WO2024104331A1 - Prodrug of levodopa - Google Patents

Abstract

The present disclosure relates to a prodrug of levodopa. Specifically, the present disclosure relates to a prodrug of levodopa and a pharmaceutical composition thereof, and the use of such prodrug and pharmaceutical composition in the treatment of diseases such as Parkinson's disease.

Description

A prodrug of levodopa

This application claims the priority of Chinese patent application No. 2022114254116 filed on November 14, 2022. This application cites the entire text of the above Chinese patent application.

Technical Field

The present invention belongs to the field of medicine, and specifically relates to a prodrug of levodopa and a pharmaceutical composition thereof.

Background technique

Parkinson's disease (PD) is characterized by the loss of the ability of dopaminergic neurons in the substantia nigra to produce the neurotransmitter dopamine. PD damages motor skills, cognitive processes, autonomic nervous function and sleep. After more than 40 years of clinical application, levodopa therapy is still the most effective method for treating PD and provides the greatest improvement in motor function. Therefore, levodopa administration is the primary treatment for PD. Usually levodopa is administered orally. Orally administered levodopa enters the blood, and a portion of the levodopa in the blood passes through the blood-brain barrier and is partially metabolized into dopamine in the brain, which temporarily eliminates the motor symptoms of PD.

The main problems with the clinical use of levodopa include: 1) The need to take the drug frequently. Rapid-release and sustained-release preparations have a short duration of effect, and symptoms may not be relieved after taking the drug; 2) Peripheral adverse reactions. Since decarboxylase is widely present in peripheral organs and blood vessel walls, levodopa is mostly converted into dopamine during absorption and transport. The latter cannot enter the brain, but can also stimulate dopamine receptors in multiple systems, leading to the occurrence of peripheral adverse reactions, manifested as gastrointestinal symptoms such as nausea, vomiting, and loss of appetite; 3) Central adverse reactions. After long-term use of levodopa preparations for 3-5 years, 20-30% of patients will experience dyskinesia, such as switching phenomena, involuntary fluctuations, etc. Some patients can be relieved by reducing the dosage, but some patients experience biphasic dyskinesia, which cannot be solved clinically.

Since the problems related to levodopa treatment have not been solved, there is an urgent need for improved treatment methods. For example, by developing levodopa derivatives, especially levodopa prodrugs to improve clinical treatment effects. Several levodopa prodrugs have been disclosed, for example, US3998799A, JP2001213799A, WO2012079072, WO2015054302, WO2016155888, etc. disclose a series of levodopa prodrug compounds.

Summary of the invention

In one aspect, the present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

in,

One of R ₁ and R ₄ is selected from hydrogen, alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally substituted by one or more substituents Q ₁ ,

Another one selected from

R ₅ is selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic group, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted by one or more substituents Q ₁ ;

_L1 is or does not exist,

R ₂ and R ₃ are each independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, mercapto, oxo, -NR _i R _j , cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl are optionally substituted with one or more substituents Q ₁ , or R ₂ and R ₃ together with the carbon atom to which they are attached form a cycloalkyl or heterocyclic group optionally substituted with one or more substituents Q ₁ ;

R ₂ 'and R ₃ 'are each independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, mercapto, oxo, -NR _i R _j , cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl are optionally substituted by one or more substituents Q ₁ , or R ₂ 'and R ₃ 'and the carbon atom to which they are attached together form a cycloalkyl or heterocyclic group optionally substituted by one or more substituents Q ₁ ;

A is -CR _a R _b -, -NR _c -, -O- or -S-;

_Ra and _Rb are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a hydroxyl group, an oxo group _{, -NRiRj} , wherein the alkyl group, the alkoxy group, the haloalkyl group is optionally substituted by one or more substituents selected from halogen, hydroxyl group, thiol group, _-NRiRj , carboxyl _group , nitro group, cyano group, _C1 - _C6 alkoxy group, _C1 - _C6 alkylthioether group, _C2 - _C6 alkenyl group and _C2 - _C6 alkynyl group, or _Ra and _Rb together with the carbon atom to which they are attached form a cycloalkyl group or heterocyclic group optionally substituted by one or more substituents _Q1 ;

R _c is selected from hydrogen, alkyl, haloalkyl, alkoxy, and hydroxyl, wherein the alkyl, alkoxy, and haloalkyl are optionally substituted by one or more substituents selected from halogen, hydroxyl, mercapto, -NR _i R _j , carboxyl, nitro, cyano, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthioether, C ₂ -C ₆ alkenyl, and C ₂ -C ₆ alkynyl;

n1 is an integer from 0 to 6, and n2 is an integer from 0 to 6;

_L2 is or does not exist,

R ₁₂ and R ₁₃ are each independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, mercapto, oxo, -NR _i R _j , cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl are optionally substituted with one or more substituents Q ₁ , or R ₁₂ and R ₁₃ together with the carbon atom to which they are attached form a cycloalkyl or heterocyclic group optionally substituted with one or more substituents Q ₁ ;

R ₁₂ 'and R ₁₃ 'are each independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, mercapto, oxo, -NR _i R _j , cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl are optionally substituted with one or more substituents Q ₁ , or R ₁₂ 'and R ₁₃ 'and the carbon atom to which they are attached together form a cycloalkyl or heterocyclic group optionally substituted with one or more substituents Q ₁ ;

A' is -CR _a 'R _b '-, -NR _c '-, -O- or -S-;

_Ra ' and _Rb ' are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a hydroxyl group, an oxo group, _-NRiRj , wherein the alkyl group, the alkoxy group, the _haloalkyl group is optionally substituted by one or more substituents selected from halogen, hydroxyl group, thiol group, _-NRiRj , carboxyl _group , nitro group, cyano group, _C1 - _C6 alkoxy group, _C1 - _C6 alkylthioether group, _C2 - _C6 alkenyl group and _C2 - _C6 alkynyl group, or _Ra ' and _Rb ' together with the carbon atom to which they are attached form a cycloalkyl group or heterocyclic group optionally substituted by one or more substituents _Q1 ;

R _c ' is selected from hydrogen, alkyl, haloalkyl, alkoxy, and hydroxyl, wherein the alkyl, alkoxy, and haloalkyl are optionally substituted by one or more substituents selected from halogen, hydroxyl, mercapto, -NR _i R _j , carboxyl, nitro, cyano, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthioether, C ₂ -C ₆ alkenyl, and C ₂ -C ₆ alkynyl;

n11 is an integer from 0 to 6, and n12 is an integer from 0 to 6;

The substituent groups _Q1 are each independently selected from _C1 - _C6 alkyl, halogen, hydroxyl, thiol, _-NRiRj , _oxo , thioxo, -C(O) _Rk , -C(O) _ORk , -S(O) _Rk , -S(O) _ORk , -S(O)(O) _Rk , -S(O)(O) _ORk , -C(S) _Rk , nitro, cyano, C1- _C6 alkoxy, _C1 -C6 alkylthioether, _{C2 - C6} alkenyl, _C2 - _C6 alkynyl, 3- to 10 _- membered cycloalkyl, 3- to 10-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 8- to 12-membered fused ring aryl, and 5- to 12-membered fused heteroaryl;

R _i and R _j are each independently selected from a hydrogen atom, a hydroxyl group, a C ₁ -C ₆ alkyl group, and a C ₁ -C ₆ alkoxy group; R _{k is} independently selected from a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group, a C ₁ -C ₆ alkoxy group, a hydroxyl group, and a -NR _i R _j , wherein the alkyl group, the alkoxy group, and the haloalkyl group are optionally substituted with one or more substituents selected from a C ₁ -C ₆ alkyl group, a halogen group, a hydroxyl group, a thiol group, -NR _i R _j , an oxo group, a thioxo group, a carboxyl group, a nitro group, a cyano group, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkylthioether group, a C ₂ -C ₆ alkenyl group, a C ₂ -C ₆ alkynyl group, a 3- to 10-membered cycloalkyl group, a 3- to 10-membered heterocyclyl group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group.

In some embodiments, one of R ₁ and R ₄ is selected from hydrogen atom, C ₁ to C ₆ alkyl, 3 to 10-membered cycloalkyl, 3 to 10-membered heterocyclyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one or more substituents Q ₁ ,

Another one selected from

In some embodiments, _R2 and _R3 are each independently selected from a hydrogen atom, a _C1 - _C6 alkyl group, a _C1 - _C6 alkoxy group, a halogen, a hydroxyl group, a thiol group, an _oxo group, _-NRiRj , a 3- to 10-membered cycloalkyl group, and a 3- to 10-membered heterocyclyl group, wherein the alkyl group, the alkoxy group, the cycloalkyl group, and the heterocyclyl group are optionally substituted with one or more substituents _Q1 , or _R2 and _R3 together with the carbon atom to which they are attached form a 3- to 10-membered cycloalkyl group or a 3- to 10-membered heterocyclyl group optionally substituted with one or more substituents _Q1 .

