Compounds and applications for treating heart failure and related diseases

Abstract

The present invention discloses the use of a compound shown in Formula I, or a pharmaceutically acceptable salt or ester, prodrug, optical isomer, stereoisomer or solvate thereof in treating heart failure and related diseases. Such compounds show excellent effects in treating heart failure and related diseases, thus laying a new material foundation for the development of therapeutic drugs for heart failure and related diseases.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry. Specifically, the present invention relates to a compound having a therapeutic effect on heart failure and related diseases and its application in the preparation of a compound for treating heart failure and related diseases. Background Art

[0002] Heart failure is one of the most serious public health problems in the world. It is also known as the "last battlefield of heart disease". It is the final stage of cardiovascular disease and the main cause of death.

[0003] Heart failure (HF) is a complex clinical syndrome caused by various heart diseases progressing to a serious stage. Its main features are left ventricular and (or) right ventricular dysfunction and changes in neurohumoral regulation, often accompanied by dyspnea, fluid retention, reduced exercise tolerance and significantly shortened survival time. Patients with underlying heart disease are more likely to develop heart failure. Heart failure has complex physiological and pathological mechanisms, and a variety of neurohumoral mechanisms play an important role.

[0004] Heart failure is difficult to cure, and the goal of treatment is to prevent and delay the occurrence and development of heart failure, relieve clinical symptoms, improve quality of life, and improve long-term prognosis. Global multinational pharmaceutical companies and biotechnology companies have experienced years of research and development on a number of innovative drug projects targeting different targets and mechanisms, and have gradually ushered in a harvest period in recent years. However, in clinical practice, adverse drug reactions and high prices lead to poor patient compliance, and it is imperative to develop safe and effective anti-heart failure drugs. Summary of the invention

[0005] The purpose of the present invention is to provide a compound having a therapeutic effect on heart failure and related diseases. The compound is not only effective for heart failure and related diseases but also has the advantages of few side effects.

[0006] In the first aspect, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt or ester, prodrug, optical isomer, stereoisomer or solvate thereof, for use in the preparation of a drug for preventing or treating heart failure and related diseases.

[0007]

[0008] In the formula,

[0009] A is selected from a C6-C10 aromatic ring or carbocyclic ring, or a 5-6 membered heterocyclic ring or aromatic heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, O or S;

[0010] R1 and R4 are independently selected from H, D, OH, carbonyl, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 alkoxy, optionally substituted phenoxy, optionally substituted benzyloxy, optionally substituted NH2, NHCH3, NHCOCH3, halogen, optionally substituted C1-C10 alkylformyloxy, optionally substituted benzoyloxy, optionally substituted aminoacetoxy ( B may be various amino acid-forming groups), optionally substituted monosaccharide, disaccharide or polysaccharide groups;

[0011] R2 and R5 are independently selected from H, D, OH, carbonyl, hydroxymethyl, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 alkoxy, optionally substituted benzyloxy, optionally substituted phosphate, optionally substituted NH2, NHCH3, NHCOCH3, optionally substituted C1-C10 formyloxy, optionally substituted benzoyloxy, optionally substituted aminoacetoxy ( B can be various amino acid forming groups), COOH, COOCH3, CONH2, sulfonic acid oxygen group ( or sulfonate), halogen, optionally substituted monosaccharide, disaccharide or polysaccharide;

[0012] or

[0013] R1 and R2 or R4 and R5 are linked to form an optionally substituted 3-6 membered ring containing 0, 1 or 2 heteroatoms (preferably oxygen) selected from oxygen, nitrogen or sulfur, a cyclic carbonate lactone, a phosphate lactone or an optionally substituted cyclic boric acid lactone;

[0014] R3 is selected from H, D, optionally substituted C1-C10 alkyl, D-substituted C1-C10 alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3-6 membered ring containing 1 or 2 heteroatoms selected from O, S or N, optionally substituted C2-C10 alkylalkenyl, hydroxy, optionally substituted C1-C10 alkoxy, optionally substituted C1-C10 alkylthio, optionally substituted C1-C10 alkylformyloxy, optionally substituted C1-C10 acyl, hydroxyformyl, optionally substituted C1-C10 alkylformyloxy, nitro, optionally substituted amino, optionally substituted C1-C10 alkylamino, optionally substituted C1-C10 alkylformylamino, halogen, optionally substituted C2-6 alkynyl, optionally substituted monosaccharide, disaccharide or polysaccharide;

[0015] or,

[0016] Two adjacent R3 substituents form an optionally substituted C3-C6 carbocyclic ring or an optionally substituted C3-C6 heterocyclic ring containing 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur (preferably oxygen or nitrogen), an optionally substituted C5-C10 aromatic ring or an optionally substituted C5-C10 heteroaromatic ring containing 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur (preferably oxygen or nitrogen);

[0017] m is an integer from 1 to 5;

[0018] The hydrogens in the structures of Formula I are optionally substituted with deuterium.

[0019] In a specific embodiment, the compound represented by formula I is a compound represented by formula II,

[0020]

[0021] In the formula,

[0022] X1, X2, X3 are each independently selected from CH, N, S or O (preferably CH or N);

[0023] R1 and R4 are independently selected from H, D, OH, optionally substituted C1-C10 alkoxy, optionally substituted phenoxy, optionally substituted benzyloxy, optionally substituted NH2, NHCH3, NHCOCH3, optionally substituted C1-C10 alkylformyloxy, optionally substituted benzoyloxy, optionally substituted aminoformyloxy, optionally substituted monosaccharide, disaccharide or polysaccharide;

[0024] R2 and R5 are independently selected from H, D, OH, hydroxymethyl, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 alkoxy, optionally substituted benzyloxy, NH2, NHCH3, NHCOCH3, optionally substituted C1-C10 alkylformyloxy, optionally substituted benzoyloxy, optionally substituted carbamoyloxy, COOH, COOCH3, CONH2, optionally substituted monosaccharide, disaccharide or polysaccharide;

[0025] R1 and R2 may form an optionally substituted 3-6 membered ring containing 0, 1 or 2 heteroatoms (preferably oxygen) selected from oxygen, nitrogen or sulfur;

[0026] R3 is selected from H, D, optionally substituted C1-C10 alkyl, D-substituted C1-C10 alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3-6 membered ring containing 1 or 2 heteroatoms selected from O, S or N, optionally substituted C1-C10 alkylalkenyl, hydroxy, optionally substituted C1-C10 alkoxy, optionally substituted C1-C10 alkylthio, optionally substituted C1-C10 alkylformyloxy, formyl, hydroxyformyl, optionally substituted C1-C10 alkylformyloxy, nitro, optionally substituted amino, optionally substituted C1-C10 alkylamino, optionally substituted C1-C10 alkylformylamino, halogen, optionally substituted monosaccharide, disaccharide or polysaccharide;

[0027] or an optionally substituted C3-C6 carbocyclic ring or an optionally substituted C3-C6 heterocyclic ring containing 1 or 2 heteroatoms selected from oxygen or nitrogen is formed by two adjacent R3 substituents;

[0028] m is an integer from 1 to 5;

[0029] The hydrogen in the structure of formula II is optionally substituted with deuterium.

[0030] In a specific embodiment, the compound of formula I is a compound of formula III

[0031]

[0032] In the formula,

[0033] R1 and R4 are independently selected from H, D, OH, optionally substituted C1-C10 alkoxy, optionally substituted phenoxy, optionally substituted benzyloxy, optionally substituted NH2, NHCH3, NHCOCH3, optionally substituted C1-C10 formyloxy, optionally substituted benzoyloxy, optionally substituted carbamoyloxy, optionally substituted aminoacetoxy ( B may be various amino acid-forming groups), optionally substituted monosaccharide, disaccharide or polysaccharide groups;

[0034] R2 and R5 are independently selected from H, D, hydroxymethyl, optionally substituted C1-C10 alkyl, OH, optionally substituted C1-C10 alkoxy, optionally substituted benzyloxy, NH2, NHCH3, NHCOCH3, optionally substituted C1-C10 alkylformyloxy, optionally substituted benzoyloxy, optionally substituted carbamoyloxy, optionally substituted aminoacetoxy ( B can be various amino acid forming groups), COOH, COOCH3, CONH2, optionally substituted monosaccharide, disaccharide or polysaccharide groups;

[0035] R1 and R2 may form an optionally substituted 3-6 membered ring containing 0, 1 or 2 heteroatoms (preferably oxygen) selected from oxygen, nitrogen or sulfur;

[0036] R3 is selected from H, D, optionally substituted C1-C10 alkyl, D-substituted C1-C10 alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3-6 membered ring containing 1 or 2 heteroatoms selected from O, S or N, optionally substituted C2-C10 alkylalkenyl, hydroxy, optionally substituted C1-C10 alkoxy, optionally substituted C1-C10 alkylthio, optionally substituted C1-C10 alkylformyloxy, formyl, hydroxyformyl, optionally substituted C1-C10 alkylformyloxy, nitro, amino, optionally substituted C1-C10 alkylamino, optionally substituted C1-C10 alkylformylamino, fluorine, chlorine, bromine, optionally substituted monosaccharide, disaccharide or polysaccharide;

[0037] Alternatively, two adjacent R3 substituents form an optionally substituted C3-C6 carbocyclic ring or an optionally substituted C3-C6 heterocyclic ring containing 1 or 2 oxygens;

[0038] m is an integer from 1 to 5;

[0039] The hydrogen in the structure of formula III is optionally substituted with deuterium.

[0040] In a specific embodiment, the compound is as shown in Formula IV,

[0041]

[0042] R1 is selected from H, D, OH, NH2, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkylformyloxy, optionally substituted carbamoyloxy, optionally substituted aminoacetoxy B can be various amino acid-forming groups), optionally substituted monosaccharide groups;

[0043] R2 is selected from OH, NH2, COOH, COONH2, COONHCH3, optionally substituted C1-C3 alkoxyformyl, optionally substituted C1-C3 alkylformyloxy, optionally substituted carbamoyloxy, optionally substituted aminoacetoxy B can be various amino acid-forming groups), optionally substituted monosaccharide groups;

[0044] R3 is selected from H, D, optionally substituted C1-C5 alkyl, D-substituted C3-C5 cycloalkyl, optionally substituted 3-6 membered ring containing 1 or 2 O, optionally substituted C2-C10 alkylalkenyl, hydroxy, optionally substituted C1-C5 alkoxy, optionally substituted C1-C3 alkylthio, optionally substituted C1-C3 alkylformyloxy, formyl, optionally substituted C1-C3 alkylformyl, hydroxyformyl, nitro, amino, optionally substituted C1-C3 alkylamino, optionally substituted C1-C3 alkylformylamino, fluorine, chlorine, bromine;

[0045] Alternatively, two adjacent R3 substituents form an optionally substituted C3-C6 carbocyclic ring or an optionally substituted C3-C6 heterocyclic ring containing 1 or 2 oxygens;

[0046] m is an integer from 1 to 3;

[0047] The hydrogen in the structure of formula IV is optionally substituted with deuterium.

[0048] In a preferred embodiment, "optionally substituted" means that the group modified by the term is substituted by C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, halogen, amino, nitro, or acetyl.

[0049] In a specific embodiment, wherein,

[0050] A is selected from phenyl;

[0051] R1 and R4 are independently selected from H, D, OH, and optionally substituted C1-C6 alkoxy;

[0052] R2 and R5 are independently selected from H, D, OH, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 formyloxy;

[0053] or

[0054] R1 and R2 or R4 and R5 are linked to form an optionally substituted 3-6 membered ring containing 0, 1 or 2 heteroatoms (preferably oxygen) selected from oxygen, nitrogen or sulfur, a cyclic carbonate lactone;

[0055] R3 is selected from H, D, optionally substituted C1-C6 alkyl, D substituted C1-C6 alkyl, optionally substituted C2-C6 alkylalkenyl, optionally substituted C1-C6 acyl;

[0056] or,

[0057] Two adjacent R3 substituents form an optionally substituted C3-C6 carbocyclic ring or an optionally substituted C3-C6 heterocyclic ring containing 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur (preferably oxygen or nitrogen);

[0058] m is an integer from 1 to 3;

[0059] The hydrogens in the structures of Formula I are optionally substituted with deuterium.

[0060] In a specific embodiment, the compound is the following compound, or a salt or ester, prodrug, optical isomer or solvate thereof:

[0061]

[0062]

[0063]

[0064]

[0065]

[0066]

[0067]

[0068] Preferably, the compound is

[0069]

[0070] Most preferably, the compound is a compound selected from the group consisting of:

[0071]

[0072] In a preferred embodiment, the heart failure and its related diseases include heart failure-related diseases caused by various causes, including but not limited to heart failure induced (or caused) by various clinical therapeutic drugs, heart failure caused by myocardial infarction, coronary heart disease and other diseases, respiratory dysfunction, nocturnal sleep apnea syndrome, chronic hypoxic damage to the brain and body, etc.

[0073] In a second aspect, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt or ester, prodrug, optical isomer, stereoisomer or solvate thereof,

[0074]

[0075] In the formula,

[0076] A is selected from an optionally substituted C6-C10 aromatic ring or a 5-6 membered aromatic heterocycle containing 1, 2 or 3 heteroatoms selected from N, O or S;

[0077] R1 and R4 are independently selected from H, D, OH, NH2, carbonyl (one of R1 or R4), optionally substituted C1-C10 alkyl (preferably C1-C6 alkyl), optionally substituted C1-C10 alkoxy (preferably C1-C6 alkoxy), optionally substituted aminoacetoxy ( B can be any group that forms an amino acid);

[0078] R2 and R5 are independently selected from H, D, OH, COOH, sulfonic acid, oxygen ( Can the group in be called sulfonic acid group?), optionally substituted aminoacetoxy group ( B may be various amino acid-forming groups), optionally substituted NH2, optionally substituted C1-C10 alkyl (preferably C1-C6 alkyl), optionally substituted C1-C10 alkoxy (preferably C1-C6 alkoxy), phosphate;

[0079] or,

[0080] R1 and R2 or R4 and R5 are linked to form an optionally substituted 3-6 membered ring containing 0, 1 or 2 heteroatoms (preferably oxygen) selected from oxygen, nitrogen or sulfur, a cyclic carbonate lactone, a phosphate lactone or an optionally substituted cyclic boric acid lactone;

[0081] R3 is selected from H, D, optionally substituted C1-C10 alkyl (preferably C1-C6 alkyl) or alkenyl, optionally substituted C1-C10 alkyl (preferably C1-C6 alkyl) formyl, optionally substituted C1-C10 alkyl (preferably C1-C6 alkyl), D substituted C1-C10 alkyl, halogen, optionally substituted C3-C10 cycloalkyl, optionally substituted C2-6 alkynyl;

[0082] or,

[0083] Two adjacent R3 substituents form an optionally substituted C3-C6 carbocyclic ring or an optionally substituted C3-C6 heterocyclic ring containing 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur (preferably oxygen), an optionally substituted C5-C10 aromatic ring or an optionally substituted C5-C10 heteroaromatic ring containing 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur (preferably oxygen);

[0084] m is an integer from 1 to 5;

[0085] The hydrogens in the structures of Formula I are optionally substituted with deuterium.

[0086] In a specific embodiment, wherein,

[0087] A is selected from a C6-C10 aromatic ring or a 5-6 membered aromatic heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, O or S;

[0088] R1 and R4 are independently selected from H, D, OH, NH2, halogen, carbonyl;

[0089] R2 and R5 are independently selected from H, D, OH, COOH, optionally substituted sulfonic acid group, optionally substituted NH2, halogen, optionally substituted phosphate group;

[0090] or

[0091] R1 and R2 or R4 and R5 are linked to form an optionally substituted 3-6 membered ring containing 0, 1 or 2 heteroatoms (preferably oxygen) selected from oxygen, nitrogen or sulfur, a cyclic carbonate lactone, a phosphate lactone or an optionally substituted cyclic boric acid lactone;

[0092] R3 is selected from H, D, optionally substituted C1-C10 alkyl (preferably C1-C6 alkyl) alkenyl, formyl, optionally substituted C1-C10 alkyl (preferably C1-C6 alkyl) formyl, optionally substituted C1-C10 alkyl (preferably C1-C6 alkyl), D substituted C1-C10 alkyl, halogen, optionally substituted C3-C10 cycloalkyl, optionally substituted C2-6 alkynyl;

[0093] or,

[0094] Two adjacent R3 substituents form an optionally substituted C3-C6 carbocyclic ring or an optionally substituted C3-C6 heterocyclic ring containing 1 or 2 oxygen atoms, an optionally substituted C5-C10 aromatic ring or an optionally substituted C5-C10 heteroaromatic ring containing 1 or 2 oxygen atoms;

[0095] m is an integer from 1 to 5;

[0096] The hydrogens in the structures of Formula I are optionally substituted with deuterium.

[0097] In a specific embodiment, the compound is the following compound, or a salt or ester, prodrug, optical isomer or solvate thereof:

[0098]

[0099]

[0100] In a third aspect, the present invention provides a pharmaceutical composition comprising the compound described in the second aspect, or a pharmaceutically acceptable salt or ester, prodrug, optical isomer, stereoisomer or solvate thereof, and a pharmaceutically acceptable carrier or excipient.

[0101] In a fourth aspect, the present invention provides a method for treating heart failure and related diseases, the method comprising administering a therapeutically effective amount of the compound described in the second aspect or the pharmaceutical composition described in the third aspect to a subject in need thereof.

[0102] In a preferred embodiment, the subject is a mammal, including but not limited to humans, pets, racing animals, livestock, etc.

[0103] In a preferred embodiment, the subject is a human.

[0104] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0105] Figure 1It shows that the compound 1-R of the present invention increases the survival rate of mice with heart failure induced by doxorubicin;

[0106] Figure 2 It shows that the compound (1-S, 1-R) of the present invention improves the ultrasound indexes (EF-Ejection fraction, ejection fraction; FS-Fractional shortening, short axis shortening rate; HR-Heartrate, heart rate) of mice with heart failure induced by adriamycin;

[0107] Figure 3 It shows that the compound (1-S, 1-R) of the present invention reduces the content of myocardial injury markers (CK-creatine kinase, creatine kinase; HBDH-hydroxybutyrate dehydrogenase, hydroxybutyrate dehydrogenase; LDH-lactate dehydrogenase, lactate dehydrogenase) in mouse serum;

[0108] Figure 4 It shows that the compound 1-R of the present invention improves myocardial fibrosis in mice with heart failure induced by adriamycin;

[0109] Figure 5 It shows that the compound 1-R of the present invention improves the ultrasound indexes of mice;

[0110] Figure 6 It is shown that the compound 1-R of the present invention improves myocardial fibrosis and cell hypertrophy in heart failure mice;

[0111] Figure 7 It is shown that compound 1-R of the present invention increases the LDH level in mice with heart failure after myocardial infarction;

[0112] Figure 8 It was shown that the compound 1-R of the present invention increased the survival rate of rats with heart failure 21 days after myocardial infarction;

[0113] Fig. 9 It shows that the compound 1-R of the present invention improves the ultrasound indexes of rats with heart failure;

[0114] Fig.10 It is shown that the compound 1-R of the present invention improves myocardial fibrosis and cell hypertrophy in rats with heart failure;

[0115] Fig.11 It is shown that compound 1-R of the present invention increases the LDH level in mice with heart failure after myocardial infarction;

[0116] Fig.12 It shows that the compound 1-R of the present invention inhibits the nuclear translocation of the transcription auxiliary factor MRTF-A in cells;

[0117] Fig.13It was shown that the compound 1-R of the present invention inhibited the expression of the cardiomyocyte hypertrophy marker MyHC and the activity of cellular RhoA;

[0118] Fig.14 It was shown that the compound 1-R of the present invention inhibited the expression of collagen, a marker of myocardial fibrosis in mice;

[0119] Fig.15 A schematic diagram showing the mechanism of action of the compounds of the present invention. DETAILED DESCRIPTION

[0120] After extensive and in-depth research, the inventor unexpectedly discovered a series of compounds that have therapeutic effects on heart failure and related diseases, thus laying a new material foundation for the development of therapeutic drugs for heart failure and related diseases. On this basis, the present invention was completed.

