CN106892929B - Spiroketal derivative and preparation method and application thereof - Google Patents

Abstract

The invention relates to spiroketal derivatives of the following formula (I), a preparation method and application thereof, wherein R in the formula₁、R₂、R₃、R₄See the description for definitions of ring X and ring A. The derivative of the present invention is a sodium-dependent glucose cotransporter 2(SGLT-2) inhibitor associated with glucose reabsorption in the intestine or kidney, and has an excellent urinary glucose excretion effect, and thus is useful as a therapeutic agent for treating diabetes, hyperglycemia, and diabetic complications or obesity caused by them.

Description

Spiroketal derivative and preparation method and application thereof

Technical Field

The present invention relates to a spiroketal derivative which inhibits the activity of sodium-dependent glucose cotransporter 2(SGLT-2) associated with glucose reabsorption in the intestine or kidney, a preparation method thereof, a pharmaceutical composition containing the derivative, and applications thereof in treating diabetes, hyperglycemia, and diabetic complications or obesity caused thereby.

Background

The incidence of Diabetes (Diabetes) increases year by year, seriously harming human health. Among the diabetic patients, type I and type II (i.e. non-insulin dependent) diabetic patients are included, the vast majority being type II, characterized by insulin resistance. Hyperglycemia is a hallmark of type II diabetes and is considered to be a major risk factor for developing diabetic complications. Currently, as therapeutic agents for diabetes, metformin drugs, sulfonylurea drugs, glycosidase inhibitors, insulin sensitivity enhancers, thiazolidinedione drugs, and the like are used. However, metformin has a side effect of lactic acidosis, sulfonylurea has a side effect of hypoglycemia, glycosidase inhibitors have a side effect of diarrhea, and insulin sensitivity enhancers have side effects such as edema and obesity, and thiazolidinedione has a safety problem in long-term use. Therefore, in order to solve these problems, development of an antidiabetic agent of a novel mechanism of action is required.

Sodium-dependent glucose transporters (SGLT) is a new target for treating diabetes discovered in recent years and is divided into two subtypes, SGLT-1 and SGLT-2. SGLT-2 is expressed predominantly in the renal proximal pre-tubular S1 segment; SGLT-1 is distributed in the small intestine, heart and kidney. SGLT-2 absorbs 90% of the glucose in the raw urine, and only 10% of the glucose is absorbed back into the body through SGLT-1. Selective inhibition of SGLT-2 is expected to normalize glycemic glucose by increasing glucose excretion in the urine, thereby increasing insulin sensitivity and delaying the development of diabetic complications. Since SGLT-2 inhibitors do not intervene in glucose metabolism, they can be used as a supplement to the mainstream approach to glycemic control. Therefore, rapid development of antidiabetic agents having potent inhibitory activity against human SGLT-2 and a novel mechanism of action has been desired. It is considered that this drug can have a preventive or alleviating effect on obesity while promoting excretion of excessive glucose from urine and thus reducing glucose accumulated in the body.

A glucose derivative phlorizin (structural formula shown in the following formula) separated from natural substances can prevent reabsorption of excess glucose in kidney, promote excretion of glucose, and has the effect of reducing blood sugar (rossetti, L., et al.J. Clin. invest., Vol. 80, p. 1037, 1987; Vol. 79, p. 1510, 1987). Subsequently, the structure is modified to develop analogues such as O-carbocyclylglycoside derivatives, O-heterocyclyl glycoside derivatives, C-carbocyclylglycoside derivatives, C-heterocyclyl glycoside derivatives, N-glycoside derivatives, and the like. However, O-carbocyclylglycoside derivatives and O-heterocyclyl glycoside derivatives, which are phlorizin analogues, are susceptible to hydrolysis by glycosidases present in the intestine, and show low absorption of unchanged bodies, and rapid disappearance of pharmacological effects (Ehrenkranz, J.R., Lewis, N.G.Kahn, C.R. & Roth, J.Phlorizin: areeve.diabetes metab.Res.revs.21, 31-38(2005)) when administered orally.

International patent application WO01/27128 of Bethest, Inc. discloses SGLT-2 transporter inhibitor compounds of the following structure, representing one way to treat diabetes and its complications.

Subsequently, International patent application WO2003/099836 of BaishiGuibao corporation further discloses a compound dapagliflozin inhibiting SGLT-2, the structure of which is shown below:

dapagliflozin is a selective SGLT-2 inhibitor with good selectivity, and the IC of the Dapagliflozin on human SGLT-2₅₀IC at 1.12nM for human SGLT-1₅₀1391nM (Diabetes 57: 1723-. Has effects in regulating diabetes, controlling blood sugar, and reducing weight, and has side effects of hypoglycemia and urinary tract infection.

International patent application WO2005/012326 of Mitsubishi pharmaceutical corporation, on Pan-frontieri, discloses a compound canagliflozin for inhibiting SGLT-2, the structure of which is shown below:

IC of Canagliflozin on human SGLT-2₅₀IC at 2.2nM for human SGLT-1₅₀910nM (J.Med.chem., 2010, 53, 6355-6360), therapeutic effects were achieved by increasing the glucose content in urine through inhibition of SGLT-2, marketed in the United states in 2013.

International patent application WO2006/080421 of Chinese and foreign pharmaceutical Co., Ltd discloses a compound tofogliflozin for inhibiting SGLT-2, and the structure is shown as follows:

tofogliflozin has good selectivity and IC for human SGLT-2₅₀IC at 2.9nM for human SGLT-1₅₀8444nM (J.Med.chem., 2012, 55, 7828-7840), marketed in Japan in 2015.

International patent application WO2008/083200 discloses compounds of the formula having the ability to inhibit SGLT.

In view of the above, the search for highly potent and specific SGLT-2 inhibitors is a major hotspot in current anti-diabetic studies.

Disclosure of Invention

The present invention provides a compound represented by the following general formula (I), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof:

in the formula:

x is- (CR)₅R₆)_n-, O, S or N;

R₁、R₂each independently selected from H, -C₁-C₆Alkyl, -O-C₁-C₆Alkyl, halogen, -C₂-C₆Alkenyl, -C₂-C₆Alkynyl, -C₃-C₆Cycloalkyl, -O-C₃-C₆Cycloalkyl, -C₁-C₆Haloalkyl, -S-C₁-C₆Alkyl, -OH, -SH, -NO₂、-CN、-SO-C₁-C₆Alkyl, -SO-C₃-C₆Cycloalkyl, -SO-aryl, -SO-heteroaryl, -SO₂-C₁-C₆Alkyl, -SO₂-C₃-C₆Cycloalkyl, -SO₂-aryl, -SO₂-haloaryl, -COH, -COOH, -CO-C₁-C₆Alkyl, -CO₂-C₁-C₆Alkyl or-CONH₂；

R₃、R₄Each independently selected from H, -C₁-C₆Alkyl, -O-C₁-C₆Alkyl, -OH, -SH, -NH₂Halogen or R₃、R₄(ii) ring closure together with the carbon atom to which it is attached to form cycloalkyl or heterocycloalkyl;

R₅、R₆each independently selected from H, -C₁-C₆Alkyl, -O-C₁-C₆Alkyl, halogen, -C₃-C₆Cycloalkyl, -O-C₃-C₆Cycloalkyl, -C₁-C₆Haloalkyl, -S-C₁-C₆Alkyl, -OH, -SH or R₅、R₆Together with the carbon atom to which they are attached to form

A ring is represented by R₉Substituted aryl, heteroaryl or heterocycloalkyl;

R₉selected from H, -C₁-C₆Alkyl, -O-C₁-C₆Alkyl, halogen, -O-C₃-C₆Cycloalkyl, -O-5-7 membered heterocycloalkyl, -C₁-C₆Haloalkyl, -O-C₁-C₆Haloalkyl, -C₃-C₆Cycloalkyl, -S-C₁-C₆Alkyl, -OH, -SH, - (CR)₇R₈)_n-CO-NR₇R₈、-O-(CR₇R₈)_n-O-C₁-C₆Alkyl, -O- (CR)₇R₈)n-O-C₃-C₆Cycloalkyl, -NO₂、-CN、-SO-C₁-C₆Alkyl, -SO-C₃-C₆Cycloalkyl, -SO-aryl, -SO-heteroaryl, -SO₂-C₁-C₆Alkyl, -SO₂-C₃-C₆Cycloalkyl, -SO₂-aryl, -SO₂-haloaryl, -COH, -COOH, -CO-C₁-C₆Alkyl, -CO₂-C₁-C₆Alkyl, -CONH₂Aryl, -C₂-C₆Alkenyl, -C₂-C₆Alkynyl, -NHCO-C₁-C₆Alkyl, -NHSO₂-C₁-C₆Alkyl or by hydrogen, halogen, -OH, -NH₂、-CN、-COH、-COOH、-C₁-C₆Alkyl, -O-C₁-C₆Alkyl-substituted phenyl;

R₇、R₈each independently selected from H, -C₁-C₆Alkyl, -O-C₁-C₆Alkyl or halogen;

n is 1, 2 or 3.

The invention also provides a pharmaceutical composition which contains the compound represented by the general formula (I) and pharmaceutically acceptable salts thereof or hydrates or solvates thereof, and a pharmaceutically acceptable carrier.

The present invention also provides a pharmaceutical composition comprising the compound represented by the general formula (I) of the present invention, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, and a pharmaceutically acceptable carrier, excipient or diluent.

The invention also provides application of the compound shown in the general formula (I), the pharmaceutically acceptable salt thereof or the hydrate or solvate thereof in preparing a medicament for inhibiting the activity of sodium-dependent glucose cotransporter 2(SGLT-2) related to glucose reabsorption in the intestine or the kidney.

The invention also provides application of the compound shown in the general formula (I), the pharmaceutically acceptable salt thereof or the hydrate or solvate thereof in preparing medicines for treating diabetes, hyperglycemia and diabetic complications or obesity caused by the diabetes and hyperglycemia.

The present invention also provides a method for preventing or treating diabetes, hyperglycemia, and diabetic complications or obesity caused thereby, which comprises administering to a patient a therapeutically effective amount of a compound represented by the general formula (I), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

The diabetes mellitus of the invention comprises insulin-dependent diabetes mellitus (type I diabetes) or non-insulin-dependent diabetes mellitus (type II diabetes).

