CN111269167A - N-acyl sulfonamide salt FBPase inhibitor, preparation method, pharmaceutical composition and application thereof - Google Patents

Abstract

The present invention relates to N-acylsulfonamide salt compounds shown in formula I as FBPase inhibitors, and a preparation method thereof, a composition containing one or more such compounds, and the compounds used as medicines for the treatment of FBPase-related Diseases, and use in the preparation, prevention and/or treatment of diabetes.

Description

N-acylsulfonamide salt FBPase inhibitor, its preparation method, pharmaceutical composition and use

technical field

The present invention relates to N-acylsulfonamide salts FBPase inhibitors represented by formula I, a preparation method thereof, a composition containing one or more such compounds, and such compounds in inhibiting FBPase and treating FBPase-related diseases, And the use in the preparation, prevention and/or treatment of diabetes medicine.

Background technique

Diabetes mellitus is a chronic metabolic disease regulated by multiple genes, mainly manifested as persistent hyperglycemia and glucosuria. Sustained hyperglycemia can lead to many complications, such as retinal, renal, neurological and vascular complications. The incidence of diabetes in China is increasing rapidly. It is estimated that there are more than 92 million people with diabetes in China, and about 148 million people are at high risk of diabetes (New. Engl. J. Med., 2010, 362: 1090-1101).

Diabetes is divided into two types, insulin-dependent (type I) and non-insulin-dependent (type II), among which type II diabetes patients account for 90% to 95% of the total number of diabetic patients. Biological studies have shown that the main pathological basis leading to diabetes is insufficient insulin secretion, insulin resistance and increased hepatic glucose production. At present, there are two main types of drugs in clinical application: one is for insufficient insulin secretion, such as: sulfonylureas and glinides insulin secretagogues; the other is to improve insulin resistance, such as thiazolidinediones insulin sensitizers . So far, no antidiabetic drugs that reduce endogenous glucose production have been used clinically. Metformin reduces hepatic glucose output, but the molecular targets of action are unclear.

Studies have shown that increased endogenous glucose production is the main cause of elevated fasting blood glucose in diabetic patients. Endogenous glucose mainly comes from the liver. The liver produces glucose in two ways, one is endogenous synthesis of glucose, namely gluconeogenesis; the other is hepatic glycogenolysis (glycogenolysis). Therefore, reducing endogenous glucose production by regulating the gluconeogenesis pathway is a potential new strategy for the development of antidiabetic drugs with new mechanisms of action.

Gluconeogenesis is the process of converting three-carbon precursors such as lactic acid, glycine and glycerol into glucose under the catalysis of various enzymes. During gluconeogenesis, fructose-1,6-bisphosphatase (FBPase) catalyzes the conversion of fructose-1,6-bisphosphate to fructose-6-phosphate and releases a Molecular phosphoric acid. This catalytic reaction is one of the rate-controlling steps of endogenous glucose generation, and inhibiting the activity of FBPase can reduce endogenous glucose generation and blood sugar levels. Therefore, FBPase inhibitors may become anti-diabetic drugs with new mechanisms of action, especially in reducing fasting blood glucose levels, with more significant significance.

So far, many researchers have carried out research on FBPase inhibitors, and reported various structural types of FBPase inhibitors. In 2003, Pfizer Pharmaceuticals obtained indole carboxylic acid compounds through high-throughput screening, and the IC ₅₀ value of FBPase inhibitory activity was at the micromolar level (Bioorg.Med.Chem.Lett., 2003,13:2055-2058) . In 2006, von Geldern et al. reported benzoxazole-2-benzenesulfonamide compounds with _IC50 values of inhibitory activity against FBPase at the ^10-6-10-7 molar level ( ^{Bioorg.Med.Chem.Lett} ., 2006, 16:1811-1815). In 2010, Roche Pharmaceuticals reported the discovery of thiazole-substituted sulfonylurea FBPase inhibitors by high-throughput screening, and their inhibitory activity _IC50 values were at the ^10-7-10-8 molar level ( ^{Bioorg.Med.Chem.Lett} ). ., 2010, 20:594-599). From 2007 to 2010, Metbasis Pharmaceuticals reported the use of structure-based drug molecular design strategies to discover AMP analogs and search for FBPase inhibitors. After continuous structure optimization, they obtained benzimidazole FBPase inhibitors (J.Am.Chem. . Soc., 2007, 129: 15480-15490; J. Med. Chem., 2010, 53: 441-451) and thiazole FBPase inhibitors (J. Am. Chem. Soc., 2007, 129: 15491-15502 ; J.Med.Chem., 2011,54:153-165), MB07803 is a phosphodiamide prodrug of thiazole compounds, which is currently in phase II clinical research (US, 225259A1[P].2007-09-27. ).

The present invention designs and synthesizes N-acylsulfonamide salt compounds as FBPase inhibitors, which lays a structural foundation for obtaining FBPase inhibitors with good pharmacokinetic properties and oral administration. The sulfonamide salt compounds of this patent application have higher solubility, in vivo exposure and oral bioavailability than the prototype compounds. The present invention aims to find a novel anti-diabetic drug with strong anti-diabetic activity, good pharmacokinetic properties and effective oral administration.

SUMMARY OF THE INVENTION

The technical problem to be solved by the present invention is to provide N-acylsulfonamide salt derivatives represented by formula I, its preparation method, pharmaceutical composition, its preparation of FBPase inhibitor and its potential medicinal use, and its preparation of anti-diabetic drugs use in.

In order to solve the technical problem of the present invention, the present invention provides the following technical solutions:

The first aspect of the technical solution of the present invention is to provide the N-acylsulfonamide salt derivatives shown in general formula I:

In formula I,

R is selected from the following atoms or groups, including

H, F, Cl, Br, CN, CF ₃ , OCH ₃ , NO ₂ ;

Ar ₁ is selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight or branched chain alkane Alkyl, halogen-substituted C1-4 straight or branched chain alkyl, F, Cl, Br, NO ₂ , CN, methylenedioxy, ORa' ₁ , SRa' ₂ , NRa' ₃ Rb' ₁ , COORa' ₄ , CONRa′ ₅ Rb′ ₂ , NRa′ ₆ COORb′ ₃ , SO ₂ NRa′ ₇ Rb′ ₄ , NRa′ ₈ CORb′ ₅ , (CH ₂ )nNRa′ ₉ Rb′ ₆ , (CH ₂ )nORa′ ₁₀ , wherein the Ra′ ₁ , Ra′ ₂ , Ra′ ₃ , Rb′ ₁ , Ra′ ₄ , Ra′ ₅ , Rb′ ₂ , Ra′ ₆ , Rb′ ₃ , Ra′ ₇ , Rb′ ₄ , Ra ' ₈ , Rb' ₅ , Ra' ₉ , Rb' ₆ , Ra' ₁₀ are independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclo Amyl; the benzene ring, nitrogen-containing six-membered aromatic heterocycle, and five-membered aromatic heterocycle may be mono-substituted or multi-substituted; the six-membered aromatic heterocycle may contain 1 N atom, or multiple A nitrogen atom; the five-membered aromatic heterocycle may contain one heteroatom or multiple heteroatoms, the heteroatoms are selected from O, N, S; n is selected from 1, 2, 3; wherein the halogen includes F, Cl, Br.

Ar ₂ is selected from the following groups or structural fragments:

(1) Substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight chain or branched Alkyl, halogen substituted C1-4 straight or branched alkyl, F, Cl, Br, NO ₂ , CN, methylenedioxy, ORs ₁ , SRs ₂ , NRs ₃ Rt ₁ , NRs ₄ CORt ₂ , COORs ₅ , CONRs ₆ Rt ₃ , NRs ₇ COORt ₄ , SO ₂ NRs ₈ Rt ₅ , (CH ₂ )nNRs ₉ Rt ₆ , (CH ₂ )nORs ₁₀ , wherein the Rs ₁ , Rs ₂ , Rs ₃ , Rt ₁ , Rs ₄ , Rt ₂ , Rs ₅ , Rs ₆ , Rt ₃ , Rs ₇ , Rt ₄ , Rs ₈ , Rt ₅ , Rs ₉ , Rt ₆ , Rs ₁₀ are independently selected from H, C1-4 linear or Branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; benzene ring, nitrogen-containing six-membered aromatic heterocycle and five-membered aromatic heterocycle can be mono-substituted or multi-substituted ; The six-membered aromatic heterocycle may contain one N atom or multiple nitrogen atoms; the five-membered aromatic heterocycle may contain one heteroatom or multiple heteroatoms, and the heteroatoms are selected from O, N, S; n is selected from 1,2,3; wherein said halogen includes F, Cl, Br;

(2) Substituted or unsubstituted aromatic fused rings or fused heterocycles, substituted or unsubstituted non-aromatic fused rings or fused heterocycles, including substituted or unsubstituted naphthalene rings, substituted or unsubstituted benzos Six-membered heterocycle, substituted or unsubstituted benzofive-membered heterocycle, wherein the substituent is selected from C1-4 straight or branched chain alkyl, halogen substituted C1-4 straight or branched chain alkyl, F, Cl, Br, NO ₂ , CN, Methylenedioxy, ORs ₁ , SRs ₂ , NRs ₃ Rt ₁ , NRs ₄ CORt ₂ , COORs ₅ , CONRs ₆ Rt ₃ , NRs ₇ COORt ₄ , SO ₂ NRs ₈ Rt ₅ , (CH ₂ )nNRs ₉ Rt ₆ , (CH ₂ )nORs ₁₀ , wherein said Rs ₁ , Rs ₂ , Rs ₃ , Rt ₁ , Rs ₄ , Rt ₂ , Rs ₅ , Rs ₆ , Rt ₃ , Rs ₇ , Rt ₄ , Rs ₈ , Rt ₅ , Rs ₉ , Rt ₆ , Rs ₁₀ are independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl , cyclopentyl; wherein said naphthalene ring, benzos six-membered heterocycle or benzos five-membered heterocycle can be mono-substituted or multi-substituted; benzos six-membered heterocycle or benzos five-membered heterocycle It may contain one heteroatom or multiple heteroatoms, and the heteroatom is selected from O, N, S; n is selected from 1, 2, 3; wherein the halogen includes F, Cl, and Br.

M is independently selected from different alkali metals (lithium, sodium, potassium, cesium) or alkaline earth metal salts (calcium, magnesium, barium).

