Diketopiperazine hydroxyl, amino and aromatic acid substituted derivative and pharmaceutical composition

Abstract

The invention discloses a diketopiperazine hydroxyl, amino and aromatic acid substituted derivative and a pharmaceutical composition, and belongs to the technical field of medicines. The technical problem to be solved is to provide a diketopiperazine hydroxyl, amino and aromatic acid substituted derivative with a new structure. The key point of the technical scheme is to provide a compound as shown in a formula I or a formula II, or a pharmaceutically acceptable salt of the compound as shown in the formula I or the formula II, and drug delivery is realized in different modes. Formula I and formula II

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and more specifically, to a diketopiperazine hydroxyl, amino, and aromatic acid substituted derivative and a pharmaceutical composition thereof. Background Technology

[0002] For understanding the technical content of this invention: Drug delivery systems have always been an important area of ​​research in pharmaceutical formulation. Traditional methods are affected by the pH environment of the digestive tract and various enzymes, leading to the rapid destruction or inactivation of some bioactive substances, such as calcitonin, insulin, and mucopolysaccharides, in the gastrointestinal tract. Furthermore, due to the inherent physicochemical properties of drugs, some sensitive drugs are prone to degradation, and poorly soluble drugs have low bioavailability. Developing efficient delivery systems can enhance drug efficacy and reduce toxic side effects. Heterocyclic compounds have always been one of the most important classes of organic compounds. In organisms, they are the main components of living cells and participate in important biochemical processes. For this reason, heterocyclic compounds possess a wide range of pharmacological activities; nearly half of the currently available therapeutic drugs contain heterocyclic structures. Piperazine (PP) is an important class of biologically active N-heterocyclic natural products, composed of a six-membered nitrogen-containing heterocycle with two nitrogen atoms in opposite positions on the ring. Piperazine is one of the most widely found structures in drugs and has promising applications in biomedical fields such as drug design. This is because the nitrogen atom at the 4-position of piperazine can act as a basic amine, while the nitrogen atom at the 1-position can introduce hydrogen bond acceptors or hydrophobic groups through reactions with other compounds, thereby regulating drug interactions and hydrophilicity / hydrophobicity. Many piperazine compounds possess important pharmacological properties and show broad application prospects in antitumor, antibacterial, anti-inflammatory, and antioxidant activities. In addition, piperazine compounds have the ability to open tight junctions between cells, making them a highly efficient and low-toxicity penetration enhancer widely used in drug delivery.

[0003] Diketopiperazine compounds are a novel type of material that can enhance drug permeability by loading or adsorbing drugs onto its surface, thereby improving drug stability and penetration. Drug-loaded permeation enhancers using diketopiperazine compounds as carriers have small diameters, large surface areas, high drug loading capacities, and are simple to manufacture. They are suitable for the preparation of various types of drugs, such as cationic drugs, anionic drugs, hydrophilic / lipophilic drugs, peptides, and proteins with API molecular weights of 500-140,000 Da.

[0004] Technosphere® technology, which uses fumaroyl diketopiperazine (FDKP, CAS: 176738-91-3) as a carrier to enhance transmucosal penetration, is a novel drug delivery technology. Mannkind's Afrezza rapid-acting insulin, produced using this technology, was approved by the FDA in 2014 and is currently the only inhaled insulin formulation on the market, fully demonstrating the transmucosal penetration-enhancing function of diketopiperazine compounds as drug carriers.

[0005]

[0006] Relevant patent documents retrieved: This document, published in China (CN115991678A) on April 21, 2023, discloses a diketopiperazine compound, its preparation method, and its applications. This invention provides a diketopiperazine compound as shown in the formula, or a pharmaceutically acceptable salt thereof, which can be used as a drug delivery and penetration enhancer to achieve effective drug delivery.

[0007]

[0008] Relevant non-patent literature retrieved: The journal or book title is "Doctoral Dissertation of South China University of Technology," and the article title is "Application Research of Polymer Carriers Constructed Based on Piperazine Derivatives in Intracellular Protein Delivery." The publication date is April 2023. This article discloses a series of cationic polymer carriers based on piperazine and its derivatives, and explores their effectiveness and structure-activity relationship in intracellular protein delivery. Based on the modification of polymers with piperazine and its derivatives, a series of efficient and safe intracellular protein delivery carriers were obtained. Through the integration of piperazine molecules with other functional elements, a series of protein delivery systems meeting different application requirements were obtained.

[0009] In summary, developing a novel diketopiperazine derivative with hydroxyl, amino, and aromatic acid substitutions, which could be better applied to drug delivery systems, is a key research focus for researchers in this field. Summary of the Invention

[0010] The purpose of this invention is to provide: A novel diketopiperazine hydroxyl, amino, and aromatic acid substituted derivative thereof, its preparation method and application, and related technologies, to solve the technical problem of providing a novel diketopiperazine hydroxyl, amino, and aromatic acid substituted derivative thereof, or a combination thereof.

