N-acylsulfonamide salt fbpase inhibitors, methods of making, pharmaceutical compositions, and uses

Abstract

The present invention relates to N-acylsulfonamide salt compounds of Formula I as FBPase inhibitors, methods for their preparation, compositions containing one or more of such compounds, and the use of said compounds as medicaments, in the treatment of diseases associated with FBPase, and in the preparation, prevention and / or treatment of diabetes.

Description

Technical Field

[0001] This invention relates to N-acylsulfonamide salt FBPase inhibitors of Formula I, methods for their preparation, compositions containing one or more of these compounds, and the use of these compounds in inhibiting FBPase and treating FBPase-related diseases, as well as in the preparation, prevention and / or treatment of diabetes medications. Background Technology

[0002] Diabetes mellitus is a chronic metabolic disease regulated by multiple genes, mainly characterized by persistent hyperglycemia and glycosuria. Persistent hyperglycemia can lead to many complications, such as retinopathy, nephropathy, neuropathy, and vascular complications. The incidence of diabetes in China is rapidly increasing; it is estimated that there are over 92 million people with diabetes in China, with approximately 148 million at high risk (New Engl. J. Med., 2010, 362: 1090-1101).

[0003] Diabetes is classified into two types: insulin-dependent (Type I) and non-insulin-dependent (Type II), with Type II diabetes accounting for 90%–95% of all diabetes cases. Biological research indicates that the main pathological basis of diabetes is insufficient insulin secretion, insulin resistance, and increased hepatic glucose production. Currently, clinically used drugs mainly fall into two categories: those targeting insufficient insulin secretion, such as sulfonylureas and meglitinides (insulin secretagogues); and those improving insulin resistance, such as thiazolidinediones (insulin sensitizers). To date, no antidiabetic drugs that reduce endogenous glucose production are used clinically. Metformin can reduce hepatic glucose output, but its molecular target is still unclear.

[0004] Existing research has shown that increased endogenous glucose production is the main cause of elevated fasting blood glucose in diabetic patients. Endogenous glucose primarily originates from the liver. The liver produces glucose through two pathways: endogenous glucose synthesis, or gluconeogenesis, and glycogenolysis. Therefore, regulating the gluconeogenesis pathway to reduce endogenous glucose production is a potential new strategy for developing antidiabetic drugs with novel mechanisms of action.

[0005] Gluconeogenesis is the process by which three-carbon precursors such as lactate, glycine, and glycerol are converted 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, releasing one molecule of phosphate. This catalytic reaction is one of the rate-determining steps in endogenous glucose production; inhibiting FBPase activity can reduce endogenous glucose production and lower blood glucose levels. Therefore, FBPase inhibitors have the potential to become antidiabetic drugs with novel mechanisms of action, especially in lowering fasting blood glucose levels.

[0006] To date, numerous researchers have conducted studies on FBPase inhibitors, reporting various structural types. In 2003, Pfizer Pharmaceuticals, through high-throughput screening, identified indolecarboxylic acid compounds with an IC50 inhibitory activity against FBPase. 50 The values ​​are at the micromolar level (Bioorg. Med. Chem. Lett., 2003, 13: 2055-2058). In 2006, von Geldern et al. reported the IC50 inhibitory activity of benzoxazole-2-benzenesulfonamide compounds against FBPase. 50 Value at 10 -6 -10 -7 Molar levels (Bioorg. Med. Chem. Lett., 2006, 16: 1811-1815). In 2010, Roche Pharmaceuticals reported a thiazole-substituted sulfonylurea FBPase inhibitor discovered through high-throughput screening, with an inhibitory activity IC50 of [missing information]. 50 Value at 10 -7 -10 -8Mole level (Bioorg. Med. Chem. Lett., 2010, 20: 594-599). From 2007 to 2010, Metbasis Pharmaceuticals reported the discovery of AMP analogs and the search for FBPase inhibitors using a structure-based drug molecule design strategy. Through continuous structural 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 phosphodiacamide prodrug of a thiazole compound and is currently in Phase II clinical trials (US,225259A1[P].2007-09-27.).

[0007] This invention designs and synthesizes N-acylsulfonamide salt compounds as FBPase inhibitors, laying the structural foundation for obtaining FBPase inhibitors with favorable pharmacokinetic properties and oral administration. The sulfonamide salt compounds in this patent application exhibit higher solubility, in vivo exposure, and oral bioavailability compared to the prototype compounds. This invention aims to discover novel antidiabetic drugs with strong antidiabetic activity, favorable pharmacokinetic properties, and oral efficacy. Summary of the Invention

[0008] The technical problem solved by the present invention is to provide N-acylsulfonamide salt derivatives of Formula I, their preparation methods, pharmaceutical compositions, and their use in the preparation of FBPase inhibitors and their potential pharmaceutical uses, as well as their use in the preparation of antidiabetic drugs.

[0009] To solve the technical problem of this invention, the present invention provides the following technical solution:

[0010] The first aspect of the present invention is to provide N-acylsulfonamide salt derivatives as shown in general formula I:

[0011]

[0012] In equation I,

[0013] R is selected from the following atoms or groups, including

[0014] H, F, Cl, Br, CN, CF3, OCH3, NO2;

[0015] Ar1 is selected from substituted or unsubstituted phenyl groups, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycles, and substituted or unsubstituted five-membered aromatic heterocycles, wherein the substituents are selected from C1-4 straight-chain or branched alkyl groups, halogen-substituted C1-4 straight-chain or branched alkyl groups, F, Cl, Br, NO2, CN, methylenedioxy, ORa′1, SRa′2, NRa′3Rb′1, COORa′4, CONRa′5Rb′2, NRa′6COORb′3, SO2NRa′7Rb′4, NRa′8CORb′5, (CH2)nNRa′9Rb′6, and (CH2)nORa′ 10 , wherein 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 The components are independently selected from H, C1-4 straight-chain or branched alkyl groups, cyclopropyl, cyclopropylmethylene, cyclobutyl, and cyclopentyl; the benzene ring, nitrogen-containing six-membered aromatic heterocycle, and five-membered aromatic heterocycle may be monosubstituted or polysubstituted; 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, the heteroatom being selected from O, N, and S; n is selected from 1, 2, and 3; the halogens mentioned include F, Cl, and Br.

[0016] Ar2 is selected from the following groups or structural fragments:

[0017] (1) A substituted or unsubstituted phenyl group, a substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, a substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl groups, halogen-substituted C1-4 straight-chain or branched alkyl groups, F, Cl, Br, NO2, CN, methylenedioxy, ORs1, SRs2, NRs3Rt1, NRs4CORt2, COORs5, CONRs6Rt3, NRs7COORt4, SO2NRs8Rt5, (CH2)nNRs9Rt6, (CH2)nORs 10 The values ​​Rs1, Rs2, Rs3, Rt1, Rs4, Rt2, Rs5, Rs6, Rt3, Rs7, Rt4, Rs8, Rt5, Rs9, Rt6, and Rs 10 The halogen is independently selected from H, C1-4 straight-chain or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, and cyclopentyl; the benzene ring, nitrogen-containing six-membered aromatic heterocycle, and five-membered aromatic heterocycle may be monosubstituted or polysubstituted; 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, the heteroatom being selected from O, N, and S; n is selected from 1, 2, and 3; wherein the halogen includes F, Cl, and Br;

