CN110092768A - Composition and application method comprising white 1 inhibitor of sodium glucose co-transporter 2 - Google Patents

Abstract

The present invention relates to a sodium-glucose co-transporter 1 (SGLT1) inhibitors, a drug synthesis method comprising their compositions and their use in treating metabolic diseases, especially type 2 diabetes.

Description

Compositions comprising sodium-glucose cotransporter 1 inhibitors and methods of use

technical field

The invention relates to a sodium-glucose co-transporter 1 (SGLT1) inhibitor, a drug synthesis method comprising their composition and their use in treating metabolic diseases, especially type 2 diabetes.

Background technique

In 2012, the World Health Organization reported that the incidence of diabetes among adults over the age of 18 was greater than 9%. As the population increases, ages and people live longer, the incidence of diabetes will increase. Among obese people, the incidence of diabetes is higher. According to forecasts, by 2030, diabetes will become the seventh leading cause of death.

SGLTs are a new class of drug targets. In the past few decades, new target drugs have been developed for the treatment of diabetes. The SGLT family consists of several isoforms that function to transport carbohydrates across the cell membrane, a process that binds to the sodium ion transporter. SGLT1 is mainly expressed in the gastrointestinal tract and is mainly responsible for the absorption of glucose and galactose in the small intestine. SGLT1 is also present in the renal proximal straight tubules, where it contributes to the reabsorption of blood glucose. By inhibiting SGLT1, it hinders the absorption and utilization of blood sugar, so as to achieve the goal of lowering blood sugar levels.

Since SGLT1 inhibition may also provide an alternative therapy for glycemic control, improving glycemic control through SGLT1 inhibition is attractive because it can be independent of renal function. Current SGLT2-selective inhibitors lack efficacy in patients with moderate to severe renal impairment, which account for about 30-40% of all diabetic patients. Although Sotagliflozin is active against SGLT1 at maximum clinical doses and can partially inhibit intestinal SGLT1, the greater therapeutic efficacy of SGLT1 inhibitors that act only in the gut is the ability to achieve greater levels of glycemic control with titrated doses. Through this mechanism, an SGLT1 inhibitor that can precede gastrointestinal side effects can achieve the maximum potential efficacy of glycemic control. Through this action, diabetes-related side effects of SGLT2 inhibitors, especially genital infections, can also be avoided.

Contents of the invention

The present invention relates to the discovery of a new and potent sodium glucose cotransporter 1 (SGLT1) inhibitor. Particular inhibitors are selective inhibitors of SGLT1. Specific inhibitors were tested in vitro in cells with high SGLT-1 activity. In in vivo activity tests showed the property of delaying the absorption of sugar in the intestine through SGLT-1. Inhibitors exhibit low systemic exposure profile.

The present invention relates in part to compounds comprising the formula: and pharmaceutically acceptable salts thereof and methods of their use

in:

R ₁ may be independently optionally substituted R _1A , -N(R _1A )(R _1B ), -OR _1A , -SR _1A , -S(O)R _1A or -S(O) ₂ R _1A ;

R ₁ can be unsubstituted, monosubstituted or polysubstituted;

R _1A is optionally substituted C _1-20 straight or branched chain alkyl, aryl, heterocyclic, amino, aminoacyl, azo, carbonyl, carboxyl, cyano, formyl, guanidino, halogen, hydroxyl , imidoyl, imino, isothiocyanate, nitrile, nitro, nitroso, nitroxyl, oxy, sulfanyl, sulfonyl, thial, thiocyanate, thioketone, thiourea, Urea alkenyl, alkynyl, ester, ketone, alcohol, etc., and includes any deuterated substituents.