In a preferred embodiment of the compound represented by the general formula (I), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof according to the present invention, the compound of the formula (I) has a structure of the general formula (II):

wherein X is- (CR)₅R₆)_n-, O, S or N;

R₁、R₂each independently selected from H, -C₁-C₆Alkyl, -O-C₁-C₆Alkyl, halogen, -C₂-C₆Alkenyl, -C₂-C₆Alkynyl, -C₃-C₆Cycloalkyl, -O-C₃-C₆Cycloalkyl, -C₁-C₆Haloalkyl, -S-C₁-C₆Alkyl, -OH, -SH, -NO₂、-CN、-SO-C₁-C₆Alkyl, -SO-C₃-C₆Cycloalkyl, -SO-aryl, -SO-heteroaryl, -SO₂-C₁-C₆Alkyl, -SO₂-C₃-C₆Cycloalkyl, -SO₂-aryl, -SO₂-haloaryl, -COH, -COOH, -CO-C₁-C₆Alkyl, -CO₂-C₁-C₆Alkyl or-CONH₂；

R₃、R₄Each independently selected from H, -C₁-C₆Alkyl, -O-C₁-C₆Alkyl, -OH, -SH, -NH₂Halogen or R₃、R₄(ii) ring closure together with the carbon atom to which it is attached to form cycloalkyl or heterocycloalkyl;

R₅、R₆each independently selected from H, -C₁-C₆Alkyl, -O-C₁-C₆Alkyl, halogen, -C₃-C₆Cycloalkyl, -O-C₃-C₆Cycloalkyl, -C₁-C₆Haloalkyl, -S-C₁-C₆Alkyl, -OH, -SH or R₅、R₆Together with the carbon atom to which they are attached to form

A ring is represented by R₉Substituted aryl, heteroaryl or heterocycloalkyl;

R₉selected from H, -C₁-C₆Alkyl, -O-C₁-C₆Alkyl, halogen, -O-C₃-C₆Cycloalkyl, -O-5-7 membered heterocycloalkyl, -C₁-C₆Haloalkyl, -O-C₁-C₆Haloalkyl, -C₃-C₆Cycloalkyl, -S-C₁-C₆Alkyl, -OH, -SH, - (CR)₇R₈)_n-CO-NR₇R₈、-O-(CR₇R₈)_n-O-C₁-C₆Alkyl, -O- (CR)₇R₈)_n-O-C₃-C₆Cycloalkyl, -NO₂、-CN、-SO-C₁-C₆Alkyl, -SO-C₃-C₆Cycloalkyl, -SO-aryl, -SO-heteroaryl, -SO₂-C₁-C₆Alkyl, -SO₂-C₃-C₆Cycloalkyl, -SO₂-aryl, -SO₂-haloaryl, -COH, -COOH, -CO-C₁-C₆Alkyl, -CO₂-C₁-C₆Alkyl, -CONH₂Aryl, -C₂-C₆Alkenyl, -C₂-C₆Alkynyl, -NHCO-C₁-C₆Alkyl, -NHSO₂-C₁-C₆Alkyl or by hydrogen, halogen, -OH, -NH₂、-CN、-COH、-COOH、-C₁-C₆Alkyl, -O-C₁-C₆Alkyl-substituted phenyl;

R₇、R₈each independently selected from H, -C₁-C₆Alkyl, -O-C₁-C₆Alkyl or halogen;

n is 1, 2 or 3.

In a preferred embodiment of the compound represented by the general formula (I) of the present invention, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, X is- (CR)₅R₆)_n-, wherein R₅、R₆Each independently selected from H, -C₁-C₆Alkyl, -O-C₁-C₆Alkyl, halogen, -OH, -SH, or R₅、R₆Together with the carbon atom to which they are attached to form

n is 1, 2 or 3.

In a more preferred embodiment of the compound represented by the general formula (I) of the present invention, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, X is- (CH)₂)_n-, the structure of which is represented by the following formula (III):

wherein n is 1, 2 or 3;

R₁、R₂each independently selected from H, -C₁-C₆Alkyl, -O-C₁-C₆Alkyl, halogen, -C₂-C₆Alkenyl, -C₂-C₆Alkynyl, -C₃-C₆Cycloalkyl, -O-C₃-C₆Cycloalkyl, -C₁-C₆Haloalkyl, -S-C₁-C₆Alkyl, -OH, -SH, -NO₂、-CN、-SO-C₁-C₆Alkyl, -SO-C₃-C₆Cycloalkyl, -SO-aryl, -SO-heteroaryl, -SO₂-C₁-C₆Alkyl, -SO₂-C₃-C₆Cycloalkyl, -SO₂-aryl, -SO₂-haloaryl, -COH, -COOH, -CO-C₁-C₆Alkyl, -CO₂-C₁-C₆Alkyl or-CONH₂；

R₃、R₄Each independently selected from H, -C₁-C₆Alkyl, -O-C₁-C₆Alkyl, -OH, -SH, -NH₂Halogen or R₃、R₄(ii) ring closure together with the carbon atom to which it is attached to form cycloalkyl or heterocycloalkyl;

a ring is represented by R₉Substituted aryl, heteroaryl or heterocycloalkyl;

R₉selected from H, -C₁-C₆Alkyl, -O-C₁-C₆Alkyl, halogen, -O-C₃-C₆Cycloalkyl, -O-5-7 membered heterocycloalkyl, -C₁-C₆Haloalkyl, -O-C₁-C₆Haloalkyl, -C₃-C₆CycloalkanesRadical, -S-C₁-C₆Alkyl, -OH, -SH, - (CR)₇R₈)_n-CO-NR₇R₈、-O-(CR₇R₈)_n-O-C₁-C₆Alkyl, -O- (CR)₇R₈)_n-O-C₃-C₆Cycloalkyl, -NO₂、-CN、-SO-C₁-C₆Alkyl, -SO-C₃-C₆Cycloalkyl, -SO-aryl, -SO-heteroaryl, -SO₂-C₁-C₆Alkyl, -SO₂-C₃-C₆Cycloalkyl, -SO₂-aryl, -SO₂-haloaryl, -COH, -COOH, -CO-C₁-C₆Alkyl, -CO₂-C₁-C₆Alkyl, -CONH₂Aryl, -C₂-C₆Alkenyl, -C₂-C₆Alkynyl, -NHCO-C₁-C₆Alkyl, -NHSO₂-C₁-C₆Alkyl or by hydrogen, halogen, -OH, -NH₂、-CN、-COH、-COOH、-C₁-C₆Alkyl, -O-C₁-C₆Alkyl-substituted phenyl;

R₇、R₈each independently selected from H, -C₁-C₆Alkyl, -O-C₁-C₆Alkyl or halogen.

In a preferred embodiment of the compound represented by the general formula (I) of the present invention, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, R₁、R₂Each independently selected from H, -C₁-C₆Alkyl, -O-C₁-C₆Alkyl, halogen, -C₂-C₆Alkenyl, -C₂-C₆Alkynyl or-C₃-C₆A cycloalkyl group.

In a more preferred embodiment of the compound represented by the general formula (I) of the present invention, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, R₁、R₂Each independently selected from H, -C₁-C₆Alkyl, -O-C₁-C₆Alkyl or halogen.

The compound represented by the general formula (I) of the present invention, and a process for producing the sameIn a preferred embodiment of the pharmaceutically acceptable salt or hydrate or solvate thereof, R₃、R₄Each independently selected from H or-C₁-C₆An alkyl group.

In a preferred embodiment of the compound represented by the general formula (I) of the present invention, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, R₃、R₄Together with the carbon atom to which they are attached, form a cycloalkyl or heterocycloalkyl group.

In a preferred embodiment of the compound represented by the general formula (I) of the present invention, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, the A ring is represented by R₉Substituted aryl radicals, R₉Selected from H, -C₁-C₆Alkyl, -O-C₁-C₆Alkyl, halogen, -O-C₃-C₆Cycloalkyl, -O-5-7 membered heterocycloalkyl, -C₁-C₆Haloalkyl, -O-C₁-C₆Haloalkyl, -C₃-C₆Cycloalkyl, -S-C₁-C₆Alkyl, -OH, -SH, - (CR)₇R₈)_n-CO-NR₇R₈、-O-(CR₇R₈)_n-O-C₁-C₆Alkyl, -O- (CR)₇R₈)_n-O-C₃-C₆Cycloalkyl, -NO₂、-CN、-SO-C₁-C₆Alkyl, -SO-C₃-C₆Cycloalkyl, -SO-aryl, -SO-heteroaryl, -SO₂-C₁-C₆Alkyl, -SO₂-C₃-C₆Cycloalkyl, -SO₂-aryl, -SO₂-haloaryl, -COH, -COOH, -CO-C₁-C₆Alkyl, -CO₂-C₁-C₆Alkyl, -CONH₂Aryl, -C₂-C₆Alkenyl, -C₂-C₆Alkynyl, -NHCO-C₁-C₆Alkyl, -NHSO₂-C₁-C₆Alkyl or by hydrogen, halogen, -OH, -NH₂、-CN、-COH、-COOH、-C₁-C₆Alkyl, -O-C₁-C₆Alkyl-substituted phenyl, R₇、R₈Each is independentThe root of the earth is selected from H and C₁-C₆Alkyl, -O-C₁-C₆Alkyl or halogen, n is 1, 2 or 3.

In a more preferred embodiment of the compound represented by the general formula (I) of the present invention, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, the A ring is represented by R₉Substituted phenyl radicals, R₉Selected from H, -C₁-C₆Alkyl, -O-C₁-C₆Alkyl, halogen, -O-C₃-C₆Cycloalkyl, -O-5-7 membered heterocycloalkyl, -C₁-C₆Haloalkyl, -O-C₁-C₆Haloalkyl, -C₃-C₆Cycloalkyl, -S-C₁-C₆Alkyl, -OH, -SH, - (CR)₇R₈)_n-CO-NR₇R₈、-O-(CR₇R₈)_n-O-C₁-C₆Alkyl, -O- (CR)₇R₈)_n-O-C₃-C₆Cycloalkyl, -NO₂、-CN、-SO-C₁-C₆Alkyl, -SO-C₃-C₆Cycloalkyl, -SO-aryl, -SO-heteroaryl, -SO₂-C₁-C₆Alkyl, -SO₂-C₃-C₆Cycloalkyl, -SO₂-aryl, -SO₂-haloaryl, -COH, -COOH, -CO-C₁-C₆Alkyl, -CO₂-C₁-C₆Alkyl, -CONH₂Aryl, -C₂-C₆Alkenyl, -C₂-C₆Alkynyl, -NHCO-C₁-C₆Alkyl, -NHSO₂-C₁-C₆Alkyl or by hydrogen, halogen, -OH, -NH₂、-CN、-COH、-COOH、-C₁-C₆Alkyl, -O-C₁-C₆Alkyl-substituted phenyl, R₇、R₈Each independently selected from H, -C₁-C₆Alkyl, -O-C₁-C₆Alkyl or halogen, n is 1, 2 or 3.

In a more preferred embodiment of the compound represented by the general formula (I) of the present invention, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, the A ring is represented by R₉Substituted benzenesRadical, R₉Selected from H, -C₁-C₆Alkyl, -O-C₁-C₆Alkyl, halogen, -O-C₃-C₆Cycloalkyl, -O-5-7 membered heterocycloalkyl, -C₁-C₆Haloalkyl, -O-C₁-C₆Haloalkyl, -C₃-C₆Cycloalkyl, -S-C₁-C₆Alkyl, -OH, -SH, -O- (CR)₇R₈)_n-O-C₁-C₆Alkyl, -O- (CR)₇R₈)_n-O-C₃-C₆Cycloalkyl, -NO₂、-CN、-C₂-C₆Alkenyl or-C₂-C₆Alkynyl radical, R₇、R₈Each independently selected from H, -C₁-C₆Alkyl or halogen, n is 1 or 2.

In a more preferred embodiment of the compound represented by the general formula (I) of the present invention, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, the A ring is represented by R₉Substituted phenyl radicals, R₉Selected from H, -C₁-C₆Alkyl, -O-C₁-C₆Alkyl, halogen, -O-C₃-C₆Cycloalkyl, -O-5-7 membered heterocycloalkyl, -C₁-C₆Haloalkyl, -O-C₁-C₆Haloalkyl or-C₃-C₆A cycloalkyl group.

In a preferred embodiment of the compound represented by the general formula (I) of the present invention, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, the A ring is represented by R₉Substituted heteroaryl, R₉Selected from H, -C₁-C₆Alkyl, -O-C₁-C₆Alkyl, halogen, -O-C₃-C₆Cycloalkyl, -O-5-7 membered heterocycloalkyl, -C₁-C₆Haloalkyl, -O-C₁-C₆Haloalkyl, -C₃-C₆Cycloalkyl, -S-C₁-C₆Alkyl, -OH, -SH, -NO₂、-CN、-COH、-COOH、-CO-C₁-C₆Alkyl, -CO₂-C₁-C₆Alkyl, -CONH₂Or by hydrogen, halogen, -OH, -NH₂、-CN、-COH、-COOH、-C₁-C₆Alkyl, -O-C₁-C₆Alkyl-substituted phenyl.

In a more preferred embodiment of the compound represented by the general formula (I) of the present invention, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, the A ring is represented by R₉Substituted thienyl or benzofuranyl, R₉Selected from H, -C₁-C₆Alkyl, -O-C₁-C₆Alkyl, halogen, or by hydrogen, halogen, -OH, -NH₂、-CN、-C₁-C₆Alkyl, -O-C₁-C₆Alkyl-substituted phenyl.