[0121] Definition of terms

[0122] The terms used herein for the groups, substituents or structures of the compounds have the same meanings as understood by those skilled in the art. For the sake of clarity, the terms used in this specification are defined as follows.

[0123] In this document, "a", "an", "a kind" or "a category" are meant to include the plural forms of the objects they modify, that is, "a", "an", "a kind" or "a category" means at least one / kind / category or one / kind / category or more than one / kind / category.

[0124] In this article, the form "C 1-n " means that the group has 1-n carbon atoms, for example, "C 1-10 " means that the group has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms; similarly, "C6-C10" means that the group has 6, 7, 8, 9 or 10 carbon atoms. At the same time, the description of the range of carbon atoms in this article also includes the sub-ranges therein. For example, when 1-10 carbon atoms are mentioned in this article, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, and 1-3 carbon atoms are also included.

[0125] The term "alkyl" as used herein has the same meaning as that generally understood by those of ordinary skill in the art, and refers to various saturated or unsaturated straight-chain, side-chain or cyclic hydrocarbon groups. For example, the alkyl described herein refers to a lower alkyl group of 1-10 carbon atoms; preferably, a lower alkyl group of 1-8 carbon atoms; more preferably, a lower alkyl group of 1-6 carbon atoms. In a specific embodiment, the alkyl described herein includes, but is not limited to: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, and the like.

[0126] The term "aryl" or "aromatic ring" as used herein has the same meaning as that generally understood by those of ordinary skill in the art, and refers to a cyclic conjugated aromatic system; for example, the term "C6-C10 aryl" refers to an aromatic ring group having 6 to 10 carbon atoms without heteroatoms in the ring, such as phenyl, naphthyl, etc. The term "heteroaryl" as used herein refers to a cyclic conjugated aromatic system containing one or more heteroatoms such as N, O or S in the ring; for example, pyridyl, pyrazinyl.

[0127] The term "aminoacetyl" as used herein has the conventional meaning as understood by those of ordinary skill in the art, i.e., an acetyl group substituted with an amino group. As shown, wherein R is various amino acid substituents.

[0128] The terms "heterocyclyl" or "heterocycle" used herein have the same meaning, and both refer to saturated or partially unsaturated non-aromatic cyclic groups, including monocyclic, fused, spirocyclic or bridged rings, wherein the heterocyclic ring has at least one heteroatom selected from O, S or N as a ring member. For example, "5- or 6-membered heterocyclyl" refers to a saturated or unsaturated 5- or 6-membered cycloalkyl group containing 1 to 3 heteroatoms selected from oxygen, sulfur or nitrogen in the ring, such as dioxolanyl, etc.

[0129] The term "halogen" as used herein refers to F, Cl, Br or I.

[0130] Based on the teachings of the present invention and common knowledge in the art, those skilled in the art will appreciate that the compounds of the present invention and the various substituents defined above may be further substituted, for example, by C1-6 alkyl, C1-6 alkoxy, halogen, nitro, amino, phenyl, hydroxyl, etc., as long as the desired combination of substituents is a stable or chemically feasible combination of substituents.

[0131] The term "substituted" as used herein means that one or more hydrogen atoms on a specific group are replaced by a specific substituent. The specific substituent may be the substituent described above, or the specific substituent appearing in the examples. Therefore, in the present invention, the substituents in the general formula (I) or (II) may each independently be the corresponding group in the specific compound in the examples; that is, the present invention includes the combination of the substituents in the above-mentioned general formula (I) or (II), and also includes the combination of some of the substituents shown in the general formula (I) or (II) and other specific substituents appearing in the examples.

[0132] Unless otherwise specified, a substituted group may have a specific substituent at any substitutable position of the group, and the substituent may be the same or different at each position. A cyclic substituent, such as a heterocyclic group, may be attached to another ring, such as a cycloalkyl group, to form a spirobicyclic ring system, for example, the two rings have a common carbon atom. The substituents are, for example (but not limited to): C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, 3- to 12-membered heterocyclic group, aryl, heteroaryl, halogen, hydroxyl, carboxyl (-COOH), C 1-8 Aldehyde, C 2-10 Acyl, C 2-10 Ester group, amino group, C 1-8 Alkoxy, nitro, cyano, mercapto, amino, etc. In a specific embodiment, the hydrogen atoms on the alkyl and aryl groups are replaced by amino, halogen or other groups to become the groups defined above.

[0133] For convenience and in accordance with common understanding, the terms "optionally substituted", "optionally substituted" or "substituted or unsubstituted" only apply to sites that can be substituted by substituents, and do not include those substitutions that are chemically unfeasible.

[0134] The term "independently selected from" as used herein means that the multiple groups modified by the term can be selected relatively independently within the scope. For example, when it is mentioned herein that "R1 and R4 are independently selected from H, OH, and carbonyl", it is equivalent to disclosing "R1 is selected from H, OH or carbonyl" and "R4 is selected from H, OH or carbonyl".

[0135] Compounds of the present invention

[0136] The present invention provides a series of novel compounds having therapeutic effects on heart failure and related diseases, and these compounds have different mechanisms from existing therapeutic drugs.

[0137] In a specific embodiment, the present invention provides a compound represented by the following formula I or II, or a pharmaceutically acceptable salt or ester, prodrug, optical isomer, stereoisomer or solvate thereof:

[0138]

[0139] Each substituent in the general formula is as described above.

[0140] In a preferred embodiment, the compound represented by formula I is a compound represented by formula II,

[0141]

[0142] Each substituent in the formula is as described above.

[0143] In a preferred embodiment, the compound represented by formula I is a compound represented by formula III,

[0144]

[0145] Each substituent in the formula is as described above.

[0146] In a preferred embodiment, the compound represented by formula I is a compound represented by formula IV,

[0147]

[0148] Each substituent in the formula is as described above.

[0149] In a specific embodiment, the preferred compounds of the present invention are the following compounds:

[0150]

[0151]

[0152] Based on the compounds of the present invention, those skilled in the art can prepare pharmaceutically acceptable salts or esters, prodrugs, optical isomers, stereoisomers or solvates thereof. For example, the compounds of the present invention can be reacted with inorganic acids or organic acids to form conventional pharmaceutically acceptable salts. The inorganic acid includes hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aminosulfonic acid and phosphoric acid, and the organic acid includes various amino acids, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalene disulfonic acid, maleic acid, malic acid, malonic acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid and isethionic acid, etc.; or the compound of the present invention is reacted with an inorganic base to form a sodium salt, potassium salt, calcium salt, aluminum salt or ammonium salt; or it is reacted with an organic base to form a methylamine salt, ethylamine salt or ethanolamine salt.

[0153] Since there are chiral carbon atoms in the compounds of the present invention, the optical isomers or stereoisomers obtained by resolving the compounds of the present invention also fall within the protection scope of the present invention.

[0154] Based on the teachings of this article, those skilled in the art should understand that the compounds provided by the present invention that have therapeutic effects on heart failure and related diseases should have various properties inherent to drugs, such as therapeutic activity, drugability, pharmacokinetic activity, etc., and the compounds of the present invention should also have acceptable toxicity. Therefore, all pharmaceutically relevant activities of the compounds of the present invention are implicitly disclosed herein, and those skilled in the art can detect these properties using methods known in the art.

[0155] Based on the compound of the present invention or its pharmaceutically acceptable salt or ester, prodrug, optical isomer, stereoisomer or solvate, the present invention also provides a pharmaceutical composition comprising the compound of the present invention, wherein the pharmaceutical composition optionally comprises a pharmaceutically acceptable excipient.

[0156] In a specific embodiment, the pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.

[0157] "Pharmaceutically acceptable excipients or carriers" refer to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0158] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administrations include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0159] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0160] Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.

[0161] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.

[0162] Besides these inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and perfumes.

[0163] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances.

[0164] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0165] Dosage forms for topical administration of the compounds of the invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0166] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds. When using a pharmaceutical composition, a safe and effective amount of the compounds of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage. The compounds and pharmaceutical compositions of the present invention can be administered by oral, nasal, skin, lung or gastrointestinal tract administration. Oral administration, one-time or divided administration, is most preferred. Regardless of the method of administration, the optimal dose for an individual should be determined based on the specific treatment. Usually, it is started with a small dose and the dose is gradually increased until the most suitable dose is found. Of course, the specific dose should also take into account factors such as the route of administration and the patient's health status, which are all within the skill range of skilled physicians. In a specific embodiment, the compounds of the present invention are preferably in a form suitable for aerosol administration.

[0167] Heart failure and related diseases

[0168] In this article, the terms "heart failure" and "heart failure" have the same meaning, both referring to the inability to fully discharge venous blood from the heart due to the impairment of the heart's contractile and (or) diastolic functions, resulting in blood congestion in the venous system and insufficient blood perfusion in the arterial system, thus causing a syndrome of cardiac circulatory disorders. This syndrome is mainly manifested as pulmonary congestion and vena cava congestion. Heart failure is not an independent disease, but the terminal stage of the development of heart disease. The vast majority of heart failures begin with left heart failure.

[0169] Almost all cardiovascular diseases will eventually lead to heart failure. Myocardial damage caused by any reason, such as myocardial infarction, cardiomyopathy, hemodynamic overload, inflammation, etc., can cause changes in myocardial structure and function, and finally lead to poor ventricular pumping and (or) filling function. In addition, other factors can induce the occurrence of heart failure. Common causes of heart failure include, for example, infection, toxic side effects of drugs, inappropriate activities and emotions, etc.

[0170] According to the urgency of heart failure, it can be clinically divided into acute heart failure and chronic heart failure. According to the location of heart failure, it can be divided into left heart failure, right heart failure and whole heart failure. It can also be divided into systolic or diastolic heart failure.

[0171] In a specific embodiment, the heart failure and its related diseases include heart failure-related diseases caused by various causes, including but not limited to heart failure induced (or caused) by various clinical therapeutic drugs, heart failure (ventricular remodeling) caused by myocardial infarction, coronary heart disease and other diseases, respiratory dysfunction, nocturnal sleep apnea syndrome, and chronic hypoxic damage to the brain and body.

[0172] Advantages of the present invention:

[0173] 1. The present invention provides a series of novel compounds having therapeutic effects on heart failure and related diseases; and

[0174] 2. The compounds of the present invention lay a new material foundation for the development of new therapeutic drugs for heart failure and related diseases.

[0175] The technical scheme of the present invention is further described below in conjunction with specific implementation cases, but the following implementation cases do not constitute a limitation of the present invention, and all various application methods adopted according to the principles and technical means of the present invention belong to the scope of the present invention. The experimental methods in the following examples where specific conditions are not specified are usually carried out under conventional conditions or under conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight.

[0176] Example

[0177] Some known compounds are available for purchase.

[0178] The compounds of the present invention can be prepared according to conventional routes or methods, or can be obtained according to the methods or routes described herein.

[0179] Example 1. Synthesis of a series of compounds

[0180] 1. Synthesis of 3-ethylphenyl glycol (Compound 1)

[0181]

[0182] Synthesis of compound 1.3

[0183] Magnesium chips (2.2 g, 90 mmol) were placed in a 250 mL three-necked reaction bottle, and one grain of iodine was added. Compound 1.1 (15 g, 82 mmol) was dissolved in 120 mL of anhydrous tetrahydrofuran, and 10 mL of the tetrahydrofuran solution of compound 1 was dripped into the reaction bottle containing magnesium chips through a constant pressure dropping funnel. The reaction was initiated by heating with a hair dryer, and the remaining 110 mL of the tetrahydrofuran solution of compound 1.1 was slowly dripped in after the reaction started. After the dripping was completed, the reaction was refluxed for 3.5 hours to finally obtain a tetrahydrofuran solution of compound 1.2.

[0184] Under ice bath, the tetrahydrofuran solution of compound 1.2 was added dropwise to a solution of benzyloxyacetaldehyde (12 g, 80 mmol) in anhydrous tetrahydrofuran (80 mL). After the addition was completed, the mixture was heated to room temperature for 1 hour, and then a saturated aqueous solution of ammonium chloride was added to quench the reaction. Finally, the tetrahydrofuran was removed, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by column chromatography (PE: EA = 10: 1) to obtain 12.4 g of the target compound, with a two-step yield of 59.6%.

[0185] 1 H NMR (400MHz, DMSO): δ7.36-7.15 (m, 8H), 7.09 (d, J=7.6Hz, 1H), 5.38 (d, J=4.4Hz, 1H), 4.74-4.70 ( m, 1H), 4.51 (s, 2H), 3.53-3.44 (m, 2H), 2.61 (q, J=7.6, 2H), 1.19 (t, J=7.6, 3H). LC-MS: 255.30 (MH) - .

[0186] Synthesis of Compound 1 (including Compound 1 racemate, R-configuration 1-R of Compound 1, S-configuration 1-S of Compound 1)

[0187] Compound 1.3 (12.4 g, 48.4 mmol) was dissolved in 70 mL of ethanol, and 2.43 g of 10% palladium on carbon was added, the air was replaced, H2 was added, and the mixture was stirred at 38°C for 3 hours. After the reaction, the solvent was removed and purified by column chromatography (PE:EA=5:1) to obtain 6.42 g of the target compound with a yield of 79%.

[0188] The R-configuration of compound 1 and the S-configuration of compound 1 were obtained by chiral preparation.

[0189] 1H NMR (400MHz, CDCl3): δ7.28-7.12 (m, 4H), 4.78 (dd, J1=8.0Hz, J2=3.6Hz, 1H), 3. 74-3.62 (m, 2H), 2.64 (q, J=7.6Hz, 2H), 1.23 (t, J=7.6Hz, 3H). LC-MS: 165.10 (MH) - .

[0190] 2. Synthesis of Compound 2

[0191]

[0192] Synthesis of compound 2.6

[0193] Magnesium chips (0.17 g, 7 mmol) were placed in a 50 mL three-necked reaction bottle, 1 grain of iodine was added, compound 2.4 (1 g, 6.4 mmol) was dissolved in 12 mL of anhydrous tetrahydrofuran, 2 mL of the tetrahydrofuran solution of compound 4 was dripped into the reaction bottle through a constant pressure dropping funnel, and the reaction was initiated by heating with a hair dryer. After the reaction started, the remaining 10 mL of the tetrahydrofuran solution of compound 2.4 was slowly dripped in. After the dripping was completed, the reaction was refluxed for 3.5 hours to finally obtain a tetrahydrofuran solution of compound 2.5.

[0194] Under ice bath, the tetrahydrofuran solution of compound 2.5 was added dropwise to 8 mL of anhydrous tetrahydrofuran solution of benzyloxyacetaldehyde (0.97 g, 6.4 mmol). After the addition was completed, the mixture was heated to room temperature for 1 hour, and then saturated aqueous ammonium chloride solution was added to quench the reaction. Finally, tetrahydrofuran was removed, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by column chromatography (PE:EA=10:1) to obtain 0.98 g of the target compound, with a two-step yield of 67.6%.

[0195] 1 H NMR (400MHz, DMSO): δ7.37-7.22 (m, 10H), 5.41 (d, J=4.0Hz, 1H), 4.78-4.74 (m, 1H), 4.51 (s, 2H), 3.51-3.48 (m, 2H). LC-MS: 227.30 (MH) - .

[0196] Synthesis of compound 2

[0197] Compound 2.6 (0.9 g, 4 mmol) was dissolved in 10 mL of ethanol, and 0.2 g of 10% palladium on carbon was added, the air was replaced, H2 was added, and the mixture was stirred at 38°C for 3 hours. After the reaction, the solvent was removed and the mixture was purified by column chromatography (PE:EA=5:1) to obtain 0.24 g of the target compound with a yield of 45%.

[0198] 1 H NMR (400MHz, DMSO): δ7.34-7.28 (m, 4H), 7.24-7.20 (m, 1H), 5.24 (d, J=4.4Hz, 1H) , 4.74 (t, J=6Hz, 1H), 4.55 (q, J=6Hz, 1H), 3.43 (t, J=6Hz, 2H). LC-MS: 137.10 (MH) - .

[0199] 3. Synthesis of Compound 3

[0200]

[0201] Synthesis of compound 3.9

[0202] Magnesium chips (0.33 g, 13.8 mmol) were placed in a 100 mL three-necked reaction bottle, 1 grain of iodine was added, compound 3.7 (2 g, 11.7 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran, 3 mL of the tetrahydrofuran solution of compound 3.7 was dripped into the reaction bottle through a constant pressure dropping funnel, and the reaction was initiated by heating with a hair dryer. After the reaction started, the remaining 17 mL of the tetrahydrofuran solution of compound 7 was slowly dripped in. After the dripping was completed, the reaction was refluxed for 3.5 hours to finally obtain a tetrahydrofuran solution of compound 3.8.

[0203] Under ice bath, the tetrahydrofuran solution of compound 3.8 was added dropwise to a 14 mL solution of benzyloxyacetaldehyde (1.74 g, 11.6 mmol) in anhydrous tetrahydrofuran. After the addition was completed, the mixture was heated to room temperature for 1 hour, and then a saturated aqueous solution of ammonium chloride was added to quench the reaction. Finally, the tetrahydrofuran was removed, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by column chromatography (PE:EA=10:1) to obtain 0.95 g of the target compound, with a two-step yield of 34%.

[0204] 1 H NMR (400MHz, DMSO): δ7.34-7.04 (m, 9H), 5.34 (d, J=4.0Hz, 1H), 4.73-4.69 (m, 1H), 4.51 (s, 2H), 3.52-3.43 (m, 2H), 2.28 (s, 3H). LC-MS: 241.30 (MH) - .

[0205] Synthesis of compound 3

[0206] Compound 3.9 (0.9 g, 3.8 mmol) was dissolved in 10 mL of ethanol, and 0.2 g of 10% palladium on carbon was added. The air was replaced, H2 was added, and the mixture was stirred at 38°C for 3 hours. After the reaction, the solvent was removed and the mixture was purified by column chromatography (PE:EA=5:1) to obtain 0.28 g of the target compound with a yield of 50%.

[0207] 1 H NMR (400MHz, CDCl3): δ7.26-7.09 (m, 4H), 4.76 (dd, J1=8.0Hz, J2=3.6Hz, 1H), 3.72-3.59 (m, 2H), 3.09 (s, 2H), 2.34 (s, 3H). LC-MS: 151.10 (MH) - .

[0208] 4. Synthesis of Compound 4

[0209]

[0210] Synthesis of compound 4.12

[0211] Magnesium chips (0.31 g, 12.9 mmol) were placed in a 100 mL three-necked reaction bottle, 1 grain of iodine was added, compound 4.10 (2 g, 10.9 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran, 3 mL of the tetrahydrofuran solution of compound 10 was dripped into the reaction bottle through a constant pressure dropping funnel, and the reaction was initiated by heating with a hair dryer. After the reaction started, the remaining 17 mL of the tetrahydrofuran solution of compound 4.10 was slowly dripped in. After the addition was completed, the reaction was refluxed for 3.5 hours to finally obtain a tetrahydrofuran solution of compound 11.

[0212] Under ice bath, the tetrahydrofuran solution of compound 4.11 was added dropwise to a 14 mL solution of benzyloxyacetaldehyde (1.62 g, 10.8 mmol) in anhydrous tetrahydrofuran. After the addition was completed, the mixture was heated to room temperature for 1 hour, and then a saturated aqueous ammonium chloride solution was added to quench the reaction. Finally, the tetrahydrofuran was removed, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by column chromatography (PE:EA=10:1) to obtain 1 g of the target compound, with a two-step yield of 36%.