In some embodiments, R ₂ ' and R ₃ ' are each independently selected from a hydrogen atom, a C ₁ ~ C ₆ alkyl group, a C ₁ ~ C ₆ alkoxy group, a halogen, a hydroxyl group, a thiol group, an oxo group, -NR _i R _j , a 3 to 10-membered cycloalkyl group, and a 3 to 10-membered heterocyclyl group, wherein the alkyl group, the alkoxy group, the cycloalkyl group, and the heterocyclyl group are optionally substituted with one or more substituents Q ₁ , or R ₂ ' and R ₃ ' together with the carbon atom to which they are attached form a 3 to 10-membered cycloalkyl group or a 3 to 10-membered heterocyclyl group optionally substituted with one or more substituents Q ₁ .

In some embodiments, _Ra and _Rb are each independently selected from a hydrogen atom, a _C1 - _C6 alkyl group, a halogenated _C1 - _C6 alkyl group, a _C1 - _C6 alkoxy group, an oxo group, a hydroxyl group, _{or -NRiRj} , wherein the alkyl group, the alkoxy group, or the halogenated alkyl group is optionally substituted with one or more substituents selected from halogen, hydroxyl group, _-NRiRj , _carboxyl group, nitro group, cyano group, and _C1 - _C6 alkoxy group, or _Ra and _Rb together with the carbon atom to which they are attached form a cycloalkyl group or a heterocyclic group optionally substituted with one or more substituents _Q1 .

In some embodiments, R _c is selected from hydrogen atom, C ₁ -C ₆ alkyl, halogenated C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, wherein the alkyl, alkoxy, halogenated alkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl, -NR _i R _j , carboxyl, nitro, cyano and C ₁ -C ₆ alkoxy.

In some embodiments, R ₁₂ and R ₁₃ are each independently selected from a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a halogen, a hydroxyl group, a thiol group, an oxo group, -NR _i R _j , a 3 to 10-membered cycloalkyl group, and a 3 to 10-membered heterocyclyl group, wherein the alkyl group, the alkoxy group, the cycloalkyl group, and the heterocyclyl group are optionally substituted with one or more substituents Q ₁ , or R ₁₂ and R ₁₃ together with the carbon atom to which they are attached form a 3 to 10-membered cycloalkyl group or a 3 to 10-membered heterocyclyl group optionally substituted with one or more substituents Q ₁ .

In some embodiments, R ₁₂ ′ and R ₁₃ ′ are each independently selected from a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a halogen, a hydroxyl group, Mercapto, oxo, -NR _i R _j , 3 to 10 membered cycloalkyl and 3 to 10 membered heterocyclyl, wherein the alkyl, alkoxy, cycloalkyl and heterocyclyl are optionally substituted by one or more substituents Q ₁ , or R ₁₂ 'and R ₁₃ 'together with the carbon atom to which they are attached form a 3 to 10 membered cycloalkyl or 3 to 10 membered heterocyclyl optionally substituted by one or more substituents Q ₁ .

In some embodiments, _Ra ' and _Rb ' are each independently selected from a hydrogen atom, a _C1 - _C6 alkyl group, a halogenated _C1 - _C6 alkyl group, a _C1 - _C6 alkoxy group, an oxo group, a hydroxyl group, _{or -NRiRj} , wherein the alkyl group, the alkoxy group, or the halogenated alkyl group is optionally substituted with one or more substituents selected from halogen, hydroxyl group, _-NRiRj , carboxyl _group , nitro group, cyano group, and _C1 - _C6 alkoxy group, or _Ra ' and _Rb ' together with the carbon atom to which they are attached form a cycloalkyl group or a heterocyclic group optionally substituted with one or more substituents _Q1 .

In some embodiments, R _c ′ is selected from hydrogen, C ₁ -C ₆ alkyl, halogenated C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, wherein the alkyl, alkoxy, halogenated alkyl is optionally substituted with one or more substituents selected from halogen, hydroxy, -NR _i R _j , carboxyl, nitro, cyano and C ₁ -C ₆ alkoxy.

In some embodiments, the substituent groups Q ₁ are each independently selected from C ₁ -C ₆ alkyl, halogen, hydroxyl, thiol, -NR _i R _j , oxo, thioxo, -C(O)R _k , -C(O)OR _k , -S(O)R _k , -S(O)OR _k , -S(O)(O)R _k , -S(O)(O)OR _k , -C(S)R _k , nitro, cyano, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthioether, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl.

In some embodiments, the substituent groups Q ₁ are each independently selected from C ₁ -C ₆ alkyl, halogen, hydroxy, NR _i R _j , oxo, —C(O)R _k , —C(O)OR _k , cyano, C ₁ -C ₆ alkoxy, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynyl.

In some embodiments, _R1 is selected from hydrogen, _C1 - _C6 alkyl, 3- to 10-membered cycloalkyl and 6- to 10-membered aryl, wherein the alkyl, cycloalkyl and aryl are optionally substituted with one or more substituents selected from _C1 - _C6 alkyl, _C1 - _C6 alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano,

R ₄ is selected from

In some embodiments, _R1 is selected from hydrogen, _C1 - _C6 alkyl, phenyl and benzyl, wherein the alkyl, phenyl and benzyl are optionally substituted with one or more substituents selected from _C1 - _C6 alkyl, _C1 - _C6 alkoxy, halogen and hydroxyl.

R ₄ is selected from

In some embodiments, R ₁ is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl and benzyl, and R ₄ is selected from

In some embodiments, _R4 is selected from hydrogen, _C1 - _C6 alkyl, 3- to 10-membered cycloalkyl and 6- to 10-membered aryl, wherein the alkyl, cycloalkyl and aryl are optionally substituted with one or more substituents selected from _C1 - _C6 alkyl, _C1 - _C6 alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano,

R ₁ is selected from

In some embodiments, _R4 is selected from hydrogen, _C1 - _C6 alkyl, phenyl and benzyl, wherein the alkyl, phenyl and benzyl are optionally substituted with one or more substituents selected from _C1 - _C6 alkyl, _C1 - _C6 alkoxy, halogen and hydroxyl.

R ₁ is selected from

In some embodiments, _R4 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl and benzyl, and _R1 is selected from

In some embodiments, _R2 and _R3 are each independently selected from a hydrogen atom, a _C1 - _C6 alkyl group, a _C1 - _C6 alkoxy group, a halogen, a hydroxyl group, an oxo group, an amino group, a 3- to 10-membered cycloalkyl group, and a 3- to 10-membered heterocyclyl group, wherein the alkyl group, the alkoxy group, the cycloalkyl group, and the heterocyclyl group are optionally substituted with one or more substituents selected from the group consisting of _C1 - _C6 alkyl group, _C1 - _C6 alkoxy group, a halogen, a hydroxyl group, an amino group, a carboxyl group, a nitro group, and a cyano group, or _R2 and _R3 together with the carbon atom to which they are attached form a 3- to 10-membered cycloalkyl group or a 3- to 10-membered heterocyclyl group optionally substituted with one or more substituents selected from the group consisting of _C1 - _C6 alkyl group, _C1 - _C6 alkoxy group, a halogen, a hydroxyl group, an amino group, a carboxyl group, a nitro group, and a cyano group.

In some embodiments, R ₂ 'and R ₃ 'are each independently selected from a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a halogen, a hydroxyl group, an oxo group, an amino group, a 3- to 10-membered cycloalkyl group, and a 3- to 10-membered heterocyclyl group, wherein the alkyl group, the alkoxy group, the cycloalkyl group, and the heterocyclyl group are optionally substituted with one or more substituents selected from the group consisting of C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a halogen, a hydroxyl group, an amino group, a carboxyl group, a nitro group, and a cyano group, or R ₂ 'and R ₃ 'together with the carbon atom to which they are attached form a 3- to 10-membered cycloalkyl group or a 3- to 10-membered heterocyclyl group optionally substituted with one or more substituents selected from the group consisting of C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a halogen, a hydroxyl group, an amino group, a carboxyl group, a nitro group, and a cyano group.

In some embodiments, _R2 and _R3 are each independently selected from a hydrogen atom, a _C1 - _C6 alkyl group, a _C1 - _C6 alkoxy group, a halogen, an oxo group, a hydroxyl group, and an amino group, wherein the alkyl group and the alkoxy group are optionally substituted with one or more substituents selected from a _C1 - _C6 alkyl group, a _C1 - _C6 alkoxy group, a halogen, a hydroxyl group, an amino group, a carboxyl group, a nitro group, and a cyano group.

In some embodiments, R ₂ ' and R ₃ ' are each independently selected from a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a halogen, an oxo group, a hydroxyl group and an amino group, wherein the alkyl group and the alkoxy group are optionally substituted with one or more substituents selected from a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a halogen, a hydroxyl group, an amino group, a carboxyl group, a nitro group and a cyano group.

In some embodiments, R ₂ and R ₃ are each independently selected from a hydrogen atom, a C ₁ -C ₆ alkyl group, a halogen, and a hydroxyl group.

In some embodiments, R ₂ ′ and R ₃ ′ are each independently selected from a hydrogen atom, a C ₁ -C ₆ alkyl group, a halogen, and a hydroxyl group.

