WO2023279280A1 - N-(arylsulfonyl)-indole-2-carboxamide fbpase inhibitor and use thereof - Google Patents

N-(arylsulfonyl)-indole-2-carboxamide fbpase inhibitor and use thereof Download PDF

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WO2023279280A1
WO2023279280A1 PCT/CN2021/104953 CN2021104953W WO2023279280A1 WO 2023279280 A1 WO2023279280 A1 WO 2023279280A1 CN 2021104953 W CN2021104953 W CN 2021104953W WO 2023279280 A1 WO2023279280 A1 WO 2023279280A1
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substituted
membered aromatic
compound
aromatic heterocycle
nitrogen
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PCT/CN2021/104953
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French (fr)
Chinese (zh)
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徐柏玲
申竹芳
周洁
刘率男
扈金萍
纪文明
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中国医学科学院药物研究所
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
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    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention discloses 1-methyl-7-chloro-4-((methoxyaryl heteroyl)amino)-N-(arylsulfonyl)-indole-2-carboxamide FBPase inhibitors with new structure , and its preparation method and pharmaceutical composition and use.
  • the present invention relates to N-acylsulfonamide FBPase inhibitors represented by general formula I and general formula II and their salts, their preparation methods, compositions containing one or more such compounds, and such compounds
  • the use in the preparation of FBPase inhibitors or drugs for treating diseases related to FBPase and the use in the preparation of drugs for preventing and/or treating diabetes.
  • 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, nervous system lesions and vascular complications (New. Engl. J. Med., 2010, 362: 1090-1101). Patients with hyperglycemia are often accompanied by hyperlipidemia.
  • the number of people suffering from diabetes in China ranks first in the world. According to the latest survey of "Prevalence and Control of Adult Diabetes in China", the prevalence of diabetes in Chinese adults aged 18 and above has reached 11.6%, and the prevalence of prediabetes is even higher. It reached 50.1%.
  • Diabetes is divided into insulin-dependent (type I) and non-insulin-dependent (type II), of which type II diabetes accounts for 90% to 95% of the total number of diabetic patients.
  • Biological studies have shown that the main pathological basis of diabetes is insufficient insulin secretion, insulin resistance and increased hepatic glucose production.
  • Most antidiabetic drugs currently in clinical use increase insulin secretion (such as: sulfonylureas and glinide insulin secretagogues), or by preventing peripheral insulin resistance (such as: thiazolidinedione insulin sensitization agent) to treat diabetes.
  • Endogenous glucose production is the main cause of elevated fasting blood glucose in diabetic patients.
  • Endogenous glucose mainly comes from the liver, and gluconeogenesis and glycogenolysis are the two main ways to produce glucose in the liver.
  • the gluconeogenesis pathway is one of the main causes of elevated blood sugar in patients with type II diabetes. Therefore, reducing the production of endogenous glucose by regulating the gluconeogenesis pathway has become a new strategy for the development of anti-type II diabetes drugs with new mechanisms of action.
  • Gluconeogenesis is the process of converting three-carbon precursors such as glycerol and lactic acid into glucose under the catalysis of various enzymes.
  • Fructose 1,6-bisphosphatase, fructose 6-phosphatase and pyruvate carboxylase play key roles in gluconeogenesis; among them, fructose 1,6-bisphosphatase (FBPase) catalyzes the fructose -1,6-bisphosphate conversion to fructose-6-phosphate is one of the rate-controlling steps in the gluconeogenesis pathway; thus, fructose-1,6-bisphosphatase is a potential new mechanism of action for antidiabetic drug target.
  • Fructose-1,6-bisphosphatase inhibitors are potential novel mechanisms of antidiabetic drugs.
  • MB07803 is a phosphodiamide prodrug of thiazole compounds, and is currently in phase II clinical research (US, 225259A1[P].2007-09-27. ).
  • 2012-2014 through high-throughput screening, He et al.
  • FBPase inhibitors with various structural types, so far, only one FBPase inhibitor (MB07083) is in phase II clinical research in the form of a phosphonic acid diamide prodrug.
  • the present invention is based on the N-acyl sulfonamide inhibitors obtained earlier (patent application number: 2016101058649), the salt of the 4-position substituent of the indole ring, the 2-position sulfonamide substituent, and the acyl sulfonamide Structural modification is carried out to obtain FBPase inhibitors with high activity, and/or reasonable physicochemical properties (such as increased solubility), and/or druggability.
  • the present invention designs and synthesizes 1-methyl-7-chloro-4-((methoxyarylheteroyl)amino)-N-(arylsulfonyl)-indole-2-carboxamide and its salts with a new structure
  • the FBPase-like inhibitors have laid a structural foundation for obtaining FBPase inhibitors with good pharmacokinetic properties and which can be administered orally.
  • the present invention aims to find a novel orally effective antidiabetic drug which has strong inhibitory activity on FBP enzyme and good druggability.
  • the technical problem solved by the present invention is to provide formula I, I-A and formula II, the N-acyl sulfonamide FBPase inhibitor shown in II-A, its preparation method, the composition containing one or more such compounds, and the The use of the compound in the preparation of FBPase inhibitors or drugs for treating diseases related to FBPase, and the use in the preparation of drugs for preventing and/or treating diabetes.
  • the present invention provides the following technical solutions:
  • the first aspect of the technical solution of the present invention is to provide such as general formula I, IA and formula II, N-acyl sulfonamide derivatives shown in IIA:
  • A, B, D, E are independently selected from CR or N;
  • R is selected from H, F, Cl, CH 3 , OCH 3 ;
  • Ar 1 is selected from the following groups or structural fragments:
  • Phenyl, substituted phenyl, non-substituted nitrogen-containing six-membered aromatic heterocycles including pyridine, pyrimidine, pyridazine, pyrazine), substituted nitrogen-containing six-membered aromatic heterocycles (six-membered aromatic heterocycles including pyridine, pyrimidine , pyridazine, pyrazine);
  • substituent is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, cyclopropyl methylene, cyclobutyl, halogen substituted C1-4 straight chain Or branched chain alkyl (including CF 3 , CH 2 F, CHF 2 , CH 2 CF 3 , CF 2 CH 3 , CH 2 CH 2 CF 3 ), F, Cl, Br, NO 2 , CN, methylenedioxy Base, ORs 1 , NRs 2 Rt 1 , CONRs 3 Rt 2 ;
  • Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rt 2 are independently selected from H, C1-4 straight chain or branched chain alkyl (including methyl, ethyl, propyl, isopropyl, butyl group, isobutyl), halogen substituted C1-4 straight chain or branched chain alkyl (including CF 3 , CH 2 F, CHF 2 , CH 2 CF 3 , CF 2 CH 3 , CH 2 CH 2 CF 3 ), Cyclopropyl, cyclopropyl methylene, cyclobutyl;
  • the benzene ring and the nitrogen-containing six-membered aromatic heterocycle can be mono-substituted or multi-substituted;
  • the six-membered aromatic heterocycle can contain one N atom or multiple nitrogen atoms
  • the halogen includes F, Cl, Br.
  • A, B, D, E are independently selected from CR or N;
  • R is selected from H, F, Cl, CH 3 , OCH 3 ;
  • M 1 is independently selected from different alkali metals (lithium, sodium, potassium, cesium) or alkaline earth metal salts (calcium, magnesium, barium).
  • Ar 1 is selected from the following groups or structural fragments:
  • Phenyl, substituted phenyl, non-substituted nitrogen-containing six-membered aromatic heterocycles including pyridine, pyrimidine, pyridazine, pyrazine), substituted nitrogen-containing six-membered aromatic heterocycles (six-membered aromatic heterocycles including pyridine, pyrimidine , pyridazine, pyrazine);
  • substituent is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, cyclopropyl methylene, cyclobutyl, halogen substituted C1-4 straight chain Or branched chain alkyl (including CF 3 , CH 2 F, CHF 2 , CH 2 CF 3 , CF 2 CH 3 , CH 2 CH 2 CF 3 ), F, Cl, Br, NO 2 , CN, methylenedioxy Base, ORs 1 , NRs 2 Rt 1 , CONRs 3 Rt 2 ;
  • Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rt 2 are independently selected from H, C1-4 straight chain or branched chain alkyl (including methyl, ethyl, propyl, isopropyl, butyl group, isobutyl), halogen substituted C1-4 straight chain or branched chain alkyl (including CF 3 , CH 2 F, CHF 2 , CH 2 CF 3 , CF 2 CH 3 , CH 2 CH 2 CF 3 ), Cyclopropyl, cyclopropyl methylene, cyclobutyl;
  • the benzene ring and the nitrogen-containing six-membered aromatic heterocycle can be mono-substituted or multi-substituted;
  • the six-membered aromatic heterocycle can contain one N atom or multiple nitrogen atoms
  • the halogen includes F, Cl, Br.
  • A', B', D', E' are independently selected from CR' or N;
  • R' is selected from H, F, Cl, CH 3 , OCH 3 ;
  • Ar 2 is selected from the following groups or structural fragments:
  • Phenyl, substituted phenyl, non-substituted nitrogen-containing six-membered aromatic heterocycles including pyridine, pyrimidine, pyridazine, pyrazine), substituted nitrogen-containing six-membered aromatic heterocycles (six-membered aromatic heterocycles including pyridine, pyrimidine , pyridazine, pyrazine);
  • substituent is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, cyclopropyl methylene, cyclobutyl, halogen substituted C1-4 straight chain Or branched chain alkyl (including CF 3 , CH 2 F, CHF 2 , CH 2 CF 3 , CF 2 CH 3 , CH 2 CH 2 CF 3 ), F, Cl, Br, NO 2 , CN, methylenedioxy Base, ORs 1 , NRs 2 Rt 1 , CONRs 3 Rt 2 ;
  • Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rt 2 are independently selected from H, C1-4 straight chain or branched chain alkyl (including methyl, ethyl, propyl, isopropyl, butyl group, isobutyl), halogen substituted C1-4 straight chain or branched chain alkyl (including CF 3 , CH 2 F, CHF 2 , CH 2 CF 3 , CF 2 CH 3 , CH 2 CH 2 CF 3 ), Cyclopropyl, cyclopropyl methylene, cyclobutyl;
  • the benzene ring and the nitrogen-containing six-membered aromatic heterocycle can be mono-substituted or multi-substituted;
  • the six-membered aromatic heterocycle can contain one N atom or multiple nitrogen atoms
  • the halogen includes F, Cl, Br.
  • A', B', D', E' are independently selected from CR' or N;
  • R' is selected from H, F, Cl, CH 3 , OCH 3 ;
  • M2 is independently selected from different alkali metals (lithium, sodium, potassium, cesium) or alkaline earth metal salts (calcium, magnesium, barium).
  • Ar 2 is selected from the following groups or structural fragments:
  • Phenyl, substituted phenyl, non-substituted nitrogen-containing six-membered aromatic heterocycles including pyridine, pyrimidine, pyridazine, pyrazine), substituted nitrogen-containing six-membered aromatic heterocycles (six-membered aromatic heterocycles including pyridine, pyrimidine , pyridazine, pyrazine);
  • substituent is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, cyclopropyl methylene, cyclobutyl, halogen substituted C1-4 straight chain Or branched chain alkyl (including CF 3 , CH 2 F, CHF 2 , CH 2 CF 3 , CF 2 CH 3 , CH 2 CH 2 CF 3 ), F, Cl, Br, NO 2 , CN, methylenedioxy Base, ORs 1 , NRs 2 Rt 1 , CONRs 3 Rt 2 ;
  • Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rt 2 are independently selected from H, C1-4 straight chain or branched chain alkyl (including methyl, ethyl, propyl, isopropyl, butyl group, isobutyl), halogen substituted C1-4 straight chain or branched chain alkyl (including CF 3 , CH 2 F, CHF 2 , CH 2 CF 3 , CF 2 CH 3 , CH 2 CH 2 CF 3 ), Cyclopropyl, cyclopropyl methylene, cyclobutyl;
  • the benzene ring and the nitrogen-containing six-membered aromatic heterocycle can be mono-substituted or multi-substituted;
  • the six-membered aromatic heterocycle can contain one N atom or multiple nitrogen atoms
  • the halogen includes F, Cl, Br.
  • preferred compounds include but are not limited to the following compounds:
  • the second aspect of the technical solution of the present invention is to provide a preparation method for the compound described in the first aspect.
  • the technical solution adopted includes the following steps: in the presence of sodium ethylate and ethyl trifluoroacetate, 2-bromo-5-chloro-benzene Compound 1 was prepared by reacting formaldehyde with ethyl azidoacetate.
  • compound 1 underwent ring closure reaction at 180°C to obtain 4-bromo-7-chloro-1-H-indole-2 -Ethyl carboxylate, then methylated at the indole-1-position under the condition of cesium carbonate to give 4-bromo-7-chloro-1-methyl-indole-2-carboxylate ethyl ester; then the compound
  • the coupling reaction of 3 with the substituted arylamine under palladium catalysis gives compounds 4 and 4', and the corresponding compounds 5 and 5' with carboxyl at the 2-position are obtained after hydrolysis.
  • Reagents and reaction conditions (a) ethyl azidoacetate, ethyl trifluoroacetate, sodium, ethanol, -15°C to 0°C; (b) o-dichlorobenzene, 180°C; (c) methyl iodide, cesium carbonate , DMF, rt; (c) Ar 1 -NH 2 , Pd 2 (dba) 3, Xantphos, sodium carbonate, toluene, water, 100°C; (d) sodium hydroxide, THF, ethanol, water, rt; (e ) Ar 2 -S(O) 2 -NH 2 , HATU, DMAP, Et 3 N, rt; (g) alkali metal or alkaline earth metal base, water, rt.
  • the third aspect of the technical solution of the present invention provides a pharmaceutical composition, which includes 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 with the compound of the present invention as an active ingredient, and the composition includes 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 particle 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 the form of a unit dosage, and the route of administration can be enteral or parenteral, such as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and Respiratory tract, skin, vagina, rectum, etc.
  • the dosage form for administration may 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 colloid solutions), emulsions (including o/w type, w/o type and double emulsion), suspensions, injections (including aqueous injections, powder injections and infusion solutions), eye drops Agents, nasal drops, lotions and liniments, etc.; 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, dripping pills, suppositories, films, patches, gas (powder) aerosols, sprays, etc.; semi-solid dosage forms can be ointments, Gels, pastes, etc.
  • the compound of the present invention can be made into common preparations, sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle drug delivery systems.
  • 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 commonly used auxiliaries, such as starch, gelatin, gum arabic, silica, polyethylene glycol, and solvents used in liquid dosage forms, such as water, ethanol, propylene glycol, vegetable oil Such as corn oil, peanut oil, olive oil and so on.
  • the preparation containing the compound of the present invention may also contain other auxiliary agents, such as surfactants, lubricants, disintegrants, preservatives, flavoring agents, pigments and the like.
  • Diluents can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.
  • wetting agents can be water, ethanol, iso Propanol, etc.
  • binders can be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, arabic mucilage, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hypromellose Base cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.
  • disintegrants can be dry starch, microcrystalline cellulose, low-substi
  • Tablets can also be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.
  • the active ingredient compound of the present invention can be mixed with a diluent and a glidant, and the mixture is directly placed in a hard capsule or a soft capsule.
  • the active ingredient compound of the present invention can also be made into granules or pellets with diluents, binders, and disintegrants, and then placed in hard capsules or soft capsules.
  • Various diluents, binders, wetting agents, disintegrants, and glidants used in the preparation of tablets of the compound of the present invention can also be used in the preparation of capsules of the compound of the present invention.
  • water, ethanol, isopropanol, propylene glycol or their mixtures can be used as solvent and an appropriate amount of commonly used solubilizers, cosolvents, pH regulators and osmotic pressure regulators in this field can be added.
  • the solubilizer or co-solvent can be poloxamer, lecithin, hydroxypropyl- ⁇ -cyclodextrin, etc.
  • the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.
  • the osmotic pressure regulator can be Sodium chloride, mannitol, glucose, phosphate, acetate, etc.
  • mannitol, glucose, etc. can also be added as proppants.
  • coloring agents can also be added to the pharmaceutical preparations, if necessary.
  • the medicine 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 can vary widely depending on the nature and severity of the disease to be prevented or treated, individual conditions of the patient or animal, administration route and dosage form, etc.
  • the suitable daily dosage range of the compound of the present invention is 0.01-500 mg/Kg body weight, preferably 0.1-300 mg/Kg body weight.
  • the above-mentioned dosage can be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the doctor and the dosage regimen including the use of other therapeutic means.
  • the compound or composition of the present invention can be taken alone, or used in combination with other therapeutic drugs or symptomatic drugs.
  • the compound of the present invention has a synergistic effect with other therapeutic drugs, its dose should be adjusted according to the actual situation.
  • the fourth aspect of the technical solution of the present invention provides the use 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 the prevention and/or treatment of diseases and disorders related to FBPase.
  • Said application is characterized in that the diseases and diseases related to FBPase are selected from diabetes, chronic complications of diabetes, hyperlipidemia and obesity.
  • the diabetes is selected from type I diabetes and type II diabetes; the chronic complications of diabetes are selected from retinal, renal, nervous system lesions and vascular complications, local ischemic heart disease or atherosclerosis.
  • Described hyperlipidemia includes high glyceride and high cholesterol ester.
  • NMR nuclear magnetic resonance
  • HRMS high resolution mass spectroscopy
  • the reagents used in the experiment were chemically or analytically pure.
  • the solvents used are analytically pure, and the anhydrous solvents used are obtained from the solvent purification system produced by INNOVATIVE TECHNOLOGY in the United States. Other solvents are untreated unless otherwise specified.
  • HATU 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • the compound 1-methyl-7-chloro-4-bromo-indole-2-carboxylic acid ethyl ester (350 mg, 1.113 mmol) was dissolved in toluene (30 mL), and Pd 2 (dba) 3 ( 255mg, 0.28mmoll), Xantphos (325mg, 0.56mmol), then Na 2 CO 3 (353mg, 3.341mmol) was dissolved in (7.5mL) water and added to the reaction solution, 2-amino-6-methoxypyridine (413mg , 3.339mmol) into the reaction flask, reflux reaction 20h.
  • the compound 1-methyl-4-((6-methoxypyridin-2-yl)amino)-7-chloro-indole-2-carboxylic acid (2g, 6.04mmol) was dissolved in DCM (40mL ), add HATU (4.59g, 12.08mmol), DMAP (737mg, 6.04mmol), TEA (2.61mL, 18.12mmol) and p-methoxybenzenesulfonamide (2.265mg, 12.08mmol), stir at room temperature for about 1h, DCM (50 mL) was added, washed with 1N hydrochloric acid solution, saturated sodium bicarbonate solution, and water, a solid precipitated, suction filtered, the filter cake was washed with water, and DCM to obtain 1.2 g of a khaki solid.
  • 1-methyl-4-((4-methoxypyridin-2-yl)amino)-7-chloro-indole-2-carboxylic acid 100 mg, 0.30 mmol was dissolved in dry DCM, Add HATU (207mg, 0.54mmol), DMAP (20mg, 0.15mmol) and TEA (92mg, 0.91mmol) sequentially, stir well and add p-methoxybenzenesulfonamide (102mg, 0.54mmol), react at 35°C for 30min and stop After the reaction, the solvent was distilled off and then washed with dilute hydrochloric acid, water, and brine.
  • the compound 1-methyl-7-chloro-4-bromo-indole-2-carboxylic acid ethyl ester (190 mg, 0.60 mmol) was dissolved in toluene (20 mL), and Pd 2 (dba) 3 was added in sequence (55mg, 0.06mmol), Xantphos (70mg, 0.12mmol) and Na 2 CO 3 (191mg, 1.80mmol, 3mL H 2 O), after stirring well, 2-methoxy-5-aminopyridine (224mg, 1.80 mmol) was added, and the reaction was refluxed for 7h, and the raw material disappeared completely.
  • Ethyl 1-methyl-4-((6-methoxypyridin-3-yl)amino)-7-chloro-indole-2-carboxylate (110 mg, 0.31 mmol) was dissolved in THF/EtOH (1/ 2, v/v, 12mL), add NaOH solution (62mg, 1.53mmol, 2mL H 2 O), react overnight at room temperature, evaporate the solvent after stopping the reaction, add a small amount of water, adjust the pH to 2 with 1M hydrochloric acid, and precipitate a solid. After filtration and drying, 98 mg of a light yellow-green solid was obtained, with a yield of 97%.
