Piperidinyl alkyl pyridinone compounds, methods of making, pharmaceutical compositions, and uses thereof

Abstract

The application relates to the technical field of medicines, in particular to a piperidine alkyl pyridone compound and a pharmaceutically acceptable salt thereof, a preparation method, a pharmaceutical composition and application. The piperidine alkyl pyridone compound has the structure shown in formula (I), has strong inhibitory activity on acetylcholinesterase, A beta 1‑42 Oligomer aggregation and neuroinflammation have strong inhibitory activity; the piperidine alkyl pyridone compound can be used for preparing a drug for treating and / or preventing nervous system and muscular system diseases.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical technology, specifically to piperidine alkyl pyridinone compounds, their preparation methods, pharmaceutical compositions, and applications. Background Technology

[0002] Neurodegenerative diseases are a collective term for diseases caused by chronic, progressive degenerative changes in the central nervous system. These include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Their pathogenesis is closely related to oxidative stress, neuroinflammation, and related damage. Currently, the main treatments for neurodegenerative diseases are acetylcholinesterase (AChE) inhibitors or N-methyl-D-aspartate (NMDA) receptor antagonists. However, these drugs have limitations, such as targeting only a single point of action and poor long-term efficacy. Therefore, developing novel drugs for the treatment of neurodegenerative diseases is of great significance. Summary of the Invention

[0003] Based on this, this application provides a piperidine alkyl pyridinone compound, its preparation method, pharmaceutical composition, and application. The piperidine alkyl pyridinone compound of this application has effects on acetylcholinesterase and Aβ. 1-42 Oligomers and neuroinflammation have strong inhibitory activity and can be used in drugs for the treatment or prevention of diseases of the nervous and muscular systems.

[0004] A first aspect of this application provides a piperidine alkyl pyridinone compound having the structure shown in formula (I) or a pharmaceutically acceptable salt thereof:

[0005] ;

[0006] Wherein, R1 is selected from or R 11 Selected from C1~C5 alkyl groups;

[0007] R2 is selected from or m is any integer from 1 to 5, q is any integer from 1 to 4, and S1 is independently selected from H, halogen, cyano, C1-C5 alkyl, C1-C5 alkoxy, -NH(R) each time it appears. 21 ), -N(R 21 )2 or -NHCO-(R 21The halogens include F, Cl, Br, or I, R 21 Selected from C1~C5 alkyl groups;

[0008] n is any integer from 1 to 10.

[0009] In some of these embodiments, R 11 R1 is selected from C1-C3 alkyl groups. Optionally, R1 is selected from... or .

[0010] In some embodiments, R2 is selected from... or m is any integer from 1 to 3. q is any integer from 1 to 3. Each occurrence of S1 is independently selected from H, F, Cl, Br, I, -CN, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, -N(CH3)2, or -NHCOCH3.

[0011] In some of these embodiments, n is any integer from 1 to 5.

[0012] In some embodiments, the chiral configuration of the piperidine alkylpyridinone compound is one or both of the R and S configurations in any proportion.

[0013] In some embodiments, the piperidine alkylpyridone compound includes and One or more of them.

[0014] R2 is selected from benzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 3,4-difluorobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 2-(acetamido)benzyl, 3-(acetamido)benzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 2-methylbenzyl, 4-methylbenzyl, 2-(dimethylamino)benzyl, 3-(dimethylamino)benzyl, 4-(dimethylamino)benzyl, 2-cyanobenzyl, 4-cyanobenzyl, (2-pyridine)methyl, (3-pyridine)methyl, or (4-pyridine)methyl.

[0015] n is any integer from 1 to 5.

[0016] In some embodiments, the pharmaceutically acceptable salt is prepared by reacting the piperidine alkylpyridone compound with an acid. Suitable acids for salt formation include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, aminosulfonic acid, hydrofluoric acid, C1-C6 alkylcarboxylic acids, trifluoroacetic acid, stearic acid, pyric acid, oxalic acid, benzoic acid, phenylacetic acid, salicylic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, malic acid, lactic acid, hydroxymaleic acid, pyruvic acid, glutamic acid, ascorbic acid, lipoic acid, C1-C6 alkylsulfonic acids, camphorsulfonic acid, naphthalenesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and 1,4-butanedisulfonic acid, or one or more of these.

[0017] A second aspect of this application provides a method for preparing the piperidine alkyl pyridone compound or a pharmaceutically acceptable salt thereof as described in the first aspect, comprising the following steps:

[0018] Compound Ia With compound Ib The piperidine alkylpyridone compound was prepared by reacting under solvent and alkaline conditions.

[0019] Wherein, R1, R2 and n are as defined in the first aspect of this application.

[0020] X is selected from Cl, Br, I, benzenesulfonyloxy, p-toluenesulfonyloxy, or methanesulfonyloxy.

[0021] In some embodiments, the molar ratio of compound Ia to compound Ib is 1:(1~5).

[0022] In some embodiments, the molar ratio of compound Ia to the base providing the alkaline conditions is 1:(1~5).

[0023] In some of these embodiments, the reaction temperature is 0°C to 150°C.

[0024] In some of these embodiments, the reaction time is 1 hour to 80 hours.

[0025] In some embodiments, the base providing the alkaline conditions includes one or more of alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth metal carbonates, alkali metal bicarbonates, alkali metal hydrides, and alkaline earth metal hydrides.

[0026] In some embodiments, the solvent includes one or more of the following: fatty alcohols, fatty ketones, dichloromethane, chloroform, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, diethyl ether, benzene, toluene, acetonitrile, 1,4-dioxane, ethylene glycol dimethyl ether, and alkane solvents.

[0027] A third aspect of this application provides a pharmaceutical composition comprising the piperidine alkyl pyridone compound or a pharmaceutically acceptable salt thereof as described in the first aspect of this application; and a pharmaceutically acceptable carrier.

[0028] This application also provides a piperidine alkyl pyridinone compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the third aspect of this application, in preparation by inhibiting acetylcholinesterase and inhibiting Aβ. 1-42 Use in drugs that aggregate oligomers or treat and / or prevent neuroinflammatory diseases.

[0029] This application also provides the use of a piperidine alkyl pyridinone compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the third aspect of this application, in the preparation of a medicament for treating and / or preventing neurological or muscular diseases. The neurological and muscular diseases include vascular dementia, Alzheimer's disease, frontotemporal dementia, Prion's disease, Lewy body dementia, Parkinson's disease, Huntington's disease, HIV-related dementia, multiple sclerosis, amyotrophic lateral sclerosis, or sarcopenia.

[0030] The piperidine alkylpyridone compounds or their pharmaceutically acceptable salts provided in this application have at least the following advantages:

[0031] The piperidine alkyl pyridone compounds of this application, through rational structural design, exert their effects on acetylcholinesterase and Aβ. 1-42 Oligomer aggregation or neuroinflammation has strong inhibitory activity and can be used to treat or prevent neurodegenerative diseases or diseases of the muscular system.

[0032] Furthermore, the preparation method of piperidine alkyl pyridinone compounds provided in this application is efficient and simple, and has good raw material economy. Detailed Implementation

[0033] The following detailed description, in conjunction with specific embodiments, provides a more complete and clear account of the piperidine alkyl pyridone compounds, their preparation methods, pharmaceutical compositions, and applications. This application can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided to provide a more thorough and complete understanding of the disclosure of this application.

[0034] In this application, the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of technical features indicated. Therefore, a feature defined with "first" or "second" may explicitly or implicitly include at least one of that feature. In the description of this application, "multiple" means at least two, such as two, three, etc., unless otherwise explicitly specified.

[0035] When a numerical range is disclosed herein, the range is considered continuous and includes the minimum and maximum values ​​of the range, as well as every value between the minimum and maximum values. Furthermore, when the range refers to integers, it includes every integer between the minimum and maximum values ​​of the range. Additionally, when multiple ranges are provided to describe a feature or characteristic, the ranges may be combined. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges to which they are incorporated.