[0018] (2) Substituted or unsubstituted aromatic fused rings or fused heterocycles, substituted or unsubstituted non-aromatic fused rings or fused heterocycles, including substituted or unsubstituted naphthyl rings, substituted or unsubstituted benzo6-membered heterocycles, substituted or unsubstituted benzo5-membered heterocycles, wherein the substituents are selected from C1-4 straight-chain or branched alkyl groups, halogen-substituted C1-4 straight-chain or branched alkyl groups, F, Cl, Br, NO2, CN, methylenedioxy, ORs1, SRs2, NRs3Rt1, NRs4CORt2, COORs5, CONRs6Rt3, NRs7COORt4, SO2NRs8Rt5, (CH2)nNRs9Rt6, (CH2)nORs 10 The values ​​Rs1, Rs2, Rs3, Rt1, Rs4, Rt2, Rs5, Rs6, Rt3, Rs7, Rt4, Rs8, Rt5, Rs9, Rt6, and Rs 10 The halogen is independently selected from H, C1-4 straight-chain or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, and cyclopentyl; wherein the naphthalene ring, benzo[6]-membered heterocycle, or benzo[5]-membered heterocycle may be monosubstituted or polysubstituted; the benzo[6]-membered heterocycle or benzo[5]-membered heterocycle may contain one heteroatom or multiple heteroatoms, wherein the heteroatom is selected from O, N, and S; n is selected from 1, 2, and 3; wherein the halogen includes F, Cl, and Br.

[0019] M is independently selected from different alkali metals (lithium, sodium, potassium, cesium) or alkaline earth metal salts (calcium, magnesium, barium).

[0020] R is preferably selected from Cl and NO2.

[0021] According to general formula I of the present invention, preferred compounds of the present invention include, but are not limited to, compounds represented by general formula (IA):

[0022]

[0023] Ar1 is selected from substituted or unsubstituted phenyl groups, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycles, and substituted or unsubstituted five-membered aromatic heterocycles, wherein the substituents are selected from C1-4 straight-chain or branched alkyl groups, halogen-substituted C1-4 straight-chain or branched alkyl groups, F, Cl, Br, NO2, CN, methylenedioxy, ORa′1, SRa′2, NRa′3Rb′1, COORa′4, CONRa′5Rb′2, NRa′6COORb′3, SO2NRa′7Rb′4, NRa′8CORb′5, (CH2)nNRa′9Rb′6, and (CH2)nORa′ 10, wherein 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 The components are independently selected from H, C1-4 straight-chain or branched alkyl groups, cyclopropyl, cyclopropylmethylene, cyclobutyl, and cyclopentyl; the benzene ring, nitrogen-containing six-membered aromatic heterocycle, and five-membered aromatic heterocycle may be monosubstituted or polysubstituted; 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, the heteroatom being selected from O, N, and S; n is selected from 1, 2, and 3; the halogens mentioned include F, Cl, and Br.

[0024] Ar2 is selected from the following groups or structural fragments:

[0025] (1) A substituted or unsubstituted phenyl group, a substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, a substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl groups, halogen-substituted C1-4 straight-chain or branched alkyl groups, F, Cl, Br, NO2, CN, methylenedioxy, ORs1, SRs2, NRs3Rt1, NRs4CORt2, COORs5, CONRs6Rt3, NRs7COORt4, SO2NRs8Rt5, (CH2)nNRs9Rt6, (CH2)nORs 10 The values ​​Rs1, Rs2, Rs3, Rt1, Rs4, Rt2, Rs5, Rs6, Rt3, Rs7, Rt4, Rs8, Rt5, Rs9, Rt6, and Rs 10 The halogen is independently selected from H, C1-4 straight-chain or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, and cyclopentyl; the benzene ring, nitrogen-containing six-membered aromatic heterocycle, and five-membered aromatic heterocycle may be monosubstituted or polysubstituted; 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, the heteroatom being selected from O, N, and S; n is selected from 1, 2, and 3; wherein the halogen includes F, Cl, and Br;

[0026] (2) Substituted or unsubstituted aromatic fused rings or fused heterocycles, substituted or unsubstituted non-aromatic fused rings or fused heterocycles, including substituted or unsubstituted naphthyl rings, substituted or unsubstituted benzo6-membered heterocycles, substituted or unsubstituted benzo5-membered heterocycles, wherein the substituents are selected from C1-4 straight-chain or branched alkyl groups, halogen-substituted C1-4 straight-chain or branched alkyl groups, F, Cl, Br, NO2, CN, methylenedioxy, ORs1, SRs2, NRs3Rt1, NRs4CORt2, COORs5, CONRs6Rt3, NRs7COORt4, SO2NRs8Rt5, (CH2)nNRs9Rt6, (CH2)nORs 10 The values ​​Rs1, Rs2, Rs3, Rt1, Rs4, Rt2, Rs5, Rs6, Rt3, Rs7, Rt4, Rs8, Rt5, Rs9, Rt6, and Rs 10 The halogen is independently selected from H, C1-4 straight-chain or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, and cyclopentyl; wherein the naphthalene ring, benzo[6]-membered heterocycle, or benzo[5]-membered heterocycle may be monosubstituted or polysubstituted; the benzo[6]-membered heterocycle or benzo[5]-membered heterocycle may contain one heteroatom or multiple heteroatoms, wherein the heteroatom is selected from O, N, and S; n is selected from 1, 2, and 3; wherein the halogen includes F, Cl, and Br.

[0027] M is independently selected from different alkali metals (lithium, sodium, potassium, cesium) or alkaline earth metal salts (calcium, magnesium, barium).

[0028] According to the general formula IA of the present invention, preferred compounds of the present invention include, but are not limited to, compounds represented by general formula (IAa):

[0029]

[0030] R A It can be a single substitution or a multiple substitution;

[0031] R A It can be independently selected from the following groups or structural fragments:

[0032] C1-4 straight-chain or branched alkyl groups, halogen-substituted C1-4 straight-chain or branched alkyl groups, F, Cl, Br, NO2, CN, methylenedioxy, ORa′1, SRa′2, NRa′3Rb′1, COORa′4, CONRa′5Rb′2, NRa′6COORb′3, SO2NRa′7Rb′4, NRa′8CORb′5, (CH2)nNRa′9Rb′6, (CH2)nORa′ 10, wherein 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 Independently selected from H, C1-4 straight-chain or branched alkyl groups, cyclopropyl, cyclopropylmethylene, cyclobutyl, and cyclopentyl;

[0033] Ar2 is selected from the following groups or structural fragments:

[0034] (1) A substituted or unsubstituted phenyl group, a substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, a substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl groups, halogen-substituted C1-4 straight-chain or branched alkyl groups, F, Cl, Br, NO2, CN, methylenedioxy, ORs1, SRs2, NRs3Rt1, NRs4CORt2, COORs5, CONRs6Rt3, NRs7COORt4, SO2NRs8Rt5, (CH2)nNRs9Rt6, (CH2)nORs 10 The values ​​Rs1, Rs2, Rs3, Rt1, Rs4, Rt2, Rs5, Rs6, Rt3, Rs7, Rt4, Rs8, Rt5, Rs9, Rt6, and Rs 10 The halogen is independently selected from H, C1-4 straight-chain or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, and cyclopentyl; the benzene ring, nitrogen-containing six-membered aromatic heterocycle, and five-membered aromatic heterocycle may be monosubstituted or polysubstituted; 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, the heteroatom being selected from O, N, and S; n is selected from 1, 2, and 3; wherein the halogen includes F, Cl, and Br;

[0035] (2) Substituted or unsubstituted aromatic fused rings or fused heterocycles, substituted or unsubstituted non-aromatic fused rings or fused heterocycles, including substituted or unsubstituted naphthyl rings, substituted or unsubstituted benzo6-membered heterocycles, substituted or unsubstituted benzo5-membered heterocycles, wherein the substituents are selected from C1-4 straight-chain or branched alkyl groups, halogen-substituted C1-4 straight-chain or branched alkyl groups, F, Cl, Br, NO2, CN, methylenedioxy, ORs1, SRs2, NRs3Rt1, NRs4CORt2, COORs5, CONRs6Rt3, NRs7COORt4, SO2NRs8Rt5, (CH2)nNRs9Rt6, (CH2)nORs 10 The values ​​Rs1, Rs2, Rs3, Rt1, Rs4, Rt2, Rs5, Rs6, Rt3, Rs7, Rt4, Rs8, Rt5, Rs9, Rt6, and Rs 10The halogen is independently selected from H, C1-4 straight-chain or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, and cyclopentyl; wherein the naphthalene ring, benzo[6]-membered heterocycle, or benzo[5]-membered heterocycle may be monosubstituted or polysubstituted; the benzo[6]-membered heterocycle or benzo[5]-membered heterocycle may contain one heteroatom or multiple heteroatoms, wherein the heteroatom is selected from O, N, and S; n is selected from 1, 2, and 3; wherein the halogen includes F, Cl, and Br.