  • the compound 1-methyl-7-chloro-4-bromo-indole-2-carboxylic acid ethyl ester (750 mg, 2.39 mmol) was dissolved in toluene (40 mL), and Pd 2 (dba) 3 ( 547mg, 0.6mmol), Xantphos (694mg, 1.2mmol), then Na 2 CO 3 (847mg, 7.99mmol) was dissolved in (10mL) water and added to the reaction solution, 2-methoxy-4-aminopyrimidine (1g, 7.99mmol) into the reaction flask, reflux reaction 20h.
  • 1-methyl-4-((2-methoxypyrimidin-6-yl)amino)-7-chloro-indole-2-carboxylic acid 75 mg, 0.23 mmol was dissolved in dry DCM, Add HATU (156mg, 0.41mmol), DMAP (15mg, 0.12mmol) and TEA (70mg, 0.69mmol) sequentially, stir well and then add p-methoxybenzenesulfonamide (77mg, 0.41mmol), react at 35°C for 30min and stop After the reaction, the solvent was distilled off and then washed with dilute hydrochloric acid, water, and brine.
  • Ethyl 1-methyl-4-((4-methoxypyrimidin-6-yl)amino)-7-chloro-indole-2-carboxylate (95 mg, 0.26 mmol) was dissolved in THF/EtOH (1/ 2, v/v, 12mL), add NaOH solution (53mg, 1.32mmol, 2mL H 2 O), react overnight at room temperature, evaporate the solvent after stopping the reaction, add a small amount of water, adjust the pH to 2 with 1M hydrochloric acid, and precipitate a solid. After filtration and drying, 85 mg of a light yellow-green solid was obtained, with a yield of 96%.
  • the bacterial solution was centrifuged at 4°C and 5500rpm for 5 minutes, the supernatant was discarded, and the precipitate (bacterial cells) was added to FBPase Tris-Buffer to resuspend the bacterial cells.
  • the cells were disrupted by ultrasonication, and then centrifuged at 12,000 rpm for 1 min at 4°C. The supernatant was collected, assayed for enzyme activity, and stored at -80°C after aliquoting.
  • Measuring principle of FBPase activity Utilize the coupling reaction of FBPase with phosphoglucose isomerase and glucose-6-phosphate dehydrogenase, and use a spectrophotometer to detect the concentration of the reaction product to reflect the activity of the enzyme.
  • the reaction consumes NADP + to generate NADPH, and the change of absorbance at 340nm directly reflects the activity of the enzyme.
  • FBPase Tris-Buffer 100mM Tris, 2mM MgCl 2 , 0.1mM EDTA, pH 7.5
  • inhibitors final concentration 0.08uM, 0.4uM, 2uM or 10uM
  • FBPase final concentration 0.72unit
  • the reaction substrate mixture final concentration 0.2 mM NADP + , 0.01 units phosphoglucose isomerase, 0.01 units glucose-6-phosphate dehydrogenase and 0.2 mM FBP
  • NADPH absorbance value of the reaction product
  • Example (IC 50M ) Example (IC 50M ) 1 8.30 ⁇ 10 -8 2 1.50 ⁇ 10 -8 3 4.78 ⁇ 10 -8 4 1.81 ⁇ 10 -8 5 4.49 ⁇ 10 -8 6 3.05 ⁇ 10 -8 7 9.70 ⁇ 10 -8 8 2.71 ⁇ 10 -8
  • Adopt normal male ICR mice fast overnight, get zero o'clock blood sample (-120min) in the morning of the next day, thereafter, give embodiment compound 2 (Example 2, 150mg/kg) or positive drug metformin ( Met, 150mg/kg), the blank control group was replaced by water.
  • the post-administration blood sample was collected (0 min), and the gluconeogenesis substrate sodium pyruvate (2 g/kg) was orally administered orally, and the mouse blood sample was collected after 30 min of intragastric administration of sodium pyruvate (30 min).
  • Glucose concentration in blood samples was measured by GOD method. Compare each group 0min and 30min blood glucose difference with normal control group to compare whether there is statistical difference, measure the hypoglycemic activity of compound.
  • Experimental example 2-2 Evaluation of the antidiabetic activity of the compound of Example 2 on type 2 diabetic KKAy mice
  • Spontaneous type 2 diabetic KKAy mice male, 4-5 weeks old, were purchased from Beijing Huafukang Biotechnology Co., Ltd., and were bred in the SPF animal room of the Institute of Materia Medica, Chinese Academy of Medical Sciences, 5 mice/box, with free access to water. They were fed with high-fat feed for about 3 weeks, and they were randomly divided into groups, 10 in each group.
  • MAIN OUTCOME MEASURES non-fasting blood glucose (PBG), fasting blood glucose (FBG), percent increase in blood glucose at 30 minutes of OGTT test, blood triglyceride (TG), blood total cholesterol (TC) and body weight.
  • Gavage water was used as the model control group
  • gavage compound Example 2 100 mg/kg and 200 mg/kg suspension was used as the administration group
  • gavage compound metformin 150 mg/kg suspension was used as the positive control group.
  • Oral administration once a day for 35 consecutive days.
  • the fasting blood glucose level of the mice was dynamically monitored. The fasting blood glucose was measured on the 21st day, the random blood glucose was measured on the 27th day, and the glycosylated hemoglobin level was measured on the 33rd day.
  • Compound Example 2 can significantly reduce the fasting blood glucose level (Table 2) of spontaneous type 2 diabetes KKAy mice; it can also significantly reduce the random blood glucose level (Table 3) of KKAy mice; and make KKAy The level of glycated hemoglobin in the mice was significantly reduced (Table 4).
  • mice were randomly divided into 2 groups, the intravenous injection group of the compound of Example 2 and the oral administration group, each group of 3 rats were given the compound of Example 2 (3mg/kg) by intravenous injection in 2min, 5min , 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, and 72h each time point was taken from the orbital venous plexus, and the rats were orally given the compound of Example 2 (30mg/kg) after At 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, and 72h, blood was collected from the orbital venous plexus at each time point, and the blood was collected into a heparin-anticoagulated EP tube and placed on ice , after centrifugation at 8000r/min ⁇ 5min, separate the plasma for later use.
  • Standard curve of the compound of Example 2 Take 50 ⁇ l of SD rat blank plasma, add 480 ⁇ l of acetonitrile, and then add 10 ⁇ l of methanol solution of the compound of Example 2 at different concentrations to make the final concentration 2, 5, 10, 20, 50, 100, 200, 500, 1000, 2000, 5000, 10000, 20000, 50000ng/ml, mix well, 14000r/min ⁇ 5min high-speed centrifugation twice, take 5 ⁇ l of supernatant for HPLC-MS/MS analysis.
  • control group no inhibitor
  • positive inhibitor group the positive inhibitor group
  • test compound inhibition group 10 ⁇ M
  • three parallel samples were set up in each group. Add the inhibitor into human liver microsomes and incubate together with the probe substrates of each subtype, measure the metabolites generated by the probe substrate, and compare with the control group to reflect the degree of inhibition of the inhibitor on the isozyme.
  • CYP1A2, 2D6, 2C9, 2C19, 3A4, 2E1 substrate concentration and incubation time were phenacetin 50 ⁇ M/30min, dextromethorphan 5 ⁇ M/10min, diclofenac sodium 20 ⁇ M/10min, mephenytoin 40 ⁇ M/ 30min, midazolam 5 ⁇ M/5min, chlorzoxazone 80 ⁇ M/20min.
  • CYP1A2, 2D6, 2C9, 2C19, 3A4, and 2E1 isoenzyme positive inhibitors were as follows: furafylline 10 ⁇ M, quinidine 2 ⁇ M, sulfabenzopyrazole 5 ⁇ M, ticlopidine 5 ⁇ M, ketoconazole 1 ⁇ M, two Sodium ethyl disulfide ammonium formate 50 ⁇ M.
  • the metabolic inhibition rates of positive inhibitors to CYP1A2, 2C19, 2C9, 2D6, 3A4, and 2E1 probe substrates were 61.23%, 93.52%, 76.81%, 89.77%, 93.82%, and 80.37%.
  • the substrate has obvious inhibitory effect.
  • the inhibitory activity of the test compound on each subtype is weaker than that of the positive control inhibitor, and has good safety.
  • the results are shown in Table 6.

Abstract

Disclosed in the present invention are an inhibitor of 1-methyl-7-chloro-4-((methoxyaryl heteroyl)amino)-N-(arylsulfonyl)-indole-2-carboxamide FBPase having a novel structure, a preparation method therefor, and a pharmaceutical composition and a use thereof. Specifically, the present invention relates to an N-acylsulfonamide FBPase inhibitor and a salt thereof represented by general formula I and general formula II, a preparation method therefor, a composition containing one or more such compounds, a use of such compounds in the preparation of an FBPase inhibitor or a medicament for treating FBPase-related diseases, and a use thereof in the preparation of a drug for preventing and/or treating diabetes.

Description

N-(芳基磺酰基)-吲哚-2-甲酰胺类FBPase抑制剂及其用途N-(arylsulfonyl)-indole-2-carboxamide FBPase inhibitors and uses thereof 技术领域technical field
本发明公开了新结构的1-甲基-7-氯-4-((甲氧基芳杂基)氨基)-N-(芳基磺酰基)-吲哚-2-甲酰胺类FBPase抑制剂、及其制法和药物组合物与用途。具体而言，本发明涉及通式I及通式II所示的N-酰基磺酰胺类FBPase抑制剂及其盐，其制备方法，含有一个或多个该类化合物的组合物，和该类化合物在制备FBPase抑制剂或治疗FBPase有关的疾病药物中的用途，及在制备预防和/或治疗糖尿病药物中的用途。The present invention discloses 1-methyl-7-chloro-4-((methoxyaryl heteroyl)amino)-N-(arylsulfonyl)-indole-2-carboxamide FBPase inhibitors with new structure , and its preparation method and pharmaceutical composition and use. Specifically, the present invention relates to N-acylsulfonamide FBPase inhibitors represented by general formula I and general formula II and their salts, their preparation methods, compositions containing one or more such compounds, and such compounds The use in the preparation of FBPase inhibitors or drugs for treating diseases related to FBPase, and the use in the preparation of drugs for preventing and/or treating diabetes.
背景技术Background technique
糖尿病是一种多基因调控的慢性代谢性疾病，主要表现为持续的高血糖及糖尿。持续的高血糖会导致许多并发症的产生，如视网膜、肾脏、神经系统病变及血管并发症等(New.Engl.J.Med.,2010,362:1090-1101)。高血糖病人常常伴随高血脂症。中国糖尿病的患病人数已高居全球首位，据最新的《中国成人糖尿病流行与控制现状》调查研究显示，中国18岁及以上成人糖尿病患病率已高达11.6％，糖尿病前期的患病率更是达到了50.1％。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, nervous system lesions and vascular complications (New. Engl. J. Med., 2010, 362: 1090-1101). Patients with hyperglycemia are often accompanied by hyperlipidemia. The number of people suffering from diabetes in China ranks first in the world. According to the latest survey of "Prevalence and Control of Adult Diabetes in China", the prevalence of diabetes in Chinese adults aged 18 and above has reached 11.6%, and the prevalence of prediabetes is even higher. It reached 50.1%.
糖尿病分为胰岛素依赖型(I型)和非胰岛素依赖型(II型)，其中II型糖尿病患者占糖尿病患者总数的90％～95％。生物学研究表明，导致糖尿病的主要病理基础是胰岛素分泌不足、胰岛素抵抗和肝葡萄糖生成增加。目前临床上应用的大多数抗糖尿病药物都是增加胰岛素分泌(如：磺脲类和格列奈类促胰岛素分泌剂)，或是通过避免外周胰岛素抵抗(如：噻唑烷二酮类胰岛素增敏剂)治疗糖尿病。Diabetes is divided into insulin-dependent (type I) and non-insulin-dependent (type II), of which type II diabetes accounts for 90% to 95% of the total number of diabetic patients. Biological studies have shown that the main pathological basis of diabetes is insufficient insulin secretion, insulin resistance and increased hepatic glucose production. Most antidiabetic drugs currently in clinical use increase insulin secretion (such as: sulfonylureas and glinide insulin secretagogues), or by preventing peripheral insulin resistance (such as: thiazolidinedione insulin sensitization agent) to treat diabetes.
研究表明，内源性葡萄糖生成增加是造成糖尿病患者空腹血糖升高的主要原因。内源性葡萄糖主要来源于肝脏，糖异生作用和糖原分解是肝脏中产生葡萄糖的两种主要途径。糖异生途径是造成II型糖尿病患者血糖升高的主要原因之一。因此，通过调控糖异生途径，减少内源性葡萄糖的生成，成为开发新作用机制抗II型糖尿病药物的新策略。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, and gluconeogenesis and glycogenolysis are the two main ways to produce glucose in the liver. The gluconeogenesis pathway is one of the main causes of elevated blood sugar in patients with type II diabetes. Therefore, reducing the production of endogenous glucose by regulating the gluconeogenesis pathway has become a new strategy for the development of anti-type II diabetes drugs with new mechanisms of action.
糖异生作用是将丙三醇、乳酸等三碳前体，在多种酶的催化作用下，转化为葡萄糖的过程。在糖异生过程中果糖1,6-二磷酸酶、果糖6-磷酸酶和丙酮酸羧化酶在糖异生中起着关键作用；其中果糖1,6-二磷酸酶(FBPase)催化果糖-1,6-二磷酸 盐转化为果糖-6-磷酸盐，是糖异生途径中的控速步骤之一；因此，果糖-1,6-二磷酸酶是潜在的新作用机制的抗糖尿病药物靶标。果糖-1,6-二磷酸酶抑制剂是潜在的新机制的抗糖尿病药物。Gluconeogenesis is the process of converting three-carbon precursors such as glycerol and lactic acid into glucose under the catalysis of various enzymes. Fructose 1,6-bisphosphatase, fructose 6-phosphatase and pyruvate carboxylase play key roles in gluconeogenesis; among them, fructose 1,6-bisphosphatase (FBPase) catalyzes the fructose -1,6-bisphosphate conversion to fructose-6-phosphate is one of the rate-controlling steps in the gluconeogenesis pathway; thus, fructose-1,6-bisphosphatase is a potential new mechanism of action for antidiabetic drug target. Fructose-1,6-bisphosphatase inhibitors are potential novel mechanisms of antidiabetic drugs.
2003年，Pfizer制药公司通过高通量筛选，得到了吲哚羧酸类化合物，对FBPase抑制活性IC 50值在微摩尔水平(Bioorg.Med.Chem.Lett.,2003,13:2055-2058)。2006年，von Geldern等人报道了苯并噁唑-2-苯磺酰胺类化合物，对FBPase的抑制活性IC 50值在10 -6-10 -7摩尔水平(Bioorg.Med.Chem.Lett.,2006,16:1811-1815)。2010年，Roche制药公司报道了通过高通量筛选发现的噻唑取代的磺酰脲类FBPase抑制剂，其抑制活性IC 50值在10 -7-10 -8摩尔水平(Bioorg.Med.Chem.Lett.,2010,20:594-599)。2007-2010年，Metbasis制药公司报道了采用基于结构的药物分子设计策略发现AMP类似物，寻找FBPase抑制剂，经过不断地结构优化，他们得到了苯并咪唑类FBPase抑制剂(J.Am.Chem.Soc.,2007,129:15480-15490；J.Med.Chem.,2010,53:441-451)和噻唑类FBPase抑制剂(J.Am.Chem.Soc.,2007,129:15491-15502；J.Med.Chem.,2011,54:153-165)，MB07803为噻唑类化合物的磷酸二酰胺前药，目前正处于II期临床研究(US,225259A1[P].2007-09-27.)。2012-2014年，He等通过高通量筛选，优化后发现了噁二唑化合物对FBP酶的抑制活性IC 50值为4.51μΜ(Heterocycles,2012,85:2693-2712；Eur.J.Med.Chem,2014,83:15-25)。2019年Hang等人利用基于药效团的虚拟筛选，发现呋喃并噻吩类化合物对FBP酶的抑制活性为5.3μΜ(J.Mol.Grap.Model.2019,86:142-148)。 In 2003, Pfizer Pharmaceutical Company 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 that benzoxazole-2-benzenesulfonamide compounds had inhibitory activity IC 50 values on FBPase 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, and its inhibitory activity IC 50 value was 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 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 phosphodiamide prodrug of thiazole compounds, and is currently in phase II clinical research (US, 225259A1[P].2007-09-27. ). In 2012-2014, through high-throughput screening, He et al. found that the inhibitory activity IC 50 of oxadiazole compounds on FBP enzymes was 4.51 μM after optimization (Heterocycles, 2012, 85:2693-2712; Eur.J.Med. Chem, 2014, 83:15-25). In 2019, Hang et al. used pharmacophore-based virtual screening and found that the inhibitory activity of furothiophenes on FBP enzymes was 5.3 μM (J.Mol.Grap.Model.2019,86:142-148).
尽管有多种结构类型的FBPase抑制剂报道，但到目前为止，只有一个FBP酶抑制剂(MB07083)以膦酸二酰胺前药形式处于II期临床研究阶段，该化合物是Metabasis公司研制开发的II代FBP酶抑制剂，I代FBP酶抑制剂CS-917(同样为膦酸二酰胺前药形式)于2008年终止临床研究。因此，寻找物化性质合理的具有成药性的新型高效FBP酶抑制剂具有非常重要的临床意义。Although there are reports of FBPase inhibitors with various structural types, so far, only one FBPase inhibitor (MB07083) is in phase II clinical research in the form of a phosphonic acid diamide prodrug. The first-generation FBPase inhibitor, the first-generation FBPase inhibitor CS-917 (also in the form of phosphonic acid diamide prodrug), terminated clinical research in 2008. Therefore, it is of great clinical significance to find novel and highly effective FBPase inhibitors with reasonable physicochemical properties and druggability.
本发明是在前期获得的N-酰基磺酰胺类抑制剂的基础上(专利申请号：2016101058649)，对吲哚环4-位取代基、2-位磺酰胺取代基、及酰基磺酰胺的盐进行结构改造，获得高活性、和/或物理化学性质合理(如溶解度提高)、和/或具有成药性的FBP酶抑制剂。本发明设计合成了新结构的1-甲基-7-氯-4-((甲氧基芳杂基)氨基)-N-(芳基磺酰基)-吲哚-2-甲酰胺及其盐类FBPase抑制剂，为获得具有药代性质良好、可口服给药的FBPase抑制剂奠定了结构基础。本发明旨在寻找对FBP 酶抑制活性强，具有良好成药性的口服有效的新型抗糖尿病药物。The present invention is based on the N-acyl sulfonamide inhibitors obtained earlier (patent application number: 2016101058649), the salt of the 4-position substituent of the indole ring, the 2-position sulfonamide substituent, and the acyl sulfonamide Structural modification is carried out to obtain FBPase inhibitors with high activity, and/or reasonable physicochemical properties (such as increased solubility), and/or druggability. The present invention designs and synthesizes 1-methyl-7-chloro-4-((methoxyarylheteroyl)amino)-N-(arylsulfonyl)-indole-2-carboxamide and its salts with a new structure The FBPase-like inhibitors have laid a structural foundation for obtaining FBPase inhibitors with good pharmacokinetic properties and which can be administered orally. The present invention aims to find a novel orally effective antidiabetic drug which has strong inhibitory activity on FBP enzyme and good druggability.
发明内容Contents of the invention
本发明解决的技术问题在于提供式I，I-A及式II，II-A所示的N-酰基磺酰胺类FBPase抑制剂，其制备方法，含有一个或多个该类化合物的组合物，和该类化合物在制备FBPase抑制剂或治疗FBPase有关的疾病药物中的用途，及在制备预防和/或治疗糖尿病药物中的用途。The technical problem solved by the present invention is to provide formula I, I-A and formula II, the N-acyl sulfonamide FBPase inhibitor shown in II-A, its preparation method, the composition containing one or more such compounds, and the The use of the compound in the preparation of FBPase inhibitors or drugs for treating diseases related to FBPase, and the use in the preparation of drugs for preventing and/or treating diabetes.