[0036] 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. The terminology used herein in the specification of this application is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. Unless otherwise stated or in case of conflict, the terms or phrases used herein have the following meanings:

[0037] In this application, the terms "multiple", "various", "multiple times", "multi-dimensional", etc., unless otherwise specified, refer to a quantity greater than or equal to 2. For example, "one or more" means one or more or more.

[0038] In this application, the terms "first aspect," "second aspect," "third aspect," and "fourth aspect," etc., are used for descriptive purposes only and should not be construed as indicating or implying relative importance or quantity, nor should they be construed as implicitly indicating the importance or quantity of the indicated technical features. Moreover, "first," "second," "third," and "fourth," etc., serve only a non-exhaustive enumeration purpose and should be understood not to constitute a closed limitation on quantity.

[0039] In this application, the technical features described in an open-ended manner include both closed technical solutions consisting of the listed features and open technical solutions that include the listed features.

[0040] In this application, the terms "combinations thereof", "any combination thereof", and "any combination thereof" include all suitable combinations of any two or more of the listed items.

[0041] In this application, the term "suitable" as used in phrases such as "suitable combination," "suitable method," and "any suitable method" refers to the ability to implement the technical solution of this application, solve the technical problem of this application, and achieve the expected technical effect of this application.

[0042] In this application, terms such as "preferred," "better," "more suitable," and "ideal" are used only to describe implementation methods or embodiments with better effects, and should be understood not to constitute a limitation on the scope of protection of this application.

[0043] In this application, terms such as "further," "even further," and "particularly" are used for descriptive purposes to indicate differences in content, but should not be construed as limiting the scope of protection of this application.

[0044] In this application, the terms "optionally," "optionally," and "optional" refer to options that are optional, meaning they can be selected from either "with" or "without." If multiple "optional" options appear in a technical solution, unless otherwise specified and there are no contradictions or mutual constraints, each "optional" option is independent.

[0045] In this application, "pharmaceutically acceptable" means those ligands, materials, compositions, and / or dosage forms that are suitable for administration to patients within the bounds of reasonable medical judgment and that are commensurate with a reasonable benefit / risk ratio.

[0046] In this application, "pharmaceutically acceptable salt" refers to a salt formed by any compound in the indicated structure with an acid or base that is suitable for use as a medicine. Pharmaceutically acceptable salts include both inorganic and organic salts. Specifically, the salt is a salt formed by the compound of this invention with an acid. Acids suitable for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and hydrofluoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, and succinic acid (C1-C6 alkyl carboxylic acids); trifluoroacetic acid; stearic acid; pyruvic acid; oxalic acid; benzoic acid; phenylacetic acid; salicylic acid; maleic acid; fumaric acid; succinic acid; tartaric acid; citric acid; malic acid; lactic acid; hydroxymaleic acid; pyruvic acid; glutamic acid; ascorbic acid; lipoic acid; and organic acids such as methanesulfonic acid and ethanesulfonic acid (C1-C6 alkyl sulfonic acids); camphorsulfonic acid; naphthalenesulfonic acid; benzenesulfonic acid; p-toluenesulfonic acid; 1,4-butanedisulfonic acid; and aminosulfonic acids.

[0047] Neurodegenerative diseases are a general term for diseases caused by chronic, progressive degeneration of central nervous system tissues. Their pathogenesis is closely related to oxidative stress, neuroinflammation, and related damage. Oxidative stress is mediated by reactive oxygen species (ROS) free radicals, including superoxide anions, hydrogen peroxide, and hydroxyl radicals. Under normal physiological conditions, ROS production levels are in dynamic equilibrium with the body's antioxidant capacity. When ROS production exceeds the cellular antioxidant capacity, oxidative stress occurs. The brain is particularly sensitive to oxidative stress, thereby inducing various neurological diseases. Other studies have found that vascular dementia, HIV-related dementia, ischemic stroke, hemorrhagic stroke, and neurological damage caused by traumatic brain injury are also closely related to oxidative stress and neuroinflammation.

[0048] Vascular dementia (VD) is a clinical syndrome characterized by intellectual and cognitive impairment caused by various types of cerebrovascular diseases, including ischemic cerebrovascular disease, hemorrhagic cerebrovascular disease, and acute and chronic hypoxic cerebrovascular disease. Due to its complex pathogenesis, there are currently no drugs that can halt the progression of vascular dementia; clinical treatment focuses on improving cerebral blood circulation, brain metabolism, and enhancing brain nutrition.

[0049] Neurodegenerative diseases such as Alzheimer's disease (AD) are central nervous system degenerative diseases characterized by progressive cognitive impairment and memory loss. Their incidence is increasing year by year, making them the second most prevalent disease after cardiovascular disease and cancer. With the accelerating aging of the global population, their incidence is showing a significant upward trend. Because AD clinically manifests as a decline in memory, orientation, thinking, and judgment, as well as a reduction in daily living abilities and even abnormal mental and behavioral symptoms, patient care is challenging, placing a heavy burden on society and families. AD is a disease caused by multiple factors, with a complex pathogenesis that is not yet fully understood. However, research indicates that decreased acetylcholine levels in the brain, excessive production and deposition of β-amyloid protein, platelet aggregation in cerebral blood vessels, metal ion metabolism disorders, and calcium... 2+ Multiple factors play important roles in the pathogenesis of Alzheimer's disease (AD), including imbalance, neurofibrillary tangles caused by tau-protein hyperphosphorylation, hyperactive glutamate receptors, oxidative stress leading to large amounts of reactive oxygen species (ROS) and free radicals, and neuroinflammatory responses. Targeting these pathogenic factors, researchers have employed the traditional "one drug, one target" drug design strategy, discovering a large number of drugs with high activity and selectivity for specific targets.

[0050] Currently approved drugs for treating mild / moderate Alzheimer's disease (AD) include acetylcholinesterase (AChE) inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists for treating severe AD. However, clinical use has shown that while these drugs can alleviate AD symptoms by increasing acetylcholine levels or inhibiting the excitatory toxicity of excitatory amino acids, they cannot effectively stop or reverse the disease progression. Furthermore, they can cause side effects such as hallucinations, confusion, dizziness, nausea, liver toxicity, loss of appetite, and frequent bowel movements, resulting in less than ideal long-term efficacy. These drugs also suffer from problems such as single-target action, numerous toxic side effects during clinical use, and poor long-term efficacy in AD patients. Therefore, there is an urgent clinical need to develop novel AD treatments that can both improve AD symptoms and modify the disease progression.

[0051] As the pathogenesis of neurodegenerative diseases is increasingly elucidated, it has been discovered that the occurrence and development of these diseases are characterized by multiple mechanisms and factors, with different mechanisms interconnected and influencing each other, forming a complex network regulatory system in the course of these diseases. Clearly, developing therapeutic drugs that can simultaneously act on multiple stages of the pathological process of neurodegenerative diseases is an inevitable choice. Based on these findings, this application proposes a "multi-target drug" strategy for developing anti-neurodegenerative disease drugs. A "multi-target drug" refers to a single chemical entity that simultaneously acts on multiple targets in the disease network, producing a synergistic effect on each target, making the total effect greater than the sum of the individual effects. The main differences between multi-target drugs and multi-drug combinations or compound drugs are: reduced dosage, improved therapeutic efficacy, avoidance of drug interactions and resulting toxic side effects, uniform pharmacokinetic characteristics, and ease of use. Therefore, developing anti-neurodegenerative disease therapeutic drugs with novel chemical structures, novel mechanisms of action, multiple targets, and low toxicity is an important current direction.

[0052] Furthermore, sarcopenia, also known as muscle loss, is an age-related, progressive, and widespread disease characterized by loss of skeletal muscle mass and function, leading to decreased physical performance, reduced quality of life, and even death. It is a common disease among the elderly, and its pathogenesis is closely related to neuromuscular dysfunction, protein homeostasis imbalance, oxidative stress, inflammatory responses, and trace element homeostasis. The novel compound provided in this application also has positive effects on the treatment and / or prevention of muscle system diseases.