In a more preferred embodiment of the compound represented by the general formula (I) of the present invention, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, the A ring is represented by R₉Substituted thienyl, R₉Selected from H, -C₁-C₆Alkyl, halogen, or by hydrogen, halogen, -OH, -NH₂、-CN、-C₁-C₆Alkyl, -O-C₁-C₆Alkyl-substituted phenyl.

In a preferred embodiment of the compound represented by the general formula (I) of the present invention, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, the A ring is represented by R₉Substituted heterocycloalkyl, R₉Selected from H, -C₁-C₆Alkyl, -O-C₁-C₆Alkyl or halogen.

In a more preferred embodiment of the compound represented by the general formula (I) of the present invention, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, the A ring is represented by R₉Substituted 2, 3-dihydrobenzofuranyl, 2, 3-dihydro-1, 4-benzodioxanyl, 1, 3-benzodioxopentanyl or 1, 4-benzodioxanyl, wherein R₉Selected from H, -C₁-C₆Alkyl or halogen.

In the present invention, particularly preferred compounds of formula (I) or pharmaceutically acceptable salts thereof, or hydrates or solvates thereof, include the following:

(2 'R, 3' R, 4 'S, 5' S, 6 'R) -7-methyl-6- [ (5- (4-fluorobenzene) thiophen-2-yl) methyl ] -3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxane-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol;

(2 'R, 3' R, 4 'S, 5' S, 6 'R) -7-chloro-6- [ (2, 3-dihydrobenzofuran-5-yl) methyl ] -3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxane-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol;

(2 'R, 3' R, 4 'S, 5' S, 6 'R) -6-benzyl-3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxan-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol;

(2 'R, 3' R, 4 'S, 5' S, 6 'R) -7-methyl-6- [ (4-isopropylphenyl) methyl ] -3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxane-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol;

(2 'R, 3' R, 4 'S, 5' S, 6 'R) -7-chloro-6- [ (4-ethylphenyl) methyl ] -3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxane-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol;

(2 'R, 3' R, 4 'S, 5' S, 6 'R) -7-chloro-6- [ (4-isopropylphenyl) methyl ] -3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxane-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol;

(2 'R, 3' R, 4 'S, 5' S, 6 'R) -7-chloro-6- [ (4-fluoro-phenyl) methyl ] -3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxan-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol;

(2 'R, 3' R, 4 'S, 5' S, 6 'R) -6- [ (4-isopropylphenyl) methyl ] -3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxane-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol;

(2 'R, 3' R, 4 'S, 5' S, 6 'R) -7-methyl-6- [ (4-ethoxyphenyl) methyl ] -3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxane-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol;

(2 'R, 3' R, 4 'S, 5' S, 6 'R) -7-chloro-6- [ (4-ethoxyphenyl) methyl ] -3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxane-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol;

(2 'R, 3' R, 4 'S, 5' S, 6 'R) -7-methyl-6- [ (4- (S) -tetrahydrofuran-3-oxy) methyl ] -3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxane-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol;

(2 'R, 3' R, 4 'S, 5' S, 6 'R) -6- [ (4-ethoxyphenyl) methyl ] -3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxane-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol;

(2 'R, 3' R, 4 'S, 5' S, 6 'R) -6- [ (4-ethylphenyl) methyl ] -3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxane-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol;

(2 'R, 3' R, 4 'S, 5' S, 6 'R) -6- [ (4-fluoro-phenyl) methyl ] -3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxane-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol;

(2 'R, 3' R, 4 'S, 5' S, 6 'R) -6- [ (4-chloro-phenyl) methyl ] -3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxane-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol;

(2 'R, 3' R, 4 'S, 5' S, 6 'R) -7-chloro-6- [ (4-cyclopentyloxyphenyl) methyl ] -3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxane-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol;

(2 'R, 3' R, 4 'S, 5' S, 6 'R) -7-chloro-6- [ (4-trifluoroethoxyphenyl) methyl ] -3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxan-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol.

The present invention also provides a process for the preparation of a compound of formula (II) comprising the steps of:

in the formula, R₁、R₂、R₃、R₄Ring X, A is as defined above for formula (II); p is trityl, tert-butyldimethylsilyl or tetrahydropyranyl.

Demethylating the compound of formula (IV) in the presence of a basic nucleophile or a Lewis acid to obtain a compound (V); carrying out hydroxyl protection on the compound (V) to obtain a compound (VI); treating compound (VI) with a suitable alkyllithium and reacting with compound (VII) to give compound (VIII); followed by reacting it with compound (IX) in the presence of a suitable acid, thereby obtaining compound (X); the compounds of the formula (II) according to the invention are obtained by contact hydrogenation in the presence of palladium catalysts or by debenzylation of the compounds (X) in the presence of Lewis acids. In addition, the compound (IV) can be synthesized by, for example, a method described in the literature (j.med. chem., No. 53, p. 3249, 2010), and the compound (VII) can be synthesized by, for example, a method described in the literature (carbohydrate. res., No. 260, p. 243, 1994).

In the above preparation methods, basic nucleophiles include, but are not limited to, sodium ethanethiol, sodium thiophenolate; lewis acids include, but are not limited to, boron tribromide, boron trichloride-dimethylsulfide complex, boron trifluoride-diethylsulfide complex/ethanethiol, boron trifluoride-diethylether complex/dimethylsulfide; alkyl lithium includes, but is not limited to, n-butyl lithium, sec-butyl lithium; suitable acids for use in the step of preparing compound (X) from compound (IX) include, but are not limited to, sulfuric acid, trifluoroacetic acid; palladium catalysts include, but are not limited to, palladium hydroxide, palladium on carbon.

The present invention also provides a process for the preparation of a compound of formula (III) comprising the steps of:

in the formula, R₁、R₂、R₃、R₄Ring A and in the above general formula (III)The definitions are the same, n is 1, 2 or 3; p is trityl, tert-butyldimethylsilyl or tetrahydropyranyl; p₁Is acetyl or tert-butyldimethylsilyl;

diazotizing the compound (XI) and hydrolyzing to obtain a compound (XII); protecting hydroxyl of the compound (XII) to obtain a compound (XIII); treating compound (XIII) with an appropriate alkyllithium and reacting with compound (VII) to give compound (XIV); reacting compound (XIV) with compound (IX) in the presence of a suitable acid, thereby obtaining compound (XV); obtaining compound (XVI) by contact hydrogenation in the presence of a palladium catalyst or debenzylation of compound (XV) in the presence of a lewis acid; protecting the hydroxyl group of the compound (XVI) to obtain a compound (XVII); brominating compound (XVII) with an appropriate brominating agent to give compound (XVIII); when compound (XX) is

When the compound (XX) is a compound (XVIII), the coupling reaction is carried out in the presence of a suitable palladium catalyst

Then, the compound (XVIII) is subjected to coupling reaction with the compound (XVIII) in the presence or absence of copper chloride to obtain a compound (XVIII); dehydroxylation protection gives the compounds of the formula (III) according to the invention.

In the above preparation method, the alkyl lithium includes, but is not limited to, n-butyl lithium, sec-butyl lithium; suitable acids for use in the step of preparing compound (XV) from compound (XIV) include, but are not limited to, sulfuric acid, trifluoroacetic acid; palladium catalysts in the hydrogenation reaction include, but are not limited to, palladium hydroxide, palladium on carbon; lewis acids include, but are not limited to, boron tribromide, boron trichloride-dimethylsulfide complex, boron trifluoride-diethylsulfide complex/ethanethiol, boron trifluoride-diethylether complex/dimethylsulfide; brominating agents include, but are not limited to, bromine, N-bromosuccinimide; the palladium catalyst in the coupling reaction includes, but is not limited to, palladium acetate and palladium dichloride.

In the present invention, the term "halogen" means fluorine, chlorine, bromine, iodine and the like, preferably fluorine, chlorine, bromine, more preferably chlorine.

In the present invention, the term "C₁-C₆Alkyl "refers to an alkyl group having 1 to 6 carbon atoms, including, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, 3-methylbutyl, 2-methylbutyl, 1-ethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, and the like; preferably methyl, ethyl, propyl, isopropyl, butyl; the term "C₁-C₄Alkyl "refers to an alkyl group having 1 to 4 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl, ethyl, propyl or isopropyl.

In the present invention, the term "-O-C₁-C₆Alkyl "refers to alkoxy groups having 1 to 6 carbon atoms and includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, 3-methylbutoxy, 2-methylbutoxy, 1-ethylpropoxy, 4-methylpentoxy, 3-methylpentoxy, 2-ethylbutoxy and the like. "-O-C₁-C₄Alkyl "includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.

In the present invention, the term "C₁-C₆Haloalkyl "means C as defined herein substituted with one or more halogen, preferably one to five halogen atoms₁-C₆Alkyl groups including, but not limited to, trifluoromethyl, trifluoroethyl, difluoromethyl, 1-chloro-2-fluoroethyl, and the like. C₁-C₄Haloalkyl includes, but is not limited to, trifluoromethyl, trifluoroethyl, difluoromethyl, 1-chloro-2-fluoroethyl, and the like.

In the present invention, the term "-O-C₁-C₆Haloalkyl group "middle C₁-C₆Haloalkyl is as described above, -O-C₁-C₆Haloalkyl includes, but is not limited to, trifluoromethyloxy, trifluoroethyloxy, difluoromethyloxy,1-chloro-2-fluoroethyloxy, and the like. -O-C₁-C₄Haloalkyl includes, but is not limited to, trifluoromethyloxy, trifluoroethyloxy, difluoromethyloxy, 1-chloro-2-fluoroethyloxy, and the like.

In the present invention, the term "-S-C₁-C₆Alkyl group "in C₁-C₆Alkyl is as described above, -S-C₁-C₆Alkyl groups include, but are not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, n-pentylthio, 3-methylbutylthio, 2-methylbutylthio, 1-ethylpropylthio, n-hexylthio, 4-methylpentylthio, 3-methylpentylthio, 2-ethylbutylthio, and the like.

In the present invention, the term "-CO-C₁-C₆Alkyl group "in C₁-C₆Alkyl is as described above, -CO-C₁-C₆Alkyl groups include, but are not limited to, acetyl, n-propionyl, isopropionyl, n-butyryl, isobutyryl, sec-butyryl, tert-butyryl, n-pentanoyl, 3-methylpentanoyl, 2-ethylbutyryl, n-hexanoyl, 5-methylhexanoyl, 4-methylhexanoyl, 3-methylhexanoyl, and the like.

In the present invention, the term "-CO₂-C₁-C₆Alkyl group "in C₁-C₆Alkyl as described above, -CO₂-C₁-C₆Alkyl includes, but is not limited to, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl, n-hexoxycarbonyl, 3-methylbutoxycarbonyl, 2-methylbutoxycarbonyl, 1-ethylpropoxycarbonyl, 4-methylpentoxycarbonyl, 3-methylpentoxycarbonyl, 2-ethylbutoxycarbonyl, and the like.

In the present invention, the term "-SO-C₁-C₆Alkyl group "in C₁-C₆Alkyl is as described above, -SO-C₁-C₆Alkyl groups include, but are not limited to, methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, iso-propylsulfinylPropylsulfinyl, n-butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl, n-pentylsulfinyl, 3-methylbutylsulfinyl, 2-methylbutylsulfinyl, 1-ethylpropylsulfinyl, n-hexylsulfinyl, 4-methylpentylsulfinyl, 3-methylpentylsulfinyl, 2-ethylbutylsulfinyl and the like.