为解决本发明的技术问题，本发明提供了如下技术方案：In order to solve the technical problems of the present invention, the present invention provides the following technical solutions:
本发明技术方案的第一方面是提供了如通式I，IA及式II，IIA所示的N-酰基磺酰胺类衍生物：The first aspect of the technical solution of the present invention is to provide such as general formula I, IA and formula II, N-acyl sulfonamide derivatives shown in IIA:
Figure PCTCN2021104953-appb-000001
Figure PCTCN2021104953-appb-000001
在式I中，In Formula I,
A、B、D、E独立选自CR或N；R选自H、F、Cl、CH 3、OCH 3； A, B, D, E are independently selected from CR or N; R is selected from H, F, Cl, CH 3 , OCH 3 ;
Ar 1选自如下基团或结构片断： Ar 1 is selected from the following groups or structural fragments:
苯基、取代的苯基、非取代的含氮六元芳杂环(包括吡啶、嘧啶、哒嗪、吡嗪)、取代的含氮六元芳杂环(六元芳杂环包括吡啶、嘧啶、哒嗪、吡嗪)；Phenyl, substituted phenyl, non-substituted nitrogen-containing six-membered aromatic heterocycles (including pyridine, pyrimidine, pyridazine, pyrazine), substituted nitrogen-containing six-membered aromatic heterocycles (six-membered aromatic heterocycles including pyridine, pyrimidine , pyridazine, pyrazine);
其中所述的取代基选自甲基、乙基、丙基、异丙基、丁基、异丁基、环丙基、环丙亚甲基、环丁基、卤素取代的C1-4直链或支链烷基(包括CF 3、CH 2F、CHF 2、CH 2CF 3、CF 2CH 3、CH 2CH 2CF 3)、F、Cl、Br、NO 2、CN、亚甲二氧基、ORs 1、NRs 2Rt 1、CONRs 3Rt 2； Wherein said substituent is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, cyclopropyl methylene, cyclobutyl, halogen substituted C1-4 straight chain Or branched chain alkyl (including CF 3 , CH 2 F, CHF 2 , CH 2 CF 3 , CF 2 CH 3 , CH 2 CH 2 CF 3 ), F, Cl, Br, NO 2 , CN, methylenedioxy Base, ORs 1 , NRs 2 Rt 1 , CONRs 3 Rt 2 ;
其中所述的Rs 1、Rs 2、Rs 3、Rt 1、Rt 2独立地选自H、C1-4直链或支链烷基(包括甲基、乙基、丙基、异丙基、丁基、异丁基)、卤素取代的C1-4直链或支链烷基(包括CF 3、CH 2F、CHF 2、CH 2CF 3、CF 2CH 3、CH 2CH 2CF 3)、环丙基、环丙亚甲基、环丁基； Wherein said Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rt 2 are independently selected from H, C1-4 straight chain or branched chain alkyl (including methyl, ethyl, propyl, isopropyl, butyl group, isobutyl), halogen substituted C1-4 straight chain or branched chain alkyl (including CF 3 , CH 2 F, CHF 2 , CH 2 CF 3 , CF 2 CH 3 , CH 2 CH 2 CF 3 ), Cyclopropyl, cyclopropyl methylene, cyclobutyl;
苯环、含氮六元芳杂环上可以是单取代，也可以是多取代；The benzene ring and the nitrogen-containing six-membered aromatic heterocycle can be mono-substituted or multi-substituted;
六元芳杂环可以含有1个N原子，也可以含有多个氮原子；The six-membered aromatic heterocycle can contain one N atom or multiple nitrogen atoms;
所述的卤素包括F、Cl、Br。The halogen includes F, Cl, Br.
Figure PCTCN2021104953-appb-000002
Figure PCTCN2021104953-appb-000002
在I-A中，In I-A,
A、B、D、E独立选自CR或N；R选自H、F、Cl、CH 3、OCH 3； A, B, D, E are independently selected from CR or N; R is selected from H, F, Cl, CH 3 , OCH 3 ;
M 1独立地选自不同碱金属(锂，钠，钾，铯)或是碱土金属盐(钙，镁，钡)。 M 1 is independently selected from different alkali metals (lithium, sodium, potassium, cesium) or alkaline earth metal salts (calcium, magnesium, barium).
Ar 1选自如下基团或结构片断： Ar 1 is selected from the following groups or structural fragments:
苯基、取代的苯基、非取代的含氮六元芳杂环(包括吡啶、嘧啶、哒嗪、吡嗪)、取代的含氮六元芳杂环(六元芳杂环包括吡啶、嘧啶、哒嗪、吡嗪)；Phenyl, substituted phenyl, non-substituted nitrogen-containing six-membered aromatic heterocycles (including pyridine, pyrimidine, pyridazine, pyrazine), substituted nitrogen-containing six-membered aromatic heterocycles (six-membered aromatic heterocycles including pyridine, pyrimidine , pyridazine, pyrazine);
其中所述的取代基选自甲基、乙基、丙基、异丙基、丁基、异丁基、环丙基、环丙亚甲基、环丁基、卤素取代的C1-4直链或支链烷基(包括CF 3、CH 2F、CHF 2、CH 2CF 3、CF 2CH 3、CH 2CH 2CF 3)、F、Cl、Br、NO 2、CN、亚甲二氧基、ORs 1、NRs 2Rt 1、CONRs 3Rt 2； Wherein said substituent is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, cyclopropyl methylene, cyclobutyl, halogen substituted C1-4 straight chain Or branched chain alkyl (including CF 3 , CH 2 F, CHF 2 , CH 2 CF 3 , CF 2 CH 3 , CH 2 CH 2 CF 3 ), F, Cl, Br, NO 2 , CN, methylenedioxy Base, ORs 1 , NRs 2 Rt 1 , CONRs 3 Rt 2 ;
其中所述的Rs 1、Rs 2、Rs 3、Rt 1、Rt 2独立地选自H、C1-4直链或支链烷基(包括甲基、乙基、丙基、异丙基、丁基、异丁基)、卤素取代的C1-4直链或支链烷基(包括CF 3、CH 2F、CHF 2、CH 2CF 3、CF 2CH 3、CH 2CH 2CF 3)、环丙基、环丙亚甲基、环丁基； Wherein said Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rt 2 are independently selected from H, C1-4 straight chain or branched chain alkyl (including methyl, ethyl, propyl, isopropyl, butyl group, isobutyl), halogen substituted C1-4 straight chain or branched chain alkyl (including CF 3 , CH 2 F, CHF 2 , CH 2 CF 3 , CF 2 CH 3 , CH 2 CH 2 CF 3 ), Cyclopropyl, cyclopropyl methylene, cyclobutyl;
苯环、含氮六元芳杂环上可以是单取代，也可以是多取代；The benzene ring and the nitrogen-containing six-membered aromatic heterocycle can be mono-substituted or multi-substituted;
六元芳杂环可以含有1个N原子，也可以含有多个氮原子；The six-membered aromatic heterocycle can contain one N atom or multiple nitrogen atoms;
所述的卤素包括F、Cl、Br。The halogen includes F, Cl, Br.
Figure PCTCN2021104953-appb-000003
Figure PCTCN2021104953-appb-000003
在式II中，In Formula II,
A′、B′、D′、E′独立选自CR′或N；R′选自H、F、Cl、CH 3、OCH 3； A', B', D', E' are independently selected from CR' or N; R' is selected from H, F, Cl, CH 3 , OCH 3 ;
Ar 2选自如下基团或结构片断： Ar 2 is selected from the following groups or structural fragments:
苯基、取代的苯基、非取代的含氮六元芳杂环(包括吡啶、嘧啶、哒嗪、吡嗪)、取代的含氮六元芳杂环(六元芳杂环包括吡啶、嘧啶、哒嗪、吡嗪)；Phenyl, substituted phenyl, non-substituted nitrogen-containing six-membered aromatic heterocycles (including pyridine, pyrimidine, pyridazine, pyrazine), substituted nitrogen-containing six-membered aromatic heterocycles (six-membered aromatic heterocycles including pyridine, pyrimidine , pyridazine, pyrazine);
其中所述的取代基选自甲基、乙基、丙基、异丙基、丁基、异丁基、环丙基、环丙亚甲基、环丁基、卤素取代的C1-4直链或支链烷基(包括CF 3、CH 2F、CHF 2、CH 2CF 3、CF 2CH 3、CH 2CH 2CF 3)、F、Cl、Br、NO 2、CN、亚甲二氧基、ORs 1、NRs 2Rt 1、CONRs 3Rt 2； Wherein said substituent is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, cyclopropyl methylene, cyclobutyl, halogen substituted C1-4 straight chain Or branched chain alkyl (including CF 3 , CH 2 F, CHF 2 , CH 2 CF 3 , CF 2 CH 3 , CH 2 CH 2 CF 3 ), F, Cl, Br, NO 2 , CN, methylenedioxy Base, ORs 1 , NRs 2 Rt 1 , CONRs 3 Rt 2 ;
其中所述的Rs 1、Rs 2、Rs 3、Rt 1、Rt 2独立地选自H、C1-4直链或支链烷基(包括甲基、乙基、丙基、异丙基、丁基、异丁基)、卤素取代的C1-4直链或支链烷基(包括CF 3、CH 2F、CHF 2、CH 2CF 3、CF 2CH 3、CH 2CH 2CF 3)、环丙基、环丙亚甲基、环丁基； Wherein said Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rt 2 are independently selected from H, C1-4 straight chain or branched chain alkyl (including methyl, ethyl, propyl, isopropyl, butyl group, isobutyl), halogen substituted C1-4 straight chain or branched chain alkyl (including CF 3 , CH 2 F, CHF 2 , CH 2 CF 3 , CF 2 CH 3 , CH 2 CH 2 CF 3 ), Cyclopropyl, cyclopropyl methylene, cyclobutyl;
苯环、含氮六元芳杂环上可以是单取代，也可以是多取代；The benzene ring and the nitrogen-containing six-membered aromatic heterocycle can be mono-substituted or multi-substituted;
六元芳杂环可以含有1个N原子，也可以含有多个氮原子；The six-membered aromatic heterocycle can contain one N atom or multiple nitrogen atoms;
所述的卤素包括F、Cl、Br。The halogen includes F, Cl, Br.
Figure PCTCN2021104953-appb-000004
Figure PCTCN2021104953-appb-000004
在式II-A中，In formula II-A,
A′、B′、D′、E′独立选自CR′或N；R′选自H、F、Cl、CH 3、OCH 3； A', B', D', E' are independently selected from CR' or N; R' is selected from H, F, Cl, CH 3 , OCH 3 ;
M 2独立地选自不同碱金属(锂，钠，钾，铯)或是碱土金属盐(钙，镁，钡)。 M2 is independently selected from different alkali metals (lithium, sodium, potassium, cesium) or alkaline earth metal salts (calcium, magnesium, barium).
Ar 2选自如下基团或结构片断： Ar 2 is selected from the following groups or structural fragments:
苯基、取代的苯基、非取代的含氮六元芳杂环(包括吡啶、嘧啶、哒嗪、吡嗪)、取代的含氮六元芳杂环(六元芳杂环包括吡啶、嘧啶、哒嗪、吡嗪)；Phenyl, substituted phenyl, non-substituted nitrogen-containing six-membered aromatic heterocycles (including pyridine, pyrimidine, pyridazine, pyrazine), substituted nitrogen-containing six-membered aromatic heterocycles (six-membered aromatic heterocycles including pyridine, pyrimidine , pyridazine, pyrazine);
其中所述的取代基选自甲基、乙基、丙基、异丙基、丁基、异丁基、环丙基、环丙亚甲基、环丁基、卤素取代的C1-4直链或支链烷基(包括CF 3、CH 2F、CHF 2、CH 2CF 3、CF 2CH 3、CH 2CH 2CF 3)、F、Cl、Br、NO 2、CN、亚甲二氧基、ORs 1、NRs 2Rt 1、CONRs 3Rt 2； Wherein said substituent is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, cyclopropyl methylene, cyclobutyl, halogen substituted C1-4 straight chain Or branched chain alkyl (including CF 3 , CH 2 F, CHF 2 , CH 2 CF 3 , CF 2 CH 3 , CH 2 CH 2 CF 3 ), F, Cl, Br, NO 2 , CN, methylenedioxy Base, ORs 1 , NRs 2 Rt 1 , CONRs 3 Rt 2 ;
其中所述的Rs 1、Rs 2、Rs 3、Rt 1、Rt 2独立地选自H、C1-4直链或支链烷基(包括甲基、乙基、丙基、异丙基、丁基、异丁基)、卤素取代的C1-4直链或支链烷基(包括CF 3、CH 2F、CHF 2、CH 2CF 3、CF 2CH 3、CH 2CH 2CF 3)、环丙基、环丙亚甲基、环丁基； Wherein said Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rt 2 are independently selected from H, C1-4 straight chain or branched chain alkyl (including methyl, ethyl, propyl, isopropyl, butyl group, isobutyl), halogen substituted C1-4 straight chain or branched chain alkyl (including CF 3 , CH 2 F, CHF 2 , CH 2 CF 3 , CF 2 CH 3 , CH 2 CH 2 CF 3 ), Cyclopropyl, cyclopropyl methylene, cyclobutyl;
苯环、含氮六元芳杂环上可以是单取代，也可以是多取代；The benzene ring and the nitrogen-containing six-membered aromatic heterocycle can be mono-substituted or multi-substituted;
六元芳杂环可以含有1个N原子，也可以含有多个氮原子；The six-membered aromatic heterocycle can contain one N atom or multiple nitrogen atoms;
所述的卤素包括F、Cl、Br。The halogen includes F, Cl, Br.
为完成本发明的目的，优选的化合物包括但不限定于如下化合物：For the purpose of completing the present invention, preferred compounds include but are not limited to the following compounds:
Figure PCTCN2021104953-appb-000005
Figure PCTCN2021104953-appb-000005
Figure PCTCN2021104953-appb-000006
Figure PCTCN2021104953-appb-000006
本发明技术方案的第二方面是提供了第一方面所述化合物的制备方法，采用的技术方案包括以下步骤：在乙醇钠和三氟乙酸乙酯存在下，2-溴-5-氯-苯甲醛与叠氮乙酸乙酯发生反应制备得到化合物1，以邻二氯苯作为溶剂，化合物1在180℃条件下发生关环反应得到4-溴-7-氯-1-H-吲哚-2-羧酸乙酯，然后在碳酸铯的条件下在吲哚-1-位发生甲基化得到4-溴-7-氯-1-甲基-吲哚-2-羧酸乙酯；随后化合物3在钯催化下与取代的芳胺发生偶联反应得到化合物4和4’，经水解反应后得到相应的2-位为羧基的化合物5和5’。化合物5和5’分别与芳基磺酰胺发生缩合反应得到结构通式为I和II的化合物，最后与不同的碱发生酸碱反应得到N-酰基磺酰胺盐类化合物I-A和II-A。The second aspect of the technical solution of the present invention is to provide a preparation method for the compound described in the first aspect. The technical solution adopted includes the following steps: in the presence of sodium ethylate and ethyl trifluoroacetate, 2-bromo-5-chloro-benzene Compound 1 was prepared by reacting formaldehyde with ethyl azidoacetate. Using o-dichlorobenzene as solvent, compound 1 underwent ring closure reaction at 180°C to obtain 4-bromo-7-chloro-1-H-indole-2 -Ethyl carboxylate, then methylated at the indole-1-position under the condition of cesium carbonate to give 4-bromo-7-chloro-1-methyl-indole-2-carboxylate ethyl ester; then the compound The coupling reaction of 3 with the substituted arylamine under palladium catalysis gives compounds 4 and 4', and the corresponding compounds 5 and 5' with carboxyl at the 2-position are obtained after hydrolysis. Compounds 5 and 5' undergo condensation reactions with arylsulfonamides respectively to obtain compounds with general structural formulas I and II, and finally undergo acid-base reactions with different bases to obtain N-acylsulfonamide salt compounds I-A and II-A.
Figure PCTCN2021104953-appb-000007
Figure PCTCN2021104953-appb-000007
试剂及反应条件:(a)叠氮乙酸乙酯，三氟乙酸乙酯，钠，乙醇，-15℃至0℃；(b)邻二氯苯，180℃；(c)碘甲烷，碳酸铯，DMF，r.t.；(c)Ar 1-NH 2，Pd 2(dba) 3，Xantphos，碳酸钠，甲苯，水，100℃；(d)氢氧化钠，THF，乙醇，水，r.t.；(e)Ar 2-S(O) 2-NH 2，HATU，DMAP，Et 3N，r.t.；(g)碱金属或碱土金属的碱，水，rt。 Reagents and reaction conditions: (a) ethyl azidoacetate, ethyl trifluoroacetate, sodium, ethanol, -15°C to 0°C; (b) o-dichlorobenzene, 180°C; (c) methyl iodide, cesium carbonate , DMF, rt; (c) Ar 1 -NH 2 , Pd 2 (dba) 3, Xantphos, sodium carbonate, toluene, water, 100°C; (d) sodium hydroxide, THF, ethanol, water, rt; (e ) Ar 2 -S(O) 2 -NH 2 , HATU, DMAP, Et 3 N, rt; (g) alkali metal or alkaline earth metal base, water, rt.
本发明技术方案的第三方面是提供了一种药物组合物，所述药物组合物包括作为本发明技术方案第一方面所述的化合物和药学上的常用载体。The third aspect of the technical solution of the present invention provides a pharmaceutical composition, which includes the compound described in the first aspect of the technical solution of the present invention and a commonly used pharmaceutical carrier.
本发明还提供了以本发明化合物作为活性成份的药物组合物，该组合物包括本发明中至少一种化合物和在药学上可接受的载体。所述的药物组合物选自片剂、胶囊、丸剂、注射剂、缓释制剂、控释制剂或各种微粒给药系统。该药物组合物可根据本领域公知的方法制备。可通过将本发明化合物与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂结合，制成适于人或动物使用的任何剂型。本发明化合物在其药物组合物中的含量通常为0.1-95重量％。The present invention also provides a pharmaceutical composition with the compound of the present invention as an active ingredient, and the composition includes 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 particle 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.
本发明化合物或含有它的药物组合物可以单位剂量形式给药，给药途径可为肠 道或非肠道，如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。The compound of the present invention or the pharmaceutical composition containing it can be administered in the form of a unit dosage, and the route of administration can be enteral or parenteral, such as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and Respiratory tract, skin, vagina, rectum, etc.
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等；固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等；半固体剂型可以是软膏剂、凝胶剂、糊剂等。The dosage form for administration may 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 colloid solutions), emulsions (including o/w type, w/o type and double emulsion), suspensions, injections (including aqueous injections, powder injections and infusion solutions), eye drops Agents, nasal drops, lotions and liniments, etc.; 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, dripping pills, suppositories, films, patches, gas (powder) aerosols, sprays, etc.; semi-solid dosage forms can be ointments, Gels, pastes, etc.
本发明化合物可以制成普通制剂、也可制成缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。The compound of the present invention can be made into common preparations, sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle drug delivery systems.
这些制剂是按照本领域的技术人员所熟知的方法制备的。为制造片剂、胶囊剂、包衣剂所用的辅料是常规用的助剂，例如淀粉，明胶，阿拉伯胶，硅石，聚乙二醇，液体剂型所用的溶剂例如有水，乙醇，丙二醇，植物油类如玉米油，花生油，橄榄油等。含有本发明化合物的制剂中还可有其他助剂，例如表面活性剂，润滑剂，崩解剂，防腐剂，矫味剂，色素等。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 commonly used auxiliaries, such as starch, gelatin, gum arabic, silica, polyethylene glycol, and solvents used in liquid dosage forms, such as water, ethanol, propylene glycol, vegetable oil Such as corn oil, peanut oil, olive oil and so on. The preparation containing the compound of the present invention may also contain other auxiliary agents, such as surfactants, lubricants, disintegrants, preservatives, flavoring agents, pigments and the like.
为了将本发明化合物制成片剂，可以广泛使用本领域公知的各种赋形剂，包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等；湿润剂可以是水、乙醇、异丙醇等；粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等；崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等；润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。To form the compound of the present invention into tablets, various excipients known in the art can be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. Diluents can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; wetting agents can be water, ethanol, iso Propanol, etc.; binders can be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, arabic mucilage, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hypromellose Base cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; disintegrants can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked poly Vinylpyrrolidone, croscarmellose sodium, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitan fatty acid ester, sodium dodecylsulfonate, etc.; lubricant and flow aid The agent can be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol and the like.