[0036] M is independently selected from different alkali metals (lithium, sodium, potassium, cesium) or alkaline earth metal salts (calcium, magnesium, barium).

[0037] According to the general formula IA of the present invention, preferred compounds of the present invention include, but are not limited to, compounds represented by general formula (IAb):

[0038]

[0039] R B It can be a single substitution or a multiple substitution;

[0040] R B It can be independently selected from the following groups or structural fragments:

[0041] C1-4 straight-chain or branched alkyl groups, halogen-substituted C1-4 straight-chain or branched alkyl groups, F, Cl, Br, NO2, CN, methylenedioxy, ORa′1, SRa′2, NRa′3Rb′1, COORa′4, CONRa′5Rb′2, NRa′6COORb′3, SO2NRa′7Rb′4, NRa′8CORb′5, (CH2)nNRa′9Rb′6, (CH2)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 Independently selected from H, C1-4 straight-chain or branched alkyl groups, cyclopropyl, cyclopropylmethylene, cyclobutyl, and cyclopentyl;

[0042] Ar1 is selected from substituted or unsubstituted phenyl groups, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycles, and substituted or unsubstituted five-membered aromatic heterocycles, wherein the substituents are selected from C1-4 straight-chain or branched alkyl groups, halogen-substituted C1-4 straight-chain or branched alkyl groups, F, Cl, Br, NO2, CN, methylenedioxy, ORa′1, SRa′2, NRa′3Rb′1, COORa′4, CONRa′5Rb′2, NRa′6COORb′3, SO2NRa′7Rb′4, NRa′8CORb′5, (CH2)nNRa′9Rb′6, and (CH2)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 The components are independently selected from H, C1-4 straight-chain or branched alkyl groups, cyclopropyl, cyclopropylmethylene, cyclobutyl, and cyclopentyl; the benzene ring, nitrogen-containing six-membered aromatic heterocycle, and five-membered aromatic heterocycle may be monosubstituted or polysubstituted; 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, the heteroatom being selected from O, N, and S; n is selected from 1, 2, and 3; the halogens mentioned include F, Cl, and Br.

[0043] M is independently selected from different alkali metals (lithium, sodium, potassium, cesium) or alkaline earth metal salts (calcium, magnesium, barium).

[0044] To achieve the objectives of this invention, preferred compounds include, but are not limited to:

[0045]

[0046] The second aspect of the present invention is to provide a method for preparing the compound described in the first aspect, the method comprising the following steps:

[0047] In an ethanolic solution of sodium alkoxide, 5-R-substituted o-bromobenzaldehyde condenses with ethyl azide to give compound 1. Compound 1 undergoes cyclization at 180 °C using o-dichlorobenzene as a solvent to give 7-R-substituted ethyl 4-bromo-1-H-indole-2-carboxylate (compound 2). Then, under cesium carbonate conditions, methylation occurs at the indole-1-position to give 7-R-substituted ethyl 4-bromo-1-methyl-indole-2-carboxylate (compound 3). Subsequently, compound 3 undergoes a palladium-catalyzed coupling reaction with an aryl bromide to give compound 4. After hydrolysis, compound 4 yields compound 5, which has a carboxyl group at the 2-position. Compound 5 undergoes a condensation reaction with aryl methanesulfonamide to give compound 6. Finally, it undergoes acid-base reactions with different bases to give N-acylsulfonamide salts.

[0048]

[0049] 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; (d) Ar1-Br, Pd2(dba)3, Xantphos, sodium carbonate, toluene, water, 100°C; (e) Sodium hydroxide, THF, ethanol, water, rt; (g) Ar2-S(O)2-OH, HATU, DMAP, Et3N, rt; (g) Alkali metal or alkaline earth metal base, water, 80°C;

[0050] The definitions of R, Ar1, Ar2, and M therein are the same as those of the compounds described in the first aspect of this invention.

[0051] A third aspect of the present invention is to provide a pharmaceutical composition comprising the compound described in the first aspect of the present invention and a commonly used pharmaceutical carrier.

[0052] This invention also provides pharmaceutical compositions using compounds of the present invention as active ingredients, the compositions comprising at least one compound of the present invention and a pharmaceutically acceptable carrier. The pharmaceutical compositions are selected from tablets, capsules, pills, injections, sustained-release formulations, controlled-release formulations, or various microparticle delivery systems. The pharmaceutical compositions can be prepared according to methods known in the art. They can be formulated into any dosage form suitable for human or animal use 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 compounds of the present invention in their pharmaceutical compositions is typically 0.1-95% by weight.

[0053] The compounds of this invention or pharmaceutical compositions containing them can be administered in unit dose form via enteral or non-enteric routes, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum, etc.

[0054] Dosage forms can be liquid, solid, or semi-solid. Liquid dosage forms can include solutions (including true solutions and colloidal solutions), emulsions (including o / w, w / o, and double emulsions), suspensions, injections (including aqueous injections, powder injections, and infusions), eye drops, nasal drops, lotions, and liniments, etc.; solid dosage forms can include tablets (including regular tablets, enteric-coated tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, and orally disintegrating tablets), capsules (including hard capsules, soft capsules, and enteric-coated capsules), granules, powders, microcapsules, pellets, suppositories, films, patches, aerosols, and sprays, etc.; semi-solid dosage forms can include ointments, gels, and pastes, etc.

[0055] The compounds of this invention can be formulated into conventional formulations, sustained-release formulations, controlled-release formulations, targeted formulations, and various microparticle delivery systems.

[0056] These formulations are prepared according to methods well known to those skilled in the art. The excipients used in the manufacture of tablets, capsules, and coatings are conventionally used adjuvants, such as starch, gelatin, gum arabic, silica, and polyethylene glycol. Solvents used in liquid dosage forms include, for example, water, ethanol, propylene glycol, and vegetable oils such as corn oil, peanut oil, and olive oil. Formulations containing the compounds of this invention may also contain other adjuvants, such as surfactants, lubricants, disintegrants, preservatives, flavoring agents, and colorants.

[0057] To formulate the compounds of the present invention into tablets, a wide variety of excipients known in the art can be used, including diluents, binders, wetting agents, disintegrants, lubricants, and flow aids. Diluents can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, dicalcium phosphate, calcium carbonate, etc.; wetting agents can be water, ethanol, isopropanol, etc.; binders can be starch paste, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, gum arabic paste, gelatin paste, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; disintegrants can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfonate, etc.; lubricants and flow aids can be talc, silica, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc.

