol), DIEA (1.0 ml, 2.0 mmol), the method is the same as compound 1A-4, to obtain compound 2A-1 (126.0 mg, yield: 71%).

Compound 2A-1 (100.0 mg, 0.3 mmol), BBr ₃ DCM solution (6.0 ml, 3.0 mmol), the method is the same as compound 1B-1 in Example 1, to obtain 2B-1.

Embodiment 24

1-(3-chlorophenyl)piperazine (120.0 mg, 0.6 mmol) was used instead of 1-(2-chlorophenyl)piperazine used in Example 23. The rest was referred to Example 23 to obtain compound 2A-2 (121.0 mg, yield: 60%).

The preparation of compound 2B-2 refers to the preparation of compound 2B-1 in Example 23.

Embodiment 25

1-(2,3-dichlorophenyl)piperazine) (140.0 mg, 0.6 mmol) was used instead of 1-(2-chlorophenyl)piperazine used in Example 23, and the rest was referred to Example 23 to obtain compound 2A-3 (135.0 mg, yield: 72%).

The preparation of compound 2B-3 refers to the preparation of compound 2B-1 in Example 23.

Embodiment 26

4,4'-difluorodiphenylpiperazine (173.0 mg, 0.6 mmol) was used instead of 1-(2-chlorophenyl)piperazine used in Example 23. The other conditions were the same as those in Example 23 to obtain compound 2A-4 (125.0 mg, yield: 50%).

The preparation of compound 2B-4 was carried out according to the preparation of compound 2B-1 in Example 23.

Embodiment 27

3,4-Dimethoxybenzoic acid (Compound 5) (100.0 mg, 0.5 mmol), N-Boc-piperazine (150.0 mg, 0.6 mmol), PyBOP (312.2 mg, 0.6 mmol), DIEA (1.0 ml, 2.0 mmol), the method is the same as compound 1A-4, and the intermediate g is obtained after recrystallization with 95% EtOH.

Intermediate g (125.0 mg, 0.5 mmol), 2,3-dichlorobenzoic acid (115.0 mg, 0.6 mmol), PyBOP (312.2 mg, 0.6 mmol), DIEA (1.0 ml, 2.0 mmol), the method is the same as compound 1A-4, to obtain 2A-5 (128.0 mg, yield: 65%).

The preparation of compound 2B-5 refers to the preparation of compound 2B-1 in Example 23.

Embodiment 28

3,4-dichlorobenzoic acid (115.0 mg, 0.6 mmol) was used instead of 2,3-dichlorobenzoic acid used in Example 27. The rest was referred to Example 27 to obtain compound 2A-6 (112 mg, yield: 70%).

The preparation of compound 2B-6 refers to the preparation of compound 2B-1 in Example 23.

Embodiment 29

3,4,5-trifluorobenzoic acid (110.0 mg, 0.6 mmol) was used instead of 2,3-dichlorobenzoic acid used in Example 27. The rest was referred to Example 27 to obtain compound 2A-7 (126.0 mg, yield: 66%).

The preparation of compound 2B-7 refers to the preparation of compound 2B-1 in Example 23.

Embodiment 30

Trans-cinnamic acid (100.0 mg, 0.6 mmol) was used instead of 2,3-dichlorobenzoic acid used in Example 27. The rest was made by referring to Example 27 to obtain compound 2A-8 (104.0 mg, yield: 50%).

The preparation of compound 2B-8 refers to the preparation of compound 2B-1 in Example 23.

Embodiment 31

Phenoxyacetic acid (100.0 mg, 0.6 mmol) was used instead of 2,3-dichlorobenzoic acid used in Example 27. The rest was made by referring to Example 27 to obtain compound 2A-9 (130.0 mg, yield: 66%).

The preparation of compound 2B-9 refers to the preparation of compound 2B-1 in Example 23.