还可以将片剂进一步制成包衣片，例如糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片。Tablets can also be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.
为了将给药单元制成胶囊剂，可以将有效成分本发明化合物与稀释剂、助流 剂混合，将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物先与稀释剂、黏合剂、崩解剂制成颗粒或微丸，再置于硬胶囊或软胶囊中。用于制备本发明化合物片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明化合物的胶囊剂。In order to make the administration unit into a capsule, the active ingredient compound of the present invention can be mixed with a diluent and a glidant, and the mixture is directly placed in a hard capsule or a soft capsule. The active ingredient compound of the present invention can also be made into granules or pellets with diluents, binders, and disintegrants, and then placed in hard capsules or soft capsules. Various diluents, binders, wetting agents, disintegrants, and glidants used in the preparation of tablets of the compound of the present invention can also be used in the preparation of capsules of the compound of the present invention.
为将本发明化合物制成注射剂，可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调剂剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等；pH调剂剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等；渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂，还可加入甘露醇、葡萄糖等作为支撑剂。In order to make the compound of the present invention into injection, water, ethanol, isopropanol, propylene glycol or their mixtures can be used as solvent and an appropriate amount of commonly used solubilizers, cosolvents, pH regulators and osmotic pressure regulators in this field can be added. The solubilizer or co-solvent can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin, etc.; the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be Sodium chloride, mannitol, glucose, phosphate, acetate, etc. For preparation of freeze-dried powder injection, mannitol, glucose, etc. can also be added as proppants.
此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。In addition, coloring agents, preservatives, fragrances, flavoring agents or other additives can also be added to the pharmaceutical preparations, if necessary.
为达到用药目的，增强治疗效果，本发明的药物或药物组合物可用任何公知的给药方法给药。In order to achieve the purpose of medication and enhance the therapeutic effect, the medicine or pharmaceutical composition of the present invention can be administered by any known administration method.
本发明化合物药物组合物的给药剂量依照所要预防或治疗疾病的性质和严重程度，患者或动物的个体情况，给药途径和剂型等可以有大范围的变化。一般来讲，本发明化合物的每天的合适剂量范围为0.01-500mg/Kg体重，优选为0.1-300mg/Kg体重。上述剂量可以一个剂量单位或分成几个剂量单位给药，这取决于医生的临床经验以及包括运用其它治疗手段的给药方案。The dosage of the pharmaceutical composition of the compound of the present invention can vary widely depending on the nature and severity of the disease to be prevented or treated, individual conditions of the patient or animal, administration route and dosage form, etc. Generally, the suitable daily dosage range of the compound of the present invention is 0.01-500 mg/Kg body weight, preferably 0.1-300 mg/Kg body weight. The above-mentioned dosage can be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the doctor and the dosage regimen including the use of other therapeutic means.
本发明的化合物或组合物可单独服用，或与其他治疗药物或对症药物合并使用。当本发明的化合物与其它治疗药物存在协同作用时，应根据实际情况调整它的剂量。The compound or composition of the present invention can be taken alone, or used in combination with other therapeutic drugs or symptomatic drugs. When the compound of the present invention has a synergistic effect with other therapeutic drugs, its dose should be adjusted according to the actual situation.
本发明技术方案的第四方面是提供了本发明第一方面所述的化合物在制备FBPase抑制剂以及在制备预防和\或治疗与FBPase有关的疾病和病症药物中的应用。所述的应用，其特征在于，与FBPase有关的疾病和病症选自糖尿病、糖尿病的慢性并发症、高血脂症以及肥胖。所述的糖尿病选自I型糖尿病和II型糖尿病；所述糖尿病的慢性并发症选自视网膜、肾脏、神经系统病变及血管并发症、局部缺血性心脏病或动脉粥样硬化。所述的高血脂症包括高甘油酯和高胆固醇酯。The fourth aspect of the technical solution of the present invention provides the use 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 the prevention and/or treatment of diseases and disorders related to FBPase. Said application is characterized in that the diseases and diseases related to FBPase are selected from diabetes, chronic complications of diabetes, hyperlipidemia and obesity. The diabetes is selected from type I diabetes and type II diabetes; the chronic complications of diabetes are selected from retinal, renal, nervous system lesions and vascular complications, local ischemic heart disease or atherosclerosis. Described hyperlipidemia includes high glyceride and high cholesterol ester.
附图说明Description of drawings
图1.实施例2化合物对糖异生的抑制作用。Figure 1. The inhibitory effect of the compound of Example 2 on gluconeogenesis.
具体实施方式detailed description
以下将结合实施例对发明做进一步说明，但并不限制本发明的范围。The invention will be further described below in conjunction with the examples, but the scope of the invention is not limited.
化合物的结构是通过核磁共振(NMR)或高分辨质谱(HRMS)来确定的。NMR的测定是用Varian mercury 300或者Varian mercury 400，测定溶剂为CDCl 3、DMSO-d 6、acetone-d 6、CD 3OD，内标为TMS，化学位移是以ppm作为单位给出。Ms的测定用Thermo Exactive Plus型质谱仪。m.p.是以℃给出的熔点，温度未加校正。硅胶柱层析一般使用200～300目硅胶为载体。 Compound structures were determined by nuclear magnetic resonance (NMR) or high resolution mass spectroscopy (HRMS). NMR is measured by using Varian mercury 300 or Varian mercury 400, the measuring solvent is CDCl 3 , DMSO-d 6 , acetone-d 6 , CD 3 OD, the internal standard is TMS, and the chemical shift is given in ppm. The determination of Ms uses a Thermo Exactive Plus mass spectrometer. mp is melting point given in °C, uncorrected for temperature. Silica gel column chromatography generally uses 200-300 mesh silica gel as the carrier.
实验所用试剂为化学纯或分析纯。所用溶剂均为分析纯，所用无水溶剂由美国INNOVATIVE TECHNOLOGY生产的溶剂纯化系统而得，其它溶剂未特别指出则未经处理。The reagents used in the experiment were chemically or analytically pure. The solvents used are analytically pure, and the anhydrous solvents used are obtained from the solvent purification system produced by INNOVATIVE TECHNOLOGY in the United States. Other solvents are untreated unless otherwise specified.
缩写列表：List of abbreviations:
CDCl 3：氘代氯仿                    DMSO-d 6：氘代二甲基亚砜 CDCl 3 : deuterated chloroform DMSO-d 6 : deuterated dimethyl sulfoxide
HOBt：1-羟基苯并三氮唑             Pd(OAc) 2：醋酸钯 HOBt: 1-Hydroxybenzotriazole Pd(OAc) 2 : Palladium acetate
DCM：二氯甲烷                      NCS：N-氯代丁二酰亚胺DCM: Dichloromethane NCS: N-chlorosuccinimide
DMF：N,N-二甲基甲酰胺              DMAP：4-二甲氨基吡啶DMF: N,N-Dimethylformamide DMAP: 4-Dimethylaminopyridine
EA：乙酸乙酯                       Et 3N：三乙胺 EA: Ethyl acetate Et 3 N: Triethylamine
HATU：2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯HATU: 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate
XantPhos：4,5-双二苯基膦-9,9-二甲基氧杂蒽XantPhos: 4,5-bisdiphenylphosphine-9,9-dimethylxanthene
min：分钟；h：小时min: minute; h: hour
P/E：石油醚/乙酸乙酯；D/M：二氯甲烷/甲醇P/E: petroleum ether/ethyl acetate; D/M: dichloromethane/methanol
中间体的制备：Preparation of intermediates:
7-氯-4-溴-1-甲基-吲哚-2-甲酸乙酯7-Chloro-4-bromo-1-methyl-indole-2-carboxylic acid ethyl ester
Figure PCTCN2021104953-appb-000008
Figure PCTCN2021104953-appb-000008
a).2-叠氮基-3-(5-氯-2-溴苯基)丙烯酸乙酯a).2-Azido-3-(5-chloro-2-bromophenyl) ethyl acrylate
Figure PCTCN2021104953-appb-000009
Figure PCTCN2021104953-appb-000009
将金属钠(8.35g,363.2mmol)溶于无水乙醇(200mL)中，待金属钠完全溶解后，将反应液冷却至-15℃。将2-溴-5-氯苯甲醛(50g,227mmol)和叠氮乙酸乙酯(44g,341mmol)及三氟乙酸乙酯(TFAE,51.5g,363.2mmol)分批加入反应液中，在-15℃下反应1h后升温至-5℃反应1h后继续升温至0℃反应5h后升至室温过夜反应，将反应液倒入到饱和NH 4Cl水溶液中，用EA(300mL×3)萃取，合并有机层，用饱和氯化钠溶液(100mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(DCM：PE＝1:1)，浓缩，用PE:EA＝20:1重结晶，第一批得到产物36.5g，产率48.9％。 1H-NMR(400HMz,CDCl 3)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). Sodium metal (8.35 g, 363.2 mmol) was dissolved in absolute ethanol (200 mL). After the sodium metal was completely dissolved, the reaction solution was cooled to -15°C. 2-Bromo-5-chlorobenzaldehyde (50g, 227mmol), ethyl azidoacetate (44g, 341mmol) and ethyl trifluoroacetate (TFAE, 51.5g, 363.2mmol) were added to the reaction solution in batches, and in- React at 15°C for 1 hour, then heat up to -5°C for 1 hour, continue to heat up to 0°C for 5 hours, then rise to room temperature for overnight reaction, pour the reaction solution into saturated NH 4 Cl aqueous solution, extract with EA (300mL×3), Combine the organic layers, wash with saturated sodium chloride solution (100mL×2), dry over anhydrous magnesium sulfate, concentrate, column chromatography (DCM:PE=1:1), concentrate, and recrystallize with PE:EA=20:1 , 36.5 g of the product was obtained in the first batch, and the yield was 48.9%. 1 H-NMR (400HMz, CDCl 3 )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).
b).7-氯-4-溴-1H-吲哚-2-甲酸乙酯b).Ethyl 7-chloro-4-bromo-1H-indole-2-carboxylate
Figure PCTCN2021104953-appb-000010
Figure PCTCN2021104953-appb-000010
将化合物2-叠氮基-3-(5-氯-2-溴苯基)丙烯酸乙酯(15g)置于反应瓶中，加入邻二氯苯(15mL)中，加热至180℃反应,1h后停止反应，冷却，有固体析出，抽滤，滤饼用石油醚洗，得到白色固体7.2g产率52.7％；mp:154-155℃。 1H-NMR(400HMz,CDCl 3)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). The compound 2-azido-3-(5-chloro-2-bromophenyl) ethyl acrylate (15g) was placed in a reaction flask, added to o-dichlorobenzene (15mL), heated to 180°C for 1h Afterwards, the reaction was stopped, cooled, and a solid was precipitated, filtered with suction, and the filter cake was washed with petroleum ether to obtain 7.2 g of a white solid, with a yield of 52.7%; mp: 154-155°C. 1 H-NMR (400HMz, CDCl 3 ) 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).
c).1-甲基-7-氯-4-溴-吲哚-2-甲酸乙酯c).1-Methyl-7-chloro-4-bromo-indole-2-carboxylic acid ethyl ester
Figure PCTCN2021104953-appb-000011
Figure PCTCN2021104953-appb-000011
将化合物7-氯-4-溴-1H-吲哚-2-甲酸乙酯(26.2g,86.24mmol)置于反应瓶中，加入DMF(300mL)，加入碳酸铯(55.9g,172.58mmol)和碘甲烷(24.7g,132.58mmol)室温搅拌反应，1h后停止反应，将反应液倒入冰水中，有固体析出，抽滤，滤饼水洗，得到类白色固体26g产率94.8％。 1H-NMR(400HMz,CDCl 3)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). Compound 7-chloro-4-bromo-1H-indole-2-carboxylic acid ethyl ester (26.2g, 86.24mmol) was placed in the reaction flask, DMF (300mL) was added, cesium carbonate (55.9g, 172.58mmol) was added and Iodomethane (24.7g, 132.58mmol) was stirred at room temperature and reacted. After 1h, the reaction was stopped. The reaction solution was poured into ice water, and solids were precipitated. After suction filtration, the filter cake was washed with water to obtain 26g of an off-white solid with a yield of 94.8%. 1 H-NMR (400HMz, CDCl 3 )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).
实施例1:1-甲基-4-((6-甲氧基吡啶-2-基)氨基)-7-氯-N-(4-甲氧基苯磺酰基)-吲哚-2-甲酰胺Example 1: 1-methyl-4-((6-methoxypyridin-2-yl)amino)-7-chloro-N-(4-methoxybenzenesulfonyl)-indole-2-methyl Amide
Figure PCTCN2021104953-appb-000012
Figure PCTCN2021104953-appb-000012
a).1-甲基-4-((6-甲氧基吡啶-2-基)氨基)-7-氯-吲哚-2-甲酸乙酯a).1-Methyl-4-((6-methoxypyridin-2-yl)amino)-7-chloro-indole-2-carboxylic acid ethyl ester
Figure PCTCN2021104953-appb-000013
Figure PCTCN2021104953-appb-000013
氩气保护下，将化合物1-甲基-7-氯-4-溴-吲哚-2-甲酸乙酯(350mg,1.113mmol)溶于甲苯(30mL)中，加入Pd 2(dba) 3(255mg,0.28mmoll)，Xantphos(325mg,0.56mmol)，然后将Na 2CO 3(353mg,3.341mmol)溶于(7.5mL)水中加入反应液，将2-氨基-6-甲氧基吡啶(413mg,3.339mmol)加入反应瓶中，回流反应20h。过滤，滤液加入乙酸乙酯，用稀盐酸洗，饱和碳酸氢钠溶液洗，饱和氯化钠溶液洗，无水硫酸镁干燥，柱层析(E:P＝1:30)得到淡黄色固体300mg，产率75％。 1H-NMR(400MHz,CDCl 3)δ(ppm):7.43(t,J＝7.5Hz,1H),7.37(d,J＝8.0Hz,1H),7.32(s,1H),7.22(d,J＝7.6Hz,1H),6.66(brs,1H),6.44(d,J＝7.6Hz,1H),6.24(d,J＝7.6Hz,1H),4.47(s,3H),4.37(q,J＝7.2Hz,2H),3.93(s,3H),1.41(t,J＝7.2Hz,3H). Under the protection of argon, the compound 1-methyl-7-chloro-4-bromo-indole-2-carboxylic acid ethyl ester (350 mg, 1.113 mmol) was dissolved in toluene (30 mL), and Pd 2 (dba) 3 ( 255mg, 0.28mmoll), Xantphos (325mg, 0.56mmol), then Na 2 CO 3 (353mg, 3.341mmol) was dissolved in (7.5mL) water and added to the reaction solution, 2-amino-6-methoxypyridine (413mg , 3.339mmol) into the reaction flask, reflux reaction 20h. Filtrate, add ethyl acetate to the filtrate, wash with dilute hydrochloric acid, wash with saturated sodium bicarbonate solution, wash with saturated sodium chloride solution, dry over anhydrous magnesium sulfate, column chromatography (E:P=1:30) to obtain 300 mg of light yellow solid , yield 75%. 1 H-NMR (400MHz, CDCl 3 )δ(ppm): 7.43(t, J=7.5Hz, 1H), 7.37(d, J=8.0Hz, 1H), 7.32(s, 1H), 7.22(d, J＝7.6Hz, 1H), 6.66(brs, 1H), 6.44(d, J＝7.6Hz, 1H), 6.24(d, J＝7.6Hz, 1H), 4.47(s, 3H), 4.37(q, J＝7.2Hz, 2H), 3.93(s, 3H), 1.41(t, J＝7.2Hz, 3H).
b).1-甲基-4-((6-甲氧基吡啶-2-基)氨基)-7-氯-吲哚-2-甲酸b).1-Methyl-4-((6-methoxypyridin-2-yl)amino)-7-chloro-indole-2-carboxylic acid
Figure PCTCN2021104953-appb-000014
Figure PCTCN2021104953-appb-000014
将化合物1-甲基-4-((6-甲氧基吡啶-2-基)氨基)-7-氯-吲哚-2-甲酸乙酯(265mg,0.738mmol)溶于THF(7.5mL)和EtOH(7.5mL)的混合液中，将NaOH(88.5mg,2.214mmol)溶于2.5mL水中加入反应液中，40℃反应2h，浓缩，加入少量 水，用乙醚萃取，水层用稀盐酸调节pH至2-3，有固体析出，过滤，滤饼水洗，得到淡黄色固体210mg，产率86％。 1H-NMR(500MHz,DMSO-d 6)δ(ppm):13.04(s,1H),8.93(s,1H),8.04(d,J＝7.2Hz,1H),7.85(s,1H),7.53(t,J＝5.6Hz,1H),7.25(d,J＝7.6Hz,1H),6.71(d,J＝6.0Hz,1H),6.22(d,J＝6.4Hz,1H),4.37(s,3H),3.86(s,3H). Compound 1-methyl-4-((6-methoxypyridin-2-yl)amino)-7-chloro-indole-2-carboxylic acid ethyl ester (265 mg, 0.738 mmol) was dissolved in THF (7.5 mL) and EtOH (7.5mL), dissolved NaOH (88.5mg, 2.214mmol) in 2.5mL water and added to the reaction solution, reacted at 40°C for 2h, concentrated, added a small amount of water, extracted with ether, and the aqueous layer was washed with dilute hydrochloric acid After adjusting the pH to 2-3, solids were precipitated, filtered, and the filter cake was washed with water to obtain 210 mg of a light yellow solid with a yield of 86%. 1 H-NMR (500MHz, DMSO-d 6 )δ(ppm): 13.04(s, 1H), 8.93(s, 1H), 8.04(d, J=7.2Hz, 1H), 7.85(s, 1H), 7.53(t, J=5.6Hz, 1H), 7.25(d, J=7.6Hz, 1H), 6.71(d, J=6.0Hz, 1H), 6.22(d, J=6.4Hz, 1H), 4.37( s,3H),3.86(s,3H).
c).1-甲基-4-((6-甲氧基吡啶-2-基)氨基)-7-氯-N-(4-甲氧基苯磺酰基)-吲哚-2-甲酰胺c).1-Methyl-4-((6-methoxypyridin-2-yl)amino)-7-chloro-N-(4-methoxybenzenesulfonyl)-indole-2-carboxamide
Figure PCTCN2021104953-appb-000015
Figure PCTCN2021104953-appb-000015
Ar保护下，将1-甲基-4-((6-甲氧基吡啶-2-基)氨基)-7-氯-吲哚-2-甲酸(85mg,0.26mmol)溶于干燥DCM中，依次加入HATU(176mg，0.46mmol)，DMAP(16mg，0.14mmol)和TEA(78mg,0.77mmol)，搅拌均匀后加入对甲氧基苯磺酰胺(87mg,0.46mmol)，35度反应30min后停止反应，蒸除溶剂后依次用稀盐酸，水洗，盐水洗，合并EA层，重结晶得浅黄绿色固体82mg，产率64％。 1H-NMR(400MHz,DMSO-d 6)δ(ppm):12.58(s,1H),9.00(s,1H),7.97-7.95(d,J＝10.4Hz,1H),7.84(s,1H),7.53(m,1H),7.27-7.25(d,J＝8.4Hz,1H),7.19-7.17(d,J＝8.4Hz,1H),6.73-6.71(d,J＝8.4Hz,1H),6.26-6.24(d,J＝8.4Hz,1H),4.12(s,3H),3.86(s,3H),3.83(s,3H). 1-Methyl-4-((6-methoxypyridin-2-yl)amino)-7-chloro-indole-2-carboxylic acid (85 mg, 0.26 mmol) was dissolved in dry DCM under Ar protection, Add HATU (176mg, 0.46mmol), DMAP (16mg, 0.14mmol) and TEA (78mg, 0.77mmol) sequentially, stir well, then add p-methoxybenzenesulfonamide (87mg, 0.46mmol), react at 35°C for 30min and stop After the reaction, the solvent was distilled off and then washed with dilute hydrochloric acid, water, and brine. The EA layers were combined and recrystallized to obtain 82 mg of a light yellow-green solid with a yield of 64%. 1 H-NMR(400MHz,DMSO-d 6 )δ(ppm):12.58(s,1H),9.00(s,1H),7.97-7.95(d,J=10.4Hz,1H),7.84(s,1H ),7.53(m,1H),7.27-7.25(d,J=8.4Hz,1H),7.19-7.17(d,J=8.4Hz,1H),6.73-6.71(d,J=8.4Hz,1H) ,6.26-6.24(d,J=8.4Hz,1H),4.12(s,3H),3.86(s,3H),3.83(s,3H).