R _1A includes the following structures:

R _1B is hydrogen, deuterium hydrogen or equivalent to R _1A ;

R ₂ independently optionally substituted C _1-10 straight or branched chain alkyl, C _1-10 straight or branched alkoxy, deuterated alkyl, aryl, heterocyclyl, amino, aminoacyl, even Nitrogen, carbonyl, carboxyl, cyano, formyl, guanidino, halogen, hydroxyl, imidoyl, imino, isothiocyanate, nitrile, nitro, nitroso, nitroxyl, oxy, sulfanyl , sulfonyl, thioaldehyde, thiocyanate, thioketone, thiourea, urea alkenyl, alkynyl, ester, ketone, alcohol, etc., and include any deuterated substituents;

R ₂ can be unsubstituted, monosubstituted or polysubstituted;

R ₃ is hydrogen or optionally substituted C _1-10 alkyl, C _1-10 cycloalkyl or multi-component heterocyclic ring, the optional substitution is substituted with one or more R _3A ;

R _3A can be any substituted C _1-10 straight chain or branched chain alkyl, C _1-10 straight chain or branched chain alkoxy, deuterated alkyl, aryl, heterocyclyl, amino, aminoacyl, even Nitrogen, carbonyl, carboxyl, cyano, formyl, guanidino, halogen, hydroxyl, imidoyl, imino, isothiocyanate, nitrile, nitro, nitroso, nitroxyl, oxy, sulfanyl , sulfonyl, thioaldehyde, thiocyanate, thioketone, thiourea, urea alkenyl, alkynyl, ester, ketone, alcohol, phosphinoxy, phosphonic acid, phosphonate, etc., and includes any deuterated substituents;

R ₄ , R ₅ , and R ₆ can be independently hydrogen, deuterium hydrogen, halogen, hydroxyl, alkoxy, deuterated alkyl, single or multiple sugar groups, optionally substituted heterocycles, ester groups, sulfanyl groups, Thiol, amino, phosphoxy, phosphonic acid, phosphonate, etc.

R ₄ , R ₅ , and R ₆ may be identical or different, and may be identically substituted or differently substituted.

X is optional one or more N, O, S, C, P or corresponding various oxides.

The present invention also relates to pharmaceutical compositions comprising the compounds disclosed herein, and their use in the treatment or management of cardiovascular disease, metabolic disease (especially diabetes and its various complications), intestinal disease, renal disease and certain types of approach to cancer.

We tested the growth inhibitory effect of this compound on SGLT1, and found that this type of compound has extremely significant inhibitory activity on SGLT1, and the IC50 of one of the compounds is 26.30±4.21 μg/mL, which is shown by measuring its half maximal inhibitory concentration: The above pharmacodynamic results show that the compound has an unexpected effect of inhibiting SGLT1, so it can be expected that the compound or its pharmaceutically acceptable salt can be used as an SGLT1 inhibitor drug, especially to prevent and treat type II diabetes, that is, non-insulin-dependent diabetes drug .

In summary, the compound we prepared has both structural uniqueness and novelty in the research on the effect of inhibiting SGLT1, and found unusually low systemic exposure in pharmacokinetic tests, which is expected to become Drug candidate for inhibition of SGLT1 and treatment of diabetes. The discovery that the compounds are potent inhibitors of SGLT1 is an unexpected discovery and is definitely original.

Detailed ways

It must be noted that the embodiments of the present invention are used to illustrate the present invention rather than limit the present invention. The simple improvements made to the present invention according to the essence of the present invention all belong to the protection scope of the present invention.

When the above description explains the present invention, the purpose of providing examples is to illustrate the practical operation process of the present invention and the significance of the present invention. The practice of the present invention shall include all general changes, adaptations, or improvements when coming within the scope of the claims of the present invention and their equivalents.

Example

(2S,3S,4R,5S,6R)-2-(3-(4-((E)-4methoxy-4-oxobutyl-1-enyl)benzyl)-4-methyl Preparation of phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyltriacetate (2):

(2S,3S,4R,5S,6R)-2-(3-(4-Chlorobenzyl)-4-methylphenyl)-6-(methylsulfanyl)tetrahydro-2H-pyran -3,4,5-triyltriacetate (10g, 19mmol) was loaded into a microwave vial, and 3-butenoic acid methyl ester (5.7g, 57mmol) and tris(dibenzylideneacetone)dipalladium were added successively (Pd ₂ dba ₃ , 1.74 g, 1.9 mmol), tris(tert-butyl)phosphonium tetrafluoroborate (2.2 g, 7.6 mmol), dicyclohexylmethylamine (11.1 g, 57 mmol) and N-methyl Pyrrolidone (100 mL). The reaction vial was placed in a microwave under nitrogen protection, and heated and stirred at 160° C. for 40 minutes. After the reaction was completed, it was cooled to room temperature, and the reaction solution was filtered on diatomaceous earth and washed with ethyl acetate. The organic layer was washed successively with water, saturated sodium bisulfate and saturated brine. Dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product was chromatographed on a 100-200 mesh silica gel column and eluted with a gradient of 5% to 20% ethyl acetate/petroleum ether to give a light yellow foamy solid product (3g, 27%), unreacted raw materials (2S, 3S, 4R ,5S,6R)-2-(3-(4-Chlorobenzyl)-4-methylphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5- Triyl triacetate recycling.

