A nitrogen-containing heterocyclic compound and its application

Abstract

The present invention relates to the field of chemical medicine, and in particular to a nitrogen-containing heterocyclic compound and its application. The present invention provides a nitrogen-containing heterocyclic compound as shown in formula I, which acts on 5-HT 2A , 5‑HT 2C Receptors for 5‑HT 2A The selectivity is better than or similar to that of Pimasserin. It is used to treat behavioral disorders and psychosis associated with schizophrenia or Parkinson's disease and dementia. The antipsychotic activity of the compound of the present application is comparable to that of Pimasserin, with sedative side effects and less cardiotoxicity than Pimasserin.

Description

Technical Field

[0001] The present invention relates to the field of chemical medicine, and in particular to a nitrogen-containing heterocyclic compound and application thereof. Background Art

[0002] Schizophrenia is a latent disease with a low rate of treatment and a high lifetime prevalence. Currently, about 0.3-0.7% of the world's population is affected by schizophrenia in their lifetime. In 2016, it was estimated that there were more than 21 million schizophrenia patients worldwide. Currently, the main anti-schizophrenia drugs are typical antipsychotics and atypical antipsychotics. However, the current schizophrenia treatment drugs strongly block dopamine receptors, which leads to adverse reactions such as extrapyramidal reactions (EPS), tardive dyskinesia, and increased prolactin. In the medical field, although there are many types of active compounds acting on different targets available for the treatment of sleep disorders, adverse reactions such as addiction, drug resistance, and sequelae are still unresolved issues.

[0003] Traditionally, antipsychotic drugs that exert their pharmacological effects by blocking dopamine D2 receptors are called first-generation antipsychotic drugs, that is, "typical" antipsychotic drugs (such as haloperidol). They have a breakthrough effect on the treatment of positive symptoms of schizophrenia, but fail to treat negative symptoms and cognitive impairment. Typical antipsychotic drugs generally have serious EPS side effects and are ineffective for one-third of schizophrenia patients.

[0004] After the 1960s, a series of new-generation antipsychotics were developed, including Ziprasidone and Risperidone, which are called second-generation antipsychotics, that is, new antipsychotics. Although their pharmacological effects are not completely consistent, they have common pharmacological characteristics, namely, the effects on 5-hydroxytryptamine (5-HT) receptors (5-HT 1A、2A、2C ) and norepinephrine (NA) receptors (α1, α2) are much more avid than those for D2 receptors. Its clinical effects have more advantages than those of the first generation of antipsychotics. It is not only as effective as traditional antipsychotics for positive symptoms, but also for negative symptoms and cognitive deficits, and has a wider spectrum of action. However, these drugs have adverse reactions such as QT interval prolongation, hyperprolactinemia and weight gain. Therefore, finding drugs that are effective for positive and negative symptoms and cognitive impairment of schizophrenia and have fewer side effects is a hot topic of research now.

[0005] The serotonin system plays an important role in regulating the functions of the prefrontal cortex (PFC), including emotional control, cognitive behavior, and working memory. Pyramidal neurons and GABA interneurons of the PFC contain several serotonin receptor subtypes with particularly high densities. 1A and 5-HT 2A Recently, it has been demonstrated that PFC and NMDA receptor channels are 5-HT 1A These two receptors regulate the excitatory neurons of the cerebral cortex, thereby affecting cognitive function. In fact, various preclinical data show that 5-HT 1A R may be a new target for the development of antipsychotic drugs. Atypical antipsychotic drugs (such as olanzapine, aripiprazole, etc.) have a significant effect on 5-HT 1A The high affinity of 5-HT R and its low EPS side effects indicate that the 5-HT system plays an important role in regulating the functions of the prefrontal cortex (PFC), including emotional control, cognitive behavior, and working memory. The pyramidal neurons and GABA interneurons of the PFC contain several 5-HT receptor subtypes with a particularly high density. 1A and 5-HT 2A Recent studies have shown that 5-HT 1A Agonists are associated with atypical antipsychotic treatment and can improve negative symptoms and cognitive impairment. In the treatment of schizophrenia with the atypical antipsychotic clozapine, 5-HT 2A It plays an important role in all aspects of perception, emotion regulation and motor control. 2A The receptors can normalize the release of dopamine, thus playing an antipsychotic role. 2C The receptor is closely linked to weight gain.

[0006] Pimasserin is a 5-HT 2A High affinity inverse agonist, 5-HT 2C Antagonist, in vitro experimental results show that it has an effect on 5-HT 2A The receptor affinity [inhibition constant (Ki) is 0.4nm] is higher than that of 5-HT 2C High (Ki = 16nm), for 5-HT 2B It has no significant affinity (Ki>300nm) for cytokines, dopamine receptors (including D2 receptors), adrenergic receptors, muscarinic receptors or calcium channel receptors. The drug was approved for marketing by the US Food and Drug Administration in April 2016 under the trade name Nuplazid TM , mainly used to treat Parkinson's mental symptoms such as hallucinations and delusions.

[0007] Therefore, there is a need to find an antipsychotic drug that is effective for both positive and negative symptoms, can improve cognitive impairment, and can prevent extrapyramidal side effects, including tardive dyskinesia, Parkinson's disease; and can reduce weight gain. Summary of the invention

[0008] The present invention aims to solve at least one of the technical problems existing in the prior art. To this end, one object of the present invention is to provide a nitrogen-containing heterocyclic compound, such as a compound shown in formula I:

[0009]

[0010] Wherein, n7 is 0, 1 or 2, A is C, O or N;

[0011] n3 and n6 are independently selected from integers of 0, 1, 2, and 3, and n3 and n6 are not 0 at the same time;

[0012] n2 is an integer of 1, 2 or 3;

[0013] W is O or S;

[0014] Z, Q, and Y are independently selected from C and N, and Z and Q are not C at the same time;

[0015] R2 is selected from hydrogen, substituted or unsubstituted C1-C5 straight or branched alkyl, substituted or unsubstituted C3-C5 cycloalkyl, and the substituent is selected from methyl, ethyl, propyl, butyl, fluorine, C3-C5 cycloalkyl;

[0016] R3, R4 are selected from H, halogen, C 1- C5 straight chain or branched alkyl, phenyl, or R3 and R4 form a C 3-6 of a cycloalkyl group;

[0017] R5 is hydrogen or halogen;

[0018] R1 is selected from the structure of formula II, III, IV:

[0019]

[0020] In formula III, n5 is an integer of 0-4, R8 and R9 are independently selected from C 1-3 alkyl, or R8, R9 and N form a substituted or unsubstituted 4-6 membered heterocyclic ring, wherein the substituent is selected from methyl, ethyl, propyl, butyl, fluorine and chlorine;

[0021] In formula II, n4 is an integer from 1 to 4;

[0022] R7 is selected from methyl, ethyl, isopropyl, isobutyl, benzyl, phenyl, halogenated C1-C5 straight or branched alkyl;

[0023] R6 is halogen, methyl or hydrogen.

[0024] In one embodiment, when R3 and R4 form a C3-C6 cycloalkyl group, the compound represented by Formula I is represented by Formula I-1:

[0025]

[0026] Wherein, n1 is an integer of 1, 2 or 3.

[0027] In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound represented by formula I or a pharmaceutically acceptable salt thereof and a medically acceptable carrier.

[0028] In another aspect, the present invention provides a use of a compound of formula I and a pharmaceutical composition thereof in the preparation of a drug for treating a mental illness. The mental illness is schizophrenia. The mental illness is Parkinson's disease, dementia-related behavioral disorders and psychosis.

[0029] Compounds of formula I

[0030]

[0031] Wherein, n7 is 0, 1 or 2, A is C, O or N;

[0032] n3 and n6 are independently selected from integers of 0, 1, 2, and 3, and n3 and n6 are not 0 at the same time;

[0033] n2 is an integer of 1, 2 or 3;

[0034] W is O or S;

[0035] Z, Q, and Y are independently selected from C and N, and Z and Q are not C at the same time;

[0036] R2 is selected from hydrogen, substituted or unsubstituted C1-C5 straight or branched alkyl, substituted or unsubstituted C3-C5 cycloalkyl, and the substituent is selected from methyl, ethyl, propyl, butyl, fluorine, C3-C5 cycloalkyl;

[0037] R3, R4 are selected from H, halogen, C 1- C5 straight chain or branched alkyl, phenyl, or R3 and R4 form a C 3-6 Cycloalkyl;

[0038] R5 is hydrogen or halogen;

[0039] R1 is selected from the structure of formula II, III, IV:

[0040]

[0041] In formula III, n5 is an integer of 0-4, R8 and R9 are independently selected from C 1-3 or R8, R9 and N form a substituted or unsubstituted 4-6 membered heterocyclic ring, wherein the substituent is selected from methyl, ethyl, propyl, butyl, fluorine and chlorine;

[0042] In formula II, n4 is an integer from 1 to 4;

[0043] R7 is selected from methyl, ethyl, isopropyl, isobutyl, benzyl, phenyl, halogenated C1-C5 straight or branched alkyl;

[0044] R6 is halogen, methyl or hydrogen.

[0045] In one embodiment, when R3 and R4 form a C3-C6 cycloalkyl group, the compound represented by Formula I is represented by Formula I-1:

[0046]

[0047] Wherein, n1 is an integer of 1, 2 or 3.

[0048] In one embodiment, the compound of formula I is represented by formula V:

[0049]

[0050] In another embodiment, when R3 and R4 form a C3-C6 cycloalkyl group, the compound represented by Formula I is represented by Formula V-1:

[0051]

[0052] Wherein, n1 is an integer of 1, 2 or 3.

[0053] In the above-mentioned compound of formula V-1, when R1 is a structure of formula II, the compound of formula V-1 is a structure of formula V-2:

[0054]

[0055] In one embodiment, the compound represented by formula I is represented by formula VI:

[0056]

[0057] In another embodiment, when R3 and R4 form a C3-C6 cycloalkyl group, the compound represented by Formula I is represented by Formula VI-1:

[0058]

[0059] Wherein, n1 is an integer of 1, 2 or 3.

[0060] In the above-mentioned compound of formula VI-1, when R1 is a structure of formula II, the compound of formula VI-1 is a structure of formula VI-2:

[0061]

[0062] Wherein, n4 is an integer of 1, 2 or 3.

[0063] In one embodiment, the halogen is selected from fluorine, chlorine, bromine and iodine; the C1-C5 straight or branched alkyl is selected from methyl, ethyl, propyl, isopropyl, isobutyl and neopentyl; the C3-C5 cycloalkyl is selected from cyclopropyl, cyclobutyl and cyclopentyl; the substituted C3-C5 cycloalkyl is selected from methylcyclopropyl and ethylcyclopropyl; the halo in the haloalkyl is selected from fluoroalkyl, chloroalkyl, brominated alkyl and iodinated alkyl; the C1-C3 straight or branched alkyl is methyl, ethyl or propyl.

[0064] In one embodiment, the 4-6 membered heterocycle is selected from azetidinyl, piperazine, pyrrolidine.

[0065] In one embodiment, n2 is an integer of 1, 2 or 3. In a preferred embodiment, n2 is 1 or 2. In a particularly preferred embodiment, n2 is 1.

[0066] In one embodiment, n3 and n6 are independently selected from integers of 0, 1, 2, and 3, and n3 and n6 are not simultaneously 0. In a preferred embodiment, n3 and n6 are independently selected from integers of 0, 1, and 2, and n3 and n6 are not simultaneously 0.