Embodiment 32

2,4-dichlorophenoxyacetic acid (135.0 mg, 0.6 mmol) was used instead of 2,3-dichlorobenzoic acid used in Example 27. The other conditions were the same as those in Example 27, and compound 2A-10 (116.0 mg, yield: 60%) was obtained.

The preparation of compound 2B-10 refers to the preparation of compound 2B-1 in Example 23.

Embodiment 33

2,3-Dimethoxybenzoic acid (Compound 6) (100.0 mg, 0.5 mmol), 1-(2-chlorophenyl)piperazine (120.0 mg, 0.6 mmol), PyBOP (312.2 mg, 0.6 mmol), DIEA (1.0 ml, 2.0 mmol), the method is the same as compound 1A-4 in Example 4, to obtain 2C-1 (116.0 mg, yield: 65%).

Weigh 2C-1 (100.0 mg, 0.3 mmol) and a solution of BBr ₃ in DCM (6.0 ml, 3.0 mmol) and use the same method as compound 1B-1 in Example 1 to obtain 2D-1.

Embodiment 34

1-(3-chlorophenyl)piperazine (120.0 mg, 0.6 mmol) was used instead of 1-(2-chlorophenyl)piperazine used in Example 33. The rest was carried out as per Example 33 to obtain compound 2C-2 (113.0 mg, yield: 60%).

The preparation of compound 2D-2 was carried out according to the preparation of compound 2D-1 in Example 33.

Embodiment 35

1-(2,3-dichlorophenyl)piperazine (140.0 mg, 0.6 mmol) was used instead of 1-(2-chlorophenyl)piperazine used in Example 33. The rest was made by referring to Example 33 to obtain compound 2C-3 (136.0 mg, yield: 77%).

The preparation of compound 2D-3 was carried out according to the preparation of compound 2D-1 in Example 33.

Embodiment 36

4,4'-difluorodiphenylpiperazine (173.0 mg, 0.6 mmol) was used instead of 1-(2-chlorophenyl)piperazine used in Example 33. The other conditions were the same as those in Example 33 to obtain compound 2C-4 (126.0 mg, yield: 50%).

The preparation of compound 2D-4 was carried out according to the preparation of compound 2D-1 in Example 33.

Embodiment 37

2,3-Dimethoxybenzoic acid (Compound 6) (100.0 mg, 0.5 mmol), N-Boc-piperazine (150.0 mg, 0.6 mmol), PyBOP (312.2 mg, 0.6 mmol), DIEA (1.0 ml, 2.0 mmol), the method is the same as compound 1A-4 in Example 4, to obtain intermediate i.

Weigh intermediate i (150.0 mg, 0.5 mmol), 2,3-dichlorobenzoic acid (compound 5) (115.0 mg, 0.6 mmol), PyBOP (312.2 mg, 0.6 mmol), DIEA (1.0 ml, 2.0 mmol), and use the same method as compound 1A-4 in Example 4 to obtain 2C-5 (129.0 mg, yield: 70%).

The preparation of compound 2D-5 was carried out according to the preparation of compound 2D-1 in Example 33.

Embodiment 38

3,4,5-trifluorobenzoic acid (110.0 mg, 0.6 mmol) was used instead of 2,3-dichlorobenzoic acid used in Example 35. The rest was referred to Example 35 to obtain compound 2C-7 (114.0 mg, yield: 72%).

The preparation of compound 2D-7 was carried out according to the preparation of compound 2D-1 in Example 33.

Embodiment 39

Trans-cinnamic acid (100.0 mg, 0.6 mmol) was used instead of 2,3-dichlorobenzoic acid used in Example 35. The rest was carried out as per Example 35 to obtain compound 2C-8 (126.0 mg, yield: 66%).

The preparation of compound 2D-8 was carried out according to the preparation of compound 2D-1 in Example 33.

Embodiment 40

2,4-dichlorophenoxyacetic acid (135.0 mg, 0.6 mmol) was used instead of 2,3-dichlorobenzoic acid used in Example 35. The other conditions were the same as those in Example 35 to obtain compound 2C-10 (123.0 mg, yield: 60%).