R is preferably selected from Cl, _NO2 .

According to the general formula I of the present invention, the preferred compounds of the present invention include but are not limited to compounds represented by the general formula (I-A):

Ar ₁ is selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight or branched chain alkane Alkyl, halogen-substituted C1-4 straight or branched chain alkyl, F, Cl, Br, NO ₂ , CN, methylenedioxy, ORa' ₁ , SRa' ₂ , NRa' ₃ Rb' ₁ , COORa' ₄ , CONRa′ ₅ Rb′ ₂ , NRa′ ₆ COORb′ ₃ , SO ₂ NRa′ ₇ Rb′ ₄ , NRa′ ₈ CORb′ ₅ , (CH ₂ )nNRa′ ₉ Rb′ ₆ , (CH ₂ )nORa′ ₁₀ , wherein the Ra′ ₁ , Ra′ ₂ , Ra′ ₃ , Rb′ ₁ , Ra′ ₄ , Ra′ ₅ , Rb′ ₂ , Ra′ ₆ , Rb′ ₃ , Ra′ ₇ , Rb′ ₄ , Ra ' ₈ , Rb' ₅ , Ra' ₉ , Rb' ₆ , Ra' ₁₀ are independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclo Amyl; the benzene ring, nitrogen-containing six-membered aromatic heterocycle, and five-membered aromatic heterocycle may be mono-substituted or multi-substituted; the six-membered aromatic heterocycle may contain 1 N atom, or multiple A nitrogen atom; the five-membered aromatic heterocycle may contain one heteroatom or multiple heteroatoms, the heteroatoms are selected from O, N, S; n is selected from 1, 2, 3; wherein the halogen includes F, Cl, Br.

Ar ₂ is selected from the following groups or structural fragments:

(1) Substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight chain or branched Alkyl, halogen substituted C1-4 straight or branched alkyl, F, Cl, Br, NO ₂ , CN, methylenedioxy, ORs ₁ , SRs ₂ , NRs ₃ Rt ₁ , NRs ₄ CORt ₂ , COORs ₅ , CONRs ₆ Rt ₃ , NRs ₇ COORt ₄ , SO ₂ NRs ₈ Rt ₅ , (CH ₂ )nNRs ₉ Rt ₆ , (CH ₂ )nORs ₁₀ , wherein the Rs ₁ , Rs ₂ , Rs ₃ , Rt ₁ , Rs ₄ , Rt ₂ , Rs ₅ , Rs ₆ , Rt ₃ , Rs ₇ , Rt ₄ , Rs ₈ , Rt ₅ , Rs ₉ , Rt ₆ , Rs ₁₀ are independently selected from H, C1-4 linear or Branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; benzene ring, nitrogen-containing six-membered aromatic heterocycle and five-membered aromatic heterocycle can be mono-substituted or multi-substituted ; The six-membered aromatic heterocycle may contain one N atom or multiple nitrogen atoms; the five-membered aromatic heterocycle may contain one heteroatom or multiple heteroatoms, and the heteroatoms are selected from O, N, S; n is selected from 1,2,3; wherein said halogen includes F, Cl, Br;

(2) Substituted or unsubstituted aromatic fused rings or fused heterocycles, substituted or unsubstituted non-aromatic fused rings or fused heterocycles, including substituted or unsubstituted naphthalene rings, substituted or unsubstituted benzos Six-membered heterocycle, substituted or unsubstituted benzofive-membered heterocycle, wherein the substituent is selected from C1-4 straight or branched chain alkyl, halogen substituted C1-4 straight or branched chain alkyl, F, Cl, Br, NO ₂ , CN, Methylenedioxy, ORs ₁ , SRs ₂ , NRs ₃ Rt ₁ , NRs ₄ CORt ₂ , COORs ₅ , CONRs ₆ Rt ₃ , NRs ₇ COORt ₄ , SO ₂ NRs ₈ Rt ₅ , (CH ₂ )nNRs ₉ Rt ₆ , (CH ₂ )nORs ₁₀ , wherein said Rs ₁ , Rs ₂ , Rs ₃ , Rt ₁ , Rs ₄ , Rt ₂ , Rs ₅ , Rs ₆ , Rt ₃ , Rs ₇ , Rt ₄ , Rs ₈ , Rt ₅ , Rs ₉ , Rt ₆ , Rs ₁₀ are independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl , cyclopentyl; wherein said naphthalene ring, benzos six-membered heterocycle or benzos five-membered heterocycle can be mono-substituted or multi-substituted; benzos six-membered heterocycle or benzos five-membered heterocycle It may contain one heteroatom or multiple heteroatoms, and the heteroatom is selected from O, N, S; n is selected from 1, 2, 3; wherein the halogen includes F, Cl, and Br.

M is independently selected from different alkali metals (lithium, sodium, potassium, cesium) or alkaline earth metal salts (calcium, magnesium, barium).

According to the general formula I-A of the present invention, the preferred compounds of the present invention include but are not limited to compounds represented by the general formula (I-A-a):

R _A can be mono-substituted or poly-substituted;

R _A can be independently selected from the following groups or structural fragments:

C1-4 linear or branched alkyl, halogen-substituted C1-4 linear or branched alkyl, F, Cl, Br, NO ₂ , CN, methylenedioxy, ORa′ ₁ , SRa′ ₂ , NRa′ ₃ Rb′ ₁ , COORa′ ₄ , CONRa′ ₅ Rb′ ₂ , NRa′ ₆ COORb′ ₃ , SO ₂ NRa′ ₇ Rb′ ₄ , NRa′ ₈ CORb′ ₅ , (CH ₂ )nNRa′ ₉ Rb′ _6. (CH ₂ )nORa′ ₁₀ , wherein said Ra′ ₁ , Ra′ ₂ , Ra′ ₃ , Rb′ ₁ , Ra′ ₄ , Ra′ ₅ , Rb′ ₂ , Ra′ ₆ , Rb′ ₃ , Ra' ₇ , Rb' ₄ , Ra' ₈ , Rb' ₅ , Ra' ₉ , Rb' ₆ , Ra' ₁₀ are independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropyl Methylene, cyclobutyl, cyclopentyl;

Ar ₂ is selected from the following groups or structural fragments:

(1) Substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight chain or branched Alkyl, halogen substituted C1-4 straight or branched alkyl, F, Cl, Br, NO ₂ , CN, methylenedioxy, ORs ₁ , SRs ₂ , NRs ₃ Rt ₁ , NRs ₄ CORt ₂ , COORs ₅ , CONRs ₆ Rt ₃ , NRs ₇ COORt ₄ , SO ₂ NRs ₈ Rt ₅ , (CH ₂ )nNRs ₉ Rt ₆ , (CH ₂ )nORs ₁₀ , wherein the Rs ₁ , Rs ₂ , Rs ₃ , Rt ₁ , Rs ₄ , Rt ₂ , Rs ₅ , Rs ₆ , Rt ₃ , Rs ₇ , Rt ₄ , Rs ₈ , Rt ₅ , Rs ₉ , Rt ₆ , Rs ₁₀ are independently selected from H, C1-4 linear or Branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; benzene ring, nitrogen-containing six-membered aromatic heterocycle and five-membered aromatic heterocycle can be mono-substituted or multi-substituted ; The six-membered aromatic heterocycle may contain one N atom or multiple nitrogen atoms; the five-membered aromatic heterocycle may contain one heteroatom or multiple heteroatoms, and the heteroatoms are selected from O, N, S; n is selected from 1,2,3; wherein said halogen includes F, Cl, Br;

(2) Substituted or unsubstituted aromatic fused rings or fused heterocycles, substituted or unsubstituted non-aromatic fused rings or fused heterocycles, including substituted or unsubstituted naphthalene rings, substituted or unsubstituted benzos Six-membered heterocycle, substituted or unsubstituted benzofive-membered heterocycle, wherein the substituent is selected from C1-4 straight or branched chain alkyl, halogen substituted C1-4 straight or branched chain alkyl, F, Cl, Br, NO ₂ , CN, Methylenedioxy, ORs ₁ , SRs ₂ , NRs ₃ Rt ₁ , NRs ₄ CORt ₂ , COORs ₅ , CONRs ₆ Rt ₃ , NRs ₇ COORt ₄ , SO ₂ NRs ₈ Rt ₅ , (CH ₂ )nNRs ₉ Rt ₆ , (CH ₂ )nORs ₁₀ , wherein said Rs ₁ , Rs ₂ , Rs ₃ , Rt ₁ , Rs ₄ , Rt ₂ , Rs ₅ , Rs ₆ , Rt ₃ , Rs ₇ , Rt ₄ , Rs ₈ , Rt ₅ , Rs ₉ , Rt ₆ , Rs ₁₀ are independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl , cyclopentyl; wherein said naphthalene ring, benzos six-membered heterocycle or benzos five-membered heterocycle can be mono-substituted or multi-substituted; benzos six-membered heterocycle or benzos five-membered heterocycle It may contain one heteroatom or multiple heteroatoms, and the heteroatom is selected from O, N, S; n is selected from 1, 2, 3; wherein the halogen includes F, Cl, and Br.

M is independently selected from different alkali metals (lithium, sodium, potassium, cesium) or alkaline earth metal salts (calcium, magnesium, barium).