[0067] In one embodiment, n7 is 0, 1 or 2. In a preferred embodiment, n7 is 0 or 1. In a specific embodiment, n7 is 0. In another specific embodiment, n7 is 1.

[0068] In one embodiment, n4 is selected from an integer of 1 to 4. In a preferred embodiment, n4 is 1, 2 or 3. In a specific embodiment, n4 is 1. In another specific embodiment, n4 is 2. In yet another specific embodiment, n4 is 3.

[0069] In one embodiment, n5 is selected from an integer from 0 to 4. In a preferred embodiment, n5 is 0, 1, 2 or 3. In a specific embodiment, n5 is 0. In another specific embodiment, n5 is 1.

[0070] In one embodiment, n1 is an integer of 1, 2 or 3. In a preferred embodiment, n1 is 1 or 2. In a specific embodiment, n1 is 1. In another specific embodiment, n1 is 2.

[0071] In one embodiment, A is C, N or O. In a preferred embodiment, A is N or O.

[0072] In one embodiment, R2 is selected from hydrogen, substituted or unsubstituted C1-C5 straight or branched alkyl, substituted or unsubstituted C3-C5 cycloalkyl, and the substituent is selected from methyl, ethyl, propyl, butyl, fluorine, and C3-C5 cycloalkyl. In a preferred embodiment, R2 is selected from hydrogen, substituted or unsubstituted C1-C5 straight or branched alkyl; substituted or unsubstituted C3-C5 cycloalkyl, and the substituent is selected from methyl, ethyl, fluorine, and cyclopropyl. In a more preferred embodiment, R2 is selected from hydrogen, methyl, isopropyl, isobutyl, cyclopropyl, cyclopropylmethyl, and neopentyl.

[0073] The compound represented by the above formula I is selected from any one of the following compounds: 5-(4-isobutoxybenzyl)-7-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.5]octan-6-one; 5-(3-fluoro-1-methylpiperidin-4-yl)-7-(4-isobutoxybenzyl)-5,7-diazaspiro[2.5]octan-6-one; 5-(4-isobutoxybenzyl)-7-(1-methylpyrrolidin-3-yl)-5,7-diazaspiro[2.5]octan-6-one; 5-(2-(dimethyl)-1-piperidin-4-yl)-5,7-diazaspiro[2.5]octan-6-one; 5-(4-(amino)ethyl)-7-(4-isobutoxybenzyl)-5,7-diazaspiro[2.5]octan-6-one; 5-(4-methoxybenzyl)-7-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.5]octan-6-one; 5-(4-cyclopropyloxybenzyl)-7-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.5]octan-6-one; 5-(4-(cyclopropylmethoxy)benzyl)-7-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.5]octan-6-one;

[0074] 5-(1-benzylpiperidin-4-yl)-7-(4-isobutoxybenzyl)-5,7-diazaspiro[2.5]octan-6-one; 5-(1-(2,2-difluoroethyl)piperidin-4-yl)-7-(4-isobutoxybenzyl)-5,7-diazaspiro[2.5]octan-6-one;

[0075] 5-(4-isobutoxybenzyl)-7-(2-methyl-2-azaspiro[3.3]heptan-6-yl)-5,7-diazaspiro[2.5]octan-6-one;

[0076] 5-(1-methylpiperidin-4-yl)-7-(4-(neopentyloxy)benzyl)-5,7-diazaspiro[2.5]octan-6-one; 5-(4-isobutoxybenzyl)-7-(1-isobutylpiperidin-4-yl)-5,7-diazaspiro[2.5]octan-6-one; 5-(4-isobutoxybenzyl)-7-(1-isopropylpiperidin-4-yl)-5,7-diazaspiro[2.5]octan-6-one -one; 6-(4-isobutoxybenzyl)-8-(1-methylpiperidin-4-yl)-6,8-diazaspiro[3.5]nonan-7-one; 5-(4-isobutoxybenzyl)-7-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.5]octane-6-thione; 5-(4-hydroxybenzyl)-7-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.5]octan-6-one;

[0077] 7-(4-isobutoxybenzyl)-5-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.6]nonan-6-one; 5-(4-isobutoxybenzyl)-7-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.6]nonan-6-one; 7-[(dimethylamino)methyl]-5-(4-isobutoxybenzyl)-5-azaspiro[2.5]octan-6-one;

[0078] 7-(Dimethylamino)-5-(4-isobutoxybenzyl)-5-azaspiro[2.5]octan-6-one;

[0079] 7-(azetidin-1-yl)-5-(4-isobutoxybenzyl)-5-azaspiro[2.5]octan-6-one;

[0080] 1-(4-isobutoxybenzyl)-5-methyl-3-(1-methylpiperidin-4-yl)-5-phenyltetrahydropyrimidin-2(1H)-one; 5,5-difluoro-1-(4-isobutoxybenzyl)-3-(1-methylpiperidin-4-yl)tetrahydropyrimidin-2(1H)-one;

[0081] 1-(4-isobutoxybenzyl)-5-methyl-3-(1-methylpiperidin-4-yl)tetrahydropyrimidin-2(1H)-one;

[0082] 5-(4-isobutoxybenzyl)-7-(4-methylpiperazin-1-yl)-5-azaspiro[2.5]octan-6-one;

[0083] 7-(4-isobutoxybenzyl)-5-(1-methylpiperidin-4-yl)-5-azaspiro[2.5]octan-6-one;

[0084] 5-((6-isobutoxypyridin-3-yl)methyl)-7-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.5]octan-6-one; 5-(2-fluoro-4-isobutoxybenzyl)-7-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.5]octan-6-one; 5-(3-fluoro-4-isobutoxybenzyl)-7-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.5]octan-6-one; 5-(4-isobutoxybenzyl)-7-(1-methylazo-4-yl)-5-7-diazaoxazolo[2.5]octan-6-one; -((2R)-1,2-dimethylpiperidin-4-yl)-7-(4-isobutoxybenzyl)-5,7-diazaspiro[2.5]octan-6-one; 5-((2S)-1,2-dimethylpiperidin-4-yl)-7-(4-isobutoxybenzyl)-5,7-diazaspiro[2.5]octan-6-one; 5-(2-chloro-4-isobutoxybenzyl)-7-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.5]octan-6-one; 5-(3-isobutoxybenzyl)-7-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.5]octan-6-one;

[0085] 4-(4-isobutoxybenzyl)-6-(1-methylpiperidin-4-yl)-4,6-diazaspiro[2.4]heptan-5-one;

[0086] 6-(4-isobutoxybenzyl)-4-(1-methylpiperidin-4-yl)-4,6-diazaspiro[2.4]heptan-5-one;

[0087] 5-(1-ethylpiperidin-4-yl)-7-(4-isobutoxybenzyl)-5,7-diazaspiro[2.5]octan-6-one;

[0088] 5-(4-isopentylbenzyl)-7-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.5]octan-6-one;

[0089] 5-(4-(isobutylamino)benzyl)-7-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.5]octan-6-one;

[0090] 5-(4-(Isopropoxymethyl)benzyl)-7-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.5]octan-6-one.

[0091] Terminology explanation:

[0092] The term "comprising" is an open expression, that is, including the contents specified in the present invention, but not excluding other aspects. It should be understood that the term "comprising" can include a closed meaning, that is, "consisting of...".

[0093] As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as the general formula compounds above or as specific examples, subclasses in the examples. It should be understood that the term "optionally substituted" and the term "substituted or unsubstituted" can be used interchangeably. In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced by a specific substituent. Unless otherwise indicated, an optionally substituted group can be substituted at each substitutable position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a specific group, then the substituents can be substituted at each position in the same or different manner.

[0094] In addition, it should be noted that, unless explicitly stated otherwise, the description method of "respectively and independently" used in the present invention should be understood in a broad sense, which can mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.

[0095] In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to the group type or range. It is particularly pointed out that the present invention includes each independent secondary combination of the members of these group types and ranges. For example, the term "C1-C5 alkyl" specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, and C5 alkyl. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -C(CH3)3), n-pentyl (n-Pr, -CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -C(CH3)3), n-pentyl 2-Methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), etc.

[0096] The ranges (such as numerical ranges) listed herein may include each value in the range and each sub-range formed by each value. Thus, for example, the expression "n2 is any integer between 0 and 3" includes, for example, any integer between 0 and 2, any integer between 2 and 3, etc., such as 1, 2, and 3.

[0097] The expression "one or more" may mean 1, 2, 3, 4, 5, 6 or more.

[0098] The term "cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of carbon atoms and hydrogen atoms, preferably comprising 1 or 2 rings. The cycloalkyl can be a monocyclic, fused polycyclic, bridged or spirocyclic structure. The cycloalkyl can have 3-6 carbon atoms, i.e., "C3-C6 cycloalkyl", such as C6 cycloalkyl, C5 cycloalkyl, C4 cycloalkyl, C3 cycloalkyl. Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. The term also encompasses situations in which the C atom can be substituted by oxo (=O).

[0099] The terms "heterocycle" and "heterocyclyl" are used interchangeably and refer to a monovalent or polyvalent monocyclic, bicyclic or tricyclic ring system containing 3-12 ring atoms, wherein one or more atoms of the ring are independently replaced by heteroatoms, and the heteroatoms have the meanings as described herein, and the ring may be fully saturated or contain one or more unsaturations, but no aromatic rings. Unless otherwise specified, the heterocyclyl group may be carbon or nitrogen-based, and the -CH2- group may be optionally replaced by -C(=O)-. The sulfur atom of the ring may be optionally oxidized to S-oxide. The nitrogen atom of the ring may be optionally oxidized to N-oxide. Examples of heterocyclic groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolane, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, and the like. Examples of heterocyclic groups in which a -CH2- group is replaced by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidonyl, 3,5-dioxopiperidinyl, and pyrimidinedione. Examples of heterocyclic groups in which the sulfur atom is oxidized include, but are not limited to, sulfolane and 1,1-dioxothiomorpholinyl. The heterocyclic group may be optionally substituted with one or more substituents described herein.

[0100] The term "hydrogen (H)" refers to a single hydrogen atom. Such an atom group may be linked to other groups, such as an oxygen atom, to form a hydroxyl group.

[0101] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0102] The term "pharmaceutically acceptable salt" refers to an inorganic or organic salt of a compound of the present invention.

[0103] Beneficial technical effects of the present invention:

[0104] The compounds provided by the present invention act on 5-HT2A and 5-HT2C receptors, and have a selectivity for 5-HT2A that is superior to or similar to that of pimasserin. They are used to treat behavioral disorders and psychosis associated with schizophrenia or Parkinson's disease and dementia. The antipsychotic activity of the compounds of the present application is comparable to that of pimasserin, the sedative side effects are less than those of pimasserin, and the cardiotoxicity is less than that of pimasserin. Specific implementation methods

[0105] The present invention can be further described by the following examples, however, the scope of the present invention is not limited to the following examples. It will be appreciated by those skilled in the art that various changes and modifications may be made to the present invention without departing from the spirit and scope of the present invention.

[0106] Table 1 Compound structures and compound names

[0107]

[0108]

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116] Specific implementation methods

[0117] The following examples are for illustrative purposes only and are not intended to limit the present invention.