[0213] 1 H NMR (400MHz, DMSO): δ7.35-7.14 (m, 9H), 5.33 (d, J=4.0Hz, 1H), 4.74-4.70 (m, 1H), 4.51 (s , 2H), 3.52-3.43 (m, 2H), 2.57 (q, J=7.6Hz, 2H), 1.16 (t, J=7.6Hz, 3H). LC-MS: 255.30 (MH) - .

[0214] Synthesis of compound 4

[0215] Compound 4.12 (0.9 g, 3.5 mmol) was dissolved in 10 mL of ethanol, and 0.2 g of 10% palladium on carbon was added, the air was replaced, H2 was added, and the mixture was stirred at 38°C for 3 hours. After the reaction, the solvent was removed and the mixture was purified by column chromatography (PE:EA=5:1) to obtain 0.24 g of the target compound with a yield of 37%.

[0216] 1 H NMR (400MHz, CDCl3): δ7.20-7.10 (m, 4H), 4.72 (dd, J1=8.0Hz, J2=3.6Hz, 1H), 3.66-3.5 5 (m, 2H), 2.59 (q, J=7.6Hz, 2H), 2.46 (s, 2H), 1.15 (t, J=7.6Hz, 3H). LC-MS: 165.10 (MH) - .

[0217] 6. Synthesis of Compound 6

[0218]

[0219] Synthesis of Compound 6.18

[0220] Magnesium chips (0.31 g, 12.9 mmol) were placed in a 100 mL three-necked reaction bottle, 1 grain of iodine was added, compound 6.16 (2 g, 8.5 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran, 3 mL of the tetrahydrofuran solution of compound 16 was dripped into the reaction bottle through a constant pressure dropping funnel, and the reaction was initiated by heating with a hair dryer. After the reaction started, the remaining 17 mL of the tetrahydrofuran solution of compound 6.16 was slowly dripped in. After the addition was completed, the reaction was refluxed for 3.5 hours to finally obtain a tetrahydrofuran solution of compound 6.17.

[0221] Under ice bath, the tetrahydrofuran solution of compound 6.17 was added dropwise to a 14 mL solution of benzyloxyacetaldehyde (1.28 g, 8.5 mmol) in anhydrous tetrahydrofuran. After the addition was completed, the mixture was heated to room temperature for 1 hour, and then a saturated aqueous solution of ammonium chloride was added to quench the reaction. Finally, the tetrahydrofuran was removed, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by column chromatography (PE:EA=10:1) to obtain 0.9 g of the target compound, with a two-step yield of 32%.

[0222] 1H NMR (400MHz, DMSO): δ7.38-7.02 (m, 9H), 5.33 (d, J=4.4Hz, 1H), 4.75-4.70 (m, 1H), 4.47 (s, 2H), 3.56-3.49 (m, 2H). LC-MS: 307.30 (MH) - .

[0223] Synthesis of compound 6

[0224] Compound 6.18 (0.85 g, 2.8 mmol) was dissolved in 10 mL of ethanol, and 0.23 g of 10% palladium carbon was added, the air was replaced, H2 was added, and the mixture was stirred at 38°C for 3 hours. After the reaction, the solvent was removed and the mixture was purified by column chromatography (PE:EA=5:1) to obtain 0.2 g of the target compound with a yield of 33%.

[0225] 1 H NMR (400MHz, DMSO): δ7.35-7.29 (m, 1H), 7.19-7.13 (m, 2H), 7.02-6.98 (m, 1H), 5.34 (d, J =4Hz, 1H), 4.70 (t, J = 6Hz, 1H), 4.51 (q, J = 5.6Hz), 3.40 (t, J = 6Hz, 2H). LC-MS: 217.10 (MH) - .

[0226] 7. Synthesis of Compound 7

[0227]

[0228] Synthesis of Compound 7.21

[0229] Magnesium chips (0.31 g, 12.9 mmol) were placed in a 100 mL three-necked reaction bottle, 1 grain of iodine was added, compound 7.19 (2 g, 11.7 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran, 3 mL of the tetrahydrofuran solution of compound 19 was dripped into the reaction bottle through a constant pressure dropping funnel, and the reaction was initiated by heating with a hair dryer. After the reaction started, the remaining 7.17 mL of the tetrahydrofuran solution of compound 7.19 was slowly dripped in. After the addition was completed, the reaction was refluxed for 3.5 hours to finally obtain a tetrahydrofuran solution of compound 7.20.

[0230] Under ice bath, the tetrahydrofuran solution of compound 7.20 was added dropwise to a 14 mL solution of benzyloxyacetaldehyde (1.76 g, 11.7 mmol) in anhydrous tetrahydrofuran. After the addition was completed, the mixture was heated to room temperature for 1 hour, and then a saturated aqueous solution of ammonium chloride was added to quench the reaction. Finally, the tetrahydrofuran was removed, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by column chromatography (PE: EA = 10: 1) to obtain 1.32 g of the target compound, with a two-step yield of 47.2%.

[0231] 1 H NMR (400MHz, DMSO): δ7.44-7.14 (m, 9H), 5.36 (d, J=4.4Hz, 1H), 4.71-4.67 (m, 1H), 4.50 (s, 2H), 3.50-3.41 (m, 2H). LC-MS: 245.30 (MH) -

[0232] Synthesis of compound 7

[0233] Compound 7.21 (1.3 g, 5.4 mmol) was dissolved in 10 mL of ethanol, and 0.23 g of 10% palladium on carbon was added, the air was replaced, H2 was added, and the mixture was stirred at 38°C for 3 hours. After the reaction, the solvent was removed and purified by column chromatography (PE:EA=5:1) to obtain 0.2 g of the target compound with a yield of 33%.

[0234] 1 H NMR (400MHz, DMSO): δ7.37-7.3l (m, 1H), 7.18-7.12 (m, 2H), 7.06-7.01 (m, 1H), 5.39 (d, J=4 .4Hz, 1H), 4.77 (t, J=5.6Hz, 1H), 4.56 (q, J=5.6Hz), 3.43 (t, J=6Hz, 2H). LC-MS: 155.10 (MH) - .

[0235] 8. Synthesis of Compound 8

[0236]

[0237] Synthesis of compound 8.24

[0238] Magnesium chips (0.57 g, 22.2 mmol) were placed in a 100 mL three-necked reaction bottle, 1 iodine was added, compound 8.22 (4 g, 21.5 mmol) was dissolved in 40 mL of anhydrous tetrahydrofuran, 5 mL of the tetrahydrofuran solution of compound 8.22 was dripped into the reaction bottle through a constant pressure dropping funnel, and the reaction was initiated by heating with a hair dryer. After the reaction started, the remaining 35 mL of the tetrahydrofuran solution of compound 8.22 was slowly dripped in. After the addition was completed, the reaction was refluxed for 3.5 hours to finally obtain a tetrahydrofuran solution of compound 8.23.

[0239] Under ice bath, the tetrahydrofuran solution of compound 8.23 ​​was added dropwise to a 30 mL solution of benzyloxyacetaldehyde (3.21 g, 21.5 mmol) in anhydrous tetrahydrofuran. After the addition was completed, the mixture was heated to room temperature for 1 hour, and then a saturated aqueous solution of ammonium chloride was added to quench the reaction. Finally, the tetrahydrofuran was removed, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by column chromatography (PE:EA=10:1) to obtain 4 g of the target compound, with a two-step yield of 63.6%.

[0240] 1 H NMR (400MHz, DMSO): δ7.35-7.14 (m, 9H), 5.33 (d, J=4.0Hz, 1H), 4.74-4.70 (m, 1H), 4.51 (s, 2H), 3.73 (s, 3H), 3.52-3.43 (m, 2H). LC-MS: 257.30 (MH) - .

[0241] Synthesis of compound 8

[0242] Compound 8.24 (3.5 g, 13.6 mmol) was dissolved in 30 mL of ethanol, and 0.69 g of 10% palladium on carbon was added, the air was replaced, H2 was added, and the mixture was stirred at 38°C for 3 hours. After the reaction, the solvent was removed and the mixture was purified by column chromatography (PE:EA=5:1) to obtain 1.42 g of the target compound with a yield of 62.3%.

[0243] 1 H NMR (400MHz, DMSO): δ7.23 (t, J=8Hz, 1H), 6.91 (d, J=7.6Hz, 2H), 6.80-6.77 (m, 1H), 5.24 (d, J=4.4Hz, 1H), 4.73 (t, J=5.6Hz, 1H), 4.53 (q, J=4.8Hz, 1H), 3.73 (s, 3H), 3.43-3.36 (m, 2H). LC-MS: 167.10 (MH) - .

[0244] 9. Synthesis of Compound 9

[0245]

[0246] Synthesis of compound 9.26

[0247] Dissolve p-isopropylaniline (4 g, 29.6 mmol) in dichloromethane (40 ml), and add NBS (5.8 g, 32.6 mmol) to the dichloromethane solution in batches under an ice bath, then raise the reaction temperature to room temperature and react for 1 hour to complete. After purification, 4.6 g of the product is obtained with a yield of 74%.

[0248] 1 H NMR (400MHz, CDCl3): δ7.28 (d, J=1.6Hz, 1H), 6.98 (dd, J1=1.6Hz, J2=1.6Hz, 1H), 6.7 1(d, J=8Hz, 1H), 3.76 (s, 2H), 2.79 (m, 1H), 1.20 (d, J=6.8Hz, 6H). LC-MS: 214.10 (M+H) + .

[0249] Synthesis of Compound 9.27

[0250] Compound 9.26 (2 g, 9.3 mmol) was dissolved in a mixed solution of acetic acid (10 mL), water (4 mL) and concentrated HCl (1 mL), and then an aqueous solution (2 mL) of NaNO2 (0.78 g, 11.2 mmol) was added dropwise to the mixed solution under an ice bath. After the reaction was carried out for half an hour, the obtained reaction mixture was added dropwise to a 50% aqueous solution (12 mL) of H3PO2 under an ice bath. After the addition was completed, the reaction was continued for 8 hours, and then the reaction temperature was raised to 25 degrees Celsius for 3 days. After the reaction was completed, it was purified by column. 1.4 g of product was obtained with a yield of 75.3%.

[0251] 1 H NMR (400MHz, DMSO): δ7.42 (s, 1H), 7.37-7.34 (m, 1H), 7.25 (d, J=4.8Hz, 2H), 1.20 (d, J=6.8Hz, 6H). LC-MS: 199.20 (M+H) + .

[0252] Synthesis of Compound 9.29

[0253] Magnesium chips (0.17 g, 7.1 mmol) were placed in a 100 mL three-necked reaction bottle, 1 grain of iodine was added, compound 9.27 (1.3 g, 7.5 mmol) was dissolved in 12 mL of anhydrous tetrahydrofuran, 2 mL of the tetrahydrofuran solution of compound 9.27 was dripped into the reaction bottle through a constant pressure dropping funnel, and the reaction was initiated by heating with a hair dryer. After the reaction started, the remaining 10 mL of the tetrahydrofuran solution of compound 9.27 was slowly dripped in. After the dripping was completed, the reaction was refluxed for 3.5 hours to finally obtain a tetrahydrofuran solution of compound 9.28.

[0254] Under ice bath, the tetrahydrofuran solution of compound 9.28 was added dropwise to a 10 mL solution of benzyloxyacetaldehyde (0.98 g, 7.1 mmol) in anhydrous tetrahydrofuran. After the addition was completed, the mixture was heated to room temperature for 1 hour, and then a saturated aqueous solution of ammonium chloride was added to quench the reaction. Finally, the tetrahydrofuran was removed, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by column chromatography (PE:EA=10:1) to obtain 1 g of the target compound, with a two-step yield of 56%.

[0255] 1 H NMR (400MHz, DMSO): δ7.36-7.15 (m, 8H), 7.09 (d, J=8Hz, 1H), 5.38 (d, J=4Hz, 1H), 4.74-4.70 (m, 1 H), 4.51 (s, 2H), 3.53-3.44 (m, 2H), 2.83-2.76 (m, 1H), 1.20 (d, J=7.6Hz, 6H). LC-MS: 271.30 (M+H) + .

[0256] Synthesis of compound 9

[0257] Compound 9.28 (1 g, 3.6 mmol) was dissolved in 10 mL of ethanol, and 0.19 g of 10% palladium on carbon was added. The air was replaced, H2 was added, and the mixture was stirred at 38°C for 3 hours. After the reaction, the solvent was removed and the mixture was purified by column chromatography (PE:EA=5:1) to obtain 0.51 g of the target compound with a yield of 80%.

[0258] 1 H NMR (400MHz, CDCl3): δ7.19-7.04(m, 4H), 4.69(d, J=4.0Hz, 1H), 3.64-3.52(m, 2H), 3.22 (s, 2H), 2.83-2.76 (m, 1H), 1.15 (d, J=7.6Hz, 6H). LC-MS: 179.10 (MH) - .

[0259] 10. Synthesis of Compound 10

[0260]

[0261] Synthesis of compound 10.30 (protection of carbonyl group)

[0262] Take p-bromoacetophenone (5g, 25.4mmol) in a 100mL three-necked flask, add 60mL of toluene as solvent, add ethylene glycol (10g, 161.3mmol), p-toluenesulfonic acid (1g, 5mmol), heat to 130℃, reflux and separate water for 16h. After the reaction is completed, add brine and stir, let it stand and separate, take the organic phase, dry it with anhydrous sodium sulfate, and pass it through column chromatography to obtain 3g of compound with a yield of 48%.

[0263] 1 H NMR (400MHz, CDCl3): δ7.49-7.44 (m, 2H), δ7.37-7.34 (m, 2H), 4.05 (m, 2H), 3.77-3.73 (m, 2H), 1.62 (s, 3H). LC-MS: 242.10 (MH) - .

[0264] Synthesis of compound 10.32

[0265] Magnesium chips (0.31 g, 12.9 mmol) were placed in a 100 mL three-necked reaction bottle, 1 grain of iodine was added, p-bromobenzene acetal (2.5 g, 10.4 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran, 3 mL of tetrahydrofuran solution of acetal was dripped into the reaction bottle through a constant pressure dropping funnel, and the reaction was initiated by heating with a hair dryer. After the reaction started, the remaining 17 mL of tetrahydrofuran solution was slowly dripped in. After the dripping was completed, the reaction was refluxed for 3.5 hours to finally obtain a tetrahydrofuran solution of Grignard reagent.

[0266] Under ice bath, add the tetrahydrofuran solution of acetal to 14 mL of anhydrous tetrahydrofuran solution of benzyloxyacetaldehyde (1.5 g, 10 mmol). After the addition, warm to room temperature to react for 1 hour, then add saturated aqueous ammonium chloride to quench the reaction. Finally, remove tetrahydrofuran, extract with ethyl acetate, dry with anhydrous sodium sulfate, and purify by column (PE: EA = 10: 1) to obtain 0.8 g of the target compound, with a two-step yield of 25%.

[0267] 1H NMR (400MHz, CDCl3): δ7.44-7.29 (m, 10H), 4.90 (dd, J=8.8Hz, 3.2Hz, 1H), 4.57 (q, J=12Hz, 2H), 3.98 (t, J= 6Hz, 2H), 3.71 (t, J=6Hz, 2H), 3.60 (dd, J=8Hz, 3.2Hz), 3.39 (t, J=8Hz, 1H), 1.62 (s, 3H). LC-MS: 313.20 (MH) - .

[0268] Synthesis of compound 10.33 (debenzylation reaction)

[0269] The compound (0.75 g, 2.4 mmol) was dissolved in 10 mL of ethanol, and 0.23 g of 10% palladium on carbon was added, the air was replaced, H2 was added, and the mixture was stirred at 38°C for 3 hours. After the reaction, the solvent was removed and the mixture was purified by column chromatography (PE:EA=2:1) ​​to obtain 0.2 g of the target compound with a yield of 29%.

[0270] 1 H NMR (400MHz, DMSO): δ7.35-7.29 (m, 4H), 5.23 (d, J=4Hz, 1H), 4.74 (t, J=6Hz, 1H), 4.54- 4.49 (m, 1H), 3.98-3.94 (m, 2H), 3.43 (t, J=6.8Hz, 2H), 1.53 (s, 3H). LC-MS: 223.10 (MH) - .

[0271] Synthesis of compound 10

[0272] Compound 10.33 (0.18 g, 0.8 mmol) was added with 10 mL of ethanol and 5 drops of hydrochloric acid, and reacted at 50°C for 15 h. Water was added, and DCM was extracted. The organic phase was dried over anhydrous sodium sulfate and subjected to column chromatography to obtain 0.06 g, with a yield of 40%.

[0273] 1 H NMR (400MHz, DMSO): δ7.91 (d, J=8.4Hz, 2H), 7.49 (d, J=8.4Hz, 2H), 5.42 (d, J=4Hz, 1H), 4.80 (t, J=6Hz, 1H), 4.63 (q, J=5.6Hz, 1H), 3.46 (t, J=6Hz, 2H), 2.56 (s, 3H). LC-MS: 181.10 (M+H) + .

[0274] 11. Synthesis of Compound 11(D)

[0275]

[0276] 1. Synthesis of 3-vinylphenyl oxirane (B)

[0277] Under nitrogen protection, potassium tert-butoxide (2.214g, 0.02mol), THF (2ml), DMSO (12ml) were added dropwise to a three-necked flask containing trivinylbenzaldehyde (A, 1.215g, 0.009mol), trimethylsulfur iodide (2.118g, 0.011mol), THF (8ml), and DMSO (15ml), and the mixture was reacted under ice bath for 12h. The progress of the reaction was monitored by TLC during the reaction. After the reaction was completed, the mixture was extracted with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate, and finally separated by column chromatography (PE:EA=150:1) to obtain 0.755g (56%) of 3-vinylphenyl oxirane (B).

[0278] 1 H NMR (DMSO, 400MHz): δ7.43-7.21 (m, 4H), 6.77 (dd, J=10.817.7Hz, iH,), 5.83 (d, J=17.7Hz, 1H), 5.29 (d, J=10.8Hz, 1H), 3.93 (dd, J=2.7, 4.0Hz, 1H), 3.13 (dd, J=4.0, 5.5Hz, 1H,), 2.88 (q, J=2.7Hz, 1H).

[0279] 2. Synthesis of 3-(1-hydroxy-2-benzoyloxyethyl)styrene (C)

[0280] Benzoic acid (1.22 g, 10.0 mmol), tetrabutylammonium iodide (0.369 g, 1.0 mmol), and 3-vinylphenyl oxirane (B, 1.46 g, 10.0 mmol) were dissolved in 5 mL DMF under nitrogen protection and reacted at 100°C for 12 h. The reaction progress was monitored by TLC during the reaction. After the reaction was completed, the mixture was extracted with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate. Finally, it was separated by column chromatography (PE: EA = 10: 1) to obtain 0.818 g (30.47%) of 3-(1-hydroxy-2-benzoyloxyethyl)styrene (C).

[0281] 1 H NMR (DMSO, 400MHz): δ7.33-7.95 (m, 9H), 6.78 (dd, J=10.9, 17.6Hz, 1H), 5.85 (d, J=17.6Hz, 1H), 5.78 (d, J=4.6Hz, 1H), 5.27 (d, J=10.9, 1H), 4.96 (q, J=4.6, 1H), 4.34 (d, J=5.7Hz, 2H).

[0282] Synthesis of compound 11(D)

[0283] 3-(1-Hydroxy-2-benzoyloxyethyl)styrene (C, 0.20 g, 0.745 mmol) and sodium hydroxide (0.043 g, 1.08 mmol) were dissolved in 4 ml of methanol, and 1 ml of H2O was added after reflux reaction for 2 h. The reaction progress was monitored by TLC. After the reaction was completed, dichloromethane was used for extraction, and the organic layer was dried over anhydrous sodium sulfate, and finally separated by column chromatography (PE: EA = 1: 1) to obtain 0.07 g (57.2%) of 3-(1,2-dihydroxyethyl)styrene (D).

