Aryl glucoside derivatives and their use in medicine - Patents.com

Abstract

Compounds and pharmaceutically acceptable salts and stereoisomers thereof that inhibit sodium-glucose cotransporter 1 are disclosed. The compounds are used in pharmaceutical compositions. Methods for preparing and using the pharmaceutical compositions are also disclosed, as well as applications of the compounds in preparing drugs and compositions for treating and ameliorating diabetes, cardiovascular disease, weight loss, fatty liver, constipation, and metabolic-related diseases, as well as for cancer therapy.

Description

[Technical field]

[0001] The present invention relates to methods for the synthesis of sodium-dependent glucose transporter 1 (SGLT1) inhibitors, medicaments containing the compositions, and their use in the treatment of metabolic diseases, particularly type 2 diabetes. [Background technology]

[0002] Diabetes is a group of metabolic diseases characterized by hyperglycemia. Hyperglycemia is caused by defective insulin secretion, abnormal biological actions, or both. Long-term hyperglycemia in diabetes causes chronic damage and dysfunction of various tissues, especially eyes, kidneys, heart, blood vessels, and nerves. In 2012, the World Health Organization reported that the incidence of diabetes in adults aged 18 years and older exceeded 9%. With population growth, aging, and longer life spans, the incidence of diabetes will increase. The incidence of diabetes is higher in obese people. Diabetes is expected to become the seventh leading cause of death by 2030.

[0003] Sodium-dependent glucose transporter (SGLT) inhibitors can inhibit the reabsorption of glucose by the kidney, allowing excess glucose to be excreted through urine, lowering blood glucose. This provides a new approach for the treatment of diabetes and becomes a hotspot in the research of hypoglycemic drugs. Over the past few decades, new targeted drugs have been developed for the treatment of diabetes. In recent years, SGLT2 inhibitors, which remain on the market, have provided a new strategy for controlling blood glucose. The molecular structure of the drug, which remains on the market, is as follows:

[0004] [ka]

[0005] The SGLT family consists of several subtypes that play a role in transporting carbohydrates across cell membranes, during which they bind to sodium ion transporters.SGLT1 is mainly expressed in the digestive tract and is mainly responsible for the absorption of glucose and galactose in the small intestine.SGLT1 is also present in the proximal straight tubule of the kidney, where it contributes to the reabsorption of blood glucose.By inhibiting SGLT1, it is possible to prevent blood glucose from being absorbed and returned to the blood for use, thus achieving the goal of lowering blood glucose levels.

[0006] SGLT1 inhibition may also provide an alternative therapy for glycemic control, which is attractive because the improvement of glycemic control by SGLT1 inhibition can be independent of renal function. Current SGLT2 selective inhibitors are ineffective in patients with moderate to severe renal impairment, which accounts for approximately 30-40% of all diabetic patients. Inhibition of intestinal SGLT1 has potential efficacy in glycemic control. Through this action, it is also possible to avoid the diabetes-related side effects of SGLT2 inhibitors, especially genital infections. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Reference Journal of Medicinal Chemistry 2017, 60, 710~721 [Non-Patent Document 2] Journal of the American Chemical Society(2014), 136(20), 7205~7208 [Non-Patent Document 3] Chemistry-A European Journal(2011), 17(12), 3326~3331, S3326 / 1-S3326 / 21 [Non-Patent Document 4] Journal of Fluorescence(2013), 23(1), 181~186 [Non-Patent Document 5] Journal of Organic Chemistry(2011), 76(12), 4964~4972 [Non-Patent Document 6] Angewandte Chemie, International Edition(2019), 58(21), 6987~6992 [Non-Patent Document 7] Chemische Berichte(1985), 118(4), 1564~1574 [Non-Patent Document 8] Science of Synthesis(2010), 41, 543~612 [Non-Patent Document 9] Nature (London, United Kingdom) (2019), 574(7776), 86–89 [Non-Patent Document 10] 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 [Non-Patent Document 11] Acta Pharmaceutica Sinica 2017, 52(6):897~903 [Non-Patent Document 12] Nature Protocols (2007), 2(3), 753~762 [Non-Patent Document 13] Journal of Biochemical and Biophysical Methods (2005), 64(3), 207~215 [Non-Patent Document 14] Diabetes Technology & Therapeutics (2011), 13(7), 743~775 Summary of the Invention [Problem to be solved by the invention]

[0008] Despite recent progress in the development of intestinal SGLT1 inhibitors, there is still a need to develop new compounds with better efficacy. Through continuous efforts, the present invention designs a compound having the structure of general formula (V), and finds that the compound having such structure shows excellent effect and function, and to a greater extent, the relationship between structure and activity efficacy is more deeply and comprehensively revealed and elucidated, which has important application value. [Means for solving the problem]

[0009] The present invention relates to a compound of formula (V), its stereoisomers, tautomers or pharma- ceutically acceptable salts

[0010] [ka]

[0011] wherein U, V, W and Q are each independently selected from a nitrogen atom or CH; R 1a , R 1b , R 1c is halogen or -OR 1A , -NHR 1A where each R 1A are independently hydrogen, C1-C6 alkyl or acyl; R2 is -S(O) m -R 1A is selected from R3, R4, R5, R 6a , R 7a , R 6b , R 7b each is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, or acyl; R A , R Bis hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxyl, cyano, oxo, C2-C8 alkenyl, C2-C8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) n1 R aa , -(CH2) n1 OR aa , -SR aa , -(CH2) n1 C(O)R aa , -SR aa , -C(O)OR aa , -C(O)R aa , -S(O) m1 R aa , -(CH2) n1 S(O) m1 R aa , -NR aa R bb , -C(O)NR aa R bb , -NR aa C(O)R bb , -NR aa S(O) m1 R bb are each independently selected from Alternatively, R A , R B together with the nitrogen atom to which they are attached form a 3- to 8-membered heterocycle, which may contain one or more carbon, nitrogen, oxygen or sulfur atoms and which may be further substituted by halogen, alkyl, cycloalkyl, aryl, alkoxy, alkenyl, alkynyl or oxo; R aa , R bbare each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, deuterated alkenyl, deuterated alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, deuterated alkenyl, deuterated alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, deuterated alkenyl, deuterated alkynyl, cycloalkyl, heterocyclyl, Tetrocyclyl, aryl and heteroaryl are optionally further substituted by one or more substituents selected from hydrogen, deuterium, silyl, alkylsilyl, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; Z is selected from an oxygen atom and a sulfur atom; n1=0, 1, 2, 3, 4, m1=0, 1, 2, 3, 4, m=0, 1, 2, q=0, 1, 2, 3, X is selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C8 alkenyl, and C2-C8 alkynyl; Y has the following structure:

[0012] [ka]

[0013] {where, R E , R F , R G , R H are each independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, or acyl; E and J are selected from a chemical bond, -CH2-, oxygen, and -NH-; s1=0, 1, 2, 3, 4, 5, s2=0, 1, 2, 3, 4, 5, s3=0, 1, 2, 3, 4, 5} is a linking group selected from to provide.

[0014] The present invention relates to a compound of formula (VA), its stereoisomers, tautomers or pharma- ceutically acceptable salts

[0015] [ka]

[0016] [In the formula, R 1a , R 1b , R 1c is halogen or -OR 1A , -NHR 1A are each independently selected from 1A are independently hydrogen, C1-C6 alkyl or acyl; R2 is -S(O) m -R 1A is selected from R3, R4, R5, R 6b , R 7b each is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, or acyl; R A , R B is hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxyl, cyano, oxo, C2-C8 alkenyl, C2-C8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) n1 R aa , -(CH2) n1 OR aa , -SR aa , -(CH2) n1 C(O)R aa , -SR aa, -C(O)OR aa , -C(O)R aa , -S(O) m1 R aa , -(CH2) n1 S(O) m1 R aa , -NR aa R bb , -C(O)NR aa R bb , -NR aa C(O)R bb , -NR aa S(O) m1 R bb are each independently selected from Alternatively, R A , R B together with the nitrogen atom to which they are attached form a 3- to 8-membered heterocycle, which may contain one or more carbon, nitrogen, oxygen or sulfur atoms and which may be further substituted by halogen, alkyl, cycloalkyl, aryl, alkoxy, alkenyl, alkynyl or oxo; R aa , R bbare each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, deuterated alkenyl, deuterated alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, deuterated alkenyl, deuterated alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, deuterated alkenyl, deuterated alkynyl, cycloalkyl, heterocyclyl, Tetrocyclyl, aryl and heteroaryl are optionally further substituted by one or more substituents selected from hydrogen, deuterium, silyl, alkylsilyl, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; n1=0, 1, 2, 3, 4, m1=0, 1, 2, 3, 4, m=0, 1, 2, q=0, 1, 2, 3, X is selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, and C2-C6 alkynyl; Y has the following structure:

[0017] [ka]

[0018] {where, R E , R F , R G , R H are each independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, or acyl; E and J are selected from a chemical bond, -CH2-, oxygen, and -NH-; s1=0, 1, 2, 3, 4, 5, s2=0, 1, 2, 3, 4, 5, s3=0, 1, 2, 3, 4, 5} is a linking group selected from to provide.

[0019] The present invention relates to a compound of formula (VA-1), its stereoisomer, tautomer or pharma- ceutically acceptable salt.

[0020] [ka]

[0021] [Wherein, X is selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, and C2-C6 alkynyl; R5, R 6b , R 7b are each independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, or acyl; R A , R B is hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxyl, cyano, oxo, C2-C8 alkenyl, C2-C8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) n1 R aa , -(CH2) n1 OR aa , -SR aa , -(CH2) n1 C(O)R aa , -SR aa , -C(O)OR aa , -C(O)R aa、 -S(O) m1 R aa , -(CH2) n1 S(O) m1 R aa , -NR aa R bb , -C(O)NR aa R bb, -NR aa C(O)R bb , -NR aa S(O) m1 R bb are each independently selected from R aa , R bb are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, deuterated alkenyl, deuterated alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, deuterated alkenyl, deuterated alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, deuterated alkenyl, deuterated alkynyl, cycloalkyl, heterocyclyl, Tetrocyclyl, aryl and heteroaryl are optionally further substituted by one or more substituents selected from hydrogen, deuterium, silyl, alkylsilyl, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; n1=0, 1, 2, 3, 4, m1=0, 1, 2, 3, 4, q=0, 1, 2, 3, Y has the following structure:

[0022] [ka]

[0023] is a linking group selected from to provide.

[0024] The present invention relates to the following compounds, their stereoisomers, tautomers or pharma- ceutically acceptable salts:

[0025] [ka]

[0026] [ka]

[0027] to provide.

[0028] The present invention relates to a compound of formula (VA-2), its stereoisomer, tautomer or pharma- ceutically acceptable salt.

[0029] [ka]

[0030] [Wherein, X is selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, and C2-C6 alkynyl; R5, R 6b , R 7b each is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, or acyl; q=0, 1, 2, 3, Ring B has the following structure:

[0031] [ka]

[0032] having Y has the following structure:

[0033] [ka]

[0034] is a linking group selected from to provide.

[0035] The present invention relates to the following compounds, their stereoisomers, tautomers or pharma- ceutically acceptable salts:

[0036] [ka]

[0037] [ka]

[0038] to provide.

