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

Abstract

To provide a compound inhibiting a sodium-glucose cotransporter 1, and a pharmaceutically acceptable salt and a stereoisomer thereof, the compound being used in a pharmaceutical composition, and to provide methods for preparing and using the pharmaceutical composition, and an application in preparing a drug and a composition of the compound for treating and improving diabetes, cardiovascular diseases, weight reduction, fatty liver, constipation, and metabolism-related diseases, and cancer therapy.SOLUTION: The present invention relates to a compound inhibiting a sodium-glucose cotransporter 1, and a pharmaceutically acceptable salt and a stereoisomer thereof.SELECTED DRAWING: None

Description

[Technical Field]

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

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

[0003] Sodium-dependent glucose transporter (SGLT) inhibitors can inhibit glucose reabsorption by the kidney, allowing excess glucose to be excreted in the urine and lowering blood glucose. This provides a new approach for the treatment of diabetes and has become a hot spot 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 remaining commercially available drugs is as follows:

[0004] [ka]

[0005] The SGLT family consists of several subtypes that transport carbohydrates across cell membranes, during which they bind to sodium ion transporters. SGLT1 is primarily expressed in the gastrointestinal tract and is primarily responsible for the absorption of glucose and galactose in the small intestine. SGLT1 is also present in the proximal straight tubules of the kidney, where it contributes to the reabsorption of blood glucose. Inhibiting SGLT1 can prevent blood glucose from being absorbed and returned to the blood for use, thereby achieving the goal of lowering blood glucose levels.

[0006] SGLT1 inhibition may also offer an alternative therapy for glycemic control, making it attractive because the improvement in glycemic control achieved 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 benefits in glycemic control. Through this action, diabetes-related side effects of SGLT2 inhibitors, particularly genital infections, can also be avoided. [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 has designed a compound having the structure of general formula (V), and found that the compound having such a structure exhibits excellent effects and functions, 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 pharmaceutically 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, Tetracyclyl, 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 pharmaceutically acceptable salts:

[0015] [ka]

[0016] [In the formula, R 1a , R 1b , R 1c is halogen or -OR 1A , -NHR 1A are 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, Tetracyclyl, 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 pharmaceutically 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 said 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, Tetracyclyl, 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 pharmaceutically 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 pharmaceutically 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] and 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 pharmaceutically acceptable salts:

[0036] [ka]

[0037] [ka]

[0038] to provide.

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

[0040] [ka]

[0041] wherein 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 pharmaceutically acceptable salt.

[0043] [ka]

[0044] [In the formula, R 1a , R 1b , R 1c For or -or 1A , -NHR 1A are 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 pharmaceutically 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 pharmaceutically 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 pharmaceutically 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, and 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 pharmaceutically 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 pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0069] Any of the compounds described in this invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to the invention is 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 pharmaceutically acceptable salt thereof or a pharmaceutical composition according to the invention is used as an SGLT1 / SGLT2 inhibitor in the preparation of a medicament or pharmaceutical composition for the treatment of diseases associated with SGLT1 / SGLT2 function.

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

[0072] [Figure 1] FIG. 1 shows the results of an oral glucose tolerance test (OGTT) in rats after 14 days of continuous administration. [Figure 2] FIG. 1 shows the results of an oral glucose tolerance test (OGTT) on day 6 after 5 consecutive days of administration in mice. DETAILED DESCRIPTION OF THE INVENTION

[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 those 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 -NH2.

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

[0083] The term "nitro" as used herein refers to -NO2.

[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 and consisting of 2 to 17 carbon atoms, oxygen atoms, and nitrogen atoms. Specifically, it refers to an alkane structure (including saturated alkanes, alkenes, and alkynes) having a straight or branched chain structure, or a similar alkane structure having a carbonyl group at one end, where any carbon atom may be replaced by an oxygen atom or a nitrogen atom, and may be further substituted by a substituent group, provided that a stable chemical structure is formed, 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. 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) or polycyclic (i.e., rings having adjacent pairs of carbon atoms) group having a conjugated π-electron system. The aryl group can be covalently linked to the defined chemical structure at any carbon atom that results in a stable structure. The aryl groups described herein can 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 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, amido, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkynyl, and cycloalkoxy.