According to the general formula I-A of the present invention, the preferred compounds of the present invention include but are not limited to compounds represented by the general formula (I-A-b):

R _B can be mono-substituted or poly-substituted;

R _B can be independently selected from the following groups or structural fragments:

C1-4 linear or branched alkyl, halogen-substituted C1-4 linear or branched alkyl, F, Cl, Br, NO ₂ , CN, methylenedioxy, ORa′ ₁ , SRa′ ₂ , NRa′ ₃ Rb′ ₁ , COORa′ ₄ , CONRa′ ₅ Rb′ ₂ , NRa′ ₆ COORb′ ₃ , SO ₂ NRa′ ₇ Rb′ ₄ , NRa′ ₈ CORb′ ₅ , (CH ₂ )nNRa′ ₉ Rb′ _6. (CH ₂ )nORa′ ₁₀ , wherein said Ra′ ₁ , Ra′ ₂ , Ra′ ₃ , Rb′ ₁ , Ra′ ₄ , Ra′ ₅ , Rb′ ₂ , Ra′ ₆ , Rb′ ₃ , Ra' ₇ , Rb' ₄ , Ra' ₈ , Rb' ₅ , Ra' ₉ , Rb' ₆ , Ra' ₁₀ are independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropyl Methylene, cyclobutyl, cyclopentyl;

Ar ₁ is selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight or branched chain alkane Alkyl, halogen-substituted C1-4 straight or branched chain alkyl, F, Cl, Br, NO ₂ , CN, methylenedioxy, ORa' ₁ , SRa' ₂ , NRa' ₃ Rb' ₁ , COORa' ₄ , CONRa′ ₅ Rb′ ₂ , NRa′ ₆ COORb′ ₃ , SO ₂ NRa′ ₇ Rb′ ₄ , NRa′ ₈ CORb′ ₅ , (CH ₂ )nNRa′ ₉ Rb′ ₆ , (CH ₂ )nORa′ ₁₀ , wherein the Ra′ ₁ , Ra′ ₂ , Ra′ ₃ , Rb′ ₁ , Ra′ ₄ , Ra′ ₅ , Rb′ ₂ , Ra′ ₆ , Rb′ ₃ , Ra′ ₇ , Rb′ ₄ , Ra ' ₈ , Rb' ₅ , Ra' ₉ , Rb' ₆ , Ra' ₁₀ are independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclo Amyl; the benzene ring, nitrogen-containing six-membered aromatic heterocycle, and five-membered aromatic heterocycle may be mono-substituted or multi-substituted; the six-membered aromatic heterocycle may contain 1 N atom, or multiple A nitrogen atom; the five-membered aromatic heterocycle may contain one heteroatom or multiple heteroatoms, the heteroatoms are selected from O, N, S; n is selected from 1, 2, 3; wherein the halogen includes F, Cl, Br.

M is independently selected from different alkali metals (lithium, sodium, potassium, cesium) or alkaline earth metal salts (calcium, magnesium, barium).

For the purposes of the present invention, preferred compounds include, but are not limited to:

The second aspect of the technical solution of the present invention provides the preparation method of the compound described in the first aspect, and the adopted technical solution comprises the following steps:

In the ethanol solution of sodium alkoxide, 5-R-substituted o-bromobenzaldehyde is condensed with ethyl azide to obtain compound 1. Compound 1 uses o-dichlorobenzene as a solvent and undergoes ring closure at 180 °C to obtain 7- R-substituted ethyl 4-bromo-1-H-indole-2-carboxylate (compound 2), then methylated at the indole-1-position in the presence of cesium carbonate to give 7-R -Substituted ethyl 4-bromo-1-methyl-indole-2-carboxylate (compound 3); then compound 3 undergoes a coupling reaction with an aryl bromide under palladium catalysis to give compound 4, which is hydrolyzed Afterwards, the corresponding compound 5 whose 2-position is a carboxyl group is obtained. Compound 5 undergoes condensation reaction with arylmethanesulfonamide to obtain compound 6, and finally undergoes acid-base reaction with different bases to obtain N-acylsulfonamide salt compounds.

Reagents and reaction conditions: (a) ethyl azide, ethyl trifluoroacetate, sodium, ethanol, -15°C to 0°C; (b) o-dichlorobenzene, 180°C; (c) methyl iodide, cesium carbonate , DMF, rt; (c) Ar ₁ -Br, Pd ₂ (dba) ₃ , Xantphos, sodium carbonate, toluene, water, 100°C; (d) sodium hydroxide, THF, ethanol, water, rt; (e) Ar ₂ -S(O) ₂ -OH, HATU, DMAP, Et ₃ N, rt; (g) alkali metal or alkaline earth metal base, water, 80°C;

The definitions of R, Ar ₁ , Ar ₂ and M described therein are the same as those of the compounds described in the first aspect of the present invention.

The third aspect of the technical solution of the present invention is to provide a pharmaceutical composition, the pharmaceutical composition comprising the compound described in the first aspect of the technical solution of the present invention and a commonly used pharmaceutical carrier.

The present invention also provides a pharmaceutical composition using the compound of the present invention as an active ingredient, the composition comprising at least one compound of the present invention and a pharmaceutically acceptable carrier. The pharmaceutical composition is selected from tablets, capsules, pills, injections, sustained-release preparations, controlled-release preparations or various microparticle drug delivery systems. The pharmaceutical composition can be prepared according to methods known in the art. Any dosage form suitable for human or animal use can be prepared by combining the compounds of the present invention with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The content of the compound of the present invention in its pharmaceutical composition is usually 0.1-95% by weight.

The compound of the present invention or the pharmaceutical composition containing it can be administered in unit dosage form, and the route of administration can be enteral or parenteral, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eye, lung and Respiratory tract, skin, vagina, rectum, etc.

The dosage form for administration can be a liquid dosage form, a solid dosage form or a semi-solid dosage form. Liquid dosage forms can be solutions (including true solutions and colloidal solutions), emulsions (including o/w, w/o and double emulsion), suspensions, injections (including water injection, powder injection and infusion), eye drops solid dosage forms can be tablets (including ordinary tablets, enteric-coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules ( Including hard capsules, soft capsules, enteric-coated capsules), granules, powders, pellets, drop pills, suppositories, films, patches, gas (powder) aerosols, sprays, etc.; semi-solid dosage forms can be ointments, Gels, pastes, etc.

The compounds of the present invention can be prepared into common preparations, sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle drug delivery systems.

These formulations are prepared according to methods well known to those skilled in the art. The adjuvants used in the manufacture of tablets, capsules, and coatings are conventional adjuvants, such as starch, gelatin, acacia, silica, polyethylene glycol, and solvents for liquid dosage forms such as water, ethanol, propylene glycol, and vegetable oils. Such as corn oil, peanut oil, olive oil, etc. Other adjuvants, such as surfactants, lubricants, disintegrating agents, preservatives, flavoring agents, pigments, etc., may also be present in the formulations containing the compounds of the present invention.

In order to formulate the compounds of the present invention into tablets, various excipients well known in the art can be widely used, including diluents, binders, wetting agents, disintegrating agents, lubricants, glidants. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; Propanol, etc.; the binder can be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, acacia mucilage, gelatin slurry, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose Base cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; disintegrants can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polymer Vinylpyrrolidone, croscarmellose sodium, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfonate, etc.; lubricants and flow aids The agent may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol and the like.

The tablets can also be further prepared as coated tablets, such as sugar-coated, film-coated, enteric-coated, or bilayer and multi-layer tablets.

In order to make the dosage unit into capsules, the active ingredients of the compounds of the present invention can be mixed with diluents and glidants, and the mixture can be directly placed in hard capsules or soft capsules. The compound of the present invention can also be made into granules or pellets with diluents, binders and disintegrating agents, and then placed in hard capsules or soft capsules. The various diluents, binders, wetting agents, disintegrants, and glidants used to prepare tablets of the compounds of the present invention can also be used to prepare capsules of the compounds of the present invention.

To prepare the compounds of the present invention into injections, water, ethanol, isopropanol, propylene glycol or their mixtures can be used as solvents and appropriate amount of solubilizers, cosolvents, pH adjusters and osmotic pressure adjusters commonly used in the art can be added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin, etc.; the pH adjuster can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure adjuster can be It is sodium chloride, mannitol, glucose, phosphate, acetate, etc. For example, in the preparation of freeze-dried powder injection, mannitol, glucose, etc. can also be added as proppant.

In addition, colorants, preservatives, fragrances, flavors, or other additives can also be added to the pharmaceutical preparations, if desired.

In order to achieve the purpose of medication and enhance the therapeutic effect, the medicament or pharmaceutical composition of the present invention can be administered by any known administration method.

The dosage of the pharmaceutical composition of the compound of the present invention may vary widely according to the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration and the dosage form. In general, a suitable daily dosage range of the compounds of the present invention is 0.01-500 mg/Kg body weight, preferably 0.1-300 mg/Kg body weight. The above doses may be administered in a single dosage unit or divided into several dosage units, depending on the clinical experience of the physician and the dosing regimen including the use of other therapeutic means.

The compounds or compositions of the present invention may be administered alone or in combination with other therapeutic or symptomatic drugs. When the compound of the present invention has a synergistic effect with other therapeutic drugs, its dosage should be adjusted according to the actual situation.

The fourth aspect of the technical solution of the present invention provides the application of the compound described in the first aspect of the present invention in the preparation of FBPase inhibitors and in the preparation of drugs for preventing and/or treating diseases and disorders related to FBPase. The application is characterized in that the diseases and conditions related to FBPase are selected from diabetes, chronic complications of diabetes and obesity. The diabetes is selected from type I diabetes and type II diabetes; the chronic complications of diabetes are selected from retinal, renal, neurological and vascular complications, ischemic heart disease or atherosclerosis.

Detailed ways

The invention will be further described below with reference to the examples, but the scope of the invention is not limited.

The structures of the compounds were determined by nuclear magnetic resonance (NMR) or high resolution mass spectrometry (HRMS). NMR was measured using Varian mercury 300 or Varian mercury 400, the measurement solvent was CDCl ₃ , DMSO-d ₆ , acetone-d ₆ , CD ₃ OD, the internal standard was TMS, and chemical shifts were given in ppm. Ms was measured with a Thermo Exactive Plus mass spectrometer. mp is the melting point given in °C, temperature uncorrected. Silica gel column chromatography generally uses 200-300 mesh silica gel as a carrier.

The reagents used in the experiments were chemically or analytically pure. All solvents used are of analytical grade, and the anhydrous solvents used are obtained from a solvent purification system produced by INNOVATIVE TECHNOLOGY in the United States, and other solvents are untreated unless otherwise specified.