[0284] 1 H NMR (CDCl3, 400MHz): δ7.12-7.29 (m, 4H), 6.65 (dd, J=11.1, 17.7Hz, 1H), 5.69 (d, J=17.7Hz, 1H) , 5.19 (d, J=11.1Hz, 1H), 4.71 (dd, J=3.3, 8.3Hz, 1H), 3.65 (m, 2H), 3.07 (s, 2H). MS (EI): 164.1.

[0285] 12. Synthesis of Compound 12

[0286]

[0287] Compound 1 (1.66 g, 0.01 mol) was dissolved in 7 mL of DCM, and 1 drop of concentrated sulfuric acid was added. After slight heating, an exothermic reaction began. After the reaction was completed, 20 mL of solvent was added, and the mixture was washed with sodium bicarbonate solution, dried, concentrated, and purified by column (PE: EA = 10: 1) to obtain 2.00 g of the target compound with a yield of 80%.

[0288] 1 H NMR (400MHz, CDCl3): δ7.21-7.00 (m, 4H), 4.75 (dd, J1=8.0Hz, J2=3.6Hz, 1H), 3.72-3.60 (m, 2H ), 2.66 (q, J=7.6Hz, 2H), 2.21 (s, 3H), 2.10 (s, 3H), 1.25 (t, J=7.6Hz, 3H). LC-MS: 251.17 (M+H) + .

[0289] 13. Synthesis of 1-(3-cyclopropylphenyl)-1,2-ethanediol (Compound 13)

[0290]

[0291] Synthesis of 1-(3-cyclopropylphenyl)ethanone

[0292] Weigh 3-bromoacetophenone (5g, 25.12mmol), cyclopropaneboronic acid (3.25g, 37.68mmol), anhydrous potassium phosphate (16g, 75.36mmol) and tricyclohexylphosphine (1.4lg, 5.02mmol) in a 100ml round-bottom flask, dissolve with 20mL toluene / water (v:v=100:1), add palladium acetate (563mg, 2.52mmol), heat to 100℃ under nitrogen protection for 20 hours, and track the reaction progress by TLC. After the reaction is completed, wait for the system to cool to room temperature, wash with water, extract with ethyl acetate 3 times, combine the organic layers, dry with anhydrous sodium sulfate, and evaporate the solvent under reduced pressure. Purify with silica gel column (PE:EA=100:1) to obtain 3.6g of light yellow oil with a yield of 89%.

[0293] 1 H NMR (400MHz, DMSO) δ7.74-7.69 (m, 1H), 7.64 (t, J=1.6Hz, 1H), 7.39 (t, J=7.6Hz, 1H), 7.34-7 .30 (m, 1H), 2.56 (s, 3H), 2.01 (tt, J=8.4, 5.1Hz, 1H), 1.03-0.95 (m, 2H), 0.75-0.70 (m, 2H).

[0294] Synthesis of 3-cyclopropylbenzoic acid

[0295] Copper bromide (6.03 g, 26.98 mmol) was placed in EA to make a suspension, heated and stirred to reflux, and 1-(3-cyclopropylphenyl)ethanone (3.6 g, 22.49 mmol) in EA was added dropwise with a constant pressure dropping funnel, and refluxed for reaction. TLC spot plate was used to monitor the reaction progress. After the reaction was completed, it was filtered with a diatomaceous earth pad and the filter cake was washed with EA. After the mother liquor was dried, it was extracted with EA / water for 3 times, and the organic phases were combined and dried over anhydrous sodium sulfate and then dried. The obtained 6.2 g oily substance was dissolved in 20 mL of methanol, 5 g of sodium formate was added, and the reaction was refluxed for 12 hours. The reaction progress was monitored by TLC spot plate. After the reaction was complete, the solvent was evaporated under reduced pressure, extracted with EA / water for three times, and the organic layers were combined and dried over anhydrous sodium sulfate. Purification on a silica gel column (PE: EA = 50: 1) gave 1.2 g of a slightly yellow oily substance with a yield of 30%.

[0296] 1H NMR (400MHz, DMSO) δ7.73-7.63 (m, 1H), 7.61 (dd, J=3.9, 2.4Hz, 1H), 7.39 (dd, J=14.6, 6.9Hz, 1H), 7.34-7.28 ( m, 1H), 5.03 (t, J=5.5Hz, 1H), 4.78 (d, J=3.6Hz, 1H), 2.04-1.95 (m, 1H), 1.02-0.94 (m, 2H), 0.75-0.66 (m, 2H).

[0297] Synthesis of 1-(3-cyclopropylphenyl)-1,2-ethanediol

[0298] 3-Cyclopropylbenzoic acid (750 mg, 4.26 mmol) was dissolved in anhydrous tetrahydrofuran, and sodium borohydride (242 mg, 6.39 mmol) dissolved in THF was slowly added dropwise under ice bath conditions, and the reaction progress was monitored by TLC spot plate. After the reaction was complete, saturated ammonium chloride solution was slowly added dropwise to quench the reaction, and DCM was extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Purification on a silica gel column (PE: EA = 2: 1) gave 180 mg of a white solid with a yield of 24%.

[0299] 1 H NMR (400MHz, DMSO) δ7.16 (t, J=7.6Hz, 1H), 7.10-7.03 (m, 2H), 6.91 (d, J=7.6Hz, 1H), 5.15 (d, J=3.9Hz, 1H), 4.67 (t, J=5.1Hz, 1H), 4 .48 (dd, J=9.5, 5.7Hz, 1H), 3.40 (t, J=5.5Hz, 2H), 1.93-1.85 (m, 1H), 0.95-0.88 (m, 2H), 0.67-0.59 (m, 2H). LC-MS: m / z: 177.20 (MH) - , t R :7.537min.

[0300] The following compounds were synthesized by similar routes as above:

[0301] 14. Synthesis of Compound 1-(3-ethylphenyl)-2-hydroxyethane-1-one (Compound 14)

[0302]

[0303] The compound was a colorless oil with a yield of 36.7%.

[0304] 1H NMR (400MHz, DMSO) δ7.80-7.71 (m, 2H), 7.48 (t, J=7.6Hz, 1H), 7.46-7.40 (m, 1H), 5. 04 (t, J=5.4Hz, 1H), 4.79 (d, J=4.9Hz, 2H), 2.67 (q, J=7.6Hz, 2H), 1.23-1.16 (m, 3H).

[0305] 15. Synthesis of Compound 1-(3-methoxyphenyl)-1,2-ethylenediol (Compound 15)

[0306]

[0307] The compound was a light yellow solid with a yield of 50%.

[0308] 1 H NMR (400MHz, DMSO) δ7.24-7.17 (m, 1H), 6.90 (d, J=7.4Hz, 2H), 6.82-6.75 (m, 1H), 4.5 0 (t, J=5.9Hz, 1H), 3.73 (s, 3H), 3.42 (dd, J=8.9, 4.6Hz, 2H). LC-MS: m / z: 167.15 (MH) - .t R :6.105min.

[0309] 16. Synthesis of Compound 1-(2,3-dihydro-5-benzofuranyl)-1,2-ethanediol (Compound 16)

[0310]

[0311] The compound was a light yellow solid with a yield of 44%.

[0312] 1 H NMR (400MHz, DMSO) δ7.17 (s, 1H), 7.01 (dd, J=8.1, 1.0Hz, 1H), 6.67 (d, J=8.1Hz, 1H), 5.05 (d, J=4.1Hz, 1H), 4.63 (t, J= 5.8Hz, 1H), 4.48 (t, J=8.7Hz, 2H), 4.46-4.41 (m, 1H), 3.40-3.34 (m, 2H), 3.13 (t, J=8.7Hz, 2H). LC-MS: m / z: 179.15 (MH) - , t R :5.922min.

[0313] 17. Synthesis of Compound 1-(2,3-dihydro-1,4-benzodiazepine-6-yl)-1,2-ethanediol (Compound 17)

[0314]

[0315] The compound was a yellow oil with a yield of 37.7%.

[0316] 1 H NMR (400MHz, DMSO) δ6.80 (s, 1H), 6.76 (s, 2H), 5.09 (d, J = 4.3Hz, 1H), 4.64 (t, J = 5.8Hz, 1H) , 4.40 (dd, J=10.4, 5.9Hz, 1H), 4.20 (s, 4H), 3.37 (d, J=5.9Hz, 2H). LC-MS: m / z: 195.15 (MH) - , tR: 5.776min.

[0317] 18. Synthesis of Compound 1-(1,3-benzodiazole-5-yl)-1,2-ethylenediol (Compound 18)

[0318]

[0319] The compound was a yellow solid with a yield of 40%.

[0320] 1 H NMR (400MHz, DMSO) δ6.86 (d, J=8.9Hz, 1H), 6.83 (d, J=7.9Hz, 1H), 6.79 (d, J=8.0Hz, 1H), 5.96 (d, J=1.8Hz, 2 H), 5.16 (d, J=3.5Hz, 1H), 4.66 (s, 1H), 4.44 (d, J=2.6Hz, 1H), 3.37 (d, J=4.4Hz, 2H). LC-MS: m / z: 181.15 (MH) - , tR: 5.803min.

[0321] 19. Synthesis of Compound 1-(4-hydroxyphenyl)-1,2-ethylene glycol (Compound 19)

[0322]

[0323] The compound was a white solid with a yield of 42%.

[0324] 1H NMR (400MHz, DMSO) δ9.20 (s, 1H), 7.11 (d, J = 8.4Hz, 2H), 6.69 (d, J = 8.5Hz, 2H), 5.01 (d, J = 4.1Hz, 1 H), 4.61 (t, J=5.8Hz, 1H), 4.42 (dd, J=10.4, 5.7Hz, 1H), 3.39-3.35 (m, 2H). LC-MS: m / z: 153.15 (MH) - , t R :2.187min.

[0325] 20. Synthesis of Compound 1-(3,4-dimethoxy)-1,2-ethylenediol (Compound 20)

[0326]

[0327] The compound was a white solid with a yield of 45%.

[0328] 1 H NMR (400MHz, DMSO) δ6.92 (d, J=1.5Hz, 1H), 6.87 (d, J=8.2Hz, 1H), 6.83 (dd, J=8.2, 1.6Hz, 1H), 5.12 (d, J=4.1Hz, 1H), 4. 64 (t, J=5.8Hz, 1H), 4.46 (dd, J=10.3, 5.9Hz, 1H), 3.72 (d, J=6.0Hz, 6H), 3.39 (t, J=5.9Hz, 2H). LC-MS: m / z: 197.20 (MH) - , t R :5.529min.

[0329] 21. Synthesis of Compound 1-(4-methoxyphenyl)propane-1,2-diol (Compound 21)

[0330]

[0331] The compound was a white solid with a yield of 49.0%.

[0332] 1 H NMR (400MHz, DMSO-d6) δ7.03 (dd, J=148.6, 8.7Hz, 4H), 5.02 (d, J=4.3Hz, 1H), 4.38 (d, J=5. 4Hz, 1H), 4.28 (t, J=4.8Hz, 1H), 3.72 (s, 3H), 3.60 (q, J=5.5Hz, 1H), 0.97 (d, J=6.3Hz, 3H).

[0333] 22. Synthesis of Compound 1-(2-methoxyphenyl)ethane-1,2-diol (Compound 22)

[0334]

[0335] The compound was a white solid with a yield of 16.5%.

[0336] 1 H NMR (400MHz, DMSO-d6) δ7.41 (dd, J=7.7, 1.7Hz, 1H), 7.21 (td, J=7.6, 1.9Hz, 1H), 6.93 (t, J=7.2Hz, 2H), 5.08 (d, J=4.5Hz, 1H), 4.89 (d t, J=7.9, 3.6Hz, 1H), 4.69 (dd, J=6.4, 5.4Hz, 1H), 3.77 (s, 3H), 3.47 (ddd, J=11.1, 6.5, 3.1Hz, 1H), 3.22 (ddd, J=11.0, 7.9, 5.4Hz, 1H).

[0337] 23. Synthesis of Compound 1-(4-methoxyphenyl)ethane-1,2-diol (Compound 23)

[0338]

[0339] The compound was a white solid with a yield of 6.5%.

[0340] 1 H NMR (400MHz, DMSO-d6) δ7.24 (d, J=8.7Hz, 2H), 6.86 (d, J=8.7Hz, 2H), 5.13 (d, J=4. 2Hz, 1H), 4.68 (t, J=5.8Hz, 1H), 4.58-4.35 (m, 1H), 3.72 (s, 3H), 3.46-3.29 (m, 2H).

[0341] 24. Synthesis of Compound 1-(4-bromophenyl)ethane-1,2-diol (Compound 24)

[0342]

[0343] The compound was a white solid with a yield of 6.3%.

[0344] 1H NMR (400MHz, DMSO-d6) δ7.49 (d, J=8.4Hz, 2H), 7.29 (d, J=8.4Hz, 2H), 5.34 (d, J=4.3Hz , 1H), 4.75 (t, J=5.8Hz, 1H), 4.51 (dt, J=6.5, 4.8Hz, 1H), 3.39 (tt, J=11.4, 5.7Hz, 2H).

[0345] 25. Synthesis of Compound 1-(4-hydroxy-2-methoxyphenyl)ethane-1,2-diol (Compound 25)

[0346]

[0347] The compound was a light brown oily liquid with a yield of 33%.

[0348] 1 H NMR (400MHz, DMSO-d6) δ9.28 (s, 1H), 7.13 (d, J=7.9Hz, 1H), 6.40-6.29 (m, 3H), 4.85 (d, J= 4.0Hz, 1H), 4.81-4.68 (m, 2H), 4.59 (t, J=5.6Hz, 1H), 3.70 (s, 3H).LCMS: calculated[MH] - C9H 11 O4 - =183.07, found:183.10.

[0349] 26. Synthesis of Compound 1-(3-Hydroxyphenyl)ethane-1,2-diol (Compound 26)

[0350]

[0351] The compound was a light brown oily liquid with a yield of 35%.

[0352] 1 H NMR (400MHz, DMSO-d6) δ9.27 (s, 1H), 7.08 (t, J=7.8Hz, 1H), 6.76 (s, 1H), 6.73 (d, J=7.6Hz, 1H), 6.6l (dd, J=8.0, 2.0Hz, 1H ), 5.17 (d, J = 4.0Hz, 1H), 4.71 (t, J = 5.8Hz, 1H), 4.44 (dd, J = 10.6, 5.1Hz, 1H), 3.38 (t, J = 5.3Hz, 2H). LCMS: calculated [MH] - C8H9O3 - =153.06, found:153.10.

[0353] 27. Synthesis of Compound 1-phenylpropane-1,2-diol (Compound 27)

[0354]

[0355] The compound was a white solid with a yield of 67%.

[0356] 1 H NMR (400MHz, DMSO-d6) δ7.35-7.17(m, 5H), 5.20-5.11(m, 1H), 4.64-4.44(m, 1H) , 4.37-4.26(m, 1H), 3.70-3.61(m, 1H), 1.05-0.79(m, 3H).LCMS: calculated[MH] - C9H 11 O2 - =151.08, found:151.15.

[0357] 28. Synthesis of Compound 1-(3-ethynylphenyl)ethane-1,2-diol (Compound 28)

[0358]

[0359] The compound was a brown solid with a yield of 25%.

[0360] 1 H NMR (400MHz, DMSO-d6) δ7.43 (s, 1H), 7.38-7.31 (m, 3H), 5.32 (d, J=4.3Hz, 1H), 4.74 (t, J=5.6 Hz, 1H), 4.52 (dd, J=10.6, 5.4Hz, 1H), 4.14 (s, 1H), 3.46-3.38 (m, 2H).LCMS: calculated[MH] - C 10 H9O2 - =161.06, found:161.15.

[0361] 29. Synthesis of Compound 1-(3-(tert-butyl)phenyl)ethane-1,2-diol (Compound 29)

[0362]

[0363] The compound was a light yellow solid with a yield of 27%.

[0364] 1H NMR (400MHz, DMSO-d6) δ7.35 (s, 1H), 7.27-7.19 (m, 2H), 7.12 (d, J = 6.9Hz, 1H), 5.18 (d, J = 4.2Hz, 1H), 4.69 (t, J=5.8Hz, 1H), 4.51 (dd, J=10.3, 5.9Hz, 1H), 3.41 (t, J=5.9Hz, 2H), 1.27 (s, 9H).LCMS: calculated[MH] - C 12 H 17 O2 - =193.12, found:193.20.

[0365] 30. Structure of 1-(3-hydroxy-4-methoxyphenyl)ethane-1,2-diol (Compound 30)

[0366]

[0367] The compound was a light yellow solid with a yield of 30%.

[0368] 1 H NMR (400MHz, DMSO-d6) δ 8.82 (s, 1H), 6.82 (d, J = 8.2Hz, 1H), 6.76 (d, J = 1.5Hz, 1H), 6.68 (dd, J = 8.1, 1.5Hz, 1H), 5.04 (d, J = 4.0Hz, 1H), 4.62 (t, J=5.8Hz, 1H), 4.38 (dd, J=10.0, 5.7Hz, 1H), 3.72 (s, 3H), 3.34 (t, J=5.9Hz, 2H).LCMS: calculated[MH] - C9H 11 O4 - =183.07, found:183.15.

[0369] 31. Synthesis of Compound 1-(1,3-diethyl-2-hydroxy)-1,2-ethylenediol (Compound 31)

[0370]

[0371] Synthesis of ethyl 2-(2,4-diethyl-3-hydroxyphenyl)-2-oxoacetate

[0372] Weigh 2,6-diethylphenol (1g, 6.67mmol) and place it in a 100mL single-mouth round-bottom flask, add 20mL 1,2-dichloroethane to dissolve, slowly add anhydrous aluminum chloride (2.7g, 19.99mmol) at 0℃ and stir for 10min, slowly add ethyl oxalyl chloride (1g, 7.34mmol) dropwise, and react at 0℃ for 10min. TLC spot plate tracks the reaction progress. After the reaction is completed, slowly pour the reaction solution into ice water, extract it with DCM / H2O 3 times, combine the organic phases, dry it over anhydrous sodium sulfate, and spin dry. The product is a white solid, no purification is required, and the yield is 90%.

[0373] 1 H NMR (400MHz, DMSO) δ9.69 (s, 1H), 7.54 (s, 2H), 4.40 (q, J=7.1Hz, 2H), 2.65 (q, J=7.5Hz, 4H), 1.32 (t, J=7.1Hz, 3H), 1.14 (t, J=7.5Hz, 6H).

[0374] Synthesis of 1-(2,4-diethyl-3-hydroxyphenyl)-1,2-ethanediol

[0375] Dissolve ethyl 2-(2,4-diethyl-3-hydroxyphenyl)-2-oxoacetate (627 mg, 2.52 mmol) in 10 mL of methanol, slowly add sodium borohydride (426.9 mg, 11.29 mmol) in batches under ice bath stirring, and react at 0°C for one hour. TLC spot plate tracks the reaction progress. After the reaction is complete, saturated ammonium chloride aqueous solution is added dropwise to quench, EA / H2O is extracted 3 times, the organic phases are combined, dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure. The product is recrystallized as a white solid with a yield of 60%.

[0376] 1 H NMR (400MHz, DMSO) δ7.91 (s, 1H), 6.86 (s, 2H), 4.94 (d, J=4.0Hz, 1H), 4.57 (t, J=5.8Hz, 1H), 4.38 (dd, J=10 .1, 5.9Hz, 1H), 3.36 (t, J=6.0Hz, 2H), 2.55 (q, J=7.5Hz, 4H), 1.11 (t, J=7.5Hz, 6H). LC-MS: m / z: 209.20 (MH) - , t R :6.736min.

[0377] The following compounds were prepared by a synthetic route similar to 1-(2,4-diethyl-3-hydroxyphenyl)-1,2-ethanediol (73):

[0378] 32. Synthesis of Compound 1-(3,4-dihydro-1-benzopyran-6-yl)-1,2-ethanediol (Compound 32)

[0379]

[0380] The compound was a white solid with a yield of 25%.