[0091] The term "cycloalkyl," as used herein, refers to a cyclic alkyl group having from 3 to 10 carbon atoms and having mono- or polycyclic rings (including fused, bridged, and spiro ring systems). Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The 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 group, 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 spirocyclic, bicyclic, or bridged ring, and the optionally substituted N and 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 from 3 to 10 ring atoms overall. A heterocycloalkyl group may be covalently attached to the defined chemical structure at any heteroatom or carbon atom that 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 (e.g., morpholine N-oxide, thiomorpholine S-oxide, thiomorpholine S,S-dioxide, etc.). Heterocycloalkyl groups may contain one or more oxo groups, such as phthalimido, piperidinone, oxazolidinone, 2,4(1H,3H)-dioxo-pyrimidinyl, pyridine-2(1H)-keto, etc. The 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 group, amido, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkenyloxy, alkynyl, cycloalkoxy, aryl, or heteroaryl.

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

[0096] The term "alkyl," as used herein, refers to saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms, and the term includes both straight-chain 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 can 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 group, 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 a group consisting of HC(O)-, R 9 R 10 refers to 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., by an oxygen atom, and representative structures formed after oxidation of a carbon atom, a nitrogen atom, a sulfur atom, etc., by 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 a group consisting of R 11 R 12 NS(O)2-, cycloalkyl-S(O)2-, cycloalkenyl-S(O)2-, aryl-S(O)2-, heteroaryl-S(O)2-, heterocycloalkyl-S(O)2-, and alkyl-S(O)2-, 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 to refer to a group represented by R 13 R 14 refers to 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 alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocycloalkyl, etc. groups 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 groups are as defined herein.

[0106] The term "optional" or "possibly" means that the event or circumstance described thereafter may occur, but does not necessarily occur, and the description includes instances where the event or circumstance occurs and does not occur.

[0107] The term "optionally substituted with" means that a structure is unsubstituted or substituted with one or more substituents described in this invention. The term "substituted," as used herein, refers to single or multiple substitution of any group with the specified substituent(s), provided that such single or multiple substitutions (including multiple substitutions on the same moiety) are chemically permissible, and 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 an overly unstable molecule. When there are two or more substituents in any group, each substituent is defined independently of any other substituent and, therefore, may be the same or different.

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

[0109] The term "compounds of the invention" (unless specifically indicated) as used herein refers to compounds of Formula (I) and Formula (II) and all pure and mixed stereoisomers, geometric isomers, tautomers, solvates, prodrugs, and isotopically labeled compounds, as well as any pharmaceutically acceptable salts thereof. Solvates of the compounds of the invention refer to compounds or salts thereof in combination with stoichiometric and non-stoichiometric solvents, such as hydrates, ethylates, methylates, acetonates, and the like. 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 "pharmaceutically 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 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 "tautomer" as used herein refers to structural isomers with different energies that can cross a low energy barrier and thus be interconverted. An example is proton tautomers, including tautomers that interconvert via proton migration, such as enol-keto tautomers and imine-enamine tautomers, or tautomeric forms of heteroaryl groups containing ring atoms bonded to ring -NH- and ring =N- moieties, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole. Valence tautomers include those that interconvert via recombination of some bonding electrons.

[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 compounds of the present invention include: 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] The compounds of the present invention, their stereoisomers, tautomers or pharmaceutically acceptable salts, as well as compounds of the above forms that contain the above isotopes and / or isotopes of other atoms, are all within the scope of the present invention. 3 H or 14 Certain isotopically labeled compounds of the invention, such as those labeled with 1C, may be used in drug tissue distribution assays; 3 H or 14 C isotopes are particularly preferred due to their ease of preparation and detectability. 2 Certain compounds of the invention 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 number of 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 do not in any 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 for practicing the present invention and do not in any way limit the scope of the present invention.