[0011] Terminology Explanation: Unless otherwise defined, all technical terms in this document have the same meanings as commonly understood by one of ordinary skill in the art to which the subject matter of the claims pertains. Unless otherwise stated, all patents, patent inventions, and publications cited in this document are incorporated herein by reference in their entirety. If multiple definitions exist for terms in this document, the definitions in this chapter shall prevail.

[0012] It should be understood that the above brief description and the following detailed description are exemplary and for illustrative purposes only, and do not limit the subject matter of the invention in any way. In this invention, the singular is used in conjunction with the plural unless otherwise specifically stated. It should also be noted that, unless otherwise stated, the use of “or” or “or” means “and / or”. Furthermore, the use of the term “comprising” and other forms such as “including,” “containing,” and “contains” are not limiting.

[0013] The definition of standard chemical terms can be found in the reference "Basic Organic Chemistry (Volumes 1 & 2), Xing Qiyi, Higher Education Press, 3rd Edition, 2005-06."

[0014] Unless specifically defined herein, the use of all commercially available products herein employs standard techniques. For example, it may be carried out using the manufacturer's instructions for use with the kit, or in accordance with methods known in the art or the description of this invention. The techniques and methods described herein can generally be implemented according to conventional methods well known in the art, based on the descriptions in the various summary and more specific documents cited and discussed in this specification.

[0015] As used herein, the term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable, non-toxic alkali or acid. When the compounds of the present invention are acidic, their corresponding salts can be readily prepared from inorganic or organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (copper and cuprous), iron, ferrous, lithium, magnesium, manganese (manganese and manganese), potassium, sodium, zinc, etc. Preferred are ammonium, calcium, magnesium, potassium, and sodium salts. Salts prepared from organic bases include primary, secondary, and tertiary amines derived from natural and synthetic sources. Pharmaceutically acceptable non-toxic organic bases that can form salts include arginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydrabamine, isopropylamine, dicyclohexylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. When the compounds of the present invention are basic, their corresponding salts can be readily prepared from inorganic or organic acids. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, hydroxyethylsulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, viscous acid, nitric acid, pyric acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, etc.

[0016] The term "alkyl" refers to a branched or straight-chain saturated aliphatic hydrocarbon group with a specific number of carbon atoms, including all isomers. Common abbreviations for alkyl groups include methyl ("Me" or CH3), ethyl ("Et" or CH2CH3), propyl ("Pr" or CH2CH2CH3), and butyl ("Bu" or CH2CH2CH2CH3), etc. For example, "C..." 1-6 Alkyl (or "C1-C6 alkyl") refers to a straight-chain or branched alkyl group having a specific number of carbon atoms, including all isomers.

[0017] The term "aryl" itself, or as part of another substituent, refers to an aromatic monocyclic or polycyclic carbocyclic group having 6-14 carbon atoms or 6-10 carbon atoms, in one embodiment being phenyl. Exemplary aryl groups include fused cycloalkyl, heterocycloalkyl, or heteroaryl rings (e.g., 1-3 other rings). When the "aryl" group includes a fused cycloalkyl, heterocycloalkyl, or heteroaryl group, then the "aryl" group is linked via an aryl ring (e.g., a phenyl ring) to a group that is a substituent for said aryl ring. "Optionally substituted aryl" groups are optionally one or more.

[0018] The term “substitution” means that one or more hydrogen atoms are removed from the chemical group and that it is substituted by a substituent. As used herein, the term “substituent” has the common meaning known in the art and refers to a chemical moiety covalently attached to, or appropriately fused to, the parent group. As used herein, the terms “optionally substituted” or “optionally…substituted” mean that the chemical group may be without a substituent (i.e., unsubstituted) or may have one or more substituents (i.e., substituted). It should be understood that substitution at a given atom is limited by the valence of the atom.

[0019] The term "alkoxy" refers to a substituted or unsubstituted alkyl group, which is attached to other parts of the molecule via an oxygen atom. The alkyl group is as described above. Where the alkyl group indicating the alkoxy group is optionally substituted with one or more substituents, typically 1, 2, 3, 4, or 5, and 1, 2, 3, or 4, and 1, 2, or 3, and 1 or 2, or 1, wherein the multiple substituents are chosen independently unless otherwise indicated. It should be understood that any substitution of the alkoxy group or an alkoxy group substituted on another part, attached at any available atom, provides a stable compound.

[0020] The term "heteroatoms" includes oxygen (O), nitrogen (N), sulfur (S), silicon (Si), boron (B), and phosphorus (P).