In some embodiments, _Ra and _Rb are each independently selected from a hydrogen atom, a _C1 - _C6 alkyl group, a _C1 - _C6 alkoxy group, a halogen, a hydroxyl group, an oxo group, an amino group, a 3- to 10-membered cycloalkyl group, and a 3- to 10-membered heterocyclyl group, wherein the alkyl group, the alkoxy group, the cycloalkyl group, and the heterocyclyl group are optionally substituted with one or more substituents selected from _C1 - _C6 alkyl group, _C1 - _C6 alkoxy group, a halogen, a hydroxyl group, an amino group, a carboxyl group, a nitro group, and a cyano group, or _Ra and _Rb together with the carbon atom to which they are attached form a 3- to 10-membered cycloalkyl group or a 3- to 10-membered heterocyclyl group optionally substituted with one or more substituents selected from _C1 - _C6 alkyl group, _C1 - _C6 alkoxy group, a halogen, a hydroxyl group, an amino group, a carboxyl group, a nitro group, and a cyano group.

In some embodiments, _Ra and _Rb are each independently selected from a hydrogen atom, a _C1 - _C6 alkyl group, a _C1 - _C6 alkoxy group, a halogen, an oxo group, a hydroxyl group, and an amino group, wherein the alkyl group and the alkoxy group are optionally substituted with one or more substituents selected from a _C1 - _C6 alkyl group, a _C1 - _C6 alkoxy group, a halogen, a hydroxyl group, an amino group, a carboxyl group, a nitro group, and a cyano group.

In some embodiments, _Ra and _Rb are each independently selected from a hydrogen atom, a _C1 - _C6 alkyl group, a halogen, and a hydroxyl group.

In some embodiments, R _c is selected from hydrogen atom, C ₁ -C ₆ alkyl, halogenated C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, wherein the alkyl, alkoxy, halogenated alkyl is optionally substituted with one or more substituents selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano.

In some embodiments, R _c is selected from a hydrogen atom, a C ₁ -C ₆ alkyl group, a halogenated C ₁ -C ₆ alkyl group, and a C ₁ -C ₆ alkoxy group.

In some embodiments, R ₁₂ and R ₁₃ are each independently selected from a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a halogen, a hydroxyl group, an oxo group, an amino group, a 3- to 10-membered cycloalkyl group, and a 3- to 10-membered heterocyclyl group, wherein the alkyl group, the alkoxy group, the cycloalkyl group, and the heterocyclyl group are optionally substituted with one or more substituents selected from the group consisting of C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, a halogen, a hydroxyl group, an amino group, a carboxyl group, a nitro group, and a cyano group, or R ₁₂ and R ₁₃ together with the carbon atom to which they are attached form a 3- to 10-membered cycloalkyl group or a 3- to 10-membered heterocyclyl group optionally substituted with one or more substituents selected from the group consisting of C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a halogen, a hydroxyl group, an amino group, a carboxyl group, a nitro group, and a cyano group.

In some embodiments, R ₁₂ 'and R ₁₃ 'are each independently selected from a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a halogen, a hydroxyl group, an oxo group, an amino group, a 3- to 10-membered cycloalkyl group, and a 3- to 10-membered heterocyclyl group, wherein the alkyl group, the alkoxy group, the cycloalkyl group, and the heterocyclyl group are optionally substituted with one or more substituents selected from the group consisting of C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a halogen, a hydroxyl group, an amino group, a carboxyl group, a nitro group, and a cyano group; or R ₁₂ 'and R ₁₃ 'together with the carbon atom to which they are attached form a 3- to 10-membered cycloalkyl group or a 3- to 10-membered heterocyclyl group optionally substituted with one or more substituents selected from the group consisting of C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a halogen, a hydroxyl group, an amino group, a carboxyl group, a nitro group, and a cyano group.

In some embodiments, R ₁₂ and R ₁₃ are each independently selected from a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a halogen, an oxo group, a hydroxyl group, and an amino group, wherein the alkyl group and the alkoxy group are optionally substituted with one or more substituents selected from a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a halogen, a hydroxyl group, an amino group, a carboxyl group, a nitro group, and a cyano group.

In some embodiments, R ₁₂ ' and R ₁₃ ' are each independently selected from a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a halogen, an oxo group, a hydroxyl group and an amino group, wherein the alkyl group and the alkoxy group are optionally substituted with one or more substituents selected from a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a halogen, a hydroxyl group, an amino group, a carboxyl group, a nitro group and a cyano group.

In some embodiments, R ₁₂ and R ₁₃ are each independently selected from a hydrogen atom, a C ₁ -C ₆ alkyl group, a halogen, and a hydroxyl group.

In some embodiments, R ₁₂ ′ and R ₁₃ ′ are each independently selected from a hydrogen atom, a C ₁ -C ₆ alkyl group, a halogen, and a hydroxyl group.

In some embodiments, _Ra ' and _Rb ' are each independently selected from a hydrogen atom, a _C1 - _C6 alkyl group, a _C1 - _C6 alkoxy group, a halogen, a hydroxyl group, an oxo group, an amino group, a 3- to 10-membered cycloalkyl group, and a 3- to 10-membered heterocyclyl group, wherein the alkyl group, the alkoxy group, the cycloalkyl group, and the heterocyclyl group are optionally substituted with one or more substituents selected from the group consisting of _C1 - _C6 alkyl group, _C1 - _C6 alkoxy group, a halogen, a hydroxyl group, an amino group, a carboxyl group, a nitro group, and a cyano group, or Ra _' and _Rb ' together with the carbon atom to which they are attached form a 3- to 10-membered cycloalkyl group or a 3- to 10-membered heterocyclyl group optionally substituted with one or more substituents selected from the group consisting of _C1 - _C6 alkyl group, _C1 - _C6 alkoxy group, a halogen, a hydroxyl group, an amino group, a carboxyl group, a nitro group, and a cyano group.

In some embodiments, _Ra ' and _Rb ' are each independently selected from a hydrogen atom, a _C1 - _C6 alkyl group, a _C1 - _C6 alkoxy group, a halogen, an oxo group, a hydroxyl group, and an amino group, wherein the alkyl group and the alkoxy group are optionally substituted with one or more substituents selected from a _C1 - _C6 alkyl group, a _C1 - _C6 alkoxy group, a halogen, a hydroxyl group, an amino group, a carboxyl group, a nitro group, and a cyano group.

In some embodiments, Ra _' and _Rb ' are each independently selected from a hydrogen atom, a _C1 - _C6 alkyl group, a halogen, and a hydroxyl group.

In some embodiments, R _c ' is selected from hydrogen atom, C ₁ -C ₆ alkyl, halogenated C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, wherein the alkyl, alkoxy, halogenated alkyl is optionally substituted with one or more substituents selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano.

In some embodiments, R _c ′ is selected from a hydrogen atom, a C ₁ -C ₆ alkyl group, a halogenated C ₁ -C ₆ alkyl group, and a C ₁ -C ₆ alkoxy group.

In some embodiments, R ₅ is selected from a hydrogen atom, a C ₁ -C ₆ alkyl group, a halogenated C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a hydroxyl group, and -NR _i R _j , wherein the alkyl group, the alkoxy group, and the halogenated alkyl group are optionally substituted with one or more substituents selected from halogen, hydroxyl group, -NR _i R _j , carboxyl group, nitro group, cyano group, and C ₁ -C ₆ alkoxy group.

In some embodiments, R ₅ is selected from hydrogen, C ₁ -C ₆ alkyl, halogenated C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy, wherein the alkyl, alkoxy and halogenated alkyl are optionally substituted with one or more substituents selected from halogen, hydroxyl and amino.

In some embodiments, R ₅ is selected from the group consisting of a hydrogen atom, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group, a n-pentyl group, an isopentyl group, a sec-pentyl group, and a neopentyl group.

In some embodiments, R _i and R _j are each independently selected from a hydrogen atom, a hydroxyl group, a C ₁ -C ₆ alkyl group, and a C ₁ -C ₆ alkoxy group.

In some embodiments, R _k is independently selected from a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group, a C ₁ -C ₆ alkoxy group, a hydroxyl group, and -NR _i R _j .

In some embodiments, it is a compound represented by formula (I-1) or formula (I-2) or a pharmaceutically acceptable salt thereof,

wherein R ₁ , R ₂ , R ₃ , R ₅ , n1, R ₁₂ , R ₁₃ and n11 are as described above.

In some embodiments, the compound is selected from

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is

In some embodiments, the compound is

The present disclosure also provides isotope substitutions of the aforementioned compounds or pharmaceutically acceptable salts thereof, preferably the isotope substitution is deuterium atom substitution.

The "alkyl group" described in the present disclosure is preferably a C ₁ -C ₆ alkyl group.

The "alkenyl group" described in the present disclosure is preferably a C ₂ -C ₆ alkenyl group.

The "alkynyl" described in the present disclosure is preferably a C ₂ -C ₆ alkynyl.

The "alkoxy group" described in the present disclosure is preferably a C ₁ -C ₆ alkoxy group.