The preparation of compound 2D-10 refers to the preparation of compound 2D-1 in Example 33.

Embodiment 41

Synthesis method of compound (4-(2,3-dichlorophenyl)piperazin-1-yl)(3-methoxyphenyl)methanone(3B-3)

3-Methoxybenzoic acid (Compound 9) (100.0 mg, 0.65 mmol), 1-(2,3-dichlorophenyl)piperazine (139.0 mg, 0.8 mmol), PyBOP (416.3 mg, 0.8 mmol), DIEA (1.0 ml, 2.0 mmol), the method was the same as compound 1A-4 in Example 4, to obtain 3B-3 (126 mg, yield: 79%).

The structures, NMR, MS and cell infection rate data of the compounds prepared in Examples 1 to 41 are shown in Table 1:

Table 1

Embodiment 42The synthetic method of MZD-8:

3,4-methylenedioxyphenylacrylic acid (96.1 mg, 0.5 mmol) was placed in a 100 ml round-bottom flask, DMF (10.0 ml) was added to dissolve it, and then 1-chlorobenzhydrylpiperazine (171.7 mg, 0.6 mmol), PyBOP (312.2 mg, 0.6 mmol), and DIEA (1.0 ml, 2.0 mmol) were added in sequence. After the addition was completed, the mixture was stirred at room temperature for 4 h, and TLC was performed (DCM: MeOH = 10: 1). When the reaction was completed, 100.0 ml of water was added for quenching, and the mixture was stirred at room temperature for 1 h to observe whether solids were precipitated. If solids were precipitated, the mixture was filtered, and the filter cake was dried in an oven. Compound MZD-8 (57.7 mg, yield: 60%) was obtained after recrystallization with 95% EtOH.

Embodiment 43The synthetic method of MZD-35:

4-Fluorobenzylic acid (83.1 mg, 0.5 mmol) was placed in a 100 ml round-bottom flask, DMF (10.0 ml) was added to dissolve it, then diphenylmethylpiperazine (151.3 mg, 0.6 mmol), PyBOP (312.2 mg, 0.6 mmol), and DIEA (1.0 ml, 2.0 mmol) were added in sequence, and stirred at room temperature for 4 h after the addition was completed, and TLC was detected (DCM: MeOH = 10: 1), and the reaction was completed. 100.0 ml of water was added for quenching, and stirred at room temperature for 1 h to observe whether there was solid precipitation. If there was solid precipitation, filter it, dry the filter cake in an oven, and recrystallize it with 95% EtOH to obtain compound MZD-35 (118.0 mg, yield: 60%).

Embodiment 44The synthetic method of MZD-57:

4-Methylphenylacrylic acid (81.1 mg, 0.5 mmol) was placed in a 100 ml round-bottom flask, DMF (10.0 ml) was added to dissolve it, and then 4,4'-difluorophenylpiperazine (173.0 mg, 0.6 mmol), PyBOP (312.2 mg, 0.6 mmol), and DIEA (1.0 ml, 2.0 mmol) were added in sequence. After the addition was completed, the mixture was stirred at room temperature for 4 h, and TLC was detected (DCM: MeOH = 10: 1). After the reaction was completed, 100.0 ml of water was added for quenching, and the mixture was stirred at room temperature for 1 h to observe whether solids were precipitated. If solids were precipitated, the mixture was filtered, and the filter cake was placed in an oven for drying. Compound MZD-57 (60.8 mg, yield: 75%) was obtained after recrystallization with 95% EtOH.