[0118] The process for preparing a compound of formula (I), its stereoisomer, tautomer or pharmaceutically 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), wherein 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), wherein 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. The starting materials are usually commercially available, for example, purchased from companies such as Alfa Aesar®, Sigma-Aldrich®, TCI®, J&K®, Shaoyuan Chemical Co., Energy Chemical Co., etc., or prepared by methods well known to those skilled in the art.

[0124] The compounds of the present invention and corresponding preparation methods are further described and listed below using examples and preparations. Typical or preferred reaction conditions (reaction temperature, time, molar ratio of reactants, reaction solvent and pressure, etc.) are described in specific examples, but it should be understood that other reaction conditions can also be used by those skilled in the art. Optimal reaction conditions may vary with the specific reaction substrates or solvents 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). Using an NMR spectrometer, the compounds were dissolved in appropriate deuterated reagents and TMS was used as an internal standard. 1 H-NMR was performed 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 can 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-prepared plates (0.9-1 mm) were used for TLC separation and purification. 300-400 mesh silica gel was used as the support for column chromatography.

[0128] Commercially available solvents and reagents used in the tests can 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) can be varied. Generally, the progress of the reaction can be monitored by TLC, and an appropriate time can be selected to terminate the reaction, and work-up can be carried out accordingly. The purification conditions of the compounds can also be varied, and generally, a suitable column chromatography eluent can be used to elute the compounds according to the R of TLC. f The corresponding compounds are selected according to their values, or are separated 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 dimethyl sulfoxide (16.2 ml) and N,N-dimethylformamide (3.6 ml) were added dropwise in succession. 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 added successively. 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 1 M dilute hydrochloric acid, and the liquid was separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined, washed with saturated brine, 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 and cooled to 0° C. 4-chlorophenylmagnesium bromide (1 M in EtO) was added dropwise, and after the dropwise addition, the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate. 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 and cooled to 0° C. Boron trifluoride etherate (54.6 ml) was slowly added dropwise. After the addition, the mixture was stirred at 0° C. for 30 minutes, and then heated to 65° C. and stirred for 2 hours. After the reaction was completed, the reaction solution was cooled to 0° C., saturated aqueous sodium bicarbonate solution was slowly added until no bubbles were generated, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (eluting 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 and cooled to -78 °C. n-Butyllithium (1.6 M in hexane) was slowly added dropwise and stirred for 10 minutes. The freshly prepared Grignard reaction solution was then added. After the addition, the mixture was allowed to warm to room temperature and continued stirring for 1 hour. After the reaction was completed, the reaction solution was poured into saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate. 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 and cooled to 0 °C in an ice bath. 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 and extracted three times with ethyl acetate. 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 subsequent 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 and azeotropically distilled with toluene three times. The residue was dissolved in 130 ml of acetonitrile, triethylamine (44.5 ml) was added, and a solution (65 ml) of acetic anhydride (30.1 ml) in acetonitrile was slowly added dropwise at 35 °C under nitrogen protection. After the addition, the mixture was allowed to cool to room temperature and stirred for 15 hours. The reaction solution was diluted with ethyl acetate, water was added, and the liquids were separated. 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), and 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, and iodomethane (5.1 ml) and N,N-diisopropylethylamine (27.1 ml) were added successively. The mixture was stirred at room temperature for 15 hours. Ethyl acetate and water were added, and the mixture was stirred and separated. 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. After nitrogen replacement, the mixture was heated to 160 °C in a microwave and reacted for 1 hour. This operation process was repeated 10 times for a total of 10 g of raw materials. The reaction solution was combined, diluted with ethyl acetate, water was added, and the liquid was separated. 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, and hydrogen exchange was performed three times. 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. After the addition, the mixture was stirred at room temperature for 4 hours. The reaction solution was diluted with water and 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, and extracted three times with ethyl acetate. The organic phases were 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) and 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 (5.5 g) and tetrahydrofuran (50 ml) were added to a 500 ml reaction flask under nitrogen protection and cooled to -78 °C. n-Butyllithium (1.6 M in hexane, 14.9 ml) was slowly added and stirred for 10 minutes after the addition. The freshly prepared Grignard reaction solution described above was added, and after the addition, the mixture was allowed to return to room temperature and stirred for 1 hour. The reaction solution was poured into saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate. 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 4.0 g 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 and cooled to 0°C in an ice bath. 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 and 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-tetrayltetraacetate (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 and azeotropically distilled with toluene three times. The residue was dissolved in 30 ml of acetonitrile, triethylamine (13.3 ml) was added, and a solution (18 ml) of acetic anhydride (9.0 ml) in acetonitrile 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 the liquids were separated. 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), and 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, and 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 the liquid was separated. 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. After purging with nitrogen, the mixture was heated to 60°C in a microwave oven 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 the addition, the mixture was allowed to warm to room temperature and stirred for 15 hours. The reaction solution was poured into saturated aqueous ammonium chloride solution and 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 and 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 aqueous HCl and 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), and dichloromethane (6 ml) were added to a 50 ml reaction flask and cooled to 0° C. in an ice bath. A solution (2 ml) of methyl chloroformate (0.5 ml) in dichloromethane was added dropwise. After the addition, the mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction solution was poured into a 1N aqueous HCl solution and 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 three-necked flask, and after purging with nitrogen, 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, and the above catalyst was added after nitrogen replacement. The reaction was irradiated in a microwave at 80° C. for 12 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography to give 540 mg of an oily substance. 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 and 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, and extracted three times with ethyl acetate. The organic phases were 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)etha-1,2-diamine

