CN115925606B - 5- (3- (sulfonamide) phenyl) -1H-pyrrole-2-carboxylic acid derivative and preparation method and application thereof - Google Patents

Abstract

The invention relates to the technical field of pharmaceutical chemistry, in particular to a 5- (3- (sulfonamide) phenyl) -1H-pyrrole-2-carboxylic acid derivative, and a preparation method and application thereof. The invention provides a 5- (3- (sulfonamido) phenyl) -1H-pyrrole-2-carboxylic acid derivative, which can interfere Keap1-Nrf2 interaction, activate Nrf2 and downstream factors, reduce inflammatory injury, has potential anti-inflammatory activity, and can be used for preparing Cheng Kangyan medicines for inflammatory injury of a plurality of inflammatory diseases.

Description

A kind of 5-(3-(sulfonamido)phenyl)-1H-pyrrole-2-carboxylic acid derivative and preparation thereof Preparation methods and applications

Technical field

The present invention relates to the technical field of medicinal chemistry, and in particular to a 5-(3-(sulfonamido)phenyl)-1H-pyrrole-2-carboxylic acid derivative and its preparation method and application.

Background technique

Oxidative stress is a state of redox imbalance in the body. Continuous stress can damage the normal physiological functions of biological macromolecules such as nucleic acids, proteins, and lipids in cells, which can lead to a variety of related inflammatory diseases, such as neurodegeneration. diseases (multiple sclerosis, Alzheimer's disease or Parkinson's disease), inflammation, cardiovascular and cerebrovascular diseases (atherosclerosis), diabetes or cancer, etc. A large number of studies have found that targeting Kelch like ECH-associated protein 1 (Keap1)-nuclear factor E2-related factor 2 (Nrf2)-antioxidant redox Activation of Nrf2 by element, ARE) signaling pathway can play a protective role in various stress- and inflammation-related diseases.

There are two main ways to activate Nrf2: covalent activation and non-covalent activation. Nrf2 covalent activator mainly interacts covalently with the cysteine residues of Keap1 (such as: Cys151, Cys257, Cys273, Cys288, Cys297, Cys434, Cys613), causing the conformation of Keap1 to change, thereby dissociating and Activates Nrf2 to exert cytoprotective effects. For example, dimethyl fumarate (DMF) has been approved by the FDA for the treatment of psoriasis and relapsing multiple sclerosis. Bardoxolone (CDDO) analogue is a typical electrophilic Nrf2 covalent activator, and its methyl modification accelerated bardoxolone methyl (CDDO-Me) is being developed for the treatment of pulmonary arterial hypertension ( PAH) phase II clinical trials. However, Nrf2 covalent activators are not selective for Keap1 and other cysteine-rich targets ubiquitous in cells. This non-specific binding may increase the risk in clinical development, making it difficult to achieve therapeutic selectivity and Specificity.

Another way to activate Nrf2 is to non-covalently block the Keap1-Nrf2 protein-protein interaction (PPI), release Nrf2 and achieve the effect of activating Nrf2. Therefore, providing a substance that is competitive, specific, reversible and highly selective, while avoiding the potential toxicity of covalently activating Nrf2, is currently a hot topic in studying Nrf2 activators as therapeutic drugs for inflammatory diseases.

Contents of the invention

The object of the present invention is to provide a 5-(3-(sulfonamido)phenyl)-1H-pyrrole-2-carboxylic acid derivative and its preparation method and application. The 5-(3-(sulfonamido)phenyl)-1H-pyrrole-2-carboxylic acid derivative and its pharmaceutically acceptable salt have very good inhibitory effects on Keap1-Nrf2 protein-protein interaction.

In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

The invention provides a 5-(3-(sulfonylamino)phenyl)-1H-pyrrole-2-carboxylic acid derivative, which has the structure shown in Formula I:

Wherein, R ₁ is H, C1-10 alkyl group, halogen-substituted C1-10 alkyl group, cyano-substituted C1-10 alkyl group, carboxyl-substituted C1-10 alkyl group, three-membered ring substituted C1～10 alkyl group, four-membered ring substituted C1～10 alkyl group, five-membered ring substituted C1～10 alkyl group, six-membered ring substituted C1～10 alkyl group, vinyl-substituted C1～10 an alkyl group, an aryl-substituted C1-10 alkyl group, a C1-10 alkyl group of a five-membered heterocyclic ring or a C1-10 alkyl group of a six-membered heterocyclic ring; the C1-10 alkyl group of the five-membered heterocyclic ring The five-membered heterocyclic ring in the alkyl group or the six-membered heterocyclic ring in the C1-10 alkyl group contains N, O or S;

R ₂ is H, carboxyl, carboxyl-substituted C1-10 alkyl, amide or amide-substituted C1-10 alkyl;

X is H, phenyl, halogen-substituted phenyl, methoxy-substituted phenyl or naphthalene ring.

Preferably, the R ₁ is

The R ₂ is

The X is

Where R is H, F, Cl, Br or methoxy.

Preferably, the 5-(3-(sulfonylamino)phenyl)-1H-pyrrole-2-carboxylic acid derivative is 5-(3-((N-(carboxymethyl))-3-methoxy Phenyl)sulfonamido)phenyl)-1-methyl-1H-pyrrole-2-carboxylic acid, 5-(3-((N-(carboxymethyl)-3-methoxyphenyl)sulfonamide base)phenyl)-1-ethyl-1H-pyrrole-2-carboxylic acid, 3-((N-(carboxymethyl)-3-methoxyphenyl)sulfonamido)phenyl)-1- Propyl-1H-pyrrole-2-carboxylic acid, 1-allyl-5-(3-((N-(carboxymethyl)-3-methoxyphenyl)sulfonamido)phenyl)-1H -pyrrole-2-carboxylic acid, 1-butyl-5-(3-((N-(carboxymethyl)-3-methoxyphenyl)sulfonamido)phenyl)-1H-pyrrole-2- Carboxylic acid, 5-(3-((N-(carboxymethyl)-3-methoxyphenyl)sulfonamido)phenyl)-1-(cyclopropylmethyl)-1H-pyrrole-2- Carboxylic acid, 5-(3-((N-(carboxymethyl)-3-chlorophenyl)sulfonamido)phenyl)-1-ethyl-1H-pyrrole-2-carboxylic acid, 5-(3 -((3-bromo-N-(carboxymethyl)phenyl)sulfonamido)phenyl)-1-ethyl-1H-pyrrole-2-carboxylic acid, 5-(3-((N-(carboxylic acid) Methyl)-3-methoxyphenyl)sulfonamido)phenyl)-1-(3-cyanopropyl)-1H-pyrrole-2-carboxylic acid, 5-(3-((N-( Carboxymethyl)-3-methoxyphenyl)sulfonamide)phenyl)-1-(cyanomethyl)-1H-pyrrole-2-carboxylic acid, 5-(3-((N-(carboxylic acid) Methyl)-3-methoxyphenyl)sulfonamide)phenyl)-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylic acid, 1-(carboxymethyl)-5-( 3-((N-(carboxymethyl)-3-methoxyphenyl)sulfonamide)phenyl)-1H-pyrrole-2-carboxylic acid, 5-(3-((N-(carboxymethyl) )-3-methoxyphenyl)sulfonamido)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylic acid, 5 -(3-((N-(Carboxymethyl)-3-methoxyphenyl)sulfonamide)phenyl)-1-(2-morpholinoethyl)-1H-pyrrole-2-carboxylic acid , 1-benzyl-5-(3-((N-(carboxymethyl)-3-methoxyphenyl)sulfonamido)phenyl)-1H-pyrrole-2-carboxylic acid, 5-(3 -((N-(carboxymethyl)-4-methoxyphenyl)sulfonamido)phenyl)-1-methyl-1H-pyrrole-2-carboxylic acid, 5-(3-((N- (Carboxymethyl)-4-methoxyphenyl)sulfonamide)phenyl)-1-ethyl-1H-pyrrole-2-carboxylic acid, 5-(3-((N-(carboxymethyl) -4-Methoxyphenyl)sulfonamido)phenyl)-1-propyl-1H-pyrrole-2-carboxylic acid, 1-allyl-5-(3-((N-(carboxymethyl) )-4-methoxyphenyl)sulfonamido)phenyl)-1H-pyrrole-2-carboxylic acid, 1-butyl-5-(3-((N-(carboxymethyl)-4-methyl Oxyphenyl)sulfonamido)phenyl)-1H-pyrrole-2-carboxylic acid, 5-(3-((N-(carboxymethyl)-4-methoxyphenyl)sulfonamido)benzene base)-1-(cyclopropylmethyl)-1H-pyrrole-2-carboxylic acid, 5-(3-((N-(carboxymethyl)-2-methoxyphenyl)sulfonamido)benzene base)-1-ethyl-1H-pyrrole-2-carboxylic acid, 5-(3-((N-(carboxymethyl)-4-methoxyphenyl)sulfonamido)phenyl)-1- (2-fluoroethyl)-1H-pyrrole-2-carboxylic acid, 5-(3-((N-(carboxymethyl)-4-methoxyphenyl)sulfonamido)phenyl)-1- (Cyanomethyl)-1H-pyrrole-2-carboxylic acid, 5-(3-((N-(carboxymethyl)-4-methoxyphenyl)sulfonamido)phenyl)-1-( 3-cyanopropyl)-1H-pyrrole-2-carboxylic acid, 5-(3-((N-(carboxymethyl)-3-fluorophenyl)sulfonamido)phenyl)-1-ethyl -1H-pyrrole-2-carboxylic acid, 1-allyl-5-(3-((N-(carboxymethyl)-3-fluorophenyl)sulfonamido)phenyl)-1H-pyrrole-2 -Carboxylic acid, 1-allyl-5-(3-((N-(carboxymethyl)-3-chlorophenyl)sulfonamido)phenyl)-1H-pyrrole-2-carboxylic acid, 5- (3-(N-(Carboxymethyl)naphthalene-2-sulfonamido)phenyl)-1-ethyl-1H-pyrrole-2-carboxylic acid, 1-allyl-5-(3-((3 -Bromo-N-(carboxymethyl)phenyl)sulfonamido)phenyl)-1H-pyrrole-2-carboxylic acid, 1-allyl-5-(3-((N-(carboxymethyl)) -2-Methoxyphenyl)sulfonamido)phenyl)-1H-pyrrole-2-carboxylic acid, 1-allyl-5-(3-(N-(carboxymethyl)naphthalene-2-sulfonate) Amino)phenyl)-1H-pyrrole-2-carboxylic acid, 5-(3-((N-(carboxymethyl)-2-methoxyphenyl)sulfonamido)phenyl)-1-( 2-Fluoroethyl)-1H-pyrrole-2-carboxylic acid, 5-(3-(N-(carboxymethyl)naphthalene-2-sulfonamido)phenyl)-1-(2-fluoroethyl)- 1H-pyrrole-2-carboxylic acid, 5-(3-((N-(carboxymethyl)-3-fluorophenyl)sulfonamido)phenyl)-1-(2-fluoroethyl)-1H- Pyrrole-2-carboxylic acid, 5-(3-((3-bromo-N-(carboxymethyl)phenyl)sulfonamido)phenyl)-1-(2-fluoroethyl)-1H-pyrrole- 2-carboxylic acid, 5-(3-((N-(carboxymethyl)-3-chlorophenyl)sulfonamido)phenyl)-1-(2-fluoroethyl)-1H-pyrrole-2- Carboxylic acid, 5-(3-((N-(carboxymethyl)-2-methoxyphenyl)sulfonamido)phenyl)-1-methyl-1H-pyrrole-2-carboxylic acid, 5- (3-((N-(Carboxymethyl)-3-fluorophenyl)sulfonamido)phenyl)-1-methyl-1H-pyrrole-2-carboxylic acid, 5-(3-((N- (Carboxymethyl)-3-chlorophenyl)sulfonamido)phenyl)-1-methyl-1H-pyrrole-2-carboxylic acid, 5-(3-((3-bromo-N-(carboxymethyl) base)phenyl)sulfonamido)phenyl)-1-methyl-1H-pyrrole-2-carboxylic acid, 5-(3-((N-(carboxymethyl)-2-methoxyphenyl) Sulfonamido)phenyl)-1-propyl-1H-pyrrole-2-carboxylic acid, 5-(3-((N-(carboxymethyl)-3-fluorophenyl)sulfonamido)phenyl) -1-propyl-1H-pyrrole-2-carboxylic acid, 5-(3-((N-(carboxymethyl)-3-chlorophenyl)sulfonamido)phenyl)-1-propyl-1H -pyrrole-2-carboxylic acid, 5-(3-((3-bromo-N-(carboxymethyl)phenyl)sulfonamido)phenyl)-1-propyl-1H-pyrrole-2-carboxylic acid , 5-(3-(N-(carboxymethyl)naphthalene-2-sulfonamido)phenyl)-1-propyl-1H-pyrrole-2-carboxylic acid, 5-(3-((N-( 2-amino-2-oxyethyl)-3-methoxyphenyl)sulfonamide)phenyl)-1-propyl-1H-pyrrole-2-carboxylic acid, 1-allyl-5-( 3-((N-(2-amino-2-oxyethyl)-3-methoxyphenyl)sulfonamido)phenyl)-1H-pyrrole-2-carboxylic acid, 5-(3-(( N-(2-amino-2-oxoethyl)-3-methoxyphenyl)sulfonamide)phenyl)-1-ethyl-1H-pyrrole-2-carboxylic acid or 5-(3- ((N-(2-amino-2-oxyethyl)-3-methoxyphenyl)sulfonamide)phenyl)-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylic acid .