[0053] Based on this, a first aspect of this application provides a piperidine alkyl pyridinone compound having the structure shown in formula (I) or a pharmaceutically acceptable salt thereof:

[0054] ;

[0055] Wherein, R1 is selected from or R 11 Selected from C1~C5 alkyl groups.

[0056] Furthermore, R 11 R1 is selected from C1-C3 alkyl groups. Optionally, R1 is selected from... or .

[0057] In this application, " "" refers to the connection site.

[0058] "Alkyl" refers to a saturated hydrocarbon group containing a primary (normal) carbon atom, or a secondary carbon atom, or a tertiary carbon atom, or a quaternary carbon atom, or a combination thereof. Phrases containing this term, such as "C1~C5 alkyl", refer to alkyl groups containing 1 to 5 carbon atoms, and each time it appears, it can be independently referred to as C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl. Suitable examples include, but are not limited to: methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-propyl, n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-butyl, n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), tert-butyl (1,1-dimethylethyl, 2-methyl-1-propyl ...i-1-dimethylethyl, 2-methyl-1-propyl), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (i-Bu, i-butyl, -CH(CH3)CH2CH3), tert-butyl (i-1-dimethylethyl, i-1-dimethylethyl), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH2CH3), 2-methyl-1- 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2) or 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3).

[0059] R2 is selected from or m is any integer from 1 to 5. m includes, but is not limited to, 1, 2, 3, 4, or 5. q is any integer from 1 to 4. Understandably, q is the number of S1 substitution sites on the benzene ring. For example, q includes, but is not limited to, 1, 2, 3, or 4. In this application, single bonds drawn on the ring (such as...) () indicates any substituted position on the ring. Each occurrence of S1 is independently selected from H, halogen, cyano, C1-C5 alkyl, C1-C5 alkoxy, -NH(R) 21 ), -N(R 21 )2 or -NHCO-(R 21 Understandably, the S1 substituents on the benzene ring can be the same or different. For example, when q is 2, the S1 substituents can each independently be H, halogen, cyano, C1-C5 alkyl, C1-C5 alkoxy, or -NH(R) 21 ), -N(R 21 )2 or -NHCO-(R 21 The halogens include F, Cl, Br, or I. 21Selected from C1-C5 alkyl groups. The definition of “C1-C5 alkyl groups” is as described above.

[0060] In this application, "alkoxy" refers to a group having an -O-alkyl group, i.e., an alkyl group as defined above connected to the parent nucleus via an oxygen atom. Phrases containing this term, such as "C1-C5 alkoxy," refer to alkyl moieties containing 1-5 carbon atoms, and each occurrence can be independently C1 alkoxy, C4 alkoxy, or C5 alkoxy. Suitable examples include, but are not limited to: methoxy (-O-CH3 or -OMe), ethoxy (-O-CH2CH3 or -OEt), and tert-butoxy (-OC(CH3)3 or -OtBu).

[0061] In this application, "halogen" includes, but is not limited to, F, Cl, Br or I.

[0062] Furthermore, R2 is selected from or m is any integer from 1 to 3. q is any integer from 1 to 3. Understandably, q represents the number of S1 substitution sites on the benzene ring. For example, q includes, but is not limited to, 1, 2, or 3. Each occurrence of S1 is independently selected from H, F, Cl, Br, I, -CN, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, -N(CH3)2, or -NHCOCH3.

[0063] As a further example, R2 is selected from benzyl (-CH2Ph), 2-fluorobenzyl (-CH2Ph(2'-F)), 3-fluorobenzyl (-CH2Ph(3'-F)), 4-fluorobenzyl (-CH2Ph(4'-F)), 3,4-difluorobenzyl (-CH2Ph(3',4'-F2)), 2-chlorobenzyl (-CH2Ph(2'-Cl)), 3-chlorobenzyl (-CH2Ph(3'-Cl)), 4-chlorobenzyl (-CH2Ph(4'-Cl)), 2-bromobenzyl (-CH2Ph(2'-Br)), 3-bromobenzyl (-CH2Ph(3'-Br)), 2-(acetamido)benzyl (-CH2Ph(2'-NHCOCH3)), 3-(acetamido)benzyl (-CH2Ph(3'-NHC)), 2-(acetamido)benzyl (-CH2Ph(3'-NHC)), 3-(acetamido)benzyl (-CH2Ph(3'-NHC)). OCH3), 2-methoxybenzyl (-CH2Ph(2'-OCH3)), 3-methoxybenzyl (-CH2Ph(3'-OCH3)), 4-methoxybenzyl (-CH2Ph(4'-OCH3)), 2-methylbenzyl (-CH2Ph(2'-CH3)), 4-methylbenzyl (-CH2Ph(4'-CH3)), 2-(dimethylamino)benzyl (-CH2Ph(2'-N(CH3)2)), 3-(dimethylamino)benzyl (-CH2Ph(3'-N(CH3)2)), 4-(dimethylamino)benzyl (-CH2Ph(4'-N(CH3)2)), 2-cyanobenzyl (-CH2Ph(2'-CN)), 4-cyanobenzyl (-CH2Ph(4'-CN)), (2-pyridine)methyl ( ), (3-pyridine)methyl ( ) or (4-pyridine)methyl ( ).

[0064] Where n is any integer from 1 to 10. Further, n is any integer from 1 to 5.

[0065] In some of these examples, the chiral configuration of the piperidine alkylpyridone compound is one or more of the R and S configurations. It is understood that the piperidine alkylpyridone compound can be the R configuration, the S configuration, or any mixture of the R and S configurations in any proportion.

[0066] In some of these examples, the piperidine alkylpyridone compounds include and One or more of them.

[0067] Wherein, R2 is selected from benzyl (-CH2Ph), 2-fluorobenzyl (-CH2Ph(2'-F)), 3-fluorobenzyl (-CH2Ph(3'-F)), 4-fluorobenzyl (-CH2Ph(4'-F)), 3,4-difluorobenzyl (-CH2Ph(3',4'-F2)), 2-chlorobenzyl (-CH2Ph(2'-Cl)), 3-chlorobenzyl (-CH2Ph(3'-Cl)), 4-chlorobenzyl (-CH2Ph(3'-Cl)). h(4'-Cl)), 2-bromobenzyl (-CH2Ph(2'-Br)), 3-bromobenzyl (-CH2Ph(3'-Br)), 4-bromobenzyl (-CH2Ph(4'-Br)), 2-(acetamino)benzyl (-CH2Ph(2'-NHCOCH3)), 3-(acetamino)benzyl (-CH2Ph(3'-NHCOCH3)), 4-(acetamino)benzyl (-CH2Ph(4'-NH)) COCH3), 2-methoxybenzyl (-CH2Ph(2'-OCH3)), 3-methoxybenzyl (-CH2Ph(3'-OCH3)), 4-methoxybenzyl (-CH2Ph(4'-OCH3)), 2-methylbenzyl (-CH2Ph(2'-CH3)), 3-methylbenzyl (-CH2Ph(3'-CH3)), 4-methylbenzyl (-CH2Ph(4'-CH3)), 2-(dimethylamino)benzyl (-CH2Ph(2'-N(CH3)2)), 3-(dimethylamino)benzyl (-CH2Ph(3'-N(CH3)2)), 4-(dimethylamino)benzyl (-CH2Ph(4'-N(CH3)2)), 2-cyanobenzyl (-CH2Ph(2'-CN)), 3-cyanobenzyl (-CH2Ph(3'-CN)), 4-cyanobenzyl (-CH2Ph(4'-CN)), (2-pyridine)methyl ( ), (3-pyridine)methyl ( ) or (4-pyridine)methyl ( ).

[0068] Understandably, in this application, "ph" represents phenyl.