[0118] Synthetic Examples

[0119] Example 1. 5-(4-isobutoxybenzyl)-7-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.5]octan-6-one (1)

[0120] Reaction 1

[0121]

[0122] 1.1 Preparation of methyl 1-([[4-(2-methylpropoxy)phenyl]methyl]carbamoyl)cyclopropane-1-carboxylate

[0123] Dissolve 1-[4-(2-methylpropoxy)phenyl]methylamine (800.00 mg, 4.463 mmol), 1-(methoxycarbonyl)cyclopropane-1-carboxylic acid (643.19 mg, 4.463 mmol), HATU (2036.23 mg, 5.355 mmol) and DIEA (1153.55 mg, 8.925 mmol) in 20 ml of DMF and stir at room temperature for 2 hours. After the reaction is completed, pour the reaction solution into water and extract with ethyl acetate. Evaporate the solvent and purify by column chromatography (PE:EA=4:1) to obtain 1100 mg of 1-([[4-(2-methylpropoxy)phenyl]methyl]carbamoyl)cyclopropane-1-carboxylic acid methyl ester, yield: 80.72%.

[0124] 1.2 Preparation of [1-[([[4-(2-methylpropoxy)phenyl]methyl]amino)methyl]cyclopropyl]methanol

[0125] Dissolve 1-([[4-(2-methylpropoxy)phenyl]methyl]carbamoyl)cyclopropane-1-carboxylic acid methyl ester (1.10 g, 3.602 mmol) and BH3-THF (10.00 mL, 104.490 mmol) in 10 ml THF and heat under reflux to react overnight. After the reaction is completed, cool to room temperature, add 2N HCl solution to quench the reaction, stir at room temperature for 1 hour, wash the aqueous phase with ethyl acetate, adjust the pH of the aqueous phase to 10 with 4N-NaOH solution, extract with dichloromethane, and evaporate the solvent to obtain 800 mg of crude [1-[([[4-(2-methylpropoxy)phenyl]methyl]amino)methyl]cyclopropyl]methanol. 1.3 Preparation of benzyl N-[[1-(hydroxymethyl)cyclopropyl]methyl]-N-[[4-(2-methylpropoxy)phenyl]methyl]carbamate

[0126] [1-[([[4-(2-methylpropoxy)phenyl]methyl]amino)methyl]cyclopropyl]methanol (800.00 mg, 3.037 mmol) and CbzCl (777.25 mg, 4.556 mmol) were added to a mixed solution of 10 ml NaHCO3 and 10 ml THF, and stirred at room temperature for 2 hours. After the reaction was completed, water was added and extracted with ethyl acetate. The solvent was removed and purified by column chromatography (PE:EA=1:1) to obtain 800 mg of N-[[1-(hydroxymethyl)cyclopropyl]methyl]-N-[[4-(2-methylpropoxy)phenyl]methyl]carbamate, with a yield of 66.26%.

[0127] 1.4 Preparation of benzyl N-[(1-formylcyclopropyl)methyl]-N-[[4-(2-methylpropoxy)phenyl]methyl]carbamate

[0128] N-[[1-(Hydroxymethyl)cyclopropyl]methyl]-N-[[4-(2-methylpropoxy)phenyl]methyl]carbamate (700.00 mg, 1.761 mmol) and PCC (759.16 mg, 3.522 mmol) were dissolved in 20 ml of dichloromethane, stirred at room temperature for 2 hours, and filtered to obtain a solution. The solvent was removed to obtain 500 mg of benzyl N-[(1-formylcyclopropyl)methyl]-N-[[4-(2-methylpropoxy)phenyl]methyl]carbamate, with a yield of 71.79%.

[0129] 1.5 Preparation of benzyl N-[(1-[(1-methylpiperidin-4-yl)amino]methyl]cyclopropyl)methyl]-N-[[4-(2-methylpropoxy)phenyl]methyl]carbamate

[0130] Benzyl N-[(1-formylcyclopropyl)methyl]-N-[[4-(2-methylpropoxy)phenyl]methyl]carbamate (500.00mg, 1.264mmol), 1-methyl-4-piperidinamine (216.55mg, 1.896mmol), NaBH3CN (158.89mg, 2.528mmol) were added to a mixed solution of 10ml ethanol and 1ml acetic acid, and stirred at room temperature overnight. After the reaction was completed, the reaction solution was poured into a saturated NaHCO3 solution and extracted with ethyl acetate. The solvent was removed, and the mixture was separated and purified by column chromatography (DCM:MeOH=10:1) to obtain 350mg of benzyl N-[(1-[(1-methylpiperidin-4-yl)amino]methyl]cyclopropyl)methyl]-N-[[4-(2-methylpropoxy)phenyl]methyl]carbamate, with a yield of 56.08%.

[0131] 1.6 Preparation of 1-methyl-N-([1-[([[4-(2-methylpropoxy)phenyl]methyl]amino)methyl]cyclopropyl]methyl)piperidin-4-amine

[0132] Benzyl N-[(1-[(1-methylpiperidin-4-yl)amino]methyl]cyclopropyl)methyl]-N-[[4-(2-methylpropoxy)phenyl]methyl]carbamate (100.00 mg, 0.203 mmol) and Pd(OH)2 / C (20.00 mg) were added to 10 ml of CF3CH2OH solution, hydrogen was introduced, and the mixture was stirred at room temperature overnight. After the reaction was completed, the mixture was filtered to obtain a filtrate, and the solvent was removed to obtain 50 mg of 1-methyl-N-([1-[([[4-(2-methylpropoxy)phenyl]methyl]amino)methyl]cyclopropyl]methyl)piperidin-4-amine, with a yield of 68.65%.

[0133] 1.7 Preparation of 5-(1-methylpiperidin-4-yl)-7-[[4-(2-methylpropoxy)phenyl]methyl]-5,7-diazaspiro[2.5]octan-6-one

[0134] 1-Methyl-N-([1-[([[4-(2-methylpropoxy)phenyl]methyl]amino)methyl]cyclopropyl]methyl)piperidin-4-amine (50.00 mg, 0.139 mmol) was dissolved in 5 ml of THF, triphosgene (50.00 mg, 0.139 mmol) was added to the solution, and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was poured into saturated NaHCO3, extracted with ethyl acetate, the solvent was removed, and column chromatography was separated and purified (DCM:MeOH=20:1) to obtain 5-(1-methylpiperidin-4-yl)-7-[[4-(2-methylpropoxy)phenyl]methyl]-5,7-diazaspiro[2.5]octan-6-one 17 mg, yield 31.7%. 1 H-NMR (400MHz, Methanol-d4): δ7.21–7.09(m,2H),6.98–6.83(m,2H),4.47(s,2H),3. 73(d,J=6.5Hz,2H),3.59(d,J=12.5Hz,2H),3.17(dt,J=16.5,5.3Hz,2H),3.02(d,J=1 2.2Hz,4H),2.90(s,3H),2.07(dq,J=13.3,6.7Hz,1H),1.96(t,J=11.7Hz,3H),1.04(d ,J=6.7Hz,6H),0.59(d,J=4.6Hz,2H),0.52(d,J=4.7Hz,2H).LCMS(ES,m / z):386[M+H] + .

[0135] Example 2. 5-(3-fluoro-1-methylpiperidin-4-yl)-7-(4-isobutoxybenzyl)-5,7-diazaspiro[2.5]octan-6-one (2)

[0136] The reaction raw material 1-methylpiperidin-4-amine was replaced by 3-fluoro-1-methylpiperidin-4-amine, and the target compound was prepared according to the method of Example 1. The structural formula is shown in No. (2) in Table 1. 1 H NMR(400MHz, Methanol-d4)δ7.18(dq,J=8.7,2.3,1.6Hz,2H),6.95–6.81(m,2H),4.67– 4.39(m,3H),3.73(dd,J=6.5,1.1Hz,2H),3.46(ddt,J=13.3,10.4,3.1Hz,1H),3.13–2. 87(m,3H),2.85–2.66(m,1H),2.60(s,3H),2.32–2.18(m,1H),2.06(hept,J=6.7Hz,1H) ,1.81–1.70(m,1H),1.04(d,J=6.6Hz,6H),0.68–0.44(m,4H).LCMS(ES,m / z):404[M+H] + .

[0137] Example 3. 5-(4-isobutoxybenzyl)-7-(1-methylpyrrolidin-3-yl)-5,7-diazaspiro[2.5]octan-6-one (3)

[0138] The reaction raw material 1-methylpiperidin-4-amine was replaced by 1-methylpyrrolidine-3-amine, and the target compound was prepared according to the method of Example 1. The structural formula is shown in No. (3) in Table 1. 1H NMR (400MHz, DMSO-d6) δ7.17–7.05(m,2H),6.93–6.81(m,2H),4.98(qd,J=9.5,9.0,5.8Hz,1H),4.41–4.29(m,2 H),3.70(d,J=6.5Hz,2H),3.12–3.01(m,2H),2.91(d,J=2.4Hz,2H),2.85(td,J=8.3,3.4Hz,1H),2.68(dd,J=10 .3,4.9Hz,1H),2.60(dd,J=10.3,8.5Hz,1H),2.40(q,J=8.3Hz,1H),2.34(s,3H),2.12–1.90(m,2H),1.69(dt,J =13.6,7.3Hz,1H),0.97(d,J=6.7Hz,6H),0.54(q,J=3.5Hz,2H),0.42(q,J=3.5Hz,2H).LCMS(ES,m / z):298[M+H] + .

[0139] Example 4. 5-(2-(Dimethylamino)ethyl)-7-(4-isobutoxybenzyl)-5,7-diazaspiro[2.5]octan-6-one (4)

[0140] The reaction raw material 1-methylpiperidin-4-amine was replaced by N,N-dimethylethane-1,2-diamine, and the target compound was prepared according to the method of Example 1. The structural formula is shown in No. (4) in Table 1. 1 H NMR (400MHz, DMSO-d6) δ7.17–7.11(m,2H),6.90–6.84(m,2H),4.36(s,2H),3.71(d,J=6.4Hz,2H),3.62(s,1H),3.27–3.11(m,5H),2.94(s,2H) ,2.80(d,J=4.9Hz,6H),1.99(tt,J=12.8,6.1Hz,1H),0.97(d,J=6.7Hz,7H),0.57(t,J=2.8Hz,2H),0.46–0.38(m,2H).LCMS(ES,m / z):360[M+H] + .

[0141] Example 5. 5-(4-methoxybenzyl)-7-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.5]octan-6-one (5)

[0142] The reaction raw material 1-[4-(2-methylpropoxy)phenyl]methylamine was replaced by 4-methoxybenzylamine, and the target compound was prepared according to the method of Example 1. The structural formula is shown in No. (5) in Table 1. 1 H NMR (400MHz, DMSO-d6) δ7.14(d,J=8.2Hz,2H),6.88(d,J=8.3Hz,2H),4.37(s,3H),3.73(s,3H),3.13(m,2H),3.00(m,2H),2. 92(s,4H),2.71(d,J=4.9Hz,3H),2.00–1.85(m,2H),1.69(d,J=13.3Hz,2H),0.52(d,J=5.5Hz,4H).LCMS(ES,m / z):344[M+H] + .