[0039] The present invention relates to a compound of formula (I), its stereoisomers, tautomers or pharma- ceutically acceptable salts

[0040] [ka]

[0041] [In the formula, R1 is F or -OR 1A , -NHR 1A where R 1A are independently hydrogen, C1-C6 alkyl or acyl; R2 is -S(O) m -R 1A where m=0, 1, 2; Each of R3, R4, R5, R6, R7, R8, and R9 is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, or acyl; m2=0, 1, 2, 3, n2=0, 1, 2, 3, X is selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, and C2-C6 alkynyl; Y is a linking group, which is a linking arm consisting of 2 to 17 carbon, oxygen and nitrogen atoms; Z is O, S or hydrogen. to provide.

[0042] The present invention relates to a compound of formula (I-1), its stereoisomer, tautomer or pharma- ceutically acceptable salt.

[0043] [ka]

[0044] [In the formula, R 1a , R 1b , R 1c F or -OR 1A , -NHR 1A are each independently selected from 1A are independently hydrogen, C1-C6 alkyl or acyl; R2 is -S(O) m -R 1A where m=0, 1, 2; Each of R3, R4, R5, R6, R7, R8, and R9 is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, cycloalkyl, cycloalkylalkyl, acyl, and alkynylalkyl; m2=0, 1, 2, 3, n2=0, 1, 2, 3, X is selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, and C2-C6 alkynyl; Y1 has the following structure:

[0045] [ka]

[0046] {where, R E , R F , R G , R H are each independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, or acyl; E and J are selected from a chemical bond, -CH2-, oxygen, and -NH-; s1=0, 1, 2, 3, 4, 5, s2=0, 1, 2, 3, 4, 5, s3=0, 1, 2, 3, 4, 5} is a linking group selected from to provide.

[0047] The present invention relates to compounds of formula (I), including compounds of the following structure of general formula (II), their stereoisomers, tautomers or pharma- ceutically acceptable salts:

[0048] [ka]

[0049] [Wherein, X is selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, and C2-C6 alkynyl; R8 and R9 are selected from hydrogen, deuterium, halogen, C1-C6 alkyl or acyl groups; m2=0, 1, 2, 3, n2=1, Y is a linking group, which is a linking arm consisting of 2 to 17 carbon, oxygen and nitrogen atoms. to provide.

[0050] The present invention relates to compounds of formula (I), including compounds of the following general structure (II-1), their stereoisomers, tautomers or pharma- ceutically acceptable salts:

[0051] [ka]

[0052] [Wherein, X is selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, and C2-C6 alkynyl; R8 and R9 are each independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, cycloalkyl, cycloalkylalkyl, acyl, and alkynylalkyl; m2=0, 1, 2, 3, n2=1, Y1 has the following structure:

[0053] [ka]

[0054] {where, R E , R F , R G , R H are each independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, or acyl; E and J are selected from a chemical bond, -CH2-, oxygen, and -NH-; s1=0, 1, 2, 3, 4, 5, s2=0, 1, 2, 3, 4, 5, s3=0, 1, 2, 3, 4, 5} is a linking group selected from to provide.

[0055] The present invention relates to compounds of formula (II), including compounds of the following structure of general formula (III), their stereoisomers, tautomers or pharma- ceutically acceptable salts:

[0056] [ka]

[0057] [Wherein, X is selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, and C2-C6 alkynyl; R8 and R9 are each independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, or acyl; m2=0, 1, 2, 3, n2=1, Y1 has the following structure:

[0058] [ka]

[0059] is a linking group selected from to provide.

[0060] The present invention provides compounds of formula (III) wherein X is selected from hydrogen, deuterium, fluoro, bromo, iodo, methyl, ethyl, vinyl and ethynyl.

[0061] The present invention provides compounds of formula (III) wherein R9 is selected from hydrogen, deuterium, fluoro, bromo, iodo, methyl, ethyl, C3-C8 cycloalkyl, vinyl and ethynyl.

[0062] The present invention relates to the following compounds, their stereoisomers, tautomers or pharma- ceutically acceptable salts:

[0063] [ka]

[0064] [ka]

[0065] [ka]

[0066] [ka]

[0067] to provide.

[0068] The present invention provides a pharmaceutical composition comprising a therapeutically effective dose of any one of the compounds of the present invention, or a stereoisomer, tautomer, or pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0069] Any of the compounds described in this invention or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition according to the invention are used in the treatment and amelioration of diabetes, cardiovascular and cerebrovascular diseases, weight loss, fatty liver, metabolic related diseases and in the treatment of tumors.

[0070] Any of the compounds described in this invention or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition according to the invention are used as SGLT1 / SGLT2 inhibitors in the preparation of a medicament or pharmaceutical composition for the treatment of diseases related to SGLT1 / SGLT2 function.

[0071] Use of the present invention where the patient has taken or is currently taking other therapeutic agents including antihypertensives, lipid lowering agents, antidiabetic agents, hypoglycemic agents, weight loss agents or appetite suppressants. [Brief description of the drawings]

[0072] [Figure 1] FIG. 1 shows the results of oral glucose tolerance test (OGTT) in rats after 14 days of continuous administration. [Diagram 2] FIG. 1 shows the results of an oral glucose tolerance test (OGTT) on the sixth day after five consecutive days of administration in mice. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0073] As used above and elsewhere in this specification, the following terms and abbreviations have the meanings defined below. Unless defined, all technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art.

[0074] The term "hydrogen" as used herein refers to -H.

[0075] The term "halogen" as used herein refers to -F, -Cl, -Br and -I.

[0076] The term "fluoro" as used herein refers to --F.

[0077] The term "chloro" as used herein refers to --Cl.

[0078] The term "bromo" as used herein refers to --Br.

[0079] The term "iodo" as used herein refers to -I.

[0080] The term "cyano" as used herein refers to --CN.

[0081] The term "amino" as used herein refers to --NH.sub.2.

[0082] The term "hydroxyl" as used herein refers to --OH.

[0083] The term "nitro" as used herein refers to --NO.

[0084] The term "carboxy" as used herein refers to -COOH.

[0085] The term "nitroso" as used herein refers to --NO.

[0086] The term "linking arm" as used herein refers to a chemical structure having a linking function composed of 2 to 17 carbon atoms, oxygen atoms, and nitrogen atoms. Specifically, it refers to an alkane structure (including saturated alkanes, alkenes, and alkynes) with a straight or branched chain structure, or a similar alkane structure with a carbonyl group at one end, where any carbon atom may be replaced by an oxygen atom, a nitrogen atom, and may be further substituted by a substituent group, where the substituent group includes fluoro, chloro, bromo, iodo, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, acylamino, ester group, amide, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkynyl, and cycloalkoxy, provided that a stable chemical structure is formed. The "linking arm" described herein has the following chemical structure:

[0087] [ka]

[0088] Including but not limited to:

[0089] The term "aryl" as used herein refers to a 6- to 10-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms), polycyclic (i.e., rings having adjacent pairs of carbon atoms) group having a conjugated pi-electron system. The aryl group may be covalently linked to the defined chemical structure at any carbon atom, which results in a stable structure. The aryl groups described herein may be optionally substituted with one or more of the following substituents: fluoro, chloro, bromo, iodo, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, acylamino, ester groups, amido, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkynyl, and cycloalkoxy.

[0090] The term "heteroaryl" as used herein refers to an aromatic group consisting of 5 to 10 atoms and containing at least one heteroatom selected from N, O, or S. This term may be a single ring (non-limiting examples include furan, thiophene, imidazole, pyrazole, pyridine, pyrazine, oxazole, thiazole, etc.) or multiple condensed rings (non-limiting examples include benzothiophene, benzofuran, indole, isoindole, etc.), where the condensed rings may or may not be aromatic groups containing heteroatoms, provided that the point of attachment is through an atom of the aromatic heteroaryl group. Heteroaryls as described herein may be optionally substituted with one or more of the following substituents: fluoro, chloro, bromo, iodo, cyano, nitro, hydroxy, amino, alkyl, alkoxy, acyl, acyloxy, acylamino, ester groups, amide, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkynyl, and cycloalkoxy.

[0091] The term "cycloalkyl" as used herein refers to cyclic alkyl groups having from 3 to 10 carbon atoms having monocyclic or polycyclic rings (including fused, bridged, and spiro ring systems). Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. Cycloalkyl groups described herein can be optionally substituted with one or more of the following substituents: fluoro, chloro, bromo, iodo, cyano, nitro, hydroxy, carboxy, amino, alkyl, oxo, alkoxy, acyl, acyloxy, acylamino ester groups, amido, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkenyloxy, alkynyl, cycloalkoxy, aryl, or heteroaryl.

[0092] The term "heterocyclyl" refers to a substituted or unsubstituted, saturated or unsaturated aromatic or non-aromatic ring containing at least 1 to 5 heteroatoms selected from N, O or S, which may be a 3- to 10-membered monocyclic ring, a 4- to 20-membered spiro, bicyclic or bridged ring, and the optionally substituted N, S in the heterocyclyl ring may be oxidized to various oxidation states. 3- to 12-membered heterocycles are preferred. Non-limiting examples include oxiranyl, oxetanyl, oxolanyl, oxanyl, oxanyl, oxocanyl, aziridinyl, azetidinyl, azolidinyl, azacyclohexyl, azacyclopropenyl, 1,3-dioxocyclopentyl, 1,4-dioxocyclopentyl, 1,3-dioxocyclopentyl, 1,3-dioxacyclohexyl, 1,3-dithiocyclohexyl, azacycloheptenyl, morpholinyl, piperazinyl, pyridyl, furyl, thienyl, pyrrolyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, thiomorpholinyl, dihydropyranyl, thiadiazolyl, oxazolyl, oxadiazolyl, pyrazolyl, 1,4-dioxacyclohexadienyl, and the like.

[0093] The term "heterocycloalkyl" refers to a non-aromatic cycloalkyl group containing at least one heteroatom selected from O, N, and S, and optionally containing one or more double or triple bonds. A heterocycloalkyl group may have 3 to 10 ring atoms in total. A heterocycloalkyl group may be covalently linked to the defined chemical structure at any heteroatom or carbon atom, which results in a stable structure. Non-limiting examples of heterocycloalkyl groups include pyrrolinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, pyranyl, and the like. One or more N or S atoms in a heterocycloalkyl group may be oxidized (morpholine N-oxide, thiomorpholine S-oxide, thiomorpholine S,S-dioxide, and the like). Heterocycloalkyl groups may contain one or more oxo groups, such as phthalimido, piperidinone, oxazolidinone, 2,4(1H,3H)-dioxo-pyrimidinyl, pyridine-2(1H)-keto groups, etc. Heterocycloalkyl groups described herein may be optionally substituted with one or more of the following substituents: fluoro, chloro, bromo, iodo, cyano, nitro, hydroxy, carboxy, amino, alkyl, alkoxy, oxo, acyl, acyloxy, acylamino, ester groups, amido, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkenyloxy, alkynyl, cycloalkoxy, aryl, or heteroaryl.

[0094] The term "alkenyl" as used herein refers to an alkenyl group having 2 to 8 carbon atoms and at least one site of alkenyl unsaturation. Non-limiting examples of alkenyl groups include ethenyl, propenyl, allyl, isopropenyl, butenyl, isobutenyl, and the like. The alkenyl groups described herein can be optionally substituted with one or more of the following substituents: deuterium, fluoro, chloro, bromo, iodo, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxyl, acyl, acylamino, ester groups, amido, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, cycloalkoxy, mercapto, alkylmercapto, deuterated alkylmercapto, sulfonyl, sulfoxide groups, amino, silyl, phosphonyl, deuterated alkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, alkenyl, arylalkyl, ester groups.