[0069] Further, R2 is selected from benzyl (-CH2Ph), 2-fluorobenzyl (-CH2Ph(2'-F)), 3-fluorobenzyl (-CH2Ph(3'-F)), 4-fluorobenzyl (-CH2Ph(4'-F)), 3,4-difluorobenzyl (-CH2Ph(3',4'-F2)), 2-chlorobenzyl (-CH2Ph(2'-Cl)), 3-chlorobenzyl (-CH2Ph(3'-Cl)), 4-chlorobenzyl (-CH2Ph(4'-Cl)), 2-bromobenzyl (-CH2Ph(2'-Br)), 3-bromobenzyl (-CH2Ph(3'-Br)), 2-(acetamido)benzyl (-CH2Ph(2'-NHCOCH3)), 3-(acetamido)benzyl (-CH2Ph(3'-NHCOCH3)), 2-(acetamido)benzyl (-CH2Ph(3'-NHCOCH3)), 3-(acetamido)benzyl (-CH2Ph(3'-NHCOCH3)). H3), 2-methoxybenzyl (-CH2Ph(2'-OCH3)), 3-methoxybenzyl (-CH2Ph(3'-OCH3)), 4-methoxybenzyl (-CH2Ph(4'-OCH3)), 2-methylbenzyl (-CH2Ph(2'-CH3)), 4-methylbenzyl (-CH2Ph(4'-CH3)), 2-(dimethylamino)benzyl (-CH2Ph(2'-N(CH3)2)), 3-(dimethylamino)benzyl (-CH2Ph(3'-N(CH3)2)), 4-(dimethylamino)benzyl (-CH2Ph(4'-N(CH3)2)), 2-cyanobenzyl (-CH2Ph(2'-CN)), 4-cyanobenzyl (-CH2Ph(4'-CN)), (2-pyridine)methyl ( ), (3-pyridine)methyl ( ) or (4-pyridine)methyl ( ).

[0070] Furthermore, the piperidine alkyl pyridone compound is selected from one or more of the following compounds: .

[0071] A second aspect of this application provides a method for preparing piperidine alkyl pyridinone compounds, comprising the following steps:

[0072] Compound Ia With compound Ib The piperidine alkylpyridone compound was prepared by reacting under solvent and alkaline conditions.

[0073] Wherein, R1, R2 and n are as defined in the first aspect of this application.

[0074] X is selected from Cl, Br, I, benzenesulfonyloxy, p-toluenesulfonyloxy, or methanesulfonyloxy.

[0075] In this application, "benzenesulfonyloxy" refers to -OS(O)2-ph "p-Toluenesulfonyloxy" refers to "Methanesulfonyloxy" refers to -OS(O)2-CH3 .

[0076] Understandably, compounds Ia and Ib of this application can be prepared using commercially available or commonly used techniques in the art. For example, methods for preparing the pyridone compounds of compound Ia include, but are not limited to, the methods disclosed in the following documents: 1. R. Heath et al. ChemCatChem, 2014, 6, 996-1002; 2. M. Shibagaki et al. WO 9407903.

[0077] In some examples, the molar ratio of compound Ia to compound Ib is 1:(1~5). Preferably, the molar ratio of compound Ia to compound Ib is 1:(1~2.5). For example, the molar ratio of compound Ia to compound Ib includes, but is not limited to, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5 or 1:5, or any of the above two point values ​​as endpoints.

[0078] In some examples, the molar ratio of compound Ia to the base providing the alkaline conditions is 1:(1~5). Preferably, the molar ratio of compound Ia to the base providing the alkaline conditions is 1:(1~3). For example, the molar ratio of compound Ia to the base providing the alkaline conditions includes, but is not limited to, 1:1, 1:2, 1:3, 1:4 or 1:5, or a range formed by any two of the above point values ​​as endpoints.

[0079] In some examples, the reaction temperature is 0°C to 150°C. Preferably, the reaction temperature is 20°C to 100°C. For example, the reaction temperature includes, but is not limited to, 0°C, 20°C, 40°C, 60°C, 80°C, or 100°C, or any two of the above values ​​as endpoints. For example, the reaction time is 1 hour to 80 hours. Preferably, the reaction time is 2 hours to 60 hours.

[0080] In some examples, the base providing the alkaline conditions includes one or more of alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth metal carbonates, alkali metal bicarbonates, alkali metal hydrides, and alkaline earth metal hydrides. For example, the base used to provide the alkaline conditions includes, but is not limited to, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, or sodium hydride.

[0081] In some examples, the solvent includes one or more of fatty alcohols, fatty ketones, dichloromethane, chloroform, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, diethyl ether, benzene, toluene, acetonitrile, 1,4-dioxane, ethylene glycol dimethyl ether, and alkane solvents. Further, the fatty alcohol solvent includes, but is not limited to, C1-C8 fatty alcohols. The fatty ketone solvent includes, but is not limited to, C3-C8 fatty ketones. The alkane solvent includes, but is not limited to, C5-C8 alkanes. Preferably, the solvent includes one or more of methanol, ethanol, acetone, dichloromethane, acetonitrile, tetrahydrofuran, toluene, and N,N-dimethylformamide.

[0082] Understandably, pharmaceutically acceptable salts of the aforementioned piperidine alkyl pyridone compounds can be prepared by combining the piperidine alkyl pyridone compounds with acids using conventional pharmaceutical salt-forming methods. Suitable acids for salt formation include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and hydrofluoric acid; C1-C6 alkyl carboxylic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, and succinic acid; trifluoroacetic acid, stearic acid, pyric acid, oxalic acid, benzoic acid, phenylacetic acid, salicylic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, malic acid, lactic acid, hydroxymaleic acid, pyruvic acid, glutamic acid, ascorbic acid, and lipoic acid; and C1-C6 alkyl sulfonic acids such as methanesulfonic acid and ethanesulfonic acid; camphorsulfonic acid; naphthalenesulfonic acid; benzenesulfonic acid; p-toluenesulfonic acid; 1,4-butanedisulfonic acid; and aminosulfonic acids.

[0083] In a third aspect, this application provides a pharmaceutical composition comprising a piperidine alkyl pyridone compound or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

[0084] Understandably, the pharmaceutical composition comprises a therapeutically effective amount of a piperidine alkyl pyridone compound or a pharmaceutically acceptable salt thereof.

[0085] "Therapeutic effective amount" refers to the amount of a drug or agent that elicits a biological or pharmaceutical response in a tissue, system, or animal targeted by an investigator or physician. "Composition" refers to a product made by mixing one or more substances or components.

[0086] "Pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or medium, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials. As used herein, the term "pharmaceutically acceptable carrier" includes buffers compatible with drug administration, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and absorption delay agents, and the like. Each carrier must be "pharmaceutically acceptable" in the sense of compatibility with other components in the formulation and harmlessness to the patient. Suitable examples include, but are not limited to: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch, potato starch and substituted or unsubstituted β-cyclodextrins; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth gum; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn... Rice oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer; (21) other non-toxic compatible substances used in pharmaceutical formulations.

[0087] Furthermore, in the pharmaceutical compositions of this application, the active ingredient comprises 2% to 99.5% by weight of a piperidine alkyl pyridinone compound or a pharmaceutically acceptable salt thereof.

[0088] In a fourth aspect of this application, a piperidine alkyl pyridone compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the third aspect of this application, is provided for preparation by inhibiting acetylcholinesterase, inhibiting Aβ... 1-42 Applications of oligomers in the treatment and / or prevention of neuroinflammatory diseases.

[0089] The fifth aspect of this application provides the use of a piperidine alkyl pyridinone compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the third aspect of this application, in the preparation of a medicament for treating and / or preventing neurological or muscular diseases.

[0090] For example, the diseases mentioned include, but are not limited to, vascular dementia, Alzheimer's disease, frontotemporal dementia, Prion's disease, Lewy body dementia, Parkinson's disease, Huntington's disease, HIV-related dementia, multiple sclerosis, amyotrophic lateral sclerosis, sarcopenia, etc.