In the present invention, the term "-SO₂-C₁-C₆Alkyl group "in C₁-C₆Alkyl is as described above, -SO₂-C₁-C₆Alkyl groups include, but are not limited to, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl, 3-methylbutylsulfonyl, 2-methylbutylsulfonyl, 1-ethylpropylsulfonyl, n-hexylsulfonyl, 4-methylpentylsulfonyl, 3-methylpentylsulfonyl, 2-ethylbutylsulfonyl, and the like.

In the present invention, the term "-O- (CR)₇R₈)_n-O-C₁-C₆Alkyl "," -NHCO-C₁-C₆Alkyl "and" -NHSO₂-C₁-C₆C in alkyl₁-C₆The alkyl group is as described above.

In the present invention, alkenyl means a monovalent radical derived from a hydrocarbon group, the term "C₂-C₆Alkenyl "means alkenyl containing 2 to 6 carbon atoms and at least one carbon-carbon double bond, and includes, but is not limited to, ethenyl, propenyl, butenyl, 2-methyl-2-butene, 2-methyl-2-pentene, and the like.

In the present invention, alkynyl means a monovalent radical derived from a hydrocarbon group, the term "C₂-C₆Alkynyl "refers to alkynyl groups containing 2 to 6 carbon atoms and at least one carbon-carbon triple bond, including, but not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, and the like.

In the present invention, the term "cycloalkyl" refers to a saturated or unsaturated ring system consisting of a single or multiple ringsMonovalent radicals derived from partially unsaturated aliphatic carbocyclic cyclic compounds, e.g. C₃～C₈Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclooctenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and C₉～C₁₂Cycloalkyl groups include, but are not limited to, bicyclo [2.2.1]Heptyl and bicyclo [2.2.1]Octyl, and the like. The term "C₃-C₆Cycloalkyl "includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and the like, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

In the present invention, the term "-O-C₃-C₆Cycloalkyl radical "in C₃-C₆Cycloalkyl radicals being as described above, -O-C₃-C₆Cycloalkyl groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cyclopropenyloxy, cyclobutenyloxy, cyclopentenyloxy, cyclohexenyloxy, and the like, with cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, or cyclohexyloxy being preferred.

In the present invention, the term "-SO-C₃-C₆Cycloalkyl radical "in C₃-C₆Cycloalkyl is as described above, -SO-C₃-C₆Cycloalkyl groups include, but are not limited to, cyclopropylsulfinyl, cyclobutylsulfinyl, cyclopentylsulfinyl, cyclohexylsulfinyl, cyclopropenylsulfinyl, cyclobutenylsulfinyl, cyclopentenylsulfinyl, cyclohexenylsulfinyl, and the like.

In the present invention, the term "-SO₂-C₃-C₆Cycloalkyl radical "in C₃-C₆Cycloalkyl radicals being as described above, -SO₂-C₃-C₆Cycloalkyl groups include, but are not limited to, cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl, cyclopropenylsulfonyl, cyclobutenylsulfonyl, cyclopentenylsulfonyl, cyclohexenylsulfonyl and the like.

In the present invention, the term "-O- (CR)₇R₈)_n-O-C₃-C₆Cycloalkyl radical "in C₃-C₆Cycloalkyl groups are as described above.

In the present invention, the term "heterocycloalkyl" refers to a monovalent monocyclic group of three to eight ring atoms, preferably 4 to 7 ring members, which is saturated or partially unsaturated but not aromatic, wherein 1 to 4 ring heteroatoms are independently selected from O, S, N and the remaining ring atoms are carbon, including but not limited to azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, pyrazolidinyl, pyrazolinyl, imidazolinyl, imidazolidinyl, [1, 3] dioxolane (dioxanone), dihydropyridinyl, tetrahydropyridinyl, hexahydropyridinyl, oxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, tetrahydrothiazolyl, or tetrahydrofuranyl and the like, and the term "5 to 7 membered heterocycloalkyl" includes but is not limited to pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, pyrazolidinyl, tetrahydrofuranyl, and the like, Pyrazolinyl, imidazolinyl, imidazolidinyl, [1, 3] dioxolane (dioxolane), dihydropyridinyl, tetrahydropyridinyl, hexahydropyridinyl, oxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, tetrahydrothiazolyl, or tetrahydrofuranyl and the like; or "heterocycloalkyl" refers to a monovalent fused bicyclic group of five to twelve ring atoms, preferably 7 to 10 membered rings, which are saturated or partially unsaturated but not aromatic, wherein 1 to 4 ring heteroatoms are independently selected from O, S, N and the remaining ring atoms are carbon, including but not limited to 2, 3-dihydrobenzofuranyl, 2, 3-dihydro-1, 4-benzodioxanyl, 1, 3-benzodioxanyl, 1, 4-benzodioxanyl, benzothiadiazolyl, 1, 2, 3, 4-tetrahydroisoquinolinyl, and the like, preferably 2, 3-dihydrobenzofuranyl, 2, 3-dihydro-1, 4-benzodioxanyl, 1, 3-benzodioxanyl, or 1, 4-benzodioxanyl.

In the present invention, the term "-O-5-to 7-membered heterocycloalkyl" includes 5-to 7-membered heterocycloalkyl as described above, and-O-5-to 7-membered heterocycloalkyl includes, but is not limited to

And the like.

In the present invention, the term "aryl" refers to an aromatic cyclic hydrocarbon group, a carbocyclic ring system having one or more aromatic rings, fused rings or non-fused rings, including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl, and the like, preferably an aryl group having 6 to 14, more preferably 6 to 10 carbon atoms, such as phenyl and naphthyl, more preferably phenyl.

In the present invention, the aryl group in the term "-SO-aryl" is as described above, and the-SO-aryl group includes, but is not limited to, phenylsulfinyl, naphthylsulfinyl and the like, with phenylsulfinyl being preferred.

In the present invention, the term "haloaryl" refers to an aryl group as defined herein substituted with one or more halogens, preferably one to three halogen atoms, including but not limited to fluorophenyl, chlorophenyl, bromophenyl, difluorophenyl, dichlorophenyl, 1-fluoro-3-chlorophenyl or 1-fluoro-4-chlorophenyl and the like.

In the present invention, the term "-SO₂In "haloaryl" the haloaryl group is as described above, -SO₂Halogenated aryl groups include, but are not limited to

And the like.

In the present invention, the term "-SO₂Aryl in aryl "aryl is as described above, -SO₂Aryl includes but is not limited to

Etc.;

in the present invention, the term "heteroaryl" means a 5-to 6-membered monocyclic heteroaryl group containing 1 to 4 heteroatoms selected from N, S or O, or a bicyclic heteroaryl group thereof fused with a benzene ring, a pyridine ring or a pyrrole ring. Heteroaryl groups include, but are not limited to, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolinyl, isoquinolinyl, quinazolinyl, pyrrolo [2, 3-c ] bipyridyl, pyrrolo [3, 2-c ] bipyridyl, pyrrolo [2, 3-b ] bipyridyl, pyrrolo [3, 2-b ] bipyridyl, pyrrolo [2, 3-b ] bipyridyl, indolin-2-onyl, preferably thienyl, benzofuranyl.

In the present invention, heteroaryl in the term "-SO-heteroaryl" as described above includes, but is not limited to, -SO-monocyclic heteroaryl

And the like.

The invention also comprises pharmaceutically acceptable salts of the compounds of general formula (I). The term "pharmaceutically acceptable salt" refers to acid addition salts or base addition salts of the compounds of the present invention that are relatively non-toxic. The acid addition salts are salts of the compounds of formula (I) according to the invention with suitable inorganic or organic acids, which salts can be prepared in the final isolation and purification of the compounds or by reacting the purified compounds of formula (I) in their free base form with suitable organic or inorganic acids. Representative acid addition salts include, but are not limited to, hydrobromide, hydrochloride, sulfate, bisulfate, sulfite, acetate, oxalate, valerate, oleate, palmitate, stearate, metasilicate, borate, benzoate, lactate, phosphate, hydrogen phosphate, carbonate, bicarbonate, toluate, citrate, maleate, fumarate, succinate, tartrate, benzoate, methanesulfonate, p-toluenesulfonate, gluconate, lactobionate, laurylsulfonate, and the like. The base isAddition salts are salts of the compounds of formula (I) with suitable inorganic or organic bases, including, for example, salts with alkali metal, alkaline earth metal, quaternary ammonium cations, such as sodium, lithium, potassium, calcium, magnesium, tetramethylquaternary ammonium, tetraethylquaternary ammonium, and the like; amine salts, including with ammonia (NH)₃) And salts of primary, secondary or tertiary amines, such as methylamine salt, dimethylamine salt, trimethylamine salt, triethylamine salt, ethylamine salt, etc.

The compound represented by the general formula (I), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof of the present invention can be administered to mammals including humans, and can be administered orally, rectally, parenterally (intravenously, intramuscularly, or subcutaneously), topically (in the form of powder, ointment, drops, or the like), or the like.

The compound represented by the general formula (I), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof according to the present invention may be formulated into solid dosage forms for oral administration, including, but not limited to, capsules, tablets, pills, powders, granules, and the like. In these solid dosage forms, the compound represented by the general formula (I) of the present invention, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, is mixed as an active ingredient with at least one conventional inert excipient (or carrier), for example, with sodium citrate or dicalcium phosphate, or with the following ingredients: (1) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol, silicic acid, and the like; (2) binders such as hydroxymethyl cellulose, alginate, gelatin, polyvinyl pyrrolidone, sucrose, gum arabic and the like; (3) humectants, such as glycerol and the like; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, sodium carbonate, and the like; (5) a slow solvent such as paraffin and the like; (6) absorption accelerators, for example, quaternary ammonium compounds and the like; (7) wetting agents such as cetyl alcohol and glyceryl monostearate and the like; (8) adsorbents, for example, kaolin, and the like; and (9) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof, and the like. Capsules, tablets and pills may also contain buffering agents.

The solid dosage forms, such as tablets, dragees, capsules, pills, and granules, can be coated or microencapsulated with coating and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active ingredient in such compositions may be delayed in a certain portion of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the compounds of the present invention or pharmaceutically acceptable salts thereof may also be in microencapsulated form with one or more of the above excipients.

The compound represented by the general formula (I), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof according to the present invention may be formulated into liquid dosage forms for oral administration, including, but not limited to, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, tinctures, and the like. In addition to the compound represented by the general formula (I), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient, the liquid dosage form may contain inert diluents conventionally used in the art, such as water and other solvents, solubilizing agents and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, and oils, particularly, cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, sesame oil and the like, or a mixture of these substances, and the like. In addition to these inert diluents, the liquid dosage forms of the present invention may also contain conventional adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, perfuming agents and the like.

In addition to the compound represented by the general formula (I) of the present invention, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, the suspension may contain a suspending agent, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan ester, microcrystalline cellulose, aluminum methoxide and agar, or the like, or a mixture of these substances, and the like.

The compounds represented by the general formula (I) of the present invention, pharmaceutically acceptable salts thereof, or hydrates or solvates thereof may be formulated into dosage forms for parenteral injection, including, but not limited to, physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

The compound represented by the general formula (I) of the present invention, a pharmaceutically acceptable salt thereof or a hydrate or solvate thereof may also be formulated into dosage forms for topical administration, including, for example, ointments, powders, suppositories, drops, sprays, inhalants and the like. The compound represented by the general formula (I), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof of the present invention as an active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and optionally a preservative, a buffer, or a propellant as may be required.

The present invention also provides a pharmaceutical composition comprising a compound represented by the general formula (I) of the present invention, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient, and a pharmaceutically acceptable carrier, excipient or diluent. In the preparation of the pharmaceutical composition, the compound represented by the general formula (I), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof of the present invention is usually mixed with a pharmaceutically acceptable carrier, excipient, or diluent.