(2S,3S,4R,5S,6R)-2-(3-(4-(4-Methoxy-4-oxobutyl)benzyl)-4-methylphenyl)-6-(methyl Preparation (3) of tetrahydro-2H-pyran-3,4,5-triyltriacetate

(2S,3S,4R,5S,6R)-2-(3-(4-((E)-4methoxy-4-oxobutyl-1-enyl)benzyl)-4-methyl phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyltriacetate (3 g, 5 mmol) dissolved in 1:1 (V:V) THF/ Then add Pd/C (10% wet, 200 mg) into the methanol solution, and cover with a hydrogen balloon for hydrogenation reaction at 35° C. for 3 hours. TCL spots the plate, after the reaction is completed, it is filtered with diatomaceous earth and washed with ethyl acetate. Concentration under reduced pressure gave the target product (3 g, 99% yield) as a pale yellow solid.

4-(4-(2-methyl-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylsulfanyl)tetrahydro-2H-pyran -2-yl) benzyl) phenyl) butanoic acid preparation (4):

(2S,3S,4R,5S,6R)-2-(3-(4-(4-methoxy-4-oxobutyl)benzyl)-4-methylphenyl)-6-( Methylthio)tetrahydro-2H-pyran-3,4,5-triyltriacetate (3g, 5mmol) was dissolved in a mixture of methanol/THF/water (50mL, volume ratio 2:1:2) To the solution, lithium hydroxide monohydrate (2.1 g, 50 mmol) was added, and the reaction was stirred at room temperature for 1 hour. Spot the plate with TCL, acidify with saturated sodium bisulfate to pH=1-2 after the reaction is completed. The acidic aqueous layer was extracted three times with ethyl acetate, the organic phases were combined, washed twice with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a foamy solid crude product. The crude product was dissolved in 30% aqueous sodium bicarbonate solution, extracted twice with ethyl acetate to remove impurities. The basic aqueous phase was acidified to pH=1-2 with saturated sodium bisulfate, and extracted three times with ethyl acetate. The organic phases were combined, washed twice with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the target compound (2 g, 89% yield) as a white solid.

Compound 5 preparation:

4-(4-(2-methyl-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylsulfanyl)tetrahydro-2H-pyridine Fyran-2-yl)benzyl)phenyl)butanoic acid (1g, 2.2mmol) was dissolved in 4mL DMF, and 2-(7-benzotriazole oxide)-N,N,N',N '-Tetramethyluronium hexafluorophosphate (HATU, 1 g, 2.6 mmol), DIPEA (0.77 mL, 4.4 mmol) and 2-amino-2-methyl-1-(pyrrolidin-1-yl)propane-1 - Ketone (406 mg, 2.6 mmol). The reaction was stirred at room temperature for 3 hours. After the reaction was completed, it was quenched with saturated sodium bicarbonate, extracted three times with ethyl acetate, combined the organic phases, and washed three times with saturated brine. It was dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by a 100-200 mesh silica gel column, eluting with dichloromethane:methanol=20:1, and the solvent was concentrated to obtain the target compound as a foamy white solid (600 mg, 47% yield). ¹ H NMR (400MHz, CDCl ₃ )δ7.24–7.15(m,2H),7.15–7.03(m,5H),4.41(d,J=9.5Hz,1H),4.17(d,J=9.3Hz, 1H), 3.95(s, 2H), 3.67(t, J=8.8Hz, 1H), 3.61–3.47(m, 6H), 2.62(t, J=7.2Hz, 2H), 2.26(d, J=11.6 Hz, 3H), 2.19(s, 3H), 2.17–2.12(m, 2H), 1.94(d, J=7.4Hz, 4H), 1.84(s, 3H), 1.63(d, J=15.5Hz, 6H ).