[0091] The following detailed embodiments illustrate this application in more detail. It should also be understood that the following embodiments are for further explanation only and should not be construed as limiting the scope of protection of this application. Any non-essential improvements and adjustments made by those skilled in the art based on the above description of this application fall within the scope of protection of this application. The specific process parameters, etc., in the following embodiments are merely examples within a suitable range; that is, those skilled in the art can make appropriate selections within the range based on the description herein, and are not necessarily limited to the specific values ​​in the embodiments below.

[0092] Example 1

[0093] Piperidine alkylpyridone compounds and their preparation methods, including the following steps:

[0094] Compound Ia (2.5 mmol), compound Ib (3.0 mmol), potassium carbonate (3.0 mmol), and DMF (40 ml) were added to a reaction flask, and the reaction was carried out at 20 °C–60 °C for 2.0–32.0 h (the reaction progress was monitored by TLC). After the reaction was completed, deionized water (60 ml) was added, and the reaction solution was extracted with ethyl acetate. The resulting organic layer was dried over anhydrous Na₂SO₄ and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography (eluent: petroleum ether-ethyl acetate = 10:1 v / v) to obtain the corresponding piperidine alkyl pyridinone compounds in yield of 42.5%–70.6%. The chemical structures of all compounds were determined by [further details needed]. 1 H-NMR, 13 The purity of the obtained target compounds was confirmed by C-NMR and ESI-MS, and determined by HPLC to be greater than 96.0%. The structures of the target compounds prepared by the above general method are shown in Tables 1 and 2 below:

[0095] Table 1. Structures of piperidine alkyl pyridone compounds

[0096]

[0097]

[0098]

[0099]

[0100]

[0101]

[0102]

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109]

[0110] Table 2 Structures of piperidine alkyl pyridone compounds

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128]

[0129]

[0130] The NMR data for some compounds are as follows:

[0131]

[0132] 1 H NMR (CDCl3): 7.34 (dd, J1 = 9.2 Hz, J2 = 2.4 Hz, 1H), 7.33-7.20 (m,5H), 7.07 (d, J = 2.4 Hz, 1H), 6.55 (d, J = 9.2 Hz, 1H), 3.77 (d, J = 7.2 Hz,2H), 3.49 (s, 2H), 3.18 (t, J = 8.4 Hz, 1H), 2.89 (d, J = 10.8 Hz, 2H), 2.77(t, J = 8.4 Hz, 1H), 2.23 (q, J = 9.2 Hz, 1H), 2.15 (s, 3H), 2.11-2.02 (m,1H), 2.01-1.83 (m, 4H), 1.82-1.71 (m, 1H), 1.71-1.56 (m, 3H), 1.43-1.30 (m, 2H); 13 C NMR (CDCl3): 162.7, 139.3, 138.1, 136.1, 129.2, 128.2, 127.0, 121.2,120.0, 67.8, 63.2, 56.6, 55.9, 53.1, 40.2, 34.8, 33.9, 29.7, 22.3.

[0133]

[0134] 1H NMR (CDCl3): 7.42-7.31 (m, 2H), 7.27-7.19 (m, 1H), 7.14-7.06 (m,2H), 7.02 (t, J = 9.2 Hz, 1H), 6.55 (d, J = 9.2 Hz, 1H), 3.77 (d, J = 7.2 Hz,2H), 3.60 (s, 2H), 3.19 (t, J = 8.4 Hz, 1H), 2.93 (d, J = 10.8 Hz, 2H), 2.79(t, J = 8.4 Hz, 1H), 2.25 (q, J = 9.2 Hz, 1H), 2.15 (s, 3H), 2.12-2.00 (m,3H), 2.00-1.84 (m, 2H), 1.84-1.73 (m, 1H), 1.72-1.57 (m, 3H), 1.46-1.32 (m,2H); 13 C NMR (CDCl3): 162.7, 161.4 (d, J C-F = 244.6 Hz), 139.3, 136.2, 131.7(d, J C-F = 4.5 Hz), 128.9 (d, J C-F = 8.2 Hz), 124.3 (d, J C-F = 13.5 Hz), 123.9(d, J C-F = 3.6 Hz), 121.3, 119.9, 115.2 (d, J C-F = 22.2 Hz), 67.8, 56.6, 55.8,55.3, 52.8, 40.1, 34.6, 33.8, 29.6, 22.3。

[0135]

[0136] 1H NMR (CDCl3): 7.38-7.22 (m, 6H), 7.13 (d, J = 2.4 Hz, 1H), 6.54 (d,J = 9.2 Hz, 1H), 4.02-3.83 (m, 2H), 3.49 (s, 2H), 3.18 (t, J = 8.4 Hz, 1H),2.87 (d, J = 10.8 Hz, 2H), 2.79 (t, J = 8.4 Hz, 1H), 2.24 (q, J = 9.2 Hz,1H), 2.16 (s, 3H), 2.13-2.03 (m, 1H), 2.01-1.84 (m, 3H), 1.83-1.74 (m, 1H),1.74-1.59 (m, 5H), 1.41-1.26 (m, 3H); 13 C NMR (CDCl3): 162.5, 139.2, 138.3,135.0, 129.2, 128.1, 126.9, 121.2, 120.6, 67.8, 63.4, 56.7, 53.6, 47.6, 40.2,36.0, 33.9, 33.5, 32.1, 22.2。

[0137]

[0138] 1H NMR (CDCl3): 7.40-7.34 (m, 1H), 7.33(dd, J1 = 9.2 Hz, J2 = 2.4 Hz,1H), 7.25-7.19 (m, 1H), 7.14 (d, J = 2.4 Hz, 1H), 7.10 (t, J = 7.6 Hz, 1H),7.01 (t, J = 9.2 Hz, 1H), 6.54 (d, J = 9.2 Hz, 1H), 4.01-3.85 (m, 2H), 3.57(s, 2H), 3.18 (t, J = 8.4 Hz, 1H), 2.90 (d, J = 10.8 Hz, 2H), 2.79 (t, J =8.4 Hz, 1H), 2.24 (q, J = 9.2 Hz, 1H), 2.16 (s, 3H), 2.12-2.05 (m, 1H), 2.05-1.96 (m, 2H), 1.94-1.83 (m, 1H), 1.83-1.75 (m, 1H), 1.74-1.60 (m, 5H), 1.40-1.28 (m, 3H); 13 C NMR (CDCl3): 162.5, 161.3 (d, J C-F = 244.4 Hz), 139.2, 135.0,131.7(d, J C-F = 4.5 Hz), 128.7 (d, J C-F = 8.2 Hz), 124.8 (d, J C-F = 14.6 Hz),123.8 (d, J C-F = 5.6 Hz), 121.2, 120.6, 115.2 (d, J C-F = 22.4 Hz), 67.8, 56.7,55.5, 53.4, 47.5, 40.2, 35.9, 33.9, 33.4, 32.1, 22.3。

[0139]

[0140] 1H NMR (CDCl3): 7.33 (dd, J1 = 9.2 Hz, J2 = 2.4 Hz, 1H), 7.32-7.21 (m,5H), 7.14 (d, J = 2.4 Hz, 1H), 6.55 (d, J = 9.2 Hz, 1H), 3.96-3.80 (m, 2H),3.48 (s, 2H), 3.18 (t, J = 8.4 Hz, 1H), 2.86 (d, J = 10.8 Hz, 2H), 2.79 (t, J= 8.4 Hz, 1H), 2.24 (q, J = 9.2 Hz, 1H), 2.16 (s, 3H), 2.12-2.03 (m, 1H),1.96-1.85 (m, 3H), 1.81-1.71 (m, 3H), 1.69-1.60 (m, 3H), 1.32-1.19 (m, 5H); 13 C NMR (CDCl3): 162.5, 139.2, 138.2, 135.2, 129.3, 128.1, 127.0, 121.2,120.5, 67.8, 63.4, 56.7, 53.8, 50.0, 40.2, 35.4, 33.9, 33.4, 32.2, 26.6,22.3。

[0141]