[0095] The term "alkynyl" as used herein refers to an alkyl group in which two adjacent carbon atoms are joined by a triple bond, where alkyl is as defined herein. Alkynyl refers to an unsaturated alkyl group as defined above, composed of at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl. An alkynyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from deuterium, fluoro, chloro, bromo, iodo, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxyl, acyl, acylamino, ester groups, amido, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, cycloalkoxy, mercapto, alkylmercapto, deuterated alkylmercapto, sulfonyl, sulfoxide groups, amino, silyl, phosphonyl, deuterated alkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, alkenyl, arylalkyl, and ester groups.

[0096] The term "alkyl" as used herein refers to saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms, the term including both straight and branched chain hydrocarbyl groups. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, and the like. The alkyl groups described herein may be optionally substituted with one or more of the following substituents: fluoro, chloro, bromo, iodo, cyano, nitro, hydroxy, carboxyl, amino, alkyl, alkoxy, acyl, acyloxy, oxo, acylamino, ester groups, amido, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkenyloxy, alkynyl, cycloalkoxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aryl, or heteroaryl.

[0097] The term "heteroalkyl," as used herein, refers to an alkyl group that includes at least one heteroatom.

[0098] The term "alkoxy" as used herein refers to an alkyl group attached to the remainder of the molecule via an oxygen atom (-O-alkyl), where alkyl is as defined herein. Non-limiting examples of alkoxy groups include methoxy, ethoxy, trifluoromethoxy, difluoromethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, n-pentyloxy, and the like.

[0099] The term "acylamino" as used herein refers to -NR 8 -C(O)-alkyl, -NR 8 -C(O)-cycloalkyl, -NR 8 -C(O)-cycloalkenyl, -NR 8 -C(O)-aryl, -NR 8 -C(O)-heteroaryl and -NR 8 -C(O)-heterocycloalkyl, where R8 is hydrogen, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycloalkyl, and alkyl, where groups such as hydrogen, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycloalkyl, and alkyl are as defined herein.

[0100] The term "acyl" as used herein refers to HC(O)-, R 9 R 10 NC(O)-, alkyl-C(O)-, cycloalkyl-C(O)-, cycloalkenyl-C(O)-, heterocycloalkyl-C(O)-, aryl-C(O)-, and heteroaryl-C(O)-, where R 9 and R 10 are each independently selected from hydrogen, hydroxyl, alkyl, heterocycloalkyl, aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl, acyl, or cycloalkyl, where groups such as hydrogen, hydroxyl, alkyl, heterocycloalkyl, aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl, acyl, and cycloalkyl are as defined herein.

[0101] The term "oxo" refers to a description of the oxidation state of a carbon atom, a nitrogen atom, a sulfur atom, etc., with an oxygen atom, and representative structures formed after oxidation of a carbon atom, a nitrogen atom, a sulfur atom, etc., with an oxygen atom include, but are not limited to, functional groups such as hydroxyl, alkoxy, carbonyl, oxynitride, sulfoxide, and sulfone.

[0102] The term "sulfonyl" is used herein to refer to 11 R 12 NS(O)-, cycloalkyl-S(O)-, cycloalkenyl-S(O)-, aryl-S(O)-, heteroaryl-S(O)-, heterocycloalkyl-S(O)-, and alkyl-S(O)-, where R 11 and R 12are each independently selected from hydrogen, hydroxyl, alkyl, heterocycloalkyl, aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl, acyl, or cycloalkyl, where groups such as hydrogen, hydroxyl, alkyl, heterocycloalkyl, aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl, acyl, and cycloalkyl are as defined herein.

[0103] The term "sulfinyl" is used herein as defined by R 13 R 14 NS(O)-, cycloalkyl-S(O)-, cycloalkenyl-S(O)-, aryl-S(O)-, heteroaryl-S(O)-, heterocycloalkyl-S(O)- or alkyl-S(O)-, where R 13 and R 14 are each independently selected from hydrogen, hydroxyl, alkyl, heterocycloalkyl, aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl, acyl, or cycloalkyl, where groups such as hydrogen, hydroxyl, alkyl, heterocycloalkyl, aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl, acyl, and cycloalkyl are as defined herein.

[0104] The term "acyloxy," as used herein, refers to -OC(O)-alkyl, -OC(O)-cycloalkyl, -OC(O)-cycloalkenyl, -OC(O)-aryl, -OC(O)-heteroaryl, and -OC(O)-heterocycloalkyl, where groups such as alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocycloalkyl are as defined herein.

[0105] The term "ester group," as used herein, refers to alkyl-OC(O)-, cycloalkyl-OC(O)-, cycloalkenyl-OC(O)-, heterocycloalkyl-OC(O)-, aryl-OC(O)-, and heteroaryl-OC(O)-, where alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, and heteroaryl are as defined herein.

[0106] The terms "optionally" or "optionally" mean that the event or circumstance described thereafter may occur, but will not necessarily occur, and the description includes instances where the event or circumstance does and does not occur.

[0107] The term "optionally substituted with..." means that the structure is unsubstituted or substituted with one or more substituents described in this invention. The term "substituted" as used herein means single or multiple substitution of any group with the specified substituents, provided that such single or multiple substitutions (including multiple substitutions on the same moiety) are chemically permissible, where each substituent may be located at any available position in the group and may be attached via any available atom in the substituent. "Any available position" refers to any position in the group that is chemically accessible by methods known in the art or as taught herein, and does not create a molecule that is overly unstable. When there are two or more substituents in any group, each substituent is defined independently of any other substituent, and thus may be the same or different.

[0108] At various places in the present specification, substituents of compounds of the invention are disclosed in the form of groups or ranges. This specifically means that the invention includes each and every member of such groups or ranges, or each subgroup of members. 1~6By "alkyl" it is specifically meant that methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl are separately disclosed.

[0109] The term "compound of the invention" refers herein (unless otherwise specifically indicated) to the compounds of formula (I) and formula (II) and all pure and mixed stereoisomers, geometric isomers, tautomers, solvates, prodrugs and isotopically labeled compounds and any pharma- ceutically acceptable salts thereof. Solvates of the compounds of the invention refer to the compounds or their salts combined with stoichiometric and non-stoichiometric solvents, such as hydrates, ethylates, methylates, acetonates, etc. The compounds may exist in one or more crystalline states, i.e., as co-crystals, polymorphs, or as amorphous solids. All such forms are encompassed by the claims.

[0110] The term "pharmacologically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients that make up the formulation and / or with the mammal being treated therewith.

[0111] The term "stereoisomer," as used herein, refers to compounds with different chiral properties, having one or more stereocenters, including enantiomers and diastereomers.

[0112] The term "tautomers" as used herein refers to structural isomers with different energies that can cross a low energy barrier and thus be converted into each other. An example is proton tautomers, including tautomers that interconvert by proton transfer, such as enol-keto tautomers and imine-enamine tautomers, or tautomeric forms of heteroaryl groups that contain ring atoms bonded to ring-NH- and ring=N- moieties, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole. Valence tautomers include those that interconvert by some of the bond electrons recombining.

[0113] The term "prodrug" as used herein refers to any derivative of a compound of the present invention that, when administered to a subject, directly or indirectly provides a compound of the present invention, its active metabolite or residue. Particularly preferred are derivatives or prodrugs that increase the bioavailability, metabolic stability and tissue targeting of the compounds of the present invention.

[0114] The compounds of the present invention can be used in the form of salts, such as "pharmaceutically acceptable salts" derived from inorganic or organic acids. These include, but are not limited to, the following: acetate, adipate, alginate, citrate, aspartate, benzoate, besylate, ethanesulfonate, disulfate, butyrate, camphor, camphorsulfonate, digluconate, cyclopentanepropionate, lauryl sulfate, ethanesulfonate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, ethanesulfonate, hydrochloride, 2-naphthalenesulfonate, oxalate, pectinate, sulfate, 3-phenylpropionate, picrate, trimethylacetate, propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate, and decanoate. Additionally, basic nitrogen-containing groups can be quaternized with the following reagents to form quaternary ammonium salts: lower alkyl halides including chlorides, bromides, and iodides of methyl, ethyl, propyl, and butyl groups; dialkyl sulfates including dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and dipentyl sulfate; long chain halides including chlorides, bromides, and iodides of decyl, lauryl, myristyl, and stearyl; aralkyl halides such as benzyl and phenethyl bromides.

[0115] The present invention also includes isotopically labeled compounds of the present invention which are identical in structure to those disclosed above, except that one or more atoms are replaced by atoms having the same number of protons but a different number of neutrons. Examples of isotopes that can be incorporated into the compounds of the present invention are: 2 H, 3H, 13 C. 14 C. 15 N, 18 O. 17 O. 35 S, 18 F, 36 Cl and 131 I, etc., includes isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, and iodine.

[0116] All of the compounds of the present invention, their stereoisomers, tautomers or pharma- ceutically acceptable salts, as well as compounds of the above forms that contain the above isotopes and / or isotopes of other atoms, are within the scope of the present invention. 3 H or 14 Certain isotopically labeled compounds of the invention, such as those labeled with C, may be used in drug tissue distribution assays and thus, 3 H or 14 C isotopes are particularly preferred due to their ease of preparation and detectability. 2 Certain compounds of the invention that are substituted with heavier isotopes such as H have certain therapeutic advantages due to better metabolic stability such as increased in vivo half-life and lower doses, and therefore 2 H is also preferred in some cases.

[0117] Detailed Description The present invention will be further illustrated using the following examples, but the present invention is not limited thereto. Throughout this application, various examples of the compounds and methods of the present invention are referred to herein. The various examples described are intended to provide a few illustrative examples and should not be interpreted as descriptions of alternatives. At the same time, it should be noted that the examples discussed herein (including various methods and parameters) are intended only to illustrate the present invention and in no way limit the scope of protection of the present invention. For the purpose of describing the present invention, specific examples are specified below. However, it should be understood that the present invention is not limited to these examples, and the following examples are intended only to provide a method of practicing the present invention and in no way limit the scope of the present invention.

[0118] The process for preparing a compound of formula (I), its stereoisomer, tautomer or pharma- ceutically acceptable salt in any aspect of the present invention comprises the following steps: Scheme 1:

[0119] [ka]

[0120] SM1-1 and SM2-1 are reacted under certain chemical reaction conditions to prepare a compound of general formula (I), where each substituent is defined as above. Scheme 2:

[0121] [ka]

[0122] SM1-2 and SM2-2 are reacted under certain chemical reaction conditions to prepare a compound of general formula (I), where each substituent is defined as above.

[0123] The compounds provided by the present invention can be prepared by standard synthetic methods well known in the art, and the present specification provides general methods for preparing the compounds of the present invention. Starting materials are usually commercially available, for example, purchased from companies such as Alfa Aesar®, Sigma-Aldrich®, TCI, J&K®, Shaoyuan Chemical, Energy Chemical, etc., or prepared by methods well known to those skilled in the art.