[0381] 1 H NMR (400MHz, DMSO) δ7.02-6.95 (m, 2H), 6.68-6.61 (m, 1H), 5.04 (d, J=3.7Hz, 1H), 4.64 (t, J=5.2Hz, 1H), 4.40 (d, J= 3.0Hz, 1H), 4.17-3.97 (m, 2H), 3.40-3.35 (m, 2H), 2.71 (t, J=6.4Hz, 2H), 1.97-1.80 (m, 2H). LC-MS: m / z: 193.20 (MH) - , t R :6.462min.

[0382] 33. Synthesis of Compound 1-(4-hydroxy-3-methoxy)-1,2-ethylenediol (Compound 33)

[0383]

[0384] The compound was a light yellow oil with a yield of 30%.

[0385] 1 H NMR (400MHz, DMSO) δ8.75 (s, 1H), 6.87 (s, 1H), 6.69 (s, 2H), 5.04 (d, J=4.0Hz, 1H), 4.61 (t, J=5.7 Hz, 1H), 4.41 (dd, J=10.2, 5.9Hz, 1H), 3.74 (s, 3H), 3.37 (t, J=6.0Hz, 2H). LC-MS: m / z: 183.15 (MH) - , t R :2.213min.

[0386] 34. Synthesis of Compound 1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,2-ethanediol (Compound 34)

[0387]

[0388] The compound was a white solid with a yield of 55%.

[0389] 1H NMR (400MHz, DMSO) δ7.00 (d, J=8.3Hz, 2H), 6.96 (d, J=7.7Hz, 1H), 5.09 (d, J=4.2Hz, 1H), 4.66 (t, J=5.8Hz, 1H), 4 .43 (dd, J=10.2, 5.9Hz, 1H), 3.39-3.35 (m, 2H), 2.68 (d, J=5.2Hz, 4H), 1.76-1.66 (m, 4H). LC-MS: m / z: 191.20 (MH) - , t R :8.760min.

[0390] 35. Synthesis of Compound 1-(3-ethyl-4-methylphenyl)-1,2-ethylenediol (Compound 35)

[0391]

[0392] The compound was a light yellow oil with a yield of 60%.

[0393] 1 H NMR (400MHz, DMSO) δ7.26-6.80(m, 3H), 5.15-5.04(m, 1H), 4.74-4.64(m, 1H), 4.49-4.40(m, 1H), 3.40-3.35( m, 2H), 2.55 (dt, J=12.5, 7.3Hz, 2H), 2.28-2.19 (m, 3H), 1.13 (tt, J=7.5, 4.9Hz, 3H). LC-MS: m / z: 179.20 (MH) - , tR: 8.718min.

[0394] 36. Synthesis of Compound 1-(2,3-dihydro-1H-indan-5-yl)-1,2-ethanediol (Compound 36)

[0395]

[0396] The compound was a white solid with a yield of 65%.

[0397] 1H NMR (400MHz, DMSO) δ7.17 (s, 1H), 7.13 (d, J = 7.7Hz, 1H), 7.05 (d, J = 7.6Hz, 1H), 5.10 (d, J = 4.1Hz, 1H), 4.65 (t, J = 5.8Hz, 1H), 4. 48 (dd, J=10.3, 5.7Hz, 1H), 3.38 (t, J=5.9Hz, 2H), 2.81 (dd, J=12.1, 7.1Hz, 4H), 1.99 (p, J=7.4Hz, 2H). LC-MS: m / z: 177.20 (MH) - , t R :8.265min.

[0398] 37. Synthesis of Compound 1-(3-ethyl-4-hydroxyphenyl)-1,2-ethanediol (Compound 37)

[0399]

[0400] The compound was a white solid with a yield of 53%.

[0401] 1 H NMR (400MHz, DMSO) δ9.06 (s, 1H), 7.00 (d, J = 1.7Hz, 1H), 6.92 (dd, J = 8.1, 2.0Hz, 1H), 6.69 (d, J = 8.1Hz, 1H), 4.97 (d, J = 4.0Hz, 1H), 4.59 (t, J=5.8Hz, 1H), 4.39 (dd, J=10.1, 5.9Hz, 1H), 3.37 (dd, J=8.0, 3.9Hz, 2H), 2.54-2.50 (m, 2H), 1.11 (t, J=7.5Hz, 3H). LC-MS: m / z: 181.20 (MH) - , t R :5.947min.

[0402] 38. Synthesis of Compound 3-(3-ethylphenyl)tetrahydrofuran-3-ol (Compound 38)

[0403]

[0404] 3-Bromoethylbenzene (200 mg, 1.08 mmol), an appropriate amount of magnesium stick, 2 iodine grains, and 20 mL of anhydrous tetrahydrofuran were added to a dried 100 mL reaction bottle. The reaction was carried out at room temperature under argon protection. After the Grignard reagent was prepared, 2-2H-furanone (112 mg, 1.30 mmol) was dissolved in anhydrous THF and then added dropwise to the prepared Grignard reagent. The reaction was carried out at room temperature. The reaction was complete when detected by TLC. The reaction was quenched with saturated ammonium chloride and separated and purified by silica gel column to obtain 80 mg of a colorless oil with a yield of 38.5%.

[0405] 1 H NMR (400MHz, CDCl3) δ7.31 (s, 1H), 7.26 (dd, J=6.8, 4.8Hz, 2H), 7.15-7.07 (m, 1H), 4.79-4.67 (m, 1H), 4.21-4.13 (m, 1H), 4.08 (td, J=8.6, 3.4Hz, 1H), 3.98-3.85 (m, 2H), 2.70 (s, 1H), 2.65 (q, J=7.6Hz, 2H), 2.39 (dt, J=13.0, 9.1Hz, 1H), 2.28-2.18 (m, 1H), 1.23 (t, J=7.6Hz, 3H).

[0406] 39. Synthesis of Compound 1-(5-ethylthiophen-3-yl)ethane-1,2-diol (Compound 39)

[0407]

[0408] Synthesis of 4-bromo-2-ethylthiophene

[0409] Thiophene acetone (2.05 g, 10 mmol) was dissolved in 80 mL of dry THF, sodium borohydride (1.89 g, 50 mmol) was added in batches under an ice bath, and finally anhydrous aluminum chloride (3.66 g, 27.5 mmol) was added in batches, and refluxed at 80°C under nitrogen protection. The reaction progress was monitored by TLC (developing solvent: heptane), and the reaction was complete after 2 hours. 30 mL of water was carefully added to quench the reaction, and the solvent THF was removed by rotation and extracted with dichloromethane. After conventional post-treatment, the residue was purified by column chromatography (eluent: heptane) to obtain 0.98 g of pure reduced product with a yield of 51.3%.

[0410] Synthesis of (5-ethylthiophen-3-yl)magnesium bromide

[0411] Add magnesium chips (31 mg, 1.3 mmol) and a small particle of iodine to the reaction flask, add 0.5 mL of dry THF after nitrogen is passed, and then add the THF (1.5 mL) solution of the above product (191 mg, 1 mmol). Heat to 35°C to initiate the reaction, and continue to drop the THF solution of the bromide under heat preservation to keep the reaction liquid slightly boiling. After the dropwise addition, continue the reaction at 35°C for 1 hour, and cool to room temperature for use after the reaction.

[0412] Synthesis of ethyl 2-(5-ethylthiophen-3-yl)-2-oxyacetate

[0413] Diethyl oxalate (0.41 mL, 3 mmol) and 2 mL of THF were added to the reaction flask, cooled to -78°C under nitrogen protection, and the prepared Grignard reagent was slowly added dropwise. After the addition was completed, the mixture was kept at -78°C for 2 h. The reaction was quenched with 1 mL of saturated ammonium chloride, extracted with EA, and subjected to conventional post-treatment. The crude product was purified by column chromatography (PE / EA=200:1 to 100:1) to obtain 180 mg of a pure product with a yield of 85.7%.

[0414] Synthesis of 1-(5-ethylthiophen-3-yl)ethane-1,2-diol

[0415] The above product (170 mg, 0.8 mmol) and 4 mL of methanol were added to the reaction flask, mixed evenly, and sodium borohydride (91 mg, 2.4 mmol) was added in batches under an ice bath. After the addition was complete, the mixture was brought to room temperature. The reaction progress was monitored by TLC (dichloromethane / methanol = 25:1), and 30 mg of pure product was obtained, with a yield of 22.2%.

[0416] 1 H NMR (400MHz, CDCl3) δ6.98 (s, 1H), 6.72 (s, 1H), 4.77 (dd, J1=7.6Hz, J1=2.8Hz, 1H), 3.74 (m, 1H), 3.66 (m, 1H), 3.16 (s, 2H), 2.79 (q, J=7.6Hz, 2H), 1.28 (t, J=7.6Hz, 3H).

[0417] 40. Synthesis of deuterated compound 3-ethylphenyl glycol (Compound 40)

[0418]

[0419] Weigh 3-ethylacetophenone (5.00g, 33.7mmol) in a 50mL three-necked flask, add 25mL 1,4-dioxane, dilute with 25mL methanol, and add nitrogen protection, stirring under ice bath for 10min. Use a syringe to draw liquid bromine (5.39g, 33.7mmol) and dissolve it in 25mL methanol. Slowly add it to the reaction solution with a dropping funnel under ice bath. After the drop is complete, continue stirring under ice bath, and monitor the progress of the reaction with a plate. After 5 hours, the reaction is complete. Add an appropriate amount of anhydrous sodium sulfite solution to quench the reaction. Rotary evaporation to remove the solvent. Extract the reaction solution with ethyl acetate and water, wash the extract with ethyl acetate and saturated sodium chloride solution, and dry it with anhydrous sodium sulfate. Rotary evaporation of the resulting product gives 6.15g of crude product.

[0420] Weigh compound A (1.08 g, 4.76 mmol), sodium formate (0.65 g, 9.56 mmol), and 10 mL of methanol in a 100 mL single-mouth bottle, heat to 80 ° C and reflux, monitor the progress of the reaction by TLC spot plate, and the reaction is complete after 4.5 hours. Rotary evaporate to remove the solvent. Extract the reaction solution with ethyl acetate and water, wash the extract with ethyl acetate and saturated sodium chloride solution, and add anhydrous sodium sulfate to dry. Rotary evaporate the obtained product to obtain 0.75 g of crude product. Crude yield = 95.96% (including impurities).

[0421] Weigh compound B (0.10g, 0.61mmol) in a 50mL single-mouth bottle, add 10mL methanol to dilute, and stir for 10min in an ice bath. Weigh sodium borodeuteride (0.013g, 0.31mmol) and add it to the reaction solution in batches in an ice bath. Remove the ice bath after adding and react at room temperature. Monitor the progress of the reaction by spot plate. Remove the solvent by rotary evaporation, extract the reaction solution with ethyl acetate and water, wash the extract with ethyl acetate and saturated sodium chloride solution, add anhydrous sodium sulfate to dry, and rotary evaporation. Add appropriate amount of dichloromethane and silica gel, mix well, and rotary evaporation to prepare samples. Dry column loading, dry sample loading, petroleum ether: ethyl acetate = 4:1. The product obtained by rotary evaporation is 0.02g. Yield = 19.63%.

[0422] 1 H NMR (400MHz, DMSO-d6) δ7.21 (t, J=7.5Hz, 1H), 7.17 (s, 1H), 7.12 (d, J=7.6Hz, 1H), 7.06 (d, J=7.4Hz, 1H), 5.14 (s, 1H), 4.67 (t, J=5.8Hz, 1H), 3.40 (d, J=5.8Hz, 2H), 2.58 (q, J=7.5Hz, 2H), 1.17 (t, J=7.6Hz, 3H).LCMS[MH]-: 166.20

[0423] 41. Synthesis of deuterated compound 3-ethylphenyl glycol (Compound 41)

[0424]

[0425] Weigh 3-ethylacetophenone (0.50g, 3.4mmol) in a 25mL single-mouth bottle, add 4mL of tetrahydrofuran, and stir at room temperature. Weigh N-bromosuccinimide (0.59g, 3.4mmol) and slowly add it to the reaction solution, continue stirring, and monitor the progress of the reaction by tapping the plate. The reactants cannot react completely, and the reaction is stopped when the raw materials no longer react. Add an appropriate amount of water to quench. Rotary evaporate to remove the solvent. Extract the reaction solution with ethyl acetate and water, wash the extract with ethyl acetate and saturated sodium chloride solution, and dry it over anhydrous sodium sulfate. Rotary evaporate the obtained product to obtain 0.52g of crude product. (The product and the raw material have little difference in polarity, which is difficult to purify, so it is directly used in the next step)

[0426] Crude yield = 67.08% (including impurities)

[0427] Weigh compound A (1.30 g, 5.72 mmol) in a 50 mL single-mouth bottle, add 26 mL toluene, 1.95 mL deuterated water and potassium carbonate (0.20 g, 1.45 mmol), and heat to 87 ° C reflux. After 4 hours, separate the water layer at 40-50 ° C, add 1.95 mL deuterated water and potassium carbonate (0.20 g, 1.45 mmol), and continue the reaction. Repeat the operation once after 8 hours, and the reaction is complete after 12 hours. Separate the water layer and wash it with ethyl acetate. Rotary evaporate to remove the solvent. Extract the reaction solution with ethyl acetate and water, wash the extract with ethyl acetate and saturated sodium chloride solution, and add anhydrous sodium sulfate to dry. Rotary evaporate the obtained product to obtain 1.01 g of crude product. Crude yield = 77.11% (containing impurities)

[0428] Weigh compound A (1.00 g, 4.36 mmol), sodium formate (0.60 g, 8.82 mmol), and 5 mL of methanol in a 50 mL single-mouth bottle, heat to 80 ° C and reflux, monitor the progress of the reaction with a thin layer chromatography plate, and the reaction is complete after 4.5 hours. Rotary evaporate to remove the solvent. Extract the reaction solution with ethyl acetate and water, wash the extract with ethyl acetate and saturated sodium chloride solution, and add anhydrous sodium sulfate to dry. Rotary evaporate the obtained product to obtain 0.72 g of crude product. Crude yield = 99.35% (including impurities)

[0429] Weigh compound C (1.00g, 6.02mmol) in a 50mL single-mouth bottle, add 5mL of methanol to dilute, and stir for 10min in an ice bath. Weigh sodium borohydride (0.23g, 6.02mmol) and add it to the reaction solution in batches in an ice bath. Remove the ice bath after adding and react at room temperature. Monitor the progress of the reaction by spot plate. Remove the solvent by rotary evaporation, extract the reaction solution with ethyl acetate and water, wash the extract with ethyl acetate and saturated sodium chloride solution, dry with anhydrous sodium sulfate, and rotary evaporate. Add appropriate amount of dichloromethane and silica gel, mix well, and rotary evaporate to prepare samples. Dry column loading, dry sample loading, petroleum ether: ethyl acetate = 4:1. The product obtained by rotary evaporation is 0.21g. Yield = 20.74%

[0430] 1 H NMR (600MHz, Chloroform-d) δ7.35 (d, J=7.6Hz, 1H), 7.33 (s, 1H), 7.24-7.20 (m, 2H), 4.85 (s, 1H), 3.81 (dd, J=11.4, 3.5Hz, 1H), 2.76 (s, 2H), 2.72 (q, J=7.6Hz, 2H), 1.31 (t, J=7.6Hz, 3H). LCMS [M+H]+: 169.1

[0431] 42. Synthesis process of compounds 42-44

[0432] Synthesis of 1-(3-(1-hydroxy-1-deutero-ethyl)phenyl)-1-deutero-ethanol (2)

[0433]

[0434] Weigh 1,3-diacetylbenzene (3.00 g, 18.50 mmol) into a 100 mL single-mouth bottle, add 20 mL of methanol to dissolve, and stir at 0 ° C. Take sodium borodeuteride (0.39 g, 9.29 mmol) and slowly add it to the reaction solution. After the addition is complete, stir at room temperature for 3 hours. Remove the solvent by rotary evaporation, extract the reactant with ethyl acetate, wash the extract with saturated sodium chloride solution, and dry it with anhydrous sodium sulfate. The crude product is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1, v / v) to obtain 2.83 g of colorless crystalline solid with a yield of 91.1%.

[0435] 1 H NMR (400MHz, DMSO-d6) δ7.32 (t, J=1.5Hz, 1H), 7.26-7.15 (m, 3H), 5.09 (s, 2H), 1.30 (s, 6H).MS

[0436] Synthesis of 1,3-di(1-dideuteroethyl)benzene (3a)

[0437]

[0438] Weigh 1-(3-(1-hydroxy-1-deuterated-ethyl)phenyl)-1-deuterated-ethanol (12.00 g, 71.33 mmol) and place it in a 250 mL two-necked bottle, add 50 mL of deuterated ethanol to dissolve. Take 10% palladium carbon (2.00 g, 25%) and add it to the reaction solution, and replace the deuterium gas 3 times. Use a syringe to take 1 mL of deuterated hydrochloric acid, slowly drip it into the reaction solution, and stir at room temperature overnight. The reaction solution is filtered through diatomaceous earth, the filtrate is extracted with dichloromethane, and the extract is washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. Remove dichloromethane by rotary evaporation at 40°C. 8.20 g of crude colorless transparent liquid is obtained, with a yield of 83.3%.

[0439] 1 H NMR (400MHz, DMSO-d6) δ7.17 (t, J=7.5Hz, 1H), 7.03 (s, 1H), 7.00 (d, J=7.5Hz, 2H), 1.15 (s, 6H).MS

[0440] Synthesis of 1,3-di(1-deuterated-ethyl)benzene (3b)

[0441]

[0442] Weigh 1-(3-(1-hydroxy-1-deuterated-ethyl)phenyl)-1-deuterated-ethanol (1.00g, 5.94mmol) and place it in a 100mL two-necked bottle, add 5mL of dichloromethane to dissolve, and stir at 0°C. Take triethylsilane (4.90g, 42.14mmol) and slowly add it to the reaction solution under nitrogen protection. Take boron trifluoride ether (5.90g, 41.57mmol) with a 10mL syringe and slowly drip it into the reaction solution at 0°C. After the dripping is completed, slowly warm it to room temperature and stir overnight. Add saturated sodium bicarbonate solution to quench until no bubbles are generated. Extract the reaction solution with dichloromethane and water, wash the extract with dichloromethane and saturated sodium chloride solution, and add anhydrous sodium sulfate to dry. Remove dichloromethane by rotary evaporation at 40°C. Obtain 0.50g of crude colorless transparent liquid with a yield of 61.7%.

[0443] 1 H NMR (400MHz, Chloroform-d) δ7.12 (t, J=7.6Hz, 1H), 6.97-6.90 (m, 3H), 2.53 (q, J=7.6Hz, 2H), 1.14 (d, J=7.6Hz, 6H).MS

[0444] Synthesis of 1-(3-(1-dideuteroethyl)phenyl)ethanone (4a)

[0445]

[0446] Weigh 1,3-di(1-dideuterated ethyl)benzene (8.20g, 59.31mmol) and N-hydroxyphthalimide (3.20g, 19.62mmol) in a 100mL three-necked flask, add 60mL acetonitrile to dissolve, replace oxygen three times, and heat to 40℃. Use a 10mL syringe to draw tert-butyl nitrite (6.10g, 59.15mmol) and slowly drip into the reaction solution, which gradually turns orange. After the dripping, heat to 55℃ and react for 2 hours. Remove the solvent by rotary evaporation. Add a small amount of dichloromethane, a white solid precipitates, add diatomaceous earth to filter, and take the filtrate and spin dry. The crude product is purified by silica gel column chromatography (petroleum ether / dichloromethane = 10:1, v / v) to obtain 2.80g of yellow liquid with a yield of 31.4%.

[0447] 1 H NMR (400MHz, DMSO-d6) δ7.78 (m, 2H), 7.49 (d, J=7.7Hz, 1H), 7.43 (t, J=7.4Hz, 1H), 2.57 (s, 3H), 1.19 (s, 3H).