[0021] In a first aspect, the present invention provides: a diketopiperazine hydroxyl, amino, and aromatic acid-substituted derivative, wherein the diketopiperazine hydroxyl, amino, and aromatic acid-substituted derivative is a compound represented by Formula I or Formula II, or a pharmaceutically acceptable salt of a compound represented by Formula I or Formula II: ; Formula I ; Formula II Among them, R a The substituent may be independently selected from heteroatoms, substituted or unsubstituted C1-C8 alkyl groups; the substituent may be selected from amino, carboxyl or hydroxyl groups; R b Independently selectable from -L-COOH; L can independently choose from the following groups, either self-substituted or unsubstituted: C1-C8 alkyl groups, C2-C8 heteroalkyl groups, C6-C 10 Aryl, C3-C 12Cycloalkyl, 3-7 membered heterocycloalkyl, and 5-10 membered heteroaryl; in the C2-C8 heteroalkyl, the heteroatom or heteroatom group is selected from one or more of N, O, S, S(=O), and S(=O)2, and the number of heteroatoms or heteroatom groups is 1-3, and they are linked to -L- through a carbon atom; in the 3-7 membered heterocycloalkyl, the heteroatom is selected from one or more of N, O, S, S(=O), and S(=O)2, and the number of heteroatoms is 1-3; in the 5-10 membered heteroaryl, the heteroatom is selected from one or more of N, O, and S, and the number of heteroatoms is 1-4; when there are multiple substituents, they may be the same or different; The substituents are independently selected from halogens, C1-C6 alkyl groups, C1-C6 alkyl-O-, C1-C6 alkyl groups substituted with one or more halogens, C1-C6 alkyl-O-, or =O groups substituted with one or more halogens.

[0022] Preferably, R a The alkyl group is independently selected from N, O, S, substituted or unsubstituted C1-C5; the substituent is selected from amino or hydroxyl groups; R b Independently selectable from -L-COOH; L can be independently selected from the following groups, either self-substituted or unsubstituted: C1-C5 alkyl, C2-C5 heteroalkyl, C6-C 10 Aryl; the substituent is independently selected from F, Cl, Br, I, C1-C3 alkyl, C1-C3 alkyl-O-, C1-C3 alkyl substituted with one or more halogens, C1-C3 alkyl-O- or =O substituted with one or more halogens.

[0023] More preferably, wherein R a The substituent may be independently selected from N, substituted or unsubstituted C1-C3 alkyl groups; the substituent may be selected from amino groups; R b Independently selectable from -L-COOH; L can be independently selected from the following groups, either self-substituted or unsubstituted: C1-C3 alkyl groups, C2-C3 heteroalkyl groups, C6-C 10 Aryl; the substituents are independently selected from C1-C3 alkyl groups and C1-C3 alkyl-O- groups.

[0024] More preferably, wherein R a Independently choose your own or ; R b Independently choose your own or , .

[0025] Preferably, the compound is selected from the following structures: , , , , .

[0026] Preferably, the preparation method of the above-described diketopiperazine hydroxyl, amino, and aromatic acid-substituted derivatives includes the following steps, as shown in the reaction equation: ; Compound a and compound b undergo a condensation reaction to yield the compound shown in Formula I or Formula II.

[0027] Preferably, the molar ratio of compound a to compound b is (0.9-1.1):(0.9-1.1). More preferably, the molar ratio of compound a to compound b is 1:1.

[0028] Preferably, the condensing agent is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), O-azabenzotriazole tetramethylurea hexafluorophosphate (HATU), and 1-hydroxybenzotriazole (HOBt).

[0029] Preferably, the condensation reaction is carried out in the presence of a solvent.

[0030] More preferably, the solvent is selected from at least one of N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, dioxane, or tetrahydrofuran.

[0031] More preferably, the solvent is N,N-dimethylformamide.

[0032] Preferably, the present invention provides the use of the above-described diketopiperazine hydroxyl, amino, aromatic acid-substituted derivatives or pharmaceutically acceptable salts thereof as pharmaceutical excipients.

[0033] In a second aspect, the present invention provides a pharmaceutical composition comprising the above-described diketopiperazine hydroxyl, amino, aromatic acid-substituted derivatives or pharmaceutically acceptable salts thereof, and one or more pharmaceutically active ingredients.

[0034] Preferably, the pharmaceutical composition is a penetration-enhancing drug delivery system; And / or, the pharmaceutical active ingredient comprises 10%-90% by weight in the pharmaceutical composition; And / or, the active pharmaceutical ingredient may be an API with a molecular weight of 500. 140,000 Da cationic drugs, anionic drugs, Hydrophilic / lipophilic drugs, peptides, or proteins; And / or, the active pharmaceutical ingredient is a poorly soluble drug; And / or, the pharmaceutical composition further comprises a pharmaceutically acceptable pharmaceutical excipient.

