Biaryl compound, and preparation method therefor and use thereof

Abstract

The present invention relates to a biaryl compound, and a preparation method therefor and the use thereof. Specifically disclosed in the present invention is a compound of formula I, wherein the definition of each group and substituent is as described in the description and claims. Further provided in the present invention are a compound as represented by formula I and a pharmaceutical composition thereof, and the use of the compound in the preparation of a drug for treating related metabolic diseases caused by insulin resistance, endoplasmic reticulum stress, mitochondrial function damage, etc., or an antitumor drug.

Description

A class of biaryl compounds, their preparation methods and uses Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to a class of biaryl compounds, their preparation methods, and uses. Background Technology

[0002] Death-associated protein-related apoptotic kinase 2 (DRAK2) is a threonine / serine protein kinase belonging to the Ca2+ family. 2+ Calmodulin-dependent protein kinase (CaMK) is a member of the death-associated protein kinase (DAPK) family. DRAK2 is widely distributed in the immune system, particularly highly expressed in the thymus, lymph nodes, B cells, and trachea, and mildly expressed in the liver and pancreas. It plays an important role in T cell survival and differentiation, islet survival and apoptosis, and tumor cell proliferation.

[0003] Metabolic diseases are diseases caused by metabolic disorders of substances such as proteins, fats, and carbohydrates in the human body. These include obesity, hypertension, hyperlipidemia, hyperglycemia, gout, fatty liver, heart disease, and cerebrovascular diseases.

[0004] Metabolic fatty liver disease (MAFLD) has become a growing public health problem worldwide. Its pathogenesis is complex, involving genetic, epigenetic, and environmental factors, and the exact mechanisms remain unclear. The progressive form of MAFLD, MASH, is a landmark "inflection point" in pathological progression, which can further develop into liver fibrosis, liver cancer, liver failure, and even death. Currently, only Resmetirom, approved by the FDA in March 2024, is available for the treatment of MASH with significant fibrosis. Treatment options are very limited, and there is an urgent need to discover new targets and develop safe and effective therapeutic drugs.

[0005] Patients with MAFLD typically have one or more metabolic syndromes (MS), such as systemic hypertension, dyslipidemia, insulin resistance, or significant diabetes. Visceral obesity is a risk factor for MAFLD. Numerous studies have indicated that MS is a known risk factor for the development of cardiovascular disease, and there may be a link between the pathological mechanisms of cardiovascular disease and MAFLD. Insulin resistance is considered a common factor linking the pathogenesis of both conditions.

[0006] Previous studies have revealed that DRAK2 regulates alternative splicing of mitochondrial function-related genes through its interaction with the splicing factor SRSF6, mediating mitochondrial homeostasis imbalance and promoting the development of MAFLD / MASH. Furthermore, the interaction between DRAK2 and SRSF6 is independent of DRAK2 kinase activity. Abnormal phase separation of DRAK2 can mediate the interaction between DRAK2 and SRSF6.

[0007] Metabolic reprogramming of cancer cells endows them with greater proliferative potential and a better ability to adapt to unfavorable microenvironments, promoting tumorigenesis and development by facilitating immune evasion. The tumor microenvironment (TME) maintains cancer cell proliferation by inducing nutrient clearance mechanisms to deplete certain nutrients; the metabolism of endothelial cells, fibroblasts, and immune cells within the TME also regulates tumor progression. Metastasis is a leading cause of death in cancer patients. Metabolic changes are involved in multiple steps of metastasis: invasion of the basement membrane and cell migration to the surrounding vascular or lymphatic system (i.e., endocytosis); survival in circulation; extravasation into the vascular system and colonization at secondary tumor sites. DRAK2 is a positive regulator of apoptosis, playing a crucial role in tumor cell proliferation and apoptosis. Furthermore, regulation of DRAK2-related pathways can correct aberrant splicing, affect gene expression, and modulate the tumor microenvironment.

[0008] Therefore, there is an urgent need in this field to develop an inhibitor of the DRAK2-related (kinase-active or non-kinase-active) metabolic pathway, which is expected to be used in the clinical treatment of metabolic diseases and cancer. Summary of the Invention

[0009] The present invention aims to provide a novel class of biaryl compounds, or their stereoisomers, enantiomers, diastereomers, racemates, or deuterated compounds, or their pharmaceutically acceptable salts, along with their preparation methods and uses. These compounds are developed by substituting aryl or heteroaryl groups with monocyclic or bicyclic structures and extending the structural skeleton using different linkers, thus creating a series of DRAK2-related metabolic pathway inhibitors with novel structures. These compounds are intended for the prevention and / or treatment of metabolic diseases and cancer.

[0010] In a first aspect, the present invention provides a compound of Formula I, or a stereoisomer, enantiomer, diastereomer, racemate thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof.

[0011] in,

[0012] Selected from the following group: Wherein, the dashed lines represent single or double bonds, and the A ring is a saturated ring, a partially unsaturated ring, or an aromatic ring; preferably, It is an aromatic ring;

[0013] Each of Z1, Z2, Z3, Z4, Z5, and Z6 is independently selected from the following groups: -N=, -NH-, -S-, -O-, -CH=;

[0014] Each R 1 R 2 R 3 and R 4 The substituent is H or 0-3 independently selected from the group consisting of: -OH, halogen, -CN, substituted or unsubstituted amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S, substituted or unsubstituted C1-C6 alkylene -COOH, substituted or unsubstituted C1-C6 alkylene -C(O)OR 10 substituted or unsubstituted C1-C6 alkylene-C(O)NH-R 10 Substituted or unsubstituted C6-C10 aryl groups, substituted or unsubstituted 5-10 membered heteroaryl groups containing 1-3 heteroatoms selected from N, O, or S, -C(O)-R 10 -C(O)OR 10 -NH-C(O)-R 10 ;

[0015] R 10 Selected from the following group: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S, and C6-C10 aryl;

[0016] Selected from the following group: not present, C3-C8 cycloalkyl, C3-C10 heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S, C6-C10 aryl, 5-10 heteroaryl containing 1-3 heteroatoms selected from N, O or S;

[0017] Selected from the following group: Where r is selected from the following group: 0, 1, 2, 3, 4, 5 or 6;

[0018] Each R 5 R 6 and R 7Each is independently selected from the group consisting of: H, -OH, halogen, substituted or unsubstituted amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy; or, R 5 R 6 and R 7 Any two atoms can be linked together to form a substituted or unsubstituted C3-C8 cycloalkyl group, or a substituted or unsubstituted C3-C8 heterocycloalkyl group containing 1-3 heteroatoms selected from N, O or S.

[0019] The substitution refers to substitution by one or more substituents selected from the group consisting of: halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S, C1-C18 alkylene-COOH, -C(O)-R 6 -C(O)OR 6 ,

[0020] n is selected from the following groups: 1, 2, or 3;

[0021] m and q are each independently selected from the following groups: 0, 1, 2, 3 or 4;

[0022] This indicates a double bond, which can be either cis or trans configuration.

[0023] The additional condition is:

[0024] when for hour, Not for

[0025] In another preferred embodiment, for

[0026] In another preferred example, n is 1 or 2.

[0027] In another preferred embodiment, Selected from the following group:

[0028] Each of Z1, Z2, Z3, Z4, Z5, and Z6 is independently selected from the following groups: -N=, -NH-, -O-, -CH=;

[0029] R 1 and R 2 As defined above.

[0030] In another preferred embodiment, Selected from the following group:

[0031] In another preferred embodiment, Selected from the following group: C3-C8 cycloalkyl, C6-C10 aryl, 5-10 heteroaryl containing 1-3 heteroatoms selected from N, O or S.

[0032] In another preferred embodiment, Selected from the following group: cyclohexyl, piperidinyl, thienyl, furanyl, phenyl.

[0033] In another preferred embodiment, each R 4 It consists of 0-3 substituents, each independently selected from the group consisting of: -OH, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, -C(O)-R 10 -C(O)OR 10 -NH-C(O)-R 10 .

[0034] In another preferred embodiment, R 4 Selected from the following group: methyl, methoxy, halogen, benzoyl.

[0035] In another preferred embodiment, the compound of formula I is the compound of formula II.

[0036] in,

[0037] Z1, Z2, Z3, Z4, Z5, R 1 R 2 R 3 R 4 , As defined above.

[0038] In another preferred embodiment, Selected from the following group:

[0039] In another preferred embodiment, Z1 is -CH= or -N=.

[0040] In another preferred embodiment, and R 3 It is in an intermediate position.

[0041] In another preferred embodiment, the compound of formula II is the compound of formula II-a.

[0042] The groups are defined as above.

[0043] In another preferred embodiment, R 3 It does not exist.

[0044] In another preferred embodiment, R 2 and R 3 It does not exist.

[0045] In another preferred embodiment, It is in the opposite position.

[0046] In another preferred embodiment, the compound of formula I is the compound of formula III.

[0047] in,

[0048] Z1, Z2, Z3, R 1 R 3 R 4 , As defined above.

[0049] In another preferred embodiment, Z2 is N and Z3 is O.

[0050] In another preferred embodiment, Selected from the following group:

[0051] In another preferred embodiment, the compound is selected from the group consisting of M1 to M123.

[0052] A second aspect of the present invention provides a method for preparing a compound as described in the first aspect of the present invention, comprising the following steps:

[0053] In an inert solvent, under the conditions of base and catalyst, compound aa and compound bb undergo a Suzuki coupling reaction to prepare compound I.

[0054] The groups are defined as above.

[0055] In another preferred embodiment, the preparation method includes the following steps:

[0056] In an inert solvent, under the conditions of base and catalyst, the cc compound and the dd compound undergo a Suzuki coupling reaction to prepare the compound of formula I.

[0057] The groups are defined as above.

[0058] A third aspect of the present invention provides a pharmaceutical composition comprising:

[0059] (i) the compound as described in the first aspect of the invention, or its stereoisomers, enantiomers, diastereomers, racemates, or deuterated compounds thereof, or pharmaceutically acceptable salts thereof; and

[0060] (ii) Pharmaceutically acceptable carriers.

[0061] A fourth aspect of the invention provides a use of the compound as described in the first aspect of the invention.

[0062] (1) Used to prepare DRAK2-related inhibitors;

[0063] (2) Used to prepare DRAK2-SRSF6 interaction inhibitors;

[0064] (3) Used to prepare drugs for the prevention and / or treatment of metabolic diseases or cancer.

[0065] In another preferred embodiment, the metabolic disease is selected from the group consisting of: obesity, hypertension, hyperlipidemia, diabetes, atherosclerosis, metabolic-associated fatty liver disease, metabolic dysfunction-associated fatty liver disease, and cardiovascular disease.

[0066] In another preferred embodiment, the cancer is selected from the group consisting of: lung cancer, pancreatic cancer, breast cancer, liver cancer, and colorectal cancer.

[0067] A fifth aspect of the present invention provides a method for preventing and / or treating metabolic diseases or cancer, comprising the steps of administering to a test subject a compound as described in the first aspect of the present invention, or a stereoisomer, enantiomer, diastereomer, racemic mixture thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in the third aspect of the present invention.

[0068] In another preferred embodiment, the test subject is a mammal, preferably a rodent or primate mammal, more preferably a mouse, rat, or human.