[0143] Example 6. 5-(4-cyclopropyloxybenzyl)-7-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.5]octan-6-one (6)

[0144] The reaction raw material 1-[4-(2-methylpropoxy)phenyl]methylamine was replaced by (4-cyclopropyloxyphenyl)methylamine, and the target compound was prepared according to the method of Example 1. The structural formula is shown in No. (6) in Table 1. 1 H NMR(400MHz,DMSO-d6)δ7.17–7.10(m,1H),7.02–6.95(m,1H),4.37(s,1H),3.80(tt, J=6.1,3.0Hz,1H),3.16–3.11(m,1H),2.93(d,J=3.4Hz,2H),2.60(s,1H),2.49(s,2H ),1.81–1.70(m,1H),1.58(d,J=12.5Hz,1H),1.27–1.22(m,2H),0.81–0.69(m,1H),0 .67–0.58(m,1H),0.52(t,J=2.7Hz,1H),0.50–0.40(m,1H).LCMS(ES,m / z):370[M+H] + .

[0145] Example 7. 5-(4-(Cyclopropylmethoxy)benzyl)-7-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.5]octan-6-one (7)

[0146] The reaction raw material 1-[4-(2-methylpropoxy)phenyl]methylamine was replaced by (4-(cyclopropylmethoxy)phenyl)methylamine, and the target compound was prepared according to the method of Example 1. The structural formula is shown in No. (7) in Table 1. 1HNMR(400MHz, DMSO-d6)δ7.11(d,J=8.3Hz,2H),6.90–6.82(m,2H),4.34(s,2H),4.12(tt,J=12.2, 4.2Hz,1H),3.77(d,J=6.9Hz,2H),2.90(d,J=15.5Hz,4H),2.79(d,J=11.1Hz,2H),2.14(s,3H),1.9 0(td,J=11.7,2.5Hz,2H),1.56(qd,J=12.2,4.0Hz,2H),1.47–1.38(m,2H),1.21(ddt,J=12.3,7.8 ,3.8Hz,1H),0.62–0.47(m,4H),0.39(q,J=4.2Hz,2H),0.34–0.26(m,2H).LCMS(ES,m / z):384[M+H] + .

[0147] Example 8. 5-(1-Benzylpiperidin-4-yl)-7-(4-isobutoxybenzyl)-5,7-diazaspiro[2.5]octan-6-one (8)

[0148] The reaction raw material 1-methylpiperidin-4-amine was replaced by 1-benzylpiperidin-4-amine, and the target compound was prepared according to the method of Example 1. The structural formula is shown in No. (8) in Table 1. 1 H NMR(400MHz,DMSO-d6)δ7.66–7.55(m,2H),7.52–7.42(m,3H),7.16–7.07(m,2H),6.91–6.8 2(m,2H),4.50–4.35(m,1H),4.35(s,2H),4.26(d,J=5.2Hz,2H),3.70(d,J=6.5Hz,2H),3.09 (d,J=11.2Hz,2H),3.03(d,J=11.7Hz,2H),2.90(s,4H),1.99(ddd,J=13.3,7.6,5.2Hz,3H) ,1.69(d,J=12.2Hz,2H),0.96(d,J=6.7Hz,6H),0.52–0.39(m,4H).LCMS(ES,m / z):462[M+H] + .

[0149] Example 9. 5-(1-(2,2-difluoroethyl)piperidin-4-yl)-7-(4-isobutoxybenzyl)-5,7-diazaspiro[2.5]octan-6-one (9)

[0150] The reaction raw material 1-methylpiperidin-4-amine was replaced by 1-(difluoromethyl)piperidin-4-amine, and the target compound was prepared according to the method of Example 1. The structural formula is shown in No. (9) in Table 1. 1 H NMR(400MHz,DMSO-d6)δ7.15–7.08(m,1H),6.90–6.83(m,1H),4.35(s,1H),3.71 (d,J=6.5Hz,1H),2.92(d,J=19.2Hz,3H),2.73(d,J=14.6Hz,1H),2.22(t,J=11. 4Hz,1H),2.00(dt,J=13.2,6.6Hz,0H),1.57(d,J=13.0Hz,1H),1.44(d,J=11.8H z,1H),0.97(d,J=6.7Hz,3H),0.51(s,1H),0.40(s,1H).LCMS(ES,m / z):436[M+H] + .

[0151] Example 10. 5-(4-isobutoxybenzyl)-7-(2-methyl-2-azaspiro[3.3]heptane-6-yl)-5,7-diazaspiro[2.5]octan-6-one (10)

[0152] The reaction raw material 1-methylpiperidin-4-amine was replaced by 2-methyl-2-azaspiro[3.3]heptane-6-amine, and the target compound was prepared according to the method of Example 1. The structural formula is shown in No. (10) in Table 1. 1 H NMR (400MHz, DMSO-d6) δ7.10(d,J=8.3Hz,2H),6.86(d,J=8.5Hz,2H),4.71(q,J=8.8H z,1H),4.32(s,2H),3.70(d,J=6.5Hz,2H),3.42(s,2H),3.26(s,2H),2.99(s,2H),2.8 9(s,2H),2.32(s,3H),2.15(d,J=8.9Hz,3H),1.98(dq,J=13.3,6.6Hz,1H),1.36(s,1H ),0.97(d,J=6.7Hz,6H),0.52(d,J=4.5Hz,2H),0.40(s,2H).LCMS(ES,m / z):398[M+H] + .

[0153] Example 11. 5-(1-methylpiperidin-4-yl)-7-(4-(neopentyloxy)benzyl)-5,7-diazaspiro[2.5]octan-6-one (11)

[0154] The reaction raw material 1-[4-(2-methylpropoxy)phenyl]methylamine was replaced by (4-(neopentyloxy)phenyl)methylamine, and the target compound was prepared according to the method of Example 1. The structural formula is shown in No. (11) in Table 1. 1 H NMR(400MHz, Methanol-d4)δ7.21–7.14(m,2H),6.92–6.84(m,2H),4.59–4. 41(m,3H),3.63–3.55(m,4H),3.17(td,J=12.9,3.3Hz,2H),3.06(s,2H),3.0 0(s,2H),2.89(s,3H),2.03(qd,J=13.1,3.9Hz,2H),1.96–1.87(m,2H),1.0 5(s,9H),0.68–0.56(m,2H),0.50(t,J=3.0Hz,2H).LCMS(ES,m / z):427[M+H] + .

[0155] Example 12. 5-(4-isobutoxybenzyl)-7-(1-isobutylpiperidin-4-yl)-5,7-diazaspiro[2.5]octan-6-one (12)

[0156] The reaction raw material 1-methylpiperidin-4-amine was replaced by 1-isobutylpiperidin-4-amine, and the target compound was prepared according to the method of Example 1. The structural formula is shown in No. (12) in Table 1. 1 H NMR(400MHz,DMSO-d6)δ7.15–7.07(m,2H),6.91–6.83(m,2H),4.35(s,2H),4.20–4.03(m, 1H),3.71(d,J=6.5Hz,2H),2.94(s,2H),2.87(d,J=12.2Hz,4H),2.07–1.87(m,5H),1.74(d q,J=13.6,6.9Hz,1H),1.63–1.50(m,2H),1.45(d,J=11.5Hz,2H),0.97(d,J=6.7Hz,6H),0. 84(d,J=6.5Hz,6H),0.52(q,J=4.1Hz,2H),0.39(q,J=4.1Hz,2H).LCMS(ES,m / z):428[M+H] + .

[0157] Example 13. 5-(4-isobutoxybenzyl)-7-(1-isopropylpiperidin-4-yl)-5,7-diazaspiro[2.5]octan-6-one (13)

[0158] The reaction raw material 1-methylpiperidin-4-amine was replaced by 1-isopropylpiperidin-4-amine, and the target compound was prepared according to the method of Example 1. The structural formula is shown in No. (13) in Table 1. 1 H NMR(400MHz,DMSO-d6)δ7.15–7.08(m,2H),6.90–6.83(m,2H),4.35(s,2H),4.15(dt ,J=11.2,6.0Hz,1H),3.71(d,J=6.5Hz,2H),2.91(d,J=16.9Hz,4H),2.85(s,2H),2.8 1–2.70(m,1H),2.23(t,J=11.0Hz,2H),2.06–1.91(m,1H),1.51(s,5H),0.97(dd,J= 6.6,2.1Hz,12H),0.50(d,J=4.4Hz,2H),0.43–0.36(m,2H).LCMS(ES,m / z):414[M+H] + .

[0159] Example 14. 6-(4-isobutoxybenzyl)-8-(1-methylpiperidin-4-yl)-6,8-diazaspiro[3.5]nonan-7-one (14)

[0160] The reaction raw material 1-(methoxycarbonyl)cyclopropane-1-carboxylic acid was replaced by 1-(ethoxycarbonyl)cyclobutane-1-carboxylic acid, and the target compound was prepared according to the method of Example 1. The structural formula is shown in No. (14) in Table 1. 1 H NMR (400MHz, DMSO-d6) δ7.14(d,J=8.1Hz,2H),6.87(d,J=8.2Hz,2H),4.35(s,3H),3.71(d,J=6.5Hz,2H),3.42(d,J=11.9Hz,2H),3.15–3.05(m,6H), 2.72(d,J=4.8Hz,3H),2.00(td,J=13.3,11.8,4.8Hz,3H),1.90–1.81(m,2 H),1.68(d,J=11.5Hz,6H),0.97(d,J=6.7Hz,6H).LCMS(ES,m / z):400[M+H] + .

[0161] Example 15. 5-(4-isobutoxybenzyl)-7-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.5]octane-6-thione (15)

[0162] The reaction raw material triphosgene was replaced by thiophosgene, and the target compound was prepared according to the method of Example 1. The structural formula is shown in No. (15) in Table 1. 1H NMR (400MHz, DMSO-d6) δ7.23(d,J=8.3Hz,2H),6.88(d,J=8.4Hz,2H),5.65(tt,J=11. 4,4.7Hz,1H),5.11(s,2H),3.71(d,J=6.5Hz,2H),3.41(d,4H),3.11(d,J=11.3Hz,1H) ,3.06(d,J=10.2Hz,4H),2.73(t,J=5.7Hz,3H),1.99(qd,J=12.7,12.0,5.8Hz,1H),1 .88(s,3H),0.97(d,J=6.7Hz,6H),0.53(s,2H),0.45(s,2H).LCMS(ES,m / z):402[M+H] + .

[0163] Example 16. 5-(4-Hydroxybenzyl)-7-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.5]octan-6-one (16) Reaction Scheme 2

[0164]

[0165] 5-(4-methoxybenzyl)-7-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.5]octan-6-one (100 mg, 0.0291 mmol) (prepared according to the method of Example 5) was mixed with 20 ml of dichloromethane, cooled in an ice-water bath, and protected by nitrogen. Boron tribromide (7.5 mg, 0.0300 mmol) dissolved in dichloromethane was slowly added dropwise. After the addition was completed, the mixture was allowed to react at room temperature. After the reaction was completed, water was added dropwise to quench the reaction, and the organic phase was washed with a saturated sodium bicarbonate solution. The solvent was removed and the mixture was separated and purified by column chromatography (DCM:MeOH=20:1) to obtain 67 mg of 5-(4-hydroxybenzyl)-7-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.5]octan-6-one with a yield of 70.0%. 1 HNMR(400MHz,DMSO-d6)δ9.26(s,1H),7.04–6.97(m,2H),6.72–6.65(m,2H),4.30(s,3H),2.90(d,J=17.3Hz,4H),2.79(d,J=11.1Hz,2H),2.14(s,3 H),1.90(t,J=11.1Hz,2H),1.56(td,J=13.1,9.3Hz,2H),1.42(d,J=11.6H z,2H),0.54–0.47(m,2H),0.40(t,J=2.9Hz,2H).LCMS(ES,m / z):330[M+H] + .