实施例2 1-甲基-4-((6-甲氧基吡啶-2-基)氨基)-7-氯-N-(4-甲氧基苯磺酰基)-吲哚-2-甲酰胺钠盐Example 2 1-methyl-4-((6-methoxypyridin-2-yl)amino)-7-chloro-N-(4-methoxybenzenesulfonyl)-indole-2-carboxamide sodium salt
Figure PCTCN2021104953-appb-000016
Figure PCTCN2021104953-appb-000016
Ar保护下，将化合物1-甲基-4-((6-甲氧基吡啶-2-基)氨基)-7-氯-吲哚-2-甲酸(2g,6.04mmol)溶于DCM(40mL)中，加入HATU(4.59g,12.08mmol)，DMAP(737mg,6.04mmol)和TEA(2.61mL,18.12mmol)以及对甲氧基苯磺酰胺(2.265mg,12.08mmol)，室温搅拌1h左右，加入DCM(50mL)，用1N盐酸溶液洗，饱和 碳酸氢钠溶液洗，水洗，有固体析出，抽滤，滤饼水洗，DCM洗，得到土黄色固体1.2g。 1H-NMR(400MHz,DMSO-d 6)δ(ppm):8.84(s,1H),7.96(d,J＝8.4Hz,1H)，7.70-7.81(m,2H),7.48(t,J＝4.0Hz,2H),7.05(d,J＝8.4Hz,1H),6.91-6.95(m,2H),6.72(d,J＝8.0Hz,1H),6.16(d,J＝7.6Hz,1H),4.30(s,3H),3.85(s,3H),3.78(s,3H). Under the protection of Ar, the compound 1-methyl-4-((6-methoxypyridin-2-yl)amino)-7-chloro-indole-2-carboxylic acid (2g, 6.04mmol) was dissolved in DCM (40mL ), add HATU (4.59g, 12.08mmol), DMAP (737mg, 6.04mmol), TEA (2.61mL, 18.12mmol) and p-methoxybenzenesulfonamide (2.265mg, 12.08mmol), stir at room temperature for about 1h, DCM (50 mL) was added, washed with 1N hydrochloric acid solution, saturated sodium bicarbonate solution, and water, a solid precipitated, suction filtered, the filter cake was washed with water, and DCM to obtain 1.2 g of a khaki solid. 1 H-NMR (400MHz, DMSO-d 6 ) δ (ppm): 8.84 (s, 1H), 7.96 (d, J = 8.4Hz, 1H), 7.70-7.81 (m, 2H), 7.48 (t, J =4.0Hz, 2H), 7.05(d, J=8.4Hz, 1H), 6.91-6.95(m, 2H), 6.72(d, J=8.0Hz, 1H), 6.16(d, J=7.6Hz, 1H ),4.30(s,3H),3.85(s,3H),3.78(s,3H).
实施例3 1-甲基-4-((4-甲氧基吡啶-2-基)氨基)-7-氯-N-(4-甲氧基苯磺酰基)-吲哚-2-甲酰胺Example 3 1-methyl-4-((4-methoxypyridin-2-yl)amino)-7-chloro-N-(4-methoxybenzenesulfonyl)-indole-2-carboxamide
Figure PCTCN2021104953-appb-000017
Figure PCTCN2021104953-appb-000017
a).1-甲基-4-((4-甲氧基吡啶-2-基)氨基)-7-氯-吲哚-2-甲酸乙酯a).1-Methyl-4-((4-methoxypyridin-2-yl)amino)-7-chloro-indole-2-carboxylic acid ethyl ester
Figure PCTCN2021104953-appb-000018
Figure PCTCN2021104953-appb-000018
氩气保护下，将化合物1-甲基-7-氯-4-溴-吲哚-2-甲酸乙酯(133mg，0.42mmol)溶于甲苯(20mL)中，依次加入Pd 2(dba) 3(40mg，0.04mmol)，Xantphos(50mg，0.09mmol)和Na 2CO 3(135mg，1.26mmol，3mL H 2O)，搅拌均匀后，将4-甲氧基-2-氨基吡啶(156mg，1.26mmol)加入，回流反应9h，原料完全消失。冷却至室温，浓缩，加入EA(20mL)溶解残留物，水洗，盐洗，柱层析得浅黄固体115mg，产率为76％。 1H-NMR(400MHz,CDCl 3)δ(ppm):8.05(s,3H),7.32(s,1H),7.24-7.22(m,2H),7.02(br,1H),6.39(s,2H),4.47(s,3H),4.36(m,2H),3.77(s,3H),1.39(t,J＝8.0Hz,3H). Under argon protection, the compound 1-methyl-7-chloro-4-bromo-indole-2-carboxylic acid ethyl ester (133 mg, 0.42 mmol) was dissolved in toluene (20 mL), and Pd 2 (dba) 3 was added in sequence (40mg, 0.04mmol), Xantphos (50mg, 0.09mmol) and Na 2 CO 3 (135mg, 1.26mmol, 3mL H 2 O), after stirring evenly, 4-methoxy-2-aminopyridine (156mg, 1.26 mmol) was added, refluxed for 9h, and the raw material disappeared completely. Cool to room temperature, concentrate, add EA (20 mL) to dissolve the residue, wash with water and salt, and column chromatography gives 115 mg of light yellow solid with a yield of 76%. 1 H-NMR (400MHz, CDCl 3 )δ(ppm): 8.05(s,3H),7.32(s,1H),7.24-7.22(m,2H),7.02(br,1H),6.39(s,2H ),4.47(s,3H),4.36(m,2H),3.77(s,3H),1.39(t,J=8.0Hz,3H).
b).1-甲基-4-((4-甲氧基吡啶-2-基)氨基)-7-氯-吲哚-2-甲酸b).1-Methyl-4-((4-methoxypyridin-2-yl)amino)-7-chloro-indole-2-carboxylic acid
Figure PCTCN2021104953-appb-000019
Figure PCTCN2021104953-appb-000019
将化合物1-甲基-4-((4-甲氧基吡啶-2-基)氨基)-7-氯-吲哚-2-甲酸乙酯(100mg，0.28mmol)溶于THF/EtOH(1/2,v/v,12mL)中，加入NaOH溶液(56mg，1.39mmol，2mL H 2O)，室温反应过夜，停止反应后蒸除溶剂，加入少量水，1M盐酸调节pH至2，析出固体，过滤干燥，得浅黄绿色固体89mg，产率96％。 1H-NMR(400MHz,DMSO-d 6)δ(ppm):13.36(s,1H),10.68(s,1H),7.94(d,J＝6.4Hz,1H),7.44-7.28(m,3H),6.71(d,J＝7.6Hz,2H),4.40(s,3H),3.92(s,3H). The compound 1-methyl-4-((4-methoxypyridin-2-yl)amino)-7-chloro-indole-2-carboxylic acid ethyl ester (100 mg, 0.28 mmol) was dissolved in THF/EtOH (1 /2, v/v, 12mL), add NaOH solution (56mg, 1.39mmol, 2mL H 2 O), react overnight at room temperature, evaporate the solvent after stopping the reaction, add a small amount of water, adjust the pH to 2 with 1M hydrochloric acid, and precipitate a solid , filtered and dried to obtain 89 mg of a light yellow-green solid, with a yield of 96%. 1 H-NMR (400MHz, DMSO-d 6 ) δ (ppm): 13.36 (s, 1H), 10.68 (s, 1H), 7.94 (d, J=6.4Hz, 1H), 7.44-7.28 (m, 3H ), 6.71(d, J=7.6Hz, 2H), 4.40(s, 3H), 3.92(s, 3H).
c).1-甲基-4-((4-甲氧基吡啶-2-基)氨基)-7-氯-N-(4-甲氧基苯磺酰基)-吲哚-2-甲酰胺c).1-Methyl-4-((4-methoxypyridin-2-yl)amino)-7-chloro-N-(4-methoxybenzenesulfonyl)-indole-2-carboxamide
Figure PCTCN2021104953-appb-000020
Figure PCTCN2021104953-appb-000020
Ar保护下，将1-甲基-4-((4-甲氧基吡啶-2-基)氨基)-7-氯-吲哚-2-甲酸(100mg,0.30mmol)溶于干燥DCM中，依次加入HATU(207mg，0.54mmol)，DMAP(20mg，0.15mmol)和TEA(92mg,0.91mmol)，搅拌均匀后加入对甲氧基苯磺酰胺(102mg,0.54mmol)，35度反应30min后停止反应，蒸除溶剂后依次用稀盐酸，水洗，盐水洗，合并EA层，柱分离得微黄色固体(84mg，55％)。 1H NMR(400MHz,DMSO-d 6)δ(ppm):12.54(s,1H),9.04(s,1H),8.00(d,J＝6.0Hz,1H),7.94(dd,J 1＝8.4Hz,J 2＝4.0Hz,3H),7.74(s,1H),7.24(d,J＝8.4Hz,1H),7.18-7.11(m,2H),6.67(d,J＝2.4Hz,1H),6.50(dd,J 1＝6.0,J 1＝2.4Hz,1H),4.14(s,3H),3.86(s,3H),3.82(s,3H).HRMS(ESI):m/z,calcd.for C 23H 20N 4O 5ClS[M-H] -:499.08,found 499.06 Under Ar protection, 1-methyl-4-((4-methoxypyridin-2-yl)amino)-7-chloro-indole-2-carboxylic acid (100 mg, 0.30 mmol) was dissolved in dry DCM, Add HATU (207mg, 0.54mmol), DMAP (20mg, 0.15mmol) and TEA (92mg, 0.91mmol) sequentially, stir well and add p-methoxybenzenesulfonamide (102mg, 0.54mmol), react at 35°C for 30min and stop After the reaction, the solvent was distilled off and then washed with dilute hydrochloric acid, water, and brine. The EA layers were combined and separated by a column to obtain a yellowish solid (84 mg, 55%). 1 H NMR (400MHz, DMSO-d 6 )δ(ppm): 12.54(s, 1H), 9.04(s, 1H), 8.00(d, J=6.0Hz, 1H), 7.94(dd, J 1 =8.4 Hz,J 2 =4.0Hz,3H),7.74(s,1H),7.24(d,J=8.4Hz,1H),7.18-7.11(m,2H),6.67(d,J=2.4Hz,1H) ,6.50(dd,J 1 =6.0,J 1 =2.4Hz,1H),4.14(s,3H),3.86(s,3H),3.82(s,3H).HRMS(ESI):m/z,calcd .for C 23 H 20 N 4 O 5 ClS[MH] - :499.08,found 499.06
实施例4 1-甲基-4-((5-甲氧基吡啶-3-基)氨基)-7-氯-N-(4-甲氧基苯磺酰基)-吲哚-2-甲酰胺Example 4 1-methyl-4-((5-methoxypyridin-3-yl)amino)-7-chloro-N-(4-methoxybenzenesulfonyl)-indole-2-carboxamide
Figure PCTCN2021104953-appb-000021
Figure PCTCN2021104953-appb-000021
a).1-甲基-4-((5-甲氧基吡啶-3-基)氨基)-7-氯-吲哚-2-甲酸乙酯a).1-Methyl-4-((5-methoxypyridin-3-yl)amino)-7-chloro-indole-2-carboxylic acid ethyl ester
Figure PCTCN2021104953-appb-000022
Figure PCTCN2021104953-appb-000022
氩气保护下，将化合物1-甲基-7-氯-4-溴-吲哚-2-甲酸乙酯(195mg，0.62mmol)溶于甲苯(20mL)中，依次加入Pd 2(dba) 3(58mg，0.06mmol)，Xantphos(72mg，0.12mmol)和Na 2CO 3(192mg，1.85mmol，3mL H 2O)，搅拌均匀后，将5-甲氧基-3-氨基吡啶(230mg，1.85mmol)加入，回流反应8h，原料完全消失。冷却至室温，浓缩，加入EA(20mL)溶解残留物，水洗，盐洗，柱层析得浅黄固体133mg，产率为60％。 1H-NMR(400MHz,CDCl 3)δ(ppm):8.07(s,1H),7.91(s,1H),7.27(s,1H),7.18(d,J＝8.0Hz,1H),6.95(s,1H),6.85(d,J＝8.0Hz,1H),6.06(s,1H),4.47(s,3H),4.40-4.32(m,2H),3.82(s,3H),1.39(t,J＝4.0Hz,3H). Under the protection of argon, the compound 1-methyl-7-chloro-4-bromo-indole-2-carboxylic acid ethyl ester (195 mg, 0.62 mmol) was dissolved in toluene (20 mL), and Pd 2 (dba) 3 was added successively (58mg, 0.06mmol), Xantphos (72mg, 0.12mmol) and Na 2 CO 3 (192mg, 1.85mmol, 3mL H 2 O), after stirring well, 5-methoxy-3-aminopyridine (230mg, 1.85 mmol) was added, the reaction was refluxed for 8h, and the raw material disappeared completely. Cool to room temperature, concentrate, add EA (20 mL) to dissolve the residue, wash with water and salt, and column chromatography gives 133 mg of light yellow solid with a yield of 60%. 1 H-NMR (400MHz, CDCl 3 )δ(ppm): 8.07(s, 1H), 7.91(s, 1H), 7.27(s, 1H), 7.18(d, J=8.0Hz, 1H), 6.95( s,1H),6.85(d,J=8.0Hz,1H),6.06(s,1H),4.47(s,3H),4.40-4.32(m,2H),3.82(s,3H),1.39(t ,J＝4.0Hz,3H).
b).1-甲基-4-((5-甲氧基吡啶-3-基)氨基)-7-氯-吲哚-2-甲酸b).1-Methyl-4-((5-methoxypyridin-3-yl)amino)-7-chloro-indole-2-carboxylic acid
Figure PCTCN2021104953-appb-000023
Figure PCTCN2021104953-appb-000023
将化合物1-甲基-4-((5-甲氧基吡啶-3-基)氨基)-7-氯-吲哚-2-甲酸乙酯(100mg，0.28mmol)溶于THF/EtOH(1/2,v/v,12mL)中，加入NaOH溶液(56mg，1.39mmol，2mLH 2O)，室温反应过夜，停止反应后蒸除溶剂，加入少量水，1M盐酸调节pH至2，析出固体，过滤干燥，得浅黄绿色固体90mg，产率97％。 The compound 1-methyl-4-((5-methoxypyridin-3-yl)amino)-7-chloro-indole-2-carboxylic acid ethyl ester (100 mg, 0.28 mmol) was dissolved in THF/EtOH (1 /2, v/v, 12mL), add NaOH solution (56mg, 1.39mmol, 2mLH 2 O), react overnight at room temperature, evaporate the solvent after stopping the reaction, add a small amount of water, adjust the pH to 2 with 1M hydrochloric acid, and precipitate a solid. After filtration and drying, 90 mg of a light yellow-green solid was obtained, with a yield of 97%.
1H-NMR(400MHz,DMSO-d 6)δ(ppm):13.17(s,1H),8.97(m,1H),8.12(s,1H),7.96(s,1H),7.53(s,1H),7.34(s,1H),7.25(d,J＝8.4Hz,1H),6.98(d,J＝8.4Hz,1H),4.37(s,3H),3.85(s,3H). 1 H-NMR(400MHz,DMSO-d 6 )δ(ppm):13.17(s,1H),8.97(m,1H),8.12(s,1H),7.96(s,1H),7.53(s,1H ),7.34(s,1H),7.25(d,J=8.4Hz,1H),6.98(d,J=8.4Hz,1H),4.37(s,3H),3.85(s,3H).
c).1-甲基-4-((5-甲氧基吡啶-3-基)氨基)-7-氯-N-(4-甲氧基苯磺酰基)-吲哚-2-甲酰胺c).1-Methyl-4-((5-methoxypyridin-3-yl)amino)-7-chloro-N-(4-methoxybenzenesulfonyl)-indole-2-carboxamide
Figure PCTCN2021104953-appb-000024
Figure PCTCN2021104953-appb-000024
Ar保护下，将1-甲基-4-((5-甲氧基吡啶-3-基)氨基)-7-氯-吲哚-2-甲酸(75mg,0.23mmol)溶于干燥DCM中，依次加入HATU(155mg，0.41mmol)，DMAP(14mg，0.11mmol)和TEA(70mg,0.68mmol)，搅拌均匀后加入对甲氧基苯磺酰胺(76mg,0.41mmol)，35度反应50min后停止反应，蒸除溶剂后依次用稀盐酸，水洗，盐水洗，合并EA层，柱分离得微黄色固体(60mg，52％)。 1H-NMR(400MHz,DMSO-d 6)δ(ppm):11.96(s,1H),8.59(s,1H),8.07(s,1H),7.94(d,J＝8.4Hz,2H),7.85(s,1H),7.63(s,1H),7.19(m,3H),7.08(s,1H),6.90(d,J＝10.4Hz,1H),4.14(s,3H),3.86(s,3H),3.79(s,3H). 1-Methyl-4-((5-methoxypyridin-3-yl)amino)-7-chloro-indole-2-carboxylic acid (75 mg, 0.23 mmol) was dissolved in dry DCM under Ar protection, Add HATU (155mg, 0.41mmol), DMAP (14mg, 0.11mmol) and TEA (70mg, 0.68mmol) sequentially, stir well and then add p-methoxybenzenesulfonamide (76mg, 0.41mmol), react at 35°C for 50min and stop After the reaction, the solvent was distilled off and then washed with dilute hydrochloric acid, water, and brine. The EA layers were combined and separated by a column to obtain a yellowish solid (60 mg, 52%). 1 H-NMR (400MHz, DMSO-d 6 )δ(ppm): 11.96(s, 1H), 8.59(s, 1H), 8.07(s, 1H), 7.94(d, J=8.4Hz, 2H), 7.85(s,1H),7.63(s,1H),7.19(m,3H),7.08(s,1H),6.90(d,J=10.4Hz,1H),4.14(s,3H),3.86(s ,3H),3.79(s,3H).