[0157] [ka]

[0158] 2-(Boc-amino)ethyl bromide Tetrahydrofuran (4 ml), water (4 ml), and bromoethylamine hydrobromide (2.05 g) were successively added to a 25 ml reaction flask, cooled to 10° C., and sodium bicarbonate (2.1 g), 4-dimethylaminopyridine (61 mg), and di-tert-butyl dicarbonate (2.05 g) were added, followed by stirring for 8 hours at 10° C. The reaction solution was filtered, and the filtrate was subjected to liquid separation. The aqueous phase was extracted twice with dichloromethane, and the organic phases were 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)etha-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. 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. The mixture was cooled to room temperature, filtered through diatomaceous earth, washed with acetonitrile, and the filtrate was concentrated to dryness to give 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 minutes. 1 -methyl-N 1 450 mg of 4-(prop-2-yn-1-yl)etha-1,2-diamine was added, and 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 the liquid was separated. The aqueous phase was extracted three times with dichloromethane. The combined organic phases were washed once with saturated brine, 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 5 ml of acetonitrile, 2 ml of concentrated hydrochloric acid was slowly added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to dryness, 10 ml of acetonitrile was added to dissolve the product, 1.93 g of potassium carbonate was added, and the mixture was stirred at 35°C for 3 hours. The mixture was 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 slowly added. 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 return to room temperature and stirred for 3 hours. The reaction solution was diluted with dichloromethane, water was added, and the liquid was separated. The aqueous phase was extracted three times with dichloromethane. The organic phases were 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 added dropwise slowly, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to dryness, and acetonitrile (10 ml) was added to dissolve the product. Potassium carbonate (4.14 g, 30 mmol) was added, and the mixture was stirred at 35°C for 3 hours. The mixture was 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 the liquid was separated. 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 oil. 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 slowly added. 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 returned to room temperature and stirred for 3 hours. Dichloromethane was added to the reaction flask to dilute, and water was added to separate the liquids. The aqueous phase was extracted three times with dichloromethane. 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 oil. The product was dissolved in acetonitrile (10 ml), concentrated hydrochloric acid (4 ml) was slowly added dropwise, 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 [Example]

[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, the mixture was diluted with saturated aqueous ammonium chloride solution and 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] + . [Example]

[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 the reaction was completed, the mixture was diluted with saturated aqueous ammonium chloride solution and 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] + . [Example]

[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 the reaction was completed, the mixture was diluted with saturated aqueous ammonium chloride solution and 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= MS:m / z 557.3,[M+H] + . [Example]