The present invention also provides a method for preventing or treating diabetes including type I and type II diabetes, particularly type II diabetes, hyperglycemia, and diabetic complications or obesity caused by them, which comprises the step of administering to a patient in need of treatment 0.01 to 50mg/kg body weight/day of a compound represented by the general formula (I), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

The compounds of the present invention or pharmaceutically acceptable salts thereof may be administered alone or in combination with other pharmaceutically acceptable therapeutic agents, particularly in combination with other antidiabetic agents. Such therapeutic agents include, but are not limited to: biguanides, such as metformin; thiazolidinediones, such as troglitazone, rosiglitazone, pioglitazone; alpha-glucosidase inhibitors, such as acarbose, peglybose, miglitol; sulfonylurea insulin secretagogues, such as glibenclamide, glipizide, glibornuride, gliclazide, glimepiride; repaglinide, a postprandial blood glucose regulator, and the like; PPAR alpha/gamma dual agonists; a DPP-IV inhibitor; PTP1B inhibitors, and the like. The components to be combined may be administered simultaneously or sequentially, in a single formulation or in separate formulations. Such combinations include not only combinations of a compound of the invention and one other active agent, but also combinations of a compound of the invention and two or more other active agents.

Experiments prove that the compound has good inhibition effect on human SGLT-2. The compound can effectively promote the excretion of urine glucose and can be used for preparing the medicine for treating diabetes.

The efficacy of the compounds in promoting urinary glucose excretion can be determined by conventional methods, and a preferred method of evaluation is to examine the effect of the compounds of the present invention on urinary glucose excretion in ICR mice. The test method is as follows: ICR mice, male, 60, 30-40g (12 weeks old), were randomly assigned to 6 groups of 10 mice per group by body weight. The tested compound of the invention, with a purity of 99.00%, was formulated with 0.5% MC (methyl cellulose); the positive control, tolgliflozin (Tofogliflozin), was 98.7% pure and was formulated with 0.5% MC. The medicine is orally taken in three dosage of low, medium and high. The placebo group was orally administered with 0.5% MC solution. After administration, the mice were placed in a metabolism cage, the time of administration was recorded, and 24 hours after administration of the drug was collected in urine. Urine volume was calculated and urine glucose concentration was measured.

The data are expressed by mean value plus or minus standard deviation, statistical analysis is carried out on the data by Student-t test, and the statistical difference is that p is less than 0.05.

Drawings

FIG. 1 is a graph of the urinary excretion 24 hour after oral administration of the compound of example 9 and the positive control drug Tofogliflozin (Tofogliflozin) to ICR mice.

FIG. 2 is a graph showing 24-hour urinary glucose excretion values after oral administration of the compound of example 9 and a positive control drug, Tofogliflozin (Tofogliflozin) to ICR mice.

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Parts and percentages are parts by weight and percentages by weight, respectively, unless otherwise indicated.

In the examples, the abbreviations have their art-known meaning, e.g. n-BuLi stands for n-butyllithium; TrO-represents triphenylmethoxy; BnO-represents benzyloxy; NBS represents N-bromosuccinimide; NEt₃Represents triethylamine; NaSEt represents sodium ethanethiol; ph₃CCl stands for triphenylchloromethane.

Detailed Description

I. Preparation examples of Compounds of the present invention

Example 1: (2 'R, 3' R, 4 'S, 5' S, 6 'R) -7-methyl-6- [ (5- (4-fluorobenzene) thiophen-2-yl) methyl ] -3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxane-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol

The title compound was prepared by the following several procedures

1) Synthesis of Compound 1 (b):

dissolving 1(a) (4g, 10.2mmol) in 30ml dichloromethane, cooling to-78 ℃, slowly adding boron tribromide (3.07g, 12.3mmol), reacting for 1 hour under controlled temperature, naturally raising the temperature to room temperature, adding saturated sodium bicarbonate to terminate the reaction, diluting with ethyl acetate, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain a crude product 1(b) which is a yellow oily substance (3.8 g).

MS(ESI)：375.0[M-H]⁺

2) Synthesis of Compound 1 (c):

1(b) (3.8g, 10mmol) was dissolved in 50ml of dichloromethane, and triphenylchloromethane (2.79g, 10mmol) and triethylamine (1.06g, 10.5mmol) were added in this order to react at room temperature for 30min, and after the reaction was terminated by adding water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and recrystallized from ethyl acetate, 1(c) was obtained as a white powdery solid (5.0g, 80.76%).

2) Synthesis of Compound 1 (d):

under the protection of nitrogen flow, 1(c) (5.0g, 8.07mmol) was dissolved in 50ml of tetrahydrofuran solution, cooled to-78 ℃ and slowly added dropwise with n-hexane solution of n-butyllithium (3.55ml, 2.5M) at controlled temperature. After the reaction was continued for 1 hour, a solution of 2, 3, 4, 6-tetrabenzyl-D-glucopyranosid-1, 5-olide (4.14g, 8.87mmol) in tetrahydrofuran (15ml) was slowly added dropwise under controlled temperature. After the reaction was carried out for 1 hour under controlled temperature, water was added to quench the reaction, and the reaction solution was allowed to spontaneously warm to room temperature. Extraction with ethyl acetate, merging of organic phases, washing with saturated brine, drying over anhydrous sodium sulfate, filtration and concentration to obtain a light yellow oily substance 1(d) crude product (8.2g), which can be used in the next reaction without purification. Ms (esi): 1102[ M + Na ]]⁺

3) Synthesis of Compound 1 (e):

1(d) (8.2g) was dissolved in 25ml of glacial acetic acid, heated to 80 ℃ and successively added paraformaldehyde (0.93g, 31.44mmol) and concentrated sulfuric acid (0.48g, 5mmol) to conduct the reaction for 1 hour, and then added with sodium acetate (0.80g, 10mmol) to terminate the reaction. The solvent was concentrated under reduced pressure, diluted with ethyl acetate, washed with saturated sodium bicarbonate, water, and saturated brine in this order, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (petroleum ether: ethyl acetate: 10: 1) to give 1(e) as a white oil (2.33g, yield in two steps: 34%).

MS(ESI)：871.4[M+Na]⁺

4) Synthesis of Compound 1:

under the protection of nitrogen flow, 1(d) (2.33g, 2.74mmol), pentamethylbenzene (6.93g, 41.16mmol) were dissolved in 50ml of dichloromethane, cooled to-78 deg.C, and a solution of boron trichloride in dichloromethane (13.7ml, 1M) was slowly added dropwise at controlled temperature. After further reaction for 4 hours, the reaction mixture was quenched by addition of methanol, allowed to warm to room temperature naturally, the solvent was concentrated under reduced pressure, diluted with ethyl acetate, washed with saturated sodium bicarbonate, water and saturated brine in this order, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (dichloromethane: methanol: 12: 1) to obtain compound 1(557mg, 41.2%).

¹H NMR(600MHz，MeOD)δ7.53(dd，J＝8.7，5.3Hz，2H)，7.24(s，1H)，7.10(d，J＝3.5Hz，1H)，7.06(t，J＝8.7Hz，2H)，6.74(s，1H)，6.68(d，J＝3.5Hz，1H)，5.25(q，J＝5.5Hz，2H)，4.11(d，J＝7.7Hz，2H)，3.85(dd，J＝11.7，1.6Hz，1H)，3.78-3.68(m，4H)，3.45(t，J＝9.3Hz，1H)，2.26(s，3H).

MS(ESI)：489.2[M+1]⁺

Example 2: (2 'R, 3' R, 4 'S, 5' S, 6 'R) -7-chloro-6- [ (2, 3-dihydrobenzofuran-5-yl) methyl ] -3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxane-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol

The title compound was prepared by the following several procedures

1) Synthesis of compound 2 (b):

dissolving 2(a) (2.5g, 7.5mmol) in 10ml formamide, adding a DMF solution (10ml) of sodium ethanethiolate (3eq, 22.5mmol), heating to 90 ℃, reacting for 3 hours, cooling to room temperature, adding dilute hydrochloric acid to terminate the reaction, diluting with ethyl acetate, washing with saturated sodium bicarbonate, water and saturated brine in sequence, drying over anhydrous sodium sulfate, filtering, and concentrating to obtain 2(b) crude yellow oily substance (2 g).

MS(ESI)：317.1[M-H]⁺

2) Synthesis of compound 2 (c):

2(b) (2g, 5.9mmol) was dissolved in 50ml of dichloromethane, and triphenylchloromethane (1.64g, 5.9mmol) and triethylamine (0.63g, 6.2mmol) were added in this order to react at room temperature for 30min, and after the reaction was terminated by addition of water and washing with saturated brine, drying over anhydrous sodium sulfate, filtration, concentration and recrystallization from ethyl acetate gave 2(c) as a white powdery solid (3.0g, 87.54%).

3) Synthesis of Compound 2 (d):

under the protection of nitrogen flow, 2(c) (3.0g, 5.15mmol) was dissolved in 30ml of tetrahydrofuran solution, cooled to-78 ℃, and a solution of n-butyllithium in n-hexane (2.27ml, 2.5M) was slowly added dropwise at controlled temperature. After the reaction was continued for 1 hour, a solution of 2, 3, 4, 6-tetrabenzyl-D-glucopyranosonic acid-1, 5-lactone (3.05g, 6.53mmol) in tetrahydrofuran (15ml) was slowly added dropwise under controlled temperature. After the reaction was carried out for 1 hour under controlled temperature, water was added to quench the reaction, and the reaction solution was allowed to spontaneously warm to room temperature. Extraction with ethyl acetate, merging of organic phases, washing with saturated brine, drying over anhydrous sodium sulfate, filtration and concentration to obtain a crude light yellow oily substance 2(d) (5.5g), which can be used in the next reaction without purification. Ms (esi): 1063[ M + Na]⁺

4) Synthesis of compound 2 (e):

2(d) (5.5g) was dissolved in 25ml of glacial acetic acid, heated to 80 ℃ and successively added paraformaldehyde (0.56g, 18.83mmol) and concentrated sulfuric acid (0.29g, 3mmol) to continue the reaction for 1 hour, and then added with sodium acetate (0.48g, 6mmol) to terminate the reaction. The solvent was concentrated under reduced pressure, diluted with ethyl acetate, washed with saturated sodium bicarbonate, water, and saturated brine in this order, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (petroleum ether: ethyl acetate: 10: 1) to give 2(e) as a white oil (1.37g, 33% yield in two steps).

MS(ESI)：871.4[M+Na]⁺

5) Synthesis of Compound 2:

2(e) (1.37g, 1.69mmol) was dissolved in a mixed solution of ethyl acetate (6ml) and methanol (4ml), and a catalytic amount of palladium hydroxide (59.3mg, 0.84mmol) and hydrochloric acid (2d, 2M) were added to conduct reduction reaction with a hydrogen balloon for 12 hours. The reaction mixture was concentrated, diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (dichloromethane: methanol: 12: 1) to obtain compound 2.

MS(ESI)：923.2[2M+Na]⁺

Example 3: (2 'R, 3' R, 4 'S, 5' S, 6 'R) -6-benzyl-3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxane-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol

The title compound was prepared by the following several procedures

1) Synthesis of compound 3 (b):

3(a) (10g, 45.7mmol) was dissolved in 120ml of acetic acid solution, the temperature was controlled at 20 ℃ and slowly added to a concentrated sulfuric acid solution (24ml) of sodium nitrite (3.7g, 53.6mmol), the reaction was stirred for 1 hour, the reaction solution was added to a boiling 80% aqueous solution (25ml) of sulfuric acid, and the boiling reaction was continued for 4 hours. The reaction was quenched with ice, extracted with ethyl acetate, and the organic phase washed with water, concentrated and distilled under reduced pressure to give colorless oil 3(b) (5.5g, 54.7%).

2) Synthesis of compound 3 (c):

3(b) (5.5g, 29.4mmol) was dissolved in 50ml of dichloromethane, and triphenylchloromethane (8.2g, 29.4mmol) and triethylamine (3.12g, 30.88mmol) were added in this order to react at room temperature for 30min, and after the reaction was terminated by addition of water and washing with saturated brine, the reaction mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and recrystallized from ethyl acetate to obtain 3(c) as a white powdery solid (10.2g, 80.8%).