The “alkylthioether group” described in the present disclosure is preferably a C ₁ -C ₆ alkylthioether group.

The "cycloalkyl group" described in the present disclosure is preferably a 3- to 12-membered, more preferably a 3- to 10-membered cycloalkyl group.

The "spirocycloalkyl" described in the present disclosure is preferably a 6- to 14-membered, more preferably a 7- to 10-membered spirocycloalkyl.

The "bridged cycloalkyl group" described in the present disclosure is preferably a 6- to 14-membered, more preferably a 7- to 10-membered, bridged cycloalkyl group.

The "fused cycloalkyl" described in the present disclosure is preferably a 6- to 14-membered, more preferably a 7- to 10-membered fused cycloalkyl.

The "heterocyclic group" described in the present disclosure is preferably a 3- to 12-membered, more preferably a 3- to 10-membered heterocyclic group.

The "spiro heterocyclic group" described in the present disclosure is preferably a 6- to 14-membered, more preferably a 7- to 10-membered spiro heterocyclic group.

The "bridged heterocyclic group" described in the present disclosure is preferably a 6- to 14-membered, more preferably a 7- to 10-membered bridged heterocyclic group.

The "fused heterocyclic group" described in the present disclosure is preferably a 6- to 14-membered, more preferably a 7- to 10-membered fused heterocyclic group.

The "aryl group" described in the present disclosure is preferably a 6- to 14-membered group, more preferably a 6- to 10-membered aryl group.

The "fused ring aryl group" described in the present disclosure preferably has 8 to 14 members, and more preferably has 8 to 12 members.

The "heteroaryl group" described in the present disclosure is preferably a 5- to 12-membered group, and more preferably a 5- to 10-membered heteroaryl group.

The “fused heteroaryl group” described in the present disclosure is preferably a 5- to 14-membered, more preferably a 5- to 12-membered, fused heteroaryl group.

The present disclosure also provides a pharmaceutical composition, comprising at least one of the aforementioned compounds or a pharmaceutically acceptable salt or isotope substitute thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

In some embodiments, the pharmaceutical composition contains 0.01%-99.99% of the aforementioned compound based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1%-99.9% of the aforementioned compound. In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound. In some embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound. In some embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound.

In some embodiments, the pharmaceutical composition contains 0.01%-99.99% of a pharmaceutically acceptable carrier, diluent or excipient, based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1%-99.9% of a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, the pharmaceutical composition contains 1%-99% of a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, the pharmaceutical composition contains 2%-98% of a pharmaceutically acceptable carrier, diluent or excipient.

The active compound can be prepared into a form suitable for administration by any appropriate route, and the composition of the present disclosure can be prepared by conventional methods using one or more pharmaceutically acceptable carriers. Therefore, the active compound of the present disclosure can be formulated into various dosage forms for oral administration, injection (e.g., intravenous, intramuscular or subcutaneous) administration, inhalation or insufflation administration. The compounds of the present disclosure can also be formulated into dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges or syrups.

The present disclosure also provides the use of the compounds described in the present disclosure, their pharmaceutically acceptable salts or isotopic substitutions or pharmaceutical compositions in the preparation of a method for treating and/or preventing a disease, wherein the disease is selected from Parkinson's disease, depression, attention deficit disorder, schizophrenia, manic depression, cognitive disorders, restless legs syndrome, periodic limb movement disorder, tardive dyskinesia, Huntington's disease, Tourette's syndrome, hypertension, addictive diseases, stroke, congestive heart failure, excessive daytime sleepiness, dystonia, memory and learning disorders or loss, and Lewy body disease. In certain embodiments, the disease is selected from depression, attention deficit disorder, schizophrenia, manic depression, cognitive disorders, restless legs syndrome, periodic limb movement disorder, tardive dyskinesia, Huntington's disease, Tourette's syndrome, hypertension, addictive diseases, congestive heart failure, stroke, excessive daytime sleepiness, dystonia, and memory and learning impairment or loss.

The present disclosure further provides a method for treating a disease, wherein the mammal may be a human or a non-human mammal, for therapeutic purposes, comprising administering the compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in the present disclosure to the mammal.

The present disclosure further provides a kit comprising the compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in the present disclosure.

Terminology explanation:

Unless stated otherwise, the terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof. More preferred are alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include cycloalkyls of spirocyclic, condensed and bridged rings. "Carbocycle" refers to the ring system in a cycloalkyl.

The term "spirocycloalkyl" refers to a polycyclic group in which a carbon atom (called a spiro atom) is shared between 5 to 20 monocyclic rings, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14, more preferably 7 to 10. According to the number of shared spiro atoms between rings, the spirocycloalkyl is divided into a single spirocycloalkyl, a double spirocycloalkyl or a multi-spirocycloalkyl, preferably a single spirocycloalkyl and a double spirocycloalkyl. More preferably, it is a 4-yuan/4-yuan, 4-yuan/5-yuan, 4-yuan/6-yuan, 5-yuan/5-yuan or 5-yuan/6-yuan single spirocycloalkyl. "Spiro carbocycle" refers to the ring system in the spirocycloalkyl. Non-limiting examples of spirocycloalkyl include:

The term "condensed cycloalkyl" refers to a 5-20-membered, all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6-14 members, more preferably 7-10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl. The alkyl group is preferably a bicyclic or tricyclic ring, and more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl group. "Fused carbocycle" refers to the ring system in a fused cycloalkyl group. Non-limiting examples of fused cycloalkyl groups include:

The term "bridged cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, and more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably a bicyclic, tricyclic or tetracyclic, and more preferably a bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. The cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen or S(O) _m (wherein m is an integer from 0 to 2), but excluding the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 6 ring atoms. Non-limiting examples of monocyclic heterocyclyls include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc., preferably piperidinyl, pyrrolidinyl. Polycyclic heterocyclyls include spirocyclic, fused and bridged heterocyclyls. "Heterocycle" refers to the ring system in the heterocyclyl.

The term "spiro heterocyclic group" refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between 5 to 20 monocyclic rings, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of spiro atoms shared between rings, the spiro heterocyclic group is divided into a single spiro heterocyclic group, a double spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a single spiro heterocyclic group and a double spiro heterocyclic group. More preferably, it is a 4-member/4-member, 4-member/5-member, 4-member/6-member, 5-member/5-member or 5-member/6-member single spiro heterocyclic group. "Spiro heterocycle" refers to the ring system in the spiro heterocyclic group. Non-limiting examples of spiro heterocyclic groups include:

The term "fused heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 20 members, each ring in the system shares a pair of atoms adjacent to other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic group, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. "Fussed heterocycle" refers to the ring system in a fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:

The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:

wait.

The heterocyclic group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently is selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group with a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, wherein the ring that is attached to the parent structure is the aryl ring. "Aromatic ring" refers to the ring system in an aryl group. Non-limiting examples of aryl groups include:

The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate, preferably phenyl.

The term "condensed ring aryl" can be an unsaturated aromatic condensed ring structure containing 8-14 ring atoms formed by two or more ring structures sharing two adjacent atoms, preferably 8-12 ring atoms. For example, it includes all unsaturated condensed ring aryl groups, such as naphthalene, phenanthrene, etc., and also includes partially saturated condensed ring aryl groups, such as benzo 3-8 membered saturated monocyclic cycloalkyl, benzo 3-8 membered partially saturated monocyclic cycloalkyl. "Condensed aromatic ring" refers to the ring system in the condensed ring aryl group. Specific examples of condensed ring aryl groups include 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, etc.

The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 12 members, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, pyrazolyl, pyrimidyl or thiazolyl; more preferably pyrazolyl or thiazolyl. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring. "Heteroaromatic ring" refers to the ring system in a heteroaryl group. Non-limiting examples of heteroaryl include:

The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

The term "fused heteroaryl" may be an unsaturated fused ring structure with aromaticity containing 5-14 ring atoms (including at least one heteroatom) formed by two or more ring structures sharing two adjacent atoms to form a structure, wherein the carbon atoms, nitrogen atoms and sulfur atoms may be substituted with oxygen, preferably "5-12 membered fused heteroaryl", "7-12 membered fused heteroaryl", "9-12 membered fused heteroaryl" and the like, for example, benzofuranyl, benzisofuranyl, benzothiophenyl, indolyl, isoindole, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolyl, 2-quinolinone, 4-quinolinone, 1-isoquinolinone, isoquinolyl, acridinyl, phenanthridinyl, benzopyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, phenolazinyl, pteridinyl, purinyl, naphthyridinyl, phenazine, phenothiazine and the like. "Fused heteroaryl ring" refers to the ring system in a fused heteroaryl group.

The fused heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

The term "alkoxy" refers to-O-(alkyl) and-O-(unsubstituted cycloalkyl), wherein the definition of alkyl is as described above. The non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

The term "alkylthio" refers to -S-(alkyl) and -S-(non-substituted cycloalkyl), wherein the definition of alkyl is as described above. Non-limiting examples of alkylthio include: methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio. Alkylthio can be optionally substituted or non-substituted, and when substituted, substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio and one or more substituents.