Compound 6 preparation:

4-(4-(2-methyl-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylsulfanyl)tetrahydro-2H-pyridine Fen-2-yl)benzyl)phenyl)butanoic acid (100mg, 0.22mmol) was dissolved in 4mL DMF, HATU (125mg, 0.33mmol), DIPEA (77μL, 0.44mmol) and 2-amino-2 -Methyl-1-(4-(2-oxo-2(pyrrolidin-1-yl)ethyl)piperazin-1-yl)propan-1-one (74 mg, 0.26 mmol). The reaction was stirred at room temperature for 3 hours. After the reaction was completed, it was quenched with saturated sodium bicarbonate, extracted three times with ethyl acetate, combined the organic phases, and washed three times with saturated brine. It was dried over anhydrous sodium sulfate, concentrated by filtration, and the crude product was purified by a 100-200 mesh silica gel column, eluting with dichloromethane:methanol=10:1, and the solvent was concentrated to obtain the target compound as a foamy white solid (68 mg, 44% yield). ¹ H NMR (400MHz, MeOD) δ8.28(s, 1H), 7.50–7.41(m, 1H), 7.23–7.14(m, 4H), 7.10(q, J=8.1Hz, 4H), 4.41(d ,J=9.4Hz,1H),4.15(d,J=9.1Hz,1H),3.98(s,2H),3.78(s,3H),3.52–3.39(m,9H),3.37(s,2H) ,2.77(s,3H),2.62(t,J=7.4Hz,2H),2.21(d,J=12.9Hz,5H),2.16(s,4H),2.01–1.83(m,6H),1.45( s,6H).

Compound 7 preparation:

4-(4-(2-methyl-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylsulfanyl)tetrahydro-2H-pyridine Fen-2-yl)benzyl)phenyl)butanoic acid (100mg, 0.22mmol) was dissolved in 2mL DMF, and HATU (125mg, 0.33mmol), DIPEA (77μL, 0.44mmol) and 2,2,6 , 6-Tetramethylpiperidin-4-amine (41 mg, 0.26 mmol). The reaction was stirred at room temperature for 3 hours. After the reaction was completed, it was quenched with saturated sodium bicarbonate, extracted three times with ethyl acetate, combined the organic phases, and washed three times with saturated brine. It was dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by a 100-200 mesh silica gel column, eluting with dichloromethane:methanol=30:1, and the solvent was concentrated to obtain the target compound as a foamy white solid (80 mg, 62% yield). ¹ H NMR (400MHz, MeOD) δ7.21–7.14(m,4H),7.12–7.06(m,4H),4.41(dd,J=9.5,2.4Hz,1H),4.29(dd,J=9.8, 6.0Hz, 1H), 4.17–4.12(m, 1H), 3.98(s, 2H), 3.52–3.39(m, 4H), 3.37(s, 3H), 2.61(t, J＝7.6Hz, 2H), 2.22(d, J=4.8Hz, 5H), 2.16(s, 3H), 2.05(dd, J=14.0, 3.6Hz, 2H), 1.92(dd, J=15.1, 7.7Hz, 2H), 1.57(s ,2H),1.53(s,6H),1.46(s,6H).

Compound 8 Preparation:

4-(4-(2-methyl-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylsulfanyl)tetrahydro-2H-pyridine Fyran-2-yl)benzyl)phenyl)butanoic acid (100mg, 0.22mmol) was dissolved in 2mL DMF, and HATU (125mg, 0.33mmol), DIPEA (77μL, 0.44mmol) and 2-amino-2 -Methyl-N-(2-(methylamino)ethyl)propanamide (41 mg, 0.26 mmol). The reaction was stirred at room temperature for 3 hours. After the reaction was completed, it was quenched with saturated sodium bicarbonate, extracted three times with ethyl acetate, combined the organic phases, and washed three times with saturated brine. It was dried over anhydrous sodium sulfate, concentrated by filtration, and the crude product was purified by a 100-200 mesh silica gel column, eluting with dichloromethane:methanol=30:1, and the solvent was concentrated to obtain the title compound (31 mg, 24% yield) as a foamy white solid. ¹ H NMR (400MHz, MeOD) δ7.21-7.15(m, 4H), 7.11-7.06(m, 3H), 5.50(s, 1H), 4.41(d, J=9.4Hz, 1H), 4.15(d ,J=9.1Hz,1H),3.95(d,J=15.6Hz,3H),3.55–3.40(m,6H),3.35(s,3H),3.09-2.92(m,2H),2.96–2.72( m,2H),2.67–2.60(m,2H),2.44–2.31(m,2H),2.22(s,3H),2.16(s,3H),1.90(dd,J＝9.4,5.5Hz,2H) ,1.30(s,6H).