[0035] More preferably, the diketopiperazine hydroxyl, amino, aromatic acid-substituted derivatives or pharmaceutically acceptable salts thereof, as described above, are used as penetration enhancers; And / or, the pharmaceutical active ingredient comprises 20%-80% by weight in the pharmaceutical composition; And / or, the drug is a poorly soluble drug, and the poorly soluble drug is selected from insulin, dulutegravir, and sildenafil; And / or, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient selected from excipients, buffers, emulsifiers, stabilizers, diluents, binders, preservatives, lubricants, pH adjusters, cryoprotectants, flavoring agents, fillers, or antioxidants.

[0036] Preferably, the excipient is selected from at least one of microcrystalline cellulose, lactose, pregelatinized starch, cyclodextrin, carboxymethyl cellulose, mannitol, magnesium stearate, starch, calcium phosphate, ethyl cellulose, methyl cellulose, alginate, gelatin, gum arabic, glyceryl monostearate, sodium glycolate starch glycolate, guar gum, glycerol, and propylene glycol.

[0037] Preferably, the buffer is selected from at least one of sodium dihydrogen phosphate, sodium bicarbonate, ammonium bicarbonate, sodium acetate, citrate, histidine, and succinate.

[0038] Preferably, the emulsifier is selected from at least one of magnesium stearate, zinc stearate, calcium stearate, glyceryl stearate, sorbitan isostearate, sorbitan oleate, and polyglycerol-3 polyricinoleate.

[0039] Preferably, the stabilizer is selected from at least one of farnesian gum, agar, alginate, cellulose ether, and carboxymethyl chitosan.

[0040] Preferably, the diluent is selected from at least one of erythritol, mannitol, sorbitol, xylitol, lactose, sucrose, corn starch, potato starch, calcium phosphate, calcium citrate, and crystalline cellulose.

[0041] Preferably, the adhesive is selected from at least one of ethanol, starch paste, pregelatinized starch, dextrin, syrup, hydroxypropyl methylcellulose, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyvinyl alcohol, polyethylene glycol, sodium alginate, polyvinylpyrrolidone, gum arabic, gelatin, and alginic acid.

[0042] Preferably, the preservative is selected from at least one of methylparaben, propylparaben, methylparaben, ethylparaben, propylparaben, chlorobutanol, thimerosal, mercuric oxycyanide, phenoxyethanol, chlorhexidine, benzoic acid, sodium benzoate, chlorocresol, benzalkonium bromide, benzalkonium chloride, and ethylparaben.

[0043] Preferably, the lubricant is selected from at least one of magnesium stearate, zinc stearate, glyceryl monostearate, polyethylene glycol, stearic acid, talc, sodium chloride, sodium oleate, sodium lauryl sulfate, magnesium lauryl sulfate, sodium stearate fumarate, and poloxamer.

[0044] Preferably, the pH adjuster is selected from at least one of citric acid, fumaric acid, succinic acid, tartaric acid, malic acid, and ascorbic acid.

[0045] Preferably, the flavoring agent is selected from at least one of sweet orange flavoring, vanilla flavoring, strawberry flavoring, milk flavoring, banana flavoring, and cherry flavoring.

[0046] Preferably, the filler is selected from at least one of mannitol, xylitol, sorbitol, maltose, microcrystalline cellulose, glucose, lactose, sucrose, dextrin, starch, sodium alginate, and sodium bicarbonate.

[0047] Preferably, the antioxidant may be selected from at least one of L-cysteine ​​hydrochloride, L-cysteine ​​base, 4,4-(2,3-dimethyltetramethylenediamine), tocopherol-rich extracts (natural vitamin E), α-tocopherol (synthetic vitamin E), β-tocopherol, 6-tocopherol, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate, octyl gallate, dodecyl gallate, tert-butylhydroquinone (TBHQ), fumaric acid, malic acid, ascorbic acid (vitamin C), sodium ascorbate, calcium ascorbate, potassium ascorbate, ascorbate palmitate, and ascorbate stearate.

[0048] Preferably, the present invention provides a method for preparing the above-described pharmaceutical composition, comprising the following steps: adding a solution containing the active pharmaceutical ingredient to an alkaline solution containing the diketopiperazine hydroxyl, amino, aromatic acid substituted derivative or its pharmaceutically acceptable salt, and adjusting the pH until a solid precipitates to obtain the pharmaceutical composition.