[0069] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0070] Figure 1 shows the inhibitory effect of seven embodiments, including M57, on molecular-level phase separation.

[0071] Figure 2 shows the inhibitory effect of five embodiments, including M86, on molecular-level phase separation.

[0072] Figure 3 shows the inhibitory effect of 10 embodiments, including M90, on molecular-level phase separation. Detailed Implementation

[0073] Through extensive and in-depth research, the inventors unexpectedly developed a series of compounds with novel structures. These compounds, by introducing monocyclic or bicyclic structures onto an aryl or heteroaryl base and modifying the backbone with different linking chains, can effectively inhibit DRAK2 kinase activity, significantly inhibit DRAK2-SRSF6 interaction, significantly inhibit DRAK2 phase separation, improve abnormal lipid metabolism in hepatocytes, and restore mitochondrial structure and function. Therefore, they hold promise for applications in the preparation of therapeutic drugs for metabolic diseases or cancer. Based on this, the inventors completed this invention.

[0074] the term

[0075] In this invention, unless otherwise specified, the terms used have the general meanings known to those skilled in the art.

[0076] In this invention, the term "halogen" refers to F, Cl, Br, or I.

[0077] In this invention, "C1-C6 alkyl" refers to a straight-chain or branched alkyl group comprising 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, pteropentyl, or similar groups. The similar term "C1-C4 alkyl" has a similar definition.

[0078] In this invention, the term "C1-C6 alkoxy" refers to a straight-chain or branched alkoxy group having 1 to 6 carbon atoms, including but not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, etc. Similar terms such as "C1-C4 alkoxy" have similar definitions.

[0079] In this invention, the term "C2-C6 alkenyl" refers to a straight-chain or branched alkenyl group having 2 to 6 carbon atoms and containing at least one double bond, including but not limited to vinyl, propenyl, butenyl, isobutenyl, pentenyl, and hexenyl.

[0080] In this invention, the term "C2-C6 ynyl" refers to a straight-chain or branched ynyl group having 2 to 6 carbon atoms and containing at least one triple bond, including but not limited to ethynyl, propynyl, butynyl, isobutynyl, pentynyl, and hexynyl.

[0081] In this invention, the term "C3-C8 cycloalkyl" represents a cyclic aliphatic hydrocarbon group consisting of 3 to 8 cyclic carbon atoms, and so on. It should be understood that "cycloalkyl" as used in this invention includes not only monocyclic aliphatic hydrocarbon groups, but also fused ring, spiro ring, and bridged ring systems composed of multiple cyclic aliphatic hydrocarbons. "Cycloalkyl" as used in this invention includes not only aliphatic hydrocarbon groups with fully saturated carbon atoms, but also aliphatic hydrocarbon groups with some carbon atoms having unsaturated bonds. Examples of "cycloalkyl" as used in this invention include, but are not limited to: When "cycloalkyl" is used as a substituent, the connection site with the main molecule can occur at any position allowed by the chemical bonds on the "cycloalkyl". Terms such as "C3-C6 cycloalkyl" have similar definitions.

[0082] In this invention, the term "aryl" refers to a monocyclic or bicyclic system consisting of a specific number of carbon atoms that obeys Hückel's rule. It should be understood that when "aryl" in this invention refers to a bicyclic system, it includes not only the case where all rings are aromatic rings, but also the case where only one ring is an aromatic ring and the other ring is a non-aromatic aliphatic ring.

[0083] In this invention, the term "C6-C10 aryl" refers to a cyclic system having 6 to 10 carbon atoms, and at least one ring being an aromatic ring; examples of "aryl" in this invention include, but are not limited to, those described in this invention. When "aryl" is used as a substituent, the connection site with the main molecule occurs on the aromatic ring.

[0084] In this invention, the term "heterocyclic alkyl" refers to a non-aromatic cyclic group that indicates a specific number of cyclic atoms, contains at least one cyclic heteroatom (N, O, or S), and is saturated or partially unsaturated. It should be understood that the "heterocyclic group" described in this invention includes not only monocyclic heterocyclic systems but also polycyclic heterocyclic systems, such as fused rings, spirocyclic rings, and bridged rings. When the "heterocyclic group" is a polycyclic system, at least one ring contains a cyclic heteroatom, and the other rings may contain cyclic heteroatoms or be cyclic alkyl groups. For example, the term "4-8 membered heterocyclic alkyl" refers to a monocyclic or polycyclic system having 4 to 8 cyclic atoms, at least one of which is a heteroatom, and is saturated or partially unsaturated. The definitions of other similar terms follow the same pattern. More preferably, the number of heteroatoms is 1 to 3. This includes (but is not limited to) the following groups: It is important to understand that when a "heterocyclic group" acts as a substituent, its connection site with the molecular body can occur at any position permitted by chemical bonds on the "heterocyclic group." In the aforementioned heterocyclic group, the heteroatom may have an H atom for equilibrium valence, or it may be substituted by a substituent, as defined in the specification. Typically, the heteroatom does not have any substitutions other than those defined; for example, unless specifically defined, substituents on the heteroatom do not include =NH, etc.

[0085] In this invention, the term "heteroaryl" refers to a cyclic group with a specific number of cyclic atoms, containing at least one cyclic heteroatom (N, O, or S), and possessing aromaticity. Unless otherwise defined, the "heteroaryl" in this invention includes not only monocyclic heteroaryl systems but also polycyclic heteroaryl systems, such as bicyclic, tricyclic, and tetracyclic heteroaryl systems. When the "heteroaryl" is a polycyclic heteroaryl system, at least one ring is aromatic, and the other rings can be aromatic or non-aromatic. The heteroatom can be located in an aromatic ring or a non-aromatic ring. Polycyclic heteroaryl systems include not only fused ring systems but also bridged and spirocyclic systems. The term "5-7 membered heteroaryl" refers to a cyclic group having 5 to 7 cyclic atoms, at least one of which is a heteroatom, and possessing aromaticity. The definitions of other similar terms follow the same pattern.

[0086] In this invention, the term "optionally" means that when there is a series of candidate groups to choose from, some of them can be selected, or none can be selected.

[0087] In this invention, "each independently" means that when several substituents defined at the same time are selected from the same series of candidate groups, they do not affect each other, and they may be the same or different.

[0088] In this invention, the term "substitution" refers to the replacement of one or more hydrogen atoms on a specific group by a specific substituent. The specific substituent is either the substituent described accordingly above or the substituent appearing in the various embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substituted site of that group, and the substituents at each position may be the same or different. Those skilled in the art will understand that the combinations of substituents contemplated in this invention are those that are stable or chemically feasible.

[0089] In this invention, the term "1-6" refers to having 1, 2, 3, 4, 5 or 6, and other similar terms each have a similar meaning independently.

[0090] It should be understood that when a group exists simultaneously at multiple different positions in a compound, its definition at each position is independent and can be the same or different. That is, the term "selected from the following group:" and the term "each independently selected from the following group:" have the same meaning.

[0091] Compounds and their preparation methods

[0092] For the first or second aspect of the present invention, general formula (I) indicates that the compound may contain one or more chiral centers, which exist as enantiomers and diastereomers. General formula (I) of the present invention also indicates that the compound may contain many geometric isomers such as alkenes, C=N double bonds, and amides. Unless otherwise specified, all chiral (enantiomers, diastereomers, axial chiral isomers), racemic, cis geometric isomers, trans geometric isomers, mixtures of cis and trans geometric isomers, rotational isomers, and mixtures thereof described above are included within the scope of the present invention. Those skilled in the art can use commonly used laboratory separation or synthesis methods to separate or prepare compounds containing asymmetric centers in the present invention to obtain single isomers. For example, for enantiomers, two enantiomers can be obtained using general chiral resolution methods or asymmetric synthesis methods; for diastereomers, they can be separated by stepwise recrystallization or chromatographic separation, etc., without compromising the novelty of the compounds of the present invention.

[0093] The compounds of this invention have the structure shown in Formula I:

[0094] The groups are defined as above.

[0095] The additional condition is:

[0096] when for hour, Not for

[0097] Better place, for

[0098] Better place, Selected from the following group:

[0099] Preferably, the compound of formula I is the same as the compound of formula II.

[0100] The groups are defined as above.

[0101] Ideally, R 3 It does not exist.

[0102] Preferably, the compound of formula I is the same as the compound of formula III.

[0103] The groups are defined as above.

[0104] In another preferred embodiment, in the compound, Z1, Z2, Z3, Z4, Z5, Z6, R 1 R 2 R 3 R 4 R 5 R 6 R 7 Each of R10, m, n, and q is an independent group corresponding to the specific compound described in this invention.

[0105] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by a positively charged group on a compound of formula (I) and an anion, or a salt formed by a negatively charged group on a compound of formula (I) and a cation. Suitable anions include, but are not limited to, chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, acetate, malate, toluenesulfonate, tartrate, fumarate, glutamate, glucuronide, lactate, glutarate, or maleate. Suitable cations include, but are not limited to, sodium, potassium, magnesium, calcium, and ammonium ions.

[0106] In another preferred embodiment, the pharmaceutically acceptable salt of the present invention refers to a salt formed by a compound of general formula (I) with an acid from the group below, such as, but not limited to: hydrofluoric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, sulfuric acid, nitric acid, methanesulfonic acid, aminosulfonic acid, salicylic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, maleic acid, citric acid, acetic acid, lactic acid, tartaric acid, succinic acid, oxalic acid, pyruvic acid, malic acid, glutamic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, malonic acid, and fumaric acid. Propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, acetic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, and hydroxyethanesulfonic acid, etc.; or salts formed by compounds of general formula (I) with inorganic bases, such as, but not limited to, sodium salts, potassium salts, calcium salts, aluminum salts, or ammonium salts; or salts formed by compounds of general formula (I) with organic bases, such as, but not limited to, methylamine salts, ethylamine salts, ethanolamine salts, hydroxymethylaminomethane (TRIS) ammonium salts, etc.

[0107] Replacing hydrogen atoms with deuterium atoms to alter the physicochemical properties of compounds is a well-known structural modification method among those skilled in the art. Unless otherwise stated, this invention intends to include the deuterated form of compounds represented by general formula (I) in the scope of the invention.

[0108] The embodiments of this invention specifically describe the preparation method of the compound with structure (I) of this invention, but these specific methods do not constitute any limitation on this invention. The compounds of this invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, such combinations can be easily performed by those skilled in the art.

[0109] Typically, the preparation process of the compounds of the present invention is as follows, wherein the raw materials and reagents used can be purchased commercially unless otherwise specified.

[0110] In an inert solvent, under the conditions of base and catalyst, compound aa and compound bb undergo a Suzuki coupling reaction to prepare compound I.

[0111] The groups are defined as above.

[0112] In another preferred embodiment, the preparation method includes the following steps:

[0113] In an inert solvent, under the conditions of base and catalyst, the cc compound and the dd compound undergo a Suzuki coupling reaction to prepare the compound of formula I.

[0114] The groups are defined as above.