Compound 9 Preparation:

4-(4-(2-methyl-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylsulfanyl)tetrahydro-2H-pyridine Fen-2-yl)benzyl)phenyl)butanoic acid (100 mg, 0.22 mmol) was dissolved in DMF, and HATU (125 mg, 0.33 mmol), DIPEA (77 μL, 0.44 mmol) and (1-aminocyclopropane ) (Octahydro-2H-isoindol-2-yl)methanone (54 mg, 0.26 mmol). The reaction was stirred at room temperature for 3 hours. After the reaction was completed, it was quenched with saturated sodium bicarbonate, extracted three times with ethyl acetate, combined the organic phases, and washed three times with saturated brine. It was dried over anhydrous sodium sulfate, concentrated by filtration, and the crude product was purified by a 100-200 mesh silica gel column, eluting with dichloromethane:methanol=40:1, and the solvent was concentrated to obtain the title compound (71 mg, 49%) as a foamy white solid. ¹ H NMR (400MHz, MeOD) δ7.17 (dd, J = 20.8, 7.0Hz, 4H), 7.11–7.04 (m, 4H), 4.41 (d, J = 9.4Hz, 1H), 4.15 (d, J =9.1Hz,1H),3.96(s,2H),3.61–3.40(m,5H),3.38(s,1H),3.33(dd,J=3.3,1.6Hz,2H),2.60(t,J= 7.6Hz, 2H), 2.29–2.18(m, 6H), 2.16(s, 4H), 1.94–1.85(m, 2H), 1.59(dd, J＝15.3, 7.1Hz, 2H), 1.53–1.30(m ,9H),0.93(dd,J=5.8,3.4Hz,2H).

Compound 10 Preparation:

4-(4-(2-methyl-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylsulfanyl)tetrahydro-2H-pyridine Fyran-2-yl)benzyl)phenyl)butanoic acid (100mg, 0.22mmol) was dissolved in DMF, and HATU (125mg, 0.33mmol), DIPEA (77μL, 0.44mmol) and (2R)-2- Amino-1,4-bis(octahydro-2H-isoindol-2-yl)n-butane-1,4-dione (91 mg, 0.26 mmol). The reaction was stirred at room temperature for 3 hours. After the reaction was completed, it was quenched with saturated sodium bicarbonate, extracted three times with ethyl acetate, combined the organic phases, and washed three times with saturated brine. It was dried over anhydrous sodium sulfate, concentrated by filtration, and the crude product was purified by a 100-200 mesh silica gel column, eluting with dichloromethane:methanol=30:1, and the solvent was concentrated to obtain the title compound as a foamy white solid (47 mg, 27% yield). 1H NMR (400MHz, MeOD) δ7.23–7.03(m, 7H), 5.09(dd, J=8.2, 6.3Hz, 1H), 4.41(d, J=9.5Hz, 1H), 4.15(d, J= 9.2Hz,1H),3.96(s,2H),3.83–3.59(m,2H),3.58–3.25(m,10H),3.05–2.84(m,1H),2.65–2.53(m,2H),2.37 –2.26(m,2H),2.26–2.17(m,7H),2.15(s,3H),1.90(dd,J＝14.2,6.8Hz,2H),1.70–1.33(m,17H).HRMS(ESI ) calcd for C ₄₄ H ₆₁ N ₃ O ₇ S[M+H] ⁺ :776.4264; found: 776.4259.