实施例5 1-甲基-4-((6-甲氧基吡啶-3-基)氨基)-7-氯-N-(4-甲氧基苯磺酰基)-吲哚-2-甲酰胺Example 5 1-methyl-4-((6-methoxypyridin-3-yl)amino)-7-chloro-N-(4-methoxybenzenesulfonyl)-indole-2-carboxamide
Figure PCTCN2021104953-appb-000025
Figure PCTCN2021104953-appb-000025
a).1-甲基-4-((6-甲氧基吡啶-3-基)氨基)-7-氯-吲哚-2-甲酸乙酯a).1-Methyl-4-((6-methoxypyridin-3-yl)amino)-7-chloro-indole-2-carboxylic acid ethyl ester
Figure PCTCN2021104953-appb-000026
Figure PCTCN2021104953-appb-000026
氩气保护下，将化合物1-甲基-7-氯-4-溴-吲哚-2-甲酸乙酯(190mg，0.60mmol)溶于甲苯(20mL)中，依次加入Pd 2(dba) 3(55mg，0.06mmol)，Xantphos(70mg，0.12mmol)和Na 2CO 3(191mg，1.80mmol，3mL H 2O)，搅拌均匀后，将2-甲氧 基-5-氨基吡啶(224mg，1.80mmol)加入，回流反应7h，原料完全消失。冷却至室温，浓缩，加入EA(20mL)溶解残留物，水洗，盐洗，柱层析得浅黄固体130mg，产率为59％。 1H-NMR(400MHz,CDCl 3)δ(ppm):8.09(s,1H),7.52(d,J＝8.4Hz,1H),7.31(s,1H),7.09(d,J＝7.6Hz,1H),6.77(d,J＝10.0Hz,1H),6.47(s,1H),5.90(s,1H),4.46(s,3H),4.36(m,2H),3.97(s,3H),1.40(t,J＝7.2Hz,3H). Under argon protection, the compound 1-methyl-7-chloro-4-bromo-indole-2-carboxylic acid ethyl ester (190 mg, 0.60 mmol) was dissolved in toluene (20 mL), and Pd 2 (dba) 3 was added in sequence (55mg, 0.06mmol), Xantphos (70mg, 0.12mmol) and Na 2 CO 3 (191mg, 1.80mmol, 3mL H 2 O), after stirring well, 2-methoxy-5-aminopyridine (224mg, 1.80 mmol) was added, and the reaction was refluxed for 7h, and the raw material disappeared completely. Cooled to room temperature, concentrated, added EA (20 mL) to dissolve the residue, washed with water and salt, and column chromatography gave 130 mg of light yellow solid with a yield of 59%. 1 H-NMR (400MHz, CDCl 3 )δ(ppm): 8.09(s, 1H), 7.52(d, J=8.4Hz, 1H), 7.31(s, 1H), 7.09(d, J=7.6Hz, 1H), 6.77(d, J=10.0Hz, 1H), 6.47(s, 1H), 5.90(s, 1H), 4.46(s, 3H), 4.36(m, 2H), 3.97(s, 3H), 1.40(t,J=7.2Hz,3H).
b).1-甲基-4-((6-甲氧基吡啶-3-基)氨基)-7-氯-吲哚-2-甲酸b).1-Methyl-4-((6-methoxypyridin-3-yl)amino)-7-chloro-indole-2-carboxylic acid
Figure PCTCN2021104953-appb-000027
Figure PCTCN2021104953-appb-000027
将1-甲基-4-((6-甲氧基吡啶-3-基)氨基)-7-氯-吲哚-2-甲酸乙酯(110mg，0.31mmol)溶于THF/EtOH(1/2,v/v,12mL)中，加入NaOH溶液(62mg，1.53mmol，2mL H 2O)，室温反应过夜，停止反应后蒸除溶剂，加入少量水，1M盐酸调节pH至2，析出固体，过滤干燥，得浅黄绿色固体98mg，产率97％。 1H-NMR(400MHz,DMSO-d 6)δ(ppm):8.07(s,1H),7.65(s,2H),7.09(d,J＝8.4Hz,1H),6.87(d,J＝8.4Hz,1H),6.48(d,J＝8.8Hz,1H),4.34(s,3H),3.85(s,3H). Ethyl 1-methyl-4-((6-methoxypyridin-3-yl)amino)-7-chloro-indole-2-carboxylate (110 mg, 0.31 mmol) was dissolved in THF/EtOH (1/ 2, v/v, 12mL), add NaOH solution (62mg, 1.53mmol, 2mL H 2 O), react overnight at room temperature, evaporate the solvent after stopping the reaction, add a small amount of water, adjust the pH to 2 with 1M hydrochloric acid, and precipitate a solid. After filtration and drying, 98 mg of a light yellow-green solid was obtained, with a yield of 97%. 1 H-NMR (400MHz, DMSO-d 6 )δ(ppm): 8.07(s, 1H), 7.65(s, 2H), 7.09(d, J=8.4Hz, 1H), 6.87(d, J=8.4 Hz,1H),6.48(d,J=8.8Hz,1H),4.34(s,3H),3.85(s,3H).
c).1-甲基-4-((6-甲氧基吡啶-3-基)氨基)-7-氯-N-(4-甲氧基苯磺酰基)-吲哚-2-甲酰胺c).1-Methyl-4-((6-methoxypyridin-3-yl)amino)-7-chloro-N-(4-methoxybenzenesulfonyl)-indole-2-carboxamide
Figure PCTCN2021104953-appb-000028
Figure PCTCN2021104953-appb-000028
Ar保护下，将1-甲基-4-((6-甲氧基吡啶-3-基)氨基)-7-氯-吲哚-2-甲酸(76mg,0.23mmol)溶于干燥DCM中，依次加入HATU(158mg，0.41mmol)，DMAP(14mg，0.11mmol)和TEA(70mg,0.69mmol)，搅拌均匀后加入对甲氧基苯磺酰胺(78mg,0.41mmol)，35度反应1.0h后停止反应，蒸除溶剂后依次用稀盐酸，水洗，盐水洗，合并EA层，柱分离得微黄色固体(61mg，53％)。 1H-NMR(400MHz,DMSO-d 6)δ(ppm):12.50(s,1H),8.24(s,1H),8.06(s,1H),7.95(d,J＝8.8Hz,2H),7.66(s,1H),7.59(dd,J 1＝8.4Hz,J 2＝2.4Hz,1H),7.18(d,J＝8.8Hz,2H),7.10(d,J＝8.4Hz,1H),6.83(d,J＝8.4Hz,1H),6.48(d,J＝8.4Hz,1H),4.10(s,3H),3.87(s, 3H),3.84(s,3H).HRMS(ESI):m/z,calcd.for C 23H 20N 4O 5ClS[M-H] -:499.08,found499.06. 1-Methyl-4-((6-methoxypyridin-3-yl)amino)-7-chloro-indole-2-carboxylic acid (76 mg, 0.23 mmol) was dissolved in dry DCM under Ar protection, Add HATU (158mg, 0.41mmol), DMAP (14mg, 0.11mmol) and TEA (70mg, 0.69mmol) sequentially, stir evenly, add p-methoxybenzenesulfonamide (78mg, 0.41mmol), react at 35°C for 1.0h The reaction was stopped, the solvent was distilled off, and then washed with dilute hydrochloric acid, water, and brine. The EA layers were combined and separated by a column to obtain a yellowish solid (61 mg, 53%). 1 H-NMR (400MHz, DMSO-d 6 ) δ (ppm): 12.50 (s, 1H), 8.24 (s, 1H), 8.06 (s, 1H), 7.95 (d, J = 8.8Hz, 2H), 7.66(s,1H),7.59(dd,J 1 =8.4Hz,J 2 =2.4Hz,1H),7.18(d,J=8.8Hz,2H),7.10(d,J=8.4Hz,1H), 6.83(d,J=8.4Hz,1H),6.48(d,J=8.4Hz,1H),4.10(s,3H),3.87(s,3H),3.84(s,3H).HRMS(ESI): m/z,calcd.for C 23 H 20 N 4 O 5 ClS[MH] - :499.08,found499.06.
实施例6 1-甲基-4-((2-甲氧基嘧啶-6-基)氨基)-7-氯-N-(4-甲氧基苯磺酰基)-吲哚-2-甲酰胺Example 6 1-methyl-4-((2-methoxypyrimidin-6-yl)amino)-7-chloro-N-(4-methoxybenzenesulfonyl)-indole-2-carboxamide
Figure PCTCN2021104953-appb-000029
Figure PCTCN2021104953-appb-000029
a).1-甲基-4-((2-甲氧基嘧啶-6-基)氨基)-7-氯-吲哚-2-甲酸乙酯a).1-Methyl-4-((2-methoxypyrimidin-6-yl)amino)-7-chloro-indole-2-carboxylic acid ethyl ester
Figure PCTCN2021104953-appb-000030
Figure PCTCN2021104953-appb-000030
氩气保护下，将化合物1-甲基-7-氯-4-溴-吲哚-2-甲酸乙酯(750mg,2.39mmol)溶于甲苯(40mL)中，加入Pd 2(dba) 3(547mg,0.6mmol)，Xantphos(694mg,1.2mmol)，然后将Na 2CO 3(847mg,7.99mmol)溶于(10mL)水中加入反应液，将2-甲氧基-4-氨基嘧啶(1g,7.99mmol)加入反应瓶中，回流反应20h。过滤，滤液加入乙酸乙酯，用稀盐酸洗，饱和碳酸氢钠溶液洗，饱和氯化钠溶液洗，无水硫酸镁干燥，柱层析得到类白色固体720mg，产率83％。 1H-NMR(400MHz,CDCl 3)δ(ppm):8.09(d,J＝4.4Hz,1H),7.25-7.28(m,3H),7.07(s,1H),6.33(s,1H),4.48(s,3H),4.37(q,J＝6.4Hz,2H),3.97(s,3H),1.39(t,J＝6.4Hz,3H). Under the protection of argon, the compound 1-methyl-7-chloro-4-bromo-indole-2-carboxylic acid ethyl ester (750 mg, 2.39 mmol) was dissolved in toluene (40 mL), and Pd 2 (dba) 3 ( 547mg, 0.6mmol), Xantphos (694mg, 1.2mmol), then Na 2 CO 3 (847mg, 7.99mmol) was dissolved in (10mL) water and added to the reaction solution, 2-methoxy-4-aminopyrimidine (1g, 7.99mmol) into the reaction flask, reflux reaction 20h. Filtrate, add ethyl acetate to the filtrate, wash with dilute hydrochloric acid, wash with saturated sodium bicarbonate solution, wash with saturated sodium chloride solution, dry over anhydrous magnesium sulfate, and obtain 720 mg of off-white solid by column chromatography, with a yield of 83%. 1 H-NMR (400MHz, CDCl 3 ) δ (ppm): 8.09 (d, J=4.4Hz, 1H), 7.25-7.28 (m, 3H), 7.07 (s, 1H), 6.33 (s, 1H), 4.48(s,3H),4.37(q,J=6.4Hz,2H),3.97(s,3H),1.39(t,J=6.4Hz,3H).
b).1-甲基-4-((2-甲氧基嘧啶-6-基)氨基)-7-氯-吲哚-2-甲酸b).1-methyl-4-((2-methoxypyrimidin-6-yl)amino)-7-chloro-indole-2-carboxylic acid
Figure PCTCN2021104953-appb-000031
Figure PCTCN2021104953-appb-000031
将化合物1-甲基-4-((2-甲氧基嘧啶-6-基)氨基)-7-氯-吲哚-2-甲酸乙酯(650mg, 1.805mmol)溶于THF(10mL)和EtOH(10mL)的混合液中，将NaOH(217mg,5.42mmol)溶于3.5mL水中加入反应液中，40℃反应2h，浓缩，加入少量水，用乙醚萃取，水层用稀盐酸调节pH至2-3，有固体析出，过滤，滤饼水洗，得到淡黄色固体600mg，产率99％。 1H-NMR(400MHz,DMSO-d 6)δ(ppm):10.82(s,1H),8.17(dd,J 1＝8.4Hz,J 2＝1.2Hz,1H),7.78(t,J＝8.0Hz,1H),7.69(s,1H),7.38(dd,J 1＝8.4Hz,J 2＝1.2Hz,1H),6.94(d,J＝8.4Hz,1H),4.39(s,3H),3.96(s,3H). The compound 1-methyl-4-((2-methoxypyrimidin-6-yl)amino)-7-chloro-indole-2-carboxylic acid ethyl ester (650 mg, 1.805 mmol) was dissolved in THF (10 mL) and In a mixture of EtOH (10 mL), NaOH (217 mg, 5.42 mmol) was dissolved in 3.5 mL of water and added to the reaction liquid, reacted at 40°C for 2 h, concentrated, added a small amount of water, extracted with ether, and the pH of the aqueous layer was adjusted to 2-3, solids were precipitated, filtered, and the filter cake was washed with water to obtain 600 mg of a light yellow solid with a yield of 99%. 1 H-NMR (400MHz, DMSO-d 6 ) δ (ppm): 10.82 (s, 1H), 8.17 (dd, J 1 = 8.4Hz, J 2 = 1.2Hz, 1H), 7.78 (t, J = 8.0 Hz,1H),7.69(s,1H),7.38(dd,J 1 =8.4Hz,J 2 =1.2Hz,1H),6.94(d,J=8.4Hz,1H),4.39(s,3H), 3.96(s,3H).
c).1-甲基-4-((2-甲氧基嘧啶-6-基)氨基)-7-氯-N-(4-甲氧基苯磺酰基)-吲哚-2-甲酰胺c).1-Methyl-4-((2-methoxypyrimidin-6-yl)amino)-7-chloro-N-(4-methoxybenzenesulfonyl)-indole-2-carboxamide
Figure PCTCN2021104953-appb-000032
Figure PCTCN2021104953-appb-000032
Ar保护下，将1-甲基-4-((2-甲氧基嘧啶-6-基)氨基)-7-氯-吲哚-2-甲酸(75mg,0.23mmol)溶于干燥DCM中，依次加入HATU(156mg，0.41mmol)，DMAP(15mg，0.12mmol)和TEA(70mg,0.69mmol)，搅拌均匀后加入对甲氧基苯磺酰胺(77mg,0.41mmol)，35度反应30min后停止反应，蒸除溶剂后依次用稀盐酸，水洗，盐水洗，合并EA层，柱分离得微黄色固体(63mg，54％)。 1H-NMR(400MHz,DMSO-d 6)δ(ppm):12.63(s,1H),9.60(s,1H),8.15(s,1H),7.93(d,J＝8.8Hz,2H),7.82(d,J＝8.4Hz,1H),7.72(s,1H),7.32(d,J＝8.4Hz,1H),7.15(d,J＝8.7Hz,2H),6.66(s,1H),4.16(s,3H),3.85(s,3H),3.83(s,3H). Under Ar protection, 1-methyl-4-((2-methoxypyrimidin-6-yl)amino)-7-chloro-indole-2-carboxylic acid (75 mg, 0.23 mmol) was dissolved in dry DCM, Add HATU (156mg, 0.41mmol), DMAP (15mg, 0.12mmol) and TEA (70mg, 0.69mmol) sequentially, stir well and then add p-methoxybenzenesulfonamide (77mg, 0.41mmol), react at 35°C for 30min and stop After the reaction, the solvent was distilled off and then washed with dilute hydrochloric acid, water, and brine. The EA layers were combined and separated by a column to obtain a yellowish solid (63 mg, 54%). 1 H-NMR(400MHz,DMSO-d 6 )δ(ppm):12.63(s,1H),9.60(s,1H),8.15(s,1H),7.93(d,J=8.8Hz,2H), 7.82(d, J=8.4Hz, 1H), 7.72(s, 1H), 7.32(d, J=8.4Hz, 1H), 7.15(d, J=8.7Hz, 2H), 6.66(s, 1H), 4.16(s,3H),3.85(s,3H),3.83(s,3H).
实施例7 1-甲基-4-((2-甲氧基嘧啶-6-基)氨基)-7-氯-N-(4-甲氧基苯磺酰基)-吲哚-2-甲酰胺钠盐Example 7 1-methyl-4-((2-methoxypyrimidin-6-yl)amino)-7-chloro-N-(4-methoxybenzenesulfonyl)-indole-2-carboxamide sodium salt
Figure PCTCN2021104953-appb-000033
Figure PCTCN2021104953-appb-000033
Ar保护下，将1-甲基-4-((2-甲氧基嘧啶-6-基)氨基)-7-氯-吲哚-2-甲酸(498mg,1.5mmol)溶于DCM(30mL)中，加入HATU(1.14g,3mmol)，DMAP(91.5mg, 0.75mmol)和TEA(0.65mL,4.5mmol)以及对甲氧基苯磺酰胺(563mg,3mmol)，室温搅拌1h左右，加入DCM(25mL)，用1N盐酸溶液洗，饱和碳酸氢钠溶液洗，水洗，有固体析出，抽滤，滤饼水洗，DCM洗，得到土黄色固体470mg，产率62％。 1H-NMR(400MHz,DMSO-d 6)δ(ppm):9.41(s,1H),8.08(d,J＝6.0Hz,1H),7.89(d,J＝8.0Hz,1H),7.78(d,J＝8.8Hz,2H),7.40(s,1H),7.12(d,J＝8.4Hz,1H),6.93(d,J＝8.8Hz,2H),6.73(d,J＝6.0Hz,1H),4.31(s,3H),3.85(s,3H),3.78(s,3H). 1-Methyl-4-((2-methoxypyrimidin-6-yl)amino)-7-chloro-indole-2-carboxylic acid (498 mg, 1.5 mmol) was dissolved in DCM (30 mL) under Ar protection , add HATU (1.14g, 3mmol), DMAP (91.5mg, 0.75mmol) and TEA (0.65mL, 4.5mmol) and p-methoxybenzenesulfonamide (563mg, 3mmol), stir at room temperature for about 1h, add DCM ( 25 mL), washed with 1N hydrochloric acid solution, washed with saturated sodium bicarbonate solution, washed with water, a solid precipitated out, filtered with suction, washed the filter cake with water, and washed with DCM to obtain 470 mg of a khaki solid, with a yield of 62%. 1 H-NMR (400MHz, DMSO-d 6 ) δ (ppm): 9.41 (s, 1H), 8.08 (d, J = 6.0Hz, 1H), 7.89 (d, J = 8.0Hz, 1H), 7.78 ( d,J=8.8Hz,2H),7.40(s,1H),7.12(d,J=8.4Hz,1H),6.93(d,J=8.8Hz,2H),6.73(d,J=6.0Hz, 1H), 4.31(s,3H), 3.85(s,3H), 3.78(s,3H).
实施例8 1-甲基-4-((4-甲氧基嘧啶-6-基)氨基)-7-氯-N-(4-甲氧基苯磺酰基)-吲哚-2-甲酰胺Example 8 1-methyl-4-((4-methoxypyrimidin-6-yl)amino)-7-chloro-N-(4-methoxybenzenesulfonyl)-indole-2-carboxamide
Figure PCTCN2021104953-appb-000034
Figure PCTCN2021104953-appb-000034
a).1-甲基-4-((4-甲氧基嘧啶-6-基)氨基)-7-氯-吲哚-2-甲酸乙酯a).1-Methyl-4-((4-methoxypyrimidin-6-yl)amino)-7-chloro-indole-2-carboxylic acid ethyl ester
Figure PCTCN2021104953-appb-000035
Figure PCTCN2021104953-appb-000035
氩气保护下，将化产物1-甲基-7-氯-4-溴-吲哚-2-甲酸乙酯(158mg，0.50mmol)溶于甲苯(20mL)中，依次加入Pd 2(dba) 3(46mg，0.05mmol)，Xantphos(58mg，0.10mmol)和Na 2CO 3(160mg，1.50mmol，3mL H 2O)，搅拌均匀后，将6-甲氧基-4-氨基嘧啶(188mg，1.50mmol)加入，回流反应10h，原料完全消失。冷却至室温，浓缩，加入EA(20mL)溶解残留物，水洗，盐洗，柱层析(PE/EA＝10/1-5/1)柱分得浅黄固体108mg，产率为60％。 1H-NMR(400MHz,CDCl 3)δ(ppm):8.39(s,1H),7.30(s,1H),7.10(d,J＝8.4Hz,1H),6.03(s,1H),4.48(s,3H),4.36(d,J＝6.8Hz,2H),3.92(s,3H),1.41(d,J＝8.0Hz,3H). Under the protection of argon, the product 1-methyl-7-chloro-4-bromo-indole-2-carboxylic acid ethyl ester (158 mg, 0.50 mmol) was dissolved in toluene (20 mL), and Pd 2 (dba) was added successively 3 (46mg, 0.05mmol), Xantphos (58mg, 0.10mmol) and Na 2 CO 3 (160mg, 1.50mmol, 3mL H 2 O), after stirring well, 6-methoxy-4-aminopyrimidine (188mg, 1.50mmol) was added, refluxed for 10h, and the raw material disappeared completely. Cool to room temperature, concentrate, add EA (20 mL) to dissolve the residue, wash with water, wash with salt, and column chromatography (PE/EA=10/1-5/1) column to obtain 108 mg of light yellow solid with a yield of 60%. 1 H-NMR (400MHz, CDCl 3 ) δ (ppm): 8.39 (s, 1H), 7.30 (s, 1H), 7.10 (d, J = 8.4Hz, 1H), 6.03 (s, 1H), 4.48 ( s,3H),4.36(d,J=6.8Hz,2H),3.92(s,3H),1.41(d,J=8.0Hz,3H).