[0166] Example 17. 7-(4-isobutoxybenzyl)-5-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.6]nonan-6-one (17)

[0167] Reaction 3

[0168]

[0169] 17.1 Preparation of 2-(1-formylcyclopropyl)acetonitrile

[0170] 2-[1-(Hydroxymethyl)cyclopropyl]acetonitrile (2.50 g, 22.493 mmol) and silica gel (2.50 g, 41.608 mmol) were added to 25.00 dichloromethane, protected by nitrogen, cooled to 0°C, added with PCC (7.27 g, 33.727 mmol), stirred for 2 hours, and after the reaction was completed, filtered, the filter cake was washed with dichloromethane, and the solvent was removed under pressure to obtain 3 g of 2-(1-formylcyclopropyl)acetonitrile with a yield of 122.22% as a brown-yellow oil.

[0171] 17.2 Preparation of 2-[1-[(1-methylpiperidin-4-yl)amino]methyl]cyclopropylacetonitrile

[0172] 2-(1-Formylcyclopropyl)acetonitrile (2.80 g, 25.658 mmol) and acetic acid (7.70 g, 128.222 mmol) were added to 30.00 mL of dichloromethane, nitrogen protection, 1-methylpiperidin-4-amine (3.21 g, 28.210 mmol) was added, stirred for 30 minutes, STAB (8.16 g, 38.501 mmol) was added, and the temperature was lowered to 0 ° C for reaction. After the reaction was completed, 30 ml of water was added dropwise at room temperature to quench the reaction. Extract with dichloromethane (3 x 10 ml), wash the organic phase with saturated brine, and dry over anhydrous Na2SO4. Filter, concentrate the filtrate to dryness, and proceed directly to the next step without purification.

[0173] 17.3 Preparation of benzyl (1-(cyanomethyl)cyclopropyl)methyl) (1-methylpiperidin-4-yl)carbamate

[0174] 2-[1-[(1-methylpiperidin-4-yl)amino]methyl]cyclopropylacetonitrile (3.03g, 14.655mmol) and Na2CO3 (4.66g, 43.967mmol) were added to a 50ml THF / H2O mixed solution, nitrogen was protected, the temperature was lowered to 0°C, benzyl chloroformate (2.75g, 16.121mmol) was slowly added dropwise, and the temperature was raised to room temperature for reaction. After the reaction was completed, 20ml of water was added at room temperature to quench the reaction. It was extracted with ethyl acetate (3x 10ml), the organic phase was washed with saturated brine, and the organic phase was dried with anhydrous Na2SO4. Filtered, the filtrate was concentrated to dryness, and column chromatography was separated and purified (n-hexane / EA=5:1) to obtain 1.9g of benzyl (1-(cyanomethyl)cyclopropyl)methyl) (1-methylpiperidin-4-yl) carbamate, with a yield of 38.1%, as a yellow oil.

[0175] 17.4 Preparation of benzyl[[1-(2-aminoethyl)cyclopropyl]methyl](1-methylpiperidin-4-yl)carbamate

[0176] Benzyl (1-(cyanomethyl) cyclopropyl) methyl) (1-methylpiperidin-4-yl) carbamate (1.52 g, 4.444 mmol) and Raney-Ni (200.00 mg, 2.334 mmol) were added to 20.00 ml of methanolamine solution, hydrogen was introduced, and stirred at room temperature. After the reaction was completed, the mixture was filtered, the filter cake was washed with methanol, and the filtrate was concentrated to dryness under reduced pressure. The obtained product was directly used for the next step without purification.

[0177] 17.5 Preparation of benzyl [[1-[2-[(4-isobutoxybenzyl)amino]ethyl]cyclopropyl]methyl](1-methylpiperidin-4-yl)carbamate

[0178] Add benzyl [[1-(2-aminoethyl) cyclopropyl] methyl] (1-methylpiperidin-4-yl) carbamate (1.92 g, 5.561 mmol) and MgSO4 (2.68 g, 22.265 mmol) to 25.00 ml of ethanol, and add 4-isobutoxybenzaldehyde (1.09 g, 6.116 mmol) in batches under nitrogen protection. Cool to 0°C, add NaBH4 (0.53 g, 14.009 mmol), and after the addition is complete, let it react at room temperature. After the reaction is complete, cool to 0°C, add 20 ml of water to quench the reaction, extract with ethyl acetate (3×10 ml), wash the organic phase with saturated sodium chloride solution, and dry with anhydrous Na2SO4. The mixture was filtered and the filtrate was concentrated to dryness under reduced pressure to obtain 1.4 g of benzyl [[1-[2-[(4-isobutoxybenzyl)amino]ethyl]cyclopropyl]methyl](1-methylpiperidin-4-yl)carbamate as a yellow oil with a yield of 49.6%.

[0179] 17.6 Preparation of N-[[1-[2-[(4-isobutoxybenzyl)amino]ethyl]cyclopropyl]methyl]-1-methylpiperidin-4-amine

[0180] Benzyl [[1-[2-[(4-isobutoxybenzyl)amino]ethyl]cyclopropyl]methyl](1-methylpiperidin-4-yl)carbamate (1.40 g, 2.358 mmol) was added to 15.00 ml of tetrahydrofuran, and Pd / C (200.00 mg, 1.879 mmol) was added in batches. The reaction was placed in a hydrogen environment and reacted at room temperature. After the reaction was completed, the mixture was filtered and the filter cake was washed with tetrahydrofuran. The filtrate was concentrated under reduced pressure to dryness, and the obtained product was directly subjected to the next step without purification.

[0181] 17.7 Preparation of 7-(4-isobutoxybenzyl)-5-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.6]nonan-6-one

[0182] N-[[1-[2-[(4-isobutoxybenzyl)amino]ethyl]cyclopropyl]methyl]-1-methylpiperidin-4-amine (0.65 g, 1.740 mmol) and triethanolamine (0.70 g, 6.909 mmol) were added to 10.00 ml of tetrahydrofuran, cooled to -78 ° C, and triphosgene (0.21 g, 0.714 mmol) was slowly added under nitrogen protection. After the reaction was completed, 4 ml of saturated NaHCO3 solution was added to quench the reaction at room temperature. The aqueous phase was extracted with ethyl acetate (3 x 10 ml), the organic phase was washed with saturated sodium chloride solution, and dried over anhydrous Na2SO4. The filtrate was filtered and concentrated to dryness under reduced pressure. The residue was separated and purified by column chromatography (DCM:MeOH=20:1) to obtain 0.12 g of 7-(4-isobutoxybenzyl)-5-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.6]nonan-6-one in a yield of 17.4%. 1 H NMR (400MHz, DMSO-d6) δ7.24(d,J=8.0Hz,2H),6.87(d,J=8.1Hz,2H),4.28(s,2H),3.87(s,2H),3.71(s,2H),3.39(d,J=11.1Hz,5H),2.85(s,2H), 2.68(s,3H),2.03–1.95(m,3H),1.79(d,J=12.9Hz,2H),1.39–1.33(m,2H ),0.97(d,J=6.7Hz,6H),0.37(d,J=11.5Hz,4H).LCMS(ES,m / z):400[M+H] + .

[0183] Example 18. 5-(4-isobutoxybenzyl)-7-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.6]nonan-6-one (18)

[0184] The reaction raw material 1-methylpiperidin-4-amine was replaced by (4-isobutoxyphenyl)methylamine, and 4-isobutoxybenzaldehyde was replaced by 1-methyl-4-piperidone. The target compound was prepared according to the method of Example 17. The structural formula is shown in No. (18) in Table 1. 1 H NMR(400MHz,DMSO-d6)δ7.24–7.18(m,2H),6.90–6.82(m,2H),4.20(s,2H),3.92(s,1 H),3.71(d,J=6.6Hz,2H),3.13(s,2H),3.06(d,J=12.0Hz,2H),2.81(s,2H),2.75(d,J =4.9Hz,3H),2.56(m,2H),2.05(m,2H),1.92(m,1H),1.88(s,2H),1.40(s,2H),0.97(d ,J=6.7Hz,6H),0.26(d,J=4.5Hz,2H),0.17(d,J=4.4Hz,2H).LCMS(ES,m / z):400[M+H] + .

[0185] Example 19. 7-[(Dimethylamino)methyl]-5-(4-isobutoxybenzyl)-5-azaspiro[2.5]octan-6-one (19) Reaction Scheme 4

[0186]

[0187] 19.1 Preparation of 5-[[4-(2-methylpropoxy)phenyl]methyl]-6-oxo-5-azaspiro[2.5]octane-7-carbaldehyde

[0188] 5-[[4-(2-methylpropoxy)phenyl]methyl]-5-azaspiro[2.5]octane-6-one (1.00g, 3.479mmol) and LiHMDS (5.00ml) were added to 5.00ml tetrahydrofuran solution, nitrogen was protected, the temperature was lowered to -78°C for reaction for 1 hour, DMF (508.65mg, 6.959mmol) was slowly added dropwise to the reaction solution, and the reaction was carried out at -78°C for 1 hour. After the reaction was completed, 10ml of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (3x 10ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 600mg of 5-[[4-(2-methylpropoxy)phenyl]methyl]-6-oxo-5-azaspiro[2.5]octane-7-carbaldehyde with a yield of 54.7%. It was a light brown oil.

[0189] 19.2 Preparation of 7-(Hydroxymethyl)-5-[[4-(2-methylpropoxy)phenyl]methyl]-5-azaspiro[2.5]octan-6-one

[0190] 5-[[4-(2-methylpropoxy)phenyl]methyl]-6-oxo-5-azaspiro[2.5]octane-7-carbaldehyde (600.00 mg, 1.902 mmol) and 5.00 ml methanol were added to a 25 mL round bottom flask, nitrogen protection, cooled to 0 ° C, and NaBH4 (215.91 mg, 5.707 mmol) was added. After the addition was completed, the temperature was raised to room temperature and reacted for 30 minutes. After the reaction was completed, 10 ml of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 x 10 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 600 mg of 7-(hydroxymethyl)-5-[[4-(2-methylpropoxy)phenyl]methyl]-5-azaspiro[2.5]octane-6-one, with a yield of 99.36%.

[0191] 19.3 (5-[[4-(2-methylpropoxy)phenyl]methyl]-6-oxo-5-azaspiro[2.5]octan-7-yl)methyl methanesulfonate

[0192] 7-(Hydroxymethyl)-5-[[4-(2-methylpropoxy)phenyl]methyl]-5-azaspiro[2.5]octan-6-one (150.00mg, 0.473mmol), 2.00ml tetrahydrofuran and triethylamine (95.64mg, 0.945mmol) were added to an 8mL sealed tube, nitrogen protection, cooled to 0°C, MsCl (81.20mg, 0.709mmol) was added, and after the addition was completed, the temperature was raised to room temperature and reacted for 30 minutes. After the reaction was completed, the reaction solution was extracted with ethyl acetate (3x 10ml), the organic phase was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. 110mg of (5-[[4-(2-methylpropoxy)phenyl]methyl]-6-oxo-5-azaspiro[2.5]octan-7-yl)methyl methanesulfonate was obtained, with a yield of 58.86%, as a light brown oil.