Biological test:

The inhibitory activity of SGLT1 was tested according to the method described in the literature (Journal of Medicinal Chemistry 2017, 60, 710-721, Discovery of LX2761, a Sodium-Dependent Glucose Cotransporter 1 (SGLT1) Inhibitor Restricted to the Intestinal Lumen, for the Treatment of Diabetes).

Experimental results show that the SGLT1 inhibitory activities of the compounds of the present invention are all <150nM.

Claims (18)

1. a kind of compound such as following formula:

Or its officinal salt, in which:

R₁It can be the R independently arbitrarily replaced_1A、-N(R_1A)(R_1B)、-OR_1A、-SR_1A、-S(O)R_1AOr-S (O)₂R_1A；

R₁It can be and not replace, is monosubstituted or polysubstituted；

R_1AIt is the C optionally replaced_1-20Linear or branched alkyl group, aryl, heterocycle, amino, aminoacyl, azo, carbonyl, carboxyl, Cyano, formoxyl, guanidine radicals, halogen, hydroxyl, imido acyl group, imino group, isothiocyanates, nitrile, nitro, nitroso, nitroxyl, Oxygroup, sulfanyl, sulfonyl, thioaldehydes, thiocyanates, thioketones, thiocarbamide, urea alkenyl, alkynyl, ester, ketone, alcohol etc., and including any Deuterated substituent group, R_1AIncluding with flowering structure:

R_1BIt is hydrogen, deuterium hydrogen or is equal to R_1A；

R₂The C independently arbitrarily replaced_1-10Linear or branched alkyl group, C_1-10It is straight or branched alkoxyl, deuteroalkyl, aryl, miscellaneous It is ring group, amino, aminoacyl, azo, carbonyl, carboxyl, cyano, formoxyl, guanidine radicals, halogen, hydroxyl, imido acyl group, imino group, different Thiocyanates, nitrile, nitro, nitroso, nitroxyl, oxygroup, sulfanyl, sulfonyl, thioaldehydes, thiocyanates, thioketones, thiocarbamide, urea Alkenyl, alkynyl, ester, ketone, alcohol etc., and including any deuterated substituent group；

R₂It can be and not replace, is monosubstituted or polysubstituted；

R₃It is hydrogen or the C optionally replaced_1-10Alkyl, C_1-10Naphthenic base or multicomponent heterocycle, the optional substitution are with one or more A R_3AReplace；

R_3AIt can be any substituted C_1-10Linear or branched alkyl group, C_1-10It is straight or branched alkoxyl, deuteroalkyl, aryl, miscellaneous It is ring group, amino, aminoacyl, azo, carbonyl, carboxyl, cyano, formoxyl, guanidine radicals, halogen, hydroxyl, imido acyl group, imino group, different Thiocyanates, nitrile, nitro, nitroso, nitroxyl, oxygroup, sulfanyl, sulfonyl, thioaldehydes, thiocyanates, thioketones, thiocarbamide, urea Alkenyl, alkynyl, ester, ketone, alcohol, phosphine oxygroup, phosphonic acid base, phosphonate group etc., and including any deuterated substituent group；

R₄、R₅、R₆It can be independently hydrogen, deuterium hydrogen, halogen, hydroxyl, alkoxy, deuteroalkyl, single or multiple glycosyls, any Substituted heterocycle, ester group, sulfanyl, mercaptan, amino, phosphine oxygroup, phosphonic acid base, phosphonate group etc.,

R₄、R₅、R₆It can be equal or different, can be identical substitution or different substitutions；

X is the optional various oxides of one or more N, O, S, C, P or corresponding.

2. the compound of claim 1, wherein R₃It is the C optionally replaced_1-10Alkyl, hydrogen, deuterium hydrogen, deuteroalkyl, phosphine oxygroup, phosphine Acidic group, phosphonate group；Especially methyl, ethyl.

3. the compound of claim 1, wherein R₄、R₅、R₆It can be hydrogen, deuterium hydrogen, deuteroalkyl, deuterated alkoxy, halogen, hydroxyl Base, deuterium hydroxyl, the alkyl of any carbochain or alkoxy, single or multiple glycosyls, the heterocycle arbitrarily replaced, ester group, sulfanyl, sulphur Alcohol, amino；Especially hydroxyl, deuterium hydroxyl, ester group, deuterated ester group.