[0448] Synthesis of 1-(3-(1-deuterated ethyl)phenyl)ethanone (4b)

[0449]

[0450] The synthesis steps were the same as those of 4a, and a yellow liquid was obtained with a yield of 29.9%.

[0451] 1 H NMR (400MHz, DMSO-d6) δ7.76-7.80 (m, 2H), 7.41-7.51 (m, 2H), 2.66 (q, J=7.6Hz, 1H), 2.57 (s, 3H), 1.20 (d, J=7.6Hz, 3H).

[0452] Synthesis of 1-(3-(1-deuterated ethyl)phenyl)ethanone (15c)

[0453]

[0454] The synthesis steps were the same as those of 4a, and a yellow liquid was obtained with a yield of 35.3%.

[0455] 1 H NMR (600MHz, DMSO-d6) δ7.79-7.76 (m, 2H), 7.48 (d, J=7.6Hz, 1H), 7.43 (t, J=7.5Hz, 1H), 2.68 (q, J=7.6Hz, 2H), 2.57 (s, 3H), 1.20 (t, J=7.6Hz, 3H).

[0456] Synthesis of 1-(3-(1-dideuteroethyl)phenyl)-2-bromoethanone (5a)

[0457]

[0458] Weigh 1-(3-(1-bis-deuterated ethyl)phenyl)ethanone (2.80 g, 18.64 mmol) and p-toluenesulfonic acid (1.66 g, 9.64 mmol) in a 100 mL single-mouth bottle, add 20 mL of acetonitrile to dissolve, and stir at 0°C. Weigh N-bromosuccinimide (3.64 g, 20.45 mmol) and slowly add it to the reaction solution, react at 40°C, and the reaction is completed after 3 hours. Add an appropriate amount of water to quench the reaction. Remove the solvent by rotary evaporation. Extract the reaction solution with ethyl acetate and water, wash the extract with ethyl acetate and saturated sodium chloride solution, and dry it with anhydrous sodium sulfate. The crude product is purified by silica gel column chromatography (petroleum ether / dichloromethane = 10:1, v / v) to obtain 2.12 g of yellow liquid with a yield of 50.1%.

[0459] Synthesis of 1-(3-(1-deuterated ethyl)phenyl)-2-bromoethanone (5b)

[0460]

[0461] The synthetic steps were the same as those of 5a to obtain a yellow liquid, which was directly used in the next step without purification.

[0462] Synthesis of 1-(3-(1-ethyl)phenyl)-2-bromoethanone (5c)

[0463]

[0464] The synthetic steps were the same as those of 5a to obtain a yellow liquid, which was directly used in the next step without purification.

[0465] Synthesis of 1-(3-(1-dideuteroethyl)phenyl)-2-hydroxyethanone (6a)

[0466]

[0467] Weigh 1-(3-(1-di-deuterated ethyl)phenyl)-2-bromoethanone (2.12 g, 9.25 mmol), sodium formate (1.26 g, 18.53 mmol), and 20 mL of methanol in a 100 mL single-mouth bottle, heat to 80 °C and reflux. After 5 hours, the reaction is complete. Rotate and evaporate to remove the solvent. Extract the reaction solution with ethyl acetate and water, wash the extract with ethyl acetate and saturated sodium chloride solution, and dry it with anhydrous sodium sulfate. The crude product is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1, v / v) to obtain 0.93 g of yellow liquid with a yield of 60.2%.

[0468] 1 H NMR (400MHz, Chloroform-d) δ7.77 (s, 1H), 7.72 (d, J=7.5Hz, 1H), 7.47 (d, J=7.5Hz, 1H), 7.42 (d, J=7.6Hz, 1H), 4.87 (s, 2H), 1.20 (s, 3H).

[0469] Synthesis of 1-(3-(1-deuterated ethyl)phenyl)-2-hydroxyethanone (6b)

[0470]

[0471] The synthesis steps were the same as those of 6a to obtain a yellow liquid with a yield of 45.1%.

[0472] 1 H NMR (400MHz, DMSO-d6) δ7.72-7.77 (m, 2H), 7.50 (d, J=7.6Hz, 1H), 7.43 (t, J=7.6Hz, 1H), 4.79 (s, 2H), 2.66 (q, J=7.6Hz, 1H), 1.19 (d, J=7.6Hz, 3H).

[0473] Synthesis of 1-(3-ethylphenyl)-2-hydroxyethanone (17c)

[0474]

[0475] The synthesis steps were the same as those of 6a to obtain a yellow liquid with a yield of 56.3%.

[0476] 1 H NMR (400MHz, Chloroform-d) δ7.76 (s, 1H), 7.72 (d, J = 7.6Hz, 1H), 7.47 (d, J = 7.7Hz, 1 H), 7.41 (t, J=7.6Hz, 1H), 4.87 (s, 2H), 2.72 (q, J=7.6Hz, 2H), 1.27 (t, J=7.6Hz, 3H).

[0477] Synthesis of 1-(3-(1-dideuteroethyl)phenyl)-ethylene glycol (Compound 42)

[0478]

[0479] Weigh 1-(3-(1-di-deuterated ethyl)phenyl)-2-hydroxyethanone (0.93g, 5.60mmol) in a 50mL single-mouth bottle, add 10mL methanol to dissolve, and stir at 0℃. Weigh sodium borohydride (0.11g, 2.89mmol) and slowly add it to the reaction solution under an ice bath. After the addition is complete, react at room temperature. Remove the solvent by rotary evaporation, extract the reaction solution with ethyl acetate and water, wash the extract with ethyl acetate and saturated sodium chloride solution, and dry it with anhydrous sodium sulfate. The crude product is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1, v / v) to obtain 0.77g of colorless solid with a yield of 81.4%.

[0480] 1 H NMR (400MHz, DMSO-d6) δ7.21 (t, J=7.5Hz, 1H), 7.17 (s, 1H), 7.13 (d, J=7.6Hz, 1H), 7.06 (d, J=7.4Hz, 1H) , 5.15 (d, J=4.2Hz, 1H), 4.66 (t, J=5.8Hz, 1H), 4.50 (q, J=5.8Hz, 1H), 3.42 (t, J=5.9Hz, 2H), 1.16 (s, 3H). 13 C NMR (151MHz, DMSO) δ143.90, 143.59, 128.25, 126.68, 126.19, 124.16, 74.41, 68.02, 28.26, 28.13, 28.00, 27.87, 27.75, 16.00.HRMS (ESI): exact mass calcd for C 10 H 12 D2O2[M+Na] + , 191.1015; found191.1017.HPLC purity: 95.5%, retention time=7.642min.

[0481] Synthesis of 1-(3-(1-deuterated ethyl)phenyl)-ethylene glycol (Compound 43)

[0482]

[0483] The synthesis steps were the same as TJH1 to obtain a colorless solid with a yield of 80.1%.

[0484] 1H NMR (400MHz, DMSO-d6) δ7.20 (t, J=7.5Hz, 1H), 7.16 (s, 1H), 7.12 (d, J=7.5Hz, 1H), 7.06 (d, J=7.5Hz, 1H), 5.17 (d, J=4.1H z, 1H), 4.68 (t, J=5.8Hz, 1H), 4.49 (q, J=5.6Hz, 1H), 3.40 (t, J=5.9Hz, 2H), 2.56 (q, J=7.6Hz, 1H), 1.16 (d, J=7.6Hz, 3H). 13 C NMR (151MHz, DMSO) δ143.90, 143.61, 128.25, 126.68, 126.18, 124.16, 74.41, 68.02, 28.48, 28.36, 28.23, 16.08.HRMS (ESI): exact mass calcd for C 10 H 13 DO2[M+Na] + , 190.0952; found 190.0954.HPLC purity: 97.2%, retention time=7.625min.

[0485] Synthesis of 1-(3-ethylphenyl)-1-deuterated-ethylene glycol (Compound 44)

[0486]

[0487] The synthesis steps were the same as TJH1 to obtain a colorless solid with a yield of 79.8%.

[0488] 1 H NMR (400MHz, DMSO-d6) δ7.21 (t, J=7.5Hz, 1H), 7.17 (s, 1H), 7.12 (d, J=7.6Hz, 1H), 7.06 (d, J=7.4Hz, 1H), 5.16 (s, 1H ), 4.69 (t, J=5.8Hz, 1H), 3.40 (d, J=5.8Hz, 2H), 2.58 (q, J=7.6Hz, 2H), 1.17 (t, J=7.6Hz, 3H). LC-MS: m / z: 166.20[MH] - .

[0489] 43. Synthesis process of compounds 45-49

[0490] Synthesis of 1-(3-(1-ethylphenyl)-ethylene glycol (7)

[0491]

[0492] Weigh 1-(3-ethylphenyl)-2-hydroxyethanone (0.87g, 5.30mmol) in a 50mL single-mouth bottle, add 10mL methanol to dissolve, and stir at 0℃. Weigh sodium borohydride (0.22g, 5.30mmol) and slowly add it to the reaction solution under an ice bath. After the addition is complete, react at room temperature. Remove the solvent by rotary evaporation, extract the reaction solution with ethyl acetate and water, wash the extract with ethyl acetate and saturated sodium chloride solution, and dry it with anhydrous sodium sulfate. The crude product is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1, v / v) to obtain 0.75g of colorless solid with a yield of 85.2%.

[0493] 1 H NMR (400MHz, DMSO-d6) δ7.21 (t, J=7.5Hz, 1H), 7.17 (s, 1H), 7.13 (d, J=7.6Hz, 1H), 7.06 (d, J=7.4Hz, 1H), 5.18 (d, J=4.2H z, 1H), 4.69 (t, J=5.8Hz, 1H), 4.50 (q, J=5.9Hz, 1H), 3.41 (t, J=5.9Hz, 2H), 2.59 (q, J=7.6Hz, 2H), 1.17 (t, J=7.6Hz, 3H).

[0494] Synthesis of 1-(3-ethylphenyl)ethane-1,2-diacetic acid diester (Compound 45)

[0495]

[0496] Weigh 1-(3-ethylphenyl)-ethylene glycol (0.50, 3.01mmol) in a 50mL single-mouth bottle, add 5mL of dichloromethane to dissolve, and stir at room temperature. Weigh 4-dimethylaminopyridine (0.04g, 0.33mmol) and acetic anhydride (1.23g, 12.05mmol) and add them to the reaction solution, and react at room temperature. Remove the solvent by rotary evaporation, extract the reaction solution with ethyl acetate and water, wash the extract with ethyl acetate and saturated sodium chloride solution, and dry it with anhydrous sodium sulfate. The crude product is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 25:1, v / v) to obtain 0.61g of colorless clear liquid, with a yield of 81.0%.

[0497] 1 H NMR (400MHz, Chloroform-d) δ7.27 (d, J=8.6Hz, 1H), 7.20-7.15 (m, 3H), 6.00 (dd, J=7.9, 4.1Hz, 1H), 4.35-4.27 (m, 2H), 2.66 (q, J=7.6Hz, 2H), 2.12 (s, 3H), 2.06 (s, 3H), 1.24 (t, J=7.6Hz, 3H).

[0498] Synthesis of 4-(3-ethylphenyl)-1,3-dioxolane-2-one (Compound 46)

[0499]

[0500] Weigh 1-(3-ethylphenyl)-ethylene glycol (0.50, 3.01mmol) in a 50mL single-mouth bottle, add 5mL toluene to dissolve. Weigh di(2-pyridyl) carbonate (1.30g, 6.01mmol) and add to the reaction solution, heat to 60℃ for reaction. Remove the solvent by rotary evaporation, extract the reaction solution with ethyl acetate and water, wash the extract with ethyl acetate and saturated sodium chloride solution, and dry with anhydrous sodium sulfate. The crude product is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1, v / v) to obtain 0.38g of colorless clear liquid, with a yield of 65.7%.

[0501] 1 H NMR (400MHz, Chloroform-d) δ7.35 (t, J=7.6Hz, 1H), 7.26 (d, J=7.6Hz, 1H), 7.19 (s, 1H), 7.17 (d, J=7.7Hz, 1H), 5 .65 (t, J=8.0Hz, 1H), 4.79 (t, J=8.4Hz, 1H), 4.35 (t, J=8.3Hz, 1H), 2.68 (q, J=7.6Hz, 2H), 1.25 (t, J=7.6Hz, 3H).

[0502] Synthesis of 4-(3-ethylphenyl)-2,2-dimethyl-1,3-dioxolane (Compound 47)

[0503]

[0504] Weigh 1-(3-ethylphenyl)-ethylene glycol (0.50, 3.01mmol) in a 50mL single-mouth bottle, add 3mL tetrahydrofuran to dissolve. Weigh ferric chloride (0.17g, 1.50mmol) and 3mL acetone to the reaction solution, react at room temperature, and the reaction solution is brown. Remove the solvent by rotary evaporation at room temperature, extract the reaction solution with dichloromethane and water, wash the extract with dichloromethane and saturated sodium chloride solution, add anhydrous sodium sulfate to dry, and remove dichloromethane by rotary evaporation at room temperature. The crude product is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50:1, v / v) to obtain 0.52g of light yellow liquid with a yield of 83.7%.

[0505] 1H NMR (400MHz, Chloroform-d) δ7.27 (t, J=7.5Hz, 1H), 7.20 (s, 1H), 7.18 (d, J=7.7Hz, 1H), 7.14 (d, J=7.4Hz, 1H), 5.05 (dd, J=8.0, 6.3 Hz, 1H), 4.29 (dd, J=8.1, 6.2Hz, 1H), 3.71 (t, J=8.2Hz, 1H), 2.65 (q, J=7.6Hz, 2H), 1.55 (s, 3H), 1.49 (s, 3H), 1.24 (t, J=7.6Hz, 3H).

[0506] Synthesis of 4-(3-ethylphenyl)-2-methyl-1,3-dioxolane (Compound 48)

[0507]

[0508] Weigh 1-(3-ethylphenyl)-ethylene glycol (0.50, 3.01mmol) in a 50mL single-mouth bottle, add 3mL tetrahydrofuran to dissolve. Weigh ferric chloride (0.17g, 1.50mmol) and acetaldehyde (0.54g, 12.27mmol) and add to the reaction solution, react at room temperature, and the reaction solution is brown. Remove the solvent by rotary evaporation at room temperature, extract the reaction solution with dichloromethane and water, wash the extract with dichloromethane and saturated sodium chloride solution, add anhydrous sodium sulfate to dry, and remove dichloromethane by rotary evaporation at room temperature. The crude product is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50:1, v / v) to obtain 0.36g of light yellow liquid, with a yield of 62.1%.

[0509] 1 H NMR (400MHz, Chloroform-d) δ7.30-7.25 (m, 1H), 7.20 (s, 1H), 7.18 (d, J=7.8Hz, 1H), 7.14 (d, J=7.5Hz, 1H), 5.23 (q, J=4.8Hz, 1H), 5.00 ( t, J=6.8Hz, 1H), 4.18 (t, J=7.5Hz, 1H), 3.79 (dd, J=7.8, 6.4Hz, 1H), 2.66 (q, J=7.6Hz, 2H), 1.53 (d, J=4.8Hz, 3H), 1.24 (t, J=7.6Hz, 3H).

[0510] Synthesis of 2-(3-ethylphenyl)oxirane (Compound 49)

[0511]

[0512] Weigh 2-bromo-1-(3-ethylphenyl)ethane-1-one (0.50, 2.20mmol) in a 50mL single-mouth bottle, add 5mL of anhydrous methanol to dissolve, and stir at 0℃. Weigh sodium borohydride (0.08g, 2.11mmol) and add it to the reaction solution. After the addition is complete, remove the ice bath, react at room temperature, and monitor the reaction progress by tapping the plate. After the reaction of the raw materials is completed, weigh potassium carbonate (0.60g, 4.40mmol) in the reaction solution and stir at room temperature overnight. Remove the solvent by rotary evaporation, extract the reaction solution with dichloromethane and water, wash the extract with dichloromethane and saturated sodium chloride solution, and dry it with anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100:1, v / v) to obtain 0.11g of colorless liquid with a yield of 33.7%.

[0513] 1 H NMR (400MHz, Chloroform-d) δ7.26 (t, J=7.4Hz, 1H), 7.15-7.09 (m, 3H), 3.84 (dd, J=3.9, 2.7Hz, 1H), 3 .13 (dd, J=5.5, 4.1Hz, 1H), 2.80 (dd, J=5.5, 2.6Hz, 1H), 2.65 (q, J=7.6Hz, 2H), 1.23 (t, J=7.6Hz, 3H).

[0514] (R)-2-(3-Ethylphenyl)-2-hydroxyethyl-L-valine (Compound 50)

[0515]

[0516] Step 1 (R)-2-(3-ethylphenyl)-2-hydroxyethyl (tert-butoxycarbonyl)-L-valine (50-1)

[0517] In a 100mL single-mouth round-bottom flask, (R)-1-(3-ethylphenyl)ethane-1,2-diol (8.00g, 48.0mmol), (tert-butyloxycarbonyl)-L-valine (2.10g, 9.60mmol) and 4-dimethylaminopyridine (0.23g, 1.92mmol) were added in sequence, and then 40mL of dichloromethane was added as solvent. After cooling to 0°C in an ice-salt bath, dicyclohexylcarbodiimide (3.90g, 19.0mmol) was added, and after stirring for 2h in an ice bath, the mixture was warmed to room temperature and stirred for 2h. The reaction progress was monitored by thin-layer chromatography. After the reaction was completed, the reaction solution was filtered, concentrated, and extracted with ethyl acetate in sequence. The organic layers were combined and washed with 1M hydrochloric acid, water, saturated sodium bicarbonate, water, and saturated sodium chloride in sequence, and then dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure to obtain a light yellow oily liquid. The corresponding yellow oily liquid (R)-2-(3-ethylphenyl)-2-hydroxyethyl(tert-butoxycarbonyl)-L-valine (1.20 g) was separated and purified by rapid silica gel column chromatography (petroleum ether / ethyl acetate=30:4) with a yield of 34.0%.

[0518] LC-MS: m / z: 366.3 (M+H) + .

[0519] Step 2 (R)-2-(3-Ethylphenyl)-2-hydroxyethyl-L-valine (50)

[0520] In a 50mL single-mouth round-bottom flask, add (R)-2-(3-ethylphenyl)-2-hydroxyethyl (tert-butoxycarbonyl)-L-valine (1.80g, 4.90mmol) and 20ml of ethyl acetate hydrochloride as solvent. Stir at room temperature for 3h, and monitor the reaction progress by thin layer chromatography. After the reaction is completed, the reaction solution is concentrated and extracted with ethyl acetate. The organic layers are combined and washed with saturated sodium bicarbonate, water, and saturated sodium chloride in sequence, and then dried with anhydrous sodium sulfate. The solvent is removed by concentration under reduced pressure to obtain a light yellow oily liquid. Rapid silica gel column chromatography separation and purification (ethyl acetate / methanol = 10:1) separates and obtains the corresponding white oily liquid (R)-2-(3-ethylphenyl)-2-hydroxyethyl-L-valine 0.97g, with a yield of 75.0%.

[0521] 1H NMR (400MHz, DMSO-d6) δ7.29-7.08 (m, 4H), 5.69-5.51 (m, 1H), 4.74 (d, J=6.0Hz, 1H), 4.17-3.99 (m, 1H), 3.70-3.52 (m, 2H), 3.22 (d, J=5.0 Hz, 1H), 3.09 (d, J=5.1Hz, 1H), 2.60 (d, J=7.5Hz, 2H), 2.06-1.62 (m, 1H), 1.17 (q, J=7.1Hz, 3H), 0.94-0.54 (m, 6H). LC-MS: m / z: 266.3 (M+H) + .