[0115] Specifically, this invention provides a method for preparing the compound represented by general formula I, using the following routes A to D, where each substituent is defined as described above:

[0116] Synthetic Route A:

[0117] Synthetic route A includes the following steps:

[0118] (1) Compound A1 (same as compound aa) or compound A3 (same as compound cc) undergoes Miyaura borate esterification reaction with pinacol diboronic acid under the action of palladium catalyst and base to generate the corresponding aryl pinacol borate compounds A4 (same as compound dd) and A6 (same as compound bb).

[0119] (2) Using a combination of reactants A1+A6 or A3+A4, a Suzuki coupling reaction occurs in a suitable solvent system under the catalysis of a base and tetra-triphenylphosphine palladium to generate compound I.

[0120] in, R 3 R 4The definitions of Z1 are as described above; when a commercially available product of a specific structure of A4 is available, it is purchased directly from a reagent company and used without undergoing the Miyaura borate esterification reaction of A1.

[0121] The intermediate A3 in route A can be further subdivided into structures as shown in A9 to A15 according to the Linker, and can be synthesized according to the method in route B below.

[0122] Synthetic Route B:

[0123] Synthetic route B follows the classic step of amide condensation:

[0124] (1) Intermediate A16 or A17 reacts with a carboxylic acid containing the target structure under the action of a condensing agent (such as HATU or DCC) to obtain intermediate A9 to A14; or, intermediate A16 or A17 reacts with an acyl chloride containing the target structure under the action of an organic base to obtain intermediate A9 to A14.

[0125] (2) Intermediate A18 reacts with an amine compound containing the target structure under the action of a condensing agent (such as HATU or DCC) to obtain intermediate A15.

[0126] The groups are defined as above.

[0127] The intermediates A10 and A13 shown in route B can also be synthesized using the method described in route C below.

[0128] Synthetic route C:

[0129] Intermediate A16 or A17 reacts with isobutyl chloroformate in anhydrous THF solution under alkaline conditions of DIPEA at room temperature to generate an active ester intermediate; subsequently, the active ester intermediate reacts with sodium azide at room temperature to generate an isocyanate intermediate, which is then reacted with substituted methanol having a B-ring structure in toluene to give carbamate compounds A10 / A13.

[0130] The groups are defined as above.

[0131] According to R 5 R 6 R 7 The structural differences resulting from connecting any two elements into a ring mean that intermediates A17 and A18 in synthetic route B can be prepared according to one or more of the methods described in synthetic route D.

[0132] Synthetic route D:

[0133] Synthetic route D includes the following synthetic methods:

[0134] (i) Aryl cyanide A19 reacts with ethyl magnesium bromide and tetraisopropyl titanate in a solution of diethyl ether at -78°C, and then with the participation of boron trifluoride diethyl ether, to give the aryl-substituted cyclopropylamine A20.

[0135] (ii) Aryl acetonitrile compound A21 reacts with 1,3-dibromopropane in the presence of KOH, using DMSO as solvent, at 15–20 °C, and then reacts at room temperature to give aryl-substituted cyclobutyl nitrile compound A22; compound A22 is hydrolyzed by heating in a mixed solution of water and tert-butanol under alkaline conditions of KOH to give the corresponding aryl-substituted cyclobutylcarboxylic acid A23; compound A23 reacts with isobutyl chloroformate in anhydrous THF solution under alkaline conditions of DIPEA at room temperature to generate an active ester intermediate, which then reacts with sodium azide at room temperature to generate an isocyanate intermediate, which is then reacted with substituted methanol having a B-ring structure in toluene to give carbamate compound A24.

[0136] (iii) The arylacetic acid compound A25 was reacted with epichlorohydrin and isopropyl magnesium chloride in THF solvent to give a 1,1,3-trisubstituted cyclobutylcarboxylic acid compound A26 with a single (1s,3s) configuration; compound A26 was reacted with the fluorinating agent DAST in THF solvent at -78°C to give the configuration-inverted compound (1r,3r)-1-(aryl)-3-fluorocyclobutyl-1-carboxylic acid A27.

[0137] (iv) Compound A26 reacts with MeOH in the presence of SOCl2 to form methyl ester A28; Compound A28 reacts with benzoic acid in THF solution in the presence of DEAD and PPh3 to give compound A29 with configuration inversion to (1r,3r); Compound A29 undergoes hydrolysis in a methanol solution of sodium methoxide, simultaneously removing benzoyl and methyl groups to give compound (1r,3r)-1-(aryl)-3-hydroxycyclobutyl-1-carboxylic acid A30.

[0138] (v) Dibromoaryl compound A31 undergoes halogen-lithium exchange with n-BuLi in an anhydrous solvent, and then reacts with 3-oxacyclobutanone to give 3-aryloxa tetracycloalkanol A32; compound A32 reacts with trichloroacetonitrile in the presence of a catalytic amount of DBU to give compound A33; compound A33 reacts with a nucleophile in the presence of Cu(OTf)2 catalysis to give compound A34.

[0139] The groups are defined as above.

[0140] Pharmaceutical Compositions and Administration

[0141] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably, 5-1000 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0142] "Pharmaceutically acceptable carriers" refers to one or more compatible solid or liquid fillers or gelling substances that 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 and with the compounds of the present invention without significantly reducing the efficacy of the compounds. 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, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0143] The pharmaceutical composition is an injection, capsule, tablet, pill, powder, or granule.

[0144] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

[0145] 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: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in the dosage forms of capsules, tablets, and pills.

[0146] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0147] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0148] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0149] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0150] Compositions for parenteral injection may comprise 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.

[0151] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0152] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as antitumor drugs).

[0153] The treatment method of the present invention can be used alone or in combination with other treatment methods or drugs.

[0154] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage administered is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 5–1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skill of a skilled physician.

[0155] Compared with the prior art, the present invention has the following main advantages:

[0156] 1. The compound described in this invention has a novel structure and a simple synthesis procedure.

[0157] 2. The compounds of this invention can significantly inhibit abnormal phase separation of DRAK2.

[0158] 3. The compounds described in this invention exhibit excellent DRAK2-SRSF6 interaction inhibition activity and specificity.

[0159] 4. The compounds described in this invention can effectively improve physiological pathological processes such as abnormal lipid metabolism, insulin resistance, and mitochondrial dysfunction.

[0160] 5. The compound described in this invention inhibits lipid synthesis and suppresses the secretion of inflammatory factors in primary hepatocytes.

[0161] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions as described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight.

[0162] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0163] Unless otherwise specified, in the following examples, NMR was measured using a Bruker Avance III 400 / 500MHz NMR instrument, with NMR calibration as follows: δH 7.26ppm (CDCl3), 2.50ppm (DMSO-d6), 3.31ppm (CD3OD), 2.05ppm (Acetone-d6); mass spectrometry was performed using an Agilent 1200 Quadrupole LC / MS system; reagents were mainly provided by Shanghai Chemical Reagent Company; TLC silica gel plates were manufactured by Shandong Yantai Jiangyou Silica Gel Development Co., Ltd., model HSGF 254; normal phase column silica gel used for compound purification was manufactured by Shandong Qingdao Ocean Chemical Plant Branch, model ZCX-II, 200-300 mesh.

[0164] As used in this article, the Chinese translations of the abbreviations are as follows:

[0165] DCM: dichloromethane; THF: tetrahydrofuran; DMF: N,N-dimethylformamide; DMSO: dimethyl sulfoxide; DIPEA: diisopropylethylamine; dppf: 1,1'-bis(diphenylphosphine)ferrocene; HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazole[4,5-b]pyridine-3-oxide hexafluorophosphate; DAST: diethylaminosulfur trifluoride; DEAD: diethyl azodicarbonate; DBU: 1,5-diazabicyclo[5.4.0]-5-undecene.

[0166] Compound preparation examples

[0167] Example 1: Preparation of compound M1

[0168] The synthetic route of Example 1 is shown below:

[0169] Step a:

[0170] At 0 °C, DIPEA (803 μL, 5.78 mmol) was added to an anhydrous DCM (15 mL) solution of 5-bromopyridin-3-amine A-1 (500 mg, 2.89 mmol), followed by cyclohexyl chloride A-2 (464 μL, 3.47 mmol). After the addition was complete, the reaction system was gradually brought back to room temperature and stirred overnight. The reaction was monitored by TLC until completion. The reaction was quenched with water (10 mL), extracted with DCM (3 × 15 mL), and the organic phases were combined. The mixture was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated by rotary evaporation to remove the solvent, and purified by column chromatography (PE:EA = 88:12) to give intermediate compound A-3 as a white solid: 685 mg, yield 83.7%. 1 HNMR(400MHz,Chloroform-d)δ8.48(s,1H),8.43(s,1H),8.37(s,1H),7.63(s,1H),2.26(t,J=11.6Hz,1H ),1.94(d,J=12.9Hz,2H),1.83(d,J=9.2Hz,2H),1.71(s,1H),1.53(q,J=12.0Hz,2H),1.33-1.22(m,3H).

[0171] Step b:

[0172] 5-Bromoindole A-4 (250 mg, 1.28 mmol), pinacol diboronate (389 mg, 1.53 mmol), and KOAc (375 mg, 3.83 mmol) were placed in a three-necked round-bottom flask. 1,4-Dioxane (5 mL) was added, and the mixture was purged with argon (×3). Then, Pd(dppf)Cl2·DCM (104 mg, 0.13 mmol) was added, and the mixture was purged with argon (×3). The reaction mixture was heated to 90 °C under an argon atmosphere and reacted for 3 h. The reaction was monitored by TLC until complete. Extraction was performed using EA (10 mL × 3). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, concentrated by rotary evaporation to remove the solvent, and purified by column chromatography (PE:EA = 75:25) to give compound A-5 as a white solid: 300 mg, yield 96.8%. 1H NMR(400MHz,Chloroform-d)δ9.62(d,J=8.1Hz,1H),7.68(t,J=1.5Hz,1H),7.50(dd,J=7.5,1.5 Hz,1H),7.30(d,J=7.5Hz,1H),7.20(t,J=7.7Hz,1H),6.52(dd,J=7.5,1.0Hz,1H),1.22(s,12H).

[0173] Step c:

[0174] Compound A-3 (80 mg, 0.28 mmol), compound A-5 (82 mg, 0.34 mmol), and K₂CO₃ (234 mg, 1.70 mmol) were placed in a three-necked round-bottom flask. 1,4-dioxane / water (4 mL / 0.5 mL) was added, and the mixture was purged with argon (×3). Then, Pd(PPh₃)₄ (65 mg, 0.06 mmol) was added, and the mixture was purged with argon (×3). The reaction mixture was heated to 90 °C under an argon atmosphere and reacted for 5 h. The reaction was monitored by TLC until complete. Extraction was performed using EA (10 mL × 3). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, concentrated by rotary evaporation to remove the solvent, and purified by column chromatography (PE:EA = 70:30) to give product M1 as a white solid: 85 mg, yield 94.2%. 1 H NMR (400MHz, Methanol-d4) δ8.65(s,1H),8.53(s,1H),8.37(s,1H),7.84(s,1H),7.50(d,J=8.4Hz,1H),7.39(d,J=8.0Hz,1H),7.30(s,1H),6.53( s,1H),2.43(t,J=11.2Hz,1H),1.93(d,J=11.8Hz,2H),1.86(d,J=11.5Hz ,2H),1.74(d,J=12.1Hz,1H),1.56(q,J=12.0Hz,2H),1.44–1.24(m,3H).