List of abbreviations:

TLC: Thin Layer Chromatography DMAP: 4-Dimethylaminopyridine

CDCl ₃ : deuterated chloroform DMSO-d ₆ : deuterated dimethyl sulfoxide

acetone-d ₆ : deuterated acetone CD ₃ OD : deuterated methanol

DMAP: 4-Dimethylaminopyridine Et ₃ N: Triethylamine

EA: Ethyl acetate

HATU: 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate

XantPhos: 4,5-Bisdiphenylphosphine-9,9-dimethylxanthene

Pd ₃ (dba) ₂ : tris(dibenzylideneacetone)dipalladium

min: minutes; h: hours

P/E: petroleum ether/ethyl acetate; D/M: dichloromethane/methanol

Preparation of intermediate: 1-methyl-7-chloro-4-bromo-1H-indole-2-carboxylic acid ethyl ester

a). Ethyl 2-azido-3-(5-chloro-2-bromophenyl)acrylate

Metal sodium (8.35 g, 363.2 mmol) was dissolved in absolute ethanol (200 mL). After the metal sodium was completely dissolved, the reaction solution was cooled to -15°C. 2-Bromo-5-chlorobenzaldehyde (50 g, 227 mmol), ethyl azide (44 g, 341 mmol) and ethyl trifluoroacetate (TFAE, 51.5 g, 363.2 mmol) were added to the reaction solution in batches, and in- The reaction was carried out at 15°C for 1 h, heated to -5°C for 1 h, heated to 0°C for 5 h, raised to room temperature and reacted overnight. The reaction solution was poured into saturated aqueous NH ₄ Cl solution, extracted with EA (150 mL×3), and combined The organic layer was washed with saturated sodium chloride solution (100 mL×2), dried over anhydrous magnesium sulfate, concentrated, passed through a reduced pressure column (DCM:PE=1:1), concentrated, and recrystallized with PE:EA=20:1 , 36.5 g of off-white solid was obtained, and the yield was 48.9%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.13 (s, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.15 (s, 2H), 4.40 (q, J=7.2 Hz, 2H ),1.42(t,J=7.2Hz,3H).

b). 7-Chloro-4-bromo-1H-indole-2-carboxylic acid ethyl ester

Place 2-azido-3-(5-chloro-2-bromophenyl) ethyl acrylate (15g) in a reaction flask, add o-dichlorobenzene (15mL), heat to 180°C for reaction, after 1h The reaction was stopped, cooled, and a solid was precipitated, which was filtered off with suction to obtain 7.2 g of a white solid with a yield of 52.7%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.11 (brs, 1H), 7.27 (d, J=8.4 Hz, 2H), 7.18 (d, J=8.0 Hz, 1H), 4.44 (q, J =7.2Hz,2H),1.44(t,J=7.2Hz,3H).

c) 1-Methyl-7-chloro-4-bromo-1H-indole-2-carboxylic acid ethyl ester

7-Chloro-4-bromo-1H-indole-2-carboxylic acid ethyl ester (26.2 g, 86.24 mmol) was placed in a reaction flask, DMF (300 mL) was added, cesium carbonate (55.9 g, 172.58 mmol) and iodine were added Methane (24.7 g, 132.58 mmol) was stirred for reaction at room temperature, the reaction was stopped after 1 h, the reaction solution was poured into ice water, a solid was precipitated, and suction filtered to obtain 26 g of off-white solid with a yield of 94.8%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.32 (s, 1H), 7.19 (d, J=8.0 Hz, 1H), 7.13 (d, J=8.0 Hz, 1H), 4.46 (s, 3H) ), 4.39(q, J=7.2Hz, 2H), 1.43(t, J=7.2Hz, 3H).

Example 1 1-methyl-4-((3-methoxyphenyl)amino)-7-chloro-N-(4-methoxybenzenesulfonyl)-1H-indole-2-carboxamide sodium Salt

a).1-Methyl-4-((3-methoxyphenyl)amino)-7-chloro-1H-indole-2-carboxylic acid ethyl ester

1-Methyl-7-chloro-4-bromo-1H-indole-2-carboxylic acid ethyl ester (942 mg, 3 mmol) was dissolved in toluene (20 mL), and Pd ₂ (dba) ₃ ( 686mg, 0.75mmol), Xantphos (874mg, 0.5mmol), then Na ₂ CO ₃ (954mg, 9mmol) was dissolved in 5mL of water and the reaction solution was added, m-methoxyaniline (1mL, 9mmol) was added to the reaction flask, refluxed The reaction was carried out for 30h. Filtration, adding ethyl acetate to the filtrate, washing with dilute hydrochloric acid, washing with saturated sodium bicarbonate solution, drying over anhydrous magnesium sulfate, column chromatography (E:P=1:30) to obtain 610 mg of pale yellow solid, yield 56.8%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.30 (s, 1H), 7.20 (t, J=8.4 Hz, 1H), 7.15 (d, J=8.4 Hz, 1H), 6.88 (d, J =7.2Hz,1H),6.69(m,2H),6.53(d,J=6.8Hz,1H),4.47(s,3H),4.37(q,J=7.2Hz,2H),3.79(s,3H ),1.40(t,J=7.2Hz,3H).

b). 1-Methyl-4-((3-methoxyphenyl)amino)-7-chloro-1H-indole-2-carboxylic acid

1-Methyl-4-((3-methoxyphenyl)amino)-7-chloro-1H-indole-2-carboxylic acid ethyl ester (6.6 g, 18.4 mmol) was dissolved in THF (30 mL) and EtOH (30 mL) of the mixed solution, dissolve NaOH (2.21 g, 55.3 mmol) in 10 mL of water and add it to the reaction solution, react at 40 °C for 2 h, concentrate, add a small amount of water, extract with ether, and adjust the pH of the aqueous layer to 2 with dilute hydrochloric acid. -3, a solid was precipitated, filtered, and the filter cake was washed with water to obtain 6.0 g of a yellow-green solid with a yield of 98.6%.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 13.00 (s, 1H), 8.34 (s, 1H), 7.61 (s, 1H), 7.17 (t, J=8.0 Hz, 2H), 6.84 (d,J＝8.4Hz,1H),6.79(d,J＝8.0Hz,1H),6.75(s,1H),6.49(d,J＝8.0Hz,1H),4.35(s,3H),3.72 (s,3H).

c). 1-Methyl-4-((3-methoxyphenyl)amino)-7-chloro-N-(4-methoxybenzenesulfonyl)-1H-indole-2-carboxamide ( Compound P)

1-Methyl-4-((3-methoxyphenyl)amino)-7-chloro-1H-indole-2-carboxylic acid (13.56 g, 41.09 mmol) was dissolved in DCM (200 mL) and added sequentially HATU (23.42 g, 61.6 mmol), DMAP (2.51 g, 20.54 mmol) and Et ₃ N (17.8 mL, 123.27 mmol), after stirring, benzenesulfonamide (11.54 g, 61.6 mmol) was added, and the temperature was raised to 40° C. The reaction was carried out for 1 h, concentrated, ethyl acetate was added, washed with dilute hydrochloric acid, washed with water, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and recrystallized with ethyl acetate to obtain 10.3 g of a yellow powdery solid with a yield of 50%. .

¹ H NMR (500 MHz, DMSO-d ₆ ) δ (ppm): 8.31 (s, 1H), 7.99 (d, J=7.5 Hz, 2H), 7.24 (d, J=8.5 Hz, 1H), 7.22 (d ,J=7.5Hz,1H),7.18(d,J=7.5Hz,2H),7.06(d,J=7.5Hz,1H),6.90(d,J=7.5Hz,1H),6.87(s,1H) ), 6.56(d, J=7.0Hz, 1H), 4.24(s, 3H), 3.86(s, 3H), 3.75(s, 3H); HRMS(ESI): m/z, calcd.for C ₂₃ H ₂₂ N ₄ O ₅ ClS[M+H] ⁺ : 501.0999, found 501.0985.

d). Sodium 1-methyl-4-((3-methoxyphenyl)amino)-7-chloro-N-(4-methoxybenzenesulfonyl)-1H-indole-2-carboxamide Salt (Example 1)

1-Methyl-4-((3-methoxyphenyl)amino)-7-chloro-N-(4-methoxybenzenesulfonyl)-1H-indole-2-carboxamide (998 mg, 2 mmol), added H ₂ O (4 mL), dissolved NaOH (100 mg, 2.5 mmol) in 1 mL of water and added it to the reaction solution. After the addition was completed, the temperature was raised to 80 °C for 4 h to stop the reaction, cooled to room temperature, suction filtration, and filter cake. After washing with water, 868 mg of a khaki solid was obtained with a yield of 83%.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.20 (s, 1H), 7.78-7.77 (d, J=8.4 Hz, 2H), 7.76 (s, 1H), 7.14-7.10 (m, 1H),7.00-6.98(d,J=8.4Hz,1H),6.93-6.91(m,2H),6.79-6.41(m,3H),6.40-6.39(d,J=2.0Hz,1H),4.29 (s, 3H), 3.78(s, 3H), 3.71(s, 3H).

Example 2 Potassium 1-methyl-4-((3-methoxyphenyl)amino)-7-chloro-N-(4-methoxybenzenesulfonyl)-1H-indole-2-carboxamide Salt

1-Methyl-4-((3-methoxyphenyl)amino)-7-chloro-N-(4-methoxybenzenesulfonyl)-1H-indole-2-carboxamide (220 mg, 0.441 mmol), H ₂ O (1.5 mL) was added, KOH (25.2 mg, 0.4496 mmol) was dissolved in a small amount of water, added to the reaction flask, heated to 80° C., reacted for 1 h, the system became pale yellow and clear. The reaction was stopped, and after the water was spun off, a brownish yellow solid was obtained, which was recrystallized from ethanol to obtain 195 mg of a brownish yellow solid with a yield of 82.3%.

¹ H NMR (400MHz, DMSO-d ₆ )δ8.21(s,1H),7.78-7.76(d,J=8.8Hz,2H),7.24(s,1H),7.14-7.10(m,1H), 6.99-6.97(d,J=8.0Hz,1H),6.93-6.91(m,2H),6.79-6.41(m,3H),6.40-6.39(d,J=2.0Hz,1H),4.29(s, 3H), 3.78(s, 3H), 3.71(s, 3H).