[0142] 1H NMR (CDCl3): 7.34 (dd, J1 = 9.2 Hz, J2 = 2.4 Hz, 1H), 7.27-7.21 (m,1H), 7.15 (d, J = 2.4 Hz, 1H), 7.09-7.01 (m, 2H), 6.92 (t, J = 8.4 Hz, 1H),6.55 (d, J = 9.2 Hz, 1H), 3.96-3.82 (m, 2H), 3.46 (s, 2H), 3.19 (t, J = 8.4Hz, 1H), 2.84 (d, J = 10.8 Hz, 2H), 2.80 (t, J = 8.4 Hz, 1H), 2.24 (q, J =9.2 Hz 1H), 2.16 (s, 3H), 2.09 (m, 1H), 1.97-1.85 (m, 3H), 1.82-1.72 (m, 3H),1.70-1.59 (m, 3H), 1.31-1.22 (m, 5H); 13 C NMR (CDCl3): 162.9 (d, J C-F = 243.7Hz), 162.5, 141.5 (d, J C-F = 6.9 Hz), 139.3, 135.2, 129.5 (d, J C-F = 8.1 Hz),124.6 (d, J C-F = 2.7 Hz), 121.2, 120.5, 115.8 (d, J C-F = 21.0 Hz), 113.7 (d,J C-F = 21.1 Hz), 67.9, 62.9, 56.7, 53.8, 50.1, 40.2, 35.4, 34.0, 33.4, 32.3,26.7, 22.3。

[0143]

[0144] 1H NMR (CDCl3): 7.37-7.31 (m, 2H), 7.21 (t, J = 7.6 Hz, 1H), 7.14 (d,J = 2.4 Hz, 1H), 6.92 (t, J = 7.6 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.55 (d,J = 9.2 Hz, 1H), 3.95-3.83 (m, 2H), 3.81 (s, 3H), 3.55 (s, 2H), 3.18 (t, J =8.4 Hz, 1H), 2.92 (d, J = 10.8 Hz, 2H), 2.79 (t, J = 8.4 Hz, 1H), 2.24 (q, J= 9.2 Hz, 1H), 2.16 (s, 3H), 2.13-2.04 (m, 1H), 2.04-1.95 (m, 2H), 1.94-1.84(m, 1H), 1.83-1.71 (m, 3H), 1.69-1.59 (m, 3H), 1.33-1.20 (m, 5H); 13 C NMR(CDCl3): 162.5, 157.8, 139.3, 135.2, 130.7, 128.0, 126.3, 121.2, 120.5,120.3, 110.4, 67.9, 56.7, 56.3, 55.4, 53.8, 50.0, 40.2, 35.4, 33.9, 33.5,32.3, 26.7, 22.3。

[0145]

[0146] 1H NMR (CDCl3): 7.47 (d, J = 7.6 Hz, 1H), 7.34 (dd, J1 = 9.2 Hz, J2 =2.4 Hz, 1H), 7.20 (t, J = 7.6, 1H), 7.15 (d, J = 2.4 Hz, 1H), 7.07 (d, J =7.6 Hz, 1H), 7.02 (t, J = 7.6 Hz, 1H), 6.55 (d, J = 9.2 Hz, 1H), 3.95-3.80(m, 2H), 3.56 (s, 2H), 3.18 (t, J = 8.4 Hz, 1H), 2.89 (d, J = 10.8 Hz, 2H),2.79 (t, J = 8.4 Hz, 1H), 2.69 (s, 6H), 2.24 (q, J = 9.2 Hz, 1H), 2.16 (s,3H), 2.13-2.04 (m, 1H), 2.02-1.94 (m, 2H), 1.93-1.84 (m, 1H), 1.81-1.71 (m,3H), 1.69-1.59 (m, 3H), 1.32-1.19 (m, 5H); 13 C NMR (CDCl3): 162.5, 153.2,139.2, 135.2, 132.8, 130.2, 127.2, 122.8, 121.2, 120.5, 118.9, 67.9, 57.8,56.7, 53.9, 50.1, 45.1, 40.2, 35.6, 33.9, 33.5, 32.4, 26.7, 22.3。

[0147]

[0148] 1H NMR (CDCl3): 8.55 (d, J = 4.8 Hz, 1H), 7.64 (t, J = 7.2 Hz, 1H),7.40 (d, J = 7.2 Hz, 1H), 7.34 (dd, J1 = 9.2 Hz, J2 = 2.4 Hz, 1H), 7.17-7.12(m, 2H), 6.55 (d, J = 9.2 Hz, 1H), 3.96-3.81 (m, 2H), 3.63 (s, 2H), 3.18 (t,J = 8.4 Hz, 1H), 2.88 (d, J = 10.8 Hz, 2H), 2.80 (t, J = 8.4 Hz, 1H), 2.24(q, J = 9.2 Hz, 1H), 2.17 (s, 3H), 2.14-1.98 (m, 3H), 1.96-1.83 (m, 1H),1.83-1.71 (m, 3H), 1.70-1.59 (m, 3H), 1.32-1.23 (m, 5H); 13 C NMR (CDCl3):162.5, 158.9, 149.1, 139.2, 136.3, 135.2, 123.2, 121.9, 121.1, 120.5, 67.8,65.0, 56.7, 54.1, 50.0, 40.2, 35.3, 33.9, 33.4, 32.2, 26.6, 22.3。

[0149]

[0150] 1H NMR (CDCl3): 8.51 (s, 1H), 8.49 (d, J = 4.8 Hz, 1H), 7.65 (d, J =7.8 Hz, 1H), 7.34 (dd, J1 = 9.2 Hz, J2 = 2.4 Hz, 1H), 7.24 (dd, J = 7.8, 4.8Hz, 1H), 7.15 (d, J = 2.4 Hz, 1H), 6.55 (d, J = 9.2 Hz, 1H), 3.96-3.79 (m,2H), 3.47 (s, 2H), 3.19 (t, J = 8.4 Hz, 1H), 2.83 (d, J = 10.8 Hz, 2H), 2.79(t, J = 8.4 Hz, 1H), 2.25 (q, J = 9.2 Hz, 1H), 2.17 (s, 3H), 2.13-2.04 (m,1H), 1.98-1.85 (m, 3H), 1.83-1.71 (m, 3H), 1.70-1.61 (m, 3H), 1.33-1.19 (m,5H); 13 C NMR (CDCl3): 162.5, 150.4, 148.4, 139.2, 136.7, 135.2, 133.9, 123.2,121.1, 120.5, 67.8, 60.6, 56.6, 53.8, 50.0, 40.2, 35.4, 33.9, 33.4, 32.2,26.6, 22.2。

[0151]

[0152] 1H NMR (CDCl3): 7.35 (dd, J1 = 9.2 Hz, J2 = 2.4 Hz, 1H), 7.32-7.22 (m,5H), 7.07 (d, J = 2.4 Hz, 1H), 6.55 (d, J = 9.2 Hz, 1H), 3.77 (d, J = 7.2 Hz,2H), 3.50 (s, 2H), 3.18 (t, J = 8.4 Hz, 1H), 2.90 (d, J = 11.2 Hz, 2H), 2.77(t, J = 8.4 Hz, 1H), 2.24 (q, J = 9.2 Hz, 1H), 2.14 (s, 3H), 2.08-2.02 (m,1H), 1.99-1.85 (m, 4H), 1.81-1.73 (m, 1H), 1.68-1.56 (m, 3H), 1.41-1.32 (m, 2H); 13 C NMR (CDCl3): 162.7, 139.4, 138.1, 136.2, 129.3, 128.2, 127.1, 121.3,120.1, 67.8, 63.2, 56.7, 55.9, 53.1, 40.2, 34.8, 33.9, 29.7, 22.3.