[0058] Tablets can also be further processed into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or bilayer and multilayer tablets.

[0059] To formulate the drug delivery unit into capsules, the active ingredient, the compound of the present invention, can be mixed with a diluent and a disintegrant, and the mixture can be placed directly into hard or soft capsules. Alternatively, the active ingredient, the compound of the present invention, can be first formed into granules or microspheres with a diluent, binder, and disintegrant, and then placed into hard or soft capsules. The diluents, binders, wetting agents, disintegrants, and disintegrants used to prepare tablets of the compound of the present invention can also be used to prepare capsules of the compound of the present invention.

[0060] To prepare the compounds of this invention into injectable formulations, water, ethanol, isopropanol, propylene glycol, or mixtures thereof can be used as solvents, and appropriate amounts of commonly used solubilizers, co-solvents, pH adjusters, and osmotic pressure regulators can be added. Solubilizers or co-solvents can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin, etc.; pH adjusters can be phosphates, acetates, hydrochloric acid, sodium hydroxide, etc.; osmotic pressure regulators can be sodium chloride, mannitol, glucose, phosphates, acetates, etc. If preparing lyophilized powder injections, mannitol, glucose, etc., can also be added as supporting agents.

[0061] In addition, colorants, preservatives, flavorings, tasters or other additives may be added to pharmaceutical preparations if necessary.

[0062] To achieve the purpose of medication and enhance the therapeutic effect, the drug or drug composition of the present invention can be administered using any known method of administration.

[0063] The dosage of the pharmaceutical compositions of the present invention can vary widely depending on 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. Generally, the suitable daily dose 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 dosage can be administered as a single dose unit or divided into several dose units, depending on the physician's clinical experience and the dosing regimen, including the use of other treatment methods.

[0064] The compounds or compositions of the present invention can be taken alone or in combination with other therapeutic or symptomatic drugs. When the compounds of the present invention have a synergistic effect with other therapeutic drugs, their dosage should be adjusted according to the actual situation.

[0065] The fourth aspect of this invention is the use of the compound described in the first aspect in the preparation of FBPase inhibitors and in the preparation of medicaments for the prevention and / or treatment of FBPase-related diseases and conditions. The use is characterized in that the FBPase-related diseases and conditions are selected from diabetes, chronic complications of diabetes, and obesity. The diabetes is selected from type 1 diabetes and type 2 diabetes; the chronic complications of diabetes are selected from retinopathy, nephropathy, neurological complications, vascular complications, ischemic heart disease, or atherosclerosis. Detailed Implementation

[0066] The invention will be further described below with reference to embodiments, but this does not limit the scope of the invention.

[0067] The structure of the compound was determined by nuclear magnetic resonance (NMR) or high-resolution mass spectrometry (HRMS). NMR measurements were performed using a Varian Mercury 300 or Varian Mercury 400 spectrometer with solvents including CDCl3, DMSO-d6, acetone-d6, and CD3OD. TMS was used as the internal standard, and chemical shifts were given in ppm. Ms were measured using a Thermo Exactive Plus mass spectrometer. mp values ​​are given as melting points in °C, without temperature correction. Silica gel column chromatography typically used 200–300 mesh silica gel as the support.

[0068] The reagents used in the experiment were chemically pure or analytically pure. All solvents used were analytically pure, and the anhydrous solvents used were obtained from the solvent purification system manufactured by INNOVATIVE TECHNOLOGY, USA. Other solvents were not treated unless otherwise specified.

[0069] List of abbreviations:

[0070] TLC: Thin-layer chromatography; DMAP: 4-Dimethylaminopyridine

[0071] CDCl3: deuterated chloroform DMSO-d6: deuterated dimethyl sulfoxide

[0072] acetone-d6: deuterated acetone; CD3OD: deuterated methanol

[0073] DMAP: 4-Dimethylaminopyridine Et3N: Triethylamine

[0074] EA: Ethyl acetate

[0075] HATU: 2-(7-Azobenzotriazole)-N,N,N',N'-Tetramethylurea hexafluorophosphate

[0076] XantPhos: 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene

[0077] Pd3(dba)2: Tris(dibenzylacetone)dipalladium

[0078] min: minutes; h: hours

[0079] P / E: Petroleum ether / ethyl acetate; D / M: Dichloromethane / methanol

[0080] Preparation of intermediate: Ethyl 1-methyl-7-chloro-4-bromo-1H-indole-2-carboxylate

[0081]

[0082] a) Ethyl 2-azido-3-(5-chloro-2-bromophenyl)acrylate

[0083]

[0084] Sodium metal (8.35 g, 363.2 mmol) was dissolved in anhydrous ethanol (200 mL). After the sodium metal 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 portions. The reaction was carried out at -15 °C for 1 h, then heated to -5 °C for 1 h, then heated to 0 °C for 5 h, and finally allowed to react overnight at room temperature. The reaction solution was poured into a saturated NH4Cl aqueous solution and extracted with EA (150 mL × 3). The organic layers were combined, washed with saturated sodium chloride solution (100 mL × 2), dried over anhydrous magnesium sulfate, concentrated, and passed through a vacuum column (DCM:PE = 1:1). The solution was concentrated and recrystallized with PE:EA = 20:1 to give 36.5 g of an off-white solid, yield 48.9%.

[0085] 1 H NMR (400MHz, CDCl3) δ (ppm): 8.13 (s, 1H), 7.53 (d, J = 8.4Hz, 1H), 7.15 (s, 2H), 4.40 (q, J = 7.2Hz, 2H), 1.42 (t, J = 7.2Hz, 3H).

[0086] b) Ethyl 7-chloro-4-bromo-1H-indole-2-carboxylate

[0087]

[0088] Ethyl 2-azido-3-(5-chloro-2-bromophenyl)acrylate (15 g) was placed in a reaction flask, and o-dichlorobenzene (15 mL) was added. The mixture was heated to 180 °C and reacted. After 1 h, the reaction was stopped and cooled. A solid precipitated out. The solid was filtered to give 7.2 g of white solid, with a yield of 52.7%.

[0089] 1 H NMR (400MHz, CDCl3) δ (ppm): 9.11 (brs, 1H), 7.27 (d, J = 8.4Hz, 2H), 7.18 (d, J = 8.0Hz, 1H), 4.44 (q, J = 7.2Hz, 2H), 1.44 (t, J = 7.2Hz, 3H).

[0090] c) Ethyl 1-methyl-7-chloro-4-bromo-1H-indole-2-carboxylate

[0091]

[0092] Ethyl 7-chloro-4-bromo-1H-indole-2-carboxylate (26.2 g, 86.24 mmol) was placed in a reaction flask, and DMF (300 mL) was added. Cesium carbonate (55.9 g, 172.58 mmol) and methyl iodoform (24.7 g, 132.58 mmol) were added. The mixture was stirred at room temperature and the reaction was stopped after 1 h. The reaction solution was poured into ice water, and a solid precipitated out. The solid was filtered to give 26 g of an off-white solid, with a yield of 94.8%.

[0093] 1 H NMR (400MHz, CDCl3) δ (ppm): 7.32 (s, 1H), 7.19 (d, J = 8.0Hz, 1H), 7.13 (d, J = 8.0Hz, 1H), 4.46 (s, 3H), 4.39 (q, J = 7.2Hz, 2H), 1.43 (t, J = 7.2Hz, 3H).