The invention also provides a method for preparing the 5-(3-(sulfonylamino)phenyl)-1H-pyrrole-2-carboxylic acid derivative described in the above technical solution, which includes the following steps:

Mix a compound with the structure shown in Formula II, N-bromosuccinimide and a first organic solvent to perform a bromination reaction to obtain a compound with the structure shown in Formula III;

Mix the compound with the structure shown in formula III, NaH, the first bromide and the second organic solvent, and perform the first substitution reaction to obtain the compound with the structure shown in formula IV;

Mix the compound with the structure shown in Formula IV, 3-nitrophenylboronic acid, cesium carbonate, a catalyst, a third organic solvent and water, and perform a coupling reaction to obtain a compound with the structure shown in Formula V;

Mix the compound with the structure shown in Formula V, iron powder, ammonium chloride, the fourth organic solvent and water, and perform a reduction reaction to obtain the compound with the structure shown in Formula VI;

Mix the compound with the structure shown in Formula VI, 3-methoxybasic sulfonyl chloride and the fifth organic solvent to perform a second substitution reaction to obtain the compound with the structure shown in Formula VII;

The compound having the structure shown in Formula VII, potassium carbonate, potassium iodide, the second bromide and the sixth organic solvent are mixed, and after performing the third substitution reaction, a hydrolysis reaction is performed under alkaline conditions to obtain the 5-(3 -(Sulfonylamino)phenyl)-1H-pyrrole-2-carboxylic acid derivative;

Preferably, the molar ratio of the compound having the structure shown in formula II and N-bromosuccinimide is 1:(1.0~1.5);

The temperature of the bromination reaction is 0-60°C, and the time is 5-10 hours;

The molar ratio of the compound having the structure shown in Formula III and the first bromide is 1: (1.0~1.5);

The temperature of the first substitution reaction is 0-60°C, and the time is 1-5 hours.

Preferably, the molar ratio of the compound having the structure shown in Formula IV and 3-nitrophenylboronic acid is 1: (1.0～2.0);

The temperature of the coupling reaction is 60-90°C, and the time is 1-5 hours;

The molar ratio of the compound having the structure shown in Formula V and iron powder is 1: (1-10);

The temperature of the reduction reaction is 25-80°C, and the time is 1-5 hours.

Preferably, the molar ratio of the compound having the structure shown in Formula VI and 3-methoxybasic sulfonyl chloride is 1: (1.0~1.5);

The temperature of the second substitution reaction is 0-25°C, and the time is 1-5 hours.

Preferably, the molar ratio of the compound having the structure shown in formula VII and the second bromide is 1: (1.0～1.5);

The temperature of the third substitution reaction is 0-60°C, and the time is 1-24 hours.

The present invention also provides the 5-(3-(sulfonylamino)phenyl)-1H-pyrrole-2-carboxylic acid derivative described in the above technical solution or the 5-(3 prepared by the preparation method described in the above technical solution). Pharmaceutically acceptable salts of -(sulfonylamino)phenyl)-1H-pyrrole-2-carboxylic acid derivatives.

The invention also provides the 5-(3-(sulfonylamino)phenyl)-1H-pyrrole-2-carboxylic acid derivative described in the above technical solution, and the 5-(3 prepared by the preparation method described in the above technical solution. -(Sulfonylamino)phenyl)-1H-pyrrole-2-carboxylic acid derivatives or 5-(3-(sulfonylamino)phenyl)-1H-pyrrole-2-carboxylic acid derivatives described in the above technical solution The pharmaceutically acceptable salt of the substance is used in the preparation of Keap1-Nrf2 protein-protein interaction inhibitors or the preparation of drugs for treating or alleviating disease inflammation.

The invention provides a 5-(3-(sulfonylamino)phenyl)-1H-pyrrole-2-carboxylic acid derivative, which has the structure shown in Formula I:

Wherein, R ₁ is H, C1-10 alkyl group, halogen-substituted C1-10 alkyl group, cyano-substituted C1-10 alkyl group, carboxyl-substituted C1-10 alkyl group, three-membered ring substituted C1～10 alkyl group, four-membered ring substituted C1～10 alkyl group, five-membered ring substituted C1～10 alkyl group, six-membered ring substituted C1～10 alkyl group, vinyl-substituted C1～10 an alkyl group, an aryl-substituted C1-10 alkyl group, a C1-10 alkyl group of a five-membered heterocyclic ring or a C1-10 alkyl group of a six-membered heterocyclic ring; the C1-10 alkyl group of the five-membered heterocyclic ring The five-membered heterocyclic ring in the alkyl group or the six-membered heterocyclic ring in the C1-10 alkyl group contains N, O or S;

R ₂ is H, carboxyl, carboxyl-substituted C1-10 alkyl, amide or amide-substituted C1-10 alkyl;

X is H, phenyl, halogen-substituted phenyl, methoxy-substituted phenyl or naphthalene ring.

The R ₂ group in the 5-(3-(sulfonylamino)phenyl)-1H-pyrrole-2-carboxylic acid derivative of the present invention can interact with the ASN-414 and ARG-415 residues of the KEAP1 protein through hydrogen The pyrrole 2-carboxylic acid interacts with the ARG-483 residue of the KEAP1 protein in the form of a hydrogen bond; the sulfone oxygen interacts with the GLY-603 residue of the KEAP1 protein in the form of a hydrogen bond. Finally, this compound Binds to the KEAP1 protein to prevent its binding to Nrf2, allowing free Nrf2 to enter the cell nucleus to promote the production of related anti-inflammatory factors, ultimately reflecting the anti-inflammatory effect of this compound. The 5-(3-(sulfonylamino)phenyl)-1H-pyrrole-2-carboxylic acid derivative can interfere with Keap1-Nrf2 interaction, activate Nrf2 and downstream factors, reduce inflammatory damage, and has potential anti-inflammatory activity , can be used to prepare anti-inflammatory drugs for inflammatory damage in many inflammatory diseases.

Detailed ways

The invention provides a 5-(3-(sulfonylamino)phenyl)-1H-pyrrole-2-carboxylic acid derivative, which has the structure shown in Formula I:

Wherein, R ₁ is H, C1-10 alkyl group, halogen-substituted C1-10 alkyl group, cyano-substituted C1-10 alkyl group, carboxyl-substituted C1-10 alkyl group, three-membered ring substituted C1～10 alkyl group, four-membered ring substituted C1～10 alkyl group, five-membered ring substituted C1～10 alkyl group, six-membered ring substituted C1～10 alkyl group, vinyl-substituted C1～10 an alkyl group, an aryl-substituted C1-10 alkyl group, a C1-10 alkyl group of a five-membered heterocyclic ring or a C1-10 alkyl group of a six-membered heterocyclic ring; the C1-10 alkyl group of the five-membered heterocyclic ring The five-membered heterocyclic ring in the alkyl group or the six-membered heterocyclic ring in the C1-10 alkyl group contains N, O or S;

R ₂ is H, carboxyl, carboxyl-substituted C1-10 alkyl, amide or amide-substituted C1-10 alkyl;

X is H, phenyl, halogen-substituted phenyl, methoxy-substituted phenyl or naphthalene ring.

In the present invention, the halogen-substituted C1-10 alkyl group, the cyano-substituted C1-10 alkyl group, the carboxyl-substituted C1-10 alkyl group, the three-membered ring-substituted C1-10 alkyl group, Four-membered ring-substituted C1-10 alkyl group, five-membered ring-substituted C1-10 alkyl group, six-membered ring-substituted C1-10 alkyl group, vinyl-substituted C1-10 alkyl group, aryl-substituted The substituents in the C1-10 alkyl group, the C1-10 alkyl group of the five-membered heterocyclic ring or the C1-10 alkyl group of the six-membered heterocyclic ring are preferably end-substituted on the C1-10 alkyl group; The C1-C10 alkyl group is preferably a linear alkyl group.

In the present invention, the R ₁ is preferably

The R ₂ is preferably The X is preferably/> Among them, R is preferably H, F, Cl, Br or methoxy.

In the present invention, the 5-(3-(sulfonylamino)phenyl)-1H-pyrrole-2-carboxylic acid derivative is preferably 5-(3-((N-(carboxymethyl)-3- Methoxyphenyl)sulfonamide)phenyl)-1-methyl-1H-pyrrole-2-carboxylic acid, the structural formula is:

5-(3-((N-(Carboxymethyl)-3-methoxyphenyl)sulfonamide)phenyl)-1-ethyl-1H-pyrrole-2-carboxylic acid, the structural formula is:

3-((N-(Carboxymethyl)-3-methoxyphenyl)sulfonamide)phenyl)-1-propyl-1H-pyrrole-2-carboxylic acid, the structural formula is:

1-allyl-5-(3-((N-(carboxymethyl)-3-methoxyphenyl)sulfonamido)phenyl)-1H-pyrrole-2-carboxylic acid, the structural formula is:

1-Butyl-5-(3-((N-(carboxymethyl)-3-methoxyphenyl)sulfonamido)phenyl)-1H-pyrrole-2-carboxylic acid, the structural formula is:

5-(3-((N-(Carboxymethyl)-3-methoxyphenyl)sulfonamido)phenyl)-1-(cyclopropylmethyl)-1H-pyrrole-2-carboxylic acid, The structural formula is:

5-(3-((N-(Carboxymethyl)-3-chlorophenyl)sulfonamide)phenyl)-1-ethyl-1H-pyrrole-2-carboxylic acid, the structural formula is:

5-(3-((3-bromo-N-(carboxymethyl)phenyl)sulfonamide)phenyl)-1-ethyl-1H-pyrrole-2-carboxylic acid, the structural formula is:

5-(3-((N-(Carboxymethyl)-3-methoxyphenyl)sulfonamido)phenyl)-1-(3-cyanopropyl)-1H-pyrrole-2-carboxylic acid , the structural formula is:

5-(3-((N-(Carboxymethyl)-3-methoxyphenyl)sulfonamide)phenyl)-1-(cyanomethyl)-1H-pyrrole-2-carboxylic acid, structural formula for:

5-(3-((N-(Carboxymethyl)-3-methoxyphenyl)sulfonamide)phenyl)-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylic acid, The structural formula is:

1-(Carboxymethyl)-5-(3-((N-(carboxymethyl)-3-methoxyphenyl)sulfonamide)phenyl)-1H-pyrrole-2-carboxylic acid, the structural formula is :

5-(3-((N-(Carboxymethyl)-3-methoxyphenyl)sulfonamido)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl base)-1H-pyrrole-2-carboxylic acid, the structural formula is:

5-(3-((N-(carboxymethyl)-3-methoxyphenyl)sulfonamide)phenyl)-1-(2-morpholinoethyl)-1H-pyrrole-2-carboxy Acid, the structural formula is:

1-Benzyl-5-(3-((N-(carboxymethyl)-3-methoxyphenyl)sulfonamide)phenyl)-1H-pyrrole-2-carboxylic acid, the structural formula is:

5-(3-((N-(Carboxymethyl)-4-methoxyphenyl)sulfonamide)phenyl)-1-methyl-1H-pyrrole-2-carboxylic acid, the structural formula is:

5-(3-((N-(Carboxymethyl)-4-methoxyphenyl)sulfonamide)phenyl)-1-ethyl-1H-pyrrole-2-carboxylic acid, the structural formula is:

5-(3-((N-(Carboxymethyl)-4-methoxyphenyl)sulfonamide)phenyl)-1-propyl-1H-pyrrole-2-carboxylic acid, the structural formula is:

1-allyl-5-(3-((N-(carboxymethyl)-4-methoxyphenyl)sulfonamide)phenyl)-1H-pyrrole-2-carboxylic acid, the structural formula is:

1-Butyl-5-(3-((N-(carboxymethyl)-4-methoxyphenyl)sulfonamide)phenyl)-1H-pyrrole-2-carboxylic acid, the structural formula is:

5-(3-((N-(Carboxymethyl)-4-methoxyphenyl)sulfonamido)phenyl)-1-(cyclopropylmethyl)-1H-pyrrole-2-carboxylic acid, The structural formula is:

5-(3-((N-(Carboxymethyl)-2-methoxyphenyl)sulfonamide)phenyl)-1-ethyl-1H-pyrrole-2-carboxylic acid, the structural formula is:

5-(3-((N-(Carboxymethyl)-4-methoxyphenyl)sulfonamide)phenyl)-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylic acid, The structural formula is:

5-(3-((N-(Carboxymethyl)-4-methoxyphenyl)sulfonamido)phenyl)-1-(cyanomethyl)-1H-pyrrole-2-carboxylic acid, structural formula for:

5-(3-((N-(Carboxymethyl)-4-methoxyphenyl)sulfonamido)phenyl)-1-(3-cyanopropyl)-1H-pyrrole-2-carboxylic acid , the structural formula is:

5-(3-((N-(carboxymethyl)-3-fluorophenyl)sulfonamido)phenyl)-1-ethyl-1H-pyrrole-2-carboxylic acid, the structural formula is:

1-allyl-5-(3-((N-(carboxymethyl)-3-fluorophenyl)sulfonamido)phenyl)-1H-pyrrole-2-carboxylic acid, the structural formula is:

1-allyl-5-(3-((N-(carboxymethyl)-3-chlorophenyl)sulfonamido)phenyl)-1H-pyrrole-2-carboxylic acid, the structural formula is:

5-(3-(N-(Carboxymethyl)naphthalene-2-sulfonamido)phenyl)-1-ethyl-1H-pyrrole-2-carboxylic acid, the structural formula is:

1-allyl-5-(3-((3-bromo-N-(carboxymethyl)phenyl)sulfonamido)phenyl)-1H-pyrrole-2-carboxylic acid, the structural formula is:

1-allyl-5-(3-((N-(carboxymethyl)-2-methoxyphenyl)sulfonamide)phenyl)-1H-pyrrole-2-carboxylic acid, the structural formula is:

1-allyl-5-(3-(N-(carboxymethyl)naphthalene-2-sulfonamido)phenyl)-1H-pyrrole-2-carboxylic acid, the structural formula is:

5-(3-((N-(Carboxymethyl)-2-methoxyphenyl)sulfonamido)phenyl)-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylic acid, The structural formula is:

5-(3-(N-(Carboxymethyl)naphthalene-2-sulfonamido)phenyl)-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylic acid, the structural formula is:

5-(3-((N-(Carboxymethyl)-3-fluorophenyl)sulfonamido)phenyl)-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylic acid, the structural formula is :

5-(3-((3-bromo-N-(carboxymethyl)phenyl)sulfonamido)phenyl)-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylic acid, the structural formula is :

5-(3-((N-(Carboxymethyl)-3-chlorophenyl)sulfonamido)phenyl)-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylic acid, the structural formula is :

5-(3-((N-(Carboxymethyl)-2-methoxyphenyl)sulfonamide)phenyl)-1-methyl-1H-pyrrole-2-carboxylic acid, the structural formula is:

5-(3-((N-(carboxymethyl)-3-fluorophenyl)sulfonamide)phenyl)-1-methyl-1H-pyrrole-2-carboxylic acid, the structural formula is:

5-(3-((N-(Carboxymethyl)-3-chlorophenyl)sulfonamido)phenyl)-1-methyl-1H-pyrrole-2-carboxylic acid, the structural formula is:

5-(3-((3-bromo-N-(carboxymethyl)phenyl)sulfonamide)phenyl)-1-methyl-1H-pyrrole-2-carboxylic acid, the structural formula is:

5-(3-((N-(Carboxymethyl)-2-methoxyphenyl)sulfonamide)phenyl)-1-propyl-1H-pyrrole-2-carboxylic acid, the structural formula is:

5-(3-((N-(Carboxymethyl)-3-fluorophenyl)sulfonamido)phenyl)-1-propyl-1H-pyrrole-2-carboxylic acid, the structural formula is:

5-(3-((N-(Carboxymethyl)-3-chlorophenyl)sulfonamido)phenyl)-1-propyl-1H-pyrrole-2-carboxylic acid, the structural formula is:

5-(3-((3-bromo-N-(carboxymethyl)phenyl)sulfonamide)phenyl)-1-propyl-1H-pyrrole-2-carboxylic acid, the structural formula is:

5-(3-(N-(Carboxymethyl)naphthalene-2-sulfonamido)phenyl)-1-propyl-1H-pyrrole-2-carboxylic acid, the structural formula is:

5-(3-((N-(2-amino-2-oxyethyl)-3-methoxyphenyl)sulfonamido)phenyl)-1-propyl-1H-pyrrole-2-carboxylic acid , the structural formula is:

1-allyl-5-(3-((N-(2-amino-2-oxyethyl)-3-methoxyphenyl)sulfonamido)phenyl)-1H-pyrrole-2-carboxy Acid, the structural formula is:

5-(3-((N-(2-amino-2-oxoethyl)-3-methoxyphenyl)sulfonamido)phenyl)-1-ethyl-1H-pyrrole-2-carboxy Acid, the structural formula is:

5-(3-((N-(2-amino-2-oxyethyl)-3-methoxyphenyl)sulfonamido)phenyl)-1-(2-fluoroethyl)-1H-pyrrole -2-carboxylic acid, the structural formula is:

The invention also provides a method for preparing the 5-(3-(sulfonylamino)phenyl)-1H-pyrrole-2-carboxylic acid derivative described in the above technical solution, which includes the following steps:

Mix a compound with the structure shown in Formula II, N-bromosuccinimide and a first organic solvent to perform a bromination reaction to obtain a compound with the structure shown in Formula III;

Mix the compound with the structure shown in formula III, NaH, the first bromide and the second organic solvent, and perform the first substitution reaction to obtain the compound with the structure shown in formula IV;

Mix the compound with the structure shown in Formula IV, 3-nitrophenylboronic acid, cesium carbonate, a catalyst, a third organic solvent and water, and perform a coupling reaction to obtain a compound with the structure shown in Formula V;

Mix the compound with the structure shown in Formula V, iron powder, ammonium chloride, the fourth organic solvent and water, and perform a reduction reaction to obtain the compound with the structure shown in Formula VI;

Mix the compound with the structure shown in Formula VI, 3-methoxybasic sulfonyl chloride and the fifth organic solvent to perform a second substitution reaction to obtain the compound with the structure shown in Formula VII;

The compound having the structure shown in Formula VII, potassium carbonate, potassium iodide, the second bromide and the sixth organic solvent are mixed, and after performing the third substitution reaction, a hydrolysis reaction is performed under alkaline conditions to obtain the 5-(3 -(Sulfonylamino)phenyl)-1H-pyrrole-2-carboxylic acid derivative;

In the present invention, the preparation process of the 5-(3-(sulfonylamino)phenyl)-1H-pyrrole-2-carboxylic acid derivative is as shown in Formula 1:

In the present invention, unless otherwise specified, all preparation raw materials are commercially available products well known to those skilled in the art.

In the present invention, a compound having the structure shown in Formula II, N-bromosuccinimide and a first organic solvent are mixed, and bromination reaction is performed to obtain a compound having the structure shown in Formula III.

In the present invention, the molar ratio of the compound having the structure shown in Formula II and N-bromosuccinimide (NBS) is preferably 1: (1.0-1.5), and more preferably 1:1.0.

In the present invention, the first organic solvent is preferably methanol (MeOH) and/or tetrahydrofuran (THF), more preferably methanol and tetrahydrofuran; when the first organic solvent is methanol and tetrahydrofuran, the The volume ratio is preferably 1:1.

The present invention does not have any special restrictions on the amount of the first organic solvent, and the amount known to those skilled in the art can be used.

In the present invention, the mixing is preferably: adding the compound having the structure shown in Formula II and N-bromosuccinimide into the reactor, vacuuming, replacing it with nitrogen three times, and then adding the first organic solvent .

In the present invention, the temperature of the bromination reaction is preferably 0 to 60°C, more preferably 20 to 30°C, and most preferably 25°C; the time is preferably 5 to 10h, more preferably 6 to 8h, and most preferably 8h. In the present invention, the bromination reaction is preferably carried out under stirring conditions. The present invention does not have any special limitations on the stirring process, and it can be carried out using processes well known to those skilled in the art.

After the bromination reaction is completed, the present invention preferably also includes sequential spin-drying and purification; the present invention does not have any special limitations on the spin-drying process, and it can be carried out by using processes well known to those skilled in the art. In the present invention, the purification is preferably performed by silica gel chromatography; the chromatographic liquid used for the purification is preferably petroleum ether and ethyl acetate with a volume ratio of (100-30):1.

After obtaining the compound with the structure represented by formula III, the present invention mixes the compound with the structure represented by formula III, NaH, the first bromide and the second organic solvent, and performs the first substitution reaction to obtain the compound with the structure represented by formula IV.

In the present invention, the first bromide is preferably one or more of bromoethane, bromopropane, bromobutane and bromopentane. When the first bromide is two of the above specific selections, As mentioned above, the present invention does not have any special restrictions on the proportion of the above specific substances, and they can be mixed in any proportion.

In the present invention, the second organic solvent is preferably tetrahydrofuran (THF) and/or N,N-dimethylformamide (DMF), more preferably tetrahydrofuran; when the second organic solvent is tetrahydrofuran and N, When N-dimethylformamide is used, the present invention does not have any special restrictions on the ratio of the tetrahydrofuran and N,N-dimethylformamide, and it can be carried out by using a process well known to those skilled in the art.

In the present invention, the molar ratio of the compound having the structure shown in Formula III and the first bromide is preferably 1:(1.0~1.5), more preferably 1:(1.0~1.2), and most preferably 1:1.0.

In the present invention, the molar ratio of the compound having the structure shown in Formula III and NaH is preferably 1:(1.0~1.5), more preferably 1:(1.0~1.2), and most preferably 1:1.0.

The present invention does not have any special restrictions on the amount of the second organic solvent. The amount is well known to those skilled in the art and ensures that the compound with the structure shown in formula III, NaH and the first bromide are fully dissolved and fully reacted therein. That’s it.

In the present invention, the mixing is preferably: under stirring conditions, after mixing the compound having the structure shown in Formula III and the second organic solvent, adding NaH, continuing stirring, and finally adding the first bromide. The present invention does not have any special limitations on the rotating speed of the stirring, and it can be carried out by using a process well known to those skilled in the art. In the present invention, the time for continuing stirring is preferably 15 minutes.

In the present invention, the NaH functions as an acid binding agent to promote nucleophilic reaction.

In the present invention, the temperature of the first substitution reaction is preferably 0 to 60°C, more preferably 20 to 30°C, and most preferably 25°C; the time is preferably 1 to 5h, more preferably 1 to 4h, and most preferably It is 1~2h. In the present invention, the first substitution reaction is preferably carried out under stirring conditions. The present invention does not have any special limitations on the stirring process, and it can be carried out using processes well known to those skilled in the art.