[0124] The compounds of the present invention and the corresponding preparation methods are further described and listed below using examples and preparations. Typical or preferred reaction conditions (such as reaction temperature, time, molar ratio of reactants, reaction solvent and pressure) are described in specific examples, but it should be understood that other reaction conditions can be used by those skilled in the art. The optimal reaction conditions may vary with the specific reaction substrate or solvent used, but such conditions can be determined by those skilled in the art through routine optimization.

[0125] The structures of the compounds in the following examples were characterized by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). An NMR spectrometer was used, the compounds were dissolved in appropriate deuterated reagents, and TMS was used as an internal standard. 1 Analyzed by H-NMR at room temperature. NMR chemical shifts (δ) were measured in ppm and the following abbreviations were used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; brs, broad singlet. MS was determined by mass spectrometry (ESI).

[0126] The reaction starting materials, example intermediates, and compounds may be isolated and purified by conventional techniques, such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography (eg, column chromatography, TLC separation and purification).

[0127] HSGF254 thin layer chromatography silica gel plates (0.2±0.03 mm) were used for TLC, and HSGF254 thin layer chromatography thickness preparation plates (0.9-1 mm) were used for TLC separation and purification. 300-400 mesh silica gel was used as the carrier for column chromatography.

[0128] Commercially available solvents and reagents used in the tests may be used directly without further purification or treatment after purchase unless otherwise specified. When referring to other examples or synthetic methods, the reaction conditions (reaction temperature, reaction solvent, molar ratio of reactants or / and reaction duration) may vary. In general, the progress of the reaction may be monitored by TLC, and an appropriate time may be selected to terminate the reaction and perform post-treatment accordingly. The purification conditions of the compounds may also vary, and in general, a suitable column chromatography eluent may be used to determine the R of TLC. f Either the corresponding compounds are selected according to their value or the corresponding compounds are isolated and purified by preparative TLC.

[0129] Preparation of intermediates Intermediate: 4-(4-(2-methyl-5-(2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)phenyl)butyric acid

[0130] [ka]

[0131] 5-Bromo-N-methoxy-N,2-dimethylbenzamide 5-Bromo-2-methylbenzoic acid (24.0 g) and dichloromethane (600 ml) were added to a 1-liter reaction flask, and dimethylsulfoxide (16.2 ml) and N,N-dimethylformamide (3.6 ml) were successively added dropwise. After the dropwise addition, the mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction solution was concentrated to dryness, and dichloromethane (190 ml) and N,O-dimethylhydroxylamine hydrochloride (31.0 g) were successively added, the temperature was cooled to 0° C. in an ice bath, and triethylamine (46.5 ml) was added dropwise. After the addition, the solution was allowed to warm to room temperature and stirred for 15 hours. The reaction solution was poured into 1M dilute hydrochloric acid, liquid separation was performed, and the aqueous phase was extracted twice with dichloromethane, and the organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography to give 23.1 g of a colorless liquid.

[0132] (5-Bromo-2-methylphenyl)(4-chlorophenyl)methanone The product of the previous step (18.7 g) and tetrahydrofuran (150 ml) were added to a 500 ml reaction flask, cooled to 0° C., and 4-chlorophenylmagnesium bromide (1M in Et2O) was added dropwise, after which the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into saturated aqueous ammonium chloride solution, extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give 18.0 g of a white solid. 1 H NMR (400MHz, CDCl3): δ7.76(m,2H),7.54(dd,J=2.1,8.2Hz,1H),7.48(m,2H),7.43(d,J=2.1Hz,1H),7.20(d,J=8.2Hz,1H),2.27(s,3H).

[0133] 4-Bromo-2-(4-chlorobenzyl)-1-toluene (5-Bromo-2-methylphenyl)(4-chlorophenyl)methanone (23.0 g), acetonitrile (230 ml) and triethylsilane (52.9 ml, 331.2 mmol) were added to a 500 ml reaction flask, cooled to 0° C., and boron trifluoride etherate (54.6 ml) was slowly added dropwise, and after the addition, stirring was continued at 0° C. for 30 minutes, and then the mixture was heated to 65° C. and stirred for 2 hours. After the reaction was completed, the reaction solution was cooled to 0° C., and saturated aqueous sodium bicarbonate solution was slowly added until no bubbles were generated, and extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (eluted with petroleum ether) to obtain 18.5 g of a white solid.

[0134] (3-(4-chlorobenzyl)-4-methylphenyl)((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)methanone (3aS,5R,6S,6aS)-6-Hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)(morpholinyl)methanone (14.3 g) and tetrahydrofuran (150 ml) were added to a 500 ml reaction flask, cooled to 0° C., and tert-butylmagnesium chloride (1 M in THF, 57.5 ml, 57.5 mmol) was added dropwise and the mixture was kept stirring for 30 minutes after the addition.

[0135] 4-Bromo-2-(4-chlorobenzyl)-1-toluene (18.5 g) and tetrahydrofuran (180 ml) were added to a 1 L reaction flask under nitrogen protection, cooled to -78°C, n-butyl lithium (1.6 M in hexane) was slowly added dropwise, and stirred for 10 minutes. Then, the above freshly prepared Grignard reaction solution was added, and after the addition, the mixture was allowed to warm to room temperature and continued to stir for 1 hour. After the reaction was completed, the reaction solution was poured into a saturated aqueous ammonium chloride solution, extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 14.2 g of a white solid. 1 H NMR (400MHz, CDCl3): δ7.90-7.88(dd,J=1.8,7.9Hz,1H),7.77(d,J=1.6Hz, 1H),7.32-7.30(d,J=8.0Hz,1H),7.28-7.26(m,2H),7.08-7.06(d,J=8.4Hz, 2H),6.10(d,J=3.6Hz,1H),5.31(d,J=2.7Hz,1H),4.61(d,J=3.6Hz,1H),4. 58(s,1H),4.02(s,2H),3.09(s,1H),2.31(s,3H),1.57(s,3H),1.38(s,3H).

[0136] (3aS,5S,6R,6aS)-5-((s)-(3-(4-chlorobenzyl)-4-methylphenyl)(hydroxy)methyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol (3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)(morpholinyl)methanone (14.2 g), cerium chloride heptahydrate (15.7 g) and methanol (280 ml) were added to a 500 ml reaction flask, cooled to 0° C. in an ice bath, and a solution (16 ml) of sodium borohydride (1.6 g) in 1 M aqueous sodium hydroxide solution was slowly added dropwise. After the addition, the mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction solution was poured into saturated aqueous ammonium chloride solution, extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 13.0 g of a pale yellow solid, which was used directly in the next reaction.

[0137] (3S,4R,5S,6S)-6-(3-(4-chlorobenzyl)-4-methylphenyl)tetrahydro-2H-pyran-2,3,4,5-tetrayltetraacetate (3aS,5S,6R,6aS)-5-((s)-(3-(4-chlorobenzyl)-4-methylphenyl)(hydroxy)methyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol (13.0 g), glacial acetic acid (65 ml) and water (65 ml) were added to a 500 ml reaction flask, heated to 110° C. and stirred for 4 hours. The reaction solution was concentrated to dryness, azeotroped with toluene three times, the residue was dissolved in 130 ml of acetonitrile, triethylamine (44.5 ml) was added, and a solution of acetic anhydride (30.1 ml) in acetonitrile (65 ml) was slowly added dropwise at 35° C. under nitrogen protection. After the addition, the mixture was naturally cooled to room temperature and stirred for 15 hours. The reaction solution was diluted with ethyl acetate, water was added, and liquid separation was performed. The aqueous phase was extracted three times with ethyl acetate. The organic phases were combined, washed once with dilute hydrochloric acid and saturated brine in turn, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give 14.6 g of a yellow solid. 1 H NMR (400MHz, CDCl3): δ7.26-7.23(m,2H),7.19-7.14(m,2H),7.09(s,1H),7.01(d,J=8.5Hz,2H),5.88(d,J=8.2Hz,1H) ,5.37(t,J=9.5Hz,1H),5.28(t,J=8.9Hz,1H),5.20(t,J=9.6Hz,1H),4.50(d,J=9.9Hz,1H),3.98-3.90(m,2H),2.18(s, 3H),2.12(s,3H),2.08(s,3H),2.03(s,3H),1.78(s,3H).

[0138] (2S,3S,4R,5S,6R)-2-(3-(4-chlorobenzyl)-4-methylphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate (3S,4R,5S,6S)-6-(3-(4-chlorobenzyl)-4-methylphenyl)tetrahydro-2H-pyran-2,3,4,5-tetrayltetraacetate (14.6 g), thiourea (4.2 g), 1,4-dioxane (150 ml), trimethylsilyl trifluoromethanesulfonate (9.9 ml) were added to a 500 ml reaction flask, heated to 90° C., and stirred for 2 hours. After the reaction was completed, the solution was cooled to room temperature, iodomethane (5.1 ml) and N,N-diisopropylethylamine (27.1 ml) were added successively, and the mixture was stirred at room temperature for 15 hours. Ethyl acetate and water were added, stirred, and liquid separation was performed. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined, washed once with dilute hydrochloric acid and once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give 11.4 g of a pale yellow solid. 1 H NMR (400MHz, CDCl3): δ7.26-7.23(m,2H),7.18-7.14(m,2H),7.06(s,1H),7.03-7.00(m,2H),5.35(t,J=9.4Hz,1H),5.23(t,J=9.6Hz,1H),5.13(t ,J=9.7Hz,1H),4.53(d,J=9.9Hz,1H),4.40(d,J=9.8Hz,1H),3.99-3.88( m,2H),2.20(s,3H),2.19(s,3H),2.11(s,3H),2.03(s,3H),1.78(s,3H).

[0139] (2S,3S,4R,5S,6R)-2-(3-(4-((E)-4-methoxy-4-oxobut-1-en-1-yl)benzyl)-4-methylphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate (2S,3S,4R,5S,6R)-2-(3-(4-chlorobenzyl)-4-methylphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate (1.0 g), methyl 3-butenoate (1.0 ml), Pd2(dba)3 (366 mg), tri-tert-butylphosphine tetrafluoroborate (232 mg), dicyclohexylmethylamine (1.2 ml) and N-methylpyrrolidone (10 ml) were added to a 25 ml microwave reaction tube, and after nitrogen replacement, the mixture was heated to 160° C. by microwave and reacted for 1 hour. This operation process was repeated 10 times for a total of 10 g of raw material. The reaction solution was combined, diluted with ethyl acetate, water was added, and liquid separation was performed. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined, washed once with dilute hydrochloric acid and once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give 6.4 g of a pale yellow solid. 1 H NMR (400MHz, CDCl3): δ7.30-7.28(m,2H),7.16-7.15(m,2H),7.04-7.02(m,3H),6.47(d,J= 15.9Hz,1H),6.30-6.22(m,1H),5.35(t,J=9.4Hz,1H),5.23(t,J=9.6Hz,1H),5.13(t,J=9. 7Hz,1H),4.53(d,J=9.8Hz,1H),4.40(d,J=9.9Hz,1H),4.01-3.90(m,2H),3.73(s,3H),3.2 6(dd,J=1.2,7.1Hz,2H),2.21(s,3H),2.18(s,3H),2.11(s,3H),2.02(s,3H),1.77(s,3H).