[0094] Example 1: Sodium salt of 1-methyl-4-((3-methoxyphenyl)amino)-7-chloro-N-(4-methoxybenzenesulfonyl)-1H-indole-2-carboxamide

[0095]

[0096] a) Ethyl 1-methyl-4-((3-methoxyphenyl)amino)-7-chloro-1H-indole-2-carboxylate

[0097]

[0098] Ethyl 1-methyl-7-chloro-4-bromo-1H-indole-2-carboxylate (942 mg, 3 mmol) was dissolved in toluene (20 mL). Under argon protection, Pd₂(dba)₃ (686 mg, 0.75 mmol) and Xantphos (874 mg, 0.5 mmol) were added. Then, Na₂CO₃ (954 mg, 9 mmol) was dissolved in 5 mL of water and added to the reaction solution. m-Methoxyaniline (1 mL, 9 mmol) was added to the reaction flask, and the mixture was refluxed for 30 h. After filtration, the filtrate was added to ethyl acetate, washed with dilute hydrochloric acid, washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and subjected to column chromatography (E:P = 1:30) to give 610 mg of a pale yellow solid, with a yield of 56.8%.

[0099] 1H NMR (400MHz, CDCl3) δ (ppm): 7.30 (s, 1H), 7.20 (t, J = 8.4Hz, 1H), 7.15 (d, J = 8.4Hz, 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).

[0100] b) 1-Methyl-4-((3-methoxyphenyl)amino)-7-chloro-1H-indole-2-carboxylic acid

[0101]

[0102] Ethyl 1-methyl-4-((3-methoxyphenyl)amino)-7-chloro-1H-indole-2-carboxylate (6.6 g, 18.4 mmol) was dissolved in a mixture of THF (30 mL) and EtOH (30 mL). NaOH (2.21 g, 55.3 mmol) was dissolved in 10 mL of water and added to the reaction mixture. The reaction was carried out at 40 °C for 2 h. The mixture was concentrated, a small amount of water was added, and the mixture was extracted with diethyl ether. The pH of the aqueous layer was adjusted to 2-3 with dilute hydrochloric acid, and a solid precipitated out. The solid was filtered, and the filter cake was washed with water to obtain 6.0 g of yellow-green solid, with a yield of 98.6%.

[0103] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 13.00 (s, 1H), 8.34 (s, 1H), 7.61 (s, 1H), 7.17 (t, J = 8.0Hz, 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).

[0104] c) 1-Methyl-4-((3-methoxyphenyl)amino)-7-chloro-N-(4-methoxybenzenesulfonyl)-1H-indole-2-carboxamide (compound P)

[0105]

[0106] 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), followed by the addition of HATU (23.42 g, 61.6 mmol), DMAP (2.51 g, 20.54 mmol), and Et3N (17.8 mL, 123.27 mmol). After thorough mixing, benzenesulfonamide (11.54 g, 61.6 mmol) was added, and the mixture was heated to 40 °C and reacted for 1 h. The mixture was then concentrated, ethyl acetate was added, and the solution was washed with dilute hydrochloric acid, water, and saturated sodium chloride solution. The solution was dried over anhydrous magnesium sulfate and recrystallized from ethyl acetate to give 10.3 g of a yellow powdery solid, with a yield of 50%.

[0107] 1 H NMR (500MHz, DMSO-d6) δ (ppm): 8.31 (s, 1H), 7.99 (d, J = 7.5Hz, 2H), 7.24 (d, J = 8.5Hz, 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 N4O5ClS[M+H] + :501.0999,found 501.0985.

[0108] d) Sodium 1-methyl-4-((3-methoxyphenyl)amino)-7-chloro-N-(4-methoxybenzenesulfonyl)-1H-indole-2-carboxamide (Example 1)

[0109]

[0110] 998 mg, 2 mmol of 1-methyl-4-((3-methoxyphenyl)amino)-7-chloro-N-(4-methoxybenzenesulfonyl)-1H-indole-2-carboxamide was added to H2O (4 mL). 100 mg, 2.5 mmol of NaOH was dissolved in 1 mL of water and added to the reaction solution. After the addition was complete, the temperature was raised to 80 °C and the reaction was stopped after 4 h. The mixture was cooled to room temperature, filtered, and the filter cake was washed with water to obtain 868 mg of a yellowish-brown solid, with a yield of 83%.

[0111] 1H NMR (400MHz, DMSO-d6) δ (ppm): 8.20 (s, 1H), 7.78-7.77 (d, J = 8.4Hz, 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).

[0112] Example 2 Potassium salt of 1-methyl-4-((3-methoxyphenyl)amino)-7-chloro-N-(4-methoxybenzenesulfonyl)-1H-indole-2-carboxamide

[0113]

[0114] 1-Methyl-4-((3-methoxyphenyl)amino)-7-chloro-N-(4-methoxybenzenesulfonyl)-1H-indole-2-carboxamide (220 mg, 0.441 mmol) was added to H₂O (1.5 mL), and KOH (25.2 mg, 0.4496 mmol) was dissolved in a small amount of water and added to the reaction flask. The mixture was heated to 80 °C and reacted for 1 h, after which the system turned into a pale yellow clear liquid. The reaction was stopped, and water was removed by rotary evaporation to give a brownish-yellow solid. Recrystallization from ethanol yielded 195 mg of the brownish-yellow solid, with a yield of 82.3%.

[0115] 1 H NMR (400MHz, DMSO-d6) 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).

[0116] Example 3 Sodium salt of 1-methyl-4-((3-methoxy-4-fluorophenyl)amino)-7-chloro-N-(4-methoxybenzenesulfonyl)-1H-indole-2-carboxamide

[0117]

[0118] a) Ethyl 1-methyl-4-((3-methoxyphenyl)amino)-7-chloro-1H-indole-2-carboxylate

[0119]

[0120] Ethyl 1-methyl-7-chloro-4-bromo-1H-indole-2-carboxylate (316 mg, 1 mmol) was dissolved in toluene (10 mL). Under argon protection, Pd₂(dba)₃ (229 mg, 0.25 mmol) and Xantphos (291 mg, 0.5 mmol) were added. Then, Na₂CO₃ (318 mg, 3 mmol) was dissolved in 2.5 mL of water and added to the reaction solution. m-Methoxyaniline (0.33 mL, 3 mmol) was added to the reaction flask, and the mixture was refluxed for 30 h. After filtration, the filtrate was added to ethyl acetate, washed with dilute hydrochloric acid, washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and crystallized from EA / diethyl ether to give 272 mg of a pale yellow solid (72.1%).

[0121] b) 1-Methyl-4-((3-methoxy-4-fluorophenyl)amino)-7-chloro-1H-indole-2-carboxylic acid

[0122]

[0123] Ethyl 1-methyl-4-((3-methoxy-4-fluorophenyl)amino)-7-chloro-1H-indole-2-carboxylate (200 mg, 0.53 mmol) was dissolved in THF / EtOH (1 / 2, v / v, 9 mL), and NaOH solution (105 mg, 2.65 mmol, 3 mL H2O) was added. The reaction was carried out overnight at room temperature. After the reaction was stopped, the solvent was evaporated, a small amount of water was added, and the pH was adjusted to 2 with 1 M hydrochloric acid. The solid precipitated, filtered, and dried to give 177 mg of a pale yellow-green solid, with a yield of 96%.

[0124] 1 H NMR(400MHz,DMSO-d6)δ13.01(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);

[0125] c) 1-Methyl-4-((3-methoxy-4-fluorophenyl)amino)-7-chloro-N-(4-methoxybenzenesulfonyl)-1H-indole-2-carboxamide

[0126]

[0127] 1-Methyl-4-((3-methoxyphenyl)amino)-7-chloro-1H-indole-2-carboxylic acid (350 mg, 1 mmol) was dissolved in dry DCM. HATU (685 mg, 1.8 mmol), DMAP (65 mg, 0.5 mmol), and TEA (303 mg, 3 mmol) were added sequentially. After thorough stirring, benzenesulfonamide (560 mg, 3 mmol) was added. The reaction was carried out at 40 °C for 1.0 h. The reaction was then stopped, the solvent was evaporated, and the mixture was washed successively with dilute hydrochloric acid, water, and brine. The EA layers were combined, and the EA was recrystallized to give 395 mg of a pale yellow solid, with a yield of 77%.