[0049] Compared with the prior art, the beneficial effects of the present invention include at least the following: This invention provides a novel diketopiperazine hydroxyl, amino, and aromatic acid-substituted derivative, its preparation method, and its application. This type of compound can be used as an excipient in pharmaceutical formulations to achieve drug delivery through various methods. Detailed Implementation

[0050] The following non-limiting embodiments are intended to enable those skilled in the art to gain a more comprehensive understanding of the present invention, but do not limit the invention in any way. The following content is merely an exemplary description of the scope of protection claimed by the present invention, and those skilled in the art can make various changes and modifications to the present invention based on the disclosed content, and such changes should also fall within the scope of protection claimed by the present invention.

[0051] The present invention will be further described below by way of specific embodiments. Unless otherwise specified, all instruments, devices, equipment, reagents, products, etc., used in the embodiments of the present invention are obtained through conventional commercial means.

[0052] Example 1

[0053] Step 1: Compound 1 (5.0 g, 19.50 mmol), compound 2 (4.06 g, 19.50 mmol), HATU (8.90 g, 23.41 mmol), DIPEA (3.28 g, 25.36 mmol), and HOBt (0.26 g, 1.95 mmol) were dissolved in 50 mL of anhydrous DMF. After reacting overnight at room temperature, the reaction solution was poured into water, and a solid precipitated. After filtration and concentration, the solid was separated by column chromatography (DCM:MeOH = 10:1-5:1) to obtain 8.50 g of white foamy solid compound 3, with a yield of 68.4%.

[0054] Step 2: Dissolve compound 3 (6.0 g, 9.42 mmol) in 60 mL of a methanol:water (20:1) mixture, adjust the pH to 12 with 10% sodium hydroxide aqueous solution, react for 2 h, adjust the pH to 1-2 with 6N hydrochloric acid, precipitate a solid, filter, wash with water until neutral, and dry to obtain a white solid compound 4 in an amount of 6.9 g, yield: 73.2%.

[0055] 1 H NMR (500 MHz, DMSO- d6 , ppm, ppm): 8.10 (d, 4H, J=4.8Hz, CH), 7.65 (d, 4H, J=4.8Hz, CH), 4.24 (t, 2H, COCH), 3.86 (m, 7H, CH2), 3.02 (t, 4H, NCH2), 1.74-1.82 (m, 6H, CH2), 1.56-1.67 (m, 4H, CH2), 1,35-1.46 (m, 4H, CH2), 1.28 (m, 3H, CH3).

[0056] MS: 609.25 (M+H).

[0057] Example 2

[0058] Step 1: Compound 1 (4.0 g, 15.60 mmol), compound 2-1 (3.76 g, 15.60 mmol), HATU (7.12 g, 18.72 mmol), DIPEA (2.62 g, 20.28 mmol), and HOBt (0.21 g, 1.56 mmol) were added sequentially to 50 mL of Wushui DMF. After stirring overnight at room temperature, the reaction solution was poured into water, a solid precipitated, filtered, concentrated, and purified by column chromatography (DCM:MeOH = 10:1-5:1) to obtain a white foamy solid, compound 2-2 (7.32 g), with a yield of 66.74%.

[0059] Step 2: Dissolve compound 2-2 (6.0 g, 8.54 mmol) in 60 mL of a methanol:water (20:1) mixture, adjust the pH to 12 with 10% sodium hydroxide aqueous solution, react for 2 h, adjust the pH to 1-2 with 6N hydrochloric acid, precipitate a solid, filter, wash with water until neutral, dry, and obtain a white solid compound 2-3 (3.12 g), yield: 72.71%.

[0060] 1 H NMR (500 MHz, DMSO- d6 , ppm): 8.26 (s, 2H, NH), 8.01 (s, 2H, NH), 3.99 (m, 2H, CH), 3.02 (t, 2H, J=7.1 Hz), 2.51 (t, 4H, J=7.0 Hz), 2.15–1.585 (m,8H, CH2), 1.83-1.585 (m, 8H, CH2), 1.77 (m, 4H, CH2), 1.53 (m, 4H, CH2), 1.50 (brs, 2H, NH2), 1.25 (m, 4H, CH2).

[0061] MS: 503.33 (M+H).

[0062] Example 3

[0063] Step 1: Compound 1 (5.0 g, 19.50 mmol), compound 3-1 (5.0 g, 19.50 mmol), HATU (8.9 g, 23.41 mmol), DIPEA (3.28 g, 25.36 mmol), and HOBt (0.26 g, 1.95 mmol) were dissolved in 50 mL of anhydrous DMF. After reacting overnight at room temperature, the reaction solution was poured into water, and a solid precipitated. The solid was filtered, concentrated, and purified by column chromatography (DCM:MeOH = 10:1-5:1) to obtain a white foamy solid compound 3-2 (9.67 g), with a yield of 67.62%.