[0140] (2S,3S,4R,5S,6R)-2-(3-(4-(4-methoxy-4-oxobutyl)benzyl)-4-methylphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate (2S,3S,4R,5S,6R)-2-(3-(4-((E)-4-methoxy-4-oxobut-1-en-1-yl)benzyl)-4-methylphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate (6.8 g), methanol (60 ml), tetrahydrofuran (60 ml), and 5% palladium on carbon (1.4 g) were added to a 250 ml reaction flask, hydrogen exchange was performed three times, and the mixture was stirred at room temperature for 4 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give 5.6 g of a pale yellow solid.

[0141] 4-(4-(2-methyl-5-(2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)phenyl)butyric acid (2S,3S,4R,5S,6R)-2-(3-(4-(4-methoxy-4-oxobutyl)benzyl)-4-methylphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate (5.6 g), methanol (30 ml), tetrahydrofuran (15 ml) and water (30 ml) were added to a 250 ml reaction flask, and then lithium hydroxide monohydrate (4.0 g) was slowly added, and after the addition, the mixture was stirred at room temperature for 4 hours. The reaction solution was diluted with water, extracted three times with ethyl acetate, the organic phase was discarded, the pH of the aqueous phase was adjusted to 1 with dilute hydrochloric acid, extracted three times with ethyl acetate, the organic phase was combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 2.8 g of a white solid. 1H NMR(400MHz,DMSO-d6):δ12.04(s,1H),7.11-7.04(m,7H),5.22(d,J=5.5Hz, 1H),5.13(brs,1H),4.88(d,J=5.4Hz,1H),4.33(d,J=9.4Hz,1H),4.05(d,J= 8.9Hz,1H),3.91(s,2H),3.29-3.15(m,3H),2.53(t,J=7.4Hz,2H),2.20(t,J =7.4Hz,2H),2.17(s,3H),2.03(s,3H),1.80-1.72(quintet, J=7.7Hz,2H).MS:m / z 445.2,[MH] - .

[0142] Intermediate: 3-((4-(2-methyl-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)benzyl)oxy)propionic acid

[0143] [ka]

[0144] (3-Chloro-4-methylphenyl)((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)methanone (3aS,5R,6S,6aS)-6-Hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)(morpholinyl)methanone (5.0 g), tetrahydrofuran (50 ml) were added to a 250 ml reaction flask under nitrogen protection, cooled to 0° C., and tert-butylmagnesium chloride (1 M in THF, 20.1 mL) was added and stirred for 30 minutes.

[0145] 2-Chloro-4-iodotoluene (5.5g), tetrahydrofuran (50ml) were added to a 500ml reaction flask under nitrogen protection, cooled to -78℃, n-butyllithium (1.6M in hexane, 14.9ml) was slowly added, and stirred for 10 minutes after addition. The freshly prepared Grignard reaction solution was added, and the mixture was allowed to warm to room temperature after addition and stirred for 1 hour. The reaction solution was poured into saturated aqueous ammonium chloride solution, extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 4.0g of a white solid.

[0146] (3aS,5S,6R,6aS)-5-((S)-(3-chloro-4-methylphenyl)(hydroxy)methyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol (3-Chloro-4-methylphenyl)(3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)methanone (3.0 g), cerium chloride heptahydrate (4.3 g) and methanol (60 ml) were added to a 250 ml reaction flask, cooled to 0° C. in an ice bath, and sodium borohydride (0.4 g) in 1 M aqueous sodium hydroxide solution (5 ml) was slowly added dropwise. After the addition, the mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction solution was poured into saturated aqueous ammonium chloride solution, extracted three times with ethyl acetate, the organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 3.0 g of a pale yellow solid.

[0147] (2R,3S,4R,5S,6S)-6-(3-chloro-4-methylphenyl)tetrahydro-2H-pyran-2,3,4,5-tetrayl tetraacetate (3aS,5S,6R,6aS)-5-((S)-(3-chloro-4-methylphenyl)(hydroxy)methyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol (3.0 g), glacial acetic acid (15 ml) and water (15 ml) were added to a 150 ml reaction flask, heated to 110° C. and stirred for 4 hours. The reaction solution was concentrated to dryness, azeotroped with toluene three times, the residue was dissolved in 30 ml of acetonitrile, triethylamine (13.3 ml) was added, and a solution of acetic anhydride (9.0 ml) in acetonitrile (18 ml) was slowly added dropwise at 35° C. After the addition, the mixture was cooled to room temperature and stirred for 15 hours. The reaction solution was diluted with ethyl acetate, water was added, and liquid separation was performed. The aqueous phase was extracted three times with ethyl acetate. The organic phases were combined, washed once with dilute hydrochloric acid and once with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 4.6 g of a brown oil which was added directly to the next reaction.

[0148] (2S,3S,4R,5S,6R)-2-(3-chloro-4-methylphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate (2R,3S,4R,5S,6S)-6-(3-chloro-4-methylphenyl)tetrahydro-2H-pyran-2,3,4,5-tetrayltetraacetate (4.6 g (theoretical amount)), thiourea (1.5 g), 1,4-dioxane (40 ml), trimethylsilyl trifluoromethanesulfonate (3.5 ml) were added to a 150 ml reaction flask, heated to 90° C., and stirred for 2 hours. The reaction solution was cooled to room temperature, iodomethane (1.8 ml) and N,N-diisopropylethylamine (9.5 ml) were added, and the mixture was stirred for 15 hours. Ethyl acetate and water were added to the reaction solution, and liquid separation was performed. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined, washed once with dilute hydrochloric acid and once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give 2.4 g of a pale yellow solid. 1H NMR (CDCl3,400MHz): δ7.33(d,J=1.6Hz,1H),7.21(d,J=7.9Hz,1H),7.17-7.14(dd,J=1.6,7.8Hz,1H),5.36(t,J=9.4Hz,1H),5.23(t,J=9.7Hz,1 H),5.10(t,J=9.7Hz,1H),4.55(d,J=9.9Hz,1H),4.41(d,J=9.9Hz,1H), 2.37(s,3H),2.22(s,3H),2.12(s,3H),2.04(s,3H),1.87(s,3H).MS:m / z 453.1,[M+Na] + .

[0149] (2S,3S,4R,5S,6R)-2-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate (2S,3S,4R,5S,6R)-2-(3-chloro-4-methylphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate (1.2 g), bis(pinacolato)diboron (1.4 g), potassium acetate (0.8 g), palladium acetate (0.05 g), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0.1 g), and 1,4-dioxane (10 ml) were added to a 25 ml microwave tube, and after nitrogen replacement, the mixture was heated to 60° C. by microwave and stirred for 18 hours. The reaction solution was concentrated and then purified by column chromatography to give 1.1 g of a pale yellow solid. 1H NMR(CDCl3,400MHz):δ7.67(d,J=2.0Hz,1H),7.37(dd,J=2.1,8.0Hz,1H),7. 17(d,J=7.9Hz,1H),5.36(t,J=9.4Hz,1H),5.24(t,J=9.6Hz,1H),5.15(t,J= 9.7Hz,1H),4.54(d,J=9.9Hz,1H),4.46(d,J=9.9Hz,1H),2.52(s,3H),2.20( s,3H),2.12(s,3H),2.03(s,3H),1.85(s,3H),1.35(d,J=3.3Hz,12H).MS:m / z 545.2,[M+Na] + .

[0150] Ethyl 3-(4-formylbenzyl)oxy)propionate p-Hydroxymethylbenzaldehyde (3.0 g) and tetrahydrofuran (30 ml) were added to a 150 ml reaction flask, cooled to 0° C. in an ice bath, and a solution of ethyl 3-bromopropionate (14.1 ml) in tetrahydrofuran (15 ml) was slowly added dropwise, after addition, the mixture was allowed to warm to room temperature and stirred for 15 hours. The reaction solution was poured into a saturated aqueous ammonium chloride solution, extracted three times with ethyl acetate, the organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 800 mg of a colorless liquid. 1 H NMR(CDCl3,400MHz):δ 10.03(s,1H),7.89(d,J=8.2Hz,2H),7.52(d,J=8.0Hz,2H),4.64(s,2H),4.19(q, J=7.1Hz,2H),3.82(t,J=6.3Hz,2H),2.66(t,J=6.3Hz,2H),1.29(t,J=7.1Hz,3H).

[0151] Ethyl 3-(4-(hydroxymethyl)benzyloxy)propionate Ethyl 3-(4-formylbenzyl)oxy)propionate (800 mg) and methanol (16 ml) were added to a 50 ml reaction flask, cooled to 0° C. in an ice bath, and sodium borohydride (193 mg) was added in portions. After the addition, the mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction solution was poured into 1N HCl aqueous solution, extracted three times with ethyl acetate, the organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 600 mg of a colorless liquid. 1 H NMR(CDCl3,400MHz):δ7.36-7.32(m,4H),4.68(s,2H),4.54(s,2H),4.17(q,J=7.2Hz,2 H),3.75(t,J=6.4Hz,2H),2.62(t,J=6.4Hz,2H),2.07(brs,1H),1.27(t,J=7.1Hz,3H).

[0152] Ethyl 3-((4-(((methoxycarbonyl)oxy)methyl)benzyl)oxy)propionate Ethyl 3-(4-(hydroxymethyl)benzyloxy)propionate (600 mg), pyridine (0.4 ml), dichloromethane (6 ml) were added to a 50 ml reaction flask, cooled to 0° C. in an ice bath, and a solution (2 ml) of methyl chloroformate (0.5 ml) in dichloromethane was added dropwise, after addition, the mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction solution was poured into 1N HCl aqueous solution, extracted three times with ethyl acetate, the organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 620 mg of a colorless liquid. 1 H NMR(CDCl3,400MHz):δ7.41-7.34(m,4H),5.17(s,2H),4.55(s,2H),4.18(q,J=7.1Hz,2H), 3.81(s,3H),3.76(t,J=6.4Hz,2H),2.63(t,J=6.4Hz,2H),1.28(t,J=7.1Hz,3H).

[0153] (2S,3S,4R,5S,6R)-2-(3-(4-(3-ethoxy-3-oxopropyloxy)methyl)benzyl)-4-methylphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate 1,4-Bis(diphenylphosphino)butane (72 mg), allylpalladium(II) chloride dimer (32 mg), toluene (4 ml), and isopropanol (2 ml) were added to a 25 ml there-necked flask, and after nitrogen purging, the mixture was stirred at room temperature for 30 minutes.

[0154] (2S,3S,4R,5S,6R)-2-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate (911 mg), ethyl 3-((4-(((methoxycarbonyl)oxy)methyl)benzyl)oxy)propionate and isopropanol (8 ml) were added to a 25 ml microwave reaction tube, the above catalyst was added after nitrogen replacement, and the reaction was microwaved to 80° C. for 12 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography to give 540 mg of an oil. 1 H NMR(CDCl3,400MHz):δ7.23(d,J=8.1Hz,2H),7.18-7.13(m,2H),7.07-7.05(m,3H),5.34 (t,J=9.4Hz,1H),5.22(t,J=9.6Hz,1H),5.13(t,J=9.7Hz,1H),4.53(d,J= 9.9Hz,1H),4.50(s,2H),4.40(d,J=9.8Hz,1H),4.15(q,J=7.2Hz,2H),4.0 0-3.92(m,2H),3.75(t,J=6.4Hz,2H),2.61(t,J=6.4Hz,2H),2.21(s,3H), 2.18(s,3H),2.11(s,3H),2.02(s,3H),1.76(s,3H),1.27(t,J=6.4Hz,3H).