b).1-甲基-4-((4-甲氧基嘧啶-6-基)氨基)-7-氯-吲哚-2-甲酸b).1-methyl-4-((4-methoxypyrimidin-6-yl)amino)-7-chloro-indole-2-carboxylic acid
Figure PCTCN2021104953-appb-000036
Figure PCTCN2021104953-appb-000036
将1-甲基-4-((4-甲氧基嘧啶-6-基)氨基)-7-氯-吲哚-2-甲酸乙酯(95mg，0.26mmol)溶于THF/EtOH(1/2,v/v,12mL)中，加入NaOH溶液(53mg，1.32mmol，2mL H 2O)，室温反应过夜，停止反应后蒸除溶剂，加入少量水，1M盐酸调节pH至2，析出固体，过滤干燥，得浅黄绿色固体85mg，产率96％。 1H-NMR(400MHz,DMSO-d 6)δ(ppm):9.45(s,1H),8.43(s,1H),7.82(d,J＝8.4Hz,1H),7.66(s,1H),7.29(d,J＝8.4Hz,1H),6.38(s,1H),4.37(s,3H),3.87(s,3H). Ethyl 1-methyl-4-((4-methoxypyrimidin-6-yl)amino)-7-chloro-indole-2-carboxylate (95 mg, 0.26 mmol) was dissolved in THF/EtOH (1/ 2, v/v, 12mL), add NaOH solution (53mg, 1.32mmol, 2mL H 2 O), react overnight at room temperature, evaporate the solvent after stopping the reaction, add a small amount of water, adjust the pH to 2 with 1M hydrochloric acid, and precipitate a solid. After filtration and drying, 85 mg of a light yellow-green solid was obtained, with a yield of 96%. 1 H-NMR (400MHz, DMSO-d 6 ) δ (ppm): 9.45 (s, 1H), 8.43 (s, 1H), 7.82 (d, J=8.4Hz, 1H), 7.66 (s, 1H), 7.29(d,J=8.4Hz,1H),6.38(s,1H),4.37(s,3H),3.87(s,3H).
c).1-甲基-4-((4-甲氧基嘧啶-6-基)氨基)-7-氯-N-(4-甲氧基苯磺酰基)-吲哚-2-甲酰胺c).1-Methyl-4-((4-methoxypyrimidin-6-yl)amino)-7-chloro-N-(4-methoxybenzenesulfonyl)-indole-2-carboxamide
Figure PCTCN2021104953-appb-000037
Figure PCTCN2021104953-appb-000037
Ar保护下，将1-甲基-4-((4-甲氧基嘧啶-6-基)氨基)-7-氯-吲哚-2-甲酸(70mg,0.21mmol)溶于干燥DCM中，依次加入HATU(145mg，0.38mmol)，DMAP(14mg，0.11mmol)和TEA(64mg,0.63mmol)，搅拌均匀后加入对甲氧基苯磺酰胺(72mg,0.38mmol)，35度反应1.5h后停止反应，蒸除溶剂后依次用稀盐酸，水洗，盐水洗，合并EA层，柱分离得微黄色固体(72mg，67％)。 1H-NMR(400MHz,DMSO-d 6)δ(ppm):11.95(s,1H),9.38(s,1H),8.40(s,1H),7.96(m,2H),7.69(m,2H),7.18(m,1H),7.12(m,2H),6.26(s,1H),4.14(s,3H),3.86(s,6H). Under Ar protection, 1-methyl-4-((4-methoxypyrimidin-6-yl)amino)-7-chloro-indole-2-carboxylic acid (70 mg, 0.21 mmol) was dissolved in dry DCM, Add HATU (145mg, 0.38mmol), DMAP (14mg, 0.11mmol) and TEA (64mg, 0.63mmol) sequentially, stir well and add p-methoxybenzenesulfonamide (72mg, 0.38mmol), react at 35°C for 1.5h The reaction was stopped, the solvent was distilled off, and then washed with dilute hydrochloric acid, water, and brine. The EA layers were combined and separated by a column to obtain a yellowish solid (72 mg, 67%). 1 H-NMR(400MHz,DMSO-d 6 )δ(ppm):11.95(s,1H),9.38(s,1H),8.40(s,1H),7.96(m,2H),7.69(m,2H ),7.18(m,1H),7.12(m,2H),6.26(s,1H),4.14(s,3H),3.86(s,6H).
药理实验：Pharmacological experiment:
实验例1：化合物对FBP酶抑制活性评价Experimental Example 1: Evaluation of compound's inhibitory activity on FBP enzyme
实验方法和结果：Experimental method and results:
1.人肝FBP酶(FBPase)的重组表达1. Recombinant expression of human liver FBPase (FBPase)
将已构建的人肝FBPase基因质粒PETα8a-FBP转化感受态菌BL21(DE3)Rosetta cells(Novagen,Inc.)，取100ul含质粒的感受态菌涂于含卡那霉素(30ug/mL)的LB固体培养板上，于培养箱中37℃培养12-14h至生长出明显的单个菌落。从固体培养基上挑取单个菌落，接种至含卡那霉素(30ug/ml)的LB液体 培养基中，37℃、200rpm扩大培养12h。扩大培养后的菌液加入IPTG(使其在菌液中的终浓度为0.1mM)，在摇床中16℃、200rpm培养24h，诱导蛋白表达。然后将菌液在4℃、5500rpm离心5min后，弃上清，沉淀(菌体)加入FBPase Tris-Buffer使菌体重悬。超声破碎菌体，然后4℃、12,000rpm离心1min。收集上清，测定酶活性，分装后于-80℃保存备用。Transform the constructed human liver FBPase gene plasmid PETα8a-FBP into competent bacteria BL21(DE3) Rosetta cells (Novagen, Inc.), take 100ul of the competent bacteria containing the plasmid and apply it to the medium containing kanamycin (30ug/mL) On LB solid culture plates, culture in an incubator at 37°C for 12-14 hours until a single colony grows obviously. A single colony was picked from the solid medium, inoculated into LB liquid medium containing kanamycin (30ug/ml), and expanded at 37°C and 200rpm for 12h. Add IPTG (to make the final concentration in the bacterial solution 0.1 mM) to the expanded cultured bacterial solution, and culture in a shaker at 16° C. and 200 rpm for 24 hours to induce protein expression. Then the bacterial solution was centrifuged at 4°C and 5500rpm for 5 minutes, the supernatant was discarded, and the precipitate (bacterial cells) was added to FBPase Tris-Buffer to resuspend the bacterial cells. The cells were disrupted by ultrasonication, and then centrifuged at 12,000 rpm for 1 min at 4°C. The supernatant was collected, assayed for enzyme activity, and stored at -80°C after aliquoting.
2.FBP酶活性的测定2. Determination of FBP enzyme activity
FBPase活性测定原理：利用FBPase与磷酸葡萄糖异构酶和葡萄糖-6-磷酸脱氢酶的偶联反应，采用分光光度计，检测反应产物的浓度以反映酶的活性。反应消耗NADP +生成NADPH，在340nm处的吸光度变化直接反映酶的活性。首先反应孔中加入FBPase Tris-Buffer(100mM Tris、2mM MgCl 2、0.1mM EDTA,pH 7.5)、抑制剂(终浓度0.08uM、0.4uM、2uM或10uM，全反应孔以FBPase Tris-Buffer代替)和FBPase(终浓度0.72unit)。在37℃孵育10min后，加入反应底物混合物(终浓度0.2mM NADP +、0.01units磷酸葡萄糖异构酶、0.01units葡萄糖-6-磷酸脱氢酶和0.2mM FBP)，反应即开始。动态监测反应产物(NADPH)的吸光度值。以全反应孔的吸光度值作为100％，计算抑制剂反应孔的抑制率，即对酶活性的抑制强度。通过抑制剂的浓度和酶的活性得到抑制曲线。 Measuring principle of FBPase activity: Utilize the coupling reaction of FBPase with phosphoglucose isomerase and glucose-6-phosphate dehydrogenase, and use a spectrophotometer to detect the concentration of the reaction product to reflect the activity of the enzyme. The reaction consumes NADP + to generate NADPH, and the change of absorbance at 340nm directly reflects the activity of the enzyme. First, add FBPase Tris-Buffer (100mM Tris, 2mM MgCl 2 , 0.1mM EDTA, pH 7.5) and inhibitors (final concentration 0.08uM, 0.4uM, 2uM or 10uM to the reaction wells, replace all reaction wells with FBPase Tris-Buffer) And FBPase (final concentration 0.72unit). After incubation at 37° C. for 10 min, the reaction substrate mixture (final concentration 0.2 mM NADP + , 0.01 units phosphoglucose isomerase, 0.01 units glucose-6-phosphate dehydrogenase and 0.2 mM FBP) was added to start the reaction. Dynamically monitor the absorbance value of the reaction product (NADPH). Taking the absorbance value of the entire reaction well as 100%, the inhibition rate of the inhibitor reaction well, that is, the inhibitory intensity to the enzyme activity, was calculated. Inhibition curves were obtained by inhibitor concentration and enzyme activity.
表1.化合物对FBP酶抑制活性Table 1. Compounds have inhibitory activity against FBPase
实施例Example (IC 50M) (IC 50M ) 实施例Example (IC 50M) (IC 50M )
11 8.30×10 -8 8.30×10 -8 22 1.50×10 -8 1.50×10 -8
33 4.78×10 -8 4.78×10 -8 44 1.81×10 -8 1.81×10 -8
55 4.49×10 -8 4.49×10 -8 66 3.05×10 -8 3.05×10 -8
77 9.70×10 -8 9.70×10 -8 88 2.71×10 -8 2.71×10 -8
实验例2：动物体内药效学实验Experimental Example 2: Pharmacodynamics Experiment in Animals
实验例2-1：实施例2化合物对ICR小鼠的抗糖尿病活性评价Experimental example 2-1: Evaluation of the antidiabetic activity of the compound of Example 2 on ICR mice
实验方法和结果：Experimental method and results:
1.实验方法1. Experimental method
采用正常的雄性ICR小鼠，禁食过夜，于次日早晨取零时血样(-120min)，其后，灌胃方式分别给予实施例化合物2(Example 2，150mg/kg)或阳性药二甲双胍(Met，150mg/kg)，空白对照组以水代替。在给药2h后，采集给药后血样(0min)，口服灌胃糖异生底物丙酮酸钠(2g/kg)，并于灌胃丙酮酸钠30min后采集小鼠血样(30min)。通过GOD法测血样中葡萄糖浓度。比较各组0min与 30min血糖差异与正常对照组相比是否有统计学差异，测定化合物的降血糖活性。Adopt normal male ICR mice, fast overnight, get zero o'clock blood sample (-120min) in the morning of the next day, thereafter, give embodiment compound 2 (Example 2, 150mg/kg) or positive drug metformin ( Met, 150mg/kg), the blank control group was replaced by water. After 2 hours of administration, the post-administration blood sample was collected (0 min), and the gluconeogenesis substrate sodium pyruvate (2 g/kg) was orally administered orally, and the mouse blood sample was collected after 30 min of intragastric administration of sodium pyruvate (30 min). Glucose concentration in blood samples was measured by GOD method. Compare each group 0min and 30min blood glucose difference with normal control group to compare whether there is statistical difference, measure the hypoglycemic activity of compound.
2.实验结果2. Experimental results
结果如图1所示，实施例2化合物可显著抑制正常ICR小鼠丙酮酸钠耐量实验中的30min的血糖上升，作用优于等剂量二甲双胍。The results are shown in Figure 1, the compound of Example 2 can significantly inhibit the 30-min rise in blood sugar in the sodium pyruvate tolerance test of normal ICR mice, and the effect is better than that of metformin at the same dose.
实验例2-2：实施例2化合物对2型糖尿病KKAy小鼠的抗糖尿病活性评价Experimental example 2-2: Evaluation of the antidiabetic activity of the compound of Example 2 on type 2 diabetic KKAy mice
实验方法和结果：Experimental method and results:
1.实验方法1. Experimental method
自发性2型糖尿病KKAy小鼠，雄性，周龄4-5w，购自北京华富康生物科技股份有限公司，饲养于中国医学科学院药物研究所SPF级动物房，5只/盒，食水自由。给予高脂饲料喂养约3周，对其进行随机分组，每组10只。主要观察指标有：非禁食血糖(PBG)、空腹血糖(FBG)、OGTT实验30min血糖上升百分数、血甘油三酯(TG)、血总胆固醇(TC)以及体重。灌胃水作为模型对照组，灌胃化合物实施例2(100mg/kg和200mg/kg)混悬液作为给药组，灌胃化合物二甲双胍(150mg/kg)混悬液作为阳性对照组。每天灌胃一次，连续35天。实验期间动态监测小鼠空腹血糖水平。于第21天测定空腹血糖，第27天测定随机血糖，第33天测定糖化血红蛋白水平。 Spontaneous type 2 diabetic KKAy mice, male, 4-5 weeks old, were purchased from Beijing Huafukang Biotechnology Co., Ltd., and were bred in the SPF animal room of the Institute of Materia Medica, Chinese Academy of Medical Sciences, 5 mice/box, with free access to water. They were fed with high-fat feed for about 3 weeks, and they were randomly divided into groups, 10 in each group. MAIN OUTCOME MEASURES: non-fasting blood glucose (PBG), fasting blood glucose (FBG), percent increase in blood glucose at 30 minutes of OGTT test, blood triglyceride (TG), blood total cholesterol (TC) and body weight. Gavage water was used as the model control group, gavage compound Example 2 (100 mg/kg and 200 mg/kg) suspension was used as the administration group, and gavage compound metformin (150 mg/kg) suspension was used as the positive control group. Oral administration once a day for 35 consecutive days. During the experiment, the fasting blood glucose level of the mice was dynamically monitored. The fasting blood glucose was measured on the 21st day, the random blood glucose was measured on the 27th day, and the glycosylated hemoglobin level was measured on the 33rd day.
2.实验结果2. Experimental results
与模型对照组相比，化合物实施例2能够明显降低自发性2型糖尿病KKAy小鼠的空腹血糖水平(表2)；也能显著降低KKAy小鼠的随机血糖水平(表3)；并使KKAy小鼠血糖化血红蛋白水平明显降低(表4)。Compared with the model control group, Compound Example 2 can significantly reduce the fasting blood glucose level (Table 2) of spontaneous type 2 diabetes KKAy mice; it can also significantly reduce the random blood glucose level (Table 3) of KKAy mice; and make KKAy The level of glycated hemoglobin in the mice was significantly reduced (Table 4).
表2实施例2给药第21天对KKAy小鼠空腹血糖的影响Table 2 Example 2 Administration of the 21st day on the impact of fasting blood glucose in KKAy mice
Figure PCTCN2021104953-appb-000038
Figure PCTCN2021104953-appb-000038
*P<0.05,**P<0.01,***P<0.001,与模型组相比；数据以
Figure PCTCN2021104953-appb-000039
表示； *P<0.05, **P<0.01, ***P<0.001, compared with the model group; the data are represented by
Figure PCTCN2021104953-appb-000039
express;
表3实施例2给药第27天对KKAy小鼠随机血糖的影响The impact of table 3 embodiment 2 administration on the random blood sugar of KKAy mice on the 27th day
Figure PCTCN2021104953-appb-000040
Figure PCTCN2021104953-appb-000040
*P<0.05,**P<0.01,***P<0.001,与模型组相比；数据以
Figure PCTCN2021104953-appb-000041
表示； *P<0.05, **P<0.01, ***P<0.001, compared with the model group; the data are represented by
Figure PCTCN2021104953-appb-000041
express;
表4实施例2给药第33天对KKAy小鼠糖化血红蛋白(HbA1c)的影响The effect of table 4 embodiment 2 on the 33rd day of administration on KKAy mice glycosylated hemoglobin (HbA1c)
Figure PCTCN2021104953-appb-000042
Figure PCTCN2021104953-appb-000042
*P<0.05,**P<0.01,***P<0.001,与模型组相比；数据以
Figure PCTCN2021104953-appb-000043
表示； *P<0.05, **P<0.01, ***P<0.001, compared with the model group; the data are represented by
Figure PCTCN2021104953-appb-000043
express;
实验例3：药代实验方法和结果：Experimental example 3: Pharmacokinetic experiment method and result:
1.实验方法1. Experimental method
1.样品采集1. Sample collection
将6只SD大鼠随机分为2组，实施例2化合物静脉注射组和口服给药组，每组各3只，大鼠静脉注射给予实施例2化合物(3mg/kg)后于2min，5min，15min，30min，1h，2h，4h，6h，8h，12h，24h，36h,48h,72h各时间点分别于眼眶静脉丛取血，大鼠口服给予实施例2化合物(30mg/kg)后于5min，15min，30min，1h，2h，4h，6h，8h，12h，24h,36h,48h,72h各时间点分别于眼眶静脉丛取血，将血液收集到肝素抗凝的EP管中放置冰上，8000r/min×5min离心后，分离血浆备用。6 SD rats were randomly divided into 2 groups, the intravenous injection group of the compound of Example 2 and the oral administration group, each group of 3 rats were given the compound of Example 2 (3mg/kg) by intravenous injection in 2min, 5min , 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, and 72h each time point was taken from the orbital venous plexus, and the rats were orally given the compound of Example 2 (30mg/kg) after At 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, and 72h, blood was collected from the orbital venous plexus at each time point, and the blood was collected into a heparin-anticoagulated EP tube and placed on ice , after centrifugation at 8000r/min×5min, separate the plasma for later use.
2.标准曲线制备2. Standard curve preparation
实施例2化合物标准曲线：取SD大鼠空白血浆50μl，加入乙腈480μl，再分别加入不同浓度的实施例2化合物的甲醇溶液10μl使其终浓度为2,5,10，20，50，100，200，500，1000，2000，5000,10000,20000,50000ng/ml，混匀，14000r/min×5min高速离心2次，取上清液5μl进行HPLC-MS/MS分析。Standard curve of the compound of Example 2: Take 50 μl of SD rat blank plasma, add 480 μl of acetonitrile, and then add 10 μl of methanol solution of the compound of Example 2 at different concentrations to make the final concentration 2, 5, 10, 20, 50, 100, 200, 500, 1000, 2000, 5000, 10000, 20000, 50000ng/ml, mix well, 14000r/min×5min high-speed centrifugation twice, take 5μl of supernatant for HPLC-MS/MS analysis.
3.样品处理3. Sample Processing
取20μl血浆，加入含内标的乙腈200μl沉淀蛋白，14000r/min×5min高速离心2次后取上清液5μl进行HPLC-MS/MS分析。Take 20 μl of plasma, add 200 μl of acetonitrile containing internal standard to precipitate protein, centrifuge twice at 14000 r/min×5 min at high speed, and take 5 μl of supernatant for HPLC-MS/MS analysis.
2.实验结果2. Experimental results
血浆药代动力学参数Plasma pharmacokinetic parameters
大鼠口服和静脉注射实施例2化合物后，血浆药代动力学应用WinNonLin软件分析，经非房室模型拟合，结果见表5。After oral and intravenous injection of the compound of Example 2 in rats, the plasma pharmacokinetics were analyzed by WinNonLin software and fitted by non-compartmental model. The results are shown in Table 5.
表5大鼠口服和静脉注射实施例2化合物后血浆药代动力学参数Plasma pharmacokinetic parameters after oral and intravenous injection of the compound of Example 2 in rats of table 5
Figure PCTCN2021104953-appb-000044
Figure PCTCN2021104953-appb-000044
实验例4：对细胞色素P450(CYP)的体外抑制作用Experimental Example 4: Inhibitory effect on cytochrome P450 (CYP) in vitro
1、实验方法1. Experimental method
1.人肝微粒体温孵试验1. Body temperature incubation test of human liver microparticles
实验设3组，分别为对照组(无抑制剂)、阳性抑制剂组、待测化合物抑制组(10μM)，每组设3个平行样。将抑制剂加入人肝微粒体中与各亚型的探针底物共同温孵，测定探针底物生成的代谢产物，与对照组比较，反映抑制剂对同工酶的抑制程度。Three groups were set up in the experiment, namely the control group (no inhibitor), the positive inhibitor group, and the test compound inhibition group (10 μM), and three parallel samples were set up in each group. Add the inhibitor into human liver microsomes and incubate together with the probe substrates of each subtype, measure the metabolites generated by the probe substrate, and compare with the control group to reflect the degree of inhibition of the inhibitor on the isozyme.