[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 the reaction was completed, the mixture was diluted with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic phases were 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] + . [Example]

[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 1N-(prop-2-yn-1-yl)ethane-1,2-diamine (Compound 1B) (25 mg, 0.22 mmol) and 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) were added consecutively to a 25 ml reaction flask and stirred at room temperature for 2 hours. The reaction solution was diluted with dichloromethane and washed with water. The aqueous phase was extracted three times with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and purified by column chromatography (dichloromethane:methanol = 20:1) to give 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. [Example]

[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 27 mg of 2-(prop-2-yn-1-yl)ethane-1,2-diamine and 92 mg of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate were added successively to a 50 ml reaction flask and stirred at room temperature for 2 hours. The reaction solution was diluted with dichloromethane and washed with water. The aqueous phase was extracted three times with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and purified by column chromatography to give a white solid (53 mg). [Example]

[0187] [ka]

[0188] The compound was 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 25 mg of 2-(prop-2-yn-1-yl)etha-1,2-diamine and 84 mg of 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate were added successively to a 25 ml reaction flask and stirred at room temperature for 2 hours. The reaction solution was diluted with dichloromethane and washed with water. The aqueous phase was extracted three times with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and purified by column chromatography to give 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). 13 C 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]+ . [Example]

[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 1 N-methyl-N1-(prop-2-yn-1-yl)ethane-1,2-diamine (29 mg) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (95 mg) were added successively to a 50 ml reaction flask and stirred at room temperature for 2 hours. The reaction solution was diluted with dichloromethane and washed with water. The aqueous phase was extracted three times with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and purified by column chromatography to give a white solid (56 mg). [Example]

[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 20 mg of 2-(prop-2-yn-1-yl)ethane-1,2-diamine and 82 mg of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate were added successively to a 50 ml reaction flask and stirred at room temperature for 1.5 hours. The reaction solution was diluted with dichloromethane and washed with water. The aqueous phase was extracted three times with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and purified by column chromatography to give a white solid (16 mg). [Example]

[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 N-(prop-2-yn-1-yl)ethane-1,2-diamine (18 mg) and 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. The reaction solution was diluted with dichloromethane and washed with water. The aqueous phase was extracted three times with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and purified by column chromatography to give a pale yellow solid (19 mg).

[0207] The introduction of an "alkynyl" functional group into some compounds of the present invention has two advantages: on the one hand, the "alkynyl" functional group can be connected to a bioluminescent marker using "click chemistry," which is useful for accurately determining the distribution of compounds 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, generating a fluorescent compound with a "triazole structure." The compound of the present invention can also be linked to other biological compounds with biomarker functions to form new chemical compounds that are easy to detect, which is very useful for thoroughly studying the efficacy and safety of such compounds. On the other hand, the "alkynyl" functional group can be connected to other pharmacophore groups via "click chemistry," which facilitates the discovery of candidate compounds with better comprehensive properties. Examples are as follows:

[0208] Exploratory research using "click chemistry": (1) Preparation of labeled 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 similar biological activity 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 <IC50 <1000 nM, C represents IC 50 represents >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 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 no detectable 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 test was carried out according to the same method 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, an in vitro activity assay was used to evaluate 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 50The 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 a 96-well clear-bottom black plate 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 a dependent uptake buffer. An uptake buffer containing the test compound, followed by an uptake buffer containing 2-NBDG, was added to each well of cells for glucose uptake, and the cell plate was incubated at 37°C and 5% CO2. The compounds were serially diluted. The uptake reaction was stopped by removing the culture medium, and the cells were washed with ice-cold uptake buffer, after which the washing solution was removed. The cells were lysed by adding NaOH, and the content of 2-NBDG in the cells was detected using 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. The obtained data was analyzed using GraphPad Prism to determine the half-maximal inhibitory concentration (IC50) of the compound being 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 synthetic 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 and uniformly suspended in an 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, in which blood glucose was detected before administration (-30 min), before giving glucose (0 min), and 10, 30, 60 and 120 min after giving glucose solution, and the animals' defecation was observed.