[0175] The following compounds were synthesized using a procedure similar to that in Example 1:

[0176] Example 2 Preparation of compound M21

[0177] The synthetic route of Example 2 is shown below:

[0178] Step a:

[0179] The method for preparing compound A-5 from compound A-4 is as described in step b of Example 1.

[0180] Step b:

[0181] Under argon protection, p-methoxybenzyl alcohol A-7 (400 mg, 2.90 mmol) was dissolved in dry DCM (10 mL), DIPEA (302 μL, 1.73 mmol) was added, and the mixture was cooled in an ice-water bath. A DCM solution containing triphosgene (386 mg, 1.30 mmol) was added. The reaction mixture was stirred for 30 min under ice-water bath cooling and then gradually brought to room temperature and stirred for 1 hour. No purification was required, and the reaction proceeded directly.

[0182] Step c:

[0183] DIPEA (302 μL, 1.73 mmol) was added to the mixture from step b under an ice-water bath. The reaction mixture was then slowly added dropwise to an anhydrous DCM (5 mL) solution of 5-bromopyridine-3-amine A-1 (250 mg, 1.44 mmol). The reaction mixture was gradually brought to room temperature and allowed to react overnight. The reaction was monitored by TLC until completion. The reaction was quenched with water (10 mL), extracted with EA (3 × 15 mL), and the organic phases were combined. The mixture was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated by rotary evaporation to remove the solvent, and purified by column chromatography (PE:EA = 80:20) to give intermediate compound A-8 as a white solid: 179 mg, yield 37.0%. 1 H NMR (400MHz, Chloroform-d) δ8.38–8.25(m,3H),7.34(d,J=7.9Hz,2H),7.23(s,1H),6.90(d,J=7.9Hz,2H),5.15(s,2H),3.81(s,3H).

[0184] Step d:

[0185] Compound A-8 (60 mg, 0.18 mmol), compound A-5 (52 mg, 0.21 mmol), and K₂CO₃ (148 mg, 1.07 mmol) were placed in a three-necked round-bottom flask. 1,4-dioxane / water (4 mL / 0.5 mL) was added, and the mixture was purged with argon (×3). Then, Pd(PPh₃)₄ (41 mg, 0.04 mmol) was added, and the mixture was purged with argon (×3). The reaction mixture was heated to 90 °C under an argon atmosphere and reacted for 8 h. The reaction was monitored by TLC until complete. Extraction was performed using EA (10 mL × 3). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, concentrated by rotary evaporation to remove the solvent, and purified by column chromatography (PE:EA = 70:30–50:50) to obtain product M21 as a white solid: 32 mg, yield 48.2%. 1 H NMR (400MHz, Methanol-d4) δ8.53(s,1H),8.47(s,1H),8.24(s,1H),7.82(s,1H),7.49(d,J=8.4Hz,1 H),7.38(d,J=7.7Hz,3H),7.29(s,1H),6.93(d,J=8.0Hz,2H),6.53(s,1H),5.16(s,2H),3.79(s,3H).

[0186] The following compounds were synthesized using a procedure similar to that in Example 2:

[0187] Example 3 Preparation of compound M25

[0188] The synthetic route of Example 3 is shown below:

[0189] Step a:

[0190] Compound 5-bromo-2-fluorobenzonitrile B-1 (5 g, 25.00 mmol) was dissolved in anhydrous diethyl ether (50 mL) in a three-necked round-bottom flask. The flask was cooled to -78 °C under argon protection. Ti(iPrO)₄ (8.1 mL, 27.50 mmol) was slowly added dropwise over 20 min, followed by ethyl magnesium bromide (16.2 mL, 3.4 M methyltetrahydrofuran solution) dropwise over 30 min. The reaction mixture gradually turned yellow and deepened to brownish-black. After stirring at -78 °C for 10 min, the mixture was gradually brought to room temperature. After 1 hour, the flask was cooled in an ice-water bath. BF₃·Et₂O (6.3 mL, 50.00 mmol) was slowly added over 20 min. After the addition was complete, the mixture was gradually brought to room temperature, and the reaction was allowed to proceed for 2 hours at room temperature. The reaction was quenched by slowly adding 30 mL of 1 N HCl solution after cooling in an ice-water bath. The mixture was stirred at room temperature for 30 min, and the aqueous phase was separated. The pH was adjusted to 8–9 with 2 N NaOH solution, and the mixture was extracted with Et2O (3 × 100 mL). The organic phases were combined and washed with 50 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated by rotary evaporation to remove the solvent, and purified by column chromatography (PE:EA = 80:20) to give compound 1-(5-bromo-2-fluorophenyl)cyclopropane-1-amine B-2 as a yellow waxy solid: 3.61 g; yield 61.7%. 1 H NMR (400MHz, Chloroform-d) δ7.55 (ddd, J=7.5, 5.0, 1.5Hz, 1H), 7.50 (dd, J=5.0, 1.5Hz, 1H), 7.21–7.14 (m, 1H), 3.97 (s, 2H), 2.59–2.48 (m, 4H).

[0191] Step b:

[0192] Compound B-2 (860 mg, 3.74 mmol) was dissolved in dry THF (10 mL), cooled in an ice bath, and DIPEA (1.95 mL, 11.21 mmol) and benzyl chloroformate B-3 (627 μL, 4.49 mmol) were added. The mixture was gradually brought to room temperature and reacted overnight. The reaction was monitored by TLC until complete. The reaction was quenched with water (15 mL), extracted with DCM (3 × 20 mL), and the organic phases were combined. The mixture was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated by rotary evaporation to remove the solvent, and purified by column chromatography (PE:EA = 88:12) to give intermediate compound B-4 as a yellow solid: 1.29 g; yield 94.8%. 1H NMR (400MHz, Chloroform-d) δ7.67 (s, 1H), 7.43–7.22 (m, 6H), 6.85 (t, J = 9.3Hz, 1H), 5.83 (s, 1H), 5.00 (s, 2H), 1.15 (d, J = 19.3Hz, 4H).

[0193] Step c:

[0194] 5-Bromo-7-chloroindole B-5 (5.00 g, 21.69 mmol), pinacol diborate (8.26 g, 32.54 mmol), and KOAc (6.39 g, 65.08 mmol) were placed in a three-necked round-bottom flask. 1,4-Dioxane (100 mL) was added, and the mixture was purged with argon (×3). Pd(dppf)Cl2·DCM (886 mg, 1.08 mmol) was then added, and the mixture was purged with argon (×3). The reaction mixture was heated to 100 °C under an argon atmosphere and reacted for 20 h. The reaction was monitored by TLC until complete. The mixture was extracted with EA (80 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated by rotary evaporation to remove the solvent, and purified by column chromatography (PE:EA = 83:17) to give compound B-6 as a white solid: 6.0 g, yield 99.7%. 1 H NMR (400MHz, Chloroform-d) δ8.49(s,1H),8.10(s,1H),7.68(s,1H),7.24–7.18(m,1H),6.63–6.58(m,1H),1.38(s,12H).

[0195] Step d:

[0196] Compounds B-4 (2.1 g, 7.5 mmol), B-6 (2.3 g, 6.2 mmol), and K₂CO₃ (5.2 g, 37.4 mmol) were placed in a three-necked round-bottom flask. 1,4-dioxane / water (80 mL / 10 mL) was added, and the mixture was purged with argon (×3). Then, Pd(PPh₃)₄ (1.4 g, 1.3 mmol) was added, and the mixture was purged with argon (×3). The reaction mixture was heated to 90 °C under an argon atmosphere and reacted overnight. The reaction was monitored by TLC until complete. The mixture was filtered through diatomaceous earth, extracted with EA (50 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, concentrated by rotary evaporation to remove the solvent, and purified by column chromatography (PE:EA = 83:17) to give product M25 as a pale yellow solid: 1.61 g, yield 59.4%. 1H NMR(600MHz,Chloroform-d)δ8.40(s,1H),7.74(d,J=40.2Hz,1H),7.44(d,J=31.2Hz,2H),7.31–7.30(m,4H),7.20(d, J=46.4Hz,1H),7.08(dd,J=9.9,8.6Hz,1H),6.63(s,1H),5.59(d,J=88.6Hz,1H),5.06(d,J=37.4Hz,2H),1.24(s,4H).

[0197] The following compounds were synthesized using a procedure similar to that in Example 3:

[0198] Example 4: Preparation of compound M75

[0199] The synthetic route of Example 4 is shown below:

[0200] Step a:

[0201] Compound 3-bromobenzonitrile B-1' (5.00 g, 27.47 mmol) was dissolved in anhydrous diethyl ether (20 mL) in a three-necked round-bottom flask. The flask was cooled to -78 °C under argon protection. Ti(iPrO)₄ (8.84 mL, 30.22 mmol) was slowly added dropwise over 20 min, followed by ethyl magnesium bromide (7.90 mL, 3.0 M in Et₂O) over 30 min. The reaction mixture gradually turned yellow and deepened to brownish-black. After stirring at -78 °C for 10 min, the mixture was gradually brought to room temperature. After 1 hour, the flask was cooled in an ice-water bath. BF₃·Et₂O (6.90 mL, 54.94 mmol) was slowly added over 20 min. After the addition was complete, the mixture was gradually brought to room temperature, and the reaction was allowed to proceed for 2 hours at room temperature. The reaction was quenched by slowly adding 30 mL of 1 N HCl solution after cooling in an ice-water bath. The mixture was stirred at room temperature for 30 min, and the aqueous phase was separated. The pH was adjusted to 8–9 with 2 N NaOH solution, and the mixture was extracted with Et₂O (3 × 100 mL). The organic phases were combined and washed with 50 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated by rotary evaporation to remove the solvent, and purified by column chromatography (PE:EA = 75:25) to give compound B-2' as a yellow liquid: 1.21 g; yield 20.6%. 1H NMR(400MHz,Chloroform-d)δ7.47(t,J=1.5Hz,1H),7.36(dt,J=7.8,1.5Hz,1H),7 .24(d,J=1.5Hz,1H),7.19(t,J=7.8Hz,1H),1.24–1.20(m,2H),1.04–0.99(m,2H).

[0202] Step b:

[0203] Compound B-2' (300 mg, 1.41 mmol) was dissolved in anhydrous DMF (5 mL), followed by the addition of DIPEA (590 μL, 4.24 mmol), then HATU (645 mg, 1.70 mmol), and subsequently phenylpropionic acid (255 mg, 1.70 mmol). The mixture was heated to 90 °C and reacted overnight. The next day, the reaction was monitored by TCL until complete. The mixture was diluted with H2O (5 mL), extracted with EA (10 mL × 3), and the organic phases were combined, dried over anhydrous Na2SO4, and purified by concentrated column chromatography (PE:EA = 88:12) to obtain compound B-4' as a yellow solid: 480 mg; yield 98.6%. 1 H NMR(400MHz,Chloroform-d)δ7.29–7.21(m,5H),7.17(d,J=7.1Hz,2H),7.08(t,J=7.8Hz,1H),7.01(d,J=7.8H z,1H),6.14(s,1H),2.95(t,J=7.4Hz,2H),2.48(t,J=7.4Hz,2H),1.19(t,J=6.4Hz,2H),1.12(t,J=6.4Hz,2H).