After the first substitution reaction is completed, the present invention preferably also includes sequential extraction, washing, drying and concentration. In the present invention, the extraction preferably uses water and ethyl acetate; the extraction process preferably includes sequentially adding water and ethyl acetate to the product system obtained after the first substitution reaction for extraction. After the extraction, the organic phase is combined and the obtained organic phase is washed; the washing is preferably carried out three times with saturated brine; the drying is preferably carried out by anhydrous sodium sulfate; the concentration is preferably Vacuum concentration, the present invention does not have any special limitations on the process of vacuum concentration, and it can be carried out by using processes well known to those skilled in the art.

After obtaining the compound with the structure represented by formula IV, the present invention mixes the compound with the structure represented by formula IV, 3-nitrophenylboronic acid, cesium carbonate, catalyst, third organic solvent and water to perform a coupling reaction to obtain Compounds with the structure shown in formula V.

In the present invention, the catalyst is preferably one or more of Pd(Ph ₃ P) ₄ , Pd(PPh ₃ ) ₂ Cl ₂ , Pd(dppf)Cl ₂ and Pd(OAc) ₂ , and more preferably Pd(Ph ₃ P) ₄ ; when the catalysts are two or more of the above-mentioned specific selections, the present invention does not have any special restrictions on the proportion of the above-mentioned specific substances, and they can be mixed in any proportion.

In the present invention, the third organic solvent preferably includes one or more of N,N-dimethylformamide (DMF), tetrahydrofuran (THF) and dioxane, and more preferably dioxane. ; When the third organic solvent is two or more of the above-mentioned specific selections, the present invention does not have any special restrictions on the proportion of the above-mentioned specific substances, and they can be mixed in any proportion.

In the present invention, the molar ratio of the compound having the structure shown in Formula IV and 3-nitrophenylboronic acid is preferably 1: (1.0～2.0), more preferably 1: (1.2～1.8), most preferably 1 : (1.4～1.6).

In the present invention, the molar ratio of the compound having the structure shown in Formula IV, cesium carbonate and catalyst is preferably 1:(1.0～3.0):(0.05～0.15), more preferably 1:(1.5～2.5):( 0.09～0.11), most preferably 1:2:0.1.

In the present invention, the volume ratio of the third organic solvent and water is preferably (2-6):1, more preferably (3-5):1, and most preferably 4:1.

The present invention does not have any special restrictions on the total amount of the third organic solvent and water. The amount well known to those skilled in the art is used to ensure that the compound having the structure shown in Formula IV, 3-nitrophenylboronic acid, cesium carbonate and The catalyst can be fully dissolved and fully reacted therein.

In the present invention, the mixing preferably involves adding a compound having the structure shown in formula IV, 3-nitrophenylboronic acid, cesium carbonate and a catalyst into the mixed solution of the third organic solvent and water.

In the present invention, the cesium carbonate is a base, which accelerates the reaction rate. The function of using the mixture of the third organic solvent and water as the reaction solvent is to fully dissolve all substances in the reaction system.

In the present invention, the temperature of the coupling reaction is preferably 60 to 90°C, more preferably 70 to 90°C, and most preferably 80 to 90°C; the time is preferably 1 to 5 hours, more preferably 2 to 4 hours, and most preferably 1 to 5 hours. Preferably it is 3h.

After the coupling reaction is completed, the present invention also preferably includes sequential extraction, washing, drying, concentration and purification; in the present invention, the extraction preferably uses water and ethyl acetate; the extraction process is preferably Water and ethyl acetate were added sequentially to the product system obtained after the first substitution reaction for extraction. After the extraction, the organic phase is combined and the obtained organic phase is washed; the washing is preferably carried out three times with saturated brine; the drying is preferably carried out by anhydrous sodium sulfate; the concentration is preferably Vacuum concentration, the present invention does not have any special limitations on the process of vacuum concentration, and it can be carried out by using processes well known to those skilled in the art. In the present invention, the purification is preferably carried out by silica gel chromatography; the chromatographic liquid used for the purification is preferably petroleum ether and ethyl acetate with a volume ratio of 10:1.

After obtaining the compound with the structure represented by formula V, the present invention mixes the compound with the structure represented by formula V, iron powder, ammonium chloride, the fourth organic solvent and water, and performs a reduction reaction to obtain the compound with the structure represented by formula VI. .

In the present invention, the fourth organic solvent preferably includes methanol and/or ethanol, more preferably ethanol; when the fourth organic solvent is methanol and ethanol, the present invention does not have any influence on the dosage ratio of the methanol and ethanol. Special restrictions, just mix in any ratio.

In the present invention, the volume ratio of the fourth organic solvent and water is preferably (1-3):1, more preferably (1.5-2.5):1, and most preferably 2:1.

In the present invention, the molar ratio of the compound having the structure shown in formula V and the iron powder is preferably 1:(1-10), more preferably 1:(6-10), and most preferably 1:10.

In the present invention, the molar ratio of the compound having the structure shown in Formula V and ammonium chloride is preferably 1:(1-10), more preferably 1:(6-10), and most preferably 1:10.

The present invention does not have any special restrictions on the total amount of the fourth organic solvent and water. The amount known to those skilled in the art is used to ensure that the compound with the structure shown in Formula V, iron powder and ammonium chloride can be fully dissolved therein. and react.

In the present invention, the mixing preferably involves adding the compound having the structure shown in Formula V, iron powder and ammonium chloride into the mixed liquid of the fourth organic solvent and water.

In the present invention, the temperature of the reduction reaction is preferably 25 to 80°C, more preferably 30 to 70°C, and most preferably 40 to 60°C; the time is preferably 1 to 5 hours, more preferably 2 to 4 hours, and most preferably is 3h. In the present invention, the reduction reaction is preferably carried out under stirring conditions. The present invention does not have any special limitations on the stirring process, and it can be carried out using processes well known to those skilled in the art.

After the reduction reaction is completed, the present invention also preferably includes sequential extraction, washing, drying and concentration; in the present invention, the extraction preferably uses water and ethyl acetate; the extraction process is preferably performed in the first step. Water and ethyl acetate were added sequentially to the product system obtained after the primary substitution reaction for extraction. After the extraction, the organic phase is combined and the obtained organic phase is washed; the washing is preferably carried out three times with saturated brine; the drying is preferably carried out by anhydrous sodium sulfate; the concentration is preferably Vacuum concentration, the present invention does not have any special limitations on the process of vacuum concentration, and it can be carried out by using processes well known to those skilled in the art.

After obtaining the compound with the structure represented by Formula VI, the present invention mixes the compound with the structure represented by Formula VI, 3-methoxybasic sulfonyl chloride and the fifth organic solvent, and performs a second substitution reaction to obtain the compound with the structure represented by Formula VII compound.

In the present invention, the fifth organic solvent preferably includes one or more of dichloromethane, tetrahydrofuran and pyridine, more preferably pyridine; when the fifth organic solvent is two or more of the above specific selections , the present invention does not have any special restrictions on the proportion of the above specific substances, and they can be mixed in any proportion.

In the present invention, the molar ratio of the compound having the structure shown in Formula VI and 3-methoxybasic sulfonyl chloride is preferably 1:(1.0~1.5), more preferably 1:(1.1~1.4), and most preferably 1 : (1.2～1.3).

The present invention does not have any special restrictions on the amount of the fifth organic solvent. The amount known to those skilled in the art is used to ensure that the compound with the structure shown in Formula VI and 3-methoxybasic sulfonyl chloride can be fully dissolved and reacted therein. That’s it.

In the present invention, the mixing is preferably performed by adding the compound having the structure shown in Formula VI and 3-methoxybasic sulfonyl chloride to the fifth compound under the conditions of 0 to 25°C (i.e., the temperature of the second substitution reaction). in organic solvents.

In the present invention, the temperature of the second substitution reaction is preferably 0 to 25°C, more preferably 0 to 10°C, and most preferably 0°C; the time is preferably 1 to 5h, more preferably 2 to 4h, and most preferably is 3h. In the present invention, the second substitution reaction is preferably carried out under stirring conditions. The present invention does not have any special limitations on the stirring process, and it can be carried out using processes well known to those skilled in the art.

After the second substitution reaction is completed, the present invention also preferably includes sequential extraction, washing, drying and concentration; in the present invention, the extraction preferably uses water and ethyl acetate; the extraction process is preferably Water and ethyl acetate were added sequentially to the product system obtained after the first substitution reaction for extraction. After the extraction, the organic phase is combined and the obtained organic phase is washed; the washing is preferably carried out three times with saturated brine; the drying is preferably carried out by anhydrous sodium sulfate; the concentration is preferably Vacuum concentration, the present invention does not have any special limitations on the process of vacuum concentration, and it can be carried out by using processes well known to those skilled in the art.

After obtaining the compound with the structure represented by formula VII, the present invention mixes the compound with the structure represented by formula VII, potassium carbonate, potassium iodide, the second bromide and the sixth organic solvent, and performs the third substitution reaction under alkaline conditions. The hydrolysis reaction is carried out under the conditions to obtain the 5-(3-(sulfonylamino)phenyl)-1H-pyrrole-2-carboxylic acid derivative.

In the present invention, the second bromine compound is preferably ethyl bromoacetate or 2-bromoacetamide.

In the present invention, the sixth organic solvent is preferably tetrahydrofuran (THF) and/or N,N-dimethylformamide (DMF), more preferably N,N-dimethylformamide; when the sixth organic solvent When the six organic solvents are tetrahydrofuran and N,N-dimethylformamide, the present invention does not have any special restrictions on the dosage ratio of the tetrahydrofuran and N,N-dimethylformamide, and they can be mixed in any proportion. .

In the present invention, the molar ratio of the compound having the structure shown in formula VII and the second bromide is preferably 1: (1.0-1.5), more preferably 1: (1.1-1.4), most preferably 1: (1.2 ~1.3).

In the present invention, the molar ratio of the compound having the structure shown in formula VII, potassium carbonate and potassium iodide is preferably 1:(1.0~3):(0.05~0.15), more preferably 1:(1.5~2.5):( 0.08～0.12), most preferably 1:2:0.1.

The present invention does not have any special restrictions on the amount of the sixth organic solvent. The amount well known to those skilled in the art is used to ensure that the compound having the structure shown in formula VII, potassium carbonate, potassium iodide and the second bromide are fully dissolved therein and Just react.

The present invention does not have any special limitations on the mixing process, and it can be carried out using processes well known to those skilled in the art.

In the present invention, the potassium carbonate functions as an acid binding agent; the potassium iodide functions as a catalyst to promote nucleophilic reactions.

In the present invention, the temperature of the third substitution reaction is preferably 0 to 60°C, more preferably 20 to 30°C, and most preferably 25°C; the time is preferably 1 to 24h, more preferably 6 to 20h, and most preferably is 6h. In the present invention, the third substitution reaction is preferably carried out under stirring conditions. The present invention does not have any special limitations on the stirring process, and it can be carried out using processes well known to those skilled in the art.

After the third substitution reaction is completed, the present invention also preferably includes sequential extraction, washing, drying, concentration and purification; in the present invention, the extraction preferably uses water and ethyl acetate; the extraction process is preferably Water and ethyl acetate were added sequentially to the product system obtained after the first substitution reaction for extraction. After the extraction, the organic phase is combined and the obtained organic phase is washed; the washing is preferably carried out three times with saturated brine; the drying is preferably carried out by anhydrous sodium sulfate; the concentration is preferably Vacuum concentration, the present invention does not have any special limitations on the process of vacuum concentration, and it can be carried out by using processes well known to those skilled in the art. In the present invention, the purification is preferably carried out by silica gel chromatography; the chromatographic liquid used for the purification is preferably petroleum ether and ethyl acetate with a volume ratio of 10:1.

In the present invention, the alkaline condition is preferably provided by a strong base, and the strong base preferably includes KOH, NaOH or LiOH, and more preferably includes LiOH.

In the present invention, the molar ratio of the product obtained by the third substitution reaction and the strong base is preferably 1:(5-15), more preferably 1:(8-11), and most preferably 1:10.