Example 3 1-methyl-4-((3-methoxy-4-fluorophenyl)amino)-7-chloro-N-(4-methoxybenzenesulfonyl)-1H-indole-2 -formamide sodium salt

a).1-Methyl-4-((3-methoxyphenyl)amino)-7-chloro-1H-indole-2-carboxylic acid ethyl ester

1-Methyl-7-chloro-4-bromo-1H-indole-2-carboxylic acid ethyl ester (316 mg, 1 mmol) was dissolved in toluene (10 mL), and Pd ₂ (dba) ₃ ( 229 mg, 0.25 mmol), Xantphos (291 mg, 0.5 mmol), then Na ₂ CO ₃ (318 mg, 3 mmol) was dissolved in 2.5 mL of water and the reaction solution was added, and m-methoxyaniline (0.33 mL, 3 mmol) was added to the reaction flask , reflux reaction for 30h. Filtration, adding ethyl acetate to the filtrate, washing with dilute hydrochloric acid, washing with saturated sodium bicarbonate solution, drying over anhydrous magnesium sulfate, and crystallizing EA/diethyl ether to obtain 272 mg of pale yellow solid, 72.1%.

b). 1-Methyl-4-((3-methoxy-4-fluorophenyl)amino)-7-chloro-1H-indole-2-carboxylic acid

1-Methyl-4-((3-methoxy-4-fluorophenyl)amino)-7-chloro-1H-indole-2-carboxylic acid ethyl ester (200 mg, 0.53 mmol) was dissolved in THF/EtOH (1/2, v/v, 9 mL), add NaOH solution (105 mg, 2.65 mmol, 3 mL H ₂ O), react at room temperature overnight, after stopping the reaction, evaporate the solvent, add a small amount of water, and adjust the pH to 2 with 1 M hydrochloric acid , a solid was precipitated, filtered and dried to obtain 177 mg of a light yellow-green solid with a yield of 96%.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 13.01(s, 1H), 8.31(s, 1H), 7.61(s, 1H), 7.15-7.08(m, 2H), 6.98-6.95(dd, J =8.0,4.0Hz,1H),6.77-6.72(m,2H),4.46(s,3H),3.84(s,3H);

c). 1-Methyl-4-((3-methoxy-4-fluorophenyl)amino)-7-chloro-N-(4-methoxybenzenesulfonyl)-1H-indole-2 -Formamide

1-Methyl-4-((3-methoxyphenyl)amino)-7-chloro-1H-indole-2-carboxylic acid (350 mg, 1 mmol) was dissolved in dry DCM, followed by the addition of HATU (685 mg, 1.8mmol), DMAP (65mg, 0.5mmol) and TEA (303mg, 3mmol), stir well, add benzenesulfonamide (560mg, 3mmol), react at 40°C for 1.0h, stop the reaction, evaporate the solvent, use dilute hydrochloric acid in turn, Washed with water, washed with brine, combined the EA layers, and recrystallized EA to obtain 395 mg of a yellowish solid with a yield of 77%,

¹ H NMR (400MHz, DMSO-d ₆ ) δ 12.50(s, 1H), 8.34(s, 1H), 7.95(d, J=8.9Hz, 2H), 7.67(s, 1H), 7.22-7.08( m, 4H), 6.94(dd, J=7.7, 2.4Hz, 1H), 6.78(d, J=8.3Hz, 1H), 6.75-6.67(m, 1H), 4.11(s, 3H), 3.86(s ,3H),3.80(s,3H);

d). 1-Methyl-4-((3-methoxy-4-fluorophenyl)amino)-7-chloro-N-(4-methoxybenzenesulfonyl)-1H-indole-2 -formamide sodium salt

1-Methyl-4-((3-methoxy-4-fluorophenyl)amino)-7-chloro-N-(4-methoxybenzenesulfonyl)-1H-indole-2-methyl Water (5 mL) was added to the amide (1.0805 g, 2.0896 mmol), NaOH (86 mg, 2.1314 mmol) was dissolved in 1 mL of water, the temperature was raised to 80 °C, and the reaction was performed for 1 h. A brown-yellow solid was obtained, which was recrystallized from ethanol to obtain 919 mg of a brown-yellow solid with a yield of 81.6%.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.17 (s, 1H), 7.77 (d, J=8.6 Hz, 2H), 7.69 (d, J=8.4 Hz, 0H), 7.26 (s, 1H) ,7.10–7.02(m,1H),6.95(dd,J＝18.4,8.3Hz,4H),6.72(d,J＝8.2Hz,2H),4.29(s,3H),3.78(d,J＝2.3 Hz, 6H).

Pharmacological experiments:

Experimental Example 1. Anti-diabetic effects of Example 1 and its prototype compound P on type 2 diabetic ZDF rats

1. Experimental animals and groups

1. Spontaneous Type 2 Diabetic ZDF Rats

Spontaneous type 2 diabetic ZDF rats, male, 8 weeks old, certificate number: No.11400700293700, purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd., license number SYXK (Beijing) 2014-0023, raised in China SPF animal room, Institute of Materia Medica, Academy of Medical Sciences, 4 animals/cage, free water and water. High-quality rat chow 5008 (called purina) was fed for about 7 weeks, and the type 2 diabetes model was established for pharmacodynamic evaluation studies.

2. Normal ZDF Control Rats

Normal ZDF control rats, male, 8 weeks old, certificate number: No.11400700293705, purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd., license number SYXK (Beijing) 2014-0023, raised in the Chinese Academy of Medical Sciences Institute SPF animal room. After being fed with normal maintenance feed for about 7 weeks, it was used as the normal control group of ZDF for the experiment, 4 animals/cage, with free water and water.

3. Animal grouping

ZDF rats were fed high-fat for about 7 weeks, and multi-index prediction was performed and grouped. MAIN OUTCOME MEASURES: Random blood glucose, fasting blood glucose, percent decrease in blood glucose within 40 minutes of insulin tolerance test (ITT) experiment, blood triglyceride (TG), total cholesterol (TC) and body weight.

4. Experimental protocol

The animals were given intragastric administration, and the control group was intragastrically administered a corresponding volume of 0.5% CMC-Na solution, once a day, for 35 consecutive days.

1) On the 23rd day of administration, measure the random blood glucose, and on the 20th day of administration, measure the fasting blood sugar;

2) On the 20th day of administration, ZDF rats were subjected to sodium pyruvate tolerance test;

3) On the 34th day of administration, measure the level of glycated hemoglobin (HbA1c) in ZDF rats 2. Dose setting and preparation of the tested drug

1. Dose setting and preparation

1) Compound P (150mg/kg)

4.5 g of compound P was weighed, placed in a mortar, ground, suspended with 0.5% CMC-Na distilled water, and the volume was adjusted to 150 ml. According to 0.5ml/100g body weight gavage, that is, the dose is 150mg/kg.

2) Example 1 (150mg/kg)

4.5 g of Example 1 was weighed, placed in a mortar, ground, suspended with 0.5% CMC-Na distilled water, and the volume was adjusted to 150 ml. According to 0.5ml/100g body weight gavage, that is, the dose is 150mg/kg.

3) Metformin (150mg/kg)

4.5 g of metformin was weighed, the compound was placed in a mortar, ground, dissolved in distilled water, and the volume was adjusted to 150 ml. According to 0.5ml/100g body weight gavage, that is, the dose is 150mg/kg.

3. Main instruments and reagents

1. Main instruments

μ-Quant microplate reader (MQX200, BIO-TEK, USA), air shaker (HZQ-C, Harbin Dongming Medical Instrument Factory), low-temperature high-speed centrifuge (3-18K, SIGMA, Germany), water bath (DK- 8D, Shanghai Yiheng Technology Co., Ltd.), multi-function microplate reader (Synergy2, BIO-TEK company), analytical balance (Sartorius, BSA224S-CW), digital display electronic scale (MODUS), 1ml syringe (BD, batch number 302101) , 5ml syringe (state-owned Shanghai Medical Laser Instrument Factory), injection needle (edge brand, 0.5 × 20).

2. Main reagents

Glucose (Sinopharm Chemical Reagent Co., Ltd., 20141016), blood glucose determination GOD enzyme (sigma), glycosylated hemoglobin determination kit (Beijing Haomai Bioengineering Co., Ltd., A5911), sodium pyruvate (Beijing Bailingwei Technology Co., Ltd., 297561) Insulin ( Eli Lilly Suzhou Pharmaceutical Co., Ltd., H0219).

Fourth, the experimental method

1. Determination of fasting and random blood glucose

Blood was collected from the tail tip of animals under non-fasting conditions, and random blood glucose was measured by glucose oxidase method (the same below). After the animals were fasted overnight, blood was collected from the tail tip, and fasting blood glucose was measured.

2. Determination of HbA1c level

Take 10 μl of blood from the tail tip of the animal, add it to 150 μl of hemolytic agent, and mix well. Then operate according to the instructions of the HbA1c kit, measure the absorbance value at a wavelength of 700/800 nm, and calculate the glycated hemoglobin HbA1c level.

3. Pyruvate Sodium Tolerance Test (PTT)

On the day of the experiment, animals were fasted overnight after intragastric administration for 2 hours (17 hours of fasting), blood was collected from the tail tip (0 min), and then given sodium pyruvate solution by intragastric administration. , measure the blood glucose levels before and after pyruvate administration.

5. Experimental results

1. Effects on random blood glucose and fasting blood glucose levels in ZDF rats

The results are shown in Table 1. At the dose of 150 mg/kg, long-term administration of compound P can reduce the random blood glucose of ZDF rats (P<0.05), and the reduction percentage is 16.9%, which is better than the positive drug metformin. At a dose of 150 mg/kg, Example 1 can reduce random blood glucose (P<0.01) and fasting blood glucose (P<0.001), the percentage of random blood glucose reduction is 27.0%, and the percentage of fasting blood glucose reduction is 62.2%. The effect is better than the positive drug metformin.

Table 1. Effects of long-term compound administration on random blood glucose and fasting blood glucose in ZDF rats

Blood glucose data are expressed as mean±sd, n=10, vs Con, *P<0.05, **P<0.01, ***P<0.001.

2. Effects on glycosylated hemoglobin (HbA1c) in ZDF rats

Glycated hemoglobin (HbA1c) levels were determined on day 34 of dosing. The results are shown in Table 2. Compared with the normal control group (Nor), the blood HbA1c level of the rats in the model group (Con) was significantly increased (P<0.001). Compared with the Con group, the average HbA1c of the ZDF rats in Example 1 was significantly decreased for 34 days.

Table 2. Effects of long-term administration of compounds on glycosylated hemoglobin (HbA1c) in ZDF rats

HbA1c(%) is expressed as mean±sd, n=10. vs Con*P<0.05, **P<0.01, ***P<0.001.

