Use of PGK1 inhibitor in depression or anxiety disorders

Abstract

The present invention relates to use of a PGK1 inhibitor in depression or anxiety disorders. Specifically disclosed is a prophylactic and / or therapeutic effect of a PGK1 inhibitor represented by formula (I) on depression or anxiety disorders. The PGK1 inhibitor has excellent safety and efficacy, and the efficacy is superior to that of the clinical first-line drug fluoxetine.

Description

Use of PGK1 inhibitors in depressive or anxiety disorders TECHNICAL FIELD

[0001] The present application relates to the field of medicine, in particular to the use of PGK1 inhibitors in depressive or anxiety disorders. BACKGROUND

[0002] Depression and anxiety disorders are the most common mental disorders in modern society, often coexist in the form of comorbidity, and each disorder affects more than 300 million people worldwide. In particular, during the COVID-19 pandemic in 2019, the incidence of depression and anxiety disorders increased significantly, with an additional 70 million and 90 million patients, respectively. So far, the pathophysiological mechanisms of these mental diseases have not been elucidated, which poses a great challenge to treatment.

[0003] In the clinical treatment of depression, first-line drugs are mainly monoamine neurotransmitter reuptake inhibitors, including fluoxetine (a selective serotonin reuptake inhibitor, SSRI) and venlafaxine (a serotonin-norepinephrine reuptake inhibitor, SNRI). These drugs are also the first choice for the treatment of anxiety disorders. However, the effectiveness of these drugs in clinical application is about 30%, and is accompanied by slow onset (usually 4 to 6 weeks or longer), significant side effects, and high recurrence rate. On the other hand, the second-generation antidepressants represented by ketamine face many safety problems, such as addiction, hallucinations, and cognitive dysfunction. Currently, such drugs are mainly limited to use in patients with high suicide risk or refractory patients, and require strict monitoring and management during treatment.

[0004] Therefore, it is an urgent need in the field of psychiatry to develop new drug treatment regimens for depression and anxiety disorders with higher precision and applicability.

[0005] Phosphoglycerate kinase 1 (PGK1) is the seventh step catalytic enzyme of glycolysis, which responds to the first ATP production in the glycolysis pathway by converting 1,3-bisphosphoglycerate (1,3-BPG) to 3-phosphoglycerate (3-PG). As an enzyme in the glycolysis pathway, PGK1 inhibits oxidative phosphorylation and increases lactic acid production. In addition, under certain circumstances, PGK1 can translocate to mitochondria, phosphorylate pyruvate dehydrogenase kinase 1, and regulate mitochondrial reactive oxygen species. In addition to its glycolytic activity, PGK1 as a kinase can phosphorylate Beclin1 to initiate autophagy. Recent studies have shown that PGK1 is not only involved in the occurrence and development of tumors, but also closely related to inflammatory diseases. However, there is no correlation between PGK1 and depression, and in particular, there is no report on the use of PGK inhibitors to treat depression / anxiety-like behavior. SUMMARY

[0006] The present application aims to provide the use of a PGK1 inhibitor in the manufacture of a medicament for preventing and / or treating depressive and / or anxiety disorders.

[0007] In a first aspect, the present application provides the use of a compound of Formula I, or a pharmaceutically acceptable salt, enantiomer, diastereomer, optical isomer, racemate, deuterated derivative, solvate, hydrate, metabolite or prodrug thereof, for the manufacture of a medicament for preventing and / or treating depressive and / or anxiety disorders;

[0008] wherein,

[0009] X is selected from the group consisting of N, CH;

[0010] X1, X2are each independently selected from the group consisting of N, CR3;

[0011] R3is each independently selected from the group consisting of H, hydroxyl, substituted or unsubstituted C1-C6alkyl (preferably, C1-C3alkyl), substituted or unsubstituted C1-C3alkoxy, substituted or unsubstituted C1-C3alkyl-S-, N(R d )2, substituted or unsubstituted 4-10 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S;

[0012] R d is each independently selected from the group consisting of H, substituted or unsubstituted C1-C3alkyl, substituted or unsubstituted C4-C10cycloalkyl, substituted or unsubstituted C6-C10aryl;

[0013] A is selected from the group consisting of absent (a bond), substituted or unsubstituted C1-C3alkylene,

[0014] R a is selected from the group consisting of H, substituted or unsubstituted C1-C3alkyl, substituted or unsubstituted C3-C10cycloalkyl; or NR a forms, with X, a 3-6 membered heterocyclyl containing 1 N;

[0015] R1and R2are each independently selected from the group consisting of H, substituted or unsubstituted C1-C6alkyl (preferably, C1-C3alkyl), halogen (preferably, Cl), cyano, N(R c )2, substituted or unsubstituted C1-C3alkoxy, unsubstituted or substituted with one or more R s1 substituted C6-C10aryl ring, unsubstituted or substituted with one or more R s1 substituted 5-10 membered heteroaryl ring containing 1, 2 or 3 heteroatoms selected from N, O or S;

[0016] R s1 each independently selected from the group consisting of halogen, substituted or unsubstituted C1-C3 alkyl, cyano;

[0017] R b selected from the group consisting of H, unsubstituted or substituted by one or more R s2 substituted C1-C6 alkyl (preferably, C1-C3 alkyl),

[0018] R c each independently selected from the group consisting of H, substituted or unsubstituted C1-C3 alkyl;

[0019] R s2 each independently selected from the group consisting of D, hydroxyl, substituted or unsubstituted C1-C3 alkoxy, halogen, substituted or unsubstituted C1-C3 alkyl, cyano, -O-(C=O)-C1-C3 alkyl;

[0020] R4is selected from the group consisting of unsubstituted or substituted by one or more R s3 substituted C1-C6 alkyl (preferably, C1-C3 alkyl), unsubstituted or substituted by one or more R s3 substituted C4-C10 cycloalkyl, unsubstituted or substituted by one or more R s3 substituted 4-10 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, unsubstituted or substituted by one or more R s3 substituted C6-C10 aryl, unsubstituted or substituted by one or more R s3 substituted 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S;

[0021] R s3 each independently selected from the group consisting of hydroxyl, substituted or unsubstituted C1-C3 alkyl, halogen, substituted or unsubstituted C1-C3 alkyl-(C=O)-, substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted C1-C3 haloalkyl, substituted or unsubstituted C1-C3 hydroxyalkyl;

[0022] R5is selected from the group consisting of H, substituted or unsubstituted C1-C3 alkyl, halogen (preferably, Cl);

[0023] m, l are each independently selected from the group consisting of 0, 1, 2, 3;

[0024] Unless otherwise indicated, the substituents are optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, amino (-NH2), -N(C1-C3 alkyl)2, =0, -NH(C1-C3 alkyl), cyano, halo, or unsubstituted C6-C10 aryl.

[0025] In another preferred embodiment, X is selected from the group consisting of N, CH.

[0026] In another preferred embodiment, X is CH.

[0027] In another preferred embodiment, X1is N;

[0028] X2is CR3.

[0029] In another preferred embodiment, X1is CR3;

[0030] X2is N.

[0031] In another preferred embodiment, R3is each independently selected from the group consisting of H, hydroxy, substituted or unsubstituted C1-C6 alkyl (preferably, C1-C3 alkyl), substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted C1-C3 alkyl-S-, N(R d )2, substituted or unsubstituted 4-10 membered heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from N, O, or S.

[0032] In another preferred embodiment, R d is each independently selected from the group consisting of H, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C4-C10 cycloalkyl, substituted or unsubstituted C6-C10 aryl.

[0033] In another preferred embodiment, A is

[0034] In another preferred embodiment, R a is selected from the group consisting of H, C1-C3 alkyl.

[0035] In another preferred embodiment, R a is selected from the group consisting of H, methyl.

[0036] In another preferred embodiment, A is selected from the group consisting of absent or wherein R a is selected from the group consisting of H, C1-C3 alkyl.

[0037] In another preferred embodiment, A is wherein R a is selected from the group consisting of H, C1-C3 alkyl.

[0038] In another preferred example, A is selected from the group consisting of: not present, -NH-, -N(CH3)-.

[0039] In another preferred embodiment, A is selected from the group consisting of -NH- and -N(CH3)-.

[0040] In another preferred embodiment, R1 and R2 are different groups.

[0041] In another preferred embodiment, at least one of R1 and R2 is a halogen (such as Cl).

[0042] In another preferred embodiment, R1 is a halogen.

[0043] In another preferred embodiment, R1 and R2 are each independently selected from the group consisting of: halogens,

[0044] In another preferred embodiment, one of R1 and R2 is a halogen, and the other is...

[0045] In another preferred embodiment, R1 is a halogen and R2 is...

[0046] In another preferred embodiment, R b For not replaced or by one or more R s2 The substituted C1-C6 alkyl group (preferably C1-C3 alkyl group).

[0047] In another preferred embodiment, R s2 Each is independently selected from the group consisting of hydroxyl, substituted or unsubstituted C1-C3 alkoxy groups.

[0048] In another preferred embodiment, R s2 It is a hydroxyl group.

[0049] In another preferred embodiment, R b It is a C1-C6 hydroxyalkyl group, preferably a C1-C3 hydroxyalkyl group; more preferably, R b It is -CH2OH.

[0050] In another preferred embodiment, R1 and R2 are each independently selected from the group consisting of: halogens, And R b For not replaced or by one or more R s2 The substituted C1-C6 alkyl group (preferably C1-C3 alkyl group).

[0051] In another preferred embodiment, R1 and R2 are each independently selected from the group consisting of: halogens, R b For not replaced or by one or more R s2 The substituted C1-C6 alkyl group (preferably C1-C3 alkyl group), and Rs2 each independently selected from the group consisting of hydroxy, substituted or unsubstituted C1-C3alkoxy.

[0052] In another preferred embodiment, R1is halogen and R2is and R b is unsubstituted or substituted with one or more R s2 substituted C1-C6alkyl (preferably C1-C3alkyl).

[0053] In another preferred embodiment, R1is halogen and R2is R b is unsubstituted or substituted with one or more R s2 substituted C1-C6alkyl (preferably C1-C3alkyl), and R s2 each independently selected from the group consisting of hydroxy, substituted or unsubstituted C1-C3alkoxy.

[0054] In another preferred embodiment, R3is selected from the group consisting of H, C1-C3alkyl, N(R d )2; wherein each R d is independently selected from the group consisting of H, C1-C3alkyl.

[0055] In another preferred embodiment, R3is selected from the group consisting of H, C1-C3alkyl, NH(C1-C3alkyl).

[0056] In another preferred embodiment, R3is H or C1-C6alkyl (preferably C1-C3alkyl).

[0057] In another preferred embodiment, R4is selected from the group consisting of unsubstituted or substituted with one or more R s3 substituted C1-C6alkyl (preferably C1-C3alkyl), unsubstituted or substituted with one or more R s3 substituted C4-C6cycloalkyl, unsubstituted or substituted with one or more R s3 substituted 5-6 membered heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from N, O, or S, unsubstituted or substituted with one or more R s3 substituted phenyl, unsubstituted or substituted with one or more R s3 substituted 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, or S.

[0058] In another preferred embodiment, R4is selected from the group consisting of unsubstituted or substituted with one or more R s3 substituted 5-6 membered heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from N, O, or S, unsubstituted or substituted with one or more R s3 substituted 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, or S.

[0059] In another preferred embodiment, in R4, the heteroaryl group is a five-membered sulfur-containing heteroaryl group.

[0060] In another preferred embodiment, in R4, the heteroaryl group is a sulfur-containing heteroaryl group.

[0061] In another preferred embodiment, in R4, the heteroaryl group is a five-membered sulfur-containing heteroaryl group.

[0062] In another preferred embodiment, in R s3 each independently is selected from the group consisting of hydroxy, C1-C3 alkyl, halogen, C1-C3 alkyl-(C=0)-, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 hydroxyalkyl.

[0063] In another preferred embodiment, when R4is a 4-10 membered heterocycloalkyl group (preferably, a 5-6 membered heterocycloalkyl group) which is unsubstituted or substituted by one or more R s3 substituted C4-C10 cycloalkyl (preferably, C4-C6 cycloalkyl), unsubstituted or substituted by one or more R s3 substituted C4-C10 cycloalkyl (preferably, C4-C6 cycloalkyl), unsubstituted or substituted by one or more R

[0064] In another preferred embodiment, X is CH;

[0065] X1, X2are each independently selected from the group consisting of N, CR3;

[0066] R3is each independently selected from the group consisting of H, C1-C6 alkyl, C1-C3 alkoxy, C1-C3 alkyl-S-, 4-10 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S;

[0067] A is

[0068] R a is selected from the group consisting of H, C1-C3 alkyl;

[0069] R1and R2are each independently selected from the group consisting of H, C1-C6 alkyl, halogen, C1-C3 alkoxy;

[0070] R b is C1-C6 alkyl substituted by one or more R s2 ; and

[0071] R s2 are each independently selected from the group consisting of D, hydroxy, C1-C3 alkoxy, halogen, -0-(C=0)-C1-C3 alkyl;

[0072] R4is selected from the group consisting of 4-10 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S;

[0073] R5is selected from the group consisting of H, C1-C3 alkyl;

[0074] m, 1 are each independently selected from the group consisting of 1, 2.

[0075] In another preferred embodiment, the compound is selected from the group consisting of:

[0076] In another preferred embodiment, the compound is selected from the group consisting of:

[0077] In another preferred embodiment, the medicament is for preventing depressive and / or anxiety disorders.

[0078] In another preferred embodiment, the medicament is for treating depressive and / or anxiety disorders.

[0079] In another preferred embodiment, the medicament is for preventing and treating depressive and / or anxiety disorders.

[0080] In another preferred embodiment, the medicament is for one or more uses selected from the group consisting of:

[0081] 1 ) for shortening the immobility time of a patient suffering from depressive and / or anxiety disorders;

[0082] 2) for reducing the hopelessness of a patient suffering from depressive and / or anxiety disorders;

[0083] 3) for reducing the anxiety of a patient suffering from depressive and / or anxiety disorders.

[0084] In another preferred embodiment, the medicament is administered orally (e.g. by gavage).

[0085] In another preferred embodiment, the medicament is in the form of an oral preparation.

[0086] In another preferred embodiment, the medicament is administered before the modeling of depressive and / or anxiety disorders; and / or

[0087] the medicament is administered after the modeling of depressive and / or anxiety disorders.

[0088] In another preferred embodiment, the depression and / or anxiety disorder is a depression and / or anxiety disorder associated with peripheral monocyte / macrophage PGK1 pathway.

[0089] In another preferred embodiment, the depression and / or anxiety disorder is a depression and / or anxiety disorder with high expression of peripheral PGK1.

[0090] In another preferred embodiment, the drug does not penetrate the blood-brain barrier.

[0091] In another preferred embodiment, the drug is used to enhance the resistance of a patient with a depression and / or anxiety disorder to the "exploration-avoidance" conflict behavior, and to increase the probability of the patient's selection of exploration behavior.

[0092] In another preferred embodiment, the drug has no effect on the blood-brain barrier.

[0093] In another preferred embodiment, the drug is administered at a dose of 20-80 mg / kg, preferably 20-50 mg / kg, and more preferably 50 mg / kg.

[0094] In another preferred embodiment, the drug is administered at a dose of 20 mg / kg.

[0095] In another preferred embodiment, the depression and / or anxiety disorder is induced by LPS.

[0096] In another preferred embodiment, the depression and / or anxiety disorder is induced by a chronic restraint stress model.

[0097] It should be understood that, within the scope of the present application, each of the technical features described above and each of the technical features specifically described below (e.g., in the examples) can be combined with each other to form new or preferred technical solutions. Due to the limited space, they will not be listed one by one here. BRIEF DESCRIPTION OF DRAWINGS

[0098] Figure 1: Intragastric administration of SA11 alleviates depression and anxiety-like behavior in LPS model mice. (a) Forced swimming test results; (b) tail suspension test results; (c) elevated plus maze test results; (d) open field test results; (e) survival curve.

[0099] Figure 2: Intragastric administration of SC32 and SB9 alleviates depression and anxiety-like behavior in LPS model mice. (a) Forced swimming test results; (b) tail suspension test results; (c) elevated plus maze test results; (d) open field test results.

[0100] Figure 3: Intragastric administration of SA11 alleviates depression and anxiety-like behavior in CRS model mice. (a) Tail suspension test results; (b) forced swimming test results; (c) elevated plus maze test results; (d) open field test results.

[0101] Figure 4. Effective dose SA11 administration mode and frequency do not cause pathological damage to the heart, liver, spleen, lung and kidney of mice. (a) Representative results of H&E staining of paraffin sections of the heart, liver, spleen, lung and kidney of mice; (b) Results of liver and kidney function toxicity indicators of serum biochemical analysis of mice.

[0102] Figure 5. Drug content in plasma and brain tissue after intragastrically administering SA11.

[0103] Figure 6. SA11 protects the blood-brain barrier integrity of LPS-induced depression mice. Serum albumin infiltration (shown as green) was detected in the brain of LPS-induced depression mice, and no serum albumin infiltration was observed in the model mice after intragastrically administering SA11. Representative results of immunofluorescence double staining of frozen sections of mouse brain tissue. DETAILED DESCRIPTION

[0104] The inventors have made an innovative discovery that the compound of the present application has excellent effects on preventing and / or treating depression and / or anxiety disorders through long-term and in-depth research.

[0105] Specifically, the compound of the present application can significantly improve the depressive and / or anxiety symptoms of the research subjects when administered before modeling, i.e., has the effect of preventing the occurrence and development of depression and / or anxiety; the compound of the present application can also significantly improve the depressive and / or anxiety symptoms of the research subjects when administered after modeling, i.e., has the effect of treating the development of depression and / or anxiety. Further mechanism studies have shown that the compound of the present application mainly exerts an anti-depression effect by inhibiting the activity of PGK1 in the periphery when administered to depression model mice in the periphery. On this basis, the inventors have completed the present application.

[0106] TERMS

[0107] In the present application, the terms used have the general meanings known to those skilled in the art, unless otherwise specified.

[0108] In the present application, the term "halogen" refers to F, Cl, Br or I.

[0109] In the present application, "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, tert-pentyl, or the like. The term "C1-C3 alkyl" has a similar meaning.

[0110] In the present application, the term "C2-C6 alkenyl" refers to a straight-chain or branched alkenyl group having 2-6 carbon atoms containing one double bond, including, without limitation, ethenyl, propenyl, butenyl, isobutenyl, pentenyl and hexenyl, etc.

[0111] In the present application, the term "C2-C6alkynyl" refers to a straight or branched chain alkynyl group having from 2 to 6 carbon atoms containing one triple bond, including without limitation ethynyl, propynyl, butynyl, isobutynyl, pentynyl, and hexynyl groups.

[0112] In the present application, the term "C3-C8cycloalkyl" refers to a cyclic alkyl group having from 3 to 8 carbon atoms in the ring, including without limitation cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl groups. The terms "C4-C10cycloalkyl", "C3-C10cycloalkyl" have analogous meanings.

[0113] In the present application, the term "C1-C6alkoxy" refers to a straight or branched chain alkoxy group having from 1 to 6 carbon atoms, including without limitation methoxy, ethoxy, propoxy, isopropoxy, and butoxy groups. Preferably C1-C4alkoxy, C1-C3alkoxy.

[0114] In the present application, the term "heterocyclyl" refers to a 4-8 membered heterocyclic group containing 1, 2, or 3 heteroatoms selected from N, O, S, including without limitation the following groups:

[0115] In the present application, the terms "aromatic ring" or "aryl" have the same meaning, and preferably "C6-C10aryl". The term "C6-C10aryl" refers to an aromatic ring group having from 6 to 10 carbon atoms in the ring, containing no heteroatoms, such as phenyl, naphthyl groups.

[0116] In the present application, the terms "aromatic heterocycle" or "heteroaryl" have the same meaning, and refer to a heteroaromatic group containing one to several heteroatoms. For example, "C3-C10heteroaryl" refers to an aromatic heterocycle containing from 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen, and from 3 to 10 carbon atoms. Non-limiting examples include furanyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkyl pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl groups. The heteroaryl ring can be fused to an aryl, heterocyclyl, or cycloalkyl ring, where the ring that is attached to the parent structure is the heteroaryl ring. The heteroaryl group can be optionally substituted or unsubstituted.

[0117] In the present application, the term "halo" refers to substitution by a halogen.

[0118] In the present application, the term "deutero" refers to substitution by deuterium.

[0119] In the present application, the term "substituted" means that one or more hydrogen atoms on a specified group are replaced with a specified substituent. The specified substituent is a substituent described in the foregoing, or a substituent appearing in each embodiment. Unless otherwise specified, a substituted group can have one substituent selected from a specified group at any substitutable position of the group, which can be the same or different at each position. It will be understood by those skilled in the art that combinations of substituents contemplated by the present application are those that are stable or chemically feasible. The substituents are, for example, but not limited to, halogen, hydroxyl, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, aryl, heteroaryl, C1-C8 aldehyde group, C2-C10 acyl group, C2-C10 ester group, amino, C1-C6 alkoxy, C1-C10 sulfonyl, and the like.

[0120] In the present application, the term 1-6 means 1, 2, 3, 4, 5, or 6. Other similar terms each independently have a similar meaning. The term "a plurality of" means 2-6, such as 2, 3, 4, 5, or 6.

[0121] It will be understood that when a group is present simultaneously at a plurality of different positions of a compound, the definition thereof at each position is independent of one another, and can be the same or different. That is, the term "selected from the group consisting of" has the same meaning as the term "each independently selected from the group consisting of".

[0122] PGK1 inhibitor

[0123] The existing PGK1 inhibitors are mainly used for treating diseases such as tumors, inflammation, diabetes, etc. Among them, the tumors include liver cancer, breast cancer, pancreatic cancer, colorectal cancer, neuroblastoma, brain glioma, myeloma, lung cancer, prostate cancer, gastric cancer, and ovarian cancer, etc.

[0124] At present, there is no PGK1 inhibitor for preventing and / or treating depression and / or anxiety. Therefore, the present application first discovers the preventive and / or therapeutic effect of the PGK1 inhibitor on depression and / or anxiety disorders, which has important significance for expanding the drug selection of depression and / or anxiety disorders.

[0125] The compound SA11 of the present application is the compound S11 prepared in CN115433173A. From the data recorded in CN115433173A, it can be known that the compound SA11 (compound S11 in CN115433173A) has excellent PGK1 inhibitory activity.

[0126] The compound SB9 of the present application is the compound S9 prepared in CN115433175A. Similarly, based on the data recorded in CN115433175A, the compound also has excellent PGK1 inhibitory activity.

[0127] The compound SC32 of the present application is the compound S32 prepared in CN107814792A. Similarly, based on the data recorded in CN107814792A, the compound also has excellent PGK1 inhibitory activity.

[0128] Active ingredient

[0129] The compound of the present application has the structure shown in Formula I:

[0130] wherein each group is as defined above.

[0131] In another preferred embodiment, any one of R1, R2, R4, R5, X1, X2, X, A, m and l in the compound is independently the corresponding group in a specific compound described in the present application.

[0132] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the present application with an acid or a base suitable for use in medicine. Pharmaceutically acceptable salts include inorganic and organic salts. One preferred class of salts is a salt of a compound of the present application with an acid. Suitable acids for salt formation include, but are not limited to, inorganic acids such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, nitric, phosphoric, and the like; organic acids such as formic, acetic, trifluoroacetic, propionic, oxalic, malonic, succinic, fumaric, maleic, lactic, malic, tartaric, citric, picric, benzoic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, benzenesulfonic, naphthalenesulfonic, and the like; and amino acids such as proline, phenylalanine, aspartic acid, glutamic acid, and the like.

[0133] Another preferred class of salts is a salt of a compound of the present application with a base, such as an alkali metal salt (e.g., sodium or potassium salt), an alkaline earth metal salt (e.g., magnesium or calcium salt), an ammonium salt (e.g., lower alkylammonium salt and other pharmaceutically acceptable amine salt), such as methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, t-butylamine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salt formed by morpholine, piperazine, lysine, respectively.

[0134] The term "solvate" refers to a complex of a compound of the present application with solvent molecules in a specific stoichiometry. The term "hydrate" refers to a complex of a compound of the present application with water in a specific stoichiometry.

[0135] In addition, the compounds of the present application also include prodrugs of the compounds shown. The term "prodrug" includes compounds that can be biologically active or inactive themselves, but are converted to the compounds of the present application, or salts or solutions thereof, in vivo after administration by a suitable method, by metabolism or chemical reaction. The prodrugs include, but are not limited to, carboxylic acid esters, carbonic acid esters, phosphoric acid esters, nitric acid esters, sulfuric acid esters, sulfone esters, sulfoxide esters, amino compounds, carbamic acid salts, azo compounds, phosphoramides, glucosides, ethers, acetals, and the like.

[0136] Indications

[0137] The present application uses different depression and anxiety mouse models, and the addition of the compounds of the present application in the drugs can significantly alleviate the depression and anxiety-like behaviors of the model mice, and compared with the clinical first-line drug fluoxetine, the drugs of the present application have more advantages.

[0138] The drugs of the present application contain a safe and effective amount of the compounds of the present application or the pharmacologically acceptable salts thereof and the pharmacologically acceptable excipients or carriers. The "safe and effective amount" refers to the amount of the compound sufficient to significantly improve the condition without causing serious side effects. Generally, the drugs contain 1-2000 mg of the compounds of the present application per dose, more preferably, 10-1000 mg of the compounds of the present application per dose. Preferably, the "dose" is a capsule or a tablet.

[0139] The "pharmacologically acceptable carrier" refers to one or more compatible solid or liquid fillers or gel materials suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here refers to the fact that the components in the composition can be mixed with the compounds of the present application and among themselves without significantly reducing the efficacy of the compounds. Some examples of the pharmacologically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, 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.), polyhydric alcohols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium dodecyl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, and pyrogen-free water, etc.

[0140] The drugs are injection, capsule, tablet, pill, powder, or granule.

[0141] The administration of the compounds or drugs of the present application is not particularly limited, and the representative administration methods include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration.

[0142] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert excipient (or carrier) such as sodium citrate or dicalcium phosphate, or with such excipients as (a) fillers or extenders, e.g., starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, e.g., hydroxymethylcellulose, alginic acid, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, e.g., glycerol; (d) disintegrating agents, e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solution retarders, e.g., paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) moisturizing agents, e.g., glycerol and sorbitol; (h) respiration accelerators, e.g., high-oleic acid cottonseed oil; and (i) lubricants, e.g., magnesium stearate, calcium stearate, stearic acid, glyceryl monostearate, sodium stearyl fumarate, and talc. In the case of capsules, tablets, and pills, the dosage forms can also comprise buffering agents.

[0143] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, e.g., enteric coatings and other materials well known in the art. They can optionally contain opacifying agents, and can also be of a composition that they release the active compound or compounds in a certain part of the digestive tract. Examples of embedding compositions that can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0144] Liquid dosage forms for oral administration include pharmaceutically-acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms can include inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butanediol, dimethylformamide, and the like, as well as mixtures thereof.

[0145] Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0146] Suspensions, in addition to the active compounds, can contain suspending agents, as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, and sodium carbomate, among others.

[0147] Compositions for parenteral injection can include physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.

[0148] Dosage forms for topical administration of a compound of this application include ointments, powders, sprays, and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as can be required.

[0149] A compound of this application can be administered alone or in combination with other pharmaceutically acceptable compounds (e.g., antidepressants).

[0150] The therapeutic methods of this application can be employed in admixture with other therapeutic procedures or agents.

[0151] In using the medicaments, a safe and effective amount of a compound of this application is administered to a mammal (e.g., human) in need of treatment, where the amount is that which is pharmaceutically effective. For a 60 kg body weight, the daily amount is generally 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dose will be determined in light of a variety of factors, including the route of administration, the patient's health status, and the like, all within the skill of the art.

[0152] Compared with the prior art, the present application has the following main advantages:

[0153] (1) The compound of the present application has a significantly superior preventive effect on depressive and / or anxiety disorders;

[0154] (2) The compound of the present application has a significantly superior therapeutic effect on depressive and / or anxiety disorders;

[0155] (3) The compound of the present application has excellent safety when used for preventing and / or treating depressive and / or anxiety disorders, and does not cause pathological damage to the heart, liver, spleen, lung and kidney of the research subject;

[0156] (4) The compound of the present application does not penetrate the blood-brain barrier when used for preventing and / or treating depressive and / or anxiety disorders, and has good safety;

[0157] (5) The mechanism of action of the present application is peripheral onset, and has a good protective effect on the integrity of the blood-brain barrier.

[0158] The application will be further described in conjunction with specific examples. It should be understood that these examples are only used to illustrate the application and not used to limit the scope of the application. The experimental methods in the following examples, if not otherwise specified, are generally carried out according to the conventional conditions, such as the conditions described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or the conditions suggested by the manufacturers. Unless otherwise specified, percentages and parts are by weight.

[0159] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. In addition, any method and material similar or equivalent to those described herein can be used in the practice of the present application. The preferred methods and materials described herein are illustrative only and not intended to be limiting.

[0160] Example 1 Effect and mechanism of PGK1 inhibitor in the treatment of depression and anxiety

[0161] 1. Experimental animals:

[0162] SPF (specific pathogen free) C57BL / 6J mice, 6-12 weeks old, male, weighing about 20-28 g, purchased from Shanghai Slek Experimental Animal Co., Ltd. The experimental mice were bred and managed by the Experimental Animal Center of Shanghai Jiaotong University, and the mouse breeding level was SPF. The breeding conditions were stable, constant temperature and humidity, 12 h light, 12 h darkness. The mice could drink water and eat freely. No more than 5 mice were fed in each cage.

[0163] 2. Modeling method

[0164] 2.1 Acute depression model:

[0165] The depression and anxiety-like behavior of mice was induced by intraperitoneal injection of lipopolysaccharide (LPS) in mice, and the dose of LPS was 0.83 mg / kg. After 24 h, the mice showed depression and anxiety-like behavior.

[0166] 2.2 Chronic restraint stress (CRS) model:

[0167] The mouse fixer was used to restrict the movement of the mouse for 6 h every day, and after 14 days, the classic behavioral experiments were used to detect the despair emotion (tail suspension test and forced swimming test), anxiety emotion (elevated plus maze test) and autonomous movement ability (open field test) of the mice.

[0168] 3. Treatment method:

[0169] 3.1 Experimental treatment method related to the effect of compound SA11 / SC32 / SB9 in acute depression model mice

[0170] 3.1.1 Intervention by oral gavage of drug SA11 / SC32 / SB9

[0171] Control group: After one week of environmental adaptation, mice were orally gavaged with the corresponding drug solvent for 10 consecutive days, once a day, and intraperitoneally injected with normal saline on the eleventh day. After 24 hours, behavioral tests were performed.

[0172] Model group: After one week of environmental adaptation, mice were orally gavaged with the corresponding drug solvent for 10 consecutive days, once a day, and intraperitoneally injected with LPS (dissolved in normal saline, at a dose of 0.83 mg / kg) on the eleventh day. After 24 hours, behavioral tests were performed.

[0173] Compound SA11 / SC32 / SB9 intervention + model group: After one week of environmental adaptation, mice were orally gavaged with the drug for 10 consecutive days, once a day, at a dose of 20 mg / kg or 50 mg / kg. On the eleventh day, mice were intraperitoneally injected with LPS (dissolved in normal saline, at a dose of 0.83 mg / kg). After 24 hours, behavioral tests were performed.

[0174] Fluoxetine intervention + model group: First administration method: After one week of environmental adaptation, mice were intraperitoneally injected with fluoxetine (30 mg / kg, dissolved in double-distilled water) 30 minutes before LPS injection. Thirty minutes later, mice were intraperitoneally injected with LPS (dissolved in normal saline, at a dose of 0.83 mg / kg). Second administration method: After one week of environmental adaptation, mice were orally gavaged with fluoxetine (50 mg / kg) for 10 consecutive days, once a day. On the eleventh day, mice were intraperitoneally injected with LPS (dissolved in normal saline, at a dose of 0.83 mg / kg). After 24 hours, behavioral tests were performed.

[0175] 3.2 Role of compounds in chronic restraint stress-induced depression model

[0176] 3.2.1 Intervention by oral gavage of drug

[0177] Control group: After one week of environmental adaptation, mice were orally gavaged with the corresponding drug solvent from the fifth to the fourteenth day, once a day, and normally fed for 14 days.

[0178] Model group: After one week of environmental adaptation, mice were restrained for 6 hours per day using a mouse restrainer for 14 days, and orally gavaged with the corresponding drug solvent from the fifth to the fourteenth day, once a day.

[0179] Compound (SA11) intervention + model group: Mice were restrained for 6 hours per day using a mouse restrainer for 14 days, and orally gavaged with SA11 at a dose of 20 mg / kg from the fifth to the fourteenth day, once a day.

[0180] Fluoxetine intervention + model group: The movement of mice was limited for 6 hours per day using a mouse holder for fourteen days. From the fifth day to the fourteenth day, the mice were orally administered with fluoxetine at a dose of 20 mg / kg once a day.

[0181] All groups were subjected to various behavioral tests on the fifteenth day.

[0182] 3.3 Safety evaluation of drugs in mice

[0183] Control group: After the mice were adapted to the environment for one week, the mice were orally administered with the corresponding drug solvent once a day for 10 consecutive days.

[0184] Compound (SA11) intervention group: After the mice were adapted to the environment for one week, the mice were orally administered with SA11 at a dose of 50 mg / kg once a day for 10 consecutive days.

[0185] All groups were subjected to various behavioral tests on the second day after the last injection. After the behavioral tests, the heart, liver, spleen, lung, and kidney were taken for paraffin section HE staining to observe the effects of the drugs on the heart, liver, spleen, lung, and kidney. Blood was also taken to prepare serum for detection of liver and kidney function toxicity indicators using a biochemical analyzer.

[0186] 3.4 Content detection of drugs in mice

[0187] The mice were orally administered with SA11 (50 mg / kg), and blood was taken from the orbital cavity at 5 min, 30 min, and 2 h, respectively. Then, the mice were subjected to cardiac perfusion, and the whole brain tissue was taken. The drug content in the plasma and brain tissue was detected using LC-MS.

[0188] 3.5 Protective detection of drugs on the blood-brain barrier

[0189] The brain tissue of mice in the control group, LPS model group, and LPS model group orally administered with compound SA11 (20 mg / kg or 50 mg / kg) was selected to prepare frozen sections. Double immunofluorescence staining experiments were performed using serum albumin antibodies and blood-brain barrier endothelial cell marker CD31 antibodies to observe the protective effect of the drugs on the integrity of the blood-brain barrier.

[0190] 4 Mouse behavioral tests

[0191] 4.1 Tail suspension test (TST)

[0192] Under acoustic and visual isolation, the animals were suspended above the floor at a distance of at least 80 centimeters by a tape placed about 1 centimeter from the tail tip. The total TST duration was 6 minutes, and the immobility time was recorded for the last 4 minutes; only when passively suspended and motionless were the mice considered immobile.

[0193] 4.2 Forced swimming test (FST)

[0194] Each mouse was placed individually into a 4000 mL glass beaker containing 3000 mL of warm water (temperature 25 ± 1°C). The total FST duration was 6 minutes, and the immobility time during the last 4 minutes was recorded; a mouse was considered immobile only when it was floating motionless or only making small movements needed to keep its head above water.

[0195] 4.3 Elevated plus-maze test (EPM)

[0196] One week before the experiment, the experimental mice were stroked for 1-5 minutes every day to eliminate their fear of the experimenter. The mice were placed in the center of the maze with their heads facing the open arms, and each mouse was placed in the same position thereafter. The number of times the mice entered the open arms and the closed arms was recorded by a monitor for 5 minutes. The experimenter was required to be 1 meter away from the maze during the experiment. After the experiment, the mice were returned to the cages, and the maze was cleaned with 75% alcohol to eliminate the effects of the animals' odors on subsequent mice. The percentage of open arm entries = the number of open arm entries / (the number of open arm entries + the number of closed arm entries).

[0197] 4.4 Open field test (OFT)

[0198] The mice were placed in the central area of the experimental box, and the total distance traveled by the mice in the box was recorded by a monitor for 5 minutes. After the experiment, the mice were returned to the cages, and the maze was cleaned with 75% alcohol to eliminate the effects of the animals' odors on subsequent mice.

[0199] 5 Evaluation index

[0200] 5.1 Behavioral experiment index of mice

[0201] 5.1.1 The forced swimming test and the tail suspension test are the most commonly used experimental methods for detecting depressive-like behavior in rodents and are mainly used to assess the degree of despair in mice. Normal mice exhibit active swimming or struggling behavior for a long time when they are in an environment from which they cannot escape (a water tank or a suspended state). If a mouse is in a depressive state, it will exhibit a long period of immobility and despair after the initial swimming or struggling. We reflect the degree of despair in mice by recording the time during which the mice are immobile.

[0202] 5.1.2 Elevated plus maze is used to investigate the anxiety state of animals by taking advantage of the conflict behavior of animals to explore the new and strange environment and the fear of the high open arm. The elevated plus maze has a pair of open arms and a pair of closed arms. Rodents tend to move in the closed arms due to their preference for darkness, but they also move in the open arms due to their curiosity and exploratory nature. When faced with novel stimuli, animals simultaneously experience the urge to explore and fear, resulting in a conflict between exploration and avoidance, and thus anxiety.

[0203] 5.1.3 In the open field experiment, the total distance of mouse movement reflects the movement ability of the mouse.

[0204] 5.2 Evaluation index of whether the drug can enter the brain

[0205] The ratio of drug concentration in brain to plasma (B / P): B / P>0.3 is judged as the drug can enter the central nervous system, and B / P<0.1 is judged as the drug cannot enter the central nervous system.

[0206] 5.3 Evaluation index of blood-brain barrier integrity

[0207] Detection of the expression of serum albumin in the brain. If there is co-localization with the endothelial cells of the blood-brain barrier and invasion into the brain tissue, it is considered that the blood-brain barrier is damaged and the integrity is impaired.

[0208] 6 Experimental results:

[0209] 6.1 Compound (SA11 / SC32 / SB9) significantly improves the depression and anxiety-like behavior of acute depression model mice.

[0210] 24 hours after intraperitoneal injection of LPS, mice showed depression and anxiety-like behavior. In the FST and TST experiments, the immobility time of mice after LPS administration was significantly higher than that of the control group (Figure 1a, b). In the EPM experiment, LPS administration significantly reduced the frequency of mice entering the open arm (Figure 1c). These results indicate that LPS successfully induced depression and anxiety-like behavior in mice, and SA11 administration significantly improved LPS-induced depression / anxiety behavior (Figure 1a-c), which was comparable to or better than the positive drug fluoxetine. There was no difference in total distance in OFT experiment among groups, which ruled out the influence of mouse voluntary movement ability on behavioral experiment (Figure 1d).

[0211] In other words, for LPS-induced depression / anxiety behavior, pre-administration of SA11 has a preventive and / or therapeutic effect.

[0212] In addition, PGK1 inhibitors SC32 and SB9 also significantly improved LPS-induced depression / anxiety behavior (Figure 2). However, using the same administration method, dose and frequency, fluoxetine caused rapid weight loss in mice on the 7th day of administration, abnormal behavior, and stopped giving fluoxetine, and mice died one after another after the 9th day. (Figure 1e)

[0213] 6.2 Compound (SA11) significantly improves depression and anxiety-like behaviors in chronic depression model mice. With the same administration method, dose and frequency, SA11 has a significantly better effect on improving depressive symptoms than the clinical first-line drug fluoxetine.

[0214] 6.2.1 For the chronic restraint stress mouse model, we used oral gavage to administer drug intervention after modeling (Figure 3), and the results showed that SA11 can significantly improve the depression and anxiety-like symptoms of model mice.

[0215] 6.2.2 We used fluoxetine, a clinical first-line drug for depression and anxiety disorders, as a positive control, and the results showed that SA11 had a significantly better effect on improving depressive symptoms than fluoxetine at the same dose and frequency (Figure 3).

[0216] In other words, for the chronic restraint stress mouse model, SA11 has excellent therapeutic effect.

[0217] 6.3 Effective dose of compound (SA11) does not cause pathological damage to the heart, liver, spleen, lung and kidney of mice.

[0218] We evaluated the safety of SA11 in mice. Immunohistochemical experiments and liver and kidney function tests on serum were performed on mice given SA11 (50 mg / kg) by gavage. The results showed that this administration method and dose did not cause pathological damage to the heart, liver, spleen, lung and kidney of mice (Figure 4).

[0219] 6.4 Peripheral administration of compound SA11 does not cross the blood-brain barrier

[0220] The experimental results showed that we orally administered 50 mg / kg SA11 to mice periphery, and the results showed that compared with plasma, only a small amount of SA11 entered the brain tissue (nM level, Figure 5), and the B / P value was less than 0.3.

[0221] This result shows that SA11 is mainly distributed in the periphery after administration, and produces antidepressant activity by inhibiting the activity of peripheral PGK1.

[0222] 6.5 Peripheral administration of compound (SA11) protects the integrity of the blood-brain barrier

[0223] Immunofluorescence results showed that the blood-brain barrier of LPS model mice was damaged, and peripheral serum albumin infiltrated into the brain, but no serum albumin infiltration was observed in the brain of mice administered with SA11 periphery (Figure 6).

[0224] The results show that peripheral administration of SA11 protects the integrity of the blood-brain barrier of LPS model mice.

[0225] All documents referred to in the present application are incorporated herein by reference as if each were individually incorporated. In addition, it is to be understood that the application can be carried out by specifically different embodiments and that each disclosed embodiment can be implemented with or without the corresponding use of the other embodiments. Other embodiments will occur to readers of the disclosure and the appended claims.

Claims

1. Use of a compound of Formula I, or a pharmaceutically acceptable salt, enantiomer, diastereomer, optical isomer, racemate, deuterated derivative, solvate, hydrate, metabolite, or prodrug thereof, characterized in that, for the preparation of a medicament for the prevention and / or treatment of depressive and / or anxiety disorders; wherein X is selected from the group consisting of N, CH; X1, X2are each independently selected from the group consisting of N, CR3; R3is each independently selected from the group consisting of H, hydroxyl, substituted or unsubstituted C1-C6alkyl (preferably, C1-C3alkyl), substituted or unsubstituted C1-C3alkoxy, substituted or unsubstituted C1-C3alkyl-S-, N(R d )2, substituted or unsubstituted 4-10 membered heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from N, O, or S; R d each independently is selected from the group consisting of H, substituted or unsubstituted C1-C3alkyl, substituted or unsubstituted C4-C10cycloalkyl, substituted or unsubstituted C6-C10aryl; A is selected from the group consisting of: absent (a bond), substituted or unsubstituted C1-C3 alkylene, R a is selected from the group consisting of H, substituted or unsubstituted C1-C3alkyl, substituted or unsubstituted C3-C10cycloalkyl; or NR a forms a 3-6 membered heterocyclyl containing 1 N with X; R1and R2are each independently selected from the group consisting of H, substituted or unsubstituted C1-C6alkyl (preferably, C1-C3alkyl), halogen (preferably, Cl), cyano, N(R c )2, substituted or unsubstituted C1-C3alkoxy, unsubstituted or substituted with one or more R s1 substituted C6-C10aromatic ring, unsubstituted or substituted with one or more R s1 substituted 5-10 membered heteroaromatic ring containing 1, 2, or 3 heteroatoms selected from N, O, or S; R s1 each independently is selected from the group consisting of halogen, substituted or unsubstituted C1-C3alkyl, cyano; R b selected from the group consisting of H, unsubstituted or substituted C1-C6 alkyl (preferably, C1-C3 alkyl), s2 substituted C1-C6 alkyl (preferably, C1-C3 alkyl), R c each independently is selected from the group consisting of H, substituted or unsubstituted C1-C3alkyl; R s2 each independently is selected from the group consisting of D, hydroxyl, substituted or unsubstituted C1-C3alkoxy, halogen, substituted or unsubstituted C1-C3alkyl, cyano, -0-(C=0)-C1-C3alkyl; R4 is selected from the group that is not substituted or is replaced by one or more R4 groups. s3 The substituted C1-C6 alkyl group (preferably C1-C3 alkyl group), unsubstituted or substituted with one or more R s3 The substituted C4-C10 cycloalkyl group, unsubstituted or substituted with one or more R s3 The substituted 4-10 membered heterocyclic alkyl group containing 1, 2, or 3 heteroatoms selected from N, O, or S, is unsubstituted or substituted with one or more R atoms. s3 The substituted C6-C10 aryl group, unsubstituted or replaced by one or more R s3 The substituted 5-10 membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O or S; R s3 each independently is selected from the group consisting of hydroxy, substituted or unsubstituted C1-C3alkyl, halogen, substituted or unsubstituted C1-C3alkyl-(C=0)-, substituted or unsubstituted C1-C3alkoxy, substituted or unsubstituted C1-C3halogenoalkyl, substituted or unsubstituted C1-C3hydroxyalkyl; R5is selected from the group consisting of H, substituted or unsubstituted C1-C3alkyl, halogen (preferably, Cl); m, l are each independently selected from the group consisting of 0, 1, 2, 3; Unless specifically indicated otherwise, the term "substituted" means that one or more hydrogens of the group is optionally replaced by a substituent selected from the group consisting of hydroxyl, halogen, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, amino (-NH2), -N(C1-C3alkyl)2, =0, -NH(C1-C3alkyl), cyano, halo or unsubstituted C6-C10aryl.

2. Use according to claim 1, characterized in that, X is CH; X1, X2are each independently selected from the group consisting of N, CR3; R3is each independently selected from the group consisting of H, C1-C6alkyl, C1-C3alkoxy, C1-C3alkyl-S-, 4-10 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S; A is R a selected from the group consisting of H, C1-C3alkyl; R1and R2are each independently selected from the group consisting of H, C1-C6alkyl, halogen, C1-C3alkoxy; R b For one or more R s2 The substituted C1-C6 alkyl groups; R s2 each independently is selected from the group consisting of D, hydroxyl, C1-C3alkoxy, halogen, -0-(C=0)-C1-C3alkyl; R4is selected from the group consisting of 4-10 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S; R5is selected from the group consisting of H, C1-C3alkyl; m, l are each independently selected from the group consisting of 1, 2.

3. Use according to claim 1, characterized in that, The compound is selected from the group consisting of:

4. The use according to claim 1, characterized in that, The compound is selected from the group consisting of:

5. The use according to claim 1, characterized in that, The medicament is for one or more uses selected from the group consisting of: 1) for shortening the immobility time of a patient suffering from a depressive and / or anxiety disorder; 2) for reducing the hopelessness level of a patient suffering from a depressive and / or anxiety disorder; 3) for reducing the anxiety level of a patient suffering from a depressive and / or anxiety disorder.

6. The use according to claim 1, characterized in that, The medicament is administered orally (e.g. by gavage).

7. The use according to claim 1, characterized in that, The medicament is administered before the modeling of the depressive and / or anxiety disorder; and / or The medicament is administered after the modeling of the depressive and / or anxiety disorder.

8. The use according to claim 1, characterized in that, The depressive and / or anxiety disorder is a depressive and / or anxiety disorder associated with a peripheral monocyte / macrophage PGK1 pathway.

9. The use according to claim 1, characterized in that, The depressive and / or anxiety disorder is a depressive and / or anxiety disorder with a high expression of PGK1 in the periphery.

10. The use according to claim 1, characterized in that, The medicament does not cross the blood-brain barrier.

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