In the present invention, the process of the hydrolysis reaction is preferably to mix the product obtained by the third substitution reaction with a solvent, and then adjust the resulting mixed liquid to be alkaline to perform the hydrolysis reaction. In the present invention, the solvent is preferably methanol and water with a volume ratio of 1:1. In the present invention, the mixing of the product obtained by the third substitution reaction and the solvent is preferably carried out under stirring conditions. The present invention does not have any special limitations on the stirring process, and it is carried out using processes well known to those skilled in the art. That’s it.

In the present invention, the temperature of the hydrolysis reaction is preferably 45-100°C, more preferably 50-70°C, and most preferably 63°C; the time is preferably 3-8h, more preferably 4-6h, and most preferably 4h. .

After the hydrolysis reaction is completed, the present invention also preferably includes adding ethyl acetate to the obtained product system for extraction 3 times, combining the water phases, adjusting the pH to 3 with 1 mol/L hydrochloric acid, and then extracting 3 times with ethyl acetate. times, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo.

The present invention also provides the 5-(3-(sulfonylamino)phenyl)-1H-pyrrole-2-carboxylic acid derivative described in the above technical solution or the 5-(3 prepared by the preparation method described in the above technical solution). Pharmaceutically acceptable salts of -(sulfonylamino)phenyl)-1H-pyrrole-2-carboxylic acid derivatives.

The invention also provides the 5-(3-(sulfonylamino)phenyl)-1H-pyrrole-2-carboxylic acid derivative described in the above technical solution, and the 5-(3 prepared by the preparation method described in the above technical solution. -(Sulfonylamino)phenyl)-1H-pyrrole-2-carboxylic acid derivatives or 5-(3-(sulfonylamino)phenyl)-1H-pyrrole-2-carboxylic acid derivatives described in the above technical solution The pharmaceutically acceptable salt of the substance is used in the preparation of Keap1-Nrf2 protein-protein interaction inhibitors or the preparation of drugs for treating or alleviating disease inflammation. The present invention does not have any special limitations on the application method, and it can be carried out by methods well known to those skilled in the art.

The 5-(3-(sulfonamido)phenyl)-1H-pyrrole-2-carboxylic acid derivatives provided by the present invention and their preparation methods and applications will be described in detail below in conjunction with the examples. However, they should not be understood as limiting the scope of this invention. Limitation of the scope of invention protection.

Example 1

Preparation of 5-(3-((N-(carboxymethyl)-3-methoxyphenyl)sulfonamide)phenyl)-1-methyl-1H-pyrrole-2-carboxylic acid:

Preparation of 5-bromo-1H-pyrrole-2-carboxylic acid ethyl ester (1a):

Add 1H-pyrrole-2-carboxylic acid ethyl ester (3.00g, 21.6mmol) and NBS (3.84g, 21.6mmol) into the reactor, evacuate, replace with nitrogen 3 times, add MeOH/THF (40mL/40mL), The reaction was stirred at room temperature for 8 hours, the solvent was removed in vacuo, and the residue was purified through a silica gel chromatography column (petroleum ether/ethyl acetate (volume ratio) = 100:1) to obtain 1a, 1.5 g of white solid (yield 32%);

Preparation of ethyl 5-bromo-1-methyl-1H-pyrrole-2-carboxylate (1b):

Add 1a (300 mg, 1.38 mmol) to DMF (5 mL) and stir, add NaH (33 mg, 1.38 mmol) in batches, stir for 15 minutes, then add methyl bromide (130.6 mg, 1.38 mmol) and stir at room temperature for 1.5 hours. Add 30 mL of water, then add ethyl acetate (3 × 30 mL) for extraction, combine the organic phases, and wash with saturated brine (3 × 30 mL). The organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo to obtain 1b, 316 mg of yellow oil ( The yield is 99%), which is directly used in the next step of reaction;

Preparation of 1-methyl-5-(3-nitrophenyl)-1H-pyrrole-2-carboxylic acid ethyl ester (1c):

Add 1b (316mg, 1.36mmol), 3-nitrobenzeneboronic acid (342mg, 2.04mmol), Cs ₂ CO ₃ (888mg, 2.72mmol) to 1,4-dioxane/water (8mL/2mL) Evacuate, replace with nitrogen three times, add tetrakis triphenylphosphine palladium (157.2 mg, 0.14 mmol), and react at 90°C for 3 hours. Add 30 mL of water, then add ethyl acetate (3 × 30 mL) for extraction, combine the organic phases, and wash with saturated brine (3 × 30 mL). The organic layer is dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by silica gel chromatography (petroleum ether/petroleum ether). Ethyl acetate (volume ratio) = 10:1) to obtain 1c, a light yellow solid (250 mg, yield 67%);

Preparation of ethyl 5-(3-aminophenyl)-1-methyl-1H-pyrrole-2-carboxylate (1d):

1c (250 mg, 0.91 mmol), iron powder (510 mg, 9.12 mmol), and ammonium chloride (488 mg, 9.12 mmol) were added to methanol/water (6 mL/3 mL) and stirred at room temperature for 3 hours. Add 30 mL of water, then add ethyl acetate (3 × 30 mL) for extraction, combine the organic phases, and wash with saturated brine (3 × 30 mL). The organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo to obtain 1d, 212 mg of light yellow oil. (yield 95%), directly used in the next step of reaction;

Preparation of 5-(3-((3-methoxyphenyl)sulfonamido)phenyl)-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (1e):

Add 1d (212 mg, 0.87 mmol) and 3-methoxybenzenesulfonyl chloride (216 mg, 1.04 mmol) to 5 mL pyridine at 0°C, stir for 3 hours, add water (30 mL), and then add ethyl acetate (3× 30 mL), combine the organic phases, and wash with saturated brine (3 × 30 mL). The organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo to obtain 1e, a light yellow solid 298 mg (yield 80%), which is directly used in the next step. reaction;

Preparation of 5-(3-((N-(carboxymethyl)-3-methoxyphenyl)sulfonamido)phenyl)-1-ethyl-1H-pyrrole-2-carboxylic acid (1f):

Add 1e (298mg, 0.65mmol) and ethyl bromoacetate (130.3mg, 0.78mmol) to DMF (5mL), add potassium carbonate (180mg, 1.3mmol) and potassium iodide (11mg, 0.07mmol) under magnetic stirring, and react for 6 hours. Add water (30 mL), then add ethyl acetate (3 × 30 mL) for extraction, combine the organic phases, and wash with saturated brine (3 × 30 mL). The organic layer is dried over anhydrous sodium sulfate, concentrated in vacuo, and purified on a silica gel column (petroleum ether). /ethyl acetate (volume ratio) = 10:1), the intermediate was obtained as a transparent oil 318 mg (yield 95%), and the obtained intermediate was directly used in the next step of the reaction;

Add the intermediate (318 mg, 0.62 mmol) to methanol/water (2 mL/2 mL) and stir, then add LiOH (148 mg, 6.18 mmol) and react at 60°C for 4 hours. Add ethyl acetate (3×0 mL) for extraction and combine. The aqueous layer was adjusted to pH 3 with 1 mol/L hydrochloric acid, and then extracted with ethyl acetate (3×30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain 1f, a white solid 142 mg (yield: 50 %); 1HNMR (400MHz, Methanol-d ₄ ) δ7.54-7.36(m,3H),7.34-7.25(m,3H),7.22(d,1H),7.19-7.14(m,1H),7.00( d,1H),6.15(d,1H),4.51(s,2H),3.79(s,3H),3.75(s,3H).

Example 2

Preparation of 5-(3-((N-(carboxymethyl)-3-methoxyphenyl)sulfonamide)phenyl)-1-ethyl-1H-pyrrole-2-carboxylic acid (2):

Referring to Example 1, the difference is that: ethyl bromide (150.4 mg, 1.38 mmol) was used instead of methyl bromide to obtain 161 mg of light yellow solid (2) (yield 55%);

1HNMR(400MHz,Methanol-d4)δ7.47-7.39(m,2H),7.34(d,1H),7.31-7.24(m,3H),7.22-7.13(m,2H),6.99(d,1H) ,6.08(d,1H),4.49(s,2H),3.76(s,3H),2.00(d,2H),1.13(t,3H).

Example 3

Preparation of 5-(3-((N-(carboxymethyl)-3-methoxyphenyl)sulfonamide)phenyl)-1-propyl-1H-pyrrole-2-carboxylic acid (3):

Referring to Example 1, the difference is that: propane bromide (169.7 mg, 1.38 mmol) was used instead of methyl bromide to obtain 157 mg of light yellow solid (3) (yield 52%);

1HNMR(400MHz,Methanol-d4)δ7.47-7.37(m,2H),7.36-7.18(m,6H),7.16-7.11(m,1H),7.00(d,1H),4.35-4.15(m, 2H),3.76(d,4H),1.64-1.43(m,3H),0.64(t,3H).

Example 4

Preparation of 1-allyl-5-(3-((N-(carboxymethyl)-3-methoxyphenyl)sulfonamido)phenyl)-1H-pyrrole-2-carboxylic acid (4) :

Referring to Example 1, the difference is that 3-bromoprop-1-ene (167.0 mg, 1.38 mmol) was used instead of methyl bromide to obtain 153 mg of light yellow solid (4) (yield 51%);

1HNMR(400MHz,Methanol-d4)δ7.46-7.34(m,2H),7.33-7.21(m,3H),7.21-7.07(m,3H),7.03(d,1H),6.21-6.08(m, 1H),4.93-4.75(m,2H),4.54(d,1H),4.48-4.34(m,3H),3.74(s,3H).

Example 5

Preparation of 1-butyl-5-(3-((N-(carboxymethyl)-3-methoxyphenyl)sulfonamido)phenyl)-1H-pyrrole-2-carboxylic acid (5):

Referring to Example 1, the difference is that 1-bromobutane (189.1 mg, 1.38 mmol) was used instead of methyl bromide to obtain 152 mg of light yellow solid (5) (yield 49%);

1HNMR(400MHz,Methanol-d4)δ7.46-7.37(m,2H),7.36–7.11(m,7H),7.00(d,1H),4.48(s,2H),3.76(s,3H),2.00 (d,2H),1.53–1.41(m,2H),1.10-0.95(m,2H),0.72(t,3H).

Example 6

5-(3-((N-(Carboxymethyl)-3-methoxyphenyl)sulfonamide)phenyl)-1-(cyclopropylmethyl)-1H-pyrrole-2-carboxylic acid ( 6) Preparation:

Referring to Example 1, the difference is that (bromomethyl)cyclopropane (186.3 mg, 1.38 mmol) was used instead of methyl bromide to obtain 6, a light yellow solid 154 mg (yield 50%);

1HNMR(400MHz,Chloroform-d)δ7.34-7.17(m,7H),7.15-7.03(m,3H),4.42(s,2H),4.14(d,2H),3.76–3.65(m,3H) ,2.25-2.13(m,1H),0.85-0.71(m,4H).

Example 7

Preparation of 5-(3-((N-(carboxymethyl)-3-chlorophenyl)sulfonamido)phenyl)-1-ethyl-1H-pyrrole-2-carboxylic acid (7):

Referring to Example 2, the difference is that 3-chlorobenzenesulfonyl chloride (349.5 mg, 1.66 mmol) was used instead of 3-methoxybenzenesulfonyl chloride to obtain 153 mg of light yellow solid (7) (yield 52%);

1HNMR(400MHz,Chloroform-d)δ7.82(s,1H),7.71(d,1H),7.60(d,1H),7.50-7.28(m,4H),7.21(d,1H),7.02(q ,1H),6.10(d,1H),4.50(s,2H),4.30(q,2H),1.37(t,3H).

Example 8

Preparation of 5-(3-((3-bromo-N-(carboxymethyl)phenyl)sulfonamido)phenyl)-1-ethyl-1H-pyrrole-2-carboxylic acid (8):

Referring to Example 2, the difference is that 3-bromobenzenesulfonyl chloride (424.1 mg, 1.66 mmol) was used instead of 3-methoxybenzenesulfonyl chloride to obtain 165 mg of light yellow solid (8) (yield 51%); 1HNMR ( 400MHz,Chloroform-d)δ7.84(s,1H),7.73(d,1H),7.63(d,1H),7.52–7.30(m,4H),7.25(s,1H),7.04(d,1H ),6.13(d,1H),4.52(s,2H),4.32(q,2H),1.39(t,3H).