[0064] Step 2: Dissolve compound 3-2 (8.0 g, 10.91 mmol) in 80 mL of a methanol:water (20:1) mixture, adjust the pH to 12 with 10% sodium hydroxide aqueous solution, react for 2 h, adjust the pH to 1-2 with 6N hydrochloric acid, precipitate a solid, filter, wash with water until neutral, and dry to obtain a white solid compound 3-3 (3.80 g), yield: 69.01%.

[0065] 1 H NMR (500 MHz, DMSO- d6 , ppm): 5.15 (br s, 2H, OH), 8.26 (s, 2H, NH), 7.70 (s, 1H, NH), 3.32 (br s, 1H, NH), 3.99 (m, 2H, CH), 3.71 (m, 2H, CH2), 3.00 (t, 2H, J=7.1 Hz, CH2), 2.53 (t, 2H, J=7.1 Hz), 2.50-1.945 (m, 6H, CH2), 2.21-1.955 (m, 2H, CH2), 2.04-1.645 (m, 4H, CH2), 1.90-1.645 (m, 4H, CH2), 1.77-1.37(m, 8H, CH2), 1.53-1.37 (m, 4H, CH2), 1.39-1.37 (m, 2H, CH2), 1.25-1.37 (m, 8H, CH2).

[0066] MS: 505.30 (M+H).

[0067] Example 4

[0068] Step 1: Compound 1 (2.5 g, 9.75 mmol), compound 4-1 (2.35 g, 9.75 mmol), HATU (4.45 g, 11.70 mmol), DIPEA (1.64 g, 12.68 mmol), and HOBt (0.13 g, 0.97 mmol) were added sequentially to 50 mL of anhydrous DMF. After reacting overnight at room temperature, the reaction solution was poured into water, and a solid precipitated. The solid was filtered, concentrated, and separated by column chromatography (DCM:MeOH = 10:1-5:1) to obtain a white, foamy solid, compound 4-2 (4.70 g), with a yield of 68.56%.

[0069] Step 2: Compound 4-2 (4.0 g, 5.69 mmol) was dissolved in 40 mL of a methanol:water (20:1) mixture. The pH was adjusted to 12 with 10% sodium hydroxide aqueous solution. After reacting for 2 h, the pH was adjusted to 1-2 with 6 N hydrochloric acid, and a solid precipitated. The solid was filtered, washed with water until neutral, and dried to obtain a white solid compound 4-3 (2.13 g). Yield: 74.46%.

[0070] 1 H NMR (500 MHz, DMSO- d6 , ppm): 8.52 (br s, 2H, NH2), 8.26 (s, 2H,NH), 7.70 (s, 1H, NH), 3.99 (m, 2H, CH), 3.71 (m, 2H, CH2), 3.32 (br s, 1H,NH), 3.00 (t, 2H, J=7.1 Hz, CH2), 2.53 (t, 2H, J=7.1 Hz), 2.42-2.175 (m, 2H,CH2), 2.12-1.875 (m, 4H, CH2), 2.12-1.865 (m, 4H, CH2), 2.04-1.37 (m, 2H,CH2), 1.81-1.565 (m, 4H, CH2), 1.77-1.37 (m, 8H, CH2), 1.53-1.37 (m, 4H, CH2), 1.39-1.37 (m, 2H, CH2), 1.25-1.37 (m, 8H, CH2).

[0071] MS: 503.33 (M+H).

[0072] Example 5

[0073] Step 1: Compound 1 (2.5 g, 9.75 mmol), compound 5-1 (2.5 g, 9.75 mmol), HATU (4.45 g, 11.7 mmol), DIPEA (1.64 g, 12.68 mmol), and HOBt (0.13 g, 0.97 mmol) were added sequentially to 30 mL of anhydrous DMF. After reacting overnight at room temperature, the reaction solution was poured into water, and a solid precipitated. The solid was filtered, concentrated, and separated by column chromatography (DCM:MeOH = 10:1-5:1) to obtain a white, foamy solid, compound 5-2 (4.82 g), with a yield of 67.41%.

[0074] Step 2: Compound 5-2 (4.0 g, 5.46 mmol) was dissolved in 40 mL of a methanol:water (20:1) mixture. The pH was adjusted to 12 with 10% sodium hydroxide aqueous solution. After reacting for 2 h, the pH was adjusted to 1-2 with 6 N hydrochloric acid, and a solid precipitated. The solid was filtered, washed with water until neutral, and dried to obtain a white solid compound 5-3 (2.01 g). Yield: 73.01%.