The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

The term "haloalkyl" refers to an alkyl group substituted with a halogen, wherein alkyl is as defined above.

The term "deuterated alkyl" refers to an alkyl group substituted with a deuterium atom, wherein alkyl is as defined above.

The term "hydroxy" refers to an -OH group.

The term "oxo" refers to a =0 group. For example, a carbon atom is connected to an oxygen atom via a double bond, wherein a ketone or aldehyde group is formed.

The term "thio" refers to a =S group. For example, a carbon atom is connected to a sulfur atom via a double bond to form a thiocarbonyl group -C(S)-.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "amino" refers to _-NH2 .

The term "cyano" refers to -CN.

The term "nitro" refers to _-NO2 .

The term "carboxy" refers to -C(O)OH.

The term "aldehyde" refers to -CHO.

The term "carboxylate" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

The term "acyl halide" refers to a compound containing the group -C(O)-halogen.

The term "sulfonyl" refers to -S(O)(O)-.

The term "sulfinyl" refers to -S(O)-.

"Isosteres" of chemical groups are other chemical groups that exhibit the same or similar properties. For example, tetrazole is an isostere of carboxylic acid because it mimics the properties of carboxylic acid, even though the two have very different molecular formulas. Tetrazole is one of many possible isosteric replacements for carboxylic acid. Other contemplated carboxylic acid isosteres include -SO ₃ H, -SO ₂ HNR, -PO ₂ (R) ₂ , -PO ₃ (R) ₂ , -CONHNHSO ₂ R, -COHNSO ₂ R, and -CONRCN, wherein R is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl as defined herein. In addition, carboxylic acid isosteres may contain 5- to 7-membered carbocyclic or heterocyclic rings containing any combination of CH ₂ , O, S, or N in any chemically stable oxidation state, wherein any one of the atoms of the ring structure is optionally substituted at one or more positions. It is contemplated that it is also contemplated that when a chemical substituent is added to a carboxyl isostere, the compound retains the property of the carboxyl isostere. It is contemplated that when a carboxyl isostere is selected from one or more parts of R as defined above and optionally substituted, then degree of substitution (substitution) and substitution position are selected so that it will not eliminate the carboxylic acid isostere property of the compound. Similarly, it is also contemplated that if one or more R substituents can destroy the carboxylic acid isostere property of the compound, the position of such substituents on carbocyclic or heterocyclic carboxylic acid isosteres is not located at the replacement of the carboxylic acid isostere property of the compound to remain intact or to be intact one or more atoms.

"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

"Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the skilled person can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g. olefinic) bonds.

In the chemical structures of the compounds disclosed herein, the bond No configuration is specified, i.e., the bond Can be or include both In the chemical structure of the compounds disclosed in the present invention, the bond The configuration is not specified, that is, it can be Z configuration or E configuration, or contain both configurations.

Although all of the above formulae are drawn in certain isomeric forms for simplicity, the present disclosure may include all isomers, such as tautomers, rotational isomers, geometric isomers, diastereomers, racemates, and enantiomers.

Tautomers are structural isomers of organic compounds that are easily interconvertible through a chemical reaction known as tautomerization. This reaction often results in the formal migration of hydrogen atoms or protons, accompanied by the conversion of single bonds and adjacent double bonds. Some common tautomeric pairs are: keto-enol, lactam-lactim. An example of a lactam-lactim equilibrium is between A and B as shown below.

All compounds in the present disclosure can be drawn as either Form A or Form B. All tautomeric forms are within the scope of the present disclosure. The naming of the compounds does not exclude any tautomers.

Any isotopically labeled derivatives of the compounds or pharmaceutically acceptable salts thereof or isomers thereof described in the present disclosure are covered by the present disclosure. Atoms that can be isotopically labeled include, but are not limited to, hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, iodine, etc. They can be labeled with isotopes. ^2H (D), ^3H , ^11C , ^13C , ^14C , ^15N , ^18F , ^31P , ^32P , ^35S , ^36Cl and ^125I , etc. Unless otherwise indicated, when a position is specifically designated as deuterium (D), the position is understood to have an abundance of deuterium (i.e., at least 45% deuterium incorporation) that is at least 3000 times greater than the natural abundance of deuterium, which is 0.015%.

Unless otherwise specified, when a position is specifically designated as deuterium (D), the position is understood to have deuterium (i.e., at least 10% deuterium incorporation) at least 1000 times greater than the natural abundance of deuterium (which is 0.015%). The natural abundance of the compound in the example may be at least 1000 times greater than deuterium, at least 2000 times greater than deuterium, at least 3000 times greater than deuterium, at least 4000 times greater than deuterium, at least 5000 times greater than deuterium, at least 6000 times greater than deuterium or more. The present disclosure also includes various deuterated forms of the formula (I) compound. Each available hydrogen atom connected to a carbon atom may be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of the formula (I) compound with reference to the relevant literature. In preparing deuterated forms of compounds of formula (I), commercially available deuterated starting materials may be used, or they may be synthesized using conventional techniques using deuterated reagents, including but not limited to deuterated borane, trideuterated borane in tetrahydrofuran, deuterated lithium aluminum hydride, deuterated iodoethane and deuterated iodomethane, and the like.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 is an in vitro conversion curve of compound 1 when the prodrug compound 1 is converted into levodopa;

FIG2 is a drug-time curve of levodopa when the prodrug compound 1 is converted into levodopa;

FIG3 is a pharmacokinetic curve of compound 1 and L-DOPA in dogs after continuous intravenous infusion for 6 hours at a dose of 120 mpk;

FIG4 shows the pharmacokinetic curves of Compound 1 and L-DOPA in dogs after continuous intravenous infusion for 6 hours at a dose of 360 mpk.

Detailed ways

The preparation of the compounds and pharmaceutically acceptable salts described in the present disclosure is further described below in conjunction with examples, but these examples are not intended to limit the scope of the present disclosure.

The experimental methods in the examples of this disclosure that do not specify specific conditions are usually carried out under conventional conditions or under conditions recommended by raw material or product manufacturers. Reagents that do not specify specific sources are conventional reagents purchased from the market.

NMR shift (δ) is given in units of 10 ^-6 (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, using deuterated dimethyl sulfoxide (DMSO-d ⁶ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD) as the solvent, and tetramethylsilane (TMS) as the internal standard.

MS was measured using Shimadzu 2010 Mass Spectrometer or Agilent 6110A MSD mass spectrometer.

HPLC determination was performed using Shimadzu LC-20A systems, Shimadzu LC-2010HT series or Agilent 1200 LC high pressure liquid chromatograph (Ultimate XB-C18 3.0*150mm column or Xtimate C18 2.1*30mm column).

Chiral HPLC analysis was performed using Chiralpak IC-3 100×4.6mm I.D., 3um, Chiralpak AD-3 150×4.6mm I.D., 3um, Chiralpak AD-3 50×4.6mm I.D., 3um, Chiralpak AS-3 150×4.6mm I.D., 3um, Chiralpak AS-3 100×4.6mm I.D., 3μm, ChiralCel OD-3 150×4.6mm I .D.,3um, Chiralcel OD-3 100×4.6mm I.D.,3μm, ChiralCel OJ-H 150×4.6mm I.D.,5um, Chiralcel OJ-3 150×4.6mm I.D.,3um chromatographic columns; thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates, the specifications of the silica gel plates used in thin layer chromatography (TLC) are 0.15mm～0.2mm, and the specifications of thin layer chromatography separation and purification products are 0.4mm～0.5mm.

Column chromatography generally uses Yantai Huanghai silica gel 100-200 mesh, 200-300 mesh or 300-400 mesh silica gel as the carrier.

Chiral preparative column using DAICEL CHIRALPAK IC (250mm*30mm,10um) or Phenomenex-Amylose-1 (250mm*30mm,5um).

The CombiFlash rapid preparation instrument uses Combiflash Rf150 (TELEDYNE ISCO).

The average kinase inhibition rate and _IC50 value were determined using NovoStar microplate reader (BMG, Germany).

The known starting materials disclosed in the present invention can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals and other companies.

Unless otherwise specified in the examples, the reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1L.

Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Clear Blue QL-500 hydrogen generator or a HC2-SS hydrogenator.

The hydrogenation reaction is usually carried out by evacuating the vacuum, filling with hydrogen, and repeating the operation three times.

Microwave reactions were performed using a CEM Discover-S 908860 microwave reactor.

Unless otherwise specified in the examples, the solution refers to an aqueous solution.

Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

The reaction progress in the embodiment is monitored by thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of column chromatography used for purifying the compound and the developing solvent system of thin layer chromatography include: A: dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: petroleum ether/ethyl acetate system, D: petroleum ether/ethyl acetate/methanol, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

The abbreviations used in the following experiments have the following meanings:

EtOAc: ethyl acetate; DCM: dichloromethane; DIPEA: N,N-diisopropylethylamine; PPTS: pyridinium p-toluenesulfonate; Boc: tert-butyloxycarbonyl, MeOH: methanol.