Example 9

5-(3-((N-(Carboxymethyl)-3-methoxyphenyl)sulfonamido)phenyl)-1-(3-cyanopropyl)-1H-pyrrole-2-carboxylic acid Preparation of (9):

Referring to Example 1, the difference is that 4-bromobutyronitrile (204.2 mg, 1.38 mmol) was used instead of methyl bromide to obtain 167 mg of light yellow solid (9) (yield 51%);

1HNMR(400MHz,Chloroform-d)δ7.40-7.25(m,4H),7.24-7.01(m,6H),4.48-4.26(m,3H),3.71(s,3H),2.07(q,2H) ,1.95-1.80(m,2H).

Example 10

5-(3-((N-(Carboxymethyl)-3-methoxyphenyl)sulfonamido)phenyl)-1-(cyanomethyl)-1H-pyrrole-2-carboxylic acid (10 ) preparation:

Referring to Example 1, the difference is that: 2-bromoacetonitrile (165.5 mg, 1.38 mmol) was used instead of methyl bromide to obtain 161 mg of light yellow solid (10) (yield 52%);

1HNMR (400MHz, Chloroform-d) δ7.36-7.21(m,5H),7.18-7.01(m,5H),4.76(s,2H),4.37(s,2H),3.69(s,3H).

Example 11

5-(3-((N-(Carboxymethyl)-3-methoxyphenyl)sulfonamide)phenyl)-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylic acid ( 11) Preparation:

Referring to Example 1, the difference is that: 1-bromo-2-fluoroethane (175 mg, 1.38 mmol) was used instead of methyl bromide to obtain 173 mg of yellow solid (11) (yield 55%);

1HNMR(400MHz,Methanol-d4)δ7.49-7.37(m,3H),7.36-7.31(m,1H),7.30–7.24(m,2H),7.24–7.17(m,1H),7.17-7.11( m,1H),7.07(d,1H),6.14(d,1H),4.57(s,2H),4.53-4.40(m,4H),3.77(s,3H).

Example 12

1-(Carboxymethyl)-5-(3-((N-(carboxymethyl)-3-methoxyphenyl)sulfonamido)phenyl)-1H-pyrrole-2-carboxylic acid (12) Preparation:

Referring to Example 1, the difference is that ethyl 2-bromoacetate (230 mg, 1.38 mmol) was used instead of methyl bromide to obtain 180 mg of light yellow solid (12) (yield 56%);

1HNMR(400MHz,Methanol-d4)δ7.46-7.38(m,2H),7.35-7.24(m,4H),7.19-7.05(m,2H),7.04(d,1H),6.92-6.79(m, 1H),4.90(s,2H),4.47(s,2H),3.76(s,2H).

Example 13

5-(3-((N-(Carboxymethyl)-3-methoxyphenyl)sulfonamido)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl Preparation of (1H-pyrrole-2-carboxylic acid (13)):

Referring to Example 1, the difference is that (2-(bromomethoxy)ethyl)trimethylsilane (291 mg, 1.38 mmol) was used instead of methyl bromide to obtain 196 mg of light yellow solid (13) (yield 53%);

1HNMR(400MHz,Chloroform-d)δ7.64-7.39(m,4H),7.39-7.29(m,2H),7.28-7.11(m,3H),6.27(d,1H),5.59(s,2H) ,4.51(s,2H),3.81(s,3H),3.54(s,2H),0.95-0.81(m,2H),0.00(s,9H).

Example 14

5-(3-((N-(carboxymethyl)-3-methoxyphenyl)sulfonamide)phenyl)-1-(2-morpholinoethyl)-1H-pyrrole-2-carboxy Preparation of acid (14):

Referring to Example 1, the difference is that: 4-(2-bromoethyl)morpholine (268 mg, 1.38 mmol) was used instead of methyl bromide to obtain 197 mg of light yellow solid (14) (yield 55%);

1HNMR(400MHz,Methanol-d4)δ7.52-7.39(m,4H),7.31-7.20(m,2H),7.20-7.06(m,3H),6.23(d,1H),4.68(t,2H) ,4.51(s,2H),4.07-3.92(m,2H),3.87-3.74(m,5H),3.57–3.42(m,4H),3.26-3.10(m,2H).

Example 15

Preparation of 1-benzyl-5-(3-((N-(carboxymethyl)-3-methoxyphenyl)sulfonamido)phenyl)-1H-pyrrole-2-carboxylic acid (15):

Referring to Example 1, the difference is that (bromomethyl)benzene (236 mg, 1.38 mmol) was used instead of methyl bromide to obtain 199 mg of light yellow solid (15) (yield 58%);

1HNMR(400MHz,DMSO-d6)δ7.47-6.99(m,12H),6.88(s,1H),6.64(d,2H),5.59(s,2H),4.11(s,2H),3.68(s ,3H).

Example 16

Preparation of 5-(3-((N-(carboxymethyl)-4-methoxyphenyl)sulfonamide)phenyl)-1-methyl-1H-pyrrole-2-carboxylic acid (16):

Referring to Example 1, the difference is that 4-methoxybenzenesulfonyl chloride (342 mg, 1.66 mmol) was used instead of 3-methoxybenzenesulfonyl chloride to obtain 148 mg of light yellow solid (16) (yield 52%);

1HNMR(400MHz,Chloroform-d)δ7.60(d,2H),7.46(s,1H),7.35-7.29(m,2H),7.12-7.04(m,2H),6.87(d,2H),6.17 (d,2H),4.42(s,2H),3.80(s,3H),3.68(s,3H).

Example 17

Preparation of 5-(3-((N-(carboxymethyl)-4-methoxyphenyl)sulfonamido)phenyl)-1-ethyl-1H-pyrrole-2-carboxylic acid (17):

Referring to Example 2, the difference is that 4-methoxybenzenesulfonyl chloride (342 mg, 1.66 mmol) was used instead of 3-methoxybenzenesulfonyl chloride to obtain 158 mg of light yellow solid (17) (yield 54%);

1HNMR(400MHz,Methanol-d4)δ7.53(s,2H),7.21-7.03(m,4H),6.98-6.85(m,3H),6.00(d,1H),4.38(s,2H),4.17 (q,2H),3.76(s,3H),1.04(t,3H).

Example 18

Preparation of 5-(3-((N-(carboxymethyl)-4-methoxyphenyl)sulfonamido)phenyl)-1-propyl-1H-pyrrole-2-carboxylic acid (18):

Referring to Example 3, the difference is that 4-methoxybenzenesulfonyl chloride (342 mg, 1.66 mmol) was used instead of 3-methoxybenzenesulfonyl chloride to obtain 166 mg of light yellow solid (18) (yield 55%);

1HNMR(400MHz,Methanol-d4)δ7.70-7.60(m,2H),7.46-7.28(m,3H),7.25(s,1H),7.02-6.77(m,3H),6.11(d,1H) ,4.48(s,2H),3.87(s,3H),3.33(d,2H),1.49-1.36(m,2H),0.67(t,3H).

Example 19

Preparation of 1-allyl-5-(3-((N-(carboxymethyl)-4-methoxyphenyl)sulfonamido)phenyl)-1H-pyrrole-2-carboxylic acid (19) :

Referring to Example 4, the difference is that 4-methoxybenzenesulfonyl chloride (342 mg, 1.66 mmol) is used instead of 3-methoxybenzenesulfonyl chloride to obtain 19, a light yellow solid 153 mg (yield 51%);

1HNMR(400MHz,Methanol-d4)δ7.65-7.58(m,2H),7.43-7.34(m,2H),7.31-7.24(m,2H),7.09-7.00(m,3H),6.19(d, 1H),5.92-5.77(m,1H),5.05-4.99(m,1H),4.91-4.86(m,2H),4.61-4.52(m,1H),4.45(s,2H),3.88(s, 3H).

Example 20

Preparation of 1-butyl-5-(3-((N-(carboxymethyl)-4-methoxyphenyl)sulfonamido)phenyl)-1H-pyrrole-2-carboxylic acid (20):

Referring to Example 5, the difference is that 4-methoxybenzenesulfonyl chloride (342 mg, 1.66 mmol) is used instead of 3-methoxybenzenesulfonyl chloride to obtain 20, 155 mg of light yellow solid (yield 50%);

1HNMR(400MHz,Methanol-d4)δ7.70–7.60(m,2H),7.58–7.28(m,3H),7.26(s,1H),7.06-6.87(m,3H),6.61(d,1H) ,4.78(s,2H),4.16(t,2H),3.81(s,3H),1.74-1.26(m,4H),0.67(t,3H).

Example 21

5-(3-((N-(Carboxymethyl)-4-methoxyphenyl)sulfonamido)phenyl)-1-(cyclopropylmethyl)-1H-pyrrole-2-carboxylic acid ( 21) Preparation:

Referring to Example 6, the difference is that 4-methoxybenzenesulfonyl chloride (342 mg, 1.66 mmol) is used instead of 3-methoxybenzenesulfonyl chloride to obtain 21, 160 mg of light yellow solid (yield 52%);

1HNMR(400MHz,Methanol-d4)δ7.99(s,1H),7.70-7.58(m,2H),7.49-7.38(m,1H),7.33-7.28(m,2H),7.27–7.17(m, 1H),7.06–6.97(m,3H),4.49(s,2H),4.24(d,2H),3.86(s,3H),1.36-0.16(m,5H).

Example 22

Preparation of 5-(3-((N-(carboxymethyl)-2-methoxyphenyl)sulfonamido)phenyl)-1-ethyl-1H-pyrrole-2-carboxylic acid (22):

Referring to Example 2, the difference is that 2-methoxybenzenesulfonyl chloride (342 mg, 1.66 mmol) is used instead of 3-methoxybenzenesulfonyl chloride to obtain 22, a light yellow solid 154 mg (yield 54%);

1HNMR(400MHz,Methanol-d4)δ7.70-7.55(m,2H),7.46-7.20(m,5H),7.02-6.92(m,2H),6.07(d,1H),4.71(s,2H) ,4.33(q,2H),4.01(s,3H),1.36(t,3H).

Example 23

5-(3-((N-(Carboxymethyl)-4-methoxyphenyl)sulfonamido)phenyl)-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylic acid ( 23) Preparation:

Referring to Example 11, the difference is that 4-methoxybenzenesulfonyl chloride (342 mg, 1.66 mmol) is used instead of 3-methoxybenzenesulfonyl chloride to obtain 23, 160 mg of light yellow solid (yield 51%);

1HNMR(400MHz,Methanol-d4)δ7.70-7.58(m,2H),7.49-7.26(m,5H),7.06-6.92(m,2H),6.09(d,1H),4.78(s,2H) ,4.49(dd,2H),4.36(dd,2H),3.81(s,3H).

Example 24

5-(3-((N-(Carboxymethyl)-4-methoxyphenyl)sulfonamide)phenyl)-1-(cyanomethyl)-1H-pyrrole-2-carboxylic acid (24 ) preparation:

Referring to Example 10, the difference is that 4-methoxybenzenesulfonyl chloride (342 mg, 1.66 mmol) is used instead of 3-methoxybenzenesulfonyl chloride to obtain 24, 170 mg of light yellow solid (yield 55%);

1HNMR(400MHz,Methanol-d4)δ7.58(d,2H),7.36(t,1H),7.33-7.27(m,2H),7.22(d,1H),7.05-6.98(m,3H),6.21 (d,1H),4.86(s,2H),4.42(s,2H),3.86(s,3H).

Example 25

5-(3-((N-(Carboxymethyl)-4-methoxyphenyl)sulfonamido)phenyl)-1-(3-cyanopropyl)-1H-pyrrole-2-carboxylic acid Preparation of (25):

Referring to Example 9, the difference is that 4-methoxybenzenesulfonyl chloride (342 mg, 1.66 mmol) is used instead of 3-methoxybenzenesulfonyl chloride to obtain 24, 174 mg of light yellow solid (yield 53%);

1HNMR(400MHz,Methanol-d4)δ7.69-7.57(m,2H),7.38–6.99(m,6H),6.84-6.77(m,1H),6.18-6.10(m,1H),4.47(s, 2H),3.88(s,3H),3.33(t,2H),2.19(t,2H),1.90–1.79(m,2H).