[0075] 1 H NMR (500 MHz, DMSO- d6 , ppm): 8.26 (s, 2H, NH), 8.01 (s, 2H, NH), 4.24 (br s, 2H, OH), 3.99 (m, 2H, CH), 3.39 (m, 4H, CH2), 3.02 (t, 2H, J=7.1Hz, CH2), 2.15-1.895 (m, 4H, CH2), 1.83-1.585 (m, 12H, CH2), 1.77-1.37 (m, 8H,CH2), 1.53-1.37 (m, 4H, CH2), 1.25–1.37 (m, 8H, CH2).

[0076] MS: 505.30 (M+H).

[0077] Example 6

[0078] Step 1: Compound 1 (5.0 g, 19.50 mmol), compound 5 (4.06 g, 19.50 mmol), HATU (8.90 g, 23.41 mmol), DIPEA (3.28 g, 25.36 mmol), and HOBt (0.26 g, 1.95 mmol) were dissolved in 50 mL of anhydrous DMF. After reacting overnight at room temperature, the reaction solution was poured into water, and a solid precipitated. After filtration and concentration, the solid was separated by column chromatography (DCM:MeOH = 10:1-5:1) to obtain a white foamy solid compound 6 (8.30 g), with a yield of 67.04%.

[0079] Step 2: Dissolve compound 6 (6.0 g, 9.45 mmol) in 60 mL of a methanol:water (20:1) mixture, adjust the pH to 12 with 10% sodium hydroxide aqueous solution, react for 2 h, adjust the pH to 1-2 with 6N hydrochloric acid, precipitate a solid, filter, wash with water until neutral, and dry to obtain a white solid compound 7 (4.2 g), yield: 73.0%.

[0080] 1 H NMR (500 MHz, DMSO- d6 , ppm): 12.71 (br s, 2H, COOH), 8.26 (s, 2H,NH), 7.70 (s, 2H, NH), 8.09 (d, 4H, J=7.5, 1.5 Hz), 7.03 (d, 4H, J=7.5, 1.5Hz), 3.99 (m, 2H, CH), 3.39 (m, 4H, CH2), 3.00 (t, 4H, J=7.1 Hz, CH2), 2.80(t, 4H, J=7.1 Hz, CH2), 2.34 (t, 4H, J=7.1 Hz, CH2), 1.77-1.37 (m, 8H, CH2),1.53-1.37 (m, 4H, CH2), 1.25–1.37 (m, 4H, CH2).

[0081] MS: 609.29 (M+H).

[0082] Example 7

[0083] Step 1: Compound 1 (3.5 g, 13.65 mmol), compound 8 (2.38 g, 13.65 mmol), HATU (6.23 g, 16.38 mmol), DIPEA (2.29 g, 17.75 mmol), and HOBt (0.18 g, 1.37 mmol) were dissolved in 50 mL of anhydrous DMF. The reaction was carried out overnight at room temperature. The reaction solution was then poured into water, and a solid precipitated out. After filtration and concentration, the solid was separated by column chromatography (DCM:MeOH = 10:1-5:1) to give 4.8 g of white foamy solid compound 9, with a yield of 68.58%.

[0084] Step 2: Dissolve compound 9 (4.0 g, 7.8 mmol) in 60 mL of a methanol:water (20:1) mixture. Adjust the pH to 12 with 10% sodium hydroxide aqueous solution. After reacting for 2 h, adjust the pH to 1-2 with 6 N hydrochloric acid. The solid precipitates out, is filtered, washed with water until neutral, and dried to obtain 2.88 g of white solid compound 10. Yield: 76.17%.

[0085] 1 H NMR (500 MHz, DMSO- d6 , ppm): 12.12 (br s, 2H, COOH), 8.26 (s, 2H,NH), 7.70 (s, 2H, NH), 3.99 (m, 4H, CH), 2.66 (m, 4H, CH), 3.00 (t, 4H, J=7.1Hz, CH2), 2.52–2.27 (m, 4H, CH2), 1.77-1.37 (m, 8H, CH2), 1.53-1.37 (m, 4H,CH2), 1.25-1.37 (m, 4H, CH2), 1.18 (t, 6H, J=6.8 Hz, CH3).

[0086] MS: 485.26 (M+H).

[0087] Example 8

[0088] Step 1: Compound 1 (4.0 g, 15.60 mmol), compound 11 (2.72 g, 15.60 mmol), HATU (7.12 g, 18.72 mmol), DIPEA (2.62 g, 20.28 mmol), and HOBt (0.21 g, 1.56 mmol) were dissolved in 50 mL of anhydrous DMF. After reacting overnight at room temperature, the reaction solution was poured into water, and a solid precipitated out. The solid was filtered, concentrated, and separated by column chromatography (DCM:MeOH = 10:1-5:1) to obtain 5.32 g of white foamy solid compound 12, with a yield of 66.51%.