3. Effects on gluconeogenesis in ZDF rats

Experiments were carried out on the 20th day of administration, and the results are shown in Table 3. After administration of sodium pyruvate, for the area of the curve under blood glucose time, Example 1 has a stronger gluconeogenesis inhibitory ability than the Con group.

Table 3. Effects on gluconeogenesis in ZDF rats

Blood glucose and AUC data are mean±sd, n=10, vs Con. *P<0.05, **P<0.01, ***P<0.001.

Experimental Example 2. Anti-diabetic effects of Example 1 and Example 3 on type 2 diabetic KKAy mice

1. Experimental animals and groups

1. Spontaneous Type 2 Diabetes KKAy Mice

Spontaneous type 2 diabetic KKAy mice, female, 11-12w, certificate number: No.11401300055400, purchased from Beijing Huafukang Biotechnology Co., Ltd., license number SCXK (Beijing) 2014-0004, raised in SPF animal room, Institute of Materia Medica, Chinese Academy of Medical Sciences, 5 animals/cage, free water and water. They were fed with high-fat diet for about 10 weeks, and the type 2 diabetes model was established for pharmacodynamic evaluation study.

2. C57BL/6J mice

Normal C57BL/6J mice, female, 6-8 weeks old, certificate number: No.11400700221894, purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd., license number SCXK (Beijing) 2016-0011, raised in China SPF animal room of the Institute of Materia Medica, Academy of Medical Sciences. After about 14 weeks of normal maintenance feed, they were used as a normal mouse control group for the experiment, 5 mice/cage, with free water and water.

3. Animal grouping

KKAy mice were fed high-fat for about 10 weeks, and multi-index prediction was performed and grouped. MAIN OUTCOME MEASURES: Random blood glucose, fasting blood glucose, percent decrease in blood glucose within 40 minutes of insulin tolerance test (ITT) test, blood triglyceride (TG), blood total cholesterol (TC) and body weight.

2. Dosage setting and preparation of the tested drug

Dose setting and preparation

1) Example 1

Set up 3 dose groups, respectively weigh 150 mg, 300 mg and 600 mg of the compound of Example 1, put them in a mortar, grind, suspend with 0.5% CMC-Na distilled water and make up to 30 ml. The dosing volume was 0.1 ml/10 g, ie the doses were 50 mg/kg, 100 mg/kg and 200 mg/kg.

2) Example 3 (100mg/kg)

300 mg was weighed, the compound was placed in a mortar, ground, suspended with 0.5% CMC-Na distilled water, and the volume was made up to 30 ml. The dosing volume was 0.1 ml/10 g, ie a dose of 100 mg/kg.

3) Metformin hydrochloride (150mg/kg)

Weigh 450mg into distilled water to dissolve, and dilute to 30ml. The dosing volume was 0.1 ml/10 g, ie a dose of 150 mg/kg.

3. Main instruments and reagents

1. Main instruments

μ-Quant microplate reader (MQX200, BIO-TEK, USA), air shaker (HZQ-C, Harbin Dongming Medical Instrument Factory), low-temperature high-speed centrifuge (3-18K, SIGMA, Germany), water bath (DK- 8D, Shanghai Yiheng Technology Co., Ltd.), multi-function microplate reader (Synergy2, BIO-TEK company), analytical balance (Sartorius, BSA224S-CW), digital display electronic scale (MODUS), 1ml syringe (BD, batch number 302101) , 0.25ml syringe (state-owned Shanghai Medical Laser Instrument Factory, B05-19-U), injection needle (edge brand, 0.5 × 20).

2. Main reagents

Glucose (Sinopharm Chemical Reagent Co., Ltd., 20141016), blood glucose determination GOD enzyme (sigma), glycosylated hemoglobin determination kit (Beijing Himile Bioengineering Co., Ltd., A5911), sodium pyruvate (Beijing Bailingwei Technology Co., Ltd., 297561), insulin (Lilly Suzhou Pharmaceutical Co., Ltd., H0219).

Fourth, the experimental method

Determination of fasting and random blood glucose

Blood was collected from the tail tip of animals under non-fasting conditions, and random blood glucose was measured by glucose oxidase method (the same below). The animals were fasted for 4 hours and the blood was collected from the tail tip to measure the fasting blood glucose.

5. Experimental results

Effects on random blood glucose and fasting blood glucose levels in KKAy mice

Mice random blood glucose and fasting blood glucose levels were measured on the 20th day of dosing. As shown in Table 4, compared with the model control group (Con), Example 1 had a lowering effect on the blood sugar level of KKAy mice at doses of 50, 100 and 200 mg/kg, and the random blood sugar decreased by 13%, 21% (P<0.05), 49% (P<0.01); fasting blood glucose decreased by -3.7%, 10.4%, 35.4% (P<0.001), respectively. Example 3 At the dose of 100 mg/kg, the random blood glucose of KKAy mice was decreased, and the decreasing range was 18.4% (P<0.05). The effect was comparable to that of Example 1 (100 mg/kg) at the same dose.

Table 4. Effects on random blood glucose and fasting blood glucose in KKAy mice

vs model group *P<0.05, **P<0.01, ***P<0.001; blood glucose data are expressed as mean±sd, n=10

Experimental Example 3. Evaluation of the antidiabetic activity of Example 1 and Example 2 on ICR mice

1. Experimental animals and grouping

(1) Experimental animals

Normal ICR mice, male, weighing 20-25 g, were purchased from the Institute of Zoology, Chinese Academy of Medical Sciences, 5 mice/cage.

(2) Grouping

Animals were randomly divided into groups according to body weight and fasted overnight (12h). Then, according to body weight, they were randomly divided into Example 1 group, Example 2 group, normal group, and metformin group.

(3) Experimental design

The test compound compound and the positive control drug metformin were given by intragastric administration respectively, and the normal group was given an equal volume of water. A sodium pyruvate tolerance test was performed two hours later.

2. Test drug, dose setting and preparation

(1) Test sample and preparation:

Example 1 (150mg/kg)

Weigh 0.060 g, put the compound in a mortar, grind, suspend with 0.5% CMC-Na distilled water, and make up to 4 ml. The administration volume is 0.1ml/10g. That is, the administration dose is 150mg/kg.

Example 2 (150mg/kg)

Weigh 0.060 g, put the compound in a mortar, grind, suspend with 0.5% CMC-Na distilled water, and make up to 4 ml. The administration volume is 0.1ml/10g. That is, the administration dose is 150mg/kg.

Metformin (150mg/kg)

Weigh 0.060 g of the compound, put the compound in a mortar, grind, dissolve with distilled water, and make up to 4 ml. 3. Main instruments and reagents

(1) Main instruments

μ-Quant microplate reader (MQX200, BIO-TEK, USA), air shaker (HZQ-C, Harbin Dongming Medical Instrument Factory), low temperature high-speed centrifuge (3-18K, SIGMA, Germany), water bath (DK- 8D, Shanghai Yiheng Technology Co., Ltd.), multi-function microplate reader (Synergy2, BIO-TEK company), analytical balance (Sartorius, BSA224S-CW), digital display electronic scale (MODUS), 1ml syringe (BD, batch number 302101) , 0.25ml syringe (state-owned Shanghai Medical Laser Instrument Factory, B05-19-U), hypodermic needle (edge brand, 0.5 × 20).

(2) Main reagents

Glucose (Sinopharm Chemical Reagent Co., Ltd., 20141016), GOD enzyme (sigma) for blood glucose determination, and sodium pyruvate (Beijing Bailingwei Technology Co., Ltd., 297561).

4. Experimental method

Sodium pyruvate tolerance test: on the day of the experiment, blood was collected from the tip of the tail (0min). Afterwards, the test compound and the positive control drug metformin were given by gavage respectively, and the normal group was given an equal volume of water (0.1 mL/10 g b.w.). Two hours later, sodium pyruvate (3.0 g/kg, 0.1 mL/10 g b.w.) was administered by gavage, and blood was collected from the tail tip at 40 and 90 min after sodium pyruvate loading, respectively, and blood glucose was measured at each time point.

5. Experimental results

The results are shown in Table 5. For Example 1, at 40 min, the inhibition rate of gluconeogenesis was 73.9% (P<0.01). Metformin (150mg/kg) inhibited gluconeogenesis by 29.7% (P<0.05). For Example 2 (150 mg/kg), the inhibition rate of gluconeogenesis was 26.2% at 40 min. Both Example 1 and Example 2 can significantly reduce the area of the curve under blood glucose time, and the effect of Example 1 is better than that of Metformin and Example 2.

Table 5. Inhibitory effect and hypoglycemic activity on gluconeogenesis in ICR mice

The above blood glucose and AUC data are mean±sd, n=10, vs normal, *P<0.05, **P<0.01, ***P<0.001.

Experimental example 4. Pharmacokinetic experiment:

1. Experimental animals

Male SD rats, weighing 180-200 g, were provided by Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd. 2. Test method

1. Establishment of standard curve for plasma samples

Example 1 was dissolved in DMSO (3 mg/mL), and diluted with acetonitrile containing internal standard (YHP836, 200 ng/mL) into a working solution with a concentration of 5, 10, 25, 50, 200, 400, 800, and 1000 ng/mL.

50 μL of blank plasma was added with 50 μL of compound P working solution of different concentrations and 50 μL of acetonitrile containing internal standard (YHP836, 200ng/mL) respectively, and centrifuged (14000rpm×5min) twice after mixing, and 3 μL of supernatant was collected for LC/MS/MS analysis .

2. Study on the pharmacokinetic properties of Example 1 and its prototype compound P by oral administration in rats

Compound P and Example 1 were formulated as a 15 mg/mL suspension with 0.5% CMC (containing Tween 80) for oral administration; 20% HP-β-CD as a 0.15 mg/mL solution for intravenous injection.

There were 13 SD rats, 5 in each group and 3 in the intravenous group. Fasting for 12h before administration, free drinking water. The test used continuous blood sampling. After 5, 15, 30 min, 1, 2, 4, 6, 8, 12, 24 h after oral administration of Example 1 and prototype compound P (150 mg/kg) in rats, blood was collected from the orbital venous plexus, and Example 1 (1.5 mg) was intravenously injected. 5, 15, 30min, 1, 2, 4, 6, 8, 12, 24h after 5, 15, 30 min, 1, 2, 4, 6, 8, 12, and 24 h, blood was collected to separate 50 μL of plasma, and 100 μL of acetonitrile containing internal standard (YHP836, 200 ng/mL) was added. 5 min) twice, and 3 μL of the supernatant was taken for LC/MS/MS analysis. Samples exceeding the standard line were diluted and determined.