Example 26

Preparation of 5-(3-((N-(carboxymethyl)-3-fluorophenyl)sulfonamido)phenyl)-1-ethyl-1H-pyrrole-2-carboxylic acid (26):

Referring to Example 2, the difference is that 3-fluorobenzenesulfonyl chloride (323 mg, 1.66 mmol) is used instead of 3-methoxybenzenesulfonyl chloride to obtain 26, 160 mg of light yellow solid (yield 56%);

1HNMR(400MHz,Methanol-d4)δ7.61-7.48(m,3H),7.46-7.23(m,6H),7.00(s,1H),4.54(s,2H),4.35-4.25(m,3H) ,1.10(m,3H).

Example 27

Preparation of 1-allyl-5-(3-((N-(carboxymethyl)-3-fluorophenyl)sulfonamido)phenyl)-1H-pyrrole-2-carboxylic acid (27):

Referring to Example 4, the difference is that 3-fluorobenzenesulfonyl chloride (323 mg, 1.66 mmol) was used instead of 3-methoxybenzenesulfonyl chloride to obtain 27, 152 mg of yellow solid (yield 52%);

1HNMR(400MHz,Methanol-d4)δ7.60-7.46(m,2H),7.45-7.35(m,4H),7.33-7.21(m,2H),7.02(d,1H),6.18(d,1H) ,5.91–5.78(m,1H),5.03–4.92(m,3H),4.60–4.51(m,1H),4.48(s,2H).

Example 28

Preparation of 1-allyl-5-(3-((N-(carboxymethyl)-3-chlorophenyl)sulfonamido)phenyl)-1H-pyrrole-2-carboxylic acid (28):

Referring to Example 4, the difference is that 3-chlorobenzenesulfonyl chloride (350 mg, 1.66 mmol) is used instead of 3-methoxybenzenesulfonyl chloride to obtain 28, 164 mg of yellow solid (yield 54%);

1HNMR(400MHz,Chloroform-d)δ7.58(s,1H),7.48(d,2H),7.37-7.29(m,4H),7.23-7.15(m,3H),6.98(d,1H),6.10 (d,1H),4.99(d,1H),4.79(s,2H),4.59(d,1H),4.39(s,2H).

Example 29

Preparation of 5-(3-(N-(carboxymethyl)naphthalene-2-sulfonamido)phenyl)-1-ethyl-1H-pyrrole-2-carboxylic acid (29):

Referring to Example 2, the difference is that: naphthalene-2-sulfonyl chloride (376 mg, 1.66 mmol) was used instead of 3-methoxybenzenesulfonyl chloride to obtain 29, 165 mg of yellow solid (yield 54%);

1HNMR(400MHz,Methanol-d4)δ8.24(s,1H),8.04-7.92(m,3H),7.75-7.59(m,3H),7.40-7.21(m,4H),6.92(d,1H) ,5.99(s,2H),4,25(q,2H),1.34(t,3H).

Example 30

Preparation of 1-allyl-5-(3-((3-bromo-N-(carboxymethyl)phenyl)sulfonamido)phenyl)-1H-pyrrole-2-carboxylic acid (30):

Referring to Example 4, the difference is that 3-bromobenzenesulfonyl chloride (424 mg, 1.66 mmol) is used instead of 3-methoxybenzenesulfonyl chloride to obtain 30, 176 mg of yellow solid (yield 53%);

1HNMR(400MHz,Methanol-d4)δ7.86–7.75(m,1H),7.74-7.62(m,2H),7.46(t,1H),7.43–7.28(m,4H),7.03(d,1H) ,6.20(d,1H),5.04–4.95(m,4H),4.92(s,2H),4.55(dd,1H).

Example 31

Preparation of 1-allyl-5-(3-((N-(carboxymethyl)-2-methoxyphenyl)sulfonamido)phenyl)-1H-pyrrole-2-carboxylic acid (31) :

Referring to Example 4, the difference is that 2-methoxybenzenesulfonyl chloride (342 mg, 1.66 mmol) is used instead of 3-methoxybenzenesulfonyl chloride to obtain 31, a light yellow solid 159 mg (yield 53%);

1HNMR(400MHz,Methanol-d4)δ7.67-7.54(m,2H),7.35-7.19(m,5H),7.04-6.92(m,2H),6.11(d,1H),5.00-4.94(m, 2H),4.80(d,2H),4.65(s,2H),4.53-4.44(m,1H),3.98(s,3H).

Example 32

Preparation of 1-allyl-5-(3-(N-(carboxymethyl)naphthalene-2-sulfonamido)phenyl)-1H-pyrrole-2-carboxylic acid (32):

Referring to Example 4, the difference is that: naphthalene-2-sulfonyl chloride (376 mg, 1.66 mmol) was used instead of 3-methoxybenzenesulfonyl chloride to obtain 32, 156 mg of yellow solid (yield 50%);

1HNMR(400MHz,Methanol-d4)δ8.22(d,1H),8.07-7.55(m,7H),7.41-7.14(m,3H),7.13-7.05(m,1H),6.99-6.91(m, 1H),5.00(s,2H),4.92-4.77(m,2H),4.74-4.63(m,1H),4.54(s,1H),4.49(s,1H).

Example 33

5-(3-((N-(Carboxymethyl)-2-methoxyphenyl)sulfonamide)phenyl)-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylic acid ( 33) Preparation:

Referring to Example 11, the difference is that 2-methoxybenzenesulfonyl chloride (342 mg, 1.66 mmol) is substituted for 3-methoxybenzenesulfonyl chloride to obtain 33, 170 mg of light yellow solid (yield 54%);

1HNMR(400MHz,Methanol-d4)δ7.67-7.53(m,2H),7.38-7.17(m,5H),7.03-6.92(m,2H),6.08(d,1H),4.67(s,2H) ,4.48(dd,2H),4.39(dd,2H),3.98(s,3H).

Example 34

Preparation of 5-(3-(N-(carboxymethyl)naphthalene-2-sulfonamido)phenyl)-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylic acid (34):

Referring to Example 11, the difference is that: naphthalene-2-sulfonyl chloride (376 mg, 1.66 mmol) was substituted for 3-methoxybenzenesulfonyl chloride to obtain 34, 170 mg of yellow solid (yield 52%);

1HNMR(400MHz,Methanol-d4)δ8.22(s,1H),8.00-7.89(m,3H),7.73-7.53(m,3H),7.39-7.27(m,3H),7.21(s,1H) ,6.94(d,1H),5.99(d,1H),4.54(s,2H),4.29-4.15(m,4H).

Example 35

5-(3-((N-(Carboxymethyl)-3-fluorophenyl)sulfonamido)phenyl)-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylic acid (35) Preparation:

Referring to Example 11, the difference is that 3-fluorobenzenesulfonyl chloride (323 mg, 1.66 mmol) was substituted for 3-methoxybenzenesulfonyl chloride to obtain 35, 162 mg of light yellow solid (yield 53%);

1HNMR(400MHz,Methanol-d4)δ8.22(s,1H),8.00-7.89(m,3H),7.73-7.53(m,3H),7.40-7.27(m,1H),7.21(s,1H) ,6.94(d,1H),5.99(d,1H),4.54(s,2H),4.29-4.15(m,4H).

Example 36

5-(3-((3-bromo-N-(carboxymethyl)phenyl)sulfonamido)phenyl)-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylic acid (36) Preparation:

Referring to Example 11, the difference is that 3-bromobenzenesulfonyl chloride (424 mg, 1.66 mmol) was substituted for 3-methoxybenzenesulfonyl chloride to obtain 36, 187 mg of light yellow solid (yield 54%);

1HNMR(400MHz,Methanol-d4)δ7.84-7.75(m,1H),7.70-7.62(m,1H),7.48-7.27(m,5H),7.05(d,1H),6.16(d,1H) ,4.58(s,2H),4.55-4.44(m,2H).

Example 37

5-(3-((N-(Carboxymethyl)-3-chlorophenyl)sulfonamido)phenyl)-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylic acid (37) Preparation:

Referring to Example 11, the difference is that 3-chlorobenzenesulfonyl chloride (350 mg, 1.66 mmol) was substituted for 3-methoxybenzenesulfonyl chloride to obtain 37, 175 mg of yellow solid (yield 55%);

1HNMR(400MHz,Methanol-d4)δ7.70-7.59(m,3H),7.57-7.50(m,1H),7.48-7.38(m,2H),7.37-7.27(m,2H),7.06(d, 1H),6.17(d,1H),4.59(s,2H),4.55-4.45(m,2H).

Example 38

Preparation of 5-(3-((N-(carboxymethyl)-2-methoxyphenyl)sulfonamido)phenyl)-1-methyl-1H-pyrrole-2-carboxylic acid (38):

Referring to Example 1, the difference is that 2-methoxybenzenesulfonyl chloride (350 mg, 1.66 mmol) is substituted for 3-methoxybenzenesulfonyl chloride to obtain 38, a light yellow solid 148 mg (yield 52%);

1HNMR(400MHz,Methanol-d4)δ7.72-7.56(m,2H),7.40-7.21(m,5H),7.04-6.90(m,2H),6.10(d,1H),4.70(s,2H) ,4.02(s,3H),3.66(s,3H).

Example 39

Preparation of 5-(3-((N-(carboxymethyl)-3-fluorophenyl)sulfonamido)phenyl)-1-methyl-1H-pyrrole-2-carboxylic acid (39):

Referring to Example 1, the difference is that 3-fluorobenzenesulfonyl chloride (323 mg, 1.66 mmol) was substituted for 3-methoxybenzenesulfonyl chloride to obtain 39, a light yellow solid 149 mg (yield 54%);

1HNMR(400MHz,Methanol-d4)δ7.60-7.48(m,2H),7.47-7.36(m,4H),7.33-7.24(m,2H),6.95(d,1H),6.13(d,1H) ,4.51(s,2H),3.74(s,2H).

Example 40

Preparation of 5-(3-((N-(carboxymethyl)-3-chlorophenyl)sulfonamido)phenyl)-1-methyl-1H-pyrrole-2-carboxylic acid (40):

Referring to Example 1, the difference is that 3-chlorobenzenesulfonyl chloride (350 mg, 1.66 mmol) was substituted for 3-methoxybenzenesulfonyl chloride to obtain 40, 149 mg of yellow solid (yield 52%);

1HNMR(400MHz,Methanol-d4)δ7.69-7.58(m,3H),7.55-7.47(m,1H),7.46-7.35(m,2H),7.33-7.24(m,2H),6.94(d, 1H),6.13(d,1H),4.50(s,2H),3.73(s,3H).

Example 41

Preparation of 5-(3-((3-bromo-N-(carboxymethyl)phenyl)sulfonamido)phenyl)-1-methyl-1H-pyrrole-2-carboxylic acid (41):

Referring to Example 1, the difference is that 3-bromobenzenesulfonyl chloride (424 mg, 1.66 mmol) was substituted for 3-methoxybenzenesulfonyl chloride to obtain 41, 161 mg of yellow solid (yield 51%);

1HNMR(400MHz,Methanol-d4)δ7.78(d,2H),7.68(d,1H),7.49-7.35(m,3H),7.32-7.22(m,2H),6.95(d,1H),6.13 (d,1H),4.50(s,2H),3.73(s,3H).

Example 42

Preparation of 5-(3-((N-(carboxymethyl)-2-methoxyphenyl)sulfonamido)phenyl)-1-propyl-1H-pyrrole-2-carboxylic acid (42):

Referring to Example 3, the difference is that 2-methoxybenzenesulfonyl chloride (424 mg, 1.66 mmol) replaced 3-methoxybenzenesulfonyl chloride to obtain 42, 166 mg of yellow solid (yield 55%);

1HNMR(400MHz,Methanol-d4)δ7.71-7.54(m,2H),7.39-7.21(m,5H),7.03-6.93(m,2H),6.08(d,1H),4.71(s,2H) ,4.17(t,2H),4.03(s,3H),1.46(q,2H),0.62(t,3H).