Embodiment 45 The synthetic method of MZD-56:

4-Methylphenylacrylic acid (81.1 mg, 0.5 mmol) was placed in a 100 ml round-bottom flask, DMF (10.0 ml) was added to dissolve it, and then 1-chlorodiphenylmethylpiperazine (171.7 mg, 0.6 mmol), PyBOP (312.2 mg, 0.6 mmol), and DIEA (1.0 ml, 2.0 mmol) were added in sequence. After the addition was completed, the mixture was stirred at room temperature for 4 h, and TLC was performed (DCM: MeOH = 10: 1). When the reaction was completed, 100.0 ml of water was added for quenching, and the mixture was stirred at room temperature for 1 h to observe whether solids were precipitated. If solids were precipitated, the mixture was filtered, and the filter cake was dried in an oven. Compound MZD-56 (48.7 mg, yield: 60%) was obtained after recrystallization with 95% EtOH.

Embodiment 46 The synthetic method of MZD-37:

4-Fluorobenzylic acid (83.1 mg, 0.5 mmol) was placed in a 100 ml round-bottom flask, DMF (10.0 ml) was added to dissolve it, and then 4,4'-difluorophenylpiperazine (173.0 mg, 0.6 mmol), PyBOP (312.2 mg, 0.6 mmol), and DIEA (1.0 ml, 2.0 mmol) were added in sequence. After the addition was completed, the mixture was stirred at room temperature for 4 h, and TLC was performed (DCM: MeOH = 10: 1). After the reaction was completed, 100.0 ml of water was added for quenching, and the mixture was stirred at room temperature for 1 h to observe whether solids were precipitated. If solids were precipitated, the mixture was filtered, and the filter cake was dried in an oven. Compound MZD-37 (66.5 mg, yield: 80%) was obtained after recrystallization with 95% EtOH.

Embodiment 47The synthetic method of MZD-36:

4-Fluorobenzylic acid (83.1 mg, 0.5 mmol) was placed in a 100 ml round-bottom flask, DMF (10.0 ml) was added to dissolve it, and then 1-chlorodiphenylmethylpiperazine (171.7 mg, 0.6 mmol), PyBOP (312.2 mg, 0.6 mmol), and DIEA (1.0 ml, 2.0 mmol) were added in sequence. After the addition was completed, the mixture was stirred at room temperature for 4 h, and TLC was performed (DCM: MeOH = 10: 1). When the reaction was completed, 100.0 ml of water was added for quenching, and the mixture was stirred at room temperature for 1 h to observe whether solids were precipitated. If solids were precipitated, the mixture was filtered, and the filter cake was dried in an oven. Compound MZD-36 (49.9 mg, yield: 60%) was obtained after recrystallization with 95% EtOH.

Embodiment 48 The synthetic method of MZD-43:

2-Fluorobenzylic acid (83.1 mg, 0.5 mmol) was placed in a 100 ml round-bottom flask, DMF (10.0 ml) was added to dissolve it, then diphenylmethylpiperazine (151.3 mg, 0.6 mmol), PyBOP (312.2 mg, 0.6 mmol), and DIEA (1.0 ml, 2.0 mmol) were added in sequence, and stirred at room temperature for 4 h after the addition was completed, and TLC was detected (DCM: MeOH = 10: 1), and the reaction was completed. 100.0 ml of water was added for quenching, and stirred at room temperature for 1 h to observe whether there was solid precipitation. If there was solid precipitation, filter it, and dry the filter cake in an oven, and recrystallize it with 95% EtOH to obtain compound MZD-43 (49.9 mg, yield: 60%).

Embodiment 49The synthetic method of MZD-40:

3-Fluorobenzylic acid (83.1 mg, 0.5 mmol) was placed in a 100 ml round-bottom flask, DMF (10.0 ml) was added to dissolve it, and then 1-chlorodiphenylmethylpiperazine (171.7 mg, 0.6 mmol), PyBOP (312.2 mg, 0.6 mmol), and DIEA (1.0 ml, 2.0 mmol) were added in sequence. After the addition was completed, the mixture was stirred at room temperature for 4 h, and TLC was performed (DCM: MeOH = 10: 1). After the reaction was completed, 100.0 ml of water was added for quenching, and the mixture was stirred at room temperature for 1 h to observe whether solids were precipitated. If solids were precipitated, the mixture was filtered, and the filter cake was dried in an oven. Compound MZD-40 (49.9 mg, yield: 60%) was obtained after recrystallization with 95% EtOH.