[0193] 19.4 Preparation of 7-[(dimethylamino)methyl]-5-[[4-(2-methylpropoxy)phenyl]methyl]-5-azaspiro[2.5]octan-6-one

[0194] (5-[[4-(2-methylpropoxy)phenyl]methyl]-6-oxo-5-azaspiro[2.5]octan-7-yl)methyl methanesulfonate (110.00 mg, 0.278 mmol), dimethylamine hydrochloride (45.36 mg, 0.556 mmol) and DIEA (107.84 mg, 0.834 mmol) were added to 3.00 ml of ethylene glycol and the temperature was raised to 80°C for reaction for 3 hours. The mixture was extracted with ethyl acetate (3 x 10 ml), the organic phase was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. Column chromatography separation and purification (DCM: MeOH = 20: 1) gave 37.7 mg of 7-[(dimethylamino)methyl]-5-[[4-(2-methylpropoxy)phenyl]methyl]-5-azaspiro[2.5]octan-6-one, with a yield of 39.35%. 1 H NMR (400MHz, Methanol-d4) δ7.28–7.14(m,2H),6.94–6.82(m,2H),4.76(d,J=14.4Hz,1H),4.3 2(d,J=14.4Hz,1H),3.74(d,J=6.5Hz,2H),3.60(d,J=12.5Hz,1H),3.49(t,J=13.0Hz,1H),3.1 0(d,J=10.0Hz,1H),2.99(d,J=13.5Hz,6H),2.59(dd,J=12.5,1.7Hz,1H),2.12–1.91(m,2H),1 .30(dd,J=13.1,5.5Hz,1H),1.04(d,J=6.7Hz,6H),0.63–0.35(m,4H).LCMS(ES,m / z):345[M+H] + .

[0195] Example 20. 7-(Dimethylamino)-5-(4-isobutoxybenzyl)-5-azaspiro[2.5]octan-6-one (20)

[0196] Reaction 5

[0197]

[0198] Dimethylamine (21.82 mg, 0.484 mmol), DMF (5.00 mL) and DIEA (125.08 mg, 0.968 mmol) were added to a 25 mL round-bottom flask, stirred for 0.5 hours, 7-iodo-5-[[4-(2-methylpropoxy)phenyl]methyl]-5-azaspiro[2.5]octan-6-one (100.00 mg, 0.242 mmol) was added, the temperature was raised to 60°C, and the reaction was allowed to proceed overnight. After the reaction was completed, the mixture was extracted with ethyl acetate (2 x 20 mL), the organic phase was washed with water (2 x 20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under pressure to dryness. Column chromatography separation and purification (DCM:MeOH=20:1) gave 63.6 mg of 7-(dimethylamino)-5-(4-isobutoxybenzyl)-5-azaspiro[2.5]octan-6-one in a yield of 69.82%. 1 H NMR (400MHz, DMSO-d6): δ7.17–7.04(m,2H),6.94–6.80(m,2H),4.54–4.32(m,2H),3. 71(d,J=6.5Hz,2H),3.57–3.39(m,2H),2.42(s,6H),2.35(dd,J=12.0,2.0Hz,1H),2. 16(t,J=12.2Hz,1H),2.00(hept,J=6.6Hz,1H),1.25(ddd,J=13.0,6.4,2.0Hz,1H),0 .97(d,J=6.7Hz,6H),0.50–0.37(m,3H),0.34–0.24(m,1H).LCMS(ES,m / z):331[M+H] + .

[0199] Example 21. 7-(azetidin-1-yl)-5-(4-isobutoxybenzyl)-5-azaspiro[2.5]octan-6-one (21)

[0200] The reaction raw material dimethylamine was replaced by azocyclobutane, and the target compound was prepared according to the method of Example 20. The structural formula is shown in No. (21) in Table 1. 1H NMR (400MHz, DMSO-d6): δ7.17–7.04(m,2H),6.94–6.80(m,2H),4.54–4.32(m,2H),3.71(d, J=6.5Hz,2H),3.57–3.39(m,2H),3.21–3.24(m,4H),2.35(dd,J=12.0,2.0Hz,1H),2.21–2. 23(m,2H),2.16(t,J=12.2Hz,1H),2.00(hept,J=6.6Hz,1H),1.25(ddd,J=13.0,6.4,2.0Hz ,1H),0.97(d,J=6.7Hz,6H),0.50–0.37(m,3H),0.34–0.24(m,1H).LCMS(ES,m / z):343[M+H] + .

[0201] Example 22. 1-(4-isobutoxybenzyl)-5-methyl-3-(1-methylpiperidin-4-yl)-5-phenyltetrahydropyrimidin-2(1H)-one (22)

[0202] The reaction raw material 1-(methoxycarbonyl)cyclopropane-1-carboxylic acid was replaced by 3-ethoxy-2-methyl-3-oxy-2-phenylpropionic acid, and the target compound was prepared according to the method of Example 1. The structural formula is shown in No. (22) in Table 1. 1 HNMR(400MHz,Methanol-d4)δ7.24(dtd,J=11.1,8.0,4.0Hz,7H),6.89(d,J=8.5Hz,2H),4.52(s,2H),4 .50–4.37(m,1H),3.75(dd,J=6.5,1.2Hz,2H),3.53(dd,J=24.8,11.9Hz,4H),3.35(s,1H),3.27(d,J=1 2.1Hz,1H),3.11(dt,J=24.3,13.1Hz,2H),2.92–2.79(m,3H),2.22–1.95(m,3H),1.88(d,J=13.7Hz,1H ),1.47(d,J=13.8Hz,1H),1.28(d,J=1.5Hz,3H),1.05(dd,J=6.7,1.2Hz,6H).LCMS(ES,m / z):450[M+H] + .

[0203] Example 23. 5,5-difluoro-1-(4-isobutoxybenzyl)-3-(1-methylpiperidin-4-yl)tetrahydropyrimidin-2(1H)-one (23)

[0204] The reaction raw material 1-(methoxycarbonyl)cyclopropane-1-carboxylic acid was replaced by 3-ethoxy-2,2-difluoro-3-oxypropane acid, and the target compound was prepared according to the method of Example 1. The structural formula is shown in No. (23) in Table 1. 1 H NMR (400MHz, Methanol-d4) δ7.21(d,J=8.4Hz,2H),6.95–6.83(m,2H),4.50(s,3H),3.74(d,J=6.4Hz,2H),3.58(dt,J=42.1,12.5Hz,6H),3. 34(s,2H),3.20(td,J=13.1,3.0Hz,2H),2.90(s,3H),2.21–2.00(m,3H),2.00–1.90(m,2H),1.04(d,J=6.7Hz,6H).LCMS(ES,m / z):396[M+H] + .

[0205] Example 24. 5,5-difluoro-1-(4-isobutoxybenzyl)-3-(1-methylpiperidin-4-yl)tetrahydropyrimidin-2(1H)-one (24)

[0206] The reaction raw material 1-(methoxycarbonyl)cyclopropane-1-carboxylic acid was replaced by 3-ethoxy-2-methyl-3-oxopropionic acid, and the target compound was prepared according to the method of Example 1. The structural formula is shown in No. (24) in Table 1. 1 H NMR(400MHz, Methanol-d4)δ7.19(d,J=8.5Hz,2H),6.90–6.85(m,2H),4.47(s ,3H),3.74(d,J=6.4Hz,2H),3.68–3.54(m,2H),3.30–3.26(m,1H),3.26–3.13 (m,3H),2.89(d,J=9.6Hz,5H),2.07(td,J=13.0,6.2Hz,4H),1.92(t,J=12.8H z,2H),1.04(d,J=6.7Hz,6H),0.99(d,J=6.7Hz,3H).LCMS:(ES,m / z):374[M+H] + .

[0207] Example 25 5-(-isobutoxybenzyl)7-(-methylpiperazin-1-yl)5-azaspiro[2.5]octan-6-one (25)

[0208] The reaction raw material dimethylamine was replaced by N-methylpiperazine, and the target compound was prepared according to the method of Example 20. The target compound has a structural formula as shown in No. (25) in Table 1. 1H NMR (400MHz, DMSO-d6) δ11.90(s,1H),7.17(dd,J=9.0,2.5Hz,2H),6.89(dd,J=9.2,2.6Hz,2H),4.59(d,J=1 4.6Hz,1H),4.48–4.43(m,2H),4.36(d,J=14.6Hz,1H),3.89(d,J=11.7Hz,1H),3.70(t,J=10.3Hz,5H),3.63– 3.33(m,5H),2.82(s,3H),2.48(d,J=9.9Hz,2H),2.00(hept,J=6.6Hz,1H),1.62(dd,J=11.9,5.9Hz,1H),0.9 7(d,J=6.7Hz,6H),0.61(d,J=2.6Hz,2H),0.59–0.49(m,1H),0.38(d,J=9.3Hz,1H).LCMS(ES,m / z):386[M+H] + .

[0209] Example 26 5-(-isobutoxybenzyl)7-(-methylpiperazin-1-yl)5-azaspiro[2.5]octan-6-one (26)

[0210] The reaction raw material 7-iodo-5-[[4-(2-methylpropoxy)phenyl]methyl]-5-azaspiro[2.5]octane-6-one was replaced by 7-iodo-5-(1-methylpiperidin-4-yl)-5-azaspiro[2.5]octane-6-one, and dimethylamine was replaced by 4-isobutoxybenzaldehyde. The target compound was prepared according to the method of Example 20. The target compound has a structural formula as shown in No. (26) in Table 1. 1H NMR (400MHz, Methanol-d4) δ7.16–7.00(m,2H),6.88–6.75(m,2H),4.41(tt,J=12.1,4.3Hz,1H),3.71(d,J=6.4Hz, 2H),3.29(d,J=12.4Hz,1H),3.17(dd,J=12.8,3.3Hz,1H),3.02–2.88(m,2H),2.84–2.61(m,3H),2.31(s,3H),2.17 (tdd,J=12.1,7.1,2.7Hz,2H),2.10–1.97(m,J=6.7Hz,1H),1.82–1.66(m,2H),1.65–1.54(m,2H),1.16(ddd,J=13. 3,6.5,1.9Hz,1H),1.04(d,J=6.7Hz,6H),0.50(dddd,J=34.8,19.0,9.7,5.1Hz,3H),0.35(dt,J=9.7,4.9Hz,1H).LC MS(ES,m / z):385[M+H] + .

[0211] Example 27 5-[(6-isobutoxypyridin-3-yl)methyl]-7-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.5]octan-6-one (27)

[0212] The reaction raw material 1-[4-(2-methylpropoxy)phenyl]methylamine was replaced by (6-isobutoxypyridin-3-yl)methylamine, and the target compound was prepared according to the method of Example 1. The structural formula is shown in No. (27) in Table 1. 1 HNMR (400MHz, Methanol-d4) δ8.43 (dd, J=9.1, 2.3Hz, 1H), 8.25 (d, J=2.3Hz, 1H), 7.61 (d, J=9. 1Hz,1H),4.59(s,2H),4.47(tt,J=12.3,4.1Hz,1H),4.28(d,J=6.5Hz,2H),3.68–3.54(m,2H), 3.19(s,3H),3.15(dd,J=12.8,2.8Hz,2H),3.11(s,2H),2.89(s,3H),2.23(hept,J=6.7Hz,1H) ,2.06(qd,J=13.3,4.0Hz,2H),1.94–1.82(m,2H),1.12(d,J=6.7Hz,6H),0.76–0.56(m,4H).LC MS(ES,m / z):387[M+H] + .