4. the compound of claim 1, wherein R₂It is the C optionally replaced_1-4Linear or branched alkyl group；Especially methyl, ethyl or Its deuterated object.

5. the compound of claim 1, wherein R₂It is halogen, alkoxy, deuteroalkyl.

6. the compound of claim 1, wherein R₂It is the monosubstituted or polysubstituted of any position.

7. the compound of claim 1, wherein R₁It is R_1A。

8. the compound of claim 1, wherein R₁It is OR_1A。

9. the compound of claim 1, wherein R₁It is the monosubstituted or polysubstituted of any position.

10. the compound of claim 1, is expressed from the next:

Wherein:

R₇It is the C optionally replaced_1-20Linear or branched alkyl group, alkoxy, deuterated alkoxy, deuterated amide, aryl, heterocycle, ammonia Base, aminoacyl, azo, carbonyl, carboxyl, cyano, formoxyl, guanidine radicals, halogen, hydroxyl, imido acyl group, imino group, isothiocyanic acid Ester, nitrile, nitro, nitroso, nitroxyl, oxygroup, sulfanyl, sulfonyl, thiocyanates, thioketones, thiocarbamide, urea alkenyl, alkynyl, Ester, ketone, alcohol etc., and including any deuterated above-mentioned substituent group；

X₁It is the optional various oxides of one or more N, O, S, C, P or corresponding；

R₂It is independently hydrogen, deuterium hydrogen, halogen, hydroxyl, deuterated hydroxyl or the C optionally replaced_1-10Linear or branched alkyl group, C_1-10Directly Chain or branched alkoxy, deuteroalkyl, deuterated alkoxy, the optional substitution is with one or more R_2AReplace；

Each R_2AIt is independently any substituted C_1-10Linear or branched alkyl group, C_1-10Straight or branched alkoxyl, aryl, heterocycle Base, amino, aminoacyl, azo, carbonyl, carboxyl, cyano, formoxyl, guanidine radicals, halogen, hydroxyl, imido acyl group, imino group, different sulphur Cyanate, nitrile, nitro, nitroso, nitroxyl, oxygroup, sulfanyl, sulfonyl, thioaldehydes, thiocyanates, thioketones, thiocarbamide, urea alkene Base, alkynyl, ester, ketone, alcohol etc., and including any deuterated above-mentioned substituent group.

11. the compound of claim 1, is expressed from the next:

Wherein:

R₇It is the C optionally replaced_1-20Linear or branched alkyl group, the optional substitution is with one or more R_7AReplace；

Each R_7AIt is independently any substituted C_1-20Linear or branched alkyl group, alkoxy, deuterated alkoxy, deuterated amide, virtue Base, heterocycle, amino, aminoacyl, deuterated aminoacyl, azo, carbonyl, carboxyl, cyano, formoxyl, guanidine radicals, halogen, hydroxyl, Asia Aminoacyl, imino group, isothiocyanates, nitrile, nitro, nitroso, nitroxyl, oxygroup, sulfanyl, sulfonyl, thiocyanates, sulphur Ketone, thiocarbamide, urea alkenyl, alkynyl, ester, ketone, alcohol etc., and including any deuterated above-mentioned substituent group.

12. the compound of claim 11, wherein R₇It is the C optionally replaced_1-20Linear or branched alkyl group, substituted-amino.

13. the compound of claim 11, wherein R_7AIt is five yuan or hexa-member heterocycle, deuterated heterocycle, deuterated amide, especially tetrahydro Pyrrole ring.

14. a kind of pharmaceutical composition, it includes the compound of any one of preceding claims and officinal salt excipient and dilutions Agent.

15. treating and improving the application in cardiovascular disease and metabolic disease patient in claim 1-14.

16. treating and improving the application in diabetic in claim 1-14.

17. treating and improving the application in diabetic's complication, including microvascular complication meeting in claim 1-14 Caused retinopathy, nephrosis and the nervous system disease.And cardiovascular disease caused by big vascular syndrome.

18. wherein the patient had taken or had just taken at present other therapeutic drug, including blood pressure lowering to claim 15-18 Medicine, hypolipidemic, antidiabetic, hypoglycemic agent, slimming drugs or appetite inhibitor.