Embodiment 50The synthetic method of MZD-55:

4-Methylphenylacrylic acid (81.1 mg, 0.5 mmol) was placed in a 100 ml round-bottom flask, DMF (10.0 ml) was added to dissolve it, then diphenylmethylpiperazine (151.3 mg, 0.6 mmol), PyBOP (312.2 mg, 0.6 mmol), and DIEA (1.0 ml, 2.0 mmol) were added in sequence, and stirred at room temperature for 4 h after the addition was completed, and TLC was detected (DCM: MeOH = 10: 1), and the reaction was completed. 100.0 ml of water was added for quenching, and stirred at room temperature for 1 h to observe whether there was solid precipitation. If there was solid precipitation, filter it, and dry the filter cake in an oven, and recrystallize it with 95% EtOH to obtain compound MZD-55 (48.7 mg, yield: 60%).

Embodiment 51The synthetic method of MZD-44:

2-Fluorobenzylic acid (83.1 mg, 0.5 mmol) was placed in a 100 ml round-bottom flask, DMF (10.0 ml) was added to dissolve it, and then 1-chlorodiphenylmethylpiperazine (171.7 mg, 0.6 mmol), PyBOP (312.2 mg, 0.6 mmol), and DIEA (1.0 ml, 2.0 mmol) were added in sequence. After the addition was completed, the mixture was stirred at room temperature for 4 h, and TLC was performed (DCM: MeOH = 10: 1). After the reaction was completed, 100.0 ml of water was added for quenching, and the mixture was stirred at room temperature for 1 h to observe whether solids were precipitated. If solids were precipitated, the mixture was filtered, and the filter cake was dried in an oven. Compound MZD-44 (49.9 mg, yield: 60%) was obtained after recrystallization with 95% EtOH.

Embodiment 52The synthetic method of MZD-39:

3-Fluorobenzylic acid (83.1 mg, 0.5 mmol) was placed in a 100 ml round-bottom flask, DMF (10.0 ml) was added to dissolve it, then diphenylmethylpiperazine (151.3 mg, 0.6 mmol), PyBOP (312.2 mg, 0.6 mmol), and DIEA (1.0 ml, 2.0 mmol) were added in sequence, and stirred at room temperature for 4 h after the addition was completed, and TLC was detected (DCM: MeOH = 10: 1), and the reaction was completed. 100.0 ml of water was added for quenching, and stirred at room temperature for 1 h to observe whether there was solid precipitation. If there was solid precipitation, filter it, and dry the filter cake in an oven, and recrystallize it with 95% EtOH to obtain compound MZD-39 (49.9 mg, yield: 60%).

Embodiment 53The synthetic method of MZD-9:

3,4-methylenedioxyphenylacrylic acid (96.1 mg, 0.5 mmol) was placed in a 100 ml round-bottom flask, DMF (10.0 ml) was added to dissolve it, and then 4,4'-difluorophenylpiperazine (173.0 mg, 0.6 mmol), PyBOP (312.2 mg, 0.6 mmol), and DIEA (1.0 ml, 2.0 mmol) were added in sequence. After the addition was completed, the mixture was stirred at room temperature for 4 h, and TLC was detected (DCM: MeOH = 10: 1). When the reaction was completed, 100.0 ml of water was added for quenching, and the mixture was stirred at room temperature for 1 h to observe whether solids were precipitated. If solids were precipitated, the mixture was filtered, and the filter cake was placed in an oven for drying. Compound MZD-9 (57.7 mg, yield: 60%) was obtained after recrystallization with 95% EtOH.