[0089] Step 2: Dissolve compound 12 (4.0 g, 7.80 mmol) in 60 mL of a methanol:water (20:1) mixture. Adjust the pH to 12 with 10% sodium hydroxide aqueous solution. After reacting for 2 h, adjust the pH to 1-2 with 6 N hydrochloric acid. The solid precipitates out, is filtered, washed with water until neutral, and dried to obtain 2.79 g of white solid compound 13. Yield: 71.71%.

[0090] 1 H NMR (500 MHz, DMSO- d6 , ppm): 12.01 (br s, 2H, COOH), 8.26 (s, 2H,NH), 7.70 (s, 2H, NH), 4.91 (br s, 1H, OH), 4.69 (t, 2H, J = 7.1 Hz, CH2), 3.99 (m, 4H, CH), 3.00 (t, 4H, J = 7.1 Hz, CH2), 2.40–2.30 (m, 6H, CH2), 2.03–1.77 (m, 8H, CH2), 1.53 (m, 4H, CH2), 1.25 (m, 4H, CH2).

[0091] MS: 499.27 (M+H).

[0092] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A diketopiperazine hydroxyl, amino, and aromatic acid-substituted derivative, characterized in that, The diketopiperazine hydroxyl, amino, and aromatic acid-substituted derivatives are compounds represented by Formula I or Formula II, or pharmaceutically acceptable salts of compounds represented by Formula I or Formula II: ； Formula I ； Formula II Among them, R a The substituent may be independently selected from heteroatoms, substituted or unsubstituted C1-C8 alkyl groups; the substituent may be selected from amino, carboxyl or hydroxyl groups; R b Independently selectable from -L-COOH; L can independently choose from the following groups, either self-substituted or unsubstituted: C1-C8 alkyl groups, C2-C8 heteroalkyl groups, C6-C 10 Aryl, C3-C 12 Cycloalkyl, 3-7 membered heterocycloalkyl, and 5-10 membered heteroaryl; in the C2-C8 heteroalkyl, the heteroatom or heteroatom group is selected from one or more of N, O, S, S(=O), and S(=O)2, and the number of heteroatoms or heteroatom groups is 1-3, and they are linked to -L- through a carbon atom; in the 3-7 membered heterocycloalkyl, the heteroatom is selected from one or more of N, O, S, S(=O), and S(=O)2, and the number of heteroatoms is 1-3; in the 5-10 membered heteroaryl, the heteroatom is selected from one or more of N, O, and S, and the number of heteroatoms is 1-4; when there are multiple substituents, they may be the same or different; The substituents are independently selected from halogens, C1-C6 alkyl groups, C1-C6 alkyl-O-, C1-C6 alkyl groups substituted with one or more halogens, C1-C6 alkyl-O-, or =O groups substituted with one or more halogens.

2. The diketopiperazine hydroxyl, amino, and aromatic acid-substituted derivative according to claim 1, characterized in that, in, R a The alkyl group is independently selected from N, O, S, substituted or unsubstituted C1-C5; the substituent is selected from amino or hydroxyl groups; R b Independently selectable from -L-COOH; L can be independently selected from the following groups, either self-substituted or unsubstituted: C1-C5 alkyl, C2-C5 heteroalkyl, C6-C 10 Aryl; the substituent is independently selected from F, Cl, Br, I, C1-C3 alkyl, C1-C3 alkyl-O-, C1-C3 alkyl substituted with one or more halogens, C1-C3 alkyl-O- or =O substituted with one or more halogens.

3. The diketopiperazine hydroxyl, amino, and aromatic acid-substituted derivative according to claim 2, characterized in that, in, R a The substituent may be independently selected from N, substituted or unsubstituted C1-C3 alkyl groups; the substituent may be selected from amino groups; R b Independently selectable from -L-COOH; L can be independently selected from the following groups, either self-substituted or unsubstituted: C1-C3 alkyl groups, C2-C3 heteroalkyl groups, C6-C 10 Aryl; the substituents are independently selected from C1-C3 alkyl groups and C1-C3 alkyl-O- groups.

4. The diketopiperazine hydroxyl, amino, and aromatic acid-substituted derivative according to claim 3, characterized in that, in, R a Independently choose your own or ; R b Independently choose your own or , .

5. The diketopiperazine hydroxyl, amino, and aromatic acid-substituted derivative according to claim 4, characterized in that, The compound is selected from the following structures: 、 、 、 、 。 6. The use of the diketopiperazine hydroxyl, amino, aromatic acid-substituted derivatives or pharmaceutically acceptable salts thereof as claimed in any one of claims 1-5 as pharmaceutical excipients.

7. A pharmaceutical composition, characterized in that, It includes the diketopiperazine hydroxyl, amino, aromatic acid-substituted derivatives or pharmaceutically acceptable salts thereof as described in any one of claims 1-5, or one or more pharmaceutically active ingredients.

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