3) Synthesis of Compound 3 (d):

under the protection of nitrogen flow, 3(c) (10.2g, 23.8mmol) was dissolved in 100ml of tetrahydrofuran solution, cooled to-78 ℃ and slowly added dropwise with n-hexane solution (10ml, 2.5M) of n-butyllithium at controlled temperature. After the reaction was continued for 1 hour, a solution of 2, 3, 4, 6-tetrabenzyl-D-glucopyranosid-1, 5-olide (15.4g, 28.5mmol) in tetrahydrofuran (50ml) was slowly added dropwise under controlled temperature. After the reaction was carried out for 1 hour under controlled temperature, water was added to quench the reaction, and the reaction solution was allowed to spontaneously warm to room temperature. Extraction with ethyl acetate, merging organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering and concentrating to obtain a light yellow oily substance 3(d) crude product (25g), and the light yellow oily substance can be directly used for the next reaction without purification.

MS(ESI)：911.4[M+Na]⁺

4) Synthesis of compound 3 (e):

3(d) (25g) was dissolved in 100ml of glacial acetic acid, heated to 80 ℃ and successively paraformaldehyde (4.73g, 157mmol) and concentrated sulfuric acid (2.32g, 23.6mmol) were added, and after 1 hour of reaction, sodium acetate (1.94g,23.6mmol) was used to terminate the reaction. The solvent was concentrated under reduced pressure, diluted with ethyl acetate, washed with saturated sodium bicarbonate, water, and saturated brine in this order, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (petroleum ether: ethyl acetate: 10: 1) to give 3(e) as a white oil (5.6g, 37.8% yield in two steps). Ms (esi): 681.4[ M + Na ]]⁺

5) Synthesis of compound 3 (f):

3(e) (5.6g, 8.5mmol) was dissolved in a mixed solution of ethyl acetate (30ml) and methanol (20ml), a catalytic amount of palladium hydroxide (298.44mg, 0.42mmol) and hydrochloric acid (1ml, 2M) were added, and reduction was carried out for 12 hours with a hydrogen balloon. The reaction mixture was concentrated, diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (dichloromethane: methanol: 12: 1) to obtain compound 3 (f).

MS(ESI)：321.2[2M+Na]⁺

6) Synthesis of Compound 3 (g):

3(f) (3g, 10mmol) was dissolved in 10ml of pyridine, and 5ml of acetic anhydride was added thereto, followed by stirring and reacting for 12 hours. The reaction mixture was concentrated, diluted with ethyl acetate, washed successively with dilute hydrochloric acid, water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated and recrystallized from ethanol to give a white powdery solid 3(g) (3.2g, 68%).

MS(ESI)：389.2[M+Na]⁺

7) Synthesis of Compound 3 (h):

3(g) (3.2g, 6.4mmol) was dissolved in 10ml of ethyl acetate, and NBS (N-bromosuccinimide) (2g, 12.78mmol) and azobisisobutyronitrile (0.3g, 1.92mmol) were added and the mixture was heated to reflux for 1 hour. Washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated and recrystallized from ethanol to give a white powdery solid 3(h) (2.7g, 72%).

MS(ESI)：603[M+Na]⁺

8) Synthesis of compound 3 (j):

3(h) (2.7g, 4.95mmol) was dissolved in 25ml of toluene, triphenylphosphine (65mg, 0.25mmol), palladium acetate (33mg, 0.15mmol), phenylboronic acid 3(i) (0.91g, 7.4mmol) and potassium phosphate (2.1g, 9.9mmol) were added in this order, heated to 80 ℃ and stirred for 10 hours. The reaction mixture was diluted with water and ethyl acetate, and washed with brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give 3(j) (1.8g) as a white oil.

MS(ESI)：565.2[M+Na]⁺

9) Synthesis of Compound 3:

3(j) (1.8g, 3.3mmol) was dissolved in 10ml of methanol, potassium carbonate (0.36g, 2.3mmol) was added, and the mixture was stirred at room temperature for 1 hour. After dilution with ethyl acetate, washing with water, washing with saturated brine, drying over anhydrous sodium sulfate, filtration, concentration, and column chromatography (dichloromethane: methanol: 12: 1), compound 3(0.56g, 45%) was obtained.

¹H NMR(600MHz，MeOD)δ7.79(d，J＝2.0Hz，1H)，7.23(d，J＝8.4Hz，2H)，7.17(d，J＝8.4Hz，2H)，7.06(dd，J＝8.4，2.1Hz，1H)，6.81(d，J＝8.4Hz，1H)，5.18(d，J＝5.4Hz，1H)，5.08(d，J＝5.4Hz，1H)，3.96(dd，J＝8.8，3.3Hz，1H)，3.90-3.79(m，3H)，3.79-3.68(m，3H)，3.64(d，J＝3.3Hz，1H).

MS(ESI)：397[M+Na]⁺

Example 4: (2 'R, 3' R, 4 'S, 5' S, 6 'R) -7-methyl-6- [ (4-isopropylphenyl) methyl ] -3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxane-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol

Referring to the procedure for synthesizing compound 1 from compound 1(a) in example 1,compound 4 was synthesized and obtained starting from compound 4 (a).

¹H NMR(400MHz，MeOD)δ7.18(s，1H)，7.12(d，J＝8.1Hz，2H)，7.04(d，J＝8.2Hz，2H)，6.73(s，1H)，5.27(d，J＝0.9Hz，2H)，3.93(s，2H)，3.87(dd，J＝11.5，1.7Hz，1H)，3.82-3.67(m，4H)，3.50-3.41(m，1H)，2.90-2.81(m，1H)，2.15(s，3H)，1.24(s，3H)，1.22(s，3H).

MS(ESI)：453.2[M+Na]⁺

Example 5: (2 'R, 3' R, 4 'S, 5' S, 6 'R) -7-chloro-6- [ (4-ethylphenyl) methyl ] -3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxane-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol

Referring to the procedure for synthesizing compound 1 from compound 1(a) in example 1, compound 5 was synthesized and obtained starting from compound 5 (a).

¹H NMR(600MHz，MeOD)δ7.32(s，1H)，7.14-7.07(m，4H)，6.99(s，1H)，5.28(dd，J＝15.2，5.5Hz，2H)，4.03(q，J＝15.3Hz，2H)，3.85(dd，J＝11.8，1.9Hz，1H)，3.81-3.65(m，4H)，3.49-3.41(m，1H)，3.36-3.30(m，1H)，2.61(q，J＝7.6Hz，2H)，1.22(t，J＝7.6Hz，3H).

MS(ESI)：459.1[M+Na]⁺

Example 6: (2 'R, 3' R, 4 'S, 5' S, 6 'R) -7-chloro-6- [ (4-isopropylphenyl) methyl ] -3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxane-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol

Referring to the procedure for synthesizing compound 1 from compound 1(a) in example 1, compound 6 was synthesized and obtained starting from compound 6 (a).

¹H NMR(400MHz，MeOD)δ7.33(s，1H)，7.19-7.06(m，4H)，6.99(s，1H)，5.28(dd，J＝11.7，5.5Hz，2H)，4.03(q，J＝15.2Hz，2H)，3.86(dd，J＝11.5，1.6Hz，1H)，3.80-3.66(m，4H)，，3.50-3.40(m，1H)，2.91-2.82(m，1H)，1.24(d，J＝6.9Hz，6H).

MS(ESI)：473.2[M+Na]⁺

Example 7: (2 'R, 3' R, 4 'S, 5' S, 6 'R) -7-chloro-6- [ (4-fluoro-phenyl) methyl ] -3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxane-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol

Referring to the procedure for synthesizing compound 2 from compound 1(a) in example 1, compound 7 was synthesized and obtained starting from compound 7 (a).

¹H NMR(600MHz，MeOD)δ7.31(s，1H)，7.17(dd，J＝8.4，5.5Hz，2H)，7.03-6.93(m，3H)，5.26(dd，J＝17.3，5.5Hz，2H)，4.07-3.99(m，2H)，3.83(dd，J＝11.6，1.5Hz，1H)，3.80-3.64(m，4H)，3.44(t，J＝9.4Hz，1H).

MS(ESI)：449.1[M+Na]⁺

Example 8: (2 'R, 3' R, 4 'S, 5' S, 6 'R) -6- [ (4-isopropylphenyl) methyl ] -3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxane-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol

Referring to the procedure for synthesizing compound 1 from compound 1(a) in example 1, compound 8 was synthesized and obtained starting from compound 8 (a).

MS(ESI)：439[M+Na]⁺

Example 9: (2 'R, 3' R, 4 'S, 5' S, 6 'R) -7-methyl-6- [ (4-ethoxyphenyl) methyl ] -3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxane-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol

Referring to the procedure for synthesizing compound 2 from compound 2(a) in example 2, compound 9(a) was synthesized and obtained as a starting material.

¹H NMR(400MHz，MeOD)δ7.15(s，1H)，7.02(d，J＝8.7Hz，2H)，6.80(d，J＝8.7Hz，2H)，6.72(s，1H)，5.26(d，J＝0.8Hz，2H)，4.00(q，J＝7.0Hz，2H)，3.89(s，2H)，3.87(dd，J＝11.5，1.7Hz，1H)，3.81-3.67(m，4H)，3.50-3.40(m，1H)，2.15(s，3H)，1.37(t，J＝7.0Hz，3H).

MS(ESI)：433.2[M+Na]⁺

Example 10: (2 'R, 3' R, 4 'S, 5' S, 6 'R) -7-chloro-6- [ (4-ethoxyphenyl) methyl ] -3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxane-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol

Referring to the procedure for synthesizing compound 2 from compound 2(a) in example 2, compound 10 was synthesized and obtained starting from compound 10 (a).

¹H NMR(600MHz，MeOD)δ7.29(s，1H)，7.09(d，J＝8.5Hz，2H)，6.98(s，1H)，6.82(d，J＝8.6Hz，2H)，5.28(dd，J＝15.0，5.5Hz，2H)，4.05-3.94(m，4H)，3.85(dd，J＝11.7，1.6Hz，1H)，3.81-3.64(m，4H)，3.45(t，J＝9.4Hz，1H)，1.38(t，J＝7.0Hz，3H).

MS(ESI)：475.1[M+Na]⁺

Example 11: (2 'R, 3' R, 4 'S, 5' S, 6 'R) -7-methyl-6- [ (4- (S) -tetrahydrofuran-3-oxy) methyl ] -3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxane-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol

Referring to the procedure for synthesizing compound 2 from compound 2(a) in example 2, compound 11 was synthesized and obtained starting from compound 11 (a).

MS(ESI)：497.2[M+Na]⁺

Example 12: (2 'R, 3' R, 4 'S, 5' S, 6 'R) -6- [ (4-ethoxyphenyl) methyl ] -3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxane-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol

Referring to the procedure for the synthesis of compound 2 from compound 2(a) in example 2, compound 12 was synthesized and obtained starting from compound 12 (a).

¹H NMR(600MHz，MeOD)δ7.24(d，J＝1.6Hz，1H)，7.09(s，4H)，7.06(dd，J＝8.4，1.8Hz，1H)，6.81(d，J＝8.4Hz，1H)，5.23(dd，J＝12.6，5.4Hz，2H)，3.87(s，2H)，3.84(dd，J＝11.8，1.7Hz，1H)，3.79-3.69(m，4H)，3.47(t，J＝9.4Hz，1H)，2.59(q，J＝7.6Hz，2H)，1.20(t，J＝7.6Hz，3H).MS(ESI)：441[M+Na]⁺

Example 13: (2 'R, 3' R, 4 'S, 5' S, 6 'R) -6- [ (4-ethylphenyl) methyl ] -3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxane-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol

Compound 13 was synthesized and obtained starting from compounds 3(a), 13(i) with reference to the procedure for synthesizing compound 3 from compounds 3(a), 3(i) in example 3.