[0128] 1 H NMR(400MHz,DMSO-d6)δ12.50(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);

[0129] d) Sodium 1-methyl-4-((3-methoxy-4-fluorophenyl)amino)-7-chloro-N-(4-methoxybenzenesulfonyl)-1H-indole-2-carboxamide

[0130]

[0131] 1.0805 g (2.0896 mmol) of 1-methyl-4-((3-methoxy-4-fluorophenyl)amino)-7-chloro-N-(4-methoxybenzenesulfonyl)-1H-indole-2-carboxamide (5 mL) and 86 mg (2.1314 mmol) of NaOH were dissolved in 1 mL of water. The mixture was heated to 80 °C and reacted for 1 h. The system turned into a light yellow clear liquid. The reaction was stopped, and water was removed by rotary evaporation to give a brownish-yellow solid. Recrystallization from ethanol gave 919 mg of the brownish-yellow solid, with a yield of 81.6%.

[0132] 1 H NMR (400MHz, DMSO-d6) δ8.17(s,1H),7.77(d,J=8.6Hz,2H),7.69(d,J=8.4Hz,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=2.3Hz,6H).

[0133] Pharmacological experiments:

[0134] Experimental Example 1. Antidiabetic effect of Example 1 and its prototype compound P on type 2 diabetic ZDF rats

[0135] I. Experimental animals and grouping

[0136] 1. Spontaneous type 2 diabetic ZDF rats

[0137] Spontaneous type 2 diabetic ZDF rats, male, 8-week-old, certificate No. No.11400700293700, were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd., with license No. SYXK (Jing) 2014-0023, and housed in the SPF-grade animal room of Institute of Materia Medica, Chinese Academy of Medical Sciences, 4 rats per cage, with free access to food and water. The rats were fed with high-quality mouse chow 5008 (referred to as purina) for about 7 weeks, and were used for pharmacodynamic evaluation after the type 2 diabetes model was established.

[0138] 2. Normal ZDF control rats

[0139] Normal ZDF control rats, male, 8-week-old, certificate No. No.11400700293705, were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd., with license No. SYXK (Jing) 2014-0023, and housed in the SPF-grade animal room of Institute of Materia Medica, Chinese Academy of Medical Sciences. After being fed with normal maintenance diet for about 7 weeks, the rats were used in the experiment as the normal control group of ZDF, 4 rats per cage, with free access to food and water.

[0140] 3. Animal grouping

[0141] ZDF rats were fed with high-fat diet for about 7 weeks, and then subjected to multi-index prediction and grouping. The main observation indicators included: random blood glucose, fasting blood glucose, percentage blood glucose reduction at 40 min in insulin tolerance test (ITT), blood triglyceride (TG), total cholesterol (TC) and body weight.

[0142] 4. Experimental protocol

[0143] Animals were administered by intragastric gavage, and the control group was gavaged with corresponding volume of 0.5% CMC-Na solution once a day for consecutive 35 days.

[0144] 1) On day 23 of administration, random blood glucose was measured, and on day 20 of administration, fasting blood glucose was measured;

[0145] 2) On day 20 of administration, ZDF rats underwent sodium pyruvate tolerance test;

[0146] 3) On day 34 of administration, the level of glycated hemoglobin (HbA1c) in ZDF rats was measured. II. Dosage setting and preparation of test drugs

[0147] 1. Dosage setting and preparation

[0148] 1) Compound P (150 mg / kg)

[0149] Weigh 4.5g of compound P, place it in a mortar, grind it, suspend it in 0.5% CMC-Na distilled water, and bring the volume to 150ml. Administer 0.5ml / 100g body weight by gavage, i.e., the dose is 150mg / kg.

[0150] 2) Example 1 (150mg / kg)

[0151] Weigh 4.5g of Example 1, place it in a mortar, grind it, suspend it in 0.5% CMC-Na distilled water, and make up to 150ml. Administer by gavage at a dose of 0.5ml / 100g body weight, i.e., a dose of 150mg / kg.

[0152] 3) Metformin (150 mg / kg)

[0153] Weigh 4.5g of metformin, place the compound in a mortar and grind it, dissolve it in distilled water, and bring the volume to 150ml. Administer 0.5ml / 100g body weight by gavage, i.e., a dose of 150mg / kg.

[0154] III. Main Instruments and Reagents

[0155] 1. Main Instruments

[0156] 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-functional microplate reader (Synergy2, BIO-TEK), analytical balance (Sartorius, BSA224S-CW), digital electronic scale (MODUS), 1ml syringe (BD, batch number 302101), 5ml syringe (Shanghai Medical Laser Instrument Factory, State-owned), injection needle (Leng brand, 0.5×20).

[0157] 2. Main reagents

[0158] Glucose (Sinopharm Chemical Reagent Co., Ltd., 20141016), blood glucose assay GOD enzyme (sigma), glycated hemoglobin assay kit (Beijing Haomai Biotechnology Co., Ltd., A5911), sodium pyruvate (Beijing Bailingwei Technology Co., Ltd., 297561), insulin (Eli Lilly Suzhou Pharmaceutical Co., Ltd., H0219).

[0159] IV. Experimental Methods

[0160] 1. Measurement of fasting and random blood glucose

[0161] Blood was collected from the tail tip of animals under non-fasting conditions, and random blood glucose was measured using the glucose oxidase method (the same below). Blood was collected from the tail tip of animals after overnight fasting, and fasting blood glucose was measured.

[0162] 2. HbA1c level measurement

[0163] Collect 10 μl of blood from the animal's tail tip and add it to 150 μl of hemolysing agent. Mix well. Then, follow the instructions of the HbA1c kit and measure the absorbance at a wavelength of 700 / 800 nm to calculate the glycated hemoglobin (HbA1c) level.

[0164] 3. Pyruvate Sodium Tolerance Test (PTT)

[0165] On the day of the experiment, animals were fasted overnight and administered the drug via gavage. Two hours after the administration (17 hours of fasting), blood was collected from the tip of the tail (0 min). Then, sodium pyruvate solution was administered via gavage. Blood was collected from the tip of the tail at 30 min and 60 min after the administration of sodium pyruvate to measure blood glucose levels before and after the administration of pyruvate.

[0166] V. Experimental Results

[0167] 1. Effects on random blood glucose and fasting blood glucose levels in ZDF rats

[0168] The results are shown in Table 1. Compound P, at a dose of 150 mg / kg, significantly reduced random blood glucose in ZDF rats (P<0.05) with a reduction percentage of 16.9%, which was superior to the positive control drug metformin. In Example 1, at a dose of 150 mg / kg, compound P reduced both random blood glucose (P<0.01) and fasting blood glucose (P<0.001), with a reduction percentage of 27.0% for random blood glucose and 62.2% for fasting blood glucose. This effect was superior to the positive control drug metformin.

[0169] Table 1. Effects of long-term administration of the compound on random blood glucose and fasting blood glucose in ZDF rats

[0170]

[0171]

[0172] Blood glucose data are expressed as mean ± SD, n = 10, vs Con, *P < 0.05, **P < 0.01, ***P < 0.001.