[0204] Step c:

[0205] The method for preparing compound A-5 from compound A-4 is as described in step b of Example 1.

[0206] Step d:

[0207] Compound B-4' (80 mg, 0.23 mmol), compound A-5 (68 mg, 0.28 mmol), and K₂CO₃ (193 mg, 1.39 mmol) were placed in a three-necked round-bottom flask. 1,4-dioxane / water (6 mL / 0.75 mL) was added, and the mixture was purged with argon (×3). Then, Pd(PPh₃)₄ (54 mg, 0.05 mmol) was added, and the mixture was purged with argon (×3). The reaction mixture was heated to 90 °C under an argon atmosphere and reacted for 4 h. The reaction was monitored by TLC until complete. Extraction was performed using EA (10 mL × 3). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, concentrated by rotary evaporation to remove the solvent, and purified by column chromatography (PE:EA = 73:27) to obtain product M75 as a white solid: 65 mg, yield 74.5%. 1 H NMR(400MHz,Chloroform-d)δ8.48(s,1H),7.75(s,1H),7.43(dd,J=17.8,7.6Hz,1H),7 .36(s,1H),7.33(s,1H),7.31(s,1H),7.29(d,J=6.2Hz,1H),7.23(d,J=4.2Hz,1H),7.2 1(s,1H),7.19(s,1H),7.17–7.11(m,5H),7.04(d,J=7.7Hz,1H),6.53(s,1H),6.06(s,1 H),2.94(t,J=7.5Hz,2H),2.44(t,J=7.5Hz,2H),1.28–1.20(m,2H),1.19–1.05(m,2H).

[0208] The following compounds were synthesized using a procedure similar to that in Example 4:

[0209] Example 5: Preparation of compound M98

[0210] The synthetic route of Example 5 is shown below:

[0211] Step a:

[0212] The experimental steps for preparing compound B-2 using compound B-1 as a raw material are as described in step a of Example 3.

[0213] Step b:

[0214] The compound 1-(5-bromo-2-fluorophenyl)cyclopropane-1-amine B-2 (150 mg, 0.65 mmol) was dissolved in dry DCM (5 mL), cooled in an ice-water bath, and DIPEA (273 μL, 1.56 mmol) and triphosgene (174 mg, 0.59 mmol) were added. The mixture was reacted at 0 °C for 30 min and then at room temperature for 1 hr.

[0215] Step c:

[0216] The reaction mixture from step b was cooled in an ice-water bath, and DIPEA (273 μL, 1.56 mmol) was added again. Then, (3-(hydroxymethyl)phenyl)(phenyl) methyl ketone (166 mg, 0.78 mmol) dissolved in 2 mL of dichloromethane was added dropwise to the reaction mixture. The reaction was carried out at 0 °C for 30 min, and then transferred to room temperature and allowed to proceed overnight. The reaction was monitored by TLC until completion. The reaction was quenched with saturated sodium bicarbonate aqueous solution (3 mL), extracted with DCM (3 × 15 mL), and the organic phases were combined. The mixture was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated by rotary evaporation to remove the solvent, and purified by column chromatography (PE:EA = 83:17) to give the intermediate compound 3-benzoylbenzyl (1-(5-bromo-2-fluorophenyl)cyclopropyl)carbamate B-9 as a yellow liquid: 107 mg; yield 35.1%. 1 H NMR(600MHz,Chloroform-d)δ7.79–7.76(m,2H),7.74(s,1H),7.71(d,J=6.7Hz,1H),7.64(s,1H),7.59(t,J=7.4Hz,1H),7.51(d ,J=7.2Hz,1H),7.48(t,J=7.6Hz,2H),7.45(d,J=7.5Hz,1H),7.33(s,1H),6.89(t,J=9.2Hz,1H),5.08(s,2H),1.23–1.15(m,4H).

[0217] Step d:

[0218] The experimental steps for preparing compound B-6 from compound B-5 are as described in step c of Example 3.

[0219] Step e:

[0220] Compound B-9 (50 mg, 0.11 mmol), compound B-6 (36 mg, 0.13 mmol), and K₂CO₃ (89 mg, 0.64 mmol) were placed in a three-necked round-bottom flask. 1,4-dioxane / water (4 mL / 0.5 mL) was added, and the mixture was purged with argon (×3). Then, Pd(PPh₃)₄ (25 mg, 0.02 mmol) was added, and the mixture was purged with argon (×3). The reaction mixture was heated to 100 °C under an argon atmosphere and reacted overnight. The reaction was monitored by TLC until complete. The mixture was filtered through diatomaceous earth, extracted with EA (10 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, concentrated by rotary evaporation to remove the solvent, and purified by column chromatography (PE:EA = 80:20) to give product M98 as a white solid: 46 mg, yield 79.9%. 1 H NMR(600MHz, Acetone-d6)δ10.60(s,1H),7.92(d,J=5.3Hz,1H),7.78–7.75(m,3H),7.70–7.40(m,9H) ,7.32(s,1H),7.13(t,J=9.3Hz,1H),6.64(s,1H),5.09(s,2H),1.27–1.26(m,2H),1.25–1.21(m,2H).

[0221] The following compounds were synthesized using a procedure similar to that in Example 5:

[0222] Example 6 Preparation of compound M100

[0223] The synthetic route of Example 6 is shown below:

[0224] Step a:

[0225] The ground KOH powder was placed in a round-bottom flask, and DMSO (15 mL) was added. The mixture was cooled to 10–15 °C in an ice-water bath. While stirring thoroughly, a DMSO (5 mL) mixture containing 3-bromo-phenylacetonitrile C-1 (1.96 g, 10.00 mmol) and 1,3-dibromopropane C-2 (2.02 g, 10.00 mmol) was slowly added dropwise, maintaining the temperature of the mixture at 15–20 °C. After the addition was complete, the reaction mixture was gradually brought to room temperature and stirred for 1.5 hours. The reaction was quenched with ice water (3–5 mL), maintaining the temperature below 30 °C. Extraction was performed using PE:EA = 1:2 (30 mL × 3). The organic phases were combined, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure using a rotary evaporator. No further purification was required to obtain a high-purity orange oily crude product C-3: 1.4 g; yield approximately 59%. 1H NMR(400MHz,Chloroform-d)δ7.55(s,1H),7.44(d,J=7.9Hz,1H),7.34(d,J=7.9Hz,1H),7.26(t,J=7.9Hz,1H),2.8 1(td,J=11.0,8.9,4.2Hz,2H),2.65–2.55(m,2H),2.44(dq,J=11.0,8.9Hz,1H),2.08(ddt,J=9.0,7.0,4.2Hz,1H).

[0226] Step b:

[0227] Compound C-3 (1.4 g, 5.93 mmol) was dissolved in EtOH (8.5 mL), and a solution of KOH (1.7 g, 29.65 mmol) in water (8.5 mL) was added. The reaction mixture was heated to reflux and reacted for 12 hours. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure to remove EtOH, and the residue was dissolved in water. The pH was adjusted to 3–4 with 2N HCl, resulting in the precipitation of a white solid. The solid was filtered, washed with water (2 mL × 3), and dried. Compound C-4 was given as a white solid: 704 mg; yield 46.5%. 1 H NMR (400MHz, Chloroform-d) δ9.98 (s, 1H), 7.50–7.30 (m, 2H), 7.30–7.11 (m, 2H), 2.84 (dd, J = 15. 5,8.4Hz,2H),2.50(dd,J=19.5,9.0Hz,2H),2.21–1.97(m,1H),1.88(m,J=14.1,9.5,4.8Hz,1H).

[0228] Step c:

[0229] Compound C-4 (200 mg, 0.78 mmol) was dissolved in anhydrous DMF (2 mL), followed by the addition of DIPEA (410 μL, 2.35 mmol) and HATU (447 mg, 1.18 mmol), then phenylethylamine. The mixture was heated to 90 °C and reacted overnight. The reaction was monitored by TCL until complete. The mixture was diluted with H2O (20 mL), extracted with PE:EA = 2:1 (10 mL × 3), and the organic phases were combined, dried over anhydrous Na2SO4, and purified by concentrated column chromatography (PE:EA = 88:12) to give compound C-5 as a yellow liquid: 278 mg; yield 99.0%. 1H NMR(400MHz,Chloroform-d)δ7.41–7.28(m,2H),7.26–7.13(m,4H),7.13–7.05(m,1H),6.92(s,2H),5.09(s,1H), 3.47–3.32(m,2H),2.80–2.69(m,2H),2.69–2.61(m,2H),2.42–2.28(m,2H),2.20–2.00(m,1H),1.90–1.74(m,1H).

[0230] Step d:

[0231] 3-Trifluoromethyl-5-bromo-1H-pyrrolo[2,3-b]pyridine C-6 (259 mg, 0.98 mmol), pinacol diboronate (744 mg, 2.93 mmol), and KOAc (288 mg, 2.93 mmol) were placed in a microwave-safe reaction tube. 1,4-Dioxane (5 mL) was added, and the mixture was purged with argon gas (×3). Then, Pd(dppf)Cl2·DCM (80 mg, 0.10 mmol) was added, and the mixture was purged with argon gas (×3). The reaction mixture was microwave-heated to 110 °C under an argon atmosphere for 30 min. The reaction was monitored by TLC until complete. Silica gel powder was added and the solvent was removed by rotary evaporation. The mixture was then purified by dry column chromatography (PE:EA = 80:20–75:25) to give compound C-7 as a yellow solid: 290 mg, yield 95.1%. 1 H NMR (600MHz, Chloroform-d) δ11.35(s,1H),8.81(s,1H),8.55(s,1H),7.72(s,1H),1.40(s,12H).

[0232] Step e:

[0233] Compounds C-5 (50 mg, 0.14 mmol), C-7 (52 mg, 0.17 mmol), and Cs₂CO₃ (68 mg, 0.21 mmol) were placed in a microwave-safe reaction tube. 1,4-Dioxane / water (2.5 mL / 0.5 mL) was added, and the mixture was purged with argon (×3). Then, Pd(dppf)Cl₂·DCM (22 mg, 0.03 mmol) was added, and the mixture was purged with argon (×3). The reaction mixture was microwave-heated to 100 °C under an argon atmosphere for 30 min. The reaction was monitored by TLC until complete. The mixture was filtered through diatomaceous earth, extracted with EA (5 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (2 mL), dried over anhydrous sodium sulfate, concentrated by rotary evaporation to remove the solvent, and purified by column chromatography (DCM:MeOH = 98:2–95:5) to obtain product M100 as a white solid: 17 mg, yield 25.8%.1 HNMR(400MHz,Chloroform-d)δ8.56(d,J=35.6Hz,1H),8.14(d,J=41.3Hz,1H),7.5 6–7.37(m,4H),7.26–7.19(m,1H),7.18–7.05(m,3H),6.93(d,J=6.9Hz,2H),6.59( s,1H),5.16(s,1H),3.45(p,J=6.2Hz,2H),2.84(dd,J=5.6,2.8Hz,2H),2.69(td,J =6.5,3.0Hz,2H),2.51(q,J=9.3Hz,2H),2.19(h,J=8.7Hz,1H),2.00–1.82(m,1H).

[0234] The following compounds were synthesized using a procedure similar to that in Example 6:

[0235] Example 7 Preparation of compound M106

[0236] The synthetic route of Example 7 is shown below:

[0237] Step a:

[0238] The method for preparing compound C-3 using compounds C-1 and C-2 as raw materials is as described in step a of Example 5.

[0239] Step b:

[0240] The method for preparing compound C-4 from compound C-3 is as described in step b of Example 5.

[0241] Step c:

[0242] Compound C-4 (500 mg, 1.96 mmol) was dissolved in anhydrous THF (30 mL), cooled in an ice-water bath, and then DIPEA (1.71 mL, 9.80 mmol) was added, followed by isobutyl chloroformate (280 μL, 2.16 mmol). The mixture was reacted in an ice bath for 30 min, and then gradually brought to room temperature for 1 hour.

[0243] Step d:

[0244] Add NaN3 (255 mg, 3.92 mmol) to the reaction mixture from step c above and react at room temperature for 12 hours. After the reaction is complete, remove the solvent using a rotary evaporator and dry the mixture under vacuum for later use.

[0245] Step e:

[0246] The residue obtained in step d was redissolved in toluene (30 mL), and benzyl alcohol C-9 (1.22 mL, 11.76 mmol) was added. The mixture was heated to 110 °C and reacted for 12 hours. The reaction was stopped by TLC. Silica gel powder was added to the reaction system, the solvent was removed by rotary evaporation, and the mixture was purified by dry column chromatography (PE:EA = 85:15) to give carbamate compound C-10 as a yellow liquid: 560 mg; yield 79.3%. 1 H NMR(400MHz,Chloroform-d)δ7.45(s,1H),7.34–6.83(m,8H),4.92(s,2H),2.42–2.16(m,4H),2.07–1.93(m,1H),1.80–1.70(m,1H).

[0247] Step f:

[0248] The method for preparing compound C-7 from compound C-6 is as described in step d of Example 5.

[0249] Step g:

[0250] Compound C-10 (40 mg, 0.11 mmol), compound C-7 (41 mg, 0.13 mmol), and K₂CO₃ (92 mg, 0.67 mmol) were placed in a three-necked round-bottom flask. 1,4-dioxane / water (4 mL / 0.5 mL) was added, and the mixture was purged with argon (×3). Then, Pd(PPh₃)₄ (26 mg, 0.02 mmol) was added, and the mixture was purged with argon (×3). The reaction mixture was microwave-heated to 100 °C under an argon atmosphere and reacted overnight. The reaction was monitored by TLC until complete. The mixture was filtered through diatomaceous earth, silica gel powder was added, the solvent was removed by rotary evaporation, and the product was purified by dry column chromatography (DCM:MeOH = 100:0–93:7) to give product M106 as a white solid: 15 mg, yield 29.0%. 1 HNMR(600MHz,Acetone-d6)δ11.33(s,1H),8.60(s,1H),8.55(s,1H),8.13(s,1H),7.78(s,1H),7.74(s,1H),7.53– 7.38(m,3H),7.26–7.20(m,4H),6.91(s,1H),4.95(s,2H),2.67–2.58(m,4H),2.18–2.10(m,1H),1.91–1.87(m,1H).

[0251] The following compounds were synthesized using a similar procedure to that in Example 7:

[0252] Example 8 Preparation of compound M113

[0253] The synthetic route of Example 8 is shown below:

[0254] Step a:

[0255] Under ice-water bath conditions, isopropyl magnesium chloride (2.0 M in THF, 25.58 mL, 51.15 mmol) was slowly added dropwise to a solution of 3-bromophenylacetic acid D-1 (5.00 g, 23.25 mmol) in anhydrous THF (40 mL). After the addition was complete, the mixture was gradually brought to room temperature and stirred for 1 hour. Subsequently, the reaction mixture was cooled under ice-water bath conditions, and epichlorohydrin D-2 (3.65 mL, 46.50 mmol) was added. The mixture was gradually brought to room temperature and stirred for 3 hours. Then, the mixture was cooled under ice-water bath conditions again, and another portion of isopropyl magnesium chloride (2.0 M in THF, 25.58 mL, 51.15 mmol) was slowly added dropwise to the reaction system. After the addition was complete, the mixture was gradually brought to room temperature and stirred overnight. The following day, TLC monitoring showed no remaining raw material. The mixture was cooled in an ice-water bath, and the pH was adjusted to 3-4 with 1N HCl. Extraction was performed using EA (50 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and silica gel powder was added. The solvent was removed by rotary evaporation, and the mixture was purified by dry column chromatography (DCM:MeOH = 90:10) to obtain a single-configuration product, (1s,3s)-1-(3-bromophenyl)-3-hydroxycyclobutane-1-carboxylic acid D-3, as a white solid: 4.01 g; yield 63.6%. 1 H NMR(800MHz, Methanol-d4)δ7.56(t,J=1.8Hz,1H),7.45–7.39(m,2H),7.36–7.32(m,1H),7.29–7.22(m,1H), 4.03(h,J=7.3Hz,1H), 2.86(dddd,J=28.4,10.0,7.1,2.7Hz,2H), 2.66(dddd,J=12.8,10.2,7.7,2.7Hz,2H).

[0256] Step b:

[0257] Compound D-3 (100 mg, 0.37 mmol) was dissolved in anhydrous DCM / THF (1 mL / 1 mL) mixed solvent, cooled in a dry ice acetone bath at -78 °C, and DAST reagent D-4 (58 μL, 0.44 mmol) was slowly added dropwise. The mixture was stirred at -78 °C for 1 hour and then gradually brought to room temperature and stirred overnight. The next day, TLC monitoring showed complete consumption of the starting material. The mixture was cooled to 0 °C, and the reaction was quenched by slow addition of H2O. Anhydrous sodium sulfate was used to remove water, and silica gel powder was added for rotary evaporation to remove the solvent. The mixture was purified by dry column chromatography (DCM:MeOH = 92:8) to give the inverted compound (1r,3r)-1-(3-bromophenyl)-3-fluorocyclobutane-1-carboxylic acid D-5 as a colorless liquid: 66 mg; yield 65.5%. 1 H NMR(800MHz,Methanol-d4)δ7.42–7.31(m,2H),7.27–7.22(m,2H),5.16(ddt,J =56.0,10.5,6.9Hz,1H),2.86(tdd,J=9.9,5.9,3.1Hz,2H),2.60–2.53(m,2H).

[0258] Step c:

[0259] Compound D-5 (250 mg, 0.91 mmol) was dissolved in anhydrous THF (20 mL), cooled in an ice-water bath, and then DIPEA (797 μL, 4.58 mmol) was added, followed by isobutyl chloroformate (143 μL, 1.10 mmol). The mixture was reacted in an ice bath for 1 hour, and then gradually heated to room temperature for another 1 hour.

[0260] Step d:

[0261] Add NaN3 (119 mg, 1.83 mmol) to the reaction mixture from step c above and react at room temperature for 12 hours. After the reaction is complete, remove the solvent using a rotary evaporator and dry the mixture under vacuum for later use.

[0262] Step e:

[0263] The residue obtained in step d was redissolved in toluene (20 mL), and benzyl alcohol D-13 (190 μL, 1.83 mmol) was added. The mixture was heated to 110 °C and reacted for 12 hours. The reaction was monitored by TLC until completion. Silica gel powder was added to the reaction system, the solvent was removed by rotary evaporation, and the mixture was purified by dry column chromatography (PE:EA = 88:12) to give carbamate compound C-14 as a colorless, transparent liquid: 185 mg; yield 53.4%. 1H NMR (600MHz, Chloroform-d) δ7.49–6.96(m,10H),5.30–5.12(m,1H),5.00(s,2H),3.11–3.00(m,2H),2.75–2.59(m,2H).

[0264] Step f:

[0265] 5-Bromo-6-fluoro-1H-pyrrolo[2,3-b]pyridine D-9 (100 mg, 0.47 mmol), pinacol diboronate (177 mg, 0.70 mmol), and KOAc (228 mg, 2.33 mmol) were placed in a three-necked round-bottom flask. 1,4-Dioxane (4 mL) was added, and the mixture was purged with argon (×3). Then, Pd(dppf)Cl2·DCM (19 mg, 0.02 mmol) was added, and the mixture was purged with argon (×3). The reaction mixture was heated to 110 °C under an argon atmosphere and reacted overnight. TLC monitoring showed that the reaction was complete. Silica gel powder was added and evaporated to remove the solvent. The mixture was purified by dry column chromatography (PE:EA = 85:15) to give compound D-10 as a yellow solid: 101 mg, yield 82.9%. 1 H NMR (400MHz, Chloroform-d) δ11.31(s,1H),8.45(d,J=8.1Hz,1H),7.36–7.28(m,1H),6.51(dd,J=3.4,2.0Hz,1H),1.38(s,12H).

[0266] Step g:

[0267] Compound D-14 (50 mg, 0.13 mmol), compound D-10 (42 mg, 0.16 mmol), and Na₂CO₃ (28 mg, 0.26 mmol) were placed in a microwave-safe reaction tube. 1,4-Dioxane / water (2.5 mL / 0.25 mL) was added, and the mixture was purged with argon gas (×3). Then, Pd(PPh₃)₄ (23 mg, 0.02 mmol) was added, and the mixture was purged with argon gas (×3). The reaction mixture was microwave-heated to 110 °C under an argon atmosphere for 40 min. The reaction was monitored by TLC until complete. The mixture was filtered through diatomaceous earth, extracted with EA (5 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (2 mL), dried over anhydrous sodium sulfate, concentrated by rotary evaporation to remove the solvent, and purified by thin-layer chromatography (PE:EA = 75:25) to obtain product M113 as a white solid: 24 mg, yield 41.9%. 1H NMR (600MHz, Acetone-d6) δ10.82(s,1H),8.15(d,J=9.2Hz,1H),7.67(s,1H),7.53–7.40(m,5H),7.34–7.20(m,4H),7.17(s,1H) ),6.62–6.55(m,1H),5.32(dp,J=56.3,6.7Hz,1H),4.99(s,2H),3.25–3.19(m,2H),2.70(dddt,J=19.9,10.0,6.6,3.0Hz,2H).

[0268] The following compounds were synthesized using a similar procedure to that in Example 8:

[0269] Example 9 Preparation of compound M118

[0270] The synthetic route of Example 9 is shown below:

[0271] Step a:

[0272] The method for preparing compound D-3 using compounds D-1 and D-2 as raw materials is as described in step a of Example 7.

[0273] Step b:

[0274] Compound D-3 (2.00 g, 7.38 mmol) was dissolved in MeOH (40 mL), cooled in an ice-water bath, and SOCl2 (2.68 mL, 36.89 mmol) was added dropwise. The mixture was heated to 80 °C and reacted for 2 hours. The reaction was monitored by TLC until complete, concentrated, and purified by column chromatography (PE:EA = 70:30) to give compound E-4 as a white solid: 1.85 g; yield 87.8%. 1 H NMR(600MHz,Chloroform-d)δ7.49(t,J=1.8Hz,1H),7.40(ddd,J=7.8,1.8,1.0Hz,1H),7.29–7.26(m, 1H),7.22(t,J=7.8Hz,1H),4.20(p,J=6.3Hz,1H),3.65(s,3H),2.92–2.87(m,2H),2.75–2.70(m,2H).

[0275] Step c:

[0276] Compound E-4 (1.85 g, 6.49 mmol) was dissolved in anhydrous THF, cooled in an ice-water bath, and benzoic acid (1.58 g, 12.98 mmol) and triphenylphosphine (3.40 g, 12.98 mmol) were added. The mixture was purged with argon gas, followed by the addition of DEAD (2.04 mL, 12.98 mmol). The mixture was gradually brought to room temperature and stirred overnight. The next day, the reaction was monitored by TLC until complete. Silica gel powder was added and evaporated to dryness. The mixture was then purified by dry column chromatography (PE:EA = 95:5) to give compound E-5, a white solid with inverted configuration, as a yield of 2.31 g (91.5%). 1 H NMR(600MHz,Chloroform-d)δ7.99(dd,J=8.3,1.2Hz,2H),7.56–7.52(m,1H),7.44–7.38(m,4H),7.22(t,J=7.6 Hz,1H),7.18(dt,J=7.8,1.4Hz,1H),5.40(p,J=7.5Hz,1H),3.71(s,3H),3.48–3.38(m,2H),2.71–2.61(m,2H).

[0277] Step d:

[0278] Compound E-5 (2.31 g, 5.93 mmol) was dissolved in methanol (40 mL), and sodium methoxide (1.60 g, 29.67 mmol) was added. The mixture was heated to 80 °C and reacted for 2 hours. The reaction was monitored by TLC until complete. The mixture was cooled in an ice-water bath, the pH was adjusted to 3 with 4N HCl, and water was removed with anhydrous Na₂SO₄. The solution was concentrated and purified by column chromatography (DCM:MeOH = 100:0–95:5) to give compound E-6 as a white solid: 505 mg; yield 31.4%.

[0279] Step e:

[0280] Compound E-8 was prepared by reacting compound E-6 with DAST using a method similar to that described in step b of Example 7, yielding a colorless liquid in 63.4% yield. 1 H NMR (600MHz, Methanol-d4) δ7.57(t,J=1.8Hz,1H),7.45(ddd,J=7.9,1.9,1.0Hz,1H),7.40(ddd,J=7.9,1.8, 1.0Hz, 1H), 7.30 (t, J = 7.9Hz, 1H), 4.95 (dp, J = 55.9, 6.4Hz, 1H), 2.98 (d, J = 6.4Hz, 2H), 2.95 (d, J = 6.4Hz, 2H).

[0281] Steps f to h:

[0282] Compound E-17 was prepared from compound E-8 using a method similar to that described in steps c, d, and e of Example 7, through steps f, g, and h, yielding a colorless liquid: yield 39.9%. 1 H NMR(600MHz,Chloroform-d)δ7.52(s,1H),7.42–7.39(m,1H),7.38–7.27(m,5H),7.22(dd ,J=8.9,4.9Hz,1H),5.50(s,1H),5.07–4.87(m,3H),3.10–3.00(m,2H),2.89–2.75(m,2H).

[0283] Step i:

[0284] The method for preparing compound D-10 from compound D-9 is as described in step f of Example 7.

[0285] Step j:

[0286] Compound E-17 (28 mg, 0.07 mmol), compound D-10 (23 mg, 0.09 mmol), and K₂CO₃ (61 mg, 0.44 mmol) were placed in a three-necked round-bottom flask. 1,4-dioxane / water (4 mL / 0.25 mL) was added, and the mixture was purged with argon (×3). Then, Pd(PPh₃)₄ (17 mg, 0.01 mmol) was added, and the mixture was purged with argon (×3). The reaction mixture was heated to 90 °C under an argon atmosphere and reacted overnight. The reaction was monitored by TLC until complete. The mixture was filtered through diatomaceous earth, silica gel powder was added, and the solvent was removed by rotary evaporation. The product was purified by dry column chromatography (PE:EA = 85:15) to obtain product M118 as a yellow solid: 23 mg, yield 71.7%. 1 H NMR (600MHz, Acetone-d6) δ10.85(s,1H),8.18–8.11(m,1H),7.73(s,1H),7.51(t,J=8.2Hz,2H),7.48–7.38(m,3H),7.38–7.15 (m,5H),6.57(dd,J=3.4,1.9Hz,1H),5.12(dp,J=56.5,6.5Hz,1H),5.00(s,2H),3.34–3.23(m,2H),3.18(qd,J=9.9,2.7Hz,2H).

[0287] The following compounds were synthesized using a similar procedure to that in Example 9:

[0288] Example 10 Preparation of compound M120

[0289] The synthetic route of Example 10 is shown below:

[0290] Step a:

[0291] Commercially available compound F-1 (100 mg, 0.44 mmol) was dissolved in dry THF (2 mL), cooled in an ice bath, and then DIPEA (231 μL, 1.33 mmol) and benzyl chloroformate (74 μL, 0.53 mmol) were added. The mixture was gradually brought to room temperature and reacted overnight. The reaction was monitored by TLC until complete. The reaction was quenched with water (5 mL), extracted with DCM (3 × 5 mL), and the organic phases were combined. The mixture was washed with saturated brine (2 mL), dried over anhydrous sodium sulfate, concentrated by rotary evaporation to remove the solvent, and purified by column chromatography (PE:EA = 88:12) to give intermediate compound F-3 as a colorless liquid: 155 mg; yield 97.3%. 1 H NMR(400MHz,Chloroform-d)δ7.39–7.33(m,4H),7.26–7.05(m,4H),6.95(s,1H ),5.19–4.87(m,3H),3.74–3.58(m,2H),2.40–2.25(m,1H),2.00–1.79(m,3H).

[0292] Step b:

[0293] Compound F-3 (70 mg, 0.19 mmol), commercially available borate ester F-5 (57 mg, 0.23 mmol), and K₂CO₃ (161 mg, 1.17 mmol) were placed in a three-necked round-bottom flask. 1,4-Dioxane / water (6 mL / 0.75 mL) was added, and the mixture was purged with argon (×3). Then, Pd(PPh₃)₄ (45 mg, 0.04 mmol) was added, and the mixture was purged with argon (×3). The reaction mixture was heated to 100 °C under an argon atmosphere and reacted overnight. The reaction was monitored by TLC until complete. The mixture was filtered through diatomaceous earth, silica gel powder was added, and the solvent was removed by rotary evaporation. The product was purified by dry column chromatography (PE:EA = 70:30) to give product M120 as a yellow solid: 53 mg, yield 68.6%. 1H NMR (400MHz, Acetone-d6) δ10.88(s,1H),8.51(s,1H),8.13(s,1H),7.74–7.68 (m,1H),7.64–7.57(m,1H),7.56–7.51(m,3H),7.46–7.36(m,2H),7.31(d,J=24. 7Hz,1H),7.22(d,J=7.6Hz,1H),7.11(s,1H),6.95(s,1H),6.60–6.45(m,1H),4. 99(dd,J=69.6,10.9Hz,3H),3.83–3.60(m,2H),2.43(s,1H),2.03–1.88(m,3H).

[0294] The following compounds were synthesized using a similar procedure to that in Example 10. It should be noted that when the boric acid / boronic ester was not readily available, it was prepared from the corresponding brominated derivative via the Muriya reaction using a method similar to that in other examples:

[0295] Example 11 Preparation of compound M123

[0296] The synthetic route of Example 11 is shown below:

[0297] Step a:

[0298] Compound 1,3-dibromobenzene (2.00 g, 8.48 mmol) was dissolved in anhydrous THF (17 mL) to form a 0.5 M solution. Under argon protection, the solution was cooled to -78 °C, and n-butyllithium (2.4 M in hexane, 4.24 mL, 10.17 mmol) was added dropwise. The mixture was stirred at -78 °C for 1 hour. Then, 3-oxetane (596 μL, 10.17 mmol) was added dropwise, and the mixture was stirred at -78 °C for 10 minutes, then gradually brought to room temperature and stirred overnight. After the reaction was complete, saturated NH4Cl solution (5 mL) was added to quench the reaction. The organic phase was separated, and the aqueous phase was extracted with EA (3 × 5 mL). The combined organic phases were washed with saturated brine (2 mL), dried over anhydrous sodium sulfate, and concentrated using a rotary evaporator to remove the solvent, yielding crude compound G-2, which required no further purification.

[0299] Step b:

[0300] The crude compound G-2 (max 1.94 g, 8.47 mmol) was dissolved in anhydrous DCM (20 mL), cooled to 0 °C, and then trichloroacetonitrile (3.40 mL, 33.88 mmol) and a catalytic amount of DBU (253 μL, 1.69 mmol) were added. The reaction was carried out at room temperature for 1 hour, and the reaction was monitored by TLC until complete. The solution was concentrated and purified by column chromatography (PE:EA = 88:12) to give compound G-3 as a colorless oily liquid: 1.70 g; the overall yield of steps a and b was 53.7%. 1 H NMR(600MHz,Chloroform-d)δ8.38(s,1H),7.76(t,J=1.9Hz,1H),7.50(dddd,J=22.4,8 .0,1.8,1.0Hz,2H),7.29(t,J=7.9Hz,1H),5.13(d,J=8.6Hz,2H),4.89(d,J=8.6Hz,2H).

[0301] Step c:

[0302] Compound G-3 (1.70 g, 4.55 mmol) and benzyl carbamate G-4 (3.44 g, 22.76 mmol) were dissolved in DCM (60 mL), cooled to 0 °C, and Cu(OTf)₂ (659 mg, 1.82 mmol) was added. The mixture was purged with argon (×3) and heated to 45 °C for 18 hours. Insoluble matter was removed by filtration, and the filtrate was evaporated to dryness with silica gel. The filtrate was purified by dry column chromatography (PE:EA = 90:10–83:17) to give compound G-5 as a colorless liquid: 291 mg; yield 17.7%. LC-MS 360.0 [MH]-.

[0303] Step d:

[0304] The method for preparing compound B-6 from compound B-5 is as described in step c of Example 3.

[0305] Step e:

[0306] Compound G-5 (30 mg, 0.08 mmol), compound B-6 (28 mg, 0.10 mmol), and K₂CO₃ (69 mg, 0.50 mmol) were placed in a three-necked round-bottom flask. 1,4-dioxane / water (4 mL / 0.5 mL) was added, and the mixture was purged with argon (×3). Then, Pd(PPh₃)₄ (19 mg, 0.02 mmol) was added, and the mixture was purged with argon (×3). The reaction mixture was heated to 90 °C under an argon atmosphere and reacted overnight. The reaction was monitored by TLC until complete. The mixture was filtered through diatomaceous earth, extracted with EA (8 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, concentrated by rotary evaporation to remove the solvent, and purified by column chromatography (PE:EA = 75:25) to give product M123 as a pale yellow solid: 14 mg, yield 39.1%. 1 H NMR(600MHz, Acetone-d6)δ10.59(s,1H),7.93–7.91(m,1H),7.81(s,1H),7.56(dd,J =7.7,1.7Hz,2H),7.47(d,J=1.3Hz,1H),7.47–7.45(m,1H),7.40(t,J=7.7Hz,1H),7. 34–7.28(m,4H),7.27–7.23(m,1H),6.64(dd,J=3.0,2.1Hz,1H),4.58(s,2H),4.22(s ,1H),3.93(dd,J=10.5,5.5Hz,1H),3.87–3.83(m,2H),3.80(dd,J=10.5,5.5Hz,1H).