[0522] (R)-2-((L-valyl)oxy)-2-(3-ethylphenyl)valine ethyl ester (Compound 51)

[0523]

[0524] Step 1 (R)-2-(((tert-butoxycarbonyl)-L-valyl)oxy)-2-(3-ethylphenyl)ethyl(tert-butoxycarbonyl)valine (51-1)

[0525] In a 25 mL single-mouth round-bottom flask, (R)-1-(3-ethylphenyl)ethane-1,2-diol (0.50 g, 3.00 mmol), (tert-butyloxycarbonyl)-L-valine (4.60 g, 21.0 mmol) and 4-dimethylaminopyridine (0.60 g, 4.80 mmol) were added in sequence, and then 5 mL of dichloromethane was added as a solvent. After cooling to 0°C in an ice-salt bath, dicyclohexylcarbodiimide (8.70 g, 42.0 mmol) was added, and after stirring for 2 h in an ice bath, the mixture was warmed to room temperature and stirred for 2 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was completed, the reaction solution was filtered, concentrated, and extracted with ethyl acetate in sequence. The organic layers were combined and washed with 1 M hydrochloric acid, water, saturated sodium bicarbonate, water, and saturated sodium chloride in sequence, and then dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure to obtain a light yellow oily liquid. The corresponding yellow oily liquid (R)-2-(((tert-butoxycarbonyl)-L-valyl)oxy)-2-(3-ethylphenyl)ethyl(tert-butoxycarbonyl)valine was separated and purified by rapid silica gel column chromatography (petroleum ether / ethyl acetate=30:4) to give 1.01 g of the corresponding yellow oily liquid (R)-2-(((tert-butoxycarbonyl)-L-valyl)oxy)-2-(3-ethylphenyl)ethyl(tert-butoxycarbonyl)valine in a yield of 60.0%.

[0526] LC-MS: m / z: 565.4 (M+H) + .

[0527] Step 2 (R)-2-((L-valyl)oxy)-2-(3-ethylphenyl)valine ethyl ester (51)

[0528] In a 50 mL single-mouth round-bottom flask, (R)-2-(((tert-butoxycarbonyl)-L-valyl)oxy)-2-(3-ethylphenyl)ethyl(tert-butoxycarbonyl)valine (1.00 g, 1.77 mmol) and 20 ml of ethyl acetate hydrochloride were added as solvent. The mixture was stirred at room temperature for 3 h, and the reaction progress was monitored by thin layer chromatography. After the reaction was completed, the reaction solution was concentrated and extracted with ethyl acetate. The organic layers were combined and washed with saturated sodium bicarbonate, water, and saturated sodium chloride in sequence, and then dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure to obtain a light yellow oily liquid. Rapid silica gel column chromatography was used for separation and purification (ethyl acetate / methanol=10:1) to obtain the corresponding white oily liquid (R)-2-((L-valyl)oxy)-2-(3-ethylphenyl)valine ethyl ester 0.45 g, with a yield of 70.0%.

[0529] 1 H NMR (400MHz, DMSO-d6) δ7.32-7.13 (m, 4H), 5.91 (dd, J=7.5, 3.7Hz, 1H), 4.38 (dd, J=11.8, 3.7 Hz, 1H), 4.27 (dd, J=11.8, 7.5Hz, 1H), 3.17 (d, J=5.2Hz, 1H), 3.09 (d, J=5.1Hz, 1H), 2.90 (d, J= 20.1Hz, 4H), 2.59 (q, J=7.6Hz, 2H), 1.85 (ddd, J=45.9, 13.0, 6.5Hz, 2H), 1.15 (t, J=7.6Hz, 3H ), 0.83 (t, J=6.5Hz, 6H), 0.77 (d, J=6.8Hz, 3H), 0.70 (d, J=6.8Hz, 3H). LC-MS: m / z: 365.3 (M+H) + .

[0530] (R)-2-(3-Ethylphenyl)-2-hydroxyethyl octanoate (52)

[0531]

[0532] Synthesis method:

[0533] In a 100mL single-mouth round-bottom flask, (R)-1-(3-ethylphenyl)ethane-1,2-diol (5.00g, 30.0mmol), n-octanoic acid (0.86g, 6.00mmol) and 4-dimethylaminopyridine (0.14g, 1.20mmol) were added in sequence, and then 50mL of dichloromethane was added as solvent. After cooling to 0°C in an ice-salt bath, dicyclohexylcarbodiimide (2.50g, 12.0mmol) was added, and after stirring for 2h in an ice bath, the mixture was warmed to room temperature and stirred for 2h. The reaction progress was monitored by thin-layer chromatography. After the reaction was completed, the reaction solution was filtered, concentrated, and extracted with ethyl acetate in sequence. The organic layers were combined and washed with 1M hydrochloric acid, water, saturated sodium bicarbonate, water, and saturated sodium chloride in sequence, and then dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure to obtain a light yellow oily liquid. The corresponding yellow oily liquid (R)-2-(3-ethylphenyl)-2-hydroxyethyl octanoate (0.45 g) was separated and purified by rapid silica gel column chromatography (petroleum ether / ethyl acetate=30:4) with a yield of 26.0%.

[0534] 1 H NMR (400MHz, DMSO-d6) δ7.33-7.03 (m, 4H), 5.73-5.42 (m, 1H), 4.84-4.64 (m, 1H), 4.06 (q, J=6.7Hz, 2H) , 2.61 (q, J=7.5Hz, 2H), 2.27 (t, J=7.5Hz, 2H), 1.48 (s, 2H), 1.34-1.07 (m, 11H), 0.86 (d, J=6.8Hz, 3H).

[0535] Compounds 53-66 were synthesized by the following method:

[0536] Synthetic route 1

[0537]

[0538] Reagents and conditions: (a) Pd(dppf)Cl2, K2CO3, 85°C, N2; (b) ADmixβ, t-BuOH, H2O at room temperature.

[0539] Synthetic route 2

[0540]

[0541] Reagents and conditions: (c) Ag2CO3, AgOTf, DCM, room temperature; (d) K2CO3, MeOH / DCM, room temperature;

[0542] Synthesis of (R)-1-(3-cyclopropylphenyl)ethane-1,2-diol (Compound 53)

[0543] Step 1: Synthesis of 1-cyclopropyl-3-vinylbenzene (Compound 53)

[0544]

[0545] 1-Bromo-3-cyclopropylbenzene (1.01mmol, 200mg), potassium trifluoroborate (1.21mmol, 162mg), Dppf palladium dichloride (0.10mmol, 73mg) and potassium carbonate (2.02mmol, 279mg) were added to a 10mL Shrek tube in sequence, and a mixture of dioxane and water (6:1) was used as a solvent. Nitrogen was used to remove oxygen, and the reaction was carried out at 85°C for 2 hours. The reaction progress was monitored by TLC. After the reaction was completed, the dioxane was concentrated to remove the dioxane, and the mixture was extracted three times with ethyl acetate and water. The organic phases were combined and concentrated, and column chromatography (pure PE) was performed to obtain the intermediate 1-cyclopropyl-3-vinylbenzene (transparent oil, 108mg, yield 74.1%).

[0546] 1 H NMR (400MHz, Chloroform-d) δ7.23 (s, 1H), 7.22-7.19 (m, 2H), 7.12 (d, J=2.1Hz, 1H), 6.99-6.91 (m, 1H), 5.73 (dd, J=17. 6, 1.0Hz, 1H), 5.22 (dd, J=10.9, 0.9Hz, 1H), 1.89 (tt, J=8.4, 5.1Hz, 1H), 1.00-0.92 (m, 2H), 0.70 (dt, J=6.6, 4.6Hz, 2H).

[0547] Step 2: Synthesis of (R)-1-(3-cyclopropylphenyl)ethane-1,2-diol (Compound 53)

[0548]

[0549] 1-Cyclopropyl-3-vinylbenzene (0.56mmol, 80mg) was added to a 50mL single-mouth bottle, AD-mix-β (0.34mmol, 261mg) was added under ice bath conditions, tert-butanol and water were used as solvents in a ratio of 1:1, and the reaction was carried out at room temperature overnight. After the reaction was completed, ethyl acetate and water were used for extraction three times, the organic phases were combined and concentrated, and column chromatography (PE:EA=5:1) was performed to obtain (R)-1-(2-ethylpyridin-4-yl)ethane-1,2-diol (white solid, 40mg, yield 40.0%).

[0550] 1H NMR (600MHz, Chloroform-d) δ7.14 (t, J=7.6Hz, 1H), 7.02 (dt, J=7.6, 1.4Hz, 1H ), 6.99 (t, J=1.8Hz, 1H), 6.89 (dt, J=7.8, 1.4Hz, 1H), 4.68 (dd, J=8.5, 3.3Hz, 1H ), 3.77-3.61(m, 1H), 3.55(dd, J=11.4, 8.4Hz, 1H), 3.25-2.71(m, 2H), 1.80(tt, .J=8.4, 5.1Hz, 1H), 0.89-0.85 (m, 2H), 0.60 (dt, J=6.7, 4.7Hz, 2H).LC-MS: Calculated value C 11 H 14 NO2[M+NH4] + : 196.10, experimental value 196.15. ee value: 97.1%.

[0551] The following compounds (54-66) were synthesized according to the method of steps ab above:

[0552] Synthesis of (R)-1-(2-ethylpyridin-4-yl)ethane-1,2-diol (Compound 54)

[0553]

[0554] 1 H NMR (600MHz, Chloroform-d) δ8.30 (d, J=5.1Hz, 1H), 7.12 (d, J=1.6Hz, 1H), 7.03 (dd, J=5.3, 1.7Hz, 1H), 5.00 (d, J=11.9Hz, 1H), 4.73 (dd, J=7.8, 3.5Hz, 1H), 3.74 (dd, J=11.4, 3.5Hz, 1H), 3.56 (dd, J=11.3, 7.7Hz, 1H), 2.72 (q, J=7.6Hz, 2H), 1.21 (t, J=7.6Hz, 3H). LC-MS: Calculated value C9H 13 NO2[M+H] + : 168.09, experimental value 168.1. ee value: 93.0%.

[0555] Synthesis of (R)-1-(3-isopropylphenyl)ethane-1,2-diol (Compound 55)

[0556]

[0557] 1H NMR (600 MHz, Chloroform-d) δ 7.28 (t, J = 7.5 Hz, 1H), 7.21 (d, J = 1.8 Hz, 1H), 7.20-7.14 (m, 2H), 4.93-4.68 (m, 1H), 3.93-3.51 (m, 2H), 2.90 (hept, J = 6.9 Hz, 1H), 2.52 (s, 2H), 1.25 (s, 3H), 1.24 (s, 3H). LC-MS: calculated value C 11 H 14 NO2[MH] - : 179.12, experimental value 179.1. ee value: 92.5%.

[0558] Synthesis of (R)-1-(3-(trifluoromethyl)phenyl)ethane-1,2-diol (Compound 56)

[0559]

[0560] 1 H NMR (600 MHz, Chloroform-d) δ 7.47 (s, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.34 (d, J = 7.7 Hz, 1H), 7.30 (t, J = 7.7 Hz, 1H), 4.69 (dd, J = 8.4, 3.1 Hz, 1H), 3.59 (dd, J = 11.8, 3.1 Hz, 1H), 3.45 (dd, J = 11.6, 8.5 Hz, 1H). LC-MS: calculated for C9H9F3O2 [M+COOH] - : 251.06, experimental value 251.1. ee value: 94.3%.

[0561] (R)-1-(3-methoxyphenyl)ethane-1,2-diol (Compound 57)

[0562]

[0563] 1 H NMR (400 MHz, DMSO-d6) δ 7.21 (t, J = 8.0 Hz, 1H), 6.93-6.88 (m, 2H), 6.81-6.76 (m, 1H), 5.22 (d, J = 4.3 Hz, 1H), 4.70 (t, J = 5.8 Hz, 1H), 4.52 (dt, J = 6.7, 4.8 Hz, 1H), 3.74 (s, 3H), 3.46-3.39 (m, 2H). LC-MS: calculated for C9H 12 O3[M+COOH] - : 213.08, measured value 213.10. ee value: 97.2%.

[0564] (R)-1-(3-(1,1-difluoroethyl)phenyl)ethane-1,2-diol (Compound 58)

[0565]

[0566] 1 H NMR (600 MHz, DMSO-d6) δ 7.53 (s, 1H), 7.45 (q, J = 4.2 Hz, 1H), 7.42 (d, J = 4.6 Hz, 2H), 5.35 (d, J = 4.4 Hz, 1H), 4.75 (td, J = 5.8, 1.7 Hz, 1H), 4.62-4.55 (m, 1H), 3.45 (dtd, J = 11.2, 5.8, 3.1 Hz, 2H), 1.95 (t, J = 18.8 Hz, 3H). LC-MS: calculated value C 10 H 12 F2O2[M+COOH] - : 247.08, measured value 247.10. ee value: 94.0%.

[0567] (R)-1-(3-Fluorophenyl)ethane-1,2-diol (Compound 59)

[0568]

[0569] 1 H NMR (500 MHz, Chloroform-d) δ 7.32 (td, J = 8.1, 6.0 Hz, 1H), 7.16-7.05 (m, 2H), 7.04-6.95 (m, 1H), 4.81 (dd, J = 8.3, 3.2 Hz, 1H), 3.76 (dd, J = 11.6, 3.2 Hz, 1H), 3.62 (dd, J = 11.4, 8.1 Hz, 1H). LC-MS: calculated for C8H9FO2 [M+COOH] - : 201.06, measured value 201.05. ee value: 92.3%.

[0570] (R)-1-(2-Chloro-5-(trifluoromethyl)phenyl)ethane-1,2-diol (Compound 60)

[0571]

[0572] 1H NMR (600 MHz, Chloroform-d) δ 7.95-7.89 (m, 1H), 7.54-7.45 (m, 2H), 5.27 (dd, J = 7.7, 3.1 Hz, 1H), 3.95 (dd, J = 11.4, 3.1 Hz, 1H), 3.56 (dd, J = 11.3, 7.8 Hz, 1H). LC-MS: calculated for C9H8ClF3O2 [M+COOH] - : 285.02, experimental value 285.0. ee value: 82.9%.

[0573] (R)-1-(4-Chloro-3-(trifluoromethyl)phenyl)ethane-1,2-diol (Compound 61)

[0574]

[0575] 1 H NMR (600 MHz, DMSO-d6) δ 7.80 (d, J = 1.9 Hz, 1H), 7.70-7.63 (m, 2H), 4.64 (q, J = 5.5 Hz, 1H), 3.51 (dt, J = 11.3, 5.7 Hz, 1H), 3.43 (dt, J = 10.9, 5.9 Hz, 1H). LC-MS: calculated for C9H8ClF3O2 [M+COOH] - : 285.02, experimental value 285.0. ee value: 91.6%.

[0576] (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethane-1,2-diol (Compound 62)

[0577]

[0578] 1 H NMR (600 MHz, Chloroform-d) δ 7.86 (s, 2H), 7.82 (s, 1H), 4.97 (dd, J = 7.8, 3.4 Hz, 1H), 3.87 (dd, J = 11.2, 3.3 Hz, 1H), 3.66 (dd, J = 11.2, 7.8 Hz, 1H). LC-MS: calculated value C 10 H8F6O2[M+COOH] - :319.04, experimental value 319.00.

[0579] (R)-1-(2-Fluoro-5-(trifluoromethyl)phenyl)ethane-1,2-diol (Compound 63)

[0580]

[0581] 1 H NMR (600MHz, Chloroform-d) δ7.82 (dd, J=6.6, 2.4Hz, 1H), 7.53 (ddd, J=7.8, 4.7, 2.4Hz, 1H), 7.11 (t, J=9.1Hz, 1H), 5 .14 ​​(dd, J=8.1, 3.0Hz, 1H), 3.83 (dd, J=11.5, 3.0Hz, 1H), 3.60 (dd, J=11.5, 8.0Hz, 1H).LC-MS: Calculated value for C9H8F4O2[M+COOH] - : 269.04, experimental value 269.00. ee value: 94.0%.

[0582] (R)-1-(3-Fluoro-5-(trifluoromethyl)phenyl)ethane-1,2-diol (Compound 64)

[0583]

[0584] 1 H NMR (600 MHz, Chloroform-d) δ 7.42 (s, 1H), 7.29 (dt, J = 9.1, 1.9 Hz, 1H), 7.25 (dt, J = 8.4, 2.0 Hz, 1H), 4.86 (dd, J = 8.0, 3.4 Hz, 1H), 3.80 (dd, J = 11.4, 3.4 Hz, 1H), 3.61 (dd, J = 11.4, 8.0 Hz, 1H). LC-MS: calculated for C9H8F4O2 [M+COOH] - : 269.05, experimental value 269.1. ee value: 90.9%.

[0585] (R)-1-(3-ethyl-4-fluorophenyl)ethane-1,2-diol (Compound 65)

[0586]

[0587] 1 H NMR (600 MHz, DMSO-d6) δ 7.24 (dd, J = 7.7, 2.2 Hz, 1H), 7.17 (ddd, J = 7.9, 5.1, 2.2 Hz, 1H), 7.04 (dd, J = 10.2, 8.4 Hz, 1H), 5.22 (d, J = 4.2 Hz, 1H), 4.69 (t, J = 5.8 Hz, 1H), 4.52-4.46 (m, 1H), 3.44-3.36 (m, 2H), 2.60 (q, J = 7.6 Hz, 2H), 1.16 (t, J = 7.6 Hz, 3H). LC-MS: calculated value C 10 H 13FO2[M+COOH] - : 229.09, measured value 229.10. ee value: 80.6%.

[0588] (R)-1-(3-ethyl-2-methylphenyl)ethane-1,2-diol (Compound 66)

[0589]

[0590] 1 H NMR (600MHz, Chloroform-d) δ7.36 (d, J=7.6Hz, 1H), 7.18 (t, J=7.6Hz, 1H), 7.13-7.09 (m, 1H), 5.13 (dd, J=8.6, 3.0Hz, 1H), 3.7 3 (dd, J=11.5, 3.0Hz, 1H), 3.60 (dd, J=11.5, 8.5Hz, 1H), 2.74 (d, J=2.6Hz, 3H), 2.65 (q, J=7.5Hz, 2H), 2.26 (s, 3H). LC-MS: Calculated value C 11 H 16 O2[M+H] + :181.12, measured value 181.15.

[0591] Synthetic route of compounds 67-69

[0592] The specific synthesis method of the above step cd is as follows:

[0593] Step 1 Synthesis of (2S, 3S, 4R, 5S)-2-(acetoxymethyl)-6-((R)-2-(3-ethylphenyl)-2-hydroxyethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound 67)

[0594]

[0595] In a 100mL single-mouth round-bottom flask, (R)-1-(3-ethylphenyl)ethane-1,2-diol (0.80mmol, 133mg), bromosugar (0.80mmol, 397mg), Ag2CO3 (0.48mmol, 132mg), silver trifluoromethanesulfonate (0.48mmol, 123mg) were added in sequence, and the reaction was monitored by TLC after stirring for 24h. After the reaction was completed, the mixture was filtered and concentrated by rotary evaporation to remove the solvent. The corresponding intermediate (2S, 3S, 4R, 5S)-2-(acetoxymethyl)-6-((R)-2-(3-ethylphenyl)-2-hydroxyethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (119mg, yield 30.0%) was obtained by column chromatography (PE: EA = 5: 1).

[0596] Synthesis of (3S,4R,5R,6S)-2-((R)-2-(3-ethylphenyl)-2-hydroxyethoxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound 67)

[0597]

[0598] In a 100 mL single round bottom flask, the intermediate (2S, 3S, 4R, 5S)-2-(acetoxymethyl)-6-((R)-2-(3-ethylphenyl)-2-hydroxyethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (0.24 mmol, 119 mg), potassium carbonate (0.24 mmol, 33 mg), dichloromethane / methanol (1:1) as solvent were added in sequence, and the reaction progress was monitored by TLC. After the reaction was completed, the mixture was concentrated by rotary evaporation and separated using a reverse column (35 mg, yield 45.0%).