¹H NMR(600MHz，MeOD)δ7.24(d，J＝1.6Hz，1H)，7.09(s，4H)，7.06(dd，J＝8.4，1.8Hz，1H)，6.81(d，J＝8.4Hz，1H)，5.23(dd，J＝12.6，5.4Hz，2H)，3.87(s，2H)，3.84(dd，J＝11.8，1.7Hz，1H)，3.79-3.69(m，4H)，3.47(t，J＝9.4Hz，1H)，2.59(q，J＝7.6Hz，2H)，1.20(t，J＝7.6Hz，3H).MS(ESI)：425[M+Na]⁺

Example 14: (2 'R, 3' R, 4 'S, 5' S, 6 'R) -6- [ (4-fluoro-phenyl) methyl ] -3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxane-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol

Referring to the procedures for synthesizing compound 3 with respect to compounds 3(a) and 3(i) in example 3, compound 14 was synthesized and obtained starting from compounds 3(a) and 14 (i).

¹H NMR(600MHz，MeOD)δ7.23(d，J＝1.8Hz，1H)，7.19(dd，J＝8.4，5.5Hz，2H)，7.07(dd，J＝8.4，2.0Hz，1H)，6.97(t，J＝8.8Hz，2H)，6.82(d，J＝8.4Hz，1H)，5.23(dd，J＝14.5，5.4Hz，2H)，3.90(s，2H)，3.83(dd，J＝11.7，1.8Hz，1H)，3.80-3.66(m，4H)，3.45(t，J＝9.4Hz，1H).

MS(ESI)：414.9[M+Na]⁺

Example 15: (2 'R, 3' R, 4 'S, 5' S, 6 'R) -6- [ (4-chloro-phenyl) methyl ] -3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxane-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol

Referring to the procedures for synthesizing compound 3 with respect to compounds 3(a), 3(i) in example 3, compound 15 was synthesized and obtained starting from compounds 3(a), 15 (i).

¹H NMR(600MHz，MeOD)δ7.24(dd，J＝9.3，5.8Hz，2H)，7.21-7.11(m，3H)，7.07(dd，J＝8.4，1.7Hz，1H)，6.81(d，J＝8.4Hz，1H)，5.23(dd，J＝12.1，5.4Hz，2H)，3.91(s，2H)，3.89-3.82(m，1H)，3.82-3.64(m，4H)，3.45(t，J＝9.4Hz，1H)，.

MS(ESI)：430.9[M+Na]⁺

Example 16: (2 'R, 3' R, 4 'S, 5' S, 6 'R) -7-chloro-6- [ (4-cyclopentyloxyphenyl) methyl ] -3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxane-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol

Referring to the procedures for synthesizing compound 3 with respect to compounds 3(a), 3(i) in example 3, compound 16 was synthesized and obtained starting from compounds 16(a), 16 (i).

¹H NMR(600MHz，MeOD)δ7.30(s，1H)，7.08(d，J＝8.0Hz，2H)，6.98(s，1H)，6.79(d，J＝8.1Hz，2H)，5.27(dd，J＝16.1，5.1Hz，2H)，3.99(q，J＝15.3Hz，2H)，3.85(d，J＝11.5Hz，1H)，3.80-3.65(m，4H)，3.46(t，J＝9.3Hz，1H)，1.90(s，2H)，1.80(d，J＝10.7Hz，4H)，1.64(s，2H).

MS(ESI)：515.1[M+Na]⁺

Example 17: (2 'R, 3' R, 4 'S, 5' S, 6 'R) -7-chloro-6- [ (4-trifluoroethoxyphenyl) methyl ] -3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxane-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol

Referring to the procedures for synthesizing compound 3 with respect to compounds 3(a), 3(i) in example 3, compound 17 was synthesized and obtained starting from compounds 16(a), 17 (i).

MS(ESI)：529.1[M+Na]⁺

Examples of Activity test of Compounds of the present invention

Test example 1: inhibition of human SGLT-2 by the compounds of the invention

The compounds of the examples of the invention and the positive control, tolgliflozin (Tofogliflozin), were diluted in DMSO to 20mM stock solutions, with final concentrations tested at 100nM and 10 nM. The positive control, tolgliflozin, was prepared with reference to international patent application WO2006/080421 example 1, with a purity of 98.7%.

50. mu.l/well of 0.2% gelatin was added to a 96-well plate and kept at 37 ℃ until use. NIH3T3-hSGLT2 cells were plated into 96-well plates, 40000/well, 100. mu.l per well. The solution was changed once the next day, and sodium butyrate was added to the medium at a final concentration of 2 mM. KRH-Na + solution 100. mu.l cells were washed 3 times, and 50. mu.l cells were incubated for 30 minutes. After that, the incubation buffer was removed and 50. mu.l of KRH-Na containing the test compound was added⁺Solution and 10. mu.l of uptake buffer (KRH-Na)⁺Addition of methyl-a-D- [ U-¹⁴C]Glucopyranose and 1.67mM methyl-a-D-glucopyranoside) were incubated at 37 ℃ for 1 h; non-specific absorption KRH-acetylcholine solution instead of KRH-Na⁺. Washing with 100 μ l PBS for 3 times, and oven drying; 50 mul of lysate and 150 mul of scintillation fluid are covered with a membrane, pressed flat, shaken and mixed evenly on a shaking instrument and centrifuged for 5min at 4 ℃ and 1200 r. Taken out, Perkin Elmer 1450-. And (6) analyzing results. The inhibition rate of the example compound on the transport activity was calculated. The results are given in table 1 below:

table 1: inhibition of hSGLT2 by each compound at 10nM and 100nM concentrations respectively

As a result: the compound of the embodiment of the invention has better inhibition effect on hSGLT2, and the inhibition rate under the same concentration is better than that of the positive control tongliflozin.

Test example 2: effect of Compounds of the invention on urine glucose excretion from Normal ICR mice

The experimental method comprises the following steps: ICR mice, male, 60, 30-40g (12 weeks old), were randomly assigned to 6 groups of 10 mice per group by body weight. The compound of the present invention was the compound of example 9, 99.00% pure, formulated with 0.5% MC (methyl cellulose) and administered orally at 1mg/kg, 3mg/kg and 10 mg/kg; the positive control, tolgliflozin (prepared according to example 1 of international patent application WO 2006/080421), was 98.7% pure, formulated with 0.5% MC (methyl cellulose) and administered orally at 1mg/kg and 3 mg/kg. The blank control group was dosed orally with 0.5% MC solution, placed in mouse metabolism cages after dosing, the dosing time was recorded, and urine was collected 24 hours after dosing. Urine volume was calculated and urine glucose concentration was measured.

The data are expressed by mean value plus or minus standard deviation, statistical analysis is carried out on the data by Student-t test, and the statistical difference is that p is less than 0.05.

Example 9 Single dosing of 1mg/kg, 3mg/kg and 10mg/kg provided a significant dose-dependent increase in urine glucose concentration, urine volume and urine glucose content in ICR mice over 24 h. The urine volume and urine glucose excretion values of each group are shown in figure 1 and figure 2.

As a result: the compound of the embodiment of the invention can promote the excretion of urine sugar, and the effect of promoting the excretion of urine sugar is stronger than that of the positive control trogliflozin treated by the same dosage.

All documents mentioned herein are incorporated by reference into this application. It should also be noted that various modifications, adaptations, and alternatives may occur to one skilled in the art without departing from the spirit and scope of the present invention after reading the foregoing disclosure of the present application, and such variations should fall within the scope of the present invention as set forth in the appended claims.

Claims (20)

1. A compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof:

in the formula:

x is- (CR)₅R₆)_n-, O, S or N;

R₁、R₂each independently selected from H, -C₁-C₆Alkyl, -O-C₁-C₆Alkyl, halogen, -C₁-C₆Haloalkyl, -S-C₁-C₆Alkyl, -OH, -SH, -NO₂、-CN、-SO-C₁-C₆Alkyl, -SO₂-C₁-C₆Alkyl, -COH, -COOH, -CO-C₁-C₆Alkyl, -CO₂-C₁-C₆Alkyl or-CONH₂；

R₃、R₄Each independently selected from H, -C₁-C₆Alkyl, -O-C₁-C₆Alkyl, -OH, -SH, -NH₂Or halogen;

R₅、R₆each independently selected from H, -C₁-C₆Alkyl, -O-C₁-C₆Alkyl, halogen or-C₁-C₆Haloalkyl, -S-C₁-C₆Alkyl, -OH, -SH or R₅、R₆Together with the carbon atom to which they are attached to form

A ring is represented by R₉A substituted 6-to 10-membered aryl, thienyl, benzofuranyl, or 7-to 10-membered heterocycloalkyl group;

R₉selected from H, -C₁-C₆Alkyl, -O-C₁-C₆Alkyl, halogen, -O-C₃-C₆Cycloalkyl, -O-5-7 membered heterocycloalkyl, -C₁-C₆Haloalkyl, -O-C₁-C₆Haloalkyl, -C₃-C₆Cycloalkyl, -S-C₁-C₆Alkyl, -OH, -SH, - (CR)₇R₈)_n-CO-NR₇R₈、-O-(CR₇R₈)_n-O-C₁-C₆Alkyl, -O- (CR)₇R₈)_n-O-C₃-C₆Cycloalkyl, -NO₂、-CN、-SO-C₁-C₆Alkyl, -SO-C₃-C₆Cycloalkyl, -SO-6-to 10-membered aryl, -SO-5-to 6-membered heteroaryl, -SO₂-C₁-C₆Alkyl, -SO₂-C₃-C₆Cycloalkyl, -SO₂-6 to 10 membered aryl, -SO₂-haloaryl, -COH, -COOH, -CO-C₁-C₆Alkyl, -CO₂-C₁-C₆Alkyl, -CONH₂6-to 10-membered aryl, -NHCO-C₁-C₆Alkyl, -NHSO₂-C₁-C₆Alkyl or by hydrogen, halogen, -OH, -NH₂、-CN、-COH、-COOH、-C₁-C₆Alkyl, -O-C₁-C₆Alkyl-substituted phenyl;

wherein the 5-to 6-membered heteroaryl, 5-to 7-membered heterocycloalkyl, or 7-to 10-membered heterocycloalkyl each comprise 1 to 4 ring heteroatoms independently selected from O, S, N;

R₇、R₈each independently selected from H, -C₁-C₆Alkyl, -O-C₁-C₆Alkyl or halogen;

n is 1, 2 or 3.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, represented by formula (II):

in the formula, X, R₁、R₂、R₃、R₄Ring A is as defined in claim 1.

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein X is- (CR)₅R₆)_n-, wherein R₅、R₆Each independently selected from H, -C₁-C₆Alkyl, -O-C₁-C₆Alkyl, halogen, -OH, -SH, or R₅、R₆Together with the carbon atom to which they are attached to form

n is 1, 2 or 3.

4. A compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein X is- (CH)₂)_n-, the structure of which is represented by the following formula (III):

wherein n is 1, 2 or 3, R₁、R₂、R₃、R₄Ring a is as defined in claim 2.

5. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R is₁、R₂Each independently selected from H, -C₁-C₆Alkyl, -O-C₁-C₆Alkyl or halogen.

6. The compound or pharmaceutically acceptable salt thereof according to claim 5, wherein R is₁、R₂Each independently selected from H, -C₁-C₆Alkyl, -O-C₁-C₆Alkyl or halogen.

7. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R is₃、R₄Each independently selected from H or-C₁-C₆An alkyl group.