3. Plasma Sample Processing

4. LC/MS/MS conditions

Chromatographic column: Zobax C18 (50mm×2.1mm, 3.5μm); column temperature: 30°C, mobile phase: methanol/water gradient; flow rate: 0.2mL/min; negative ion scanning, MRM mode detection m/z 498→108 (bjb -2936), m/z 465→297 (internal standard YHP836).

5. Data Analysis

Plasma pharmacokinetic parameters were calculated by WinNonlin software.

3. Test results

After oral administration of Example 1 and Compound P (150 mg/kg) to rats, the absorption was rapid, and the blood drug concentration maintained a high level for 1-12 h, and the average blood drug peak concentrations were 85 and 305 μg/mL, respectively. After oral administration of Example 1 (150 mg/kg) in rats, the in vivo exposure was about 4 times that of the parent compound. Oral bioavailability of Example 1 (150 mg/kg) was >100%.

Table 6 Plasma pharmacokinetic parameters of Example 1 and prototype compound P by oral and intravenous injection in rats

Claims (12)

1. N-acylsulfonamide salt compounds as shown in general formula I,

In formula I, R is selected from the following atoms or groups, including H, F, Cl, Br, CN, CF ₃ , OCH ₃ , NO ₂ ; Ar ₁ is selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight or branched chain alkane Alkyl, halogen-substituted C1-4 straight or branched chain alkyl, F, Cl, Br, NO ₂ , CN, methylenedioxy, ORa' ₁ , SRa' ₂ , NRa' ₃ Rb' ₁ , COORa' ₄ , CONRa′ ₅ Rb′ ₂ , NRa′ ₆ COORb′ ₃ , SO ₂ NRa′ ₇ Rb′ ₄ , NRa′ ₈ CORb′ ₅ , (CH ₂ )nNRa′ ₉ Rb′ ₆ , (CH ₂ )nORa′ ₁₀ , wherein the Ra′ ₁ , Ra′ ₂ , Ra′ ₃ , Rb′ ₁ , Ra′ ₄ , Ra′ ₅ , Rb′ ₂ , Ra′ ₆ , Rb′ ₃ , Ra′ ₇ , Rb′ ₄ , Ra ' ₈ , Rb' ₅ , Ra' ₉ , Rb' ₆ , Ra' ₁₀ are independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclo Amyl; the benzene ring, nitrogen-containing six-membered aromatic heterocycle, and five-membered aromatic heterocycle may be mono-substituted or multi-substituted; the six-membered aromatic heterocycle may contain 1 N atom, or multiple A nitrogen atom; the five-membered aromatic heterocycle may contain one heteroatom or multiple heteroatoms, the heteroatoms are selected from O, N, S; n is selected from 1, 2, 3; wherein the halogen includes F, Cl, Br; Ar ₂ is selected from the following groups or structural fragments: (1) Substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight chain or branched Alkyl, halogen substituted C1-4 straight or branched alkyl, F, Cl, Br, NO ₂ , CN, methylenedioxy, ORs ₁ , SRs ₂ , NRs ₃ Rt ₁ , NRs ₄ CORt ₂ , COORs ₅ , CONRs ₆ Rt ₃ , NRs ₇ COORt ₄ , SO ₂ NRs ₈ Rt ₅ , (CH ₂ )nNRs ₉ Rt ₆ , (CH ₂ )nORs ₁₀ , wherein the Rs ₁ , Rs ₂ , Rs ₃ , Rt ₁ , Rs ₄ , Rt ₂ , Rs ₅ , Rs ₆ , Rt ₃ , Rs ₇ , Rt ₄ , Rs ₈ , Rt ₅ , Rs ₉ , Rt ₆ , Rs ₁₀ are independently selected from H, C1-4 linear or Branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; benzene ring, nitrogen-containing six-membered aromatic heterocycle and five-membered aromatic heterocycle can be mono-substituted or multi-substituted ; The six-membered aromatic heterocycle may contain one N atom or multiple nitrogen atoms; the five-membered aromatic heterocycle may contain one heteroatom or multiple heteroatoms, and the heteroatoms are selected from O, N, S; n is selected from 1,2,3; wherein said halogen includes F, Cl, Br; (2) Substituted or unsubstituted aromatic fused rings or fused heterocycles, substituted or unsubstituted non-aromatic fused rings or fused heterocycles, including substituted or unsubstituted naphthalene rings, substituted or unsubstituted benzos Six-membered heterocycle, substituted or unsubstituted benzofive-membered heterocycle, wherein the substituent is selected from C1-4 straight or branched chain alkyl, halogen substituted C1-4 straight or branched chain alkyl, F, Cl, Br, NO ₂ , CN, Methylenedioxy, ORs ₁ , SRs ₂ , NRs ₃ Rt ₁ , NRs ₄ CORt ₂ , COORs ₅ , CONRs ₆ Rt ₃ , NRs ₇ COORt ₄ , SO ₂ NRs ₈ Rt ₅ , (CH ₂ )nNRs ₉ Rt ₆ , (CH ₂ )nORs ₁₀ , wherein said Rs ₁ , Rs ₂ , Rs ₃ , Rt ₁ , Rs ₄ , Rt ₂ , Rs ₅ , Rs ₆ , Rt ₃ , Rs ₇ , Rt ₄ , Rs ₈ , Rt ₅ , Rs ₉ , Rt ₆ , Rs ₁₀ are independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl , cyclopentyl; wherein said naphthalene ring, benzos six-membered heterocycle or benzos five-membered heterocycle can be mono-substituted or multi-substituted; benzos six-membered heterocycle or benzos five-membered heterocycle Can contain one heteroatom or multiple heteroatoms, the heteroatoms are selected from O, N, S; n is selected from 1, 2, 3; wherein the halogen includes F, Cl, Br; M is independently selected from alkali metals or alkaline earth metals. 2. the N-acylsulfonamide salt compound according to claim 1, is characterized in that, described compound is as shown in general formula I-A

Ar ₁ is selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight or branched chain alkane Alkyl, halogen-substituted C1-4 straight or branched chain alkyl, F, Cl, Br, NO ₂ , CN, methylenedioxy, ORa' ₁ , SRa' ₂ , NRa' ₃ Rb' ₁ , COORa' ₄ , CONRa′ ₅ Rb′ ₂ , NRa′ ₆ COORb′ ₃ , SO ₂ NRa′ ₇ Rb′ ₄ , NRa′ ₈ CORb′ ₅ , (CH ₂ )nNRa′ ₉ Rb′ ₆ , (CH ₂ )nORa′ ₁₀ , wherein the Ra′ ₁ , Ra′ ₂ , Ra′ ₃ , Rb′ ₁ , Ra′ ₄ , Ra′ ₅ , Rb′ ₂ , Ra′ ₆ , Rb′ ₃ , Ra′ ₇ , Rb′ ₄ , Ra ' ₈ , Rb' ₅ , Ra' ₉ , Rb' ₆ , Ra' ₁₀ are independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclo Amyl; the benzene ring, nitrogen-containing six-membered aromatic heterocycle, and five-membered aromatic heterocycle may be mono-substituted or multi-substituted; the six-membered aromatic heterocycle may contain 1 N atom, or multiple A nitrogen atom; the five-membered aromatic heterocycle may contain one heteroatom or multiple heteroatoms, the heteroatoms are selected from O, N, S; n is selected from 1, 2, 3; wherein the halogen includes F, Cl, Br; Ar ₂ is selected from the following groups or structural fragments: (1) Substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight chain or branched Alkyl, halogen substituted C1-4 straight or branched alkyl, F, Cl, Br, NO ₂ , CN, methylenedioxy, ORs ₁ , SRs ₂ , NRs ₃ Rt ₁ , NRs ₄ CORt ₂ , COORs ₅ , CONRs ₆ Rt ₃ , NRs ₇ COORt ₄ , SO ₂ NRs ₈ Rt ₅ , (CH ₂ )nNRs ₉ Rt ₆ , (CH ₂ )nORs ₁₀ , wherein the Rs ₁ , Rs ₂ , Rs ₃ , Rt ₁ , Rs ₄ , Rt ₂ , Rs ₅ , Rs ₆ , Rt ₃ , Rs ₇ , Rt ₄ , Rs ₈ , Rt ₅ , Rs ₉ , Rt ₆ , Rs ₁₀ are independently selected from H, C1-4 linear or Branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; benzene ring, nitrogen-containing six-membered aromatic heterocycle and five-membered aromatic heterocycle can be mono-substituted or multi-substituted ; The six-membered aromatic heterocycle may contain one N atom or multiple nitrogen atoms; the five-membered aromatic heterocycle may contain one heteroatom or multiple heteroatoms, and the heteroatoms are selected from O, N, S; n is selected from 1,2,3; wherein said halogen includes F, Cl, Br; (2) Substituted or unsubstituted aromatic fused rings or fused heterocycles, substituted or unsubstituted non-aromatic fused rings or fused heterocycles, including substituted or unsubstituted naphthalene rings, substituted or unsubstituted benzos Six-membered heterocycle, substituted or unsubstituted benzofive-membered heterocycle, wherein the substituent is selected from C1-4 straight or branched chain alkyl, halogen substituted C1-4 straight or branched chain alkyl, F, Cl, Br, NO ₂ , CN, Methylenedioxy, ORs ₁ , SRs ₂ , NRs ₃ Rt ₁ , NRs ₄ CORt ₂ , COORs ₅ , CONRs ₆ Rt ₃ , NRs ₇ COORt ₄ , SO ₂ NRs ₈ Rt ₅ , (CH ₂ )nNRs ₉ Rt ₆ , (CH ₂ )nORs ₁₀ , wherein said Rs ₁ , Rs ₂ , Rs ₃ , Rt ₁ , Rs ₄ , Rt ₂ , Rs ₅ , Rs ₆ , Rt ₃ , Rs ₇ , Rt ₄ , Rs ₈ , Rt ₅ , Rs ₉ , Rt ₆ , Rs ₁₀ are independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl , cyclopentyl; wherein said naphthalene ring, benzos six-membered heterocycle or benzos five-membered heterocycle can be mono-substituted or multi-substituted; benzos six-membered heterocycle or benzos five-membered heterocycle Can contain one heteroatom or multiple heteroatoms, the heteroatoms are selected from O, N, S; n is selected from 1, 2, 3; wherein the halogen includes F, Cl, Br; M is independently selected from alkali metals or alkaline earth metals. 3. according to the N-acyl sulfonamide salt compound of claim 2, it is characterized in that, described compound is as shown in general formula I-A-a