[0213] Example 28 5-(2-Fluoro-4-isobutoxybenzyl)-7-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.5]octan-6-one (28)

[0214] The reaction raw material 1-[4-(2-methylpropoxy)phenyl]methylamine was replaced by (2-fluoro-4-isobutyloxyphenyl)methylamine, and the target compound was prepared according to the method of Example 1. The structural formula is shown in No. (28) in Table 1. 1 HNMR(400MHz,Methanol-d4)δ7.22(t,J=8.7Hz,1H),6.73(dd,J=8.5,2.5Hz,1H),6.66(dd,J=12 .1,2.5Hz,1H),4.52(s,2H),4.28(tt,J=11.7,4.7Hz,1H),3.74(d,J=6.5Hz,2H),3.03(s,4H),2 .96(dq,J=11.6,2.8,2.0Hz,2H),2.31(s,3H),2.16(td,J=11.8,3.3Hz,2H),2.05(dh,J=13.4,6 .7Hz,1H),1.76–1.58(m,4H),1.04(d,J=6.7Hz,6H),0.64–0.56(m,2H),0.53(d,J=4.6Hz,2H).LC MS:(ES,m / z):404[M+H] + .

[0215] Example 29 5-(3-Fluoro-4-isobutoxybenzyl)-7-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.5]octan-6-one (29)

[0216] The reaction raw material 1-[4-(2-methylpropoxy)phenyl]methylamine was replaced by (3-fluoro-4-isobutyloxyphenyl)methylamine, and the target compound was prepared according to the method of Example 1. The structural formula is shown in No. (29) in Table 1. 1HNMR(400MHz,DMSO-d6)δ7.09(t,J=8.6Hz,1H),7.02(dd,J=12.3,2.0Hz,1H),6.95(dd,J=8.5,2.1Hz,1H),4 .34(s,2H),4.11(tt,J=12.1,4.1Hz,1H),3.79(d,J=6.5Hz,2H),2.93(d,J=7.2Hz,4H),2.83–2.75(m,2H),2. 14(s,3H),2.03(dh,J=13.4,6.7,6.3Hz,1H),1.90(td,J=11.8,2.5Hz,2H),1.57(qd,J=12.1,3.9Hz,2H),1.4 7–1.38(m,2H),0.97(d,J=6.7Hz,6H),0.52(q,J=4.2Hz,2H),0.42(t,J=2.8Hz,2H).LCMS(ES,m / z):404[M+H] + .

[0217] Example 30 5-(4-isobutoxybenzyl)-7-(1-methylazo-4-yl)-5-(7-diazaoxazolo[2.5]octan-6-one (30)

[0218] The reaction raw material 1-methyl-4-piperidinamine was replaced by 1-methylazepan-4-amine, and the target compound was prepared according to the method of Example 1. The structural formula is shown in No. (30) in Table 1. 1 H-NMR (400MHz, Methanol-d4): δ7.17(d,J=8.3Hz,2H),6.87(d,J=8.2Hz,2H),4.52–4.4 0(m,3H),3.73(d,J=6.4Hz,2H),3.58–3.42(m,2H),3.50(s,4H),3.25(dt,J=14.5,11.0H z,1H),3.22–2.97(m,4H),2.95(d,J=22.1Hz,1H),2.91(s,2H),2.38–1.66(m,4H),1.04 (d,J=6.7Hz,6H),0.63(d,J=3.7Hz,2H),0.48(d,J=3.2Hz,2H).LCMS(ES,m / z):400[M+H] + .

[0219] Example 31 5-((2R)-1,2-dimethylpiperidin-4-yl)-7-(4-isobutoxybenzyl)-5,7-diazaspiro[2.5]octan-6-one (31)

[0220] The reaction raw material 1-methyl-4-piperidinamine was replaced by (2R)-1,2-dimethylpiperidin-4-amine, and the target compound was prepared according to the method of Example 1. The structural formula is shown in No. (31) in Table 1. 1 H NMR(400MHz, Methanol-d4)δ7.18(d,J=8.3Hz,2H),6.87(d,J=8.4Hz,2H),4.57(tq,J=11.9,4.4Hz,1H), 4.47(s,2H),3.73(d,J=6.4Hz,2H),3.59(ddd,J=12.7,4.2,2.3Hz,1H),3.26–3.13(m,1H),3.08(s,2H), 3.00(d,J=2.1Hz,2H),2.89(s,3H),2.09(dtd,J=26.6,13.3,5.5Hz,2H),2.00–1.81(m,2H),1.46(d,J=6 .3Hz,3H),1.04(d,J=6.7Hz,6H),0.63(q,J=4.7Hz,2H),0.50(d,J=4.8Hz,2H).LCMS(ES,m / z):400[M+H] + .

[0221] Example 32 5-((2S)-1,2-dimethylpiperidin-4-yl)-7-(4-isobutoxybenzyl)-5,7-diazaspiro[2.5]octan-6-one (32)

[0222] The reaction raw material 1-methyl-4-piperidinamine was replaced by (2S)-1,2-dimethylpiperidin-4-amine, and the target compound was prepared according to the method of Example 1. The structural formula is shown in No. (32) in Table 1. 1H NMR(400MHz, Methanol-d4)δ7.18(d,J=8.2Hz,2H),6.87(d,J=8.4Hz,2H),4.75(ddt,J=12.6,7.7,3.8Hz,1H), 4.47(s,2H),3.90–3.79(m,1H),3.73(d,J=6.5Hz,2H),3.36(p,J=4.6,3.7Hz,1H),3.08–2.96(m,4H),2.82(s, 2H),2.23(td,J=13.2,5.0Hz,1H),2.06(p,J=6.8Hz,1H),1.93–1.76(m,2H),1.58(d,J=7.0Hz,1H),1.49(d,J= 6.0Hz,2H),1.04(d,J=6.7Hz,6H),0.62(q,J=5.5,4.8Hz,2H),0.50(d,J=4.6Hz,2H).LCMS(ES,m / z):400[M+H] + .

[0223] Example 33 5-(2-chloro-4-isobutoxybenzyl)-7-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.5]octan-6-one (33)

[0224] The reaction raw material 1-[4-(2-methylpropoxy)phenyl]methylamine was replaced by (2-chloro-4-isobutyloxyphenyl)methylamine, and the target compound was prepared according to the method of Example 1. The structural formula is shown in No. (33) in Table 1. 1 HNMR (400MHz, Methanol-d4) δ7.21(d,J=8.5Hz,1H),6.96(d,J=2.4Hz,1H),6.88(dd,J=8.6,2.5H z,1H),4.59(s,2H),4.56–4.45(m,1H),3.74(d,J=6.4Hz,2H),3.64–3.52(m,2H),3.26–3.14(m,2H ),3.12(s,2H),3.04(s,2H),2.88(s,3H),2.09(dtd,J=29.7,13.1,5.1Hz,3H),1.90(d,J=13.5Hz, 2H),1.03(d,J=6.7Hz,6H),0.67(d,J=4.8Hz,2H),0.57(d,J=4.8Hz,2H).LCMS(ES,m / z):420[M+H] + Example 34 5-(3-isobutoxybenzyl)-7-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.5]octan-6-one (34)

[0225] The reaction raw material 1-[4-(2-methylpropoxy)phenyl]methylamine was replaced by 1-[3-(2-methylpropoxy)phenyl]methylamine, and the target compound was prepared according to the method of Example 1. The structural formula is shown in No. (34) in Table 1. 1 H NMR (400MHz, Methanol-d4) δ7.27–7.18 (m, 1H), 6.81 (d, J = 8.3Hz, 3H), 4.51 (s, 2H), 4. 31(tt,J=11.6,4.7Hz,1H),3.74(d,J=6.5Hz,2H),3.05(s,2H),3.03–2.89(m,4H),2.31 (s,3H),2.16(td,J=11.8,3.4Hz,2H),2.06(dp,J=13.2,6.6Hz,1H),1.78–1.60(m,4H) ,1.04(d,J=6.7Hz,6H),0.64–0.53(m,2H),0.53–0.40(m,2H).LCMS(ES,m / z):386[M+H] + .

[0226] Example 35 4-(4-isobutoxybenzyl)-6-(1-methylpiperidin-4-yl)-4,6-diazaspiro[2.4]heptan-5-one (35)

[0227] The reaction raw material 1-(methoxycarbonyl)cyclopropane-1-carboxylic acid is replaced by 1-[(tert-butyloxycarbonyl)amino]cyclopropane-1-carboxylic acid, 1-[4-(2-methylpropoxy)phenyl]methylamine is replaced by 1-methyl 4-piperidinamine, and 1-methyl 4-piperidinamine is replaced by 4-(2-methylpropoxy)benzaldehyde. The target compound is prepared according to the method of Example 1. The structural formula is shown in Table 1 as No. (35). 1 H NMR(400MHz,Methanol-d4)δ7.10(d,J=8.2Hz,2H),6.87(d,J=8.2Hz,2H),6.33(s,1H),4.8 3(s,2H),4.02(tt,J=10.8,5.9Hz,1H),3.73(d,J=6.5Hz,2H),3.02(d,J=11.9Hz,2H),2.34 (d,J=12.5Hz,5H),2.22(td,J=11.4,4.3Hz,2H),2.05(hept,J=6.6Hz,1H),1.88(td,J=11. 6,10.5,3.6Hz,4H),1.12(t,J=7.4Hz,3H),1.03(d,J=6.7Hz,6H).LCMS(ES,m / z):372[M+H] + .

[0228] Example 36 6-(4-isobutoxybenzyl)-4-(1-methylpiperidin-4-yl)-4,6-diazaspiro[2.4]heptan-5-one (36)

[0229] The reaction raw material 1-(methoxycarbonyl)cyclopropane-1-carboxylic acid is replaced by 1-[(tert-butyloxycarbonyl)amino]cyclopropane-1-carboxylic acid, and 1-methyl 4-piperidinamine is replaced by 1-methylpiperidine-4-carboxaldehyde. The target compound is prepared according to the method of Example 1. The structural formula is shown in No. (36) in Table 1. 1 H NMR (400MHz, Methanol-d4) δ7.22–7.14(m,2H),6.93–6.85(m,2H),4.29(s,2H),3.74(d,J=6.5Hz,2H),3.22(s,2H),3.04–2.89(m,2H),2.5 7–2.41(m,3H),2.27(s,3H),2.13–1.99(m,3H),1.57(dt,J=9.5,2.8Hz,2H),1.07–0.97(m,8H),0.62–0.55(m,2H).LCMS(ES,m / z):372[M+H] + .

[0230] Example 37 5-(1-ethylpiperidin-4-yl)-7-(4-isobutoxybenzyl)-5,7-diazaspiro[2.5]octan-6-one (37)

[0231] The reaction raw material 1-methyl-4-piperidinamine was replaced by 1-ethyl-4-piperidinamine, and the target compound was prepared according to the method of Example 1. The structural formula is shown in No. (37) in Table 1. 1 H NMR(400MHz,Methanol-d4)δ7.23–7.11(m,2H),6.95–6.81(m,2H),4.47(s,2H),4.32(tt,J =10.8,5.7Hz,1H),3.73(d,J=6.4Hz,2H),3.33(p,J=1.6Hz,4H),3.12–3.05(m,2H),3.05–2. 96(m,4H),2.48(q,J=7.2Hz,2H),2.17–1.99(m,3H),1.74–1.61(m,4H),1.13(t,J=7.2Hz,3H ),1.04(d,J=6.7Hz,6H),0.58(t,J=3.0Hz,2H),0.50–0.45(m,2H).LCMS(ES,m / z):400[M+H] + .