Example 1

Preparation of compound 1-1

4-(Hydroxymethyl)-5-methyl-[1,3]dioxol-2-one (5.20g, 0.04mol), pyridine (3.95g, 0.05mol), 50mL of anhydrous DCM were added to the reaction bottle, cooled to -10°C, 4-nitrobenzene chloroformate (10.00g, 0.05mol) was dissolved in 50mL of anhydrous DCM, slowly added dropwise to the above reaction system, and stirred at room temperature. After the reaction was completed, 100mL of DCM was added, washed with sodium hydroxide solution, potassium bisulfate solution and purified water, the organic phase was dried with anhydrous magnesium sulfate, concentrated to dryness, the residue was dissolved in 50mL of DCM, n-hexane was added dropwise, and stirred. Filtered and dried to obtain the title product 1-1 (9g, yield: 76%)

Preparation of compound 1-2

Add levodopa (19.70 g, 0.10 mol), tert-butyldimethylsilyl chloride (52.50 g, 0.35 mol), and 300 mL of anhydrous acetonitrile to the reaction flask, cool to -25 °C and stir for 0.5 h. Slowly drip DBU (53.20 g, 0.35 mol) into the above reaction system, then return to room temperature and stir. Add about 50 mL of methanol to quench after the reaction is completed, concentrate to dryness, dissolve the residue in 100 mL of methanol, add acetonitrile dropwise, and stir. Filter and dry to obtain the title product 1-2 (34.85 g, yield: 81.9%)

Preparation of Compound 1-3

Compound 1-2 (8.30 g, 0.02 mol), compound 1-1 (8.85 g, 0.03 mol), pyridine (1.58 g, 0.02 mol) 100 mL of anhydrous tetrahydrofuran were added to the reaction flask and stirred at room temperature for 0.5 h. Triethylamine (2.02 g, 0.02 mol) was dissolved in 20 mL of anhydrous tetrahydrofuran and slowly added dropwise to the above reaction system and stirred at room temperature. After the reaction was completed, 100 mL of 10% potassium bisulfate solution was added to quench, extracted with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The title product 1-3 (9.87 g, yield: 84.9%) was obtained by silica gel column chromatography with an eluent system (MeOH: DCM = 1:20)

MS m/z(ESI):580.33[M-1] ^- .

¹ H NMR (DMSO-d ₆ ) δppm 12.73 (s, 1H), 7.72 (d, J＝8.4 Hz, 1H), 6.77-6.66 (m, 3H), 4.85-4.75 (m, 2H), 4.10-3.98(m,1H),2.96-2.87(m,1H),2.73-2.65(m,1H),2.10(s,3H),0.931(s,18H),0.149(s,12H)

Preparation of compound 1

Compound 1-3 (5.85 g, 0.01 mol) and 100 mL of anhydrous tetrahydrofuran were added to the reaction flask, triethylamine trihydrofluoride (8.05 g, 0.05 mol) was dissolved in 20 mL of anhydrous tetrahydrofuran, and slowly added dropwise to the above reaction system, and stirred at room temperature. After the reaction, 200 mL of purified water was added, extracted with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The title product 1 (3.20 g, yield: 90.6%) was obtained by silica gel column chromatography with an eluent system (MeOH:DCM=1:20)

MS m/z(ESI):703.35[2M-1] ^- .

¹ H NMR (DMSO-d ₆ ) δ ppm 12.67 (s, 1H), 8.72-8.67 (m, 2H), 7.66 (d, J＝8.4 Hz, 1H), 6.62-6.59 (m, 2H), 6.47 (dd, J ₁ ＝8 Hz, J ₂ ＝1.6 Hz, 1H), 4.82 (s, 2H), 4.07-4.02 (m, 1H), 2.86 (dd, J ₁ ＝13.6 Hz, J ₂ ＝4.4 Hz, 1H), 2.63 (dd, J ₁ ＝13.6 Hz, J ₂ ＝10.4 Hz, 1H), 2.11 (s, 3H)

Example 1-1

Compound 1 (3.25 g, 0.01 mol) and 50 mL of acetone were added to the reaction flask, and arginine (1.30 g, 0.0075 mol) was dissolved in 50 mL of deionized water and slowly added dropwise to the above reaction system and stirred at room temperature. The acetone was removed by concentration, filtration, and freeze-drying to obtain the title product 1-Arg (4.45 g, yield: 98%)

¹ H NMR (DMSO-d ₆ ) δ ppm 12.69 (s, 1H), 8.72-8.66 (m, 2H), 7.84 (d, J＝8.4 Hz, 1H), 6.63-6.56 (m, 2H), 6.46 (dd, J ₁ ＝8 Hz, J ₂ ＝2 Hz, 1H), 5.62-5.54 (m, 2H), 4.10-3.99 (m, 1H), 2.87 (dd, J ₁ ＝14 Hz, J ₂ ＝4 Hz, 1H), 2.64 (dd, J ₁ ＝14 Hz, J ₂ ＝10.4 Hz, 1H), 1.11 (s, 9H)

Example 2

Levodopa (12 g, 60.86 mmol) and 4-chloromethyl-5-methyl-1,3-dioxol-2-one (9.04 g, 60.86 mmol) were added. DMSO (120 mL) was added and stirred at room temperature until the reaction was complete. The reaction solution was purified by prep-HPLC to obtain compound 2 (8.0 g, yield: 42.5%).

MS m/z(ESI):310.1[M+1] ⁺

1H NMR (400MHz, DMSO) δ8.91 (s, 2H), 8.45 (s, 3H), 6.61 (dd, J = 21.1, 5.0 Hz, 2H), 6.39 (dd, J = 8.0, 2.0 Hz, 1H), 5.06 (s, 2H), 4.23 (t, J = 6.6 Hz, 1H), 2.92 (ddd, J = 21.2, 14.1, 6.6 Hz, 2H), 2.14 (s, 3H).

Example 3: Solubility determination

The solubility values of L-DOPA and its prodrugs in water under ambient conditions were determined by visual assessment and the results of this study are reported in Table 1.

Table 1. Solubility studies

Example 4: Stability Determination

Long-term accelerated stability study: The samples were placed at -20°C, 2-8°C and 25°C for 1 month. The properties and impurity content of compound 1 remained stable. The stability of compound 2 was significantly worse than that of compound 1 under the same storage conditions.

Table 2. Long-term and accelerated stability studies

Example 5: In vitro transformation assay

Purpose of the experiment: To investigate the stability of the prodrug molecules in human plasma, rat plasma, and rat skin homogenate and the rate of conversion to the parent drug (levodopa).

Experimental method: This experiment used HPLC-MS/MS method to establish a method for determining the concentration of prodrug and metabolite L-dopa in human, rat plasma and rat skin homogenate. The concentrations of prodrug and metabolite L-dopa were detected after incubation in human, rat plasma and rat skin homogenate samples for different times (0, 10min, 30min, 60min, 120min), and the prodrug degradation rate and half-life t1/2 were calculated.

test results:

The prodrug molecule compound 1 has a fast conversion rate in three media: human plasma, rat plasma, and rat skin homogenate, with half-lives of 32.6 min, 25.0 min, and 30.9 min, respectively.

Table 3. Half-life t1 _/2 data of prodrugs in human plasma, rat plasma, and rat skin homogenate

Example 6: In vivo transformation experiment

Purpose of the experiment: To investigate the rate at which the prodrug molecule is converted into the parent drug (levodopa) under continuous intravenous infusion in dogs and the tolerance of dogs.

Experimental method: Two dose groups (120mpk group and 360mpk group) were set up, with one female and one male dog in each group. Each dog was injected intravenously continuously and at a constant speed for 6 hours. Blood was collected at 0.25, 0.5, 1.0, 4.0, 6, 6.2, 6.5, 7.0, and 8.0h after the start of administration. About 0.5ml of venous blood was collected, and the actual blood collection time was accurately recorded. The blood concentrations of prodrug compound 1 and L-dopa were determined by HPLC-MS/MS.

Table 4. Summary of pharmacokinetic data

Experimental results: In dogs, continuous intravenous infusion of prodrug compound 1 can rapidly convert the prodrug into levodopa, and the conversion rate is not slowed down by increasing the dose.

Although the specific embodiments of the present invention are described above, it should be understood by those skilled in the art that these are only examples, and various changes or modifications may be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the protection scope of the present invention is limited by the appended claims.