Embodiment 54The synthetic method of MZD-45:

2-Fluorobenzylic acid (83.1 mg, 0.5 mmol) was placed in a 100 ml round-bottom flask, DMF (10.0 ml) was added to dissolve it, and then 4,4'-difluorophenylpiperazine (173.0 mg, 0.6 mmol), PyBOP (312.2 mg, 0.6 mmol), and DIEA (1.0 ml, 2.0 mmol) were added in sequence. After the addition was completed, the mixture was stirred at room temperature for 4 h, and TLC was performed (DCM: MeOH = 10: 1). After the reaction was completed, 100.0 ml of water was added for quenching, and the mixture was stirred at room temperature for 1 h to observe whether solids were precipitated. If solids were precipitated, the mixture was filtered, and the filter cake was dried in an oven. Compound MZD-45 (49.9 mg, yield: 60%) was obtained after recrystallization with 95% EtOH.

Embodiment 55 The synthetic method of MZD-41:

3-Fluorobenzylic acid (83.1 mg, 0.5 mmol) was placed in a 100 ml round-bottom flask, DMF (10.0 ml) was added to dissolve it, and then 4,4'-difluorophenylpiperazine (173.0 mg, 0.6 mmol), PyBOP (312.2 mg, 0.6 mmol), and DIEA (1.0 ml, 2.0 mmol) were added in sequence. After the addition was completed, the mixture was stirred at room temperature for 4 h, and TLC was detected (DCM: MeOH = 10: 1). After the reaction was completed, 100.0 ml of water was added for quenching, and the mixture was stirred at room temperature for 1 h to observe whether solids were precipitated. If solids were precipitated, the mixture was filtered, and the filter cake was placed in an oven for drying. Compound MZD-41 (49.9 mg, yield: 60%) was obtained after recrystallization with 95% EtOH.

The structures, NMR, MS and cell infection rate data of the compounds prepared in Examples 42 to 55 are shown in Table 2:

Table 2

Embodiment 56

Experimental methods for the anti-CHIKV effects of some compounds

(I) Experimental drugs, reagents and materials

1.Human hepatoma cell line Huh7 was purchased from Shanghai Institute of Cell Biology, Chinese Academy of Sciences and preserved by the Department of Biomedical Defense, Department of Naval Medicine, Naval Medical University, Chinese People's Liberation Army.

2. DMEM complete cell culture medium, containing 10% fetal bovine serum, 0.03% glutamine, non-essential amino acids, ampicillin and streptomycin 100U/mL, adjusted to pH 7.4.

3. Cell digestion solution, containing 0.25% trypsin, prepared with phosphate buffer.

2. Viruses

The Chikungunya virus (CHIKV) LR2006 strain was synthesized, and the viral genome was inserted between the non-structural gene and the structural gene. The EGFP expression frame (the EGFP promoter used the CHIKV structural gene promoter) was used to prepare the recombinant virus LR2006-EGFP, which showed obvious green fluorescence 8 hours after infecting Huh7 cells.

(III) Evaluation of antiviral activity

1. Cell inoculation: prepare several bottles of Huh7 cells in good growth condition, wash with PBS, digest with trypsin, suspend the cells with DMEM culture medium containing 10% FBS, mix the cells, and inoculate them in 96-well plates, with 100 μl of cell suspension and 15,000 cells per well. Culture for 12 hours, at which time the cells are 100% confluent, and perform drug treatment and virus infection.

2. Virus infection: Place the 96-well plate in a 4°C refrigerator; Dilute the virus to a virus infection multiplicity (MOI) of 0.1 in each well using DMEM culture medium containing 10% FBS according to the titers of the five viruses previously determined, mix the virus thoroughly, then take out the 96-well plate from the 4°C refrigerator, add 50 μl of virus diluent, and then place it in a 4°C refrigerator.