[0155] 3-((4-(2-methyl-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)benzyl)oxy)propionic acid (2S,3S,4R,5S,6R)-2-(3-(4-(3-ethoxy-3-oxopropyloxy)methyl)benzyl)-4-methylphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate (540 mg), methanol (3 ml), tetrahydrofuran (1.5 ml), water (3 ml), and lithium hydroxide monohydrate (368 mg) were added to a 25 ml reaction flask and stirred at room temperature for 15 hours. The reaction solution was diluted with water, extracted three times with ethyl acetate, the organic phase was discarded, the pH of the aqueous phase was adjusted to 1 with dilute hydrochloric acid, extracted three times with ethyl acetate, the organic phase was combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give 300 mg of a colorless foam. 1 H NMR(DMSO-d6,400MHz):δ12.19(brs,1H),7.22(d,J=8.1Hz,2H),7.13-7.11(m,5H),5.22 (brs,1H),4.89(brs,1H),4.42(s,2H),4.33(d,J=9.4Hz,1H),4.05(d,J=9.1Hz,1H),3.94(s,2H),3.61( t,J=6.3Hz,2H),3.51-3.45(m,1H),3.30-3.17(m,3H),2.48(t,J=6.3Hz,2H),2.18(s,3H),2.04(s,3H). 13 C NMR(DMSO-d6,100MHz):δ173.2,140.0,138.7,137.9,136.3,135.8,130.1,129.7,128.9,128.1, 126.0,85.8,81.8,78.6,74.8,72.7,72.2,66.0,38.9,35.2,19.5,11.5.MS:m / z 485.2,[M+Na] + .

[0156] Intermediate: N 1 -Methyl-N 1-(Prop-2-yn-1-yl)eth-1,2-diamine

[0157] [ka]

[0158] 2-(Boc-amino)ethyl bromide Tetrahydrofuran (4 ml), water (4 ml), bromoethylamine hydrobromide (2.05 g) were added successively to a 25 ml reaction flask, cooled to 10° C., sodium bicarbonate (2.1 g), 4-dimethylaminopyridine (61 mg), di-tert-butyl dicarbonate (2.05 g) were added, and after addition, the mixture was stirred for 8 hours at 10° C. The reaction solution was filtered, the filtrate was subjected to liquid separation, the aqueous phase was extracted twice with dichloromethane, the organic phase was combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2.0 g of a pale yellow liquid.

[0159] N 1 -Methyl-N 1 -(Prop-2-yn-1-yl)eth-1,2-diamine N-methylpropargylamine (0.68 g), tetrahydrofuran (20 ml), water (20 ml), potassium carbonate (2.46 g, 17.8 mmol), and a solution of 2-(Boc-amino)ethyl bromide (2.0 g) in tetrahydrofuran (5 ml) were added successively to a 100 ml reaction flask and stirred at room temperature for 2 hours after addition. The reaction solution was extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 1.72 g of a pale yellow oil. The resulting crude product was dissolved in acetonitrile (10 ml), concentrated hydrochloric acid (5 ml) was slowly added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, dissolved in 10 ml of acetonitrile, potassium carbonate (3.35 g, 24.3 mmol) was added, and the mixture was stirred at 35° C. for 3 hours, cooled to room temperature, filtered through diatomaceous earth, washed with acetonitrile, and the filtrate was concentrated to dryness to obtain 0.67 g of a pale yellow liquid. MS: m / z 112.9, [M+H]+ .

[0160] Intermediate: 2-amino-2-methyl-N-(2-(methyl(prop-2-yn-1-yl)amino)ethyl)propionamide

[0161] [ka]

[0162] 2-((tert-butoxycarbonyl)amino)-2-methylpropionic acid (894 mg) and dichloromethane (25 ml) were added successively to a 50 ml reaction flask, cooled to 0° C. in an ice bath, and CDI (713 mg) was added slowly. After the addition, the mixture was stirred at 0° C. for 30 min. 1 -Methyl-N 1 -(prop-2-yn-1-yl)eth-1,2-diamine (450 mg) was added, and after the addition, the mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction solution was diluted with dichloromethane, water was added, and liquid separation was performed. The aqueous phase was extracted with dichloromethane three times. The organic phases were combined, washed once with saturated saline, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain 1.04 g of a pale yellow liquid. The product was dissolved in acetonitrile (5 ml), concentrated hydrochloric acid (2 ml) was slowly added dropwise, and the reaction solution was concentrated to dryness, acetonitrile (10 ml) was added to dissolve, potassium carbonate (1.93 g) was added, and the mixture was stirred at 35° C. for 3 hours, cooled to room temperature, filtered through diatomaceous earth, washed with acetonitrile, and the filtrate was concentrated under reduced pressure to obtain 550 mg of a pale yellow liquid. MS: m / z 198.2, [M+H] + .

[0163] Intermediate: 2-amino-N-(2-(dimethylamino)ethyl)-2-methylpropionamide

[0164] [ka]

[0165] 2-((tert-butoxycarbonyl)amino)-2-methylpropionic acid (2.03 g) and dichloromethane (25 ml) were added successively to a 50 ml reaction flask, cooled to 0° C. in an ice bath, and CDI (1.62 g) was added slowly. After the addition, the mixture was stirred at 0° C. for 30 minutes. N,N-dimethylethylenediamine (970 mg) was added, and after the addition, the mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction solution was diluted with dichloromethane, water was added, liquid separation was performed, the aqueous phase was extracted three times with dichloromethane, the organic phase was combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1.96 g of a pale yellow liquid. The product was dissolved in acetonitrile (10 ml), concentrated hydrochloric acid (4 ml) was slowly added dropwise, stirred at room temperature for 1 hour, the reaction solution was concentrated to dryness, acetonitrile (10 ml) was added to dissolve, potassium carbonate (4.14 g, 30 mmol) was added, stirred at 35° C. for 3 hours, cooled to room temperature, filtered through diatomaceous earth, washed with acetonitrile, and the filtrate was concentrated under reduced pressure to give 930 mg of a pale yellow liquid. MS: m / z 174.2, [M+H]+.

[0166] Intermediate: 2-amino-2-methyl-N-(2-(methyl(2-(methyl(prop-2-yn-1-yl)amino)-2-oxoethyl)amino)ethyl)propionamide

[0167] [ka]

[0168] Ethyl N-(2-((tert-butoxycarbonyl)amino)ethyl)-N-methylglycine Tert-butyl 2-(methylamino)ethylcarbamate (8.7 g), acetonitrile (100 ml), potassium carbonate (10.4 g) and ethyl bromoacetate (9.2 g) were added successively to a 100 ml reaction flask, heated to 30° C. and stirred for 10 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give 9.89 g of a pale yellow oil.

[0169] 2-((2-aminoethyl)(methyl)amino)-N-methyl-N-(prop-2-yn-1-yl)acetamide Ethyl N-(2-((tert-butoxycarbonyl)amino)ethyl)-N-methylglycine (5.5 g), tetrahydrofuran (25 ml), lithium hydroxide monohydrate (0.98 g) and water (2 ml) were added successively to a 50 ml reaction flask and stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and the concentrated residue was dissolved in dichloromethane (25 ml). HATU (9.62 g), DIPEA (5.57 g) and N-methylpropargylamine (1.75 g) were added successively, and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with dichloromethane, water was added, and liquid separation was performed. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 3.2 g of a pale yellow oily substance. The product was dissolved in acetonitrile (15 ml), concentrated hydrochloric acid (5 ml) was slowly added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, acetonitrile (15 ml) was added to dissolve, potassium carbonate (6.24 g) was added, and the mixture was stirred at 35° C. for 3 hours. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, washed with acetonitrile, and the filtrate was concentrated to give 1.67 g of a pale yellow liquid.

[0170] 2-Amino-2-methyl-N-(2-(methyl(2-(methyl(prop-2-yn-1-yl)amino)-2-oxoethyl)amino)ethyl)propionamide 2-((tert-butoxycarbonyl)amino)-2-methylpropionic acid (2.03 g) and dichloromethane (25 ml) were added successively to a 50 ml reaction flask, cooled to 0° C. in an ice bath, and CDI (1.62 g) was added slowly. After the addition, the mixture was stirred at 0° C. for 30 minutes. 2-((2-aminoethyl)(methyl)amino)-N-methyl-N-(prop-2-yn-1-yl)acetamide (1.67 g) was added, and after the addition, the mixture was allowed to warm to room temperature and stirred for 3 hours. Dichloromethane was added to the reaction flask to dilute, water was added, and liquid separation was performed. The aqueous phase was extracted three times with dichloromethane, and the organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by column chromatography to obtain 2.1 g of a pale yellow oily substance. The product was dissolved in acetonitrile (10 ml), concentrated hydrochloric acid (4 ml) was added dropwise slowly, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to dryness, acetonitrile (10 ml) was added to dissolve, potassium carbonate (3.15 g, 22.8 mmol) was added, and the mixture was stirred at 35° C. for 3 hours. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, washed with acetonitrile, and the filtrate was concentrated to dryness under reduced pressure to give 1.24 g of a pale yellow oil. MS: m / z 269.2, [M+H] + .

[0171] Preparation of compounds EXAMPLES

[0172] [ka]

[0173] 4-(4-(2-methyl-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)phenyl)butyric acid (100 mg), N-(2-aminoethyl)pyrrolidine (51 mg), tetrahydrofuran (3 ml), N,N-diisopropylethylamine (85 mg, 0.66 mmol) and 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (110 mg) were added to a 50 ml one-neck flask and stirred at room temperature for 2 hours. After the reaction was completed, it was diluted by adding saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel column chromatography to obtain 20 mg of a white solid. 1 H NMR(400MHz,CD3OD3):δ=7.24-7.01(m,7H),4.41(d,J=9.4Hz,1H),4.15(d,J=9.2Hz,1H),3.97(s,2H),3.51-3.40(m,8H),3.29(t,J=6. 0Hz,2H),2.62(t,J=7.5Hz,2H),2.31-2.24(m,2H),2.23(s,3H),2.16(s,3H),2.12-2.05(m,3H),2.04(s,2H),1.96-1.91(m,2H).MS:m / z 543.3,[M+H] + . EXAMPLES

[0174] [ka]

[0175] 4-(4-(2-methyl-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)phenyl)butyric acid (100 mg), 4-methyl-1-piperazineethylamine (64 mg), tetrahydrofuran (3 ml), N,N-diisopropylethylamine (85 mg) and 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate (110 mg) were added to a 50 ml one-neck flask, and stirred at room temperature for 2 hours after addition. After the reaction was completed, it was diluted by adding saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel column chromatography to obtain 56 mg of a white solid. 1 H NMR(400MHz,CD3OD3):δ=7.23-7.04(m,7H),4.42(d,J=9.5Hz,1H),4.16(d,J=9.3Hz,1H),3.97(s,2H),3.53-3.37(m,4H),3.3 7-3.29(m,5H),3.27-2.92(m,4H),2.80(s,3H),2.66-2.54(m,4H),2.27-2.18(m,5H),2.16(s,3H),1.97-1.85(m,2H).MS:m / z 572.3,[M+H] + . EXAMPLES

[0176] [ka]