[0173] 2. Effects on glycated hemoglobin (HbA1c) in ZDF rats

[0174] Glycated hemoglobin (HbA1c) level was measured on the 34th day after administration. The results are shown in Table 2. Compared with the normal control group (Nor), the blood HbA1c level of rats in the model group (Con) was significantly increased (P<0.001). Compared with the Con group, administration of Example 1 for 34 days significantly reduced the average HbA1c of ZDF rats.

[0175] Table 2. Effect of long-term administration of the compound on glycated hemoglobin (HbA1c) in ZDF rats

[0176]

[0177] HbA1c (%) is expressed as mean±sd, n=10. vs Con *P<0.05, **P<0.01, ***P<0.001.

[0178] 3. Effect on gluconeogenesis ability of ZDF rats

[0179] The experiment was carried out on the 20th day of administration, and the results are shown in Table 3. After administration of sodium pyruvate, compared with the Con group, Example 1 had a stronger gluconeogenesis inhibition ability in terms of the area under the blood glucose-time curve.

[0180] Table 3. Effect on gluconeogenesis ability of ZDF rats

[0181]

[0182]

[0183] Both blood glucose and AUC data are presented as mean±sd, n=10, vs Con. *P<0.05, **P<0.01, ***P<0.001.

[0184] Experimental Example 2. Antidiabetic effect of Example 1 and Example 3 on type 2 diabetic KKAy mice

[0185] 1. Experimental animals and grouping

[0186] 1. Spontaneous type 2 diabetic KKAy mice

[0187] Spontaneous type 2 diabetic KKAy mice, female, 11-12 weeks of age, certificate No.: No.11401300055400, were purchased from Beijing Huafukang Bioscience Co., Ltd., with license No. SCXK (Jing) 2014-0004. They were housed in the SPF-level animal facility of the Institute of Materia Medica, Chinese Academy of Medical Sciences, 5 mice per cage, with free access to food and water. They were fed a high-fat diet for about 10 weeks, and were used for pharmacodynamic evaluation after the type 2 diabetes model was established.

[0188] 2. C57BL / 6J mice

[0189] Normal C57BL / 6J mice, female, aged 6-8 weeks, with the certificate No. 11400700221894, were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd., with the license number SCXK (Jing) 2016-0011, and housed in the SPF-grade animal room of Institute of Materia Medica, Chinese Academy of Medical Sciences. After being fed with normal maintenance diet for about 14 weeks, they were used as the normal mouse control group for the experiment, with 5 mice per cage and free access to food and water.

[0190] 3. Animal grouping

[0191] KKAy mice were fed with a high-fat diet for about 10 weeks, then subjected to multi-index prediction and grouping. The main observation indicators include: random blood glucose, fasting blood glucose, percentage of blood glucose decrease at 40 min in insulin tolerance test (ITT), blood triglyceride (TG), blood total cholesterol (TC) and body weight.

[0192] II. Dosage setting and preparation of test drug

[0193] Dosage setting and preparation

[0194] 1) Example 1

[0195] Three dose groups were set up: 150 mg, 300 mg and 600 mg of the compound of Example 1 were weighed respectively, placed in a mortar, ground, suspended in 0.5% CMC-Na distilled water and adjusted to a constant volume of 30 ml. The administration volume was 0.1 ml / 10 g, corresponding to doses of 50 mg / kg, 100 mg / kg and 200 mg / kg.

[0196] 2) Example 3 (100 mg / kg)

[0197] 300 mg of the compound was weighed, placed in a mortar, ground, suspended in 0.5% CMC-Na distilled water and adjusted to a constant volume of 30 ml. The administration volume was 0.1 ml / 10 g, corresponding to a dose of 100 mg / kg.

[0198] 3) Metformin hydrochloride (150 mg / kg)

[0199] 450 mg of metformin hydrochloride was weighed, dissolved in distilled water and adjusted to a constant volume of 30 ml. The administration volume was 0.1 ml / 10 g, corresponding to a dose of 150 mg / kg.

[0200] III. Main instruments and reagents

[0201] 1. Main instruments

[0202] 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-functional microplate reader (Synergy2, BIO-TEK), analytical balance (Sartorius, BSA224S-CW), digital electronic scale (MODUS), 1ml syringe (BD, batch number 302101), 0.25ml syringe (Shanghai Medical Laser Instrument Factory, B05-19-U), injection needle (Leng brand, 0.5×20).

[0203] 2. Main reagents

[0204] Glucose (Sinopharm Chemical Reagent Co., Ltd., 20141016), blood glucose assay GOD enzyme (sigma), glycated hemoglobin assay kit (Beijing Haomai Biotechnology Co., Ltd., A5911), sodium pyruvate (Beijing Bailingwei Technology Co., Ltd., 297561), insulin (Eli Lilly Suzhou Pharmaceutical Co., Ltd., H0219).

[0205] IV. Experimental Methods

[0206] Measurement of fasting and random blood glucose

[0207] Blood was collected from the tail tip of the animals under non-fasting conditions, and random blood glucose was measured using the glucose oxidase method (the same below). Blood was also collected from the tail tip of the animals after fasting for 4 hours to measure fasting blood glucose.

[0208] V. Experimental Results

[0209] Effects on random and fasting blood glucose levels in KKAy mice

[0210] Random and fasting blood glucose levels were measured in mice on day 20 of drug administration. As shown in Table 4, compared with the model control group (Con), Example 1 reduced blood glucose levels in KKAy mice at doses of 50, 100, and 200 mg / kg, with random blood glucose reductions of 13%, 21% (P<0.05), and 49% (P<0.01), respectively; and fasting blood glucose reductions of -3.7%, 10.4%, and 35.4% (P<0.001), respectively. Example 3 reduced random blood glucose in KKAy mice at a dose of 100 mg / kg, with a reduction of 18.4% (P<0.05). This was comparable to the effect of Example 1 (100 mg / kg) at the same dose.

[0211] Table 4. Effects on random blood glucose and fasting blood glucose in KKAy mice

[0212]

[0213] vs. model group: *P<0.05, **P<0.01, ***P<0.001; blood glucose data are expressed as mean ± SD, n=10

[0214] Experimental Example 3. Evaluation of the anti-diabetic activity of Examples 1 and 2 in ICR mice

[0215] 1. Laboratory animals and grouping

[0216] (1) Laboratory animals

[0217] Normal ICR mice, male, weighing 20-25g, were purchased from the Institute of Zoology, Chinese Academy of Medical Sciences, 5 mice per cage.

[0218] (2) Grouping

[0219] Animals were randomly grouped according to their body weight before the experiment and fasted overnight (12 hours). They were then randomly grouped according to their body weight into Example 1 group, Example 2 group, normal group, and metformin group.

[0220] (3) Experimental Design

[0221] The test compound and the positive control drug metformin were administered by gavage in a single dose, while the control group received an equal volume of water. A sodium pyruvate tolerance test was performed two hours later.

[0222] 2. Test drug, dosage setting and preparation

[0223] (1) Test sample and preparation:

[0224] Example 1 (150 mg / kg)

[0225] Weigh 0.060 g of the compound, place it in a mortar, grind it, suspend it in 0.5% CMC-Na distilled water, and bring the volume to 4 ml. The dosage is 0.1 ml / 10 g, which is 150 mg / kg.

[0226] Example 2 (150 mg / kg)

[0227] Weigh 0.060 g of the compound, place it in a mortar, grind it, suspend it in 0.5% CMC-Na distilled water, and bring the volume to 4 ml. The dosage is 0.1 ml / 10 g, which is 150 mg / kg.

[0228] Metformin (150 mg / kg)

[0229] Weigh 0.060 g of the compound, place it in a mortar, grind it, dissolve it in distilled water, and bring the volume to 4 ml. 3. Main Instruments and Reagents

[0230] (1) Main instruments

[0231] 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-functional microplate reader (Synergy2, BIO-TEK), analytical balance (Sartorius, BSA224S-CW), digital electronic scale (MODUS), 1ml syringe (BD, batch number 302101), 0.25ml syringe (Shanghai Medical Laser Instrument Factory, B05-19-U), hypodermic needle (Leng brand, 0.5×20).

[0232] (2) Main reagents

[0233] Glucose (Sinopharm Chemical Reagent Co., Ltd., 20141016), blood glucose assay GOD enzyme (Sigma), sodium pyruvate (Beijing Bailingwei Technology Co., Ltd., 297561).

[0234] 4. Experimental Methods

[0235] Sodium pyruvate tolerance test: On the day of the experiment, blood was collected from the tail tip (0 min). The test compound and the positive control drug metformin were then administered by gavage, while the normal group received an equal volume of water (0.1 mL / 10 g bw). Two hours later, sodium pyruvate (3.0 g / kg, 0.1 mL / 10 g bw) was administered by gavage. Blood samples were collected from the tail tip at 40 and 90 min after the sodium pyruvate loading, and blood glucose levels were measured at each time point.

[0236] 5. Experimental Results

[0237] The results are shown in Table 5. For Example 1, the inhibition rate of gluconeogenesis at 40 min was 73.9% (P<0.01). Metformin (150 mg / kg) had an inhibition rate of 29.7% (P<0.05). For Example 2 (150 mg / kg), the inhibition rate of gluconeogenesis at 40 min was 26.2%. Both Example 1 and Example 2 significantly reduced the area under the blood glucose curve at different times, and the effect of Example 1 was superior to that of metformin and Example 2.

[0238] Table 5. Inhibitory effect on gluconeogenesis and hypoglycemic activity in ICR mice

[0239]

[0240] All blood glucose and AUC data are mean ± sd, n = 10, vs. normal, *P < 0.05, **P < 0.01, ***P < 0.001.

[0241] Experimental Example 4. Pharmacokinetic Experiment:

[0242] I. Laboratory Animals

[0243] Male SD rats, weighing 180-200g, were provided by Beijing Vital River Laboratory Animal Technology Co., Ltd. II. Experimental Methods

[0244] 1. Establishment of standard curve for plasma samples

[0245] In Example 1, the solution was dissolved in DMSO (3 mg / mL) and serially diluted with acetonitrile containing internal standard (YHP836, 200 ng / mL) to prepare working solutions with concentrations of 5, 10, 25, 50, 200, 400, 800, and 1000 ng / mL.

[0246] Add 50 μL of blank plasma to 50 μL of working solution of compound P at different concentrations and 50 μL of acetonitrile containing internal standard (YHP836, 200 ng / mL). After vortexing, centrifuge twice (14000 rpm × 5 min). Take 3 μL of supernatant for LC / MS / MS analysis.

[0247] 2. Pharmacokinetic study of Example 1 and its prototype compound P administered orally to rats.

[0248] Compound P and that of Example 1 were prepared into a 15 mg / mL suspension using 0.5% CMC (containing Tween 80) for oral administration; and into a 0.15 mg / mL solution using 20% ​​HP-β-CD for intravenous injection.

[0249] Thirteen SD rats were used, with five in the oral administration group and three in the intravenous administration group. Rats were fasted for 12 hours before administration but had free access to water. Continuous blood sampling was used. After oral administration of Example 1 and the prototype compound P (150 mg / kg), blood was collected from the orbital venous plexus at 5, 15, 30 min, 1, 2, 4, 6, 8, 12, and 24 h. After intravenous injection of Example 1 (1.5 mg / kg), blood was collected at the same times. 50 μL of plasma was separated and 100 μL of acetonitrile containing the internal standard (YHP836, 200 ng / mL) was added. The mixture was vortexed and centrifuged twice (14000 rpm × 5 min). 3 μL of the supernatant was collected for LC / MS / MS analysis. Samples exceeding the standard line were diluted before analysis.

[0250] 3. Plasma Sample Processing

[0251] 4. LC / MS / MS conditions

[0252] Chromatographic column: Zobax C18 (50 mm × 2.1 mm, 3.5 μm); column temperature: 30 ℃; mobile phase: methanol / water gradient; flow rate: 0.2 mL / min; negative ion scanning, MRM mode detection m / z 498→108 (bjb-2936), m / z 465→297 (internal standard YHP836).

[0253] 5. Data Analysis

[0254] Plasma pharmacokinetic parameters were calculated using WinNonlin software.

[0255] III. Test Results

[0256] In rats, oral administration of Example 1 and compound P (150 mg / kg) resulted in rapid absorption, with high plasma concentrations maintained for 1-12 hours, and average peak plasma concentrations of 85 and 305 μg / mL, respectively. The in vivo exposure of Example 1 (150 mg / kg) in rats was approximately four times that of its parent compound. The bioavailability of Example 1 (150 mg / kg) was >100%.

[0257] Table 6. Plasma pharmacokinetic parameters of Example 1 and prototype compound P administered orally and intravenously to rats.

[0258]

Claims

1. One N -Acylsulfonamide salt compounds, characterized in that The compounds mentioned are as follows: 。 2. A method for preparing the N-acylsulfonamide salt compound of claim 1, characterized in that, Includes the following steps: In an ethanol solution of sodium alkoxide, 5-R-substituted o-bromobenzaldehyde condenses with ethyl azide to give compound 1. Compound 1 undergoes cyclization at 180 °C using o-dichlorobenzene as a solvent to give compound 2. Compound 2 is then methylated at the indole-1-position under cesium carbonate conditions to give compound 3. Subsequently, compound 3 undergoes a coupling reaction with m-methoxyaniline under palladium catalysis to give compound 4. Compound 4 is hydrolyzed to give compound 5, which has a carboxyl group at the 2-position. Compound 5 undergoes a condensation reaction with p-methoxybenzenesulfonamide to give compound 6. Finally, compound 6 undergoes an acid-base reaction with sodium hydroxide to give an N-acylsulfonamide salt. Reagents and reaction conditions: (a) Ethyl azide, ethyl trifluoroacetate, sodium, ethanol, -15°C to 0°C; (b) o-dichlorobenzene, 180°C; (c) iodomethane, cesium carbonate, DMF, rt; (d) m-methoxyaniline, Pd2(dba) 3， Xantphos, sodium carbonate, toluene, water, 100°C; (e) sodium hydroxide, THF, ethanol, water, rt; (f) p-methoxybenzenesulfonamide, HATU, DMAP, Et3N, rt; (g) sodium hydroxide, water, 80°C; Wherein R is Cl, Ar1 is m-methoxyphenyl, Ar2 is p-methoxyphenyl, and M is a sodium salt.

3. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises an effective dose of the N-acylsulfonamide salt compound of claim 1 and a pharmacodynamically acceptable carrier.

4. The use of the N-acylsulfonamide salt compound of claim 1 in the preparation of FBPase inhibitors.

5. Use of the N-acylsulfonamide salt compound of claim 1 in the preparation of a medicament for the prevention and / or treatment of diseases related to FBPase.

6. The application according to claim 5, characterized in that, Diseases associated with FBPase include diabetes, diabetic complications, and obesity.

7. The application according to claim 6, characterized in that, The diabetes mellitus is selected from type 1 diabetes mellitus and type 2 diabetes mellitus; the complications of diabetes mellitus are selected from retinal, renal, neurological and vascular complications, ischemic heart disease or atherosclerosis.

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