3. Drug treatment: add 250 μl of DMEM complete culture medium to each well of the 96-well plate, add an appropriate amount of drug diluent to each well of the 96-well plate so that the final drug concentration is 10 μM, shake on a shaker for 5 minutes, and place in a 37°C incubator for cell culture. DMSO is used as a negative control.

4. Virus infection detection: 12 hours after CHIKV infection, four fields of view were photographed in each well using the EVOS M7000 cell imaging system to count the number of EGFP-positive cells and determine the cell infection rate after treatment with 10 μM concentration of compound.

The cell infection rate data are shown in Table 3:

table 3

serial number Cell infection rate% 1A-1 13 1B-1 2.8 1C-1 3.5 1D-1 2.7 2A-1 4 2B-1 2.1 2C-1 3.1 2D-1 2.7 1A-2 5.7 1B-2 3.0 1C-2 4.9 1D-2 2.5 2A-2 6.4 2C-2 3.2 2D-2 3.3 1B-3 3.4 1C-3 3.8 1D-3 1.6 2A-3 4.1 2B-3 2.7 2C-3 4.7 2D-3 3.9

From the above data, it can be seen that the cell infection rate of the compounds of the present invention is very low. It is generally believed that an infection rate of less than or equal to 50% is effective. Therefore, the compounds prepared in the examples of the present invention all show a good inhibitory effect on CHIKV and can be used as anti-Chikungunya virus drugs.

The above is only a preferred embodiment of the present invention, and does not limit the present invention in any form. Although the present invention has been disclosed as a preferred embodiment as above, it is not used to limit the present invention. Any technician familiar with this patent can make some changes or modify the technical contents suggested above into equivalent embodiments without departing from the scope of the technical solution of the present invention. However, any simple modification, equivalent change and modification made to the above embodiments according to the technical essence of the present invention without departing from the content of the technical solution of the present invention still fall within the scope of the solution of the present invention.

Claims (5)

1. A substituted benzoyl piperazine compound or a medicinal salt thereof is characterized in that the structure is one of the following structures:

R ₁、R₂、R₃、R₄、R₅ is independently selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy and halogen;

R₆、R₇、R₈、R₉、R₁₀、R₁₁、R₁₂、R₁₃、R₁₄、R₁₅ Each independently selected from hydrogen, hydroxy, halogen, C1-C10 alkyl, C1-C10 alkoxy.

2. The substituted benzoylpiperazine compound or its pharmaceutically acceptable salt according to claim 1, wherein the substituted benzoylpiperazine compound is one of the following structures:

3. the application of a substituted benzoyl piperazine compound or a medicinal salt thereof in preparing a medicine for resisting chikungunya virus is characterized in that the substituted benzoyl piperazine compound has the following structural general formula:

R ₁、R₂、R₃、R₄、R₅ is independently selected from hydrogen, hydroxy, C1-C10 alkyl, C1-C10 alkoxy and halogen;

X is selected from C or N;

Y is selected from one of the following groups:

R₆、R₇、R₈、R₉、R₁₀、R₁₁、R₁₂、R₁₃、R₁₄、R₁₅ Each independently selected from hydrogen, hydroxy, halogen, C1-C10 alkyl, C1-C10 alkoxy.

4. The use of a substituted benzoylpiperazine compound or its pharmaceutically acceptable salt, according to claim 3, in the manufacture of a medicament against chikungunya virus, wherein the substituted benzoylpiperazine compound is one of the following structures:

R ₁、R₂、R₃、R₄、R₅ is independently selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy and halogen;

R₆、R₇、R₈、R₉、R₁₀、R₁₁、R₁₂、R₁₃、R₁₄、R₁₅ Each independently selected from hydrogen, hydroxy, halogen, C1-C10 alkyl, C1-C10 alkoxy.

5. The use of a substituted benzoylpiperazine compound or its pharmaceutically acceptable salt as claimed in claim 4, in the manufacture of a medicament against chikungunya virus, wherein the substituted benzoylpiperazine compound is one of the following structures: