Compounds for use in the prevention and / or treatment of neurodegenerative diseases

Abstract

The present invention relates to compounds used in the prevention and / or treatment of neurodegenerative diseases. Specifically, the compounds of the present invention have the structure shown in Formula I, wherein the definitions of each group and substituent are as described herein. The present invention further discloses methods for preparing said compounds and their use in the prevention and / or treatment of neurodegenerative diseases. [Formula 1] JPEG2026501688000098.jpg3158

Description

[Technical Field]

[0001] The present invention relates to the field of medicine, and in particular to compounds used in the prevention and / or treatment of neurodegenerative diseases. [Background technology]

[0002] Alzheimer's disease, commonly known as senile dementia, is a common neurodegenerative disease characterized by symptoms such as memory loss and neuronal cell death. The primary clinical manifestations are senile plaques and neurofibrillary tangles. The pathological changes of Alzheimer's disease are highly complex, and countries around the world are currently researching effective treatments for Alzheimer's disease, but progress has been limited. Currently, there are no specific treatments for Alzheimer's disease or treatments that slow the progression of the disease. Over a decade ago, the U.S. FDA approved five therapeutic compounds, including two types of cholinesterase inhibitors and NMDA receptor antagonists. However, these only temporarily improve symptoms and cannot halt the progression of the disease. The main pathogenic mechanisms are the deposition of beta-amyloid protein in brain tissue, activation of microglia and astrocytes in brain tissue due to abnormalities in the cerebral vasculature, production of inflammatory mediators, increased production of free radicals in brain tissue, resulting in a decrease in the body's antioxidant capacity, and an imbalance between the acetylcholine and anti-acetylcholine systems in brain tissue. This leads to structural and functional damage to the brain tissue of patients with senile dementia, an increase in the content of inflammatory mediators in the hippocampus, and a decrease in antioxidant capacity in the hippocampus, ultimately leading to Alzheimer's disease. Pharmaceutical companies have developed various vaccines targeting Aβ protein and phosphorylation inhibitors of various enzymes involved in the protein's formation process, but these efforts have so far been ineffective and have been discontinued. Because it is too late to reduce the toxicity of this protein after the onset of disease in patients, it is thought that therapeutic development should focus on reducing the toxicity of this protein.

[0003] In recent years, the mechanism of action of RAC1 in the nervous system has gradually become a hot topic of research. It has been reported that dysregulation of physiological signals in the RAC1-centered network is associated with the pathological changes of Alzheimer's disease and leads to age-dependent neurodegenerative pathology (Human Molecular Genetics, 2020, Vol. 29, No. 5). Regulating RAC1 and thus improving LTP can enhance brain learning and memory abilities (PNAS, 2007, Vol. 104, No. 2). Therefore, RAC1 has become a promising target for the treatment and prevention of neurodegenerative diseases. Summary of the Invention [Problem to be solved by the invention]

[0004] It is an object of the present invention to provide compounds according to formula I, processes for their preparation and their use in the prevention and / or treatment of neurodegenerative diseases. [Means for solving the problem]

[0005] A first aspect of the present invention provides a compound, the compound being represented by formula I or a stereoisomer, racemate or pharmaceutically acceptable salt thereof: [ka] where: Ring A is [ka] is selected from the group consisting of X1 is selected from the group consisting of O, S, NH, and NR; X2 is selected from the group consisting of O, NH, and NR; R1 is [ka] is selected from the group consisting of R2 is selected from the group consisting of H, halogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 alkoxy group, and a substituted or unsubstituted C3-C6 cycloalkyl group; R3 and R4 are independently selected from the group consisting of H, D, halogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 alkoxy group, and a substituted or unsubstituted C3-C6 cycloalkyl group, or R3 and R4 together with the carbon to which they are attached form a substituted or unsubstituted 3- to 7-membered cycloalkyl group or a substituted or unsubstituted 3- to 7-membered heterocyclic group containing one or more heteroatoms selected from O, S, or N; Each R5, R6, R7, R8, R9, R 10 is H, D, halogen, trifluoromethyl group, cyano group, hydroxy group, amino group, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C1-C6 alkoxy group, substituted or unsubstituted C1-C6 alkyl-NR 16 -, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted C3-C6 cycloalkoxy group, a substituted or unsubstituted C3-C6 cycloalkyl-NR 16 - independently selected from the group consisting of: Each R 11 , R 12 , R 13 , R 14 , R 15 is H, D, halogen, trifluoromethyl group, cyano group, hydroxy group, amino group, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C1-C6 alkoxy group, substituted or unsubstituted C1-C6 alkyl-NR 16 -, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted C3-C6 cycloalkoxy group, a substituted or unsubstituted C3-C6 cycloalkyl-NR 16 - independently selected from the group consisting of: Each R 17 , R 18 are independently selected from the group consisting of H, D, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group, and a C3-C6 cycloalkoxy group, or R 17 , R 18together with the carbons to which they are attached form a substituted or unsubstituted 3- to 7-membered cycloalkyl group or a substituted or unsubstituted 3- to 7-membered heterocyclic group containing one or more heteroatoms selected from O, S or N; each R is independently a substituted or unsubstituted C1-C6 alkyl group; The substitutions each independently represent D, halogen, a trifluoromethyl group, a cyano group, a hydroxy group, an amino group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 alkyl-NR 16 -, C3-C6 cycloalkyl group, C3-C6 cycloalkoxy group, C3-C6 cycloalkyl-NR 16 -, ... Each R 16 are independently selected from the group consisting of H, C1-C6 alkyl groups; The additional condition is that when X2 is NH and X2 is O, R3, R4, R 17 and R 18 is H, then ring A is [ka] isn't it.

[0006] In another preferred embodiment, the compound has the structure shown in Formula II: [ka] wherein ring A, X2, X2, R1, R2, R3, and R4 are as defined above.

[0007] In another preferred embodiment, the compound has the structure shown in Formula II: [ka] wherein ring A, X2, R1, R2, R3, and R4 are as defined above.

[0008] In another preferred embodiment, ring A is [ka] is selected from the group consisting of R5, R6, R7, R8, and R9 are as defined above.

[0009] In another preferred example, X1 is selected from the group consisting of O, S, NH, and NR; R is as defined above. In another preferred example, X2 is selected from the group consisting of O, NH, and NR; R is as defined above.

[0010] In another preferred embodiment, R1 is [ka] is selected from the group consisting of Each R 11 , R 12 , R 13 , R 14 , R 15 , R 17 , R 18 is as defined above.

[0011] In another preferred example, R2 is selected from the group consisting of H, halogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 alkoxy group, and a substituted or unsubstituted C3-C6 cycloalkyl group; The substitutions each independently represent D, halogen, a trifluoromethyl group, a cyano group, a hydroxy group, an amino group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 alkyl-NR 16 -, C3-C6 cycloalkyl group, C3-C6 cycloalkoxy group, C3-C6 cycloalkyl-NR 16 -, ... Each R 16 are independently selected from the group consisting of H, C1-C6 alkyl groups.

[0012] In another preferred example, R3 and R4 are independently selected from the group consisting of H, D, halogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 alkoxy group, and a substituted or unsubstituted C3-C6 cycloalkyl group; or R3 and R4 together with the carbon to which they are attached form a substituted or unsubstituted 3- to 7-membered cycloalkyl group or a substituted or unsubstituted 3- to 7-membered heterocyclic group containing one or more heteroatoms selected from O, S, or N.

[0013] In another preferred embodiment, each of R5, R6, R7, R8, R9, R 10 is H, D, halogen, trifluoromethyl group, cyano group, hydroxy group, amino group, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C1-C6 alkoxy group, substituted or unsubstituted C1-C6 alkyl-NR 16 -, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted C3-C6 cycloalkoxy group, a substituted or unsubstituted C3-C6 cycloalkyl-NR 16 - independently selected from the group consisting of: Each R 16 are independently selected from the group consisting of H, C1-C6 alkyl groups.

[0014] In another preferred embodiment, each of R5, R6, R7, R8, R9, R 10 is H, D, halogen, cyano group, hydroxy group, amino group, unsubstituted C1-C6 alkyl group, substituted or unsubstituted C1-C6 alkoxy group, substituted or unsubstituted C1-C6 alkyl-NR 16 -, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted C3-C6 cycloalkoxy group, a substituted or unsubstituted C3-C6 cycloalkyl-NR 16 - independently selected from the group consisting of: Each R 16 are independently selected from the group consisting of H, C1-C6 alkyl groups.

[0015] In another preferred embodiment, each R 11 , R 12, R 13 , R 14 , R 15 is H, D, halogen, trifluoromethyl group, cyano group, hydroxy group, amino group, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C1-C6 alkoxy group, substituted or unsubstituted C1-C6 alkyl-NR 16 -, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted C3-C6 cycloalkoxy group, a substituted or unsubstituted C3-C6 cycloalkyl-NR 16 - independently selected from the group consisting of: Each R 16 are independently selected from the group consisting of H, C1-C6 alkyl groups.

[0016] In another preferred embodiment, each R 17 , R 18 are independently selected from the group consisting of H, D, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group, and a C3-C6 cycloalkoxy group, or R 17 , R 18 together with the carbons to which they are attached form a substituted or unsubstituted 3- to 7-membered cycloalkyl group or a substituted or unsubstituted 3- to 7-membered heterocyclic group containing one or more heteroatoms selected from O, S, or N.

[0017] In another preferred embodiment, R 17 is selected from the group consisting of H and D. In another preferred embodiment, R 18 is a C1-C6 alkyl group.

[0018] In another preferred embodiment, ring A is [ka] If R3, R4, R 17 and R 18 is not H at the same time.

[0019] In another preferred embodiment, ring A is [ka] If R5, R6, R7, R8, R9 are as defined above; R3, R4 are independently selected from the group consisting of H, C1-C6 alkyl groups; R 17 , R 18 are independently selected from the group consisting of H, D, and C1-C6 alkyl groups; Also, R3, R4, R 17 and R 18 is not H at the same time.

[0020] In another preferred embodiment, ring A is [ka] If R5, R6, R7, R8, R9 are as defined above; R3 and R4 are H; R 17 , R 18 are independently selected from the group consisting of H, D, and C1-C6 alkyl groups; Also, R 17 and R 18 is not H at the same time.

[0021] In another preferred embodiment, ring A is [ka] If R5, R6, R7, R8, R9 are as defined above; R3 is H, R4 is a C1-C6 alkyl group; R 17 , R 18 is H.

[0022] In another preferred embodiment, ring A is [ka] When selected from the group consisting of R5, R6, R7, R8, R9, R 10 is as defined above, R3 and R4 are independently selected from the group consisting of H, D, halogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 alkoxy group, and a substituted or unsubstituted C3-C6 cycloalkyl group, or R3 and R4 together with the carbon to which they are attached form a substituted or unsubstituted 3- to 7-membered cycloalkyl group or a substituted or unsubstituted 3- to 7-membered heterocyclic group containing one or more heteroatoms selected from O, S, or N; Each R 17 , R 18 are independently selected from the group consisting of H, D, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group, and a C3-C6 cycloalkoxy group, or R 17 , R 18 together with the carbons to which they are attached form a substituted or unsubstituted 3- to 7-membered cycloalkyl group or a substituted or unsubstituted 3- to 7-membered heterocyclic group containing one or more heteroatoms selected from O, S or N; The substitutions each independently represent D, halogen, a trifluoromethyl group, a cyano group, a hydroxy group, an amino group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 alkyl-NR 16 -, C3-C6 cycloalkyl group, C3-C6 cycloalkoxy group, C3-C6 cycloalkyl-NR 16 -, ... Each R 16 are independently selected from the group consisting of H, C1-C6 alkyl groups.

[0023] In another preferred embodiment, ring A is [ka] If R5, R6, R7, R8 are as defined above; R3, R4 are independently selected from the group consisting of H, D, halogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 alkoxy group, and a substituted or unsubstituted C3-C6 cycloalkyl group; Each R 17 , R 18 are independently selected from the group consisting of H, D, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group, and a C3-C6 cycloalkoxy group; The substitutions each independently represent D, halogen, a trifluoromethyl group, a cyano group, a hydroxy group, an amino group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 alkyl-NR 16 -, C3-C6 cycloalkyl group, C3-C6 cycloalkoxy group, C3-C6 cycloalkyl-NR 16 -, ... Each R 16 are independently selected from the group consisting of H, C1-C6 alkyl groups.

[0024] In another preferred embodiment, ring A is [ka] If R5, R6, R7, R8 are as defined above; R3 and R4 are independently selected from the group consisting of H, D, halogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, and a C3-C6 cycloalkyl group; Each R 17 , R 18 are independently selected from the group consisting of H, D, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group, and a C3-C6 cycloalkoxy group.

[0025] In another preferred embodiment, ring A is [ka] and X1 is selected from the group consisting of NH and NR; X2 is O, R1 is [ka] and R2 is H, R3, R4 are selected from the group consisting of H, C1-C6 alkyl groups; Each of R5, R6, R7, R8, and R9 is H; Each R 11 , R 12 , R 13 , R 14 , R 15 are independently selected from the group consisting of H, halogen; Each R 17 , R 18 are independently selected from the group consisting of H, D, and C1-C6 alkyl groups; Each R is independently an unsubstituted C1-C6 alkyl group.

[0026] In another preferred embodiment, ring A is [ka] and X1 is NH; X2 is O, R1 is [ka] and R2 is H, R3, R4 are selected from the group consisting of H, C1-C6 alkyl groups; Each of R5, R6, R7, R8, and R9 is H; Each R 11 , R 12 , R 14 , R 15 is H, R 13 is a halogen, preferably F, R 17 is selected from the group consisting of H, D, R 18 is selected from the group consisting of H, D, and a C1-C6 alkyl group.

[0027] In another preferred embodiment, ring A is [ka] and X1 is selected from the group consisting of NH and NR; X2 is O, R1 is [ka] and R2 is H, R3 and R4 are H; each R5, R6, R7, R8 is independently selected from the group consisting of H, halogen; Each R 11 , R 12 , R 13 , R 14 , R 15 are independently selected from the group consisting of H, halogen; Each R 17 , R 18 are independently selected from the group consisting of H, C1-C6 alkyl groups; Each R is independently an unsubstituted C1-C6 alkyl group.

[0028] In another preferred embodiment, ring A is [ka] and X1 is NH; X2 is O, R1 is [ka] and R2 is H, R3 and R4 are H; R5 is selected from the group consisting of H, halogen; Each of R6, R7, and R8 is H; Each R 11 , R 12 , R 14 , R 15 is H, R 13 is a halogen, preferably F, R 17 is H, R 18 is selected from the group consisting of H, C1-C6 alkyl groups.

[0029] In another preferred example, R2 is selected from the group consisting of H, halogen, a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a C1-C6 alkoxy group, and a C3-C6 cycloalkyl group; R3 and R4 are independently selected from the group consisting of H, D, halogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, and a C3-C6 cycloalkyl group.

[0030] In another preferred embodiment, ring A is [ka] and R1 is [ka] and Each R5, R6, R7, R8, and R9 is independently selected from the group consisting of H, halogen, trifluoromethyl, cyano, hydroxy, amino, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C6 cycloalkoxy; Each R 11 , R 12 , R 13 , R 14 , R 15 are independently selected from the group consisting of H, halogen, trifluoromethyl, cyano, hydroxy, amino, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C6 cycloalkoxy.

[0031] In another preferred embodiment, the compound is selected from the group consisting of: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0032] In another preferred embodiment, the pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt, the inorganic acid salt is selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, and acid phosphate; The organic acid salt is selected from the group consisting of formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, salicylate, picrate, glutamate, ascorbate, camphorate, and camphorsulfonate.

[0033] A second aspect of the present invention provides a pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a safe and effective amount of one or more compounds according to the first aspect of the present invention.

[0034] A third aspect of the invention provides the use of a compound according to the first aspect of the invention for the preparation of a medicament, said medicament being for use in the prevention and / or treatment of a neurodegenerative disease.

[0035] In another preferred embodiment, the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, epilepsy, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and spinocerebellar ataxia.

[0036] A fourth aspect of the present invention provides the use of a compound according to the first aspect of the present invention for the preparation of a medicament, said medicament being used in the prevention and / or treatment of a RAC1-associated disease. In another preferred embodiment, the RAC1-associated disease is a neurodegenerative disease. [Effects of the Invention]

[0037] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (e.g., in the Examples) can be combined with each other to form new or preferred technical solutions, which will not be repeated here due to space limitations. DETAILED DESCRIPTION OF THE INVENTION

[0038] As a result of long and thorough research, the present inventors have unexpectedly prepared a compound that has excellent pharmacokinetic properties and can effectively prevent and / or treat neurodegenerative diseases, and based on this, the present inventors have completed the present invention.

[0039] term In the present invention, unless otherwise specified, the terms used have their ordinary meanings known to those skilled in the art. In the present invention, the term "halogen" refers to F, Cl, Br or I.

[0040] In the present invention, the term "C1-C6 alkyl group" refers to a straight or branched chain alkyl group containing from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, neopentyl, t-pentyl, or the like.

[0041] In the present invention, the term "C2-C6 alkenyl group" refers to a straight or branched alkenyl group containing one double bond and having 2 to 6 carbon atoms, including, but not limited to, vinyl, propenyl, butenyl, isobutenyl, pentenyl, and hexenyl groups.

[0042] In the present invention, the term "C2-C6 alkynyl group" refers to a straight or branched alkynyl group containing one triple bond and having 2 to 6 carbon atoms, including, but not limited to, ethynyl, propynyl, butynyl, isobutynyl, pentynyl, and hexynyl groups.

[0043] As used herein, the term "C3-C8 cycloalkyl group" refers to a cyclic alkyl group having from 3 to 8 carbon atoms on the ring, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. The term "C3-C6 cycloalkyl group" has an analogous meaning.

[0044] In the present invention, the term "C1-C6 alkoxy group" refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, including, but not limited to, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, and a butoxy group, etc. A C1-C4 alkoxy group is preferred.

[0045] In the present invention, the term "heterocyclic group" means [ka] and 4-8 membered heterocyclic groups containing 1, 2 or 3 heteroatoms selected from N, O and S, including but not limited to:

[0046] In the present invention, the terms "aromatic ring" and "aryl group" have the same meaning, and are preferably "C6-C10 aryl group." The term "C6-C10 aryl group" refers to an aromatic ring group having 6 to 10 carbon atoms and no heteroatoms in the ring, such as a phenyl group or a naphthyl group.

[0047] As used herein, the terms "aromatic heterocyclic" and "heteroaryl" have the same meaning and refer to a heteroaromatic group containing one to multiple heteroatoms. For example, a "C3-C10 heteroaryl" refers to an aromatic heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen and 3 to 10 carbon atoms. Non-limiting examples include furanyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring can be fused to an aryl ring, a heterocyclic ring, or a cycloalkyl ring, where the ring connected to the parent structure is the heteroaryl ring. The heteroaryl group can be optionally substituted or unsubstituted.

[0048] In the present invention, the term "halogenated" refers to substitution with halogen.

[0049] In the present invention, the term "substituted" refers to one or more hydrogen atoms of a specific group being replaced with a specific substituent. The specific substituent is the substituent described above or appears in each example. Unless otherwise specified, a specific substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituent may be the same or different at each position. Those skilled in the art will understand that the combination of substituents contemplated by the present invention is a stable or chemically achievable combination. The substituents include, but are not limited to, halogen, hydroxy, carboxy (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclic, aryl, heteroaryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amino, C1-C6 alkoxy, and C1-C10 sulfonyl.

[0050] In the present invention, the term 1 to 6 refers to 1, 2, 3, 4, 5 or 6. Other similar terms each independently have the same meaning. The term "plurality" refers to 2 to 6, for example 2, 3, 4, 5 or 6.

[0051] It is understood that when a group is simultaneously present at several different positions on a compound, its definition at each position is independent of each other and may be the same or different, i.e., the term "selected from the group consisting of:" has the same meaning as the term "each independently selected from the group consisting of:".

[0052] compound The present invention provides a compound, the compound being represented by formula I or a stereoisomer, racemate, or pharmaceutically acceptable salt thereof: [ka] wherein each group is as defined above.

[0053] In another preferred example, in the compound, any one of ring A, X2, X2, R1, R2, R3, and R4 is each independently a corresponding group in the specific compound described in the present invention.

[0054] As used herein, the term "pharmaceutically acceptable salt" refers to a medicament-compatible salt formed between the compound of the present invention and an acid or base. Pharmaceutically acceptable salts include inorganic salts and organic salts. Preferred salts are salts formed between the compound of the present invention and an acid. Acids suitable for salt formation include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid.

[0055] Other preferred salts are salts formed between the compounds of the present invention and bases, such as alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., magnesium or calcium salts), ammonium salts (e.g., lower alkanolammonium salts and other pharmaceutically acceptable amine salts), such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, t-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperazine, and lysine.

[0056] Preparation method The following schemes and examples describe methods for preparing compounds of Formula I. Raw materials and intermediates are purchased from commercial sources, prepared by known procedures, or otherwise described. In certain cases, the order of carrying out the steps of the reaction schemes can be changed to facilitate the reaction or avoid unwanted side reaction products.

[0057] The preparation method of the compound of formula I of the present invention will be described in more detail below, but these specific methods do not limit the scope of the present invention. The compound of the present invention can also be easily prepared by combining various synthetic methods described herein or known in the art, and such combinations can be easily carried out by those skilled in the art.

[0058] In general, in the preparation process, each reaction is carried out in a suitable solvent under inert gas protection at 0 to 150°C, and the reaction time is generally 2 to 24 hours.

[0059] A preferred preparation method is as follows. Method 1: [ka] Step 1: SM1 is reacted with Meldrum's acid in a solvent (dichloromethane) under basic conditions (4-dimethylaminopyridine, diisopropylethylamine) using a condensing agent (DCC, EDCI, etc.) to produce compound M1. Second step: Compound M1 is reacted under reflux conditions in an ultra-dry solvent (ethyl acetate, 1,4-dioxane, etc.) to produce compound M2. Step 3: Compound M2 is reacted with SM2 in a solvent (acetonitrile, toluene, N,N-dimethylformamide, etc.) under basic conditions (eg, diisopropylethylamine, potassium carbonate, DBU, etc.) to produce compound M3. Step 4: Compound M3 is reacted in a solvent (ethyl acetate, dichloromethane, 1,4-dioxane, etc.) under acidic conditions (hydrochloric acid, trifluoroacetic acid, etc.) to produce T (ie, the compound of formula I).

[0060] Method 2: [ka] Step 1: Compound M3 is reacted with N-bromosuccinimide (NBS) in a solvent (dichloromethane, carbon tetrachloride, etc.) to produce compound M4. Step 2: Compound M4 is reacted with SM3 or SM3' in an inert solvent (e.g., N,N-dimethylformamide, dioxane, dimethyl sulfoxide, etc.) under basic conditions (e.g., potassium carbonate, potassium phosphate, etc.) in the presence of a catalyst and a ligand (e.g., Pd(PPh3)4) to produce M5. Step 3: Compound M5 is reacted in a solvent (ethyl acetate, dichloromethane, 1,4-dioxane, etc.) under acidic conditions (hydrochloric acid, trifluoroacetic acid, etc.) to produce T (ie, the compound of formula I).

[0061] Method 3: [ka] Step 1: Compound SM4 is reacted with SM2 in a solvent (acetonitrile, toluene, N,N-dimethylformamide, etc.) under basic conditions (eg, diisopropylethylamine, potassium carbonate, DBU, etc.) to produce compound M6. Step 2: Compound M6 is reacted with (triphenylphosphoranylidene)ketene under acidic (benzoic acid) conditions in the solvent tetrahydrofuran to produce T (ie, the compound of formula I).

[0062] Method 4: [ka] Step 1: SM1 is reacted with Meldrum's acid in a solvent (dichloromethane) under basic conditions (4-dimethylaminopyridine, diisopropylethylamine) using a condensing agent (DCC, EDCI, etc.) to produce compound M1. Second step: Compound M1 is reacted under reflux conditions in an ultra-dry solvent (ethyl acetate, 1,4-dioxane, etc.) to produce compound M2. Step 3: Compound M2 is reacted with SM5 in a solvent (toluene) under acidic (p-toluenesulfonic acid) conditions to produce compound M7. Step 4: Compound M7 is reacted in a solvent (ethyl acetate, dichloromethane, 1,4-dioxane, etc.) under acidic conditions (hydrochloric acid, trifluoroacetic acid, etc.) to produce T (ie, the compound of formula I).

[0063] In the above formulas, R1, R2, R3, and R4 are as defined above. Unless otherwise stated, the above starting materials can be purchased from commercial sources or synthesized according to reported literature.

[0064] Pharmaceutical compositions and methods of administration The pharmaceutical composition of the present invention contains a compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier within a safe and effective amount. Here, "safe and effective amount" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1 to 2000 mg of the compound / agent of the present invention, more preferably 10 to 1000 mg of the compound / agent of the present invention. Preferably, the "single agent" is one capsule or tablet.

[0065] A "pharmaceutically acceptable vector" refers to one or more compatible solid or liquid fillers or gel substances that must be of sufficient purity and sufficiently low toxicity to be suitable for human use. "Compatibility" refers to the ability of the components of the composition to be blended with each other without significantly reducing the efficacy of the compounds of the present invention. Some examples of pharmaceutically acceptable vectors include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., Tween®), wetting agents (e.g., sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0066] The pharmaceutical composition is in the form of an injection, capsule, tablet, pill, powder or granule. The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0067] 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 vector), such as sodium citrate or dicalcium phosphate, or with (a) a filler or solubilizer, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) a binder, such as hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) a humectant, such as glycerin; (d) agar, calcium carbonate, potato starch, or the like. It is mixed with ingredients such as disintegrating agents such as potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (e) retarders such as paraffin, (f) absorption accelerators such as quaternary amine 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, and sodium dodecyl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also contain a buffering agent.

[0068] Solid dosage forms such as tablets, sugar pills, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They can contain opacifying agents, and the release of the active compound or compounds of such compositions can be delayed in a specific part of the digestive tract. Examples of embedding materials that can be used include polymeric substances and waxes. If necessary, the active compound can be formed into microcapsules with one or more of the above-mentioned excipients.

[0069] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, the liquid dosage form can contain an inert diluent conventionally used in the art, such as water or other solvents, and solubilizers and emulsifiers, such as 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.

[0070] Besides these inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and perfuming agents. In addition to the active compound, suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and dehydrated sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar-agar, or mixtures of these substances.

[0071] Compositions for parenteral injection can include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous vehicles, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0072] Dosage forms of the compounds of the present invention used for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable vector and any preservatives, buffers, or propellants that may be required.

[0073] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (eg, neurodegenerative disease medications). The therapeutic methods of the present invention can be used alone or in combination with other therapeutic procedures or therapeutic agents.

[0074] When a pharmaceutical composition is used, a safe and prevalent amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, and the dosage at the time of administration is the considered effective dose. For a person weighing 60 kg, the daily dose is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage must also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0075] Compared with the prior art, the present invention has the following major advantages: (1) The compounds of the present invention have better pharmacokinetic properties. (2) The compounds of the present invention have superior efficacy.

[0076] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are used only to illustrate the present invention and do not limit the scope of the present invention. In the following examples, experimental methods without specific conditions are generally in accordance with conventional conditions, such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or conditions suggested by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight.

[0077] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can all be applied to the methods of the present invention. The preferred implementation methods and materials described herein are used for demonstration purposes only.

[0078] Example 1 Compounds synthesized according to the present invention: [ka] The experimental procedure is as follows. The synthetic route is as follows: [ka]

[0079] 1. Synthesis of Compound 2 Compound SM1 (5 g, 1.0 eq), hippuric acid (2.98 g, 1.1 eq), DMAP (3.4 g, 1.5 eq), and DCM (100 mL) were mixed in a 100 mL three-neck flask and purged with nitrogen gas three times. The mixture was then stirred under nitrogen gas protection in an ice bath for 10 minutes. The internal temperature was controlled between 0 and 10 °C, and 20 mL of a DCM solution of DCC (4.2 g, 1.1 eq) was added dropwise. The mixture was then incubated at room temperature for 16 hours. The reaction completion was monitored by TLC. The reaction mixture was filtered, and the filtrate was washed six times with 50 mL of 5% aqueous potassium hydrogen sulfate. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give a white solid. 50 mL of petroleum ether was added, stirred thoroughly, and filtered to give the desired product (3.2 g, 43.4% yield) as a brown solid. This product could be used in the next step without further purification. LC-MS[M-1]: 391.1.

[0080] 2. Synthesis of Compound 3 Compound 2 (3.2 g, 1.0 eq) was added to a 100 ml three-neck flask, and the mixture was purged with nitrogen gas three times. Then, under nitrogen gas protection, ultra-dry 1,4-dioxane (45 ml) was added and the mixture was reacted at 100 °C for 2 hours. The reaction completion of the raw materials was detected by TLC. The reaction mixture was concentrated under reduced pressure to obtain 2.6 g of compound 3, which could be used in the next step without further purification. LC-MS [M-1]: 289.1.

[0081] 3. Synthesis of Compound 4 Compound 3 (1.0 g, 1.0 eq), 4-fluorobenzyl bromide (520 μl, 1.2 eq), potassium carbonate (714 mg, 1.5 eq), and acetonitrile (15 ml) were mixed homogeneously in a 100 ml three-neck flask and refluxed for 2 hours. The completion of the reaction of the raw materials was detected by TLC. The solid was removed by suction filtration, and the filtrate was separated and purified by column chromatography to obtain 120 mg of compound 4. LC-MS [M+1]: 399.1.

[0082] 4. Synthesis of Compound T-01 Compound 4 (120 mg, 1.0 eq) and DCM (2.5 ml) were added to a 100 ml round-bottom flask and stirred to dissolve. Trifluoroacetic acid (120 μl, 5.0 eq) was added dropwise and the mixture was allowed to react at room temperature for 4 hours. The reaction completion of the raw materials was monitored by TLC. The reaction mixture was adjusted to pH 7-8 with saturated Na2CO3, extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the mixture was separated and purified using a preparative plate to obtain 60 mg of compound T-01. HPLC purity: 99.7%. LC-MS [M+1]: 299.1. 1 H NMR(400MHz,Chloroform-d)δ 8.52(dt,J=4.9,1.5Hz,1H),7.61(td,J=7.7,1.9Hz,1H),7.42-7.35(m,2H),7.21-7.07(m,4H),6.23(s,1H),5.13(d,J=1 .7Hz,1H),5.06-4.91(m,2H),4.56(dd,J=10.5,3.1Hz,1H),3.38(dd,J=14.9,3.1Hz,1H),2.83(dd,J=14.8,10.4Hz,1H).

[0083] The following compounds are synthesized according to the method for compound T-01. [Table A-1] [Table A-2] [Table A-3] [Table A-4] [Table A-5] [Table A-6] [Table A-7]

[0084] Example 2 Compounds synthesized according to the present invention: [ka] The experimental procedure is as follows. The synthetic route is as follows: [ka]

[0085] 2. Synthesis of Compound 2 Compound SM1 (1 g, 1.0 eq), 4-fluorobenzyl bromide (1.14 g, 1.0 eq), DBU (1.2 g, 1.3 eq), and acetonitrile (15 ml) were added to a 100 ml three-neck flask and mixed until uniform. The mixture was purged with nitrogen gas three times, and then reacted at room temperature under nitrogen gas protection. The reaction completion of the raw materials was monitored by TLC. The solvent was removed under reduced pressure, and EA and water were added. Two-phase extraction was performed. The EA layer was washed with saturated NaCl solution, dried with anhydrous sodium sulfate, and the EA was removed by evaporation on a rotary evaporator to obtain 1.2 g of product. 1 H NMR(400MHz,DMSO)δ 7.34(dd,J=8.6,5.7Hz,2H),7.28-7.13(m,7H),5.07(s,2H),4.29(dt,J=7 .7,5.7Hz,1H),2.96(dd,J=13.7,5.3Hz,1H),2.85(dd,J=13.7,7.8Hz,1H).

[0086] 2. Synthesis of Compound T-29 Compound 2 (300 mg, 1.0 eq), (triphenylphosphoranylidene)ketene (378 mg, 1.1 eq), benzoic acid (12.5 mg, 0.1 eq), and THF (9 ml) were added to a 100 ml three-neck flask and mixed thoroughly. After purging with nitrogen gas three times, the mixture was reacted at room temperature under nitrogen gas protection. The reaction completion of the raw materials was monitored by TLC. Water and EA were added, followed by two-phase extraction. The EA layer was washed with saturated NaCl solution, dried with anhydrous sodium sulfate, and the EA was removed by rotary evaporation to obtain 700 mg of product. After purification, 87 mg of product was obtained, with an HPLC purity of 97.7%.

[0087] 1 H NMR(400MHz,DMSO)δ 7.69-7.55(m,2H),7.45-7.26(m,5H),7.21(dd,J=12.6,6.2Hz,2H),5.44(s,1H),5.31(dd,J=5.7,4. 4Hz,1H), 5.17(dd,J=33.8,11.7Hz,2H),3.24(dd,J=14.5,4.1Hz,1H),2.93(dd,J=14.5,6.4Hz,1H).

[0088] Example 3 Compounds synthesized according to the present invention: [ka] The experimental procedure is as follows.

[0089] 2. Synthesis of intermediate SM2 The synthetic route is as follows: [ka]

[0090] 2. Synthesis of Compound 2 Compound 1 (1 g, 1.0 eq) was placed in a 100 ml three-neck flask and purged with nitrogen gas three times. Under nitrogen gas protection, ultra-dry THF (30 ml) was added and dissolved. The mixture was stirred in an ice bath, the internal temperature controlled at 0-10°C, and lithium aluminum deuteride (476 mg, 2.0 eq) was added in several portions. The mixture was then left to react overnight at room temperature. The reaction was monitored by TLC, and the reaction was quenched by adding saturated ammonium chloride solution in an ice bath. The mixture was then filtered through diatomaceous earth, dried over anhydrous sodium sulfate, and spin-dried to obtain 780 mg of a colorless liquid. 1 H NMR (400MHz, Chloroform-d) δ 7.38-7.30 (m, 2H), 7.09-7.00 (m, 2H).

[0091] 2. Synthesis of Compound SM2 Compound 2 (780 mg, 1.0 eq) and dichloromethane (25 ml) were added to a 100 ml three-neck flask, and the mixture was purged with nitrogen gas three times. Under nitrogen gas protection, the mixture was stirred in an ice bath, and phosphorus tribromide (638 μl, 1.1 eq) was added dropwise. The mixture was allowed to react at room temperature for 3 hours, and the completion of the reaction of the raw materials was monitored by TLC. Water was added to quench the reaction, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain 800 mg of compound SM2. 1 H NMR (400MHz, Chloroform-d) δ 7.43-7.32 (m, 2H), 7.09-6.97 (m, 2H).

[0092] 2. Synthesis of Compound T-45 The synthetic route is as follows: [ka]

[0093] Referring to Example 1, compound T-45 is obtained. 1H NMR(400MHz,Chloroform-d)δ 7.43-7.35(m,2H),7.34-7.26(m,3H),7.22-7.16(m,2H),7.15-7.07(m,2H),5.45-5.32(m,1H),5.07(d ,J=1.6Hz,1H),4.26(dd,J=9.6,3.6Hz,1H),3.23(dd,J=13.6,3.6Hz,1H),2.63(dd,J=13.6,9.6Hz,1H).

[0094] The following compounds are synthesized according to the method for compound T-45. [Table B]

[0095] Example 4 Compounds synthesized according to the present invention: [ka]

[0096] The experimental procedure is as follows. 1. Synthesis of intermediate SM1 The synthetic route is as follows: [ka]

[0097] 1. Synthesis of Compound 3 THF (50 ml) was placed in a 250 ml three-neck flask and purged with nitrogen gas three times. Under nitrogen gas protection, the mixture was cooled to -10 °C in an ice-salt bath. A mixture of TiCl (4.64 ml, 1.5 eq) and DCM (1 ml) was slowly added dropwise. After the addition was complete, the mixture was stirred in the ice-salt bath for 20 minutes. Compound 1 (3.3 ml, 1.0 eq) was added and stirred in the ice-salt bath for 10 minutes. Compound 2 (5 g, 1.1 eq) was added and stirred in the ice-salt bath for 30 minutes. Pyridine (4.5 ml, 2.0 eq) was added, and the mixture was then warmed to room temperature and allowed to react overnight. The completion of the reaction was monitored by TLC. The mixture was quenched in an ice bath with saturated NH4Cl4 solution, extracted five times with EA, and the EA phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain 5.5 g of compound 3. LC-MS [M+1]: 265.1.

[0098] 2. Synthesis of Compound 4 Compound 3 (5.5 g, 1.0 eq) and MeOH (55 ml) were added to a 250 ml round-bottom flask, and the mixture was purged with nitrogen gas three times. Under nitrogen gas protection, sodium methoxide (227 mg, 0.2 eq) was added and the mixture was allowed to react at 70 °C overnight. The completion of the reaction of the raw materials was detected by TLC. After stopping heating and cooling to room temperature, the solvent was spin-dried, and the mixture was separated and purified by column chromatography to obtain 4.6 g of compound 4. LC-MS [M+1]: 297.1.

[0099] 3. Synthesis of Compound 5 Compound 4 (4.6 g, 1.0 eq) and MeOH (46 ml) were added to a 100 ml reaction vessel, and Pd / C (460 mg, 0.1 eq) was added. After purging with hydrogen gas three times, the mixture was reacted at 70 °C for 5.5 hours under hydrogen gas protection. Heating was stopped, the mixture was cooled to room temperature, and the reaction completion of the raw materials was confirmed by TLC. Diatomaceous earth was added, and the filtrate was suction filtered and spin-dried to obtain 5.19 g of compound 5. LC-MS [M+1]: 299.1.

[0100] 4. Synthesis of Compound 6 Compound 5 (4.19 g, 1.0 eq), HCl (3M) (104 ml, 25.0 eq), and glacial acetic acid (42 ml, 50.0 eq) were added to a 250 ml round-bottom flask, and the mixture was purged with nitrogen gas three times. The mixture was then reacted overnight at 125 °C under nitrogen gas protection. The reaction completion of the raw materials was monitored by TLC. After stopping heating and cooling to room temperature, water was added, and the mixture was suction filtered. The filtrate was then spin-dried to give 4.69 g of compound 6. LC-MS [M+1]: 181.1.

[0101] 5. Synthesis of Compound SM1 Compound 6 (4.69 g, 1.0 eq), THF (47 ml), and HO (47 ml) were added to a 250 ml round-bottom flask. The mixture was purged with nitrogen gas three times and then stirred in an ice bath under nitrogen gas protection for 10 minutes. NaOH (4.2 g, 4.0 eq) was added, followed by stirring in an ice bath for 5 minutes. Boc anhydride (6.68 ml, 1.1 eq) was added, and the mixture was warmed to room temperature and allowed to react overnight. The completion of the reaction was monitored by TLC. After evaporating the THF solvent, an appropriate amount of DCM was added and the pH was adjusted to 4-5 with 1N HCl. After stirring thoroughly for 10 minutes, the mixture was separated. The DCM phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain 2 g of compound SM1. LC-MS [M+1]: 281.1.

[0102] 2. Synthesis of compounds T-73 and T-74 The synthetic route is as follows: [ka] Compound 5 is obtained by referring to Example 1, and is separated into compounds T-73 and T-74. LC-MS [M+1]: 313.1.

[0103] The following compounds are synthesized by referring to the methods for compounds T-73 and T-74. [Table C-1] [Table C-2] [Table C-3] [Table C-4] [Table C-5] [Table C-6] [Table C-7]

[0104] Example 5 Compounds synthesized according to the present invention: [ka]

[0105] The experimental procedure is as follows. The synthetic route is as follows: [ka]

[0106] 1. Synthesis of Compound 2 Compound SM1 (10 g, 1.0 eq), Meldrum's acid (5.97 g, 1.1 eq), DMAP (6.9 g, 1.5 eq), and DCM (100 mL) were mixed in a 250 mL three-neck flask and purged with nitrogen gas three times. The mixture was then stirred under nitrogen gas protection in an ice bath for 10 minutes. The internal temperature was controlled between 0 and 10 °C, and 50 mL of a DCM solution of DCC (8.55 g, 1.1 eq) was added dropwise. The mixture was then incubated at room temperature for 16 hours. The reaction completion was monitored by TLC. The reaction mixture was filtered, and the filtrate was washed six times with 50 mL of 5% aqueous potassium hydrogen sulfate. The organic phase was dried over anhydrous sodium sulfate. The solvent was then evaporated under reduced pressure to give a white solid. 50 mL of petroleum ether was added, stirred thoroughly, and filtered to give 14.3 g of the desired product as a pale yellow solid. This product could be used in the next step without further purification. LC-MS[M-1]: 390.1.

[0107] 2. Synthesis of Compound 3 Compound 2 (14.3 g, 1.0 eq) was added to a 100 ml three-neck flask, and the mixture was purged with nitrogen gas three times. Then, under nitrogen gas protection, ultra-dry 1,4-dioxane (172 ml) was added and the mixture was reacted at 100 °C for 2 hours. The reaction completion of the raw materials was detected by TLC. The reaction mixture was concentrated under reduced pressure to obtain 11.2 g of compound 3, which could be used in the next step without further purification. LC-MS [M-1]: 288.1.

[0108] 3. Synthesis of Compound 4 Compound 3 (2.0 g, 1.0 eq), toluene (20 ml), p-fluorobenzylamine (790 μl, 1.0 eq), and p-toluenesulfonic acid (catalytic amount) were added to a 100 ml three-neck flask and mixed until uniform. After purging with nitrogen gas three times, the mixture was reacted at 100°C for 5 hours under nitrogen gas protection. The completion of the reaction of the raw materials was confirmed by TLC. Water and ethyl acetate were added, followed by extraction. The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain 965 mg of compound 4. LC-MS [M+1]: 397.1. 1H NMR(400MHz,Chloroform-d)δ 7.24(td,J=6.7,6.3,3.3Hz,3H),7.19-7.15(m,2H),7.10(dd,J=8.5,5.4Hz,2H),7.04-6.97(m,2H),4.67(dd,J=8.7,3.3Hz,1H) ,4.63(s,1H),4.45(s,1H),4.06(dd,J=5.3,1.7Hz,2H),3.52(dd,J=13.7,3.3Hz,1H),2.93(dd,J=13.7,8.7Hz,1H),1.59(s,9H).

[0109] 4. Synthesis of Compound T-81 Compound 4 (100 mg, 1.0 eq) and DCM (2.0 ml) were added to a 100 ml three-neck flask and stirred to dissolve. Trifluoroacetic acid (193 μl, 10.0 eq) was added dropwise in an ice bath and the mixture was allowed to react at room temperature for 3 hours. The completion of the reaction of the raw materials was detected by TLC. Saturated sodium bicarbonate solution and ethyl acetate were added, followed by extraction. The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified to obtain 30 mg of compound T-81. HPLC purity: 97.1%. LC-MS [M+1]: 297.1. 1 H NMR(400MHz,Chloroform-d)δ 7.30(dd,J=7.8,6.1Hz,2H),7.25(s,1H),7.23-7.17(m,4H),7.02(t,J=8.6Hz,2H),5.28(s,1H),4.67(d,J =1.5Hz,1H),4.61(t,J=5.4Hz,1H),4.23(dd,J=8.6,5.6Hz,1H),4.15(d,J=5.3Hz,2H),3.05-2.77(m,2H).

[0110] The following compounds are synthesized according to the method for compound T-81. [Table D-1] [Table D-2]

[0111] Example 6 Compounds synthesized according to the present invention: [ka]

[0112] The experimental procedure is as follows. The synthetic route is as follows: [ka]

[0113] 1. Synthesis of Compound 4 See Example 5 to obtain compound 4. 2. Synthesis of Compound 5 Compound 4 (178 mg, 1.0 eq) was placed in a 100 ml three-neck flask and purged with nitrogen gas three times. Under nitrogen gas protection, ultra-dry DMF was added to dissolve the mixture. Stirred in an ice bath for 10 minutes, 60% sodium hydride (36 mg, 2.0 eq) was added, and the mixture was stirred for 15 minutes. After that, iodomethane (31 μl, 1.1 eq) was added and the mixture was allowed to react at room temperature for 3 hours. The completion of the reaction of the raw materials was confirmed by TLC. Water and ethyl acetate were added, followed by extraction. The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain 70 mg of compound 5. LC-MS [M+1]: 411.2.

[0114] 3. Synthesis of Compound T-82 Compound 5 (70 mg, 1.0 eq) and DCM (2.0 ml) were added to a 100 ml three-neck flask and stirred to dissolve. Trifluoroacetic acid (131 μl, 10.0 eq) was added dropwise in an ice bath and the mixture was allowed to react at room temperature for 3 hours. The completion of the reaction of the raw materials was detected by TLC. Saturated sodium bicarbonate solution and ethyl acetate were added, followed by extraction. The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified to obtain 30 mg of compound T-82. HPLC purity: 95.4%. 1H NMR(400MHz,Chloroform-d)δ 7.31(q,J=8.6,8.0Hz,3H),7.20(dd,J=8.6,4.5Hz,4H),7.07(t,J=8.6Hz,2H),5.28(s,1H),4.79-4.72(m,1H),4.48(d,J=15.7Hz, 1H),4.42(dd,J=9.8,3.0Hz,1H),4.33(d,J=15.7Hz,1H),3.27(dd,J=13.9,3.0Hz,1H),2.89(s,3H),2.62(dd,J=13.8,9.8Hz,1H).

[0115] [Table E-1] The following compounds are synthesized according to the method for compound T-82. [Table E-2]

[0116] Test Example 1: Pharmacokinetics test 1. Drug Preparation Approximately 10 mg of the test sample is accurately weighed, dissolved in 10% DMSO (total volume), and slowly added with 90% 0.5% MC solvent (total volume) while stirring. The mixture is sonicated and mixed uniformly with a vortex mixer to obtain a visually uniform formulation solution with a concentration of 1 mg / mL, which is freshly prepared immediately before use. A 0.2 mL sample is drawn into a 1.5 mL centrifuge tube, stored at -80°C, and used for concentration analysis of the dosing solution.

[0117] 2. Animal Preparation The animals were housed in rat cages and fasted from the day before the test (for at least 10 hours), but were allowed to drink water. On the day of the test, each animal was weighed and marked on the tail. A blank blood sample was taken before each administration. Blood was collected from the tail vein.

[0118] 3. Administration Route of administration: oral gavage (po) Dosage concentration: 1mg / ml Dosage: 10 mg / kg Dosage volume: 10 mL / kg Procedure: Wearing a bite-resistant glove on the left hand, hold the rat and hold it upright. Then insert the needle for oral gavage through the throat of the mouth. After confirming that the needle is inserted without any obvious resistance, inject the drug into the stomach.

[0119] 4. Sample Collection 0.5, 1, 2, 4, 6, 8, 12, and 24 hours after administration, 0.1-0.2 ml of whole blood was collected from the test animals into EDTA-Na2 anticoagulant tubes, mixed by inverting 3-4 times, and centrifuged at 4°C and 2000 g for 5 minutes to separate the upper plasma layer, which was then transferred to -80°C for storage and testing. Blood was collected from the tail vein.

[0120] 5. Sample Analysis and Data Processing 5.1. Sample Analysis Shimadzu Liquid Phase and Triple Quad™ 6500 + A quantitative detection method for the test compound will be established using AB mass spectrometry. The drug substance concentration in plasma will be analyzed. The analytical results will be controlled for variation using quality control samples, and the accuracy of the quality control samples will be within the range of 80% to 120%.

[0121] 5.2 Data Processing The main pharmacokinetic parameters were calculated using the non-compartmental model of winnonlin Phoenix software: area under the drug-time curve (AUC(0-t) and AUC(0-∞)), elimination half-life (T 1 / 2 ), maximum plasma concentration (C max ), time to reach maximum plasma concentration (T max )) etc.

[0122] The pharmacokinetic data of the test samples obtained by the above detection are shown in Table 1. [Table 1] As can be seen, compounds such as T-47, T-51 and T-95 contain excellent pharmacokinetic properties.

[0123] With reference to patent WO2019029273A1, compound 50561 in the patent was synthesized, and its structural formula is as follows: [ka]

[0124] The pharmacokinetic data of the test samples obtained by the above detection are shown in Table 2. [Table 2] As can be seen from Tables 1 and 2, the compounds of the present invention have better pharmacokinetic performance.

[0125] Test Example 2: Brain Pharmacokinetics Test 1. Drug Preparation Administration solvent: 5% DMSO + 10% Solutol HS15 + 85% saline Preparation process: Weigh out the appropriate amount of powder, add the appropriate amount of DMSO, vortex, add the appropriate amount of Solutol solution, vortex, add the appropriate amount of saline, vortex, and sonicate to obtain a homogeneous and transparent preparation solution. Two samples of the formulation will be collected before administration and the remaining formulation after administration, and stored at 2-8°C until transport.

[0126] 2. Experimental Animals Experimental animals are kept in the animal room at Suzhou Xihua New Drug Development Co., Ltd. (License number: SYXK(Su)2021-0019). The animal room is equipped with an air conditioning system and is well ventilated, with the indoor temperature maintained between 20 and 26°C and the humidity maintained between 40 and 70%. Artificial lighting is used in the animal room, with a 12-hour light / dark cycle (except in situations where working lights need to be turned on during experimental operations or cleaning), and experimental animals are allowed free access to food and water.

[0127] After purchasing, the animals were kept in a normal condition for at least three days. A veterinarian examined the rats and determined that their physical examination showed no abnormalities. The rats were then enrolled in this study, and a number was labeled on each rat's tail. The animals in the oral administration group were fasted overnight the day before administration, and were allowed to resume feeding and drinking water ad libitum. The source and number of animals used in this study are shown in Table 3.

[0128] All animal manipulations in the experiments complied with the SOP requirements for laboratory animal manipulation at Suzhou Xihua New Drug Development Co., Ltd. and were approved by the Institutional Animal Welfare Committee (IACUC) of Suzhou Xihua New Drug Development Co., Ltd.

[0129] [Table 3]

[0130] 3. Administration Route of administration: oral gavage (po) Dosage concentration: 1mg / ml Dosage: 10 mg / kg Dosage volume: 10 mL / kg Dosage frequency: Single dose Before administration, inspect the condition of the dosage formulation and ensure the uniformity of the formulation by vortexing, stirring or shaking, and calculate the theoretical administration volume per SD rat in each group according to the following formula:

number

[0131] 4. Sample collection and processing Samples are taken from experimental rats at 0.5, 1, 2, 4, 6, 8 and 24 hours after administration. Plasma: 0.15 mL of whole blood was collected via the jugular vein at each time point, placed in a test tube containing the anticoagulant EDTA-K2 (3 μL, 15% EDTA-K2 solution), stored on wet ice, and centrifuged (2000 g, 2-8°C, 10 min) within 1 hour to obtain plasma. The plasma was stored in pre-cooled centrifuge tubes, flash-frozen on dry ice, and then stored in an ultra-low temperature refrigerator at -60°C or below until LC-MS / MS analysis.

[0132] Cerebrospinal fluid: Euthanize rats using the carbon dioxide method and collect ~50 μL of cerebrospinal fluid by puncture. Using a 1 mL syringe, insert the needle with the bevel facing upwards, roughly horizontally into the subarachnoid space, and slowly collect the cerebrospinal fluid. Store the sample on dry ice within 30 minutes of collection, then transfer it to a -90 to -60°C environment. Brain tissue: First, cardiac perfusion is performed to extract the brain tissue. Under deep anesthesia, cardiac perfusion is performed with approximately 8 mL of saline to flush any remaining blood from the circulation. After extraction, the brain tissue is gently washed once with freezing saline, absorbed, weighed, and frozen at -90 to -60°C.

[0133] 5. Sample Analysis and Data Processing 5.1. Sample Analysis Shimadzu Liquid Phase and Triple Quad™ 6500 + Establish a quantitative detection method for the test compound using AB mass spectrometry. Analyze the drug substance concentration in the sample. Analyze the results using quality control samples to control for variations. The accuracy of the quality control samples should be 80%-120%.

[0134] 5.2. Data Processing Pharmacokinetic parameters were measured using Winnonlin Phoenix 8.1.0.3530. max , C max , AUC(0-t), AUC(0-∞), T 1 / 2 , MRT(0-∞), etc. The pharmacokinetic data of the test samples obtained by the above detection are shown in Table 4. [Table 4] As can be seen, compound T-47 has better blood-brain barrier permeability.

[0135] Test Example 3: Electrophysiological LTP Recording 1. Experimental Animals [Table F] 2. Experimental group assignment [Table G]

[0136] 3. Experimental Method 3.1. Preparation of brain slices: C57BL / 6J mice, 6-8 weeks old, were anesthetized and quickly decapitated. The scalp was incised, and the skull and dura mater were removed. The entire brain was quickly removed and placed in artificial cerebrospinal fluid (ACSF) saturated with 95% O2 and 5% CO2 at 0-4°C for mild cooling. The cerebellum and one-third of the forebrain were removed, and the brain was divided into two halves along the midline. The hippocampus was separated from the ventromedial brain along the edge of the cortex and fixed to a carrier bath dish with adhesive. 400 μm-thick coronal brain slices were prepared using a vibrating slicer. The brain slices were placed on a nylon net immersed in the liquid of an incubator. After continuous gas mixing, the slices were incubated in a 34°C hot water bath for 0.5 hours, then incubated at room temperature (26±1°C) for 2-3 hours before the experiment.