Claims (20)

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
   

   in,

   One of R ₁ and R ₄ is selected from hydrogen, alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally substituted by one or more substituents Q ₁ ,

   Another one selected from

   R ₅ is selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic group, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted by one or more substituents Q ₁ ;

   _L1 is or does not exist,

   R ₂ and R ₃ are each independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, mercapto, oxo, -NR _i R _j , cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl are optionally substituted with one or more substituents Q ₁ , or R ₂ and R ₃ together with the carbon atom to which they are attached form a cycloalkyl or heterocyclic group optionally substituted with one or more substituents Q ₁ ;

   R ₂ 'and R ₃ 'are each independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, mercapto, oxo, -NR _i R _j , cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl are optionally substituted by one or more substituents Q ₁ , or R ₂ 'and R ₃ 'and the carbon atom to which they are attached together form a cycloalkyl or heterocyclic group optionally substituted by one or more substituents Q ₁ ;

   A is -CR _a R _b -, -NR _c -, -O- or -S-;

   _Ra and _Rb are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a hydroxyl group, an oxo group _{, -NRiRj} , wherein the alkyl group, the alkoxy group, the haloalkyl group is optionally substituted by one or more substituents selected from halogen, hydroxyl group, thiol group, _-NRiRj , carboxyl _group , nitro group, cyano group, _C1 - _C6 alkoxy group, _C1 - _C6 alkylthioether group, _C2 - _C6 alkenyl group and _C2 - _C6 alkynyl group, or _Ra and _Rb together with the carbon atom to which they are attached form a cycloalkyl group or heterocyclic group optionally substituted by one or more substituents _Q1 ;

   R _c is selected from hydrogen, alkyl, haloalkyl, alkoxy, and hydroxyl, wherein the alkyl, alkoxy, and haloalkyl are optionally substituted by one or more substituents selected from halogen, hydroxyl, mercapto, -NR _i R _j , carboxyl, nitro, cyano, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthioether, C ₂ -C ₆ alkenyl, and C ₂ -C ₆ alkynyl;

   n1 is an integer from 0 to 6, and n2 is an integer from 0 to 6;

   _L2 is or does not exist,

   R ₁₂ and R ₁₃ are each independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, mercapto, oxo, -NR _i R _j , cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl are optionally substituted with one or more substituents Q ₁ , or R ₁₂ and R ₁₃ together with the carbon atom to which they are attached form a cycloalkyl or heterocyclic group optionally substituted with one or more substituents Q ₁ ;

   R ₁₂ 'and R ₁₃ 'are each independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, mercapto, oxo, -NR _i R _j , cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl are optionally substituted with one or more substituents Q ₁ , or R ₁₂ 'and R ₁₃ 'and the carbon atom to which they are attached together form a cycloalkyl or heterocyclic group optionally substituted with one or more substituents Q ₁ ;

   A' is -CR _a 'R _b '-, -NR _c '-, -O- or -S-;

   _Ra ' and _Rb ' are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a hydroxyl group, an oxo _group , _-NRiRj , wherein the alkyl group, the alkoxy group, the haloalkyl group is optionally substituted by one or more substituents selected from _halogen , hydroxyl group, thiol group, _-NRiRj , carboxyl group, nitro group, cyano group, _C1 - _C6 alkoxy group, _C1 - _C6 alkylthioether group, _C2 -C6 _alkenyl group and _C2 - _C6 alkynyl group, or _Ra ' and _Rb ' together with the carbon atom to which they are attached form a cycloalkyl group or heterocyclic group optionally substituted by one or more substituents _Q1 ;

   R _c ' is selected from hydrogen, alkyl, alkoxy, hydroxyl, wherein the alkyl, alkoxy, haloalkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl, thiol, -NR _i R _j , carboxyl, nitro, cyano, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthioether, C ₂ -C ₆ alkenyl and C ₂ -C ₆ alkynyl;

   n11 is an integer from 0 to 6, and n12 is an integer from 0 to 6;

   The substituent groups _Q1 are each independently selected from _C1 - _C6 alkyl, halogen, hydroxyl, thiol, _-NRiRj , _oxo , thioxo, -C(O) _Rk , -C(O) _ORk , -S(O) _Rk , -S(O) _ORk , -S(O)(O) _Rk , -S(O)(O) _ORk , -C(S) _Rk , nitro, cyano, C1- _C6 alkoxy, _C1 -C6 alkylthioether, _{C2 - C6} alkenyl, _C2 - _C6 alkynyl, 3- to 10 _- membered cycloalkyl, 3- to 10-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 8- to 12-membered fused ring aryl, and 5- to 12-membered fused heteroaryl;

   R _i and R _j are each independently selected from a hydrogen atom, a hydroxyl group, a C ₁ -C ₆ alkyl group, and a C ₁ -C ₆ alkoxy group; R _{k is} independently selected from a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group, a C ₁ -C ₆ alkoxy group, a hydroxyl group, and -NR _i R _j , wherein the alkyl group and the alkoxy group are optionally substituted with one or more substituents selected from a C ₁ -C ₆ alkyl group, a halogen, a hydroxyl group, a thiol group, -NR _i R _j , an oxo group, a thioxo group, a carboxyl group, a nitro group, a cyano group, a C _{1 -C 6 alkoxy group, a C 1 -C 6 alkylthioether group, a C 2 -C 6 alkenyl group , a} C ₂ -C ₆ alkynyl group, a 3- to 10-membered cycloalkyl group, a 3- to 10-membered heterocyclyl group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group.
2. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein one of R ₁ and R ₄ is selected from a hydrogen atom, a C ₁ to C ₆ alkyl group, a 3 to 10-membered cycloalkyl group, a 3 to 10-membered heterocyclic group, a 6 to 10-membered aryl group and a 5 to 10-membered heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are optionally substituted by one or more substituents Q ₁ ,

   Another one selected from
3. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R ₂ and R ₃ are each independently selected from a hydrogen atom, a C ₁ ～C ₆ alkyl group, a C ₁ ～C ₆ alkoxy group, a halogen, a hydroxyl group, a thiol group, an oxo group, -NR _i R _j , a 3- to 10-membered cycloalkyl group, and a 3- to 10-membered heterocyclic group, wherein the alkyl group, the alkoxy group, the cycloalkyl group, and the heterocyclic group are optionally substituted by one or more substituents Q ₁ , or R ₂ and R ₃ together with the carbon atom to which they are attached form a 3- to 10-membered cycloalkyl group or a 3- to 10-membered heterocyclic group optionally substituted by one or more substituents Q ₁ ;

   R ₂ 'and R ₃ 'are each independently selected from a hydrogen atom, a C ₁ ～C ₆ alkyl group, a C ₁ ～C ₆ alkoxy group, a halogen, a hydroxyl group, a mercapto group, an oxo group, -NR _i R _j , a 3 to 10-membered cycloalkyl group and a 3 to 10-membered heterocyclic group, wherein the alkyl group, the alkoxy group, the cycloalkyl group and the heterocyclic group are optionally substituted by one or more substituents Q ₁ , or R ₂ 'and R ₃ 'together with the carbon atom to which they are attached form a group optionally substituted by one or more substituents Q ₁ The 3- to 10-membered cycloalkyl group or the 3- to 10-membered heterocyclic group.
4. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein _Ra and _Rb are each independently selected from a hydrogen atom, a _C1 - _C6 alkyl group, a halogenated _C1 - _C6 alkyl group, a _C1 - _C6 alkoxy group, an oxo group, a hydroxyl group, _{or -NRiRj} , wherein the alkyl group, the alkoxy group, or the halogenated alkyl group is optionally substituted by one or more substituents selected from halogen, hydroxyl group, _-NRiRj , _carboxyl group, nitro group, cyano group, and _C1 - _C6 alkoxy group, or _Ra and _Rb together with the carbon atom to which they are attached form a cycloalkyl group or heterocyclic group optionally substituted by one or more substituents _Q1 ;

   R _c is selected from hydrogen atom, C ₁ -C ₆ alkyl, halogenated C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, wherein the alkyl, alkoxy, halogenated alkyl are optionally substituted by one or more substituents selected from halogen, hydroxyl, -NR _i R _j , carboxyl, nitro, cyano and C ₁ -C ₆ alkoxy.
5. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R ₁₂ and R ₁₃ are each independently selected from a hydrogen atom, a C ₁ to C ₆ alkyl group, a C ₁ to C ₆ alkoxy group, a halogen, a hydroxyl group, a thiol group, an oxo group, -NR _i R _j , a 3 to 10-membered cycloalkyl group and a 3 to 10-membered heterocyclic group, wherein the alkyl group, the alkoxy group, the cycloalkyl group and the heterocyclic group are optionally substituted by one or more substituents Q ₁ , or R ₁₂ and R ₁₃ together with the carbon atoms to which they are attached form a 3 to 10-membered cycloalkyl group or a 3 to 10-membered heterocyclic group optionally substituted by one or more substituents Q ₁ ;

   R ₁₂ ' and R ₁₃ ' are each independently selected from a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a halogen, a hydroxyl group, a mercapto group, an oxo group, -NR _i R _j , a 3 to 10-membered cycloalkyl group and a 3 to 10-membered heterocyclic group, wherein the alkyl group, the alkoxy group, the cycloalkyl group and the heterocyclic group are optionally substituted by one or more substituents Q ₁ , or R ₁₂ ' and R ₁₃ ' together with the carbon atom to which they are attached form a 3 to 10-membered cycloalkyl group or a 3 to 10-membered heterocyclic group optionally substituted by one or more substituents Q ₁ .
6. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein Ra _' and _Rb ' are each independently selected from a hydrogen atom, a _C1 - _C6 alkyl group, a halogenated _C1 - _C6 alkyl group, a _C1 - _C6 alkoxy group, an oxo group, a hydroxyl group, _{or -NRiRj} , wherein the alkyl group, the alkoxy group, or the halogenated alkyl group is optionally substituted by one or more substituents selected from halogen, hydroxyl group, _-NRiRj , _carboxyl group, nitro group, cyano group, and _C1 - _C6 alkoxy group, or _Ra ' and _Rb ' together with the carbon atom to which they are attached form a cycloalkyl group or heterocyclic group optionally substituted by one or more substituents _Q1 ;