[0599] 1 H NMR (500 MHz, DMSO-d6) δ 7.37-6.94 (m, 4H), 5.38-4.39 (m, 6H), 4.12 (m, 1H), 3.81-3.42 (m, 4H), 3.23-2.84 (m, 4H), 2.59 (q, J = 7.6 Hz, 2H), 1.18 (td, J = 7.6, 2.3 Hz, 3H). LC-MS: calculated value C 16 H 24 O7[M+NH4] + : 346.18, measured value 346.20. ee value: 82.2%.

[0600] The following compounds (68-69) were synthesized according to the method of steps cd above:

[0601] (2R,3R,4R,5S)-6-((R)-2-(3-ethylphenyl)-2-hydroxyethoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (Compound 68)

[0602]

[0603] 1H NMR (400 MHz, DMSO-d6) δ 7.28-7.05 (m, 4H), 6.72 (s, 1H), 5.73 (d, J = 3.6 Hz, 1H), 5.20-4.92 (m, 2H), 4.84-4.61 (m, 1H), 4.32-4.05 (m, 1H), 3.75-3.56 (m, 2H), 3.27 (dd, J = 14.8, 8.9 Hz, 1H), 3.21-3.08 (m, 3H), 3.02 (td, J = 8.1, 3.7 Hz, 1H), 2.59 (q, J = 7.6 Hz, 2H), 1.17 (t, J = 7.6 Hz, 3H). LC-MS: calculated value C 16 H 22 O8[M+NH4] + :360.16, measured value 360.20.

[0604] (2S,3R,4S,5R,6R)-2-(((2S,4S,5S)-6-((R)-2-(3-ethylphenyl)-2-hydroxyethoxy)-4,5-dihydroxy-2-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound 69)

[0605]

[0606] 1 H NMR (500 MHz, DMSO-d6) δ 7.29-7.05 (m, 4H), 5.24-5.16 (m, 2H), 5.07-4.94 (m, 2H), 4.81-4.55 (m, 4H), 4.38-4.21 (m, 2H), 3.85-3.51 (m, 5H), 3.47-3.38 (m, 1H), 3.34-3.12 (m, 6H), 3.12-2.94 (m, 3H), 2.59 (q, J = 7.6 Hz, 2H), 1.18 (td, J = 7.6, 1.6 Hz, 3H). LC-MS: calculated value C 22 H 34 O 12 [MH] - :489.20. Measured value [MH] - :489.30.

[0607] ee value test method: The ee value analysis of all final compounds was carried out on Agilent 1260infinity series, using CHIRALCEL OD-H, 4.6mm×250mm, a flow rate of 0.5mL / min, and a solvent of 90% n-hexane / 10% ethanol.

[0608] Experimental Example 2. Experimental study on compound 1-R (1R) and compound 1-S (1S) against heart failure induced by doxorubicin (CAS No.: 24385-10-2, referred to as DOX)

[0609] 70 6-8 week old C57BL / 6 male mice were divided into 2 groups: Ctrl group (8 mice) and DOX group (62 mice). DOX was purchased from MCE (Cat. No. CS-1239).

[0610] Ctrl group: 100 μL normal saline was injected intraperitoneally once a week for 4 weeks.

[0611] DOX group: intraperitoneal injection of DOX solution, 5 mg / kg, once a week for 4 consecutive weeks, the total drug dose is 20 mg / kg, 100 μL DOX solution per mouse each time. 4 days after the fourth injection of doxorubicin, the mouse ultrasound cardiogram was detected with a portable digital color ultrasound diagnostic instrument (LAB version, Vinno Technology (Suzhou) Co., Ltd., model VINNO 6LAB) to determine the mouse heart failure model (after 4 weeks of modeling, 2 mice died within 2-4 days), and then the mice with successful modeling were randomly divided into 6 groups, 10 mice in each group, and intragastric administration was performed, respectively:

[0612] DOX model group (daily intragastric administration of normal saline)

[0613] LCZ696 (Cas: 936623-90-4) drug group 1 (60 mg / kg twice a day, morning and evening)

[0614] 1-R drug doses were divided into three groups: low, medium, and high (1, 10, and 50 mg / kg were administered orally twice a day)

[0615] 1-S drug group 1 (50 mg / kg given orally twice a day).

[0616] The drug was administered by gavage for about 2 weeks, and the condition of the mice was observed (if the condition was not good, the mice had to be killed, and the actual administration lasted for 12 days). The ultrasonic cardiogram of the mice was recorded using a portable digital color ultrasound diagnostic apparatus.

[0617] Kill the mouse and take tissue samples

[0618] 1. Sample collection

[0619] a) After weighing, remove the eyeballs and collect blood, centrifuge and collect serum. Take 50 μl of serum and mix it with 100 μl of sterile 1× PBS for biochemical analysis to detect CK (creatine kinase), HBDH (hydroxybutyrate dehydrogenase), LDH (lactate dehydrogenase), ALT (alanineaminotransferase), AST (aspartate aminotransferase), ALP (alkaline aminotransferase), and the rest of the serum is stored at -80℃.

[0620] b) The whole liver and spleen were stored at -80°C, one kidney was fixed for paraffin sectioning, and one was frozen.

[0621] c) The heart was weighed and cut transversely, the middle section was fixed, dehydrated with an automatic tissue dehydrator (Leica, HistoCorePearl), embedded in a paraffin embedding machine (Lecia, HistoCore Arcadia), and sliced ​​with a manual rotary microtome (RM2235). The slice thickness was 5 μm. Two 15 mg sections were taken for RNA extraction (400 μl trizol) and protein extraction (500 μl lysis), and the rest was frozen at -80°C.

[0622] d) Sirius red staining of paraffin sections of the heart to detect cardiac fibrosis.

[0623] The prepared paraffin sections of the heart were dewaxed by: xylene 10min-xylene 10min-100% ethanol 5min-100% ethanol 5min-95% ethanol 5min-90% ethanol 5min-80% ethanol 5min-tap water 5min-distilled water 5min. The tissue was drip-stained with Sirius red stain for 1h, then rinsed with PBS 3 times, 5min each time, to remove excess stain, and then stained the nucleus with hematoxylin, washed with water to return to blue, dehydrated: 80% ethanol 5min-90% ethanol 5min-95% ethanol 5min-100% ethanol 5min-100% ethanol 5min-xylene 5min-xylene 5min-neutral resin sealing. After drying, take pictures and count the area percentage of Sirius red staining positive area.

[0624] 2. Experimental results

[0625] 1. Drug treatment increases the survival rate of mice with doxorubicin-induced heart failure (LCZ696, 1-S, 1-R)

[0626] The results are as follows Figure 1 As shown: DOX model group (6 rats survived 12 days); LCZ696 drug group 1 (9 rats survived 12 days); 1-R drug low, medium and high dose groups (7, 6 and 9 rats survived 12 days respectively); 1-S drug group 1 (6 rats survived 12 days).

[0627] 1-R can significantly increase the survival rate of mice with heart failure induced by adriamycin, especially at high doses (50 mg / kg), which is the same as positive drugs; 1-S has no significant effect on mice with heart failure. Heart failure induced by adriamycin significantly reduces the body weight of mice.

[0628] 2. Drug treatment improves ultrasound parameters of mice with doxorubicin-induced heart failure (EF-Ejection fraction, FS-Fractional shortening, HR-Heart rate)

[0629] The results are as follows Figure 2 As shown, compounds 1-S and 1-R can antagonize the decrease in ejection fraction and short-axis shortening rate in mice caused by doxorubicin, that is, improve the cardiac function of mice.

[0630] 3. Drug treatment reduces the levels of myocardial injury markers in mouse serum (CK-creatine kinase, creatine kinase; HBDH-hydroxybutyrate dehydrogenase, hydroxybutyrate dehydrogenase; LDH-lactate dehydrogenase)

[0631] The results are as follows Figure 3 As shown, compounds 1-S and 1-R can reduce the levels of creatine kinase, lactate dehydrogenase, and hydroxybutyrate dehydrogenase in the serum of mice with heart failure.

[0632] 4. Drug treatment improves myocardial cell morphology and cardiac fibrosis in mice

[0633] The results are as follows Figure 4 As shown, compounds 1-S and 1-R can inhibit myocardial fibrosis in mice induced by doxorubicin. (Sirius red can dye collagen fibers red)

[0634] Conclusion

[0635] Compound 1-R significantly improved doxorubicin-induced heart failure in many aspects.

[0636] Example 3. Evaluation of the therapeutic effect of compound 1-R on mice with heart failure after myocardial infarction

[0637] Evaluation of the efficacy of compound 1-R in the experimental model of post-myocardial infarction heart failure induced by left anterior descending coronary artery ligation (LAD).

[0638] 1. Experimental methods:

[0639] 1. Grouping: 5-6 week old ICR male mice

[0640] The left anterior descending coronary artery was ligated to establish a heart failure model after myocardial infarction, and the model mice were randomly divided into 5 groups, with 10-11 mice in each group, namely:

[0641] Model group (11 mice)

[0642] LCZ696 (Cas: 936623-90-4) group (66 mg / kg, gavage once a day) (10 mice)

[0643] Compound 1-R was administered in three groups: low (11 rats), medium (11 rats), and high (9 rats) (administered orally once a day at 3, 10, and 33 mg / kg)

[0644] The mice were given the drug by gavage for 7 days, and their conditions were observed. Their ultrasonic cardiograms were recorded using a portable digital color ultrasound diagnostic apparatus.

[0645] Kill the mice and take tissue samples.

[0646] 1.2 Cardiac function test: After administration, the rats were anesthetized with isoflurane and the long and short axes were measured using a small animal ultrasound imaging system (Vevo TM2100, Visual Sonics, Canada). The left ventricular internal dimension systole (LVID; s), left ventricular internal dimension diastole (LVID; d), left ventricular end-systolic volume (LVESV), and left ventricular end-diastolic volume (LVEDV) were measured. The fractional shortening (FS) value was calculated according to the calculation formula of the left ventricular short axis shortening rate, which was FS (%) = (LVID; d-LVID; s) / LVID; d × 100%. The ejection fraction (EF) value was calculated according to the ejection fraction formula; the calculation formula was EF (%) = (LVEDV-LVESV) / LVEDV×100%; finally, the FS value and EF value were used to evaluate the cardiac systolic and diastolic function.

[0647] 1.3 Serum myocardial injury marker detection: (1) Weigh the abdominal aorta and collect blood, centrifuge and collect serum. Take 50μL serum and mix it with 100μL sterile 1×PBS for biochemical analysis. Fully automatic biochemical analyzer (HITACHl7080, Hitachi, Japan) detects NT-proBNP (N-Terminal Pro-Brain Natriuretic Peptide) and LDH (lactate dehydrogenase). The remaining serum is stored at -80℃. (2) Weigh the heart, cut the heart cross-section, fix the middle part and make slices, take two 15mg pieces to extract RNA (400μl trizol) and protein (500μl lysis), and the remaining part is frozen at -80℃. (3) HE staining of paraffin sections of the heart detects cardiac injury, mason staining detects cardiac fibrosis, and WGA staining detects cardiomyocyte hypertrophy.

[0648] 1.4 HE staining of myocardial tissue

[0649] (1) Dewaxing and hydration of paraffin sections: soak in xylene I for 20 min, soak in xylene II for 20 min, soak in gradient ethanol to 50% alcohol, rinse in running water for 10 min, and then slowly rinse in 0.01 mol / L PBS for 5 min, repeat 3 times;

[0650] (2) Hematoxylin staining of cell nuclei: Immerse the sections in Harris hematoxylin dye for 8 minutes, rinse with pure water after staining, and then immerse the sections in 1% hydrochloric acid alcohol. Rinse with pure water after differentiation, then immerse the sections in 0.6% ammonia water to return to blue, and finally rinse with pure water.

[0651] (3) Eosin staining of cytoplasm: Immerse the sections in eosin staining solution for 1-3 minutes.

[0652] (4) Dehydration and mounting: The sections were dehydrated in sequence to make them transparent, and then dehydrated in a gradient from 70% alcohol to anhydrous ethanol, and then immersed in xylene I and xylene II for 15 min to make them transparent, and then dried in a fume hood, and then mounted with neutral gum;

[0653] (5) Image acquisition: Examine under a microscope, acquire images, and analyze them.

[0654] 1.5 Detection of myocardial fibrosis by Masson staining of myocardial tissue

[0655] (1) Dewaxing of paraffin sections: soak in xylene I for 20 min, soak in xylene II for 20 min, hydrate in gradient from anhydrous ethanol to 50% alcohol, rinse in running water for 10 min, and then slowly rinse in 0.01 mol / L PBS for 5 min, repeat 3 times;

[0656] (2) Soak the slices in Masson A solution at room temperature overnight, and then rinse with running water for 10 minutes. After completion, proceed to the next step;

[0657] (3) After being rinsed with pure water, the sections were immersed in a dye solution composed of Masson B dye solution and Masson C dye solution in equal proportions for 1 min. After the dyeing time was completed, the sections were rinsed with running pure water for 10 min. Then, the sections were differentiated with 1% hydrochloric acid alcohol. After the dyeing time was completed, the sections were rinsed with running pure water.

[0658] (4) Immerse the pure sections in Masson D stain for 6 min, and then rinse with running pure water for 10 min.

[0659] (5) After rinsing, immerse the sections in Masson E stain for 1 min. No rinsing is required after this process is completed.

[0660] (6) After draining the slices slightly, immerse them directly in Masson F solution for 30 seconds;

[0661] (7) The slices were then rinsed and differentiated with 1% glacial acetic acid and dehydrated by immersing in anhydrous ethanol A and anhydrous ethanol B.

[0662] (8) Transparent sealing: Immerse the slices in anhydrous ethanol C for 5 min, use xylene to stain the transparent slices for 5 min, and seal the slices with neutral gum.

[0663] (9) Examine under a microscope, collect and analyze images.

[0664] 1.6 Myocardial tissue WGA staining to detect myocardial cell hypertrophy

[0665] (1) Dewaxing of paraffin sections: soak in xylene I for 20 min, soak in xylene II for 20 min, hydrate in gradient from anhydrous ethanol to 50% alcohol, rinse in running water for 10 min, and then slowly rinse in 0.01 mol / L PBS for 5 min, repeat 3 times;

[0666] (2) Antigen repair: Prepare antigen repair solution by mixing 10× stock solution of antigen repair solution with double distilled water at a ratio of 1:20. Preheat the prepared antigen repair solution in a microwave oven at high temperature for 8 minutes, then slowly soak the slices in it, and then repair them at low temperature for 6 minutes. Then, cool them naturally in an ice-water mixture, and rinse them with running pure water for 3-5 times.

[0667] (3) Staining: After washing, the slices were slightly dried and a circle was drawn around the myocardial tissue with an immunohistochemistry pen to prevent the loss of antibodies. After the circle was drawn, the diluted WGA dye solution was added to the circle, and then incubated in a constant temperature box at 37°C for 30 minutes in a light-proof environment, and then slowly rinsed with 0.01 mol / L PBS for 5 minutes, and repeated 3 times;

[0668] (4) DAPI counterstaining of cell nuclei: After washing, the slices were slightly dried, and DAPI staining solution was added to the circle. The slices were incubated at room temperature for 10 min in a dark environment, and then slowly rinsed with 0.01 mol / L PBS for 5 min. This was repeated 3 times.

[0669] (5) Sealing: After washing, the slices are slightly dried and sealed with an anti-fluorescence quenching sealing agent to reduce fluorescence quenching;

[0670] (6) Microscopic examination and photography: Examine the sample under a fluorescence microscope and collect images for analysis.

[0671] 2. Experimental results

[0672] 1. Compound 1-R improves cardiac function in mice with heart failure

[0673] The results are as follows Figure 5 As shown, 9 mice survived in the model group; 10 mice survived in the LCZ696 positive drug group; 10, 11, and 9 mice survived in the low, medium, and high dose groups of compound 1-R, respectively. That is, 82% of the model group survived; 100% of the LCZ696 positive drug group survived; 91%, 100%, and 100% of the low, medium, and high dose groups of compound 1-R survived, respectively. Compound 1-R can antagonize the decrease in ejection fraction EF and short axis shortening rate FS induced by the model in mice; that is, it improves the cardiac function of mice.

[0674] 2. The results are as follows Figure 6 As shown, compound 1-R can antagonize myocardial fibrosis and cardiomyocyte hypertrophy induced by the model in mice.

[0675] 3. Compound 1-R improves serum indicators of heart failure mice

[0676] The results are as follows Figure 7 As shown, compound 1-R can antagonize the serum LDH level of mice induced by the model; that is, it improves heart failure in mice.

[0677] Example 4: Evaluation of Compound 1-R in the Treatment of Rats with Heart Failure after Myocardial Infarction

[0678] Evaluation of the efficacy of compound 1-R in the experimental model of post-myocardial infarction heart failure induced by left anterior descending coronary artery ligation (LAD).

[0679] 1. Experimental Methods

[0680] Grouping: The left anterior descending coronary artery of 6-7 weeks old male rats was ligated to establish a heart failure model after myocardial infarction. The modeled rats were then randomly divided into 5 groups, namely:

[0681] Model group (9 mice)

[0682] LCZ696 (Cas: 936623-90-4) group (8 mice) (46.2 mg / kg, intragastrically, once a day)

[0683] Compound 1-R was administered in three groups: low (9 rats), medium (9 rats), and high (10 rats) (2.1, 7, and 23.1 mg / kg were administered orally once a day)

[0684] After intragastric administration for 21 days, the rats were observed and their ultrasonic cardiograms were recorded using a portable digital color ultrasonic diagnostic apparatus.

[0685] Kill the mice and take tissue samples.

[0686] 2. Experimental results

[0687] The results are as follows Figure 8 As shown, 6 rats survived in the model group; 6 rats survived in the LCZ696 positive drug group; 8, 7, and 8 rats survived in the low, medium, and high dose groups of compound 1-R, respectively. That is, 67% of the model group survived; 75% of the LCZ696 positive drug group survived; 89%, 78%, and 80% of the low, medium, and high dose groups of compound 1-R survived, respectively. Compound 1-R significantly improved the survival rate of rats with heart failure.

[0688] Compound 1-R improves cardiac function and myocardial remodeling in rats with heart failure

[0689] The results are as follows Fig. 9 As shown in Figure 1, compound 1-R can antagonize the decrease in rat ejection fraction EF and short axis shortening rate FS induced by the model; that is, it improves the cardiac function of rats. In addition, the results are as follows Fig.10 As shown, compound 1-R can antagonize myocardial fibrosis and cardiomyocyte hypertrophy induced by the model in rats.

[0690] Compound 1-R improves serum parameters of rats with heart failure

[0691] The results are as follows Fig.11 As shown, compound 1-R can antagonize the serum LDH level of rats induced by the model; that is, it improves rat heart failure.

[0692] 3. Mechanism and Conclusion

[0693] Compound 1-R can significantly increase the survival rate of rats after myocardial infarction induced by left anterior descending coronary artery ligation (LAD) and significantly improve heart failure, which is through regulating RhoA activity to regulate the nuclear translocation of MRTF-A ( Fig.12 , Fig.13 ), collagen and metalloproteinase MMP2 expression, thereby achieving the effect of regulating myocardial hypertrophy and fibrosis ( Fig.14 , Fig.15 ).

[0694] Example 4. According to Examples 2-4, the present inventors verified the anti-heart failure effects of the following derivatives of Compound 1 and found that these compounds also showed good anti-heart failure effects:

[0695]

[0696]

[0697] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof, for use in the preparation of a medicament for preventing or treating heart failure, 2. The use according to claim 1, characterized in that The heart failure is heart failure induced (or caused) by various clinical therapeutic drugs, heart failure caused by myocardial infarction and coronary heart disease.

3. A compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof, 4. A pharmaceutical composition comprising the compound according to claim 3, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

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