[0153] The piperidine alkyl pyridone compounds from the above embodiments were subjected to the following bioactivity screening:

[0154] (1) Inhibitory activity of piperidine alkyl pyridone compounds against acetylcholinesterase and butyrylcholinesterase

[0155] Add 30 µL of 1.0 mmol / L acetylcholine iodide or thiobutyrylcholine iodide, 40 µL of PBS buffer (pH 7.4), 20 µL of the test compound solution (DMSO content less than 1%), and 10 µL of acetylcholinesterase (AChE, 5% supernatant of rat cerebral cortex homogenate, pH 7.4 phosphate buffer as homogenizing medium) or butyrylcholinesterase (25% supernatant of rat serum, pH 7.4 phosphate buffer as homogenizing medium) solution sequentially to a 96-well plate. After adding the test compound and mixing well, incubate at 37°C for 15 min. Add 30 µL of 0.2% 5,5'-dithio-bis(2-nitrobenzoic acid) (DTNB) solution to each well for color development. Measure the optical density (OD value) of each well at 405 nm using a microplate reader. Compare with the blank wells without the test sample to calculate the inhibition rate of the compound on the enzyme (enzyme inhibition rate (%) = (1 - OD value of sample group / OD value of blank group) × 100%) Select five to six concentrations of the compound, determine their enzyme inhibition rate, and perform linear regression on the negative logarithm of the molar concentration of the compound and the enzyme inhibition rate to obtain the molar concentration at which 50% inhibition rate is obtained, which is the IC50 of the compound. 50 The test results show that the piperidine alkyl pyridone compounds, in which R2 is benzyl, substituted benzyl, or pyridine methyl substituted, disclosed in the embodiments of the present invention, all have a significant inhibitory effect on acetylcholinesterase, and their IC50 values ​​are [not specified]. 50 The values ​​ranged from 0.25 µM to 21.3 µM. The inhibitory activities of some compounds in the examples are shown in Table 3 below:

[0156] Table 3. Inhibitory activity of some compounds in the examples.

[0157]

[0158] In the table, "+" indicates IC. 50 Values ​​between 10.0 µM and 21.3 µM, with "++" indicating IC 50 Values ​​range from 1.0 µM to 10.0 µM; "++" indicates IC 50 The values ​​range from 250 nM to 1.0 µM.

[0159] However, when R2 is substituted with methyl, ethyl, or isopropyl, the corresponding piperidine alkyl pyridone compounds (such as compounds 2-1 and 2-2) have almost no inhibitory activity against acetylcholinesterase (their IC50 values ​​are approximately 100%). 50 All values ​​were greater than 60.0 µM. Furthermore, the results showed that piperidine alkyl pyridone compounds with benzyl, substituted benzyl, or pyridine methyl substituted R2 exhibited significantly higher inhibitory activity against acetylcholinesterase than against butyrylcholinesterase (selectivity greater than 5.0-fold in both cases). Currently, rivastigmine, used clinically, has an IC50 value for AChE inhibition. 50The IC50 for inhibition of butyrylcholinesterase was 15.8 µM. 50 The concentration was 6.0 µM. Furthermore, the starting material Ia (2-pyridone compound) and (S)-nicotine used in the preparation of piperidine alkyl pyridinone compounds showed almost no inhibitory activity against acetylcholinesterase (its IC50 value was 6.0 µM). 50 (All are greater than 60.0 µM). Further structure-activity relationship studies revealed that the (S)-configuration compounds in the examples and their corresponding racemates showed no significant difference in inhibitory activity against acetylcholinesterase, indicating that the chiral configuration of the compounds in the examples has no effect on the inhibitory activity against acetylcholinesterase.

[0160] (2) Piperidine alkylpyridone compounds on Aβ 1-42 Inhibitory activity of oligomers

[0161] The determination was performed according to the method reported in the literature (Qiang, XM et al. Eur. J Med. Chem. 2014, 76, 314-331), namely: pretreated Aβ 1-42 Prepare a stock solution using DMSO, and dilute to 20 μM with PBS buffer (pH 7.4) before use. Prepare a 2.5 mM stock solution of the analyte using DMSO, and dilute to the appropriate concentration with PBS buffer (pH 7.4) before use. Take 20 μL of Aβ... 1-42 Solution + 20 μL of the analyte solution, 20 μL of Aβ 1-42 Add 20 μL of PBS buffer (containing 2% DMSO) to a 96-well plate and incubate at 37°C for 24 h. Then add 160 μL of 50 mM glycine-NaOH buffer (pH=8.5) containing 5 μM thioflavone T, shake for 5 s, and immediately measure the fluorescence value using a multi-functional microplate reader at an excitation wavelength of 446 nm and an emission wavelength of 490 nm. Aβ 1-42 +The fluorescence value of the test compound is denoted as IF. i , Aβ 1-42 The fluorescence value of +PBS buffer is denoted as IF. c The fluorescence value containing only PBS buffer is recorded as IF0, and the compound inhibits Aβ. 1-42 The inhibition rate of self-aggregation is: 100 - (IF) i -IF0) / (IF c -IF0)*100; select five to six concentrations of the compound and determine their inhibition rate; repeat the test three times for each compound at each concentration, using curcumin as a positive control. The results show that all piperidine alkyl pyridone compounds disclosed in the embodiments of this invention inhibit Aβ. 1-42 It exhibits strong inhibitory activity against oligomer formation, showing a significant effect at a concentration of 25.0 µM on Aβ. 1-42The inhibition rate of oligomer formation ranged from 32.8% to 65.3%; the starting material compounds Ia (2-pyridone compounds) and (S)-nicotine at a concentration of 25.0 µM had an inhibitory effect on Aβ. 1-42 The inhibition rate of oligomer formation was less than 25.0%.

[0162] (3) Inhibitory activity of piperidine alkyl pyridone compounds against neuroinflammation

[0163] (a) Effects of compounds and lipopolysaccharide (LPS) on BV-2 cell viability

[0164] Logarithmically growing BV-2 cells were prepared into a cell suspension and seeded into 96-well plates. The plates were incubated at 37°C in a 5% CO2 incubator for 24 hours until cell attachment. Then, 90 μL of serum-free fresh culture medium was added, and 10 μL of each concentration of the test compound was added for pre-incubation for 30 minutes. Three parallel wells were used for each concentration, with a blank control group included. LPS was added or not added, and the plates were incubated at 37°C in a 5% CO2 incubator for another 24 hours. MTT solution was added, and the plates were incubated at 37°C for 4 hours. The supernatant was discarded, and 200 μL of DMSO solution was added to each well. After gentle shaking for 10 minutes, the OD value was measured at 490 nm using a microplate reader. The mean OD value of each test sample at different concentrations was calculated, and cell viability was calculated using the following formula: Cell viability (%) = Mean OD value of the drug group / Mean OD value of the control group × 100%. Test results show that all piperidine alkyl pyridinone compounds disclosed in the embodiments of the present invention, and the starting material compound Ia (2-pyridinone compound) used did not show cytotoxicity (inhibition rate less than 10%) at a concentration not exceeding 15 µM.

[0165] (b) Effects of piperidine alkyl pyridone compounds on LPS-induced release of NO and TNF-α from BV-2 cells

[0166] Logarithmically growing BV-2 cells were prepared into cell suspensions and seeded into 96-well plates. The plates were incubated at 37°C in a 5% CO2 incubator for 24 hours until cell attachment. The medium was then replaced with 90 µL of serum-free fresh culture medium. Each concentration of the test compound was added and pre-incubated for 30 minutes in triplicate. A blank control group was also included. LPS stimulation (1.0 μg / mL) was then added, and the plates were incubated at 37°C in a 5% CO2 incubator for another 24 hours. The cell culture supernatants from different treatment groups were collected, and the levels of NO and TNF-α in the supernatants were measured according to the instructions of the NO kit and ELISA kit. Test results show that all piperidine alkyl pyridone compounds disclosed in the embodiments of this invention exhibited inhibitory effects on LPS-induced NO and TNF-α production in BV-2 cells within the concentration range of 0.5 µM to 5.0 µM (with inhibition rates exceeding 20.0% for both NO and TNF-α production at 5.0 µM concentration), and showed a clear dose-response relationship; indicating that the piperidine alkyl pyridone compounds disclosed in the embodiments of this invention possess anti-neuroinflammatory activity. The study also found that the starting material compound Ia (2-pyridone compound) and (S)-nicotine used in the embodiments of this invention had weaker anti-neuroinflammatory activity (with inhibition rates of less than 15.0% for both LPS-induced NO and TNF-α production in BV-2 cells at 5.0 µM concentration).