[0137] 3.2. In vitro brain slice potential recording: Under direct vision through a surgical microscope, a bipolar metal tungsten wire stimulating electrode with an exposed tip was attached to the Schaffer collateral pathway of the CA3 area. The stimulating electrode was connected to a stimulator via an isolator, and the recording electrode was connected to a digital-to-analog converter via a microelectrode amplifier and data acquisition software.

[0138] 3.3. Electrophysiological Recordings: Before recording excitatory postsynaptic potentials (fEPSPs), the brain slice was first transferred to a recording chamber, and a gas mixture (95% O2, 5% CO2) was continuously introduced into the cerebrospinal fluid in the water bath. The stimulating electrode was inserted into the hippocampal CA3 region, and the recording electrode was inserted into the hippocampal CA1 region. As the desired site was approached, the insertion depth of the stimulating and recording electrodes was slowly and precisely adjusted. Simultaneously, a 1-ms pulse was applied every 10–20 seconds. The stimulation intensity was adjusted until the optimal fEPSP was obtained. The electrode position was then fixed, and the stimulation intensity was set to 30–40% of the maximum response at the optimal fEPSP. Recording was continued for 20–30 minutes to stabilize the baseline. Drug perfusion was then performed (initial dose 30 μM). The duration of administration was 20–30 minutes (depending on the drug's efficacy). If a drug enhances or decreases fEPSPs, it is dissolved in normal ACSF for 40-60 minutes to observe whether the enhancement effect is maintained for a long period of time. If no significant change in fEPSPs is observed, the experiment is stopped. The recorded data is collected and amplified by an electrophysiological signal acquisition and processing system, and displayed and saved on a computer. The experimental data and images are output and processed using Clampfit software.

[0139] 4. Data Statistics and Analysis: All experimental data are expressed as mean ± standard error (Mean ± SEM), and the statistical analysis method for all experiments was one-way ANOVA. Significant differences are marked *p≦0.05, **p≦0.01, and ***p≦0.001. p>0.05 indicates no significant difference.

[0140] The electrophysiological LTP recording data of the test samples obtained by the above detection are shown in Table 5. [Table 5]

[0141] As can be seen from Table 5, compound T-01 significantly enhances the electrical signal conduction in brain slices, and p≦0.05, the data is statistically significant, and the activation of LTP is higher than that of the control compound.By the same detection method, the compounds T-36, T-47, T-51, T-54, T-73, T-74, T-75, T-76, T-79, T-80, T-99 and T-100 of the present invention all show good activation effect on LTP.

[0142] All documents mentioned in this application are incorporated by reference in this application as if each document were incorporated by reference individually. Furthermore, after reading the above teachings of the present invention, those skilled in the art will be able to make various changes or modifications to the present invention, and these equivalents will also fall within the scope defined by the appended claims of this application.

Claims

1. A compound comprising: The compound is a compound of formula I or a stereoisomer, racemate, or pharmaceutically acceptable salt thereof, 【Chemistry 1】 where: Ring A is 【Chemistry 2】 is selected from the group consisting of X 1 is selected from the group consisting of O, S, NH, and NR; X ２ is selected from the group consisting of O, NH, and NR; R １ teeth, 【Transformation 3】 is selected from the group consisting of R ２ is selected from the group consisting of H, halogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 alkoxy group, and a substituted or unsubstituted C3-C6 cycloalkyl group; R ３ , R ４ are independently selected from the group consisting of H, D, halogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C3-C6 cycloalkyl group, or R ３ , R ４ together with the carbons to which they are attached form a substituted or unsubstituted 3- to 7-membered cycloalkyl group or a substituted or unsubstituted 3- to 7-membered heterocyclic group containing one or more heteroatoms selected from O, S or N; Each R ５ , R ６ , R ７ , R ８ , R ９ , R １０ is H, D, halogen, trifluoromethyl group, cyano group, hydroxy group, amino group, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C1-C6 alkoxy group, substituted or unsubstituted C1-C6 alkyl-NR １６ -, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted C3-C6 cycloalkoxy group, a substituted or unsubstituted C3-C6 cycloalkyl-NR １６ - independently selected from the group consisting of Each R １１ , R １２ , R １３ , R １４ , R １５ is H, D, halogen, trifluoromethyl group, cyano group, hydroxy group, amino group, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C1-C6 alkoxy group, substituted or unsubstituted C1-C6 alkyl-NR １６ -, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted C3-C6 cycloalkoxy group, a substituted or unsubstituted C3-C6 cycloalkyl-NR １６ - independently selected from the group consisting of Each R １７ , R １８ are independently selected from the group consisting of H, D, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group, and a C3-C6 cycloalkoxy group, or R １７ , R １８ together with the carbons to which they are attached form a substituted or unsubstituted 3- to 7-membered cycloalkyl group or a substituted or unsubstituted 3- to 7-membered heterocyclic group containing one or more heteroatoms selected from O, S or N; each R is independently a substituted or unsubstituted C1-C6 alkyl group; The substitutions each independently represent D, halogen, a trifluoromethyl group, a cyano group, a hydroxy group, an amino group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 alkyl-NR １６ -, C3-C6 cycloalkyl group, C3-C6 cycloalkoxy group, C3-C6 cycloalkyl-NR １６ - is substituted by one or more substituents selected from the group consisting of Each R １６ are independently selected from the group consisting of H, C1-C6 alkyl groups; Additional conditions are: ２ is NH and X ２ is O, then R ３ , R ４ , R １７ and R １８ is H, then ring A is 【Chemistry 4】 The compound is not

2. The compound has the structure shown in Formula II: 【Transformation 5】 Here, rings A and X １ , R １ , R ２ , R ３ , R ４ is as defined in claim 1 The compound of claim 1.

3. Ring A is 【Transformation 6】 is selected from the group consisting of R ５ , R ６ , R ７ , R ８ , R ９ is as defined in claim 1 The compound of claim 1.

4. R ２ is selected from the group consisting of H, halogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, and a C3-C6 cycloalkyl group; R ３ , R ４ are independently selected from the group consisting of H, D, halogen, C1-C6 alkyl groups, C1-C6 alkoxy groups, and C3-C6 cycloalkyl groups. The compound of claim 1.

5. Ring A is 【Transformation 7】 and R １ teeth, 【Transformation 8】 and Each R ５ , R ６ , R ７ , R ８ , R ９ are independently selected from the group consisting of H, halogen, trifluoromethyl, cyano, hydroxy, amino, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C6 cycloalkoxy; Each R １１ , R １２ , R １３ , R １４ , R １５ are independently selected from the group consisting of H, halogen, trifluoromethyl, cyano, hydroxy, amino, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C6 cycloalkoxy groups. The compound of claim 1.

6. The compound is: 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 characterized in that the compound is selected from the group consisting of The compound of claim 1.

7. 1. A pharmaceutical composition comprising:

10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a safe and effective amount of one or more compounds of claim 1.

8. Use of the compound of claim 1, 10. Use of a compound according to claim 1 for the preparation of a drug, said drug being used for the prevention and / or treatment of neurodegenerative diseases.

9. The neurodegenerative disease is selected from the group consisting of Alzheimer's disease, epilepsy, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and spinocerebellar ataxia.

9. The use according to claim 8.

10. Use of the compound of claim 1, 10. Use of a compound according to claim 1 for the preparation of a drug, said drug being used for the prevention and / or treatment of RAC1-related diseases.

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