Example 43

Preparation of 5-(3-((N-(carboxymethyl)-3-fluorophenyl)sulfonamido)phenyl)-1-propyl-1H-pyrrole-2-carboxylic acid (43):

Referring to Example 3, the difference is that 3-fluorobenzenesulfonyl chloride (323 mg, 1.66 mmol) was substituted for 3-methoxybenzenesulfonyl chloride to obtain 43, 163 mg of light yellow solid (yield 55%);

1HNMR(400MHz,Methanol-d4)δ7.57-7.32(m,7H),7.27-7.21(m,1H),6.99(d,1H),6.10(d,1H),4.51(s,2H),4.27 (t,2H),1.52(q,2H),0.65(t,3H).

Example 44

Preparation of 5-(3-((N-(carboxymethyl)-3-chlorophenyl)sulfonamido)phenyl)-1-propyl-1H-pyrrole-2-carboxylic acid (44):

Referring to Example 3, the difference is that 3-chlorobenzenesulfonyl chloride (350 mg, 1.66 mmol) was substituted for 3-methoxybenzenesulfonyl chloride to obtain 44, 162 mg of yellow solid (yield 53%);

1HNMR(400MHz,Methanol-d4)δ7.69-7.60(m,3H),7.55-7.47(m,1H),7.45-7.38(m,1H),7.38-7.29(m,2H),7.24(d, 1H),6.99(d,1H),6.11(d,1H),4.51(s,2H),4.27(t,2H),1.59-1.46(m,2H),0.65(t,3H).

Example 45

Preparation of 5-(3-((3-bromo-N-(carboxymethyl)phenyl)sulfonamido)phenyl)-1-propyl-1H-pyrrole-2-carboxylic acid (45):

Referring to Example 3, the difference is that 3-bromobenzenesulfonyl chloride (424 mg, 1.66 mmol) was substituted for 3-methoxybenzenesulfonyl chloride to obtain 45, a light yellow solid 173 mg (yield 52%);

1HNMR(400MHz,Methanol-d4)δ7.86-7.75(m,2H),7.70(d,1H),7.53-7.43(m,2H),7.40-7.32(m,2H),7.31-7.21(m, 1H),7.01(d,1H),6.14(d,1H),4.53(s,2H),4.30(t,2H),1.62-1.49(m,2H),0.68(t,3H).

Example 46

Preparation of 5-(3-(N-(carboxymethyl)naphthalene-2-sulfonamido)phenyl)-1-propyl-1H-pyrrole-2-carboxylic acid (46):

Referring to Example 3, the difference is that: naphthalene-2-sulfonyl chloride (376 mg, 1.66 mmol) was substituted for 3-methoxybenzenesulfonyl chloride to obtain 46, 170 mg of yellow solid (yield 54%);

1HNMR(400MHz,Methanol-d4)δ8.28(s,1H),8.06-7.93(m,3H),7.76–7.58(m,3H),7.42-7.23(m,4H),6.94(d,1H) ,6.01(d,1H),4.59(s,2H),4.10(t,2H),1.43-1.36(m,2H),0.54(t,3H).

Example 47

5-(3-((N-(2-amino-2-oxyethyl)-3-methoxyphenyl)sulfonamido)phenyl)-1-propyl-1H-pyrrole-2-carboxylic acid Preparation of (47):

Referring to Example 3, the difference is that 2-bromoacetamide (229 mg, 1.66 mmol) replaced ethyl 2-bromoacetate to obtain 47, 166 mg of yellow solid (yield 55%). 1HNMR(400MHz,Methanol-d4)δ7.48-7.37(m,2H),7.36–7.08(m,7H),6.99(d,1H),6.13-6.06(m,1H),4.48(s,1H) ,4.24(t,2H),3.80(s,3H),1.57–1.44(m,2H),0.65(t,3H).

Example 48

1-allyl-5-(3-((N-(2-amino-2-oxyethyl)-3-methoxyphenyl)sulfonamido)phenyl)-1H-pyrrole-2-carboxy Preparation of acid (48):

Referring to Example 3, the difference is that: 2-bromoacetamide (229 mg, 1.66 mmol) replaced ethyl 2-bromoacetate to obtain 48, 156 mg of yellow solid (yield 52%);

1HNMR(400MHz,Methanol-d4)δ7.46-7.35(m,3H),7.32-7.24(m,3H),7.14-7.06(m,2H),7.02(d,1H),6.17(d,1H) ,5.00-4.94(m,1H),4.89-4.84(m,2H),4.58-4.49(m,1H),4.45-4.36(m,3H),3.79(s,3H).

Example 49

5-(3-((N-(2-amino-2-oxoethyl)-3-methoxyphenyl)sulfonamido)phenyl)-1-ethyl-1H-pyrrole-2-carboxy Preparation of acid (49):

Referring to Example 3, the difference is that: 2-bromoacetamide (229 mg, 1.66 mmol) replaced ethyl 2-bromoacetate to obtain 49, 164 mg of yellow solid (yield 56%);

1HNMR(400MHz,Methanol-d4)δ7.47-7.33(m,2H),7.38-7.32(m,1H),7.32-7.23(m,3H),7.22-7.10(m,2H),6.98(d, 1H),6.10(d,1H),4.49(s,2H),4.25(q,2H),3.76(s,3H),1.11(t,3H).

Example 50

5-(3-((N-(2-amino-2-oxyethyl)-3-methoxyphenyl)sulfonamido)phenyl)-1-(2-fluoroethyl)-1H-pyrrole Preparation of -2-carboxylic acid (50):

Referring to Example 11, the difference is that 2-bromoacetamide (229 mg, 1.66 mmol) was substituted for ethyl 2-bromoacetate to obtain 50, a light yellow solid 170 mg (yield 54%);

1H NMR (400MHz, Methanol-d4) δ7.68-7.58(m,3H),7.51-7.40(m,1H),7.40-7.26(m,2H),7.24-7.17(m,1H),7.17-7.11 (m,1H),7.07(d,1H),6.61(d,1H),4.57(s,2H),4.53-4.36(m,4H),3.81(s,3H).

test case

The compounds prepared in Examples 2, 4, 5, 11 and 13 were subjected to an inhibition experiment on the Keap1-Nrf2 protein-protein interaction. The experimental method was:

FITC-βAla-DEETGEF-OH was used as a fluorescent probe to determine the binding affinity, and the equilibrium dissociation constant KD2 of each compound was determined using a fluorescence anisotropy assay. Add a 2-fold serial dilution of the sample (20 μL) with a mass concentration of 1% DMSO to 60 μL of the fluorescent probe solution (10 nM final concentration), and then add 400 nM Keap1 protein containing buffer. The above buffer is 10 mM HEPES. +3.4mM EDTA+150mM NaCl+0.005% Tween-20, pH=7.4. After incubating at room temperature for 60 minutes, set the excitation wavelength of the SpectraMax M5 microplate reader to 485nm and the emission wavelength to 535nm, and measure the equilibrium dissociation constant K _D2 ;

Table 1 Inhibitory activity data of compounds prepared in Examples 2, 4, 5, 11 and 13 on Keap1-Nrf2 protein-protein interaction

serial number K ₂ Example 2 +++ Example 4 ++ Example 5 + Example 11 ++ Example 13 +

Note: The measured equilibrium dissociation constant is 10nM<K _D2 <10μM, as shown in the table below, 10nM<K _D2 <100nM(+++), 100nM<K _D2 <1μM(++), 1μM<K _D2 <10μM( +);

As can be seen from Table 1, the 5-(3-(sulfonylamino)phenyl)-1H-pyrrole-2-carboxylic acid derivative prepared in the present invention exhibits high inhibitory activity on the Keap1-Nrf2 protein-protein interaction. Among them, the inhibitory activity K _D2 of Example 2 is less than 100 nM.

In summary, the present invention provides a class of 5-(3-(sulfonylamino)phenyl)-1H-pyrrole-2-carboxylic acid derivatives with good activity and novel structure as small molecule inhibitors of Keap1-Nrf2 protein-protein interaction. The agent can interfere with the Keap1-Nrf2 interaction, activate Nrf2 and downstream factors, thereby reducing inflammatory damage. It has potential anti-inflammatory activity and can be used to prepare anti-inflammatory drugs for inflammatory damage in many inflammation-related diseases.

The above are only preferred embodiments of the present invention. It should be pointed out that those of ordinary skill in the art can also make several improvements and modifications without departing from the principles of the present invention. These improvements and modifications can It should also be regarded as the protection scope of the present invention.

Claims (8)

1. A 5- (3- (sulfonylamino) phenyl) -1H-pyrrole-2-carboxylic acid derivative characterized by the following structure:

2. a process for the preparation of 5- (3- (sulfonylamino) phenyl) -1H-pyrrole-2-carboxylic acid derivatives according to claim 1, characterised in that it comprises the following steps:

mixing a structural compound shown in a formula II, N-bromosuccinimide and a first organic solvent, and performing bromination reaction to obtain a structural compound shown in a formula III;

mixing a structural compound shown in a formula III, naH, a first bromo-compound and a second organic solvent, and performing a first substitution reaction to obtain a structural compound shown in a formula IV; the first bromide is bromoethane, 3-bromoprop-1-ene, 1-bromobutane, 1-bromo-2-fluoroethane or (2- (bromomethoxy) ethyl) trimethylsilane;

mixing the compound with the structure shown in the formula IV, 3-nitrophenylboric acid, cesium carbonate, a catalyst, a third organic solvent and water, and performing a coupling reaction to obtain a compound with the structure shown in the formula V;

mixing the structural compound shown in the formula V, iron powder, ammonium chloride, a fourth organic solvent and water, and carrying out a reduction reaction to obtain a structural compound shown in the formula VI;

Mixing the compound with the structure shown in the formula VI, 3-methoxy benzene sulfonyl chloride and a fifth organic solvent, and performing a second substitution reaction to obtain a compound with the structure shown in the formula VII;

mixing the compound with the structure shown in the formula VII, potassium carbonate, potassium iodide, ethyl bromoacetate and a sixth organic solvent, performing a third substitution reaction, and performing hydrolysis reaction under alkaline conditions to obtain the 5- (3- (sulfonamido) phenyl) -1H-pyrrole-2-carboxylic acid derivative;

wherein R is ₁ Is that

X is。

3. The preparation method according to claim 2, wherein the molar ratio of the compound having the structure shown in formula II to N-bromosuccinimide is 1 (1.0-1.5);

the bromination reaction temperature is 0-60 ℃ and the time is 5-10 h;

the mol ratio of the structural compound shown in the formula III to the first bromo compound is 1 (1.0-1.5);

the temperature of the first substitution reaction is 0-60 ℃ and the time is 1-5 h.

4. The preparation method according to claim 2, wherein the molar ratio of the compound having the structure represented by formula iv to 3-nitrophenylboronic acid is 1: (1.0-2.0);

the temperature of the coupling reaction is 60-90 ℃ and the time is 1-5 h;

The mol ratio of the compound with the structure shown in the formula V to the iron powder is 1 (1-10);

the temperature of the reduction reaction is 25-80 ℃ and the time is 1-5 h.

5. The preparation method according to claim 2, wherein the molar ratio of the compound having the structure represented by formula VI to 3-methoxypresent sulfonyl chloride is 1 (1.0 to 1.5);

the temperature of the second substitution reaction is 0-25 ℃ and the time is 1-5 h.

6. The preparation method according to claim 2, wherein the molar ratio of the compound having the structure represented by formula vii to ethyl bromoacetate is 1: (1.0 to 1.5);

the temperature of the third substitution reaction is 0-60 ℃ and the time is 1-24 h.

7. A pharmaceutically acceptable salt of the 5- (3- (sulfonylamino) phenyl) -1H-pyrrole-2-carboxylic acid derivative according to claim 1.

8. Use of a 5- (3- (sulfonylamino) phenyl) -1H-pyrrole-2-carboxylic acid derivative according to claim 1 or a 5- (3- (sulfonylamino) phenyl) -1H-pyrrole-2-carboxylic acid derivative according to claim 7 in the preparation of a Keap1-Nrf2 protein-protein interaction inhibitor or in the preparation of a medicament for the treatment or alleviation of inflammation of a disease.