R _A can be mono-substituted or poly-substituted; R _A can be independently selected from the following groups or structural fragments: C1-4 linear or branched alkyl, halogen-substituted C1-4 linear or branched alkyl, F, Cl, Br, NO ₂ , CN, methylenedioxy, ORa′ ₁ , SRa′ ₂ , NRa′ ₃ Rb′ ₁ , COORa′ ₄ , CONRa′ ₅ Rb′ ₂ , NRa′ ₆ COORb′ ₃ , SO ₂ NRa′ ₇ Rb′ ₄ , NRa′ ₈ CORb′ ₅ , (CH ₂ )nNRa′ ₉ Rb′ _6. (CH ₂ )nORa′ ₁₀ , wherein said Ra′ ₁ , Ra′ ₂ , Ra′ ₃ , Rb′ ₁ , Ra′ ₄ , Ra′ ₅ , Rb′ ₂ , Ra′ ₆ , Rb′ ₃ , Ra' ₇ , Rb' ₄ , Ra' ₈ , Rb' ₅ , Ra' ₉ , Rb' ₆ , Ra' ₁₀ are independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropyl Methylene, cyclobutyl, cyclopentyl; Ar ₂ is selected from the following groups or structural fragments: (1) Substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight chain or branched Alkyl, halogen substituted C1-4 straight or branched alkyl, F, Cl, Br, NO ₂ , CN, methylenedioxy, ORs ₁ , SRs ₂ , NRs ₃ Rt ₁ , NRs ₄ CORt ₂ , COORs ₅ , CONRs ₆ Rt ₃ , NRs ₇ COORt ₄ , SO ₂ NRs ₈ Rt ₅ , (CH ₂ )nNRs ₉ Rt ₆ , (CH ₂ )nORs ₁₀ , wherein the Rs ₁ , Rs ₂ , Rs ₃ , Rt ₁ , Rs ₄ , Rt ₂ , Rs ₅ , Rs ₆ , Rt ₃ , Rs ₇ , Rt ₄ , Rs ₈ , Rt ₅ , Rs ₉ , Rt ₆ , Rs ₁₀ are independently selected from H, C1-4 linear or Branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; benzene ring, nitrogen-containing six-membered aromatic heterocycle and five-membered aromatic heterocycle can be mono-substituted or multi-substituted ; The six-membered aromatic heterocycle may contain one N atom or multiple nitrogen atoms; the five-membered aromatic heterocycle may contain one heteroatom or multiple heteroatoms, and the heteroatoms are selected from O, N, S; n is selected from 1,2,3; wherein said halogen includes F, Cl, Br; (2) Substituted or unsubstituted aromatic fused rings or fused heterocycles, substituted or unsubstituted non-aromatic fused rings or fused heterocycles, including substituted or unsubstituted naphthalene rings, substituted or unsubstituted benzos Six-membered heterocycle, substituted or unsubstituted benzofive-membered heterocycle, wherein the substituent is selected from C1-4 straight or branched chain alkyl, halogen substituted C1-4 straight or branched chain alkyl, F, Cl, Br, NO ₂ , CN, Methylenedioxy, ORs ₁ , SRs ₂ , NRs ₃ Rt ₁ , NRs ₄ CORt ₂ , COORs ₅ , CONRs ₆ Rt ₃ , NRs ₇ COORt ₄ , SO ₂ NRs ₈ Rt ₅ , (CH ₂ )nNRs ₉ Rt ₆ , (CH ₂ )nORs ₁₀ , wherein said Rs ₁ , Rs ₂ , Rs ₃ , Rt ₁ , Rs ₄ , Rt ₂ , Rs ₅ , Rs ₆ , Rt ₃ , Rs ₇ , Rt ₄ , Rs ₈ , Rt ₅ , Rs ₉ , Rt ₆ , Rs ₁₀ are independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl , cyclopentyl; wherein said naphthalene ring, benzos six-membered heterocycle or benzos five-membered heterocycle can be mono-substituted or multi-substituted; benzos six-membered heterocycle or benzos five-membered heterocycle Can contain one heteroatom or multiple heteroatoms, the heteroatoms are selected from O, N, S; n is selected from 1, 2, 3; wherein the halogen includes F, Cl, Br; M is independently selected from alkali metals or alkaline earth metals. 4. the N-acylsulfonamide salt compound according to claim 2, is characterized in that, described compound is as shown in general formula I-A-b

R _B can be mono-substituted or poly-substituted; R _B can be independently selected from the following groups or structural fragments: C1-4 linear or branched alkyl, halogen-substituted C1-4 linear or branched alkyl, F, Cl, Br, NO ₂ , CN, methylenedioxy, ORa′ ₁ , SRa′ ₂ , NRa′ ₃ Rb′ ₁ , COORa′ ₄ , CONRa′ ₅ Rb′ ₂ , NRa′ ₆ COORb′ ₃ , SO ₂ NRa′ ₇ Rb′ ₄ , NRa′ ₈ CORb′ ₅ , (CH ₂ )nNRa′ ₉ Rb′ _6. (CH ₂ )nORa′ ₁₀ , wherein said Ra′ ₁ , Ra′ ₂ , Ra′ ₃ , Rb′ ₁ , Ra′ ₄ , Ra′ ₅ , Rb′ ₂ , Ra′ ₆ , Rb′ ₃ , Ra' ₇ , Rb' ₄ , Ra' ₈ , Rb' ₅ , Ra' ₉ , Rb' ₆ , Ra' ₁₀ are independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropyl Methylene, cyclobutyl, cyclopentyl; Ar ₁ is selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight or branched chain alkane Alkyl, halogen-substituted C1-4 straight or branched chain alkyl, F, Cl, Br, NO ₂ , CN, methylenedioxy, ORa' ₁ , SRa' ₂ , NRa' ₃ Rb' ₁ , COORa' ₄ , CONRa′ ₅ Rb′ ₂ , NRa′ ₆ COORb′ ₃ , SO ₂ NRa′ ₇ Rb′ ₄ , NRa′ ₈ CORb′ ₅ , (CH ₂ )nNRa′ ₉ Rb′ ₆ , (CH ₂ )nORa′ ₁₀ , wherein the Ra′ ₁ , Ra′ ₂ , Ra′ ₃ , Rb′ ₁ , Ra′ ₄ , Ra′ ₅ , Rb′ ₂ , Ra′ ₆ , Rb′ ₃ , Ra′ ₇ , Rb′ ₄ , Ra ' ₈ , Rb' ₅ , Ra' ₉ , Rb' ₆ , Ra' ₁₀ are independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclo Amyl; the benzene ring, nitrogen-containing six-membered aromatic heterocycle, and five-membered aromatic heterocycle may be mono-substituted or multi-substituted; the six-membered aromatic heterocycle may contain 1 N atom, or multiple A nitrogen atom; the five-membered aromatic heterocycle may contain one heteroatom or multiple heteroatoms, the heteroatoms are selected from O, N, S; n is selected from 1, 2, 3; wherein the halogen includes F, Cl, Br; M is independently selected from alkali metals or alkaline earth metals. 5. The N-acylsulfonamide salt compound according to any one of claims 1-4, wherein the M is selected from lithium, sodium, potassium, cesium, calcium, magnesium, and barium. 6. The N-acylsulfonamide salt compound according to any one of claims 1-5, wherein the compound is selected from:

7. the method for preparing any one of claims 1-6 N-acylsulfonamide salt compounds, is characterized in that, comprises the steps: In the ethanol solution of sodium alkoxide, 5-R-substituted o-bromobenzaldehyde is condensed with ethyl azide to obtain compound 1. Compound 1 uses o-dichlorobenzene as a solvent and undergoes ring closure at 180 °C to obtain 7- R-substituted ethyl 4-bromo-1-H-indole-2-carboxylate (compound 2), then methylated at the indole-1-position in the presence of cesium carbonate to give 7-R -Substituted ethyl 4-bromo-1-methyl-indole-2-carboxylate (compound 3); then compound 3 undergoes a coupling reaction with an aryl bromide under palladium catalysis to give compound 4, which is hydrolyzed Afterwards, the corresponding compound 5 whose 2-position is a carboxyl group is obtained. Compound 5 undergoes condensation reaction with arylmethanesulfonamide to obtain compound 6, and finally undergoes acid-base reaction with different bases to obtain N-acylsulfonamide salt compounds;

Reagents and reaction conditions: (a) ethyl azide, ethyl trifluoroacetate, sodium, ethanol, -15°C to 0°C; (b) o-dichlorobenzene, 180°C; (c) methyl iodide, cesium carbonate , DMF, rt; (c) Ar ₁ -Br, Pd ₂ (dba) ₃ , Xantphos, sodium carbonate, toluene, water, 100°C; (d) sodium hydroxide, THF, ethanol, water, rt; (e) Ar ₂ -S(O) ₂ -OH, HATU, DMAP, Et ₃ N, rt; (g) alkali metal or alkaline earth metal base, water, 80°C; The definitions of R, Ar ₁ , Ar ₂ and M mentioned therein are the same as those in claims 1-6. 8. A pharmaceutical composition, characterized in that, the pharmaceutical composition comprises an effective dose of the N-acylsulfonamide salt compound of any one of claims 1-6 and a pharmacodynamically acceptable carrier. 9. Use of the N-acylsulfonamide salt compound of any one of claims 1-6 in the preparation of FBPase inhibitors. 10. The application of the N-acylsulfonamide salt compound of any one of claims 1-6 in the preparation of a medicine for preventing and/or treating a disease related to FBPase. 11. The use according to claim 10, wherein the disease associated with FBPase is selected from the group consisting of diabetes, diabetic complications and obesity. 12. The application according to claim 11, wherein the diabetes is selected from type I diabetes and type II diabetes; the diabetic complications are selected from retinal, kidney, neurological disease and vascular complications, ischemic Heart disease or atherosclerosis.