[0177] 4-(4-(2-methyl-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)phenyl)butyric acid (80 mg), 1-(2-aminoethyl)piperazine (30 mg), tetrahydrofuran (3 ml), N,N-diisopropylethylamine (70 mg) and 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate (89 mg) were added to a 50 ml one-neck flask, and stirred at room temperature for 2 hours after addition. After the reaction was completed, it was diluted by adding saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel column chromatography to obtain 16 mg of a white solid. 1 H NMR(400MHz,CD3OD3):δ7.22-7.05(m,7H),4.41(d,J=9.4Hz,1H),4.15(d,J=9.2Hz,1H),3.97(s,2H),3.53-3.38(m,5H),3.17(t,J= 6.0Hz,2H),2.62(t,J=7.4Hz,2H),2.30-2.20(m,5H),2.16(s,3H),1.97-1.78(m,4H),1.74-1.57(m,2H),1.36-1.28(m,6H).MS:m / z 557.3,[M+H] + . EXAMPLES

[0178] [ka]

[0179] 4-(4-(2-methyl-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)phenyl)butyric acid (80 mg), N 1 -Benzyl-N 1N,N-methylethane-1,2-diamine (30 mg), tetrahydrofuran (3 ml), N,N-diisopropylethylamine (70 mg) and 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate (89 mg) were added to a 50 ml one-neck flask, and stirred at room temperature for 2 hours after addition. After the reaction was completed, it was diluted with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel column chromatography to obtain 50 mg of a white solid. 1 H NMR(400MHz,CD3OD):δ=7.39-7.25(m,5H),7.22-7.12(m,3H),7.11-7.03(m,4H),4.40(d,J=9.4Hz,1H),4.14(d,J=9.1Hz,1H),3.96(s,2H) ),3.67(s,2H),3.52-3.34(m,5H),2.67-2.53(m,4H),2.33(s,3H),2.24-2.16(m,5H),2.15(s,3H),1.94-1.83(m,2H).MS:m / z593.3,[M+H] + . EXAMPLES

[0180] [ka]

[0181] 4-(4-(2-methyl-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)phenyl)butyric acid (prepared by the method of Reference Journal of Medicinal Chemistry 2017, 60, 710-721) (89 mg, 0.2 mmol), N,N-dimethylformamide (5 ml), N,N-diisopropylethylamine (52 mg, 0.4 mmol), N 1 -Methyl-N 1-(Prop-2-yn-1-yl)ethane-1,2-diamine (compound 1B) (25 mg, 0.22 mmol), 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) were added successively to a 25 ml reaction flask and stirred at room temperature for 2 hours. The reaction solution was diluted with dichloromethane, washed with water, the aqueous phase was extracted with dichloromethane three times, the organic phase was combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and purified by column chromatography (dichloromethane:methanol=20:1) to obtain a white solid (45 mg). 1 H NMR(400MHz,DMSO-d6):δppm 7.17-7.12(m,2H),7.09-7.02(m,5H),6.22-6.20(t,J=4.9Hz,1H), 4.36-4.34(d,J=9.5Hz,1H),4.13-4.11(d,J=9.4Hz,1H),3.96-3.88(m,2H),3.63-3.58(t,J=8.8Hz,1H),3.51-3.44(m,2H),3.28-3.25(m,4 H),2.62-2.58(t,J=7.2Hz,2H),2.54-2.51(t,J=5.8Hz,2H),2.26-2.22(m,7H),2.15(s,3H),2.14-2.10(t,J=7.8Hz,2H),1.97-1.88(m,2H). 13 C NMR(100MHz,DMSO-d6):δppm 168.5,134.8,134.4,133.0,132.2,130.7,125.7,124.2,124.1,123.9,120.8,80.9,77.2,73.2,72.9,69.9,69.0,67.3,49.4,40.9 ,36.5,34.1,31.8,30.9,30.0,22.3,14.8,7.0;MS[M+H] + =541.3. EXAMPLES

[0182] [ka]

[0183] The compound was obtained by referring to the similar preparation scheme in Example 1. ESI-MS: 543.3 [M+H] + .

[0184] The specific preparation method was as follows.

[0185] [ka]

[0186] 3-(4-(2-methyl-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)phenyloxy)propionic acid (91 mg), N,N-dimethylformamide (10 ml), N,N-diisopropylethylamine (55 mg), N 1 -Methyl-N 1 -(prop-2-yn-1-yl)ethane-1,2-diamine (27 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (92 mg) were added successively to a 50 ml reaction flask and stirred at room temperature for 2 hours after addition. The reaction solution was diluted with dichloromethane, washed with water, the aqueous phase was extracted with dichloromethane three times, the organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and purified by column chromatography to obtain a white solid (53 mg). EXAMPLES

[0187] [ka]

[0188] The compounds were obtained by referring to the similar preparation scheme in Example 1.

[0189] The specific preparation method was as follows.

[0190] [ka]

[0191] 3-(4-(2-methyl-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)benzyl)oxy)propionic acid (92 mg), N,N-dimethylformyl (5 ml), N,N-diisopropylethylamine (52 mg), N 1 -Methyl-N 1 -(Prop-2-yn-1-yl)eth-1,2-diamine (25 mg), 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate (84 mg) were added successively to a 25 ml reaction flask and stirred at room temperature for 2 hours. The reaction solution was diluted with dichloromethane, washed with water, the aqueous phase was extracted with dichloromethane three times, the organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and purified by column chromatography to obtain 45 mg of a white solid. 1 H NMR(400MHz,DMSO-d6):δ7.82(s,1H),7.22-7.10(m,7H),5.22(s,1H),5.13(s,1H),4.88(s,1H),4.40 (s,2H),4.33(d,J=9.0Hz,1H),4.05(d,J=8.3Hz,1H),3.94(s,2H),3.60(s,2H) ,3.51(s,1H),3.29-3.21(m,5H),2.39-2.34(m,4H),2.18(m,5H),2.04(s,3H). 13C NMR(100MHz,DMSO-d6):δ170.5,139.9,138.7, 137.9,136.4,135.8,130.1,129.7,128.9,128.1,126.0,85.8,81.8,79.3,78.6,7 6.3,74.8,72.7,72.1,66.6,54.7,45.5,41.7,38.9,37.1,36.6,19.5,11.5.MS:m / z 557.2737,[M+H] + . EXAMPLES

[0192] [ka]

[0193] The compound was obtained by referring to the similar preparation scheme in Example 1. ESI-MS: 539.2 [M+H] + .

[0194] The specific preparation method was as follows.

[0195] [ka]

[0196] (E)-4-(4-(2-methyl-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)phenyl)vinylacetic acid (102 mg), N,N-dimethylformamide (10 ml), N,N-diisopropylethylamine (54 mg), N 129 mg of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate was added successively to a 50 ml reaction flask and stirred at room temperature for 2 hours after addition. The reaction solution was diluted with dichloromethane, washed with water, the aqueous phase was extracted three times with dichloromethane, the organic phase was combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and purified by column chromatography to obtain a white solid (56 mg). EXAMPLES

[0197] [ka]

[0198] The compound was obtained by referring to the similar preparation scheme in Example 1. ESI-MS: 553.4 [M+H] + .

[0199] The specific preparation method was as follows.

[0200] [ka]

[0201] 3-(4-(2-ethynyl-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)phenyloxy)propionic acid (65 mg), N,N-dimethylformamide (8 ml), N,N-diisopropylethylamine (50 mg), N 1 -Methyl-N 1-(prop-2-yn-1-yl)ethane-1,2-diamine (20 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (82 mg) were added successively to a 50 ml reaction flask and stirred at room temperature for 1.5 hours after addition. The reaction solution was diluted with dichloromethane, washed with water, the aqueous phase was extracted three times with dichloromethane, the organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and purified by column chromatography to obtain a white solid (16 mg). EXAMPLES

[0202] The compound was obtained by referring to the similar preparation scheme in Example 1. ESI-MS: 555.6 [M+H] + .

[0203] [ka]

[0204] The specific preparation method was as follows.

[0205] [ka]

[0206] 5-(4-(2-methyl-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)phenyl)valeric acid (49 mg), N,N-dimethylformamide (5 ml), N,N-diisopropylethylamine (25 mg), N 1 -Methyl-N 1-(prop-2-yn-1-yl)ethane-1,2-diamine (18 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (62 mg) were added successively to a 25 ml reaction flask and stirred at room temperature for 2 hours after addition. The reaction solution was diluted with dichloromethane, washed with water, the aqueous phase was extracted three times with dichloromethane, the organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and purified by column chromatography to obtain a pale yellow solid (19 mg).

[0207] The introduction of the "alkynyl" functional group into some compounds of the present invention has two advantages: on the one hand, the "alkynyl" functional group can be connected with a bioluminescent marker using "click chemistry", which is beneficial for accurately determining the distribution of the compound in the body. For example, "click chemistry" occurs between the compound of the present invention and an "azide" compound with a fluorescent chromophore under the catalysis of a copper salt to generate a fluorescent compound with a "triazole structure". The compound of the present invention can also be linked with other biological compounds with biomarker functions to form new chemical compounds that are easy to detect, which is very significant for fully studying the efficacy and safety of such compounds. On the other hand, the "alkynyl" functional group can be connected with other pharmacophore groups via "click chemistry", which promotes the discovery of candidate compounds with better comprehensive properties. Examples are as follows:

[0208] Exploratory research using "click chemistry": (1) Preparation of labeling compounds with luminescent properties

[0209] [ka]

[0210] The compound of Example 5, copper sulfate, and 7-hydroxy-3-azidocoumarin (see Journal of the American Chemical Society (2014), 136(20), 7205-7208; Chemistry-A European Journal (2011), 17(12), 3326-3331, S3326 / 1-S3326 / 21; Journal of Fluorescence (2013), 23(1), 181-186; Journal of Organic Chemistry (2011), 76(12), 4964-4972; Angewandte Chemie, International Edition (2019), 58(21), 6987-6992) were reacted at room temperature to give the product. Rf: 0.22 (dichloromethane:methanol = 10:1).

[0211] (2) Preparation of candidate compounds with better comprehensive properties

[0212] [ka]

[0213] The compound of Example 5, copper sulfate, and cyclopropyl azide (see Chemische Berichte (1985), 118(4), 1564-1574; Science of Synthesis (2010), 41, 543-612; Nature (London, United Kingdom) (2019), 574(7776), 86-89) were reacted at room temperature to obtain the product. Rf: 0.24 (dichloromethane:methanol = 10:1). The compound has a biological activity similar to that of Example 5, and has better lipid solubility and water solubility than the compound of Example 5.

[0214] Biological testing 1. SGLT1 inhibitor activity experiment 1 The inhibitory activity of SGLT1 was tested according to the method described in the document (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).

[0215] Test results:

[0216] [Table 1]

[0217] where A is the active IC 50 <50nM, B represents 50nM <IC 50 <1000nM, C represents IC 50 >1000nM.

[0218] The experimental results show that the compounds of the present invention have significant activity in inhibiting SGLT1.

[0219] In a mouse glucose tolerance test, the compounds of the present invention have the effect of improving blood glucose levels in the test animals.

[0220] The compounds of the present invention are useful in reducing body weight, and in in vivo pharmacodynamic studies, the compounds of the present invention reduced body weight in experimental animals.