肝微粒体温孵体系包括人肝微粒体蛋白(0.5mg/mL)、NADPH发生系统、Tris-HCl缓冲液(50mM，pH＝7.4)、底物及抑制剂，反应总体积为200μL(有机溶剂含量1％)。CYP1A2、2D6、2C9、2C19、3A4、2E1底物浓度及温孵时间依次为非那西丁50μM/30min，右美沙芬5μM/10min，双氯酚酸钠20μM/10min，美芬妥英40μM/30min，咪达唑仑5μM/5min，氯唑沙宗80μM/20min。CYP1A2、2D6、2C9、2C19、3A4、2E1同工酶阳性抑制剂终浓度依次为呋拉茶碱10μM，奎尼丁2μM，磺胺苯吡唑5μM，噻氯匹定5μM，酮康唑1μM，二乙基二硫铵甲酸钠50μM。反应完毕后，加入400μL含内标的冰乙腈终止反应，混匀，14000rpm×5min离心两次，取上清液5μL进行LC-MS/MS分析，测定探针底物代谢产物含量。The liver microsome incubation system includes human liver microsomal protein (0.5mg/mL), NADPH generation system, Tris-HCl buffer (50mM, pH=7.4), substrate and inhibitor, and the total reaction volume is 200μL (organic solvent content 1%). CYP1A2, 2D6, 2C9, 2C19, 3A4, 2E1 substrate concentration and incubation time were phenacetin 50μM/30min, dextromethorphan 5μM/10min, diclofenac sodium 20μM/10min, mephenytoin 40μM/ 30min, midazolam 5μM/5min, chlorzoxazone 80μM/20min. The final concentrations of CYP1A2, 2D6, 2C9, 2C19, 3A4, and 2E1 isoenzyme positive inhibitors were as follows: furafylline 10 μM, quinidine 2 μM, sulfabenzopyrazole 5 μM, ticlopidine 5 μM, ketoconazole 1 μM, two Sodium ethyl disulfide ammonium formate 50 μM. After the reaction was completed, 400 μL of glacial acetonitrile containing an internal standard was added to terminate the reaction, mixed well, centrifuged twice at 14,000 rpm×5 min, and 5 μL of the supernatant was taken for LC-MS/MS analysis to determine the content of metabolites of the probe substrate.
2、实验结果2. Experimental results
阳性抑制剂对CYP1A2、2C19、2C9、2D6、3A4、2E1探针底物的代谢抑制 率分别为61.23％、93.52％、76.81％、89.77％、93.82％、80.37％，对6种同工酶的底物有明显抑制作用。The metabolic inhibition rates of positive inhibitors to CYP1A2, 2C19, 2C9, 2D6, 3A4, and 2E1 probe substrates were 61.23%, 93.52%, 76.81%, 89.77%, 93.82%, and 80.37%. The substrate has obvious inhibitory effect.
测试化合物对各亚型的抑制活性均弱于阳性对照抑制剂，具有良好的安全性。结果见表6。The inhibitory activity of the test compound on each subtype is weaker than that of the positive control inhibitor, and has good safety. The results are shown in Table 6.
表6化合物(10μM)对人肝微粒体CYP450同工酶的体外抑制作用Table 6 Compounds (10μM) inhibit human liver microsome CYP450 isozymes in vitro
Figure PCTCN2021104953-appb-000045
Figure PCTCN2021104953-appb-000045

Claims (15)

  1. 如通式I所示化合物或其药学上可接受的盐，Compounds as shown in general formula I or pharmaceutically acceptable salts thereof,
    Figure PCTCN2021104953-appb-100001
    Figure PCTCN2021104953-appb-100001
    在式I中，In Formula I,
    A、B、D、E独立选自CR或N；A、B、D、E中至少一个原子为N或者两个原子同时为N；R选自H、F、Cl、CH 3、OCH 3； A, B, D, E are independently selected from CR or N; at least one atom in A, B, D, E is N or two atoms are N at the same time; R is selected from H, F, Cl, CH 3 , OCH 3 ;
    Ar 1选自如下基团或结构片断： Ar 1 is selected from the following groups or structural fragments:
    苯基、取代的苯基、非取代的含氮六元芳杂环、取代的含氮六元芳杂环；Phenyl, substituted phenyl, unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted nitrogen-containing six-membered aromatic heterocycle;
    其中所述的取代基选自甲基、乙基、丙基、异丙基、丁基、异丁基、环丙基、环丙亚甲基、环丁基、卤素取代的C1-4直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORs 1、NRs 2Rt 1、CONRs 3Rt 2； Wherein said substituent is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, cyclopropyl methylene, cyclobutyl, halogen substituted C1-4 straight chain Or branched chain alkyl, F, Cl, Br, NO 2 , CN, methylenedioxy, ORs 1 , NRs 2 Rt 1 , CONRs 3 Rt 2 ;
    其中所述的Rs 1、Rs 2、Rs 3、Rt 1、Rt 2独立地选自H、C1-4直链或支链烷基、卤素取代的C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基； Wherein said Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rt 2 are independently selected from H, C1-4 straight chain or branched chain alkyl, halogen substituted C1-4 straight chain or branched chain alkyl, ring Propyl, cyclopropyl methylene, cyclobutyl;
    苯环、含氮六元芳杂环上可以是单取代，也可以是多取代；The benzene ring and the nitrogen-containing six-membered aromatic heterocycle can be mono-substituted or multi-substituted;
    六元芳杂环可以含有1个N原子，也可以含有多个氮原子；The six-membered aromatic heterocycle can contain one N atom or multiple nitrogen atoms;
    所述的卤素包括F、Cl、Br。The halogen includes F, Cl, Br.
  2. 根据权利要求1的化合物或其药学上可接受的盐，，其特征在于，所述的化合物如通式I-A所示：The compound or pharmaceutically acceptable salt thereof according to claim 1, characterized in that, said compound is shown in general formula I-A:
    Figure PCTCN2021104953-appb-100002
    Figure PCTCN2021104953-appb-100002
    在I-A中，In I-A,
    A、B、D、E独立选自CR或N；A、B、D、E中至少一个原子为N或者两个原子同时为N；R选自H、F、Cl、CH 3、OCH 3； A, B, D, E are independently selected from CR or N; at least one atom in A, B, D, E is N or two atoms are N at the same time; R is selected from H, F, Cl, CH 3 , OCH 3 ;
    M 1独立地选自不同碱金属或是碱土金属盐； M1 is independently selected from different alkali metal or alkaline earth metal salts ;
    Ar 1选自如下基团或结构片断： Ar 1 is selected from the following groups or structural fragments:
    苯基、取代的苯基、非取代的含氮六元芳杂环、取代的含氮六元芳杂环；Phenyl, substituted phenyl, unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted nitrogen-containing six-membered aromatic heterocycle;
    其中所述的取代基选自甲基、乙基、丙基、异丙基、丁基、异丁基、环丙基、环丙亚甲基、环丁基、卤素取代的C1-4直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORs 1、NRs 2Rt 1、CONRs 3Rt 2； Wherein said substituent is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, cyclopropyl methylene, cyclobutyl, halogen substituted C1-4 straight chain Or branched chain alkyl, F, Cl, Br, NO 2 , CN, methylenedioxy, ORs 1 , NRs 2 Rt 1 , CONRs 3 Rt 2 ;
    其中所述的Rs 1、Rs 2、Rs 3、Rt 1、Rt 2独立地选自H、C1-4直链或支链烷基、卤素取代的C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基； Wherein said Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rt 2 are independently selected from H, C1-4 straight chain or branched chain alkyl, halogen substituted C1-4 straight chain or branched chain alkyl, ring Propyl, cyclopropyl methylene, cyclobutyl;
    苯环、含氮六元芳杂环上可以是单取代，也可以是多取代；The benzene ring and the nitrogen-containing six-membered aromatic heterocycle can be mono-substituted or multi-substituted;
    六元芳杂环可以含有1个N原子，也可以含有多个氮原子；The six-membered aromatic heterocycle can contain one N atom or multiple nitrogen atoms;
    所述的卤素包括F、Cl、Br。The halogen includes F, Cl, Br.
  3. 根据权利要求2的化合物或其药学上可接受的盐，其特征在于，所述的M 1选自锂，钠，钾，铯，钙，镁，钡。 The compound or pharmaceutically acceptable salt thereof according to claim 2 , wherein said M is selected from lithium, sodium, potassium, cesium, calcium, magnesium and barium.
  4. 根据权利要求1-3任一项的化合物或其药学上可接受的盐，其特征在于，所述的
    Figure PCTCN2021104953-appb-100003
    片段选自如下结构片段：     The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-3, characterized in that, the
    Figure PCTCN2021104953-appb-100003
    Fragments are selected from the following structural fragments:
    Figure PCTCN2021104953-appb-100004
    Figure PCTCN2021104953-appb-100004
    R 1选自F、Cl、CH 3、OCH 3； R 1 is selected from F, Cl, CH 3 , OCH 3 ;
    所述的取代的含氮六元芳杂环或非取代的含氮六元芳杂环中，含氮六元芳杂环选自吡啶、嘧啶、哒嗪、吡嗪；In the substituted nitrogen-containing six-membered aromatic heterocycle or the non-substituted nitrogen-containing six-membered aromatic heterocycle, the nitrogen-containing six-membered aromatic heterocycle is selected from pyridine, pyrimidine, pyridazine, and pyrazine;
    所述的卤素取代的C1-4直链或支链烷基独立的选自CF 3、CH 2F、CHF 2、CH 2CF 3、CF 2CH 3、CH 2CH 2CF 3； The halogen-substituted C1-4 linear or branched alkyl is independently selected from CF 3 , CH 2 F, CHF 2 , CH 2 CF 3 , CF 2 CH 3 , CH 2 CH 2 CF 3 ;
    所述的C1-4直链或支链烷基选自甲基、乙基、丙基、异丙基、丁基、异丁基。The C1-4 linear or branched alkyl group is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl.
  5. 如通式II所示化合物或其药学上可接受的盐，Compounds as shown in general formula II or pharmaceutically acceptable salts thereof,
    Figure PCTCN2021104953-appb-100005
    Figure PCTCN2021104953-appb-100005
    在式II中，In Formula II,
    A′、B′、D′、E′独立选自CR′或N；A′、B′、D′、E′中至少一个原子为N或者两个原子同时为N；R′选自H、F、Cl、CH 3、OCH 3； A', B', D', E' are independently selected from CR' or N; at least one atom in A', B', D', E' is N or two atoms are N at the same time; R' is selected from H, F, Cl, CH3 , OCH3 ;
    Ar 2选自如下基团或结构片断： Ar 2 is selected from the following groups or structural fragments:
    苯基、取代的苯基、非取代的含氮六元芳杂环、取代的含氮六元芳杂环；Phenyl, substituted phenyl, unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted nitrogen-containing six-membered aromatic heterocycle;
    其中所述的取代基选自甲基、乙基、丙基、异丙基、丁基、异丁基、环丙基、环 丙亚甲基、环丁基、卤素取代的C1-4直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORs 1、NRs 2Rt 1、CONRs 3Rt 2； Wherein said substituent is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, cyclopropyl methylene, cyclobutyl, halogen substituted C1-4 straight chain Or branched chain alkyl, F, Cl, Br, NO 2 , CN, methylenedioxy, ORs 1 , NRs 2 Rt 1 , CONRs 3 Rt 2 ;
    其中所述的Rs 1、Rs 2、Rs 3、Rt 1、Rt 2独立地选自H、C1-4直链或支链烷基、卤素取代的C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基； Wherein said Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rt 2 are independently selected from H, C1-4 straight chain or branched chain alkyl, halogen substituted C1-4 straight chain or branched chain alkyl, ring Propyl, cyclopropyl methylene, cyclobutyl;
    苯环、含氮六元芳杂环上可以是单取代，也可以是多取代；The benzene ring and the nitrogen-containing six-membered aromatic heterocycle can be mono-substituted or multi-substituted;
    六元芳杂环可以含有1个N原子，也可以含有多个氮原子；The six-membered aromatic heterocycle can contain one N atom or multiple nitrogen atoms;
    所述的卤素包括F、Cl、Br。The halogen includes F, Cl, Br.
  6. 根据权利要求5的化合物或其药学上可接受的盐，其特征在于，所述的化合物如通式II-A所示：The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein said compound is shown in the general formula II-A:
    Figure PCTCN2021104953-appb-100006
    Figure PCTCN2021104953-appb-100006
    在式II-A中，In formula II-A,
    A′、B′、D′、E′独立选自CR′或N；A′、B′、D′、E′中至少一个原子为N或者两个原子同时为N；R′选自H、F、Cl、CH 3、OCH 3； A', B', D', E' are independently selected from CR' or N; at least one atom in A', B', D', E' is N or two atoms are N at the same time; R' is selected from H, F, Cl, CH3 , OCH3 ;
    M 2独立地选自不同碱金属或是碱土金属盐； M2 is independently selected from different alkali metal or alkaline earth metal salts;
    Ar 2选自如下基团或结构片断： Ar 2 is selected from the following groups or structural fragments:
    苯基、取代的苯基、非取代的含氮六元芳杂环、取代的含氮六元芳杂环；Phenyl, substituted phenyl, unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted nitrogen-containing six-membered aromatic heterocycle;
    其中所述的取代基选自甲基、乙基、丙基、异丙基、丁基、异丁基、环丙基、环丙亚甲基、环丁基、卤素取代的C1-4直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORs 1、NRs 2Rt 1、CONRs 3Rt 2； Wherein said substituent is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, cyclopropyl methylene, cyclobutyl, halogen substituted C1-4 straight chain Or branched chain alkyl, F, Cl, Br, NO 2 , CN, methylenedioxy, ORs 1 , NRs 2 Rt 1 , CONRs 3 Rt 2 ;
    其中所述的Rs 1、Rs 2、Rs 3、Rt 1、Rt 2独立地选自H、C1-4直链或支链烷基、卤素取代的C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基； Wherein said Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rt 2 are independently selected from H, C1-4 straight chain or branched chain alkyl, halogen substituted C1-4 straight chain or branched chain alkyl, ring Propyl, cyclopropyl methylene, cyclobutyl;
    苯环、含氮六元芳杂环上可以是单取代，也可以是多取代；The benzene ring and the nitrogen-containing six-membered aromatic heterocycle can be mono-substituted or multi-substituted;
    六元芳杂环可以含有1个N原子，也可以含有多个氮原子；The six-membered aromatic heterocycle can contain one N atom or multiple nitrogen atoms;
    所述的卤素包括F、Cl、Br。The halogen includes F, Cl, Br.
  7. 根据权利要求6的化合物或其药学上可接受的盐，其特征在于，所述的M 1选自锂，钠，钾，铯，钙，镁，钡。 The compound or pharmaceutically acceptable salt thereof according to claim 6, wherein said M is selected from lithium, sodium, potassium, cesium, calcium, magnesium and barium.
  8. 根据权利要求5-7任一项的化合物或其药学上可接受的盐，其特征在于，所述的
    Figure PCTCN2021104953-appb-100007
    片段包括如下结构片段：     The compound or pharmaceutically acceptable salt thereof according to any one of claims 5-7, characterized in that, the
    Figure PCTCN2021104953-appb-100007
    Fragments include the following structural fragments:
    Figure PCTCN2021104953-appb-100008
    Figure PCTCN2021104953-appb-100008
    R 2选自F、Cl、CH 3、OCH 3； R 2 is selected from F, Cl, CH 3 , OCH 3 ;
    所述的取代的含氮六元芳杂环或非取代的含氮六元芳杂环中，含氮六元芳杂环选自吡啶、嘧啶、哒嗪、吡嗪；In the substituted nitrogen-containing six-membered aromatic heterocycle or the non-substituted nitrogen-containing six-membered aromatic heterocycle, the nitrogen-containing six-membered aromatic heterocycle is selected from pyridine, pyrimidine, pyridazine, and pyrazine;
    所述的卤素取代的C1-4直链或支链烷基独立的选自CF 3、CH 2F、CHF 2、CH 2CF 3、CF 2CH 3、CH 2CH 2CF 3； The halogen-substituted C1-4 linear or branched alkyl is independently selected from CF 3 , CH 2 F, CHF 2 , CH 2 CF 3 , CF 2 CH 3 , CH 2 CH 2 CF 3 ;
    所述的C1-4直链或支链烷基选自甲基、乙基、丙基、异丙基、丁基、异丁基。The C1-4 linear or branched alkyl group is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl.
  9. 根据权利要求1-8中任一项的化合物或其药学上可接受的盐，其特征在于，所述的化合物选自：The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-8, wherein said compound is selected from:
    Figure PCTCN2021104953-appb-100009
    Figure PCTCN2021104953-appb-100009
    Figure PCTCN2021104953-appb-100010
    Figure PCTCN2021104953-appb-100010
  10. 制备权利要求1-9中任一项化合物或其药学上可接受盐的方法，其特征在于，包括如下步骤：The method for preparing a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-9, characterized in that it comprises the following steps:
    Figure PCTCN2021104953-appb-100011
    Figure PCTCN2021104953-appb-100011
    (1)2-溴-5-氯-苯甲醛在钠和与叠氮乙酸乙酯在乙醇钠和三氟乙酸乙酯存在下，制备得到化合物1；(1) 2-bromo-5-chloro-benzaldehyde was prepared in the presence of sodium and ethyl azidoacetate in the presence of sodium ethoxide and ethyl trifluoroacetate to obtain compound 1;
    (2)以邻二氯苯作为溶剂，化合物1在180℃条件下发生关环反应得到7-氯-4-溴-1H-吲哚-2-羧酸乙酯；(2) Using o-dichlorobenzene as a solvent, compound 1 undergoes a ring closure reaction at 180°C to obtain ethyl 7-chloro-4-bromo-1H-indole-2-carboxylate;
    (3)在碳酸铯的条件下在吲哚-1-位发生甲基化得到4-溴-7-氯-1-甲基-吲哚-2-羧酸 乙酯；(3) Under the condition of cesium carbonate, methylation occurs at the indole-1-position to obtain 4-bromo-7-chloro-1-methyl-indole-2-carboxylic acid ethyl ester;
    (4)化合物3在钯催化下与取代的芳胺发生偶联反应得到化合物4和4’；(4) Compound 3 undergoes a coupling reaction with a substituted arylamine under palladium catalysis to obtain compounds 4 and 4';
    (5)化合物4和4’经过水解反应后得到相应的2-位为羧基的化合物5和5’；(5) Compounds 4 and 4' obtain the corresponding 2-positions as carboxyl compounds 5 and 5' after the hydrolysis reaction;
    (6)化合物5和5’分别与芳基磺酰胺发生缩合反应得到结构通式为I和II的化合物；(6) Compounds 5 and 5' undergo condensation reactions with arylsulfonamides respectively to obtain compounds with general structural formulas I and II;
    (7)最后与不同的碱发生反应得到N-酰基磺酰胺类化合物的盐I-A和II-A；(7) finally react with different bases to obtain salts I-A and II-A of N-acylsulfonamide compounds;
    其中A、B、D、E、A′、B′、D′、E′、Ar 1、Ar 2、M 1、M 2如权利要求1-9任一项中所定义。 Wherein A, B, D, E, A', B', D', E', Ar 1 , Ar 2 , M 1 , M 2 are as defined in any one of claims 1-9.
  11. 一种药物组合物，其特征在于，所述的药物组合物包含有效剂量的权利要求1-9中任一项的化合物或其药学上可接受的盐和药效学上可接受的载体。A pharmaceutical composition, characterized in that the pharmaceutical composition comprises an effective dose of the compound of any one of claims 1-9 or a pharmaceutically acceptable salt thereof and a pharmacodynamically acceptable carrier.
  12. 权利要求1-9任一项的化合物或其药学上可接受的盐在制备FBPase抑制剂中的应用。Use of the compound according to any one of claims 1-9 or a pharmaceutically acceptable salt thereof in the preparation of FBPase inhibitors.
  13. 权利要求1-9任一项的化合物或其药学上可接受的盐在制备预防和\或治疗与FBPase有关的疾病的药物中的应用。Application of the compound according to any one of claims 1-9 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and/or treating diseases related to FBPase.
  14. 根据权利要求13的应用，其特征在于，与FBPase有关的疾病选自糖尿病、糖尿病并发症、高血脂以及肥胖。The use according to claim 13, characterized in that the disease related to FBPase is selected from diabetes, diabetic complications, hyperlipidemia and obesity.
  15. 根据权利要求14的应用，其特征在于，所述的糖尿病选自I型糖尿病和II型糖尿病；所述糖尿病并发症选自视网膜、肾脏、神经系统病变及血管并发症、局部缺血性心脏病或动脉粥样硬化；所述高血脂包括高甘油三脂，高胆固醇酯。According to the application of claim 14, it is characterized in that, described diabetes is selected from type I diabetes and type II diabetes; and described diabetic complication is selected from retina, kidney, nervous system lesion and vascular complication, local ischemic heart disease or atherosclerosis; the high blood lipids include high triglycerides and high cholesterol esters.
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