   R _c ' is selected from hydrogen atom, C ₁ -C ₆ alkyl, halogenated C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, wherein the alkyl, alkoxy, halogenated alkyl are optionally substituted by one or more substituents selected from halogen, hydroxyl, -NR _i R _j , carboxyl, nitro, cyano and C ₁ -C ₆ alkoxy.
7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein the substituent groups _Q1 are each independently selected from _C1 - _C6 alkyl, halogen, hydroxyl, thiol, _-NRiRj , _oxo , thio, -C(O) _Rk , -C(O) _ORk , -S(O) _Rk , -S(O) _ORk , _-S (O)(O)Rk, -S(O)(O) _ORk , _-C (S) _Rk , nitro, cyano, _C1 - _C6 alkoxy, _C1 - _C6 alkylthioether, _{C2 - C6} alkenyl or C2- _C6 alkynyl, preferably _C1 - _C6 alkyl, halogen, hydroxyl, _NRiRj , oxo, -C(O) _Rk , -C(O) _ORk , cyano, _C1 - _C6 alkoxy, _C2 - _C6 alkenyl or _C2 - _C6 alkynyl.
8. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein one of R ₁ and R ₄ is selected from a hydrogen atom, a C ₁ -C ₆ alkyl group, a 3- to 10-membered cycloalkyl group and a 6- to 10-membered aryl group, wherein the alkyl group, the cycloalkyl group and the aryl group are optionally substituted with one or more substituents selected from a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a halogen, a hydroxyl group, an amino group, a carboxyl group, a nitro group and a cyano group,

   Another one selected from

   Preferably, one of R ₁ and R ₄ is selected from hydrogen, C ₁ -C ₆ alkyl, phenyl and benzyl, wherein the alkyl, phenyl and benzyl are optionally substituted with one or more substituents selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen and hydroxyl.

   Another one selected from

   More preferably, at least one of R ₁ and R ₄ is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl and benzyl.

   Another one selected from
9. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein _R2 and _R3 are each independently selected from a hydrogen atom, a _C1 - _C6 alkyl group, a _C1 - _C6 alkoxy group, a halogen, an oxo group, a hydroxyl group and an amino group, wherein the alkyl group and the alkoxy group are optionally substituted with one or more substituents selected from a _C1 - _C6 alkyl group, a _C1 - _C6 alkoxy group, a halogen, a hydroxyl group, an amino group, a carboxyl group, a nitro group and a cyano group,

   R ₂ ' and R ₃ ' are each independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, oxo, hydroxyl and amino, wherein the alkyl and alkoxy are optionally substituted by one or more substituents selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro and cyano;

   Preferably, _R2 and _R3 are each independently selected from a hydrogen atom, a _C1 - _C6 alkyl group, a halogen and a hydroxyl group,

   R ₂ ′ and R ₃ ′ are each independently selected from a hydrogen atom, a C ₁ ˜C ₆ alkyl group, a halogen and a hydroxyl group.
10. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein _Ra and _Rb are each independently selected from a hydrogen atom, a _C1 - _C6 alkyl group, a _C1 - _C6 alkoxy group, a halogen, an oxo group, a hydroxyl group and an amino group, wherein the alkyl group and the alkoxy group are optionally substituted with one or more substituents selected from a _C1 - _C6 alkyl group, a _C1 - _C6 alkoxy group, a halogen, a hydroxyl group, an amino group, a carboxyl group, a nitro group and a cyano group,

    R _c is selected from hydrogen atom, C ₁ -C ₆ alkyl, halogenated C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, wherein the alkyl, alkoxy, halogenated alkyl is optionally substituted by one or more substituents selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano;

    Preferably, _Ra and _Rb are each independently selected from a hydrogen atom, a _C1 - _C6 alkyl group, a halogen group and a hydroxyl group,

    R _c is selected from a hydrogen atom, a C ₁ ～C ₆ alkyl group, a halogenated C ₁ ～C ₆ alkyl group, and a C ₁ ～C ₆ alkoxy group.
11. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein R ₁₂ and R ₁₃ are each independently selected from a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a halogen, an oxo group, a hydroxyl group and an amino group, wherein the alkyl group and the alkoxy group are optionally substituted with one or more substituents selected from a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a halogen, a hydroxyl group, an amino group, a carboxyl group, a nitro group and a cyano group,

    R ₁₂ 'and R ₁₃ 'are each independently selected from a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a halogen, an oxo group, a hydroxyl group and an amino group, wherein the alkyl group and the alkoxy group are optionally substituted by one or more substituents selected from a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a halogen, a hydroxyl group, an amino group, a carboxyl group, a nitro group and a cyano group;

    Preferably, R ₁₂ and R ₁₃ are each independently selected from a hydrogen atom, a C ₁ -C ₆ alkyl group, a halogen and a hydroxyl group,

    R ₁₂ ′ and R ₁₃ ′ are each independently selected from a hydrogen atom, a C ₁ ˜C ₆ alkyl group, a halogen and a hydroxyl group.
12. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein Ra _' and _Rb ' are each independently selected from a hydrogen atom, a _C1 - _C6 alkyl group, a _C1 - _C6 alkoxy group, a halogen, an oxo group, a hydroxyl group and an amino group, wherein the alkyl group and the alkoxy group are optionally substituted with one or more substituents selected from a _C1 - _C6 alkyl group, a _C1 - _C6 alkoxy group, a halogen, a hydroxyl group, an amino group, a carboxyl group, a nitro group and a cyano group,

    R _c ' is selected from hydrogen atom, C ₁ -C ₆ alkyl, halogenated C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, wherein the alkyl, alkoxy, halogenated alkyl is optionally substituted by one or more substituents selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano;

    Preferably, _Ra ' and _Rb ' are each independently selected from a hydrogen atom, a _C1 - _C6 alkyl group, a halogen and a hydroxyl group,

    R _c ' is selected from a hydrogen atom, a C ₁ ～C ₆ alkyl group, a halogenated C ₁ ～C ₆ alkyl group, and a C ₁ ～C ₆ alkoxy group.
13. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein R ₅ is selected from hydrogen atom, C ₁ to C ₆ alkyl, halogenated C ₁ to C ₆ alkyl, C ₁ to C ₆ alkoxy, hydroxyl, -NR _i R _j , wherein the alkyl, alkoxy, halogenated alkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl, -NR _i R _j , carboxyl, nitro, cyano and C ₁ to C ₆ alkoxy,

    Preferably, R ₅ is selected from C ₁ -C ₆ alkyl, halogenated C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy, wherein the alkyl, alkoxy and halogenated alkyl are optionally substituted with one or more substituents selected from halogen, hydroxyl and amino.

    More preferably, _R5 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, n-pentyl, isopentyl, sec-pentyl and neopentyl.
14. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein R _i and R _j are each independently selected from a hydrogen atom, a hydroxyl group, a C ₁ ～C ₆ alkyl group, or a C ₁ ～C ₆ alkoxy group.
15. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein R _k is independently selected from a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group, a C ₁ -C ₆ alkoxy group, a hydroxyl group, or -NR _i R _j .
16. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, which is a compound represented by formula (I-1) or formula (I-2) or a pharmaceutically acceptable salt thereof,
    

    wherein R ₁ , R ₂ , R ₃ , R ₅ , n1, R ₁₂ , R ₁₃ and n11 are as described in claim 1.
17. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from
    

    or a pharmaceutically acceptable salt thereof.
18. The isotope substitution of the compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, wherein the isotope substitution is preferably a deuterium atom substitution.
19. A pharmaceutical composition comprising the compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, or the isotope substitution according to claim 18, and a pharmaceutically acceptable excipient.
20. Use of the compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, the isotope substitution according to claim 18 or the pharmaceutical composition according to claim 19 in the preparation of a pharmaceutical composition for treating and/or preventing a disease, wherein the disease is selected from Parkinson's disease, depression, attention deficit disorder, schizophrenia, manic depression, cognitive disorders, restless leg syndrome, periodic limb movement disorder, tardive dyskinesia, Huntington's disease, Tourette syndrome, hypertension, addictive diseases, stroke, congestive heart failure, excessive daytime sleepiness, dystonia, memory and learning disorders or losses, and Lewy body disease, preferably depression, Attention deficit disorder, schizophrenia, manic-depressive illness, cognitive impairment disorders, restless legs syndrome, periodic limb movement disorder, tardive dyskinesia, Huntington's disease, Tourette's syndrome, hypertension, addictive disorders, congestive heart failure, stroke, excessive daytime sleepiness, dystonia, and memory and learning impairment or loss.