[0167] (4) Effects of piperidine alkyl pyridinone compounds on scopolamine-induced memory acquisition impairment in mice

[0168] SPF-grade male ICR mice, weighing 25-30g, were randomly divided into: a normal group, a model group, a positive control group, and high, medium, and low dose groups of the test drug (18.0mg / kg, 6.0mg / kg, and 2.0mg / kg), with 10 animals in each group. The test drug was administered via gavage once. The blank group and the model group were given 0.5% CMC-Na solvent at a volume of 0.1ml / 10g. Forty-five minutes after administration, the normal group mice were intraperitoneally injected with physiological saline, while the other groups were injected with scopolamine (3.0mg / kg). Thirty minutes after modeling, the mice were placed in a non-electrically stimulated Y-maze for behavioral testing. During the test, the mice were placed at the end of one arm and allowed to freely roam the maze for 8 minutes. The number of times they entered each arm and the number of alternations were recorded. The alternation rate was calculated using the following formula: Alternation rate % = [Number of alternations / (Total number of entries - 2)] × 100. Results are expressed as mean ± standard deviation. Differences between groups were analyzed using one-way ANOVA. The results showed that, under the experimental conditions, the tested piperidine alkyl pyridone compounds (compounds 3-5, 3-29, and 7-4 of the examples) had a dose-dependent ameliorative effect on scopolamine-induced acquired memory impairment in mice (prolonging latency and reducing the number of errors), with statistically significant differences compared with the model group (p<0.001). Moreover, their activity was significantly higher than that of (S)-nicotine at the same molar concentration (p<0.01) and stronger than that of the clinical drug rivastigmine at the same molar concentration (p<0.01).

[0169] As can be seen from the above, the piperidine alkyl pyridone compounds of this application have an effect on acetylcholinesterase and Aβ. 1-42 Oligomers have strong inhibitory activity and anti-neuroinflammatory activity.

[0170] Example 2

[0171] A method for preparing a salt of piperidine alkyl pyridinone compounds with an acid includes the following steps:

[0172] 2.0 mmol of the piperidine alkyl pyridone compound obtained in Example 1 above and 25 ml of acetone were added to the reaction flask. After stirring evenly, 4.2 mmol of the corresponding acid was added. The mixture was stirred at room temperature for 30 minutes, and the solvent was removed by vacuum evaporation. The residue was purified to obtain the salt of the piperidine alkyl pyridone compound. Its chemical structure was confirmed by 1H NMR and ESI-MS.

[0173] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0174] The embodiments described above are merely illustrative of several implementation methods of this application, intended to facilitate a detailed understanding of the technical solutions of this application, but should not be construed as limiting the scope of protection of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of this application, and these all fall within the scope of protection of this application. It should be understood that technical solutions obtained by those skilled in the art based on the technical solutions provided in this application through logical analysis, reasoning, or limited experimentation are all within the scope of protection of the appended claims. Therefore, the scope of protection of this patent application should be determined by the content of the appended claims, and the specification can be used to interpret the content of the claims.

Claims

1. A piperidine alkyl pyridinone compound having the structure shown in formula (I) or a pharmaceutically acceptable salt thereof: ； in, R1 is selected from or R 11 Selected from C1~C5 alkyl groups; R2 is selected from or m is any integer from 1 to 5, q is any integer from 1 to 4, and S1 is independently selected from H, halogen, cyano, C1-C5 alkyl, C1-C5 alkoxy, -NH(R) each time it appears. 21 ), -N(R 21 )2 or -NHCO-(R 21 The halogens include F, Cl, Br, or I, R 21 Selected from C1~C5 alkyl groups; n is any integer from 1 to 10.

2. The piperidine alkyl pyridone compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, R 11 R1 is selected from C1~C3 alkyl groups; R1 is selected from... or ; R2 is selected from or m is any integer from 1 to 3, q ​​is any integer from 1 to 3; each time S1 appears, it is independently selected from H, F, Cl, Br, I, -CN, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, -N(CH3)2 or -NHCOCH3; n is any integer from 1 to 5; The chiral configuration of the piperidine alkyl pyridinone compounds is one or both of the R and S configurations in any proportion.

3. The piperidine alkyl pyridinone compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, The piperidine alkyl pyridone compound is and One or more of the following; Wherein, R2 is selected from benzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 3,4-difluorobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 2-(acetamido)benzyl, 3-(acetamido)benzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 2-methylbenzyl, 4-methylbenzyl, 2-(dimethylamino)benzyl, 3-(dimethylamino)benzyl, 4-(dimethylamino)benzyl, 2-cyanobenzyl, 4-cyanobenzyl, (2-pyridine)methyl, (3-pyridine)methyl or (4-pyridine)methyl; n is any integer from 1 to 5.

4. The piperidine alkyl pyridinone compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that, The pharmaceutically acceptable salt is prepared by reacting the piperidine alkylpyridone compound with an acid; suitable acids for salt formation are hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, aminosulfonic acid, hydrofluoric acid, C1-C6 alkylcarboxylic acid, trifluoroacetic acid, stearic acid, pyric acid, oxalic acid, benzoic acid, phenylacetic acid, salicylic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, malic acid, lactic acid, hydroxymaleic acid, pyruvic acid, glutamic acid, ascorbic acid, lipoic acid, C1-C6 alkylsulfonic acid, camphor sulfonic acid, naphthalene sulfonic acid, benzene sulfonic acid, p-toluene sulfonic acid, and 1,4-butanedisulfonic acid, or one or more of these.

5. A method for preparing a piperidine alkyl pyridinone compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, characterized in that, Includes the following steps: Compound Ia With compound Ib The piperidine alkylpyridone compound was prepared by reacting under solvent and alkaline conditions. Wherein, R1, R2 and n are as defined in any one of claims 1 to 3; X is selected from Cl, Br, I, benzenesulfonyloxy, p-toluenesulfonyloxy, or methanesulfonyloxy.

6. The method for preparing the piperidine alkyl pyridinone compound or a pharmaceutically acceptable salt thereof according to claim 5, characterized in that, The molar ratio of compound Ia to compound Ib is 1:(1~5); The molar ratio of compound Ia to the base providing the alkaline conditions is 1:(1~5). The reaction temperature is 0℃~150℃; The reaction time is 1 hour to 80 hours.

7. The method for preparing the piperidine alkyl pyridinone compound or a pharmaceutically acceptable salt thereof according to claim 5 or 6, characterized in that, The base providing the alkaline conditions is one or more of alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth metal carbonates, alkali metal bicarbonates, alkali metal hydrides, and alkaline earth metal hydrides. The solvent is one or more selected from fatty alcohols, fatty ketones, dichloromethane, chloroform, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, diethyl ether, benzene, toluene, acetonitrile, 1,4-dioxane, ethylene glycol dimethyl ether, and alkane solvents.

8. A pharmaceutical composition, characterized in that, It includes the piperidine alkyl pyridone compounds as described in any one of claims 1 to 4, or pharmaceutically acceptable salts thereof; and pharmaceutically acceptable carriers.

9. The piperidine alkyl pyridone compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 8, in the preparation of a drug by inhibiting acetylcholinesterase and Aβ. 1-42 Applications of oligomers in drugs for treating diseases involving neuroinflammation or by promoting oligomer aggregation.

10. The use of the piperidine alkyl pyridone compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 8, in the preparation of a medicament for treating neurological or muscular diseases, wherein the neurological and muscular diseases are vascular dementia, Alzheimer's disease, frontotemporal dementia, Prion's disease, Lewy body dementia, Parkinson's disease, Huntington's disease, HIV-related dementia, multiple sclerosis, amyotrophic lateral sclerosis, or sarcopenia.

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