[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 administration 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, then divided into groups (10 mice per group) and entered the treatment phase. (2) Example Compound 5 was administered once a day at 5:00 PM from day 1 to day 5, and then the animals were fed a high-sugar free diet ad libitum, and the animals' defecation was observed. (3) On day 6, an oral glucose tolerance test was performed, and a glucose solution (2 g / kg) was orally administered. Blood glucose was measured before (0 min) and 10, 30, and 60 min after administration of the glucose solution.

[0238] Test Results: (1) From day 1 to day 5, observations of animal defecation after continuous administration 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 stools on day 1, and no animals had loose stools from day 2 to day 5. In the low dose group (0.12 mg / kg), no animals had loose stools after 5 days of continuous administration.

[0242] (2) On the sixth day, in the oral glucose tolerance test (OGTT), the results in Figure 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 administration (0), and 1, 4, 8 and 24 hours after administration, 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, with absolute bioavailability values ​​of less than 1.5%, while the absolute bioavailability of Comparative Compound 6 is 23% and that of dapagliflozin is 73%. Therefore, both Comparative Compound 6 and dapagliflozin are absorbed into the blood after oral administration, and their exposure to organs in the body (e.g., the 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 with Comparative Compound 6 and dapagliflozin, the compounds of Examples 5 and 7 of the present invention were barely detectable in vivo after oral administration. Therefore, preliminary experimental evidence suggests that the compounds of Examples 5 and 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 a high-fat and high-sugar diet. Groups: 10 animals 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 model group were given the solvent by gavage.

[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 a fecal suspension for metabolic stability determination. The mixed reaction system consisting of the rat fecal suspension and the compound of Example 5 was incubated at 37°C for 3, 6, 12, and 24 hours. The compound of Example 5 in the incubation system was analyzed to determine the total amount of remaining compound. Here, "+" represents a remaining percentage of less than 50%, "++" represents a remaining percentage of 50% to 70%, "+++" represents a remaining percentage of 70% to 90%, and "++++" represents a remaining percentage of more than 90%.

[0252] Test Results:

[0253] [Table 5]

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

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

Claims

1. Compounds of formula (I-1), stereoisomers, tautomers or pharmaceutically acceptable salts thereof 【Chemistry 1】 wherein R 1a , R 1b , and R 1c are each independently selected from —OR 1A , where each R 1A is independently hydrogen or methyl; R 2 is selected from —S(O) m —R 1A , where m=0; each of R 3 , R 4 , and R 5 is independently selected from hydrogen; each of R 6 , R 7 , R 8 , and R 9 is independently selected from hydrogen, methyl, or ethyl; m2=1 or 2, n2=1, X is selected from methyl or ethynyl; Y1 has the following structure: 【Chemistry 2】 wherein RE, RF, RG, and RH are each independently selected from hydrogen; E and J are each independently selected from —CH 2 — or oxygen; s1=0 or 1, s2=0, 1, or 2; s3=1 or 2} is a linking group selected from (However, the compound of formula (II-1), its stereoisomer, tautomer or pharmaceutically acceptable salt 【Transformation 3】 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 4】 is a linking group selected from (Except).

2. The following compound, its stereoisomer, tautomer or pharmaceutically acceptable salt: 【Chemistry 5-1】 【Chemistry 5-2】

3. The following compound, its stereoisomer, tautomer or pharmaceutically acceptable salt: 【Transformation 6】

4. The following compound, its stereoisomer, tautomer or pharmaceutically acceptable salt: 【Transformation 7】

5. 10. A pharmaceutical composition comprising a therapeutically effective dose of a compound of any one of claims 1 to 4, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

6. Use of a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 5, in the preparation of a drug or pharmaceutical composition for the treatment and improvement of diabetes, cardiovascular and cerebrovascular diseases, weight loss, fatty liver, constipation, metabolic-related diseases, and for the treatment of tumors.

7. Use of a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 5, as an SGLT1 / SGLT2 inhibitor, in the preparation of a medicament or pharmaceutical composition for the treatment of a disease associated with SGLT1 / SGLT2 function.

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