[0307] Bioactivity detection examples

[0308] Example 12: Screening experiment for DRAK2-SRSF6 protein interaction based on NanoBit principle

[0309] 1. Experimental Objective

[0310] The DRAK2-SRSF6 PPI inhibitory activity of the compounds of this invention was tested.

[0311] 2. Experimental Principle

[0312] NanoBit, based on the Nanoluc luciferase dual-subunit system, is a genetically engineered small molecule enzyme (19.1 kDa, 171 amino acids), a novel type of luciferase that produces strong blue bioluminescence with brighter light, more stable signal, and a larger signal window. The NanoBit dual-subunit system utilizes two subunits designed based on NanoLuc: Large BiT (LgBiT; 17.6 kDa) and Small BiT (SmBiT; 11 amino acids). LgBit and SmBit are then used to construct fusion proteins with DRAK2 and SRSF6, respectively. When DRAK2 and SRSF6 approach each other, the two NanoBit subunits also approach each other, forming a complete luciferase that catalyzes substrate luminescence. If a small molecule compound interferes with the interaction between the target proteins DRAK2 and SRSF6, it demonstrates signal inhibition of the luciferase reporter gene; the percentage of inhibition is calculated.

[0313] 3. Experimental Apparatus

[0314] Multimode Plate Reader EnVision(PerkinElmer)

[0315] 4. Experimental Materials

[0316] Live Cell Assay System, 1000 assays (Furimazine + Nano-Glo live cell reagent), Promega; 96-well solid polystyrene microplate, Sigma.

[0317] 5. Experimental Procedure

[0318] Inoculation: Cells in good growth condition were inoculated into 10cm cell culture dishes at a density of 250,000 / mL.

[0319] Transfection: After cells adhered and grew for 6 hours, EZ trans was used as the transfection reagent. The transfection ratio of DRAK2-SmBiT plasmid to LgBiT-SRSF6 plasmid was 10:1, and the transfection time was 12 hours.

[0320] Cell inoculation: After changing the medium, cells were inoculated into 96-well solid polystyrene microplates at a density of 250,000 / mL.

[0321] Detection: After 24 h of culture, the medium was replaced with 50 μL of phenol red-free DMEM medium (containing 0.1% BSA) containing the compound, and then 7.5 μL of a mixture of Furimazine and Nano-Glo live cell reagent was added to 17.5 μL of phenol red-free DMEM medium (containing 0.1% BSA). After incubation in the dark for 3 min, the Luciferase signal intensity was measured.

[0322] 6. Data Processing

[0323] Initial screening was conducted at two concentrations: 5 μM and 20 μM, to test the activity of the samples. Samples exhibiting activity under certain conditions, such as an inhibition rate (%Inhibitory Rate) greater than 50, showed a dose-dependent activity and proceeded to the secondary screening, where the IC50 value was determined. Generally, a previously reported compound was used as a reference for each test.

[0324] 7. Sample processing

[0325] The sample was dissolved in DMSO and stored at low temperature. The concentration of DMSO in the final system was controlled within a range that would not affect the detection activity.

[0326] 8. Experimental Results (using 64 compounds such as M5 as examples, but not limited to these compounds)

[0327] Note:

[0328] %Inhibition represents the inhibition rate of the sample compound on DRAK2-SRSF6 PPI at concentrations of 5 μM and 20 μM.

[0329] * indicates 20% ≤ % Inhibition < 40%; ** indicates 40% ≤ % Inhibition < 60%;

[0330] *** represents 60% ≤ % Inhibition < 80%; **** represents % Inhibition ≥ 80%.

[0331] IC 50 To evaluate the inhibitory activity of the sample compounds on DRAK2-SRSF6 PPI;

[0332] # represents 5μM≤IC 50 <10μM; ## represents 3μM≤IC 50 <5μM;

[0333] ### represents 1μM≤IC 50 <3μM; #### represents IC 50<1μM.

[0334] 9. Results and Discussion

[0335] The results of the above examples show that the compounds of the present invention have significant inhibitory activity against the interaction between DRAK2 and SRSF6, wherein several preferred structures have an IC50 of <1 μM for inhibiting the DRAK2-SRSF6 PPI.

[0336] Example 13 Molecular-level phase separation screening experiment

[0337] 1. Experimental Objective

[0338] Effect of compounds on DRAK2 phase separation in the test examples

[0339] 2. Experimental Principle

[0340] DRAK2 phase separation mediates the pathological process of MAFLD-MASH. Therefore, this study aims to assess the potential of small-molecule drugs targeting DRAK2 for the treatment of MAFLD-MASH by examining the degree to which they inhibit DRAK2 phase separation. DRAK2-EGFP fluorescent protein undergoes phase separation under accelerator and buffer conditions, and the degree of phase separation can be determined by imaging with a laser microscope. Co-incubating DRAK2-EGFP protein with a small molecule compound, an accelerator, and a buffer solution allows for the determination of the inhibitory effect of the small molecule drug on DRAK2 phase separation under specific buffer conditions.

[0341] 3. Experimental Apparatus

[0342] Ultra-high resolution live-cell imaging instrument, confocal culture dish, and several conventional experimental instruments such as pipettes and pipette tips.

[0343] 4. Experimental Materials

[0344] DRAK2-EGFP protein (stock solution concentration 80 μM), small molecule drug compound (stock solution concentration 10 μM), 500 μM NaCl-HCl-Tris base buffer solution (for stock solution dilution), 150 μM NaCl-HCl-Tris base buffer solution (for co-incubation).

[0345] 5. Experimental Procedure and Data Processing

[0346] An expression vector with the DRAK2-His tag was constructed, transformed with *E. coli*, and induced to express in LB medium. Cells were lysed with buffer, and the DRAK2 protein was purified. Protein expression and purity were assessed. DRAK2 protein was diluted to different concentrations using a buffer containing 150 mM NaCl and 50 mM Tris-HCl. The diluted DRAK2 protein was incubated with different concentrations of small molecule compound solutions for 10 minutes, followed by the addition of 150 mM NaCl-HCl-Tri buffer. Droplets were then added to glass dishes and incubated for another 10 minutes. The formation of visible aggregates was observed using a fluorescence microscope, and their shape, size, and quantity were recorded. The fluorescence microscope images were analyzed using ImageJ software. Finally, the phase-separating ability of the DRAK2 protein—its tendency and degree of aggregate formation at different concentrations—was determined based on the number and shape of the phase-separated droplets.

[0347] 6. Experimental Results and Discussion (Taking 22 compounds such as M57 as examples, but not limited to these compounds)

[0348] As shown in Figures 1, 2, and 3, the compounds described in the above embodiments can all inhibit the phase separation of DRAK2 at the molecular level. Furthermore, quantitative data confirm that compounds with this type of structure exhibit strong inhibitory activity against DRAK2 phase separation, with most compounds showing an inhibition rate exceeding 60%.

[0349] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A compound of Formula I, or a stereoisomer, enantiomer, diastereomer, racemate thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof. in, Selected from the following group: Wherein, the dashed lines represent single or double bonds, and the A ring is a saturated ring, a partially unsaturated ring, or an aromatic ring; preferably, It is an aromatic ring; Each of Z1, Z2, Z3, Z4, Z5, and Z6 is independently selected from the following groups: -N=, -NH-, -S-, -O-, -CH=; Each R 1 R 2 R 3 and R 4 The substituent is H or 0-3 independently selected from the group consisting of: -OH, halogen, -CN, substituted or unsubstituted amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S, substituted or unsubstituted C1-C6 alkylene -COOH, substituted or unsubstituted C1-C6 alkylene -C(O)OR 10 substituted or unsubstituted C1-C6 alkylene-C(O)NH-R 10 Substituted or unsubstituted C6-C10 aryl groups, substituted or unsubstituted 5-10 membered heteroaryl groups containing 1-3 heteroatoms selected from N, O, or S, -C(O)-R 10 -C(O)OR 10 -NH-C(O)-R 10 ; R 10 Selected from the following group: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S, and C6-C10 aryl; Selected from the following group: not present, C3-C8 cycloalkyl, C3-C10 heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S, C6-C10 aryl, 5-10 heteroaryl containing 1-3 heteroatoms selected from N, O or S; Selected from the following group: Where r is selected from the following group: 0, 1, 2, 3, 4, 5 or 6; Each R 5 R 6 and R 7 Each is independently selected from the group consisting of: H, -OH, halogen, substituted or unsubstituted amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy; or, R 5 R 6 and R 7 Any two atoms can be linked together to form a substituted or unsubstituted C3-C8 cycloalkyl group, or a substituted or unsubstituted C3-C8 heterocycloalkyl group containing 1-3 heteroatoms selected from N, O or S. The substitution refers to substitution by one or more substituents selected from the group consisting of: halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S, C1-C18 alkylene-COOH, -C(O)-R 6 -C(O)OR 6 , n is selected from the following groups: 1, 2, or 3; m and q are each independently selected from the following groups: 0, 1, 2, 3 or 4; This indicates a double bond, which can be either cis or trans configuration. The additional condition is: when for hour, Not for 2. The compound according to claim 1, characterized in that, Selected from the following group: Each of Z1, Z2, Z3, Z4, Z5, and Z6 is independently selected from the following groups: -N=, -NH-, -O-, -CH=; R 1 and R 2 As defined in claim 1.

3. The compound according to claim 1, characterized in that, Compound I is a compound of formula II. in, Z1、Z2、Z3、Z4、Z5、R 1 、R 2 、R 3 、R 4 、 As defined in claim 1.

4. The compound according to claim 1, characterized in that, Compound I is a compound of formula III. in, Z1、Z2、Z3、R 1 、R 3 、R 4 、 As defined in claim 1.

5. The compound according to claim 1, characterized in that, Selected from the following group:

6. The compound according to claim 1, characterized in that, The compounds are selected from the group consisting of:

7. A method for preparing the compound as described in claim 1, characterized in that, Includes the following steps: In an inert solvent, under the conditions of base and catalyst, compound aa and compound bb undergo a Suzuki coupling reaction to prepare compound I. Wherein, each group is as defined in claim 1.

8. A pharmaceutical composition, characterized in that, Include: (i) the compound of claim 1, or its stereoisomers, enantiomers, diastereomers, racemates, or deuterated compounds thereof, or pharmaceutically acceptable salts thereof; and (ii) Pharmaceutically acceptable carriers.

9. Use of the compound as claimed in claim 1, characterized in that, (1) Used to prepare DRAK2-related inhibitors; (2) Used to prepare DRAK2-SRSF6 interaction inhibitors; (3) Used to prepare drugs for the prevention and / or treatment of metabolic diseases or cancer.

10. A method for preventing and / or treating metabolic diseases or cancer, characterized in that, The procedure includes the following steps: administering to a test subject the compound as claimed in claim 1, or a stereoisomer, enantiomer, diastereomer, racemate thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as claimed in claim 8.

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