8. The compound, or pharmaceutically acceptable salt thereof, according to any one of claims 1-7, wherein ring A is substituted with R₉Substituted 6-to 10-membered aryl, R₉Selected from H, -C₁-C₆Alkyl, aryl, heteroaryl, and heteroaryl,-O-C₁-C₆Alkyl, halogen, -O-C₃-C₆Cycloalkyl, -O-5-7 membered heterocycloalkyl, -C₁-C₆Haloalkyl, -O-C₁-C₆Haloalkyl, -C₃-C₆Cycloalkyl, -S-C₁-C₆Alkyl, -OH, -SH, - (CR)₇R₈)_n-CO-NR₇R₈、-O-(CR₇R₈)_n-O-C₁-C₆Alkyl, -O- (CR)₇R₈)_n-O-C₃-C₆Cycloalkyl, -NO₂、-CN、-SO-C₁-C₆Alkyl, -SO-C₃-C₆Cycloalkyl, -SO-6-10 membered aryl, -SO-5-6 membered heteroaryl, -SO₂-C₁-C₆Alkyl, -SO₂-C₃-C₆Cycloalkyl, -SO₂-6-10 membered aryl, -SO₂-haloaryl, -COH, -COOH, -CO-C₁-C₆Alkyl, -CO₂-C₁-C₆Alkyl, -CONH₂6-10 membered aryl, -NHCO-C₁-C₆Alkyl, -NHSO₂-C₁-C₆Alkyl or by hydrogen, halogen, -OH, -NH₂、-CN、-COH、-COOH、-C₁-C₆Alkyl, -O-C₁-C₆Alkyl-substituted phenyl, R₇、R₈Each independently selected from H, -C₁-C₆Alkyl, -O-C₁-C₆Alkyl or halogen, n is 1, 2 or 3.

9. The compound or pharmaceutically acceptable salt thereof according to claim 8, wherein ring a is substituted with R₉Substituted phenyl radicals, R₉Selected from H, -C₁-C₆Alkyl, -O-C₁-C₆Alkyl, halogen, -O-C₃-C₆Cycloalkyl, -O-5-7 membered heterocycloalkyl, -C₁-C₆Haloalkyl, -O-C₁-C₆Haloalkyl, -C₃-C₆Cycloalkyl, -S-C₁-C₆Alkyl, -OH, -SH, - (CR)₇R₈)_n-CO-NR₇R₈、-O-(CR₇R₈)_n-O-C₁-C₆Alkyl, -O- (CR)₇R₈)_n-O-C₃-C₆Cycloalkyl, -NO₂、-CN、-SO-C₁-C₆Alkyl, -SO-C₃-C₆Cycloalkyl, -SO-6-10 membered aryl, -SO-5-6 membered heteroaryl, -SO₂-C₁-C₆Alkyl, -SO₂-C₃-C₆Cycloalkyl, -SO₂-6-10 membered aryl, -SO₂-haloaryl, -COH, -COOH, -CO-C₁-C₆Alkyl, -CO₂-C₁-C₆Alkyl, -CONH₂6-10 membered aryl, -C₂-C₆Alkenyl, -C₂-C₆Alkynyl, -NHCO-C₁-C₆Alkyl, -NHSO₂-C₁-C₆Alkyl or by hydrogen, halogen, -OH, -NH₂、-CN、-COH、-COOH、-C₁-C₆Alkyl, -O-C₁-C₆Alkyl-substituted phenyl, R₇、R₈Each independently selected from H, -C₁-C₆Alkyl, -O-C₁-C₆Alkyl or halogen, n is 1, 2 or 3.

10. The compound or pharmaceutically acceptable salt thereof according to claim 9, wherein ring a is substituted with R₉Substituted phenyl radicals, R₉Selected from H, -C₁-C₆Alkyl, -O-C₁-C₆Alkyl, halogen, -O-C₃-C₆Cycloalkyl, -O-5-7 membered heterocycloalkyl, -C₁-C₆Haloalkyl, -O-C₁-C₆Haloalkyl, -C₃-C₆Cycloalkyl, -S-C₁-C₆Alkyl, -OH, -SH, -O- (CR)₇R₈)_n-O-C₁-C₆Alkyl, -O- (CR)₇R₈)_n-O-C₃-C₆Cycloalkyl, -NO₂、-CN，R₇、R₈Each independently selected from H, -C₁-C₆Alkyl or halogen, n is 1 or 2.

11. The compound or pharmaceutically acceptable salt thereof according to claim 10, wherein ring a is substituted with R₉Substituted phenyl radicals, R₉Selected from H, -C₁-C₆Alkyl, -O-C₁-C₆Alkyl, halogen, -O-C₃-C₆Cycloalkyl, -O-5-7 membered heterocycloalkyl, -C₁-C₆Haloalkyl, -O-C₁-C₆Haloalkyl or-C₃-C₆A cycloalkyl group.

12. The compound, or pharmaceutically acceptable salt thereof, according to any one of claims 1-7, wherein ring A is substituted with R₉Substituted thienyl or benzofuranyl, R₉Selected from H, -C₁-C₆Alkyl, -O-C₁-C₆Alkyl, halogen, -O-C₃-C₆Cycloalkyl, -O-5-7 membered heterocycloalkyl, -C₁-C₆Haloalkyl, -O-C₁-C₆Haloalkyl, -C₃-C₆Cycloalkyl, -S-C₁-C₆Alkyl, -OH, -SH, -NO₂、-CN、-COH、-COOH、-CO-C₁-C₆Alkyl, -CO₂-C₁-C₆Alkyl, -CONH₂Or by hydrogen, halogen, -OH, -NH₂、-CN、-COH、-COOH、-C₁-C₆Alkyl, -O-C₁-C₆Alkyl-substituted phenyl.

13. The compound or pharmaceutically acceptable salt thereof according to claim 12, wherein ring a is substituted with R₉Substituted thienyl or benzofuranyl, R₉Selected from H, -C₁-C₆Alkyl, -O-C₁-C₆Alkyl, halogen, or by hydrogen, halogen, -OH, -NH₂、-CN、-C₁-C₆Alkyl, -O-C₁-C₆Alkyl-substituted phenyl.

14. The compound, or pharmaceutically acceptable salt thereof, according to any one of claims 1-7, wherein ring A is substituted with R₉Substituted 7-to 10-membered heterocycloalkyl, R₉Selected from H, -C₁-C₆Alkyl, -O-C₁-C₆Alkyl or halogen.

15. The compound or pharmaceutically acceptable salt thereof according to claim 14, wherein ring a is substituted with R₉Substituted 2, 3-dihydrobenzofuranyl, 2, 3-dihydro-1, 4-benzodioxanyl, 1, 3-benzodioxopentanyl or 1, 4-benzodioxanyl, wherein R₉Selected from H, -C₁-C₆Alkyl or halogen.

16. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

(2 'R, 3' R, 4 'S, 5' S, 6 'R) -7-methyl-6- [ (5- (4-fluorobenzene) thiophen-2-yl) methyl ] -3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxane-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol;

(2 'R, 3' R, 4 'S, 5' S, 6 'R) -7-chloro-6- [ (2, 3-dihydrobenzofuran-5-yl) methyl ] -3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxane-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol;

(2 'R, 3' R, 4 'S, 5' S, 6 'R) -6-benzyl-3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxan-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol;

(2 'R, 3' R, 4 'S, 5' S, 6 'R) -7-methyl-6- [ (4-isopropylphenyl) methyl ] -3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxane-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol;

(2 'R, 3' R, 4 'S, 5' S, 6 'R) -7-chloro-6- [ (4-ethylphenyl) methyl ] -3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxan 4(2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol;

(2 'R, 3' R, 4 'S, 5' S, 6 'R) -7-chloro-6- [ (4-isopropylphenyl) methyl ] -3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxane-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol;

(2 'R, 3' R, 4 'S, 5' S, 6 'R) -7-chloro-6- [ (4-fluoro-phenyl) methyl ] -3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxan-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol;

(2 'R, 3' R, 4 'S, 5' S, 6 'R) -6- [ (4-isopropylphenyl) methyl ] -3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxane-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol;

(2 'R, 3' R, 4 'S, 5' S, 6 'R) -7-methyl-6- [ (4-ethoxyphenyl) methyl ] -3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxane-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol;

(2 'R, 3' R, 4 'S, 5' S, 6 'R) -7-chloro-6- [ (4-ethoxyphenyl) methyl ] -3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxane-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol;

(2 'R, 3' R, 4 'S, 5' S, 6 'R) -7-methyl-6- [ (4- (S) -tetrahydrofuran-3-oxy) methyl ] -3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxane-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol;

(2 'R, 3' R, 4 'S, 5' S, 6 'R) -6- [ (4-ethoxyphenyl) methyl ] -3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxane-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol;

(2 'R, 3' R, 4 'S, 5' S, 6 'R) -6- [ (4-ethylphenyl) methyl ] -3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxane-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol;

(2 'R, 3' R, 4 'S, 5' S, 6 'R) -6- [ (4-fluoro-phenyl) methyl ] -3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxane-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol;

(2 'R, 3' R, 4 'S, 5' S, 6 'R) -6- [ (4-chloro-phenyl) methyl ] -3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxane-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol;

(2 'R, 3' R, 4 'S, 5' S, 6 'R) -7-chloro-6- [ (4-cyclopentyloxyphenyl) methyl ] -3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxane-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol;

(2 'R, 3' R, 4 'S, 5' S, 6 'R) -7-chloro-6- [ (4-trifluoroethoxyphenyl) methyl ] -3', 4 ', 5', 6 '-tetrahydro-6' - (hydroxymethyl) -spiro [ (1, 3) benzodioxan-4 (2H), 2 '(2H) -pyran ] -3', 4 ', 5' -triol.

17. A process for preparing a compound of formula (II) as defined in claim 2, comprising the steps of:

in the formula, R₁、R₂、R₃、R₄Ring X, A is as defined in claim 2; p is trityl, tert-butyldimethylsilyl or tetrahydropyranyl;

demethylating the compound of formula (IV) in the presence of a basic nucleophile or a Lewis acid to obtain a compound (V); carrying out hydroxyl protection on the compound (V) to obtain a compound (VI); treating compound (VI) with a suitable alkyllithium and reacting with compound (VII) to give compound (VIII); followed by reacting it with compound (IX) in the presence of a suitable acid, thereby obtaining compound (X); the compound of formula (II) is obtained by catalytic hydrogenation in the presence of a palladium catalyst or debenzylation of compound (X) in the presence of a Lewis acid.

18. A process for the preparation of a compound of formula (III) according to claim 4, comprising the steps of:

in the formula, R₁、R₂、R₃、R₄Ring A is as defined in claim 2, n is 1, 2 or 3; p is trityl, tert-butyldimethylsilyl or tetrahydropyranyl; p₁Is acetyl or tert-butyldimethylsilyl;

diazotizing the compound (XI) and hydrolyzing to obtain a compound (XII); protecting hydroxyl of the compound (XII) to obtain a compound (XIII); treating compound (XIII) with an appropriate alkyllithium and reacting with compound (VII) to give compound (XIV); reacting compound (XIV) with compound (IX) in the presence of a suitable acid, thereby obtaining compound (XV); obtaining compound (XVI) by contact hydrogenation in the presence of a palladium catalyst or debenzylation of compound (XV) in the presence of a lewis acid; protecting the hydroxyl group of the compound (XVI) to obtain a compound (XVII); brominating compound (XVII) with an appropriate brominating agent to give compound (XVIII); when compound (XX) is

When the compound (XX) is a compound (XVIII), the coupling reaction is carried out in the presence of a suitable palladium catalyst

Then, the compound (XVIII) is subjected to coupling reaction with the compound (XVIII) in the presence or absence of copper chloride to obtain a compound (XVIII); dehydroxylation protection to give the compound of formula (III).

19. A pharmaceutical composition comprising a compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

20. The use of a compound according to any one of claims 1 to 16 for the preparation of a medicament for the treatment of diabetes, hyperglycemia, and diabetic complications or obesity caused thereby.

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