[0221] The compounds of the present invention have very low or no absorption in vivo, and pharmacokinetic studies have shown that the compounds of the present invention have almost undetectable side effects in experimental animals and almost no side effects on other organs in the body.

[0222] 2. hSGLT1 inhibitor activity experiment The inhibitory activity tests were carried out according to similar methods described in the literature (Acta Pharmaceutica Sinica 2017, 52(6):897-903; Nature Protocols(2007), 2(3), 753-762; Journal of Biochemical and Biophysical Methods(2005), 64(3), 207-215; Diabetes Technology & Therapeutics(2011), 13(7), 743-775).

[0223] In this experiment, we evaluated an in vitro activity assay using the uptake of 2-NBDG (2-deoxy-2-[(7-nitro-2,1,3-benzoxadiazol-4-yl)amino]-D-glucose, CAS number: 186689-07-6) by human embryonic kidney epithelial cells (HEK293 stably expressing human SGLT1) and its half-maximal inhibitory concentration (IC 50 The SGLT1 inhibitory activity of the target compounds was determined by measuring the SGLT1 activity.

[0224] HEK293 cells capable of stably expressing the human SGLT1 gene were seeded into 96-well clear-bottom black plates containing DMEM medium. The cells were incubated in a cell incubator at 37°C and 5% CO2. The medium in the 96-well plate was aspirated, and the plate was treated with low glucose serum-free DMEM medium, once with nonspecific uptake buffer, and once with NaCl. +The cells were washed once with dependent uptake buffer. Uptake buffer containing the test compound, followed by uptake buffer containing 2-NBDG, was added to each well of cells for glucose uptake, and the cell plate was incubated at 37°C, 5% CO2. Compounds were serially diluted. The uptake reaction was stopped by removing the culture medium, and the cells were washed with ice-cold uptake buffer, followed by removing the washing solution. The cells were lysed by adding NaOH, and the content of 2-NBDG in the cells was detected by a fluorescence microplate reader. The protein concentration of the lysate was measured by the BCA method, and the uptake of 2-NBDG was quantified by fluorescence intensity / protein content, and the obtained data was analyzed using GraphPad Prism to determine the half inhibitory concentration (IC50) of the compounds to be tested. 50 ) was decided.

[0225] Comparative compound 3 is the compound numbered "3" in the document (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). It was prepared and identified according to the synthesis method described in the document.

[0226] Test results:

[0227] [Table 2]

[0228] The experimental results show that the compounds of the examples of the present invention, for example, Example 2, Example 3, Example 4, and Example 5, have significant activity in inhibiting SGLT1.

[0229] 3. Oral glucose tolerance test (OGTT) in rats after 14 days of continuous administration Experimental animals: SPF male SD rats; Compound preparation: Appropriate amounts of the compounds of Example 2, Example 3 and Example 5 were weighed out and uniformly suspended in appropriate amount of 0.5% CMC-Na solution.

[0230] Preparation of glucose solution: An appropriate amount of glucose powder was weighed and dissolved in an appropriate amount of purified water.

[0231] Dosage and method of administration: 0.012 mg / kg, oral gavage.

[0232] Experimental process: The animals were fed with normal diet with continuous administration for 14 days, and on the 15th day, a glucose tolerance test was performed to detect blood glucose before administration (-30 min), before glucose administration (0 min), and 10, 30, 60 and 120 min after glucose solution administration, and to observe the defecation of the animals.

[0233] Experimental Results: The results in Figure 1 show that the compounds of Example 2, Example 3 and Example 5 can significantly reduce the blood glucose level of rats, and no loose stools were observed in the experimental animals within 48 hours before and after the experiment.

[0234] 4. Oral glucose tolerance test (OGTT) after continuous dosing in mice Experimental animals: SPF male mice; Compound preparation: An appropriate amount of the compound of Example 5 was weighed out and uniformly suspended in an appropriate amount of 0.5% CMC-Na solution.

[0235] Preparation of glucose solution: An appropriate amount of glucose powder was weighed and dissolved in an appropriate amount of purified water.

[0236] Administration and dosage: oral gavage; blank vehicle group, high dose group (1.6 mg / kg), low dose group (0.12 mg / kg).

[0237] Experimental process: (1) Mice were fed a high-sugar diet for 6 days and then divided into groups (10 mice per group) to enter the treatment phase. (2) Example compound 5 was administered once a day at 5:00 pm on days 1 to 5, and then the animals were fed a high-sugar free diet and observed for defecation. (3) On day 6, an oral glucose tolerance test was performed and a glucose solution (2 g / kg) was orally administered. Blood glucose was detected before (0 min) and 10, 30, and 60 min after administration of the glucose solution.

[0238] Test Results: (1) Observations of animal defecation after continuous administration from day 1 to day 5 are summarized as follows:

[0239] [Table 3]

[0240] Note: The data in the table represent the total number of animals with "loose stool symptoms" and the total number of animals in the group. For example, "1 / 10" means that 1 out of 10 animals in each group had "loose stool symptoms."

[0241] (2) The results of the oral glucose tolerance test (OGTT) on day 6 are shown in Figure 2. Summary of the experiment: (1) Compound 5 of Example 5 was administered continuously from day 1 to day 5. In the high dose group (1.6 mg / kg), only one animal had loose stool on day 1, and no animals had loose stool on days 2 to 5. In the low dose group (0.12 mg / kg), no animals had loose stool after 5 days of continuous administration.

[0242] (2) On the sixth day, in the oral glucose tolerance test (OGTT), the results in FIG. 2 show that both the high and low dose groups of the compound of Example 5 can significantly reduce the blood glucose level of mice.

[0243] 5. Pharmacokinetic studies in rats Experimental animals: SPF male SD rats; Dosage and method of administration: 10 mg / kg, oral gavage. Study compounds: dapagliflozin, compound of Example 5, compound of Example 7, compound of Comparative Example 6; Test Method: Before dosing (0), and 1, 4, 8 and 24 hours after dosing, 0.2 ml of blood was collected from the orbital venous plexus, anticoagulated with heparin, and plasma was collected.

[0244] Note: Comparative compound 6 is the compound numbered "6" in the document (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). It was prepared and identified according to the synthetic method described in the document.

[0245] Pharmacokinetic Absolute Bioavailability Data in Rats:

[0246] [Table 4]

[0247] The experimental results show that the compounds of Example 5 and Example 7 have almost no absorption in vivo, and the absolute bioavailability values ​​are both less than 1.5%, while the absolute bioavailability of Comparative Compound 6 is 23%, and the absolute bioavailability of Dapagliflozin is 73%. Thus, both Comparative Compound 6 and Dapagliflozin are absorbed into the blood after oral administration, and their exposure to internal organs (e.g., brain, heart, and other organs) may lead to potential and unpredictable toxicity.

[0248] In addition to being expressed in the kidney, SGLT1 is also present in intestinal epithelial cells and organs such as the heart and brain.Compared to comparative compound 6 and dapagliflozin, the compounds of Example 5 and Example 7 of the present invention were barely detectable in vivo after oral administration.Therefore, preliminary experimental evidence suggests that the compounds of Example 5 and Example 7 of the present invention have no side effects on various organs such as the heart and brain.

[0249] 6. In vivo hypoglycemic efficacy experiments in combination with sitagliptin Model Establishment: SPF grade Balb / C male mice were used in this experiment, and the establishment of type 2 diabetes mouse model was induced by intraperitoneal injection of streptozotocin (STZ) complemented by high-fat and high-sugar diet. Groups: 10 per group Administration: normal group, model group, low-dose combined administration group (0.02 mg / kg of the compound of Example 5 + 20 mg / kg of sitagliptin), medium-dose combined administration group (0.06 mg / kg of the compound of Example 5 + 20 mg / kg of sitagliptin), high-dose combined administration group (0.1 mg / kg of the compound of Example 5 + 20 mg / kg of sitagliptin), sitagliptin group (20 mg / kg). The normal group and the model group were given the solvent by force feeding.

[0250] The experimental results show that the combination of the compound of Example 5 and sitagliptin can significantly reduce the blood glucose level of diabetic model animals, and there is a dose-effect relationship.

[0251] 7. Study on the metabolic stability of compounds in intestinal bacteria Method: Collected rat feces were processed to obtain fecal suspension for metabolic stability determination. The mixed reaction system consisting of rat fecal suspension and compound of Example 5 was incubated at 37°C for 3 hours, 6 hours, 12 hours and 24 hours. The compound of Example 5 in the incubation system was analyzed to determine the total amount of remaining compound, where "+" represents the remaining percentage is less than 50%, "++" represents the remaining percentage is 50% to 70%, "+++" represents the remaining percentage is 70% to 90%, and "++++" means the remaining percentage is more than 90%.

[0252] Test Results:

[0253] [Table 5]

[0254] The test results show that after the compound of Example 5 is incubated with microorganisms in rat feces for about 24 hours, the remaining compound of Example 5 is still relatively abundant (more than 70%).It is demonstrated that the compound of Example 5 can still maintain high stability under the metabolism of gut microorganisms.

[0255] 8. The compound of the present invention has antitumor effect.In the antitumor experiment of Hep3B xenograft tumor model, it is found that the compound of the present invention can inhibit tumor growth, and the test on the animal model induced by high-fat diet suggests that the compound of the present invention is useful for the alleviation of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, and the treatment of liver and kidney diseases related to energy absorption and metabolism.

Claims

1. Compounds of formula (VA-2), stereoisomers, tautomers or pharma- ceutically acceptable salts thereof 【Chemistry 1】 [Wherein X is methyl, R 5 , R 6b , R 7b each is independently hydrogen; q=2, Ring B has the following structure: 【Chemistry 2】 is selected from Y has the following structure: 【Chemistry 3】 is a linking group selected from the group consisting of:

2. The following compounds, their stereoisomers, tautomers, or pharma- ceutically acceptable salts: 【Chemistry 4】

3. Compounds of formula (II-1), stereoisomers, tautomers or pharma- ceutically acceptable salts thereof 【Chemistry 5】 wherein X is selected from methyl or ethynyl; R 8 is methyl, R 9 is hydrogen, m2=1, n2=1, Y1 has the following structure: 【Chemistry 6】 is a linking group selected from the group consisting of:

4. Compounds of formula (III), stereoisomers, tautomers or pharma- ceutically acceptable salts thereof 【Chemistry 7】 [Wherein X is methyl, R 8 is methyl; R 9 is hydrogen; m2=1, n2=1, Y1 has the following structure: 【Chemistry 8】 is a linking group selected from the group consisting of:

5. The following compounds, their stereoisomers, tautomers, or pharma- ceutically acceptable salts: 【Chemistry 9A】 【Chemistry 9B】

6. 10. A pharmaceutical composition comprising a therapeutically effective dose of a compound according to any one of claims 1 to 5, or a stereoisomer, tautomer, or pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

7. Use of a compound according to any one of claims 1 to 5 or a pharma- ceutical composition according to claim 6 in the preparation of a drug or pharmaceutical composition for the treatment and amelioration of diabetes, cardiovascular and cerebrovascular diseases, weight loss, fatty liver, constipation, metabolic-related diseases, and for the treatment of tumors.

8. Use of a compound according to any one of claims 1 to 5 or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition according to claim 6 as an SGLT1 / SGLT2 inhibitor in the preparation of a medicament or pharmaceutical composition for the treatment of a disease related to SGLT1 / SGLT2 function.

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