[0232] Example 38 5-(4-Isopentylbenzyl)-7-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.5]octan-6-one (38)

[0233] The reaction raw material 1-[4-(2-methylpropoxy)phenyl]methylamine was replaced by (4-isopentylphenyl)methylamine, and the target compound was prepared according to the method of Example 1. The structural formula is shown in No. (38) in Table 1. 1 H NMR (400MHz, Methanol-d4): δ7.16(s,4H),4.51(s,2H),4.49–4.41(m,1H),3.5 9(dq,J=10.6,2.3Hz,2H),3.17(td,J=12.8,3.3Hz,2H),3.05(d,J=16.6Hz,4H) ,2.90(s,3H),2.69–2.57(m,2H),2.12–1.86(m,4H),1.71–1.43(m,3H),0.95(d ,J=6.5Hz,6H),0.68–0.58(m,2H),0.58–0.47(m,2H).LCMS(ES,m / z):384[M+H] + .

[0234] Example 39 5-(4-(Isobutylamino)benzyl)-7-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.5]octan-6-one (39)

[0235] The reaction raw material 1-[4-(2-methylpropoxy)phenyl]methylamine was replaced by 4-(aminomethyl)-N-isobutylaniline, and the target compound was prepared according to the method of Example 1. The structural formula is shown in No. (39) in Table 1. 1 H NMR(400MHz,Methanol-d4)δ7.57–7.45(m,4H),4.61(s,2H),4.57–4.44(m,1H) ,3.68–3.53(m,2H),3.28(d,J=7.2Hz,2H),3.23–3.13(m,2H),3.13–3.07(m,4H) ,2.89(d,J=1.8Hz,3H),2.19–2.01(m,3H),1.92(d,J=13.8Hz,2H),1.11(d,J=6. 6Hz,6H),0.66(d,J=5.0Hz,2H),0.56(d,J=4.6Hz,2H).LCMS(ES,m / z):505[M+H] +Example 40 5-(4-(Isobutylamino)benzyl)-7-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.5]octan-6-one (40)

[0236] The reaction raw material 1-[4-(2-methylpropoxy)phenyl]methylamine was replaced by [4-(methylisopropoxy)phenyl]methylamine, and the target compound was prepared according to the method of Example 1. The structural formula is shown in No. (40) in Table 1. 1 HNMR (400MHz, Methanol-d4) δ7.32 (d, J = 8.2 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 4.53 (d, J = 10. 9Hz, 4H), 4.30 (td, J = 11.5, 5.3Hz, 1H), 3.73 (p, J = 6.2Hz, 1H), 3.05 (s, 2H), 2.98 (d, J = 18. 0Hz, 4H), 2.32 (s, 3H), 2.17 (td, J=11.7, 3.4Hz, 2H), 1.70 (ddt, J=24.2, 12.9, 6.4Hz, 4H), 1.21(d,J=6.1Hz,6H),0.64–0.56(m,2H),0.49(t,J=3.0Hz,2H).LCMS(ES,m / z):386[M+H] + .

[0237] Pharmacological Examples:

[0238] In vitro receptor binding assay

[0239] 1. Experimental methods

[0240] 1.1 Preparation of solutions required for the experiment

[0241] A: (for the preparation of 5-HT 2C Receptor membrane): 50mM Tris-HCl buffer: Dissolve 96.8g Tris in deionized water to a total volume of 4000ml, adjust the pH to 7.5 with HCl, and dilute to 16000mL, pH = 7.4

[0242] B: (for the preparation of 5-HT 2A Receptor membrane): Weigh 11.7 mg EDTA and 380.84 mg MgCl2, add 50 mM Tris-HCl buffer to a total volume of 400 mL, and adjust the pH to 7.4. The final concentrations are 0.1 mM EDTA and 10 mM MgCl2.

[0243] C: (for preparation of Dopamine receptor membrane): Weigh 2.978g HEPES, 1.17g NaCl, 0.119g MgCl2, 36.5mg EDTA, add pure water to a total volume of 250ml, adjust pH = 7.4, and make the final concentrations 50mM HEPES, 50mM NaCl, 5mM MgCl2, 0.5mM EDTA, pH 7.4.

[0244] 1.2 Preparation of receptor membrane

[0245] 1) CHO-5-HT 2A Preparation of receptor membrane

[0246] CHO-5-HT 2A After the cells are taken out of the -80℃ freezer, they are naturally thawed and centrifuged at 2000g at 4℃ for 15 minutes. Take the precipitate and discard the supernatant. Add solution B to the precipitate. Mix the cells for 20-30 seconds, then centrifuge at 50000g at 4℃ for 25 minutes. Carefully discard the upper layer, add solution B again, mix, and centrifuge at 50000g at 4℃ for 25 minutes. Store the precipitate at -80℃.

[0247] 2) 5-HT 2C Membrane preparation

[0248] The rat cortex was taken out of the -80℃ refrigerator and thawed naturally. Solution A was added and homogenized at gear 4 for 3-4s. Homogenize four times, centrifuge at 50000g, 4℃ for 25min, discard the supernatant, add solution A, mix well with a vortex mixer, centrifuge at 50000g, 4℃ for 25min, repeat the centrifugation twice, discard the supernatant, and store the precipitate at -80℃ for later use.

[0249] 3) Preparation of CHO-D2 receptor membrane

[0250] The CHO-D2 cells were taken out of the -80°C freezer and thawed naturally. The cells were centrifuged at 2000 g for 15 min, and the precipitate was added to homogenate C, mixed with a vortex mixer, and centrifuged at 50000 g, 4°C for 25 min. The supernatant was discarded, the precipitate was taken, and the C buffer was added again for washing, resuspending and centrifuging. After the centrifugation was completed, the supernatant was discarded and the precipitate was stored at -80°C for later use.

[0251] 1.3 Receptor competition binding assay

[0252] 1) 5-HT 2A Receptor competition binding assay

[0253] Step 1: First, use the prepared membrane to make a 10 mg / mL membrane suspension using homogenate B for later use.

[0254] Step 2: Add 100 μL of membrane preparation to each reaction tube.

[0255] Step 3: Add 100 μL of solution B to the total binding tube (TB) and 100 μL of Methysergide (final concentration 1.0×10 -5 M), and 100 μL of the test compound was added to each test compound tube (CB).

[0256] Step 4: Add radioligand to each reaction tube 3 H-Ketanserin 10μL, final concentration 2.98nM.

[0257] Step 5: Incubate each reaction tube at 37°C for 25 min. After the reaction is completed, the bound ligand is quickly filtered by reduced pressure. The Whatman test paper GF / C plate should be soaked in 0.5% PEI for more than 1 h in advance. After filtration, the filter membrane is dried at 60°C, and 40 μL of scintillation fluid is added after the bottom membrane is attached. The upper membrane is sealed and allowed to stand.

[0258] Step 6: Place the scintillation cup into the liquid scintillation counter for counting.

[0259] 2) 5-HT 2C Receptor competition binding assay

[0260] Step 1: First, use the prepared membrane to prepare a 210 mg / mL membrane suspension using homogenate B for later use.

[0261] Step 2: Add 100 μL of membrane preparation to each reaction tube.

[0262] Step 3: Add 100 μL of Solution B to the total binding tube (TB) and Ketanserin (final concentration 1.0×10 -5 M) 100 μL, and each test compound tube (CB) was added with 100 μL of the test compound.

[0263] Step 4: Add radioligand to each reaction tube 3 H-Mesulergine 10μL, final concentration 3nM.

[0264] Step 5: Incubate each reaction tube at 37°C for 25 min. After the reaction is complete, the bound ligand is quickly filtered under reduced pressure. The Whatman test paper GF / C is saturated with 0.5% PEI solution 1 h in advance and washed thoroughly with ice-cold Tris buffer. The filter is taken out and placed in a 4 mL scintillation cup. 1 mL of toluene scintillation fluid is added and mixed.

[0265] Step 6: Place the scintillation cup into the liquid scintillation counter for counting.

[0266] 3) CHO-D2 receptor competition binding assay

[0267] Step 1: First, use the prepared membrane to prepare a suspension of 8 mg / mL using homogenate C for later use.

[0268] Step 2: Add 100 μL of membrane preparation to each reaction tube.

[0269] Step 3: Add 100 μL of Solution C to the total binding tube (TB) and 100 μL of Haloperidol (final concentration 1.0×10 -5 M), add 100 μL of the test compound to each test compound binding tube (CB).

[0270] Step 4: Add radioligand to each reaction tube 3 H-Spiperone 10 μL, final concentration 1.176 nM.

[0271] Step 5: Incubate each reaction tube at 37°C for 25 min. After the reaction is completed, the bound ligand is quickly filtered through reduced pressure. The Whatman test paper GF / B plate should be soaked in 0.5% PEI for more than 1 hour in advance. After filtration, the filter membrane is dried at 60°C, and 40μL scintillation fluid is added after the bottom membrane is attached. The upper membrane is sealed and allowed to stand.

[0272] Step 6: Place the filter plate into the liquid scintillation counter for counting.

[0273] 2. Experimental results

[0274] Pimasserin and 5-HT 2A , 5-HT 2C The receptor Ki values ​​were 0.036 and 2.94 nM, respectively. Compound 1 and 5-HT 2A , 5-HT 2C The receptor Ki values ​​are 0.0002 and 3.54 nM, respectively, which are better than pimaselin. See the table below for details:

[0275] Table 2 In vitro receptor binding activity of each compound (Ki value, nM)

[0276] Compound No. <![CDATA[5-HT 2A (Ki value, nM)]]> <![CDATA[5-HT 2C (Ki value, nM)]]> 2C / 2A Pimasseline 0.036 2.94 81.667 1 0.0002 3.54 17700.00 8 0.07 >1000 >14285.71 15 0.015 458.50 31435.87 27 17.9499 1807.00 100.67 28 0.5700 543.60 953.68 32 0.89 106.80 120.10 33 0.19 330.60 1740.00

[0277] In vitro hERG assay

[0278] The stably transfected cells were inoculated on glass slides with a cell density of less than 50% and cultured overnight. The experimental cells were transferred to a bath of about 1 ml embedded in the inverted microscope platform and perfused with extracellular fluid at a rate of 2.7 ml / min. The experiment can be started after stabilization for 5 minutes. The membrane current was recorded using a HEKA EPC-10 patch clamp amplifier and a PATCHMASTER acquisition system (HEKA Instruments Inc. D-67466 Lambrecht, Pfalz, Germany). All experiments were performed at room temperature (22-24°C).

[0279] In the experiment, a P-97 microelectrode pulling instrument (Sutter Instrument Company, One DigitalDrive, Novato, CA 94949) was used to straighten the electrode (BF150-110-10). The inner diameter of the electrode was 1-1.5 mm, and the water resistance after being filled with internal solution was 2-4 MΩ.

[0280] The electrophysiological stimulation scheme for hERG potassium channels is to first clamp the membrane voltage at -80mV, give the cell a voltage stimulus of +20mV for 2s to activate the hERG potassium channels, and then repolarize to -50mV for 5s to generate an outward tail current. The stimulation frequency is once every 15s. The current value is the peak value of the tail current.

[0281] The whole-cell recording mode was used to record the channel current in the experiment. First, the extracellular fluid was perfused (approximately 2 ml per minute) and the recording was continued, and the current was waited for to stabilize (the current decay (Run-Down) was less than 5% within 5 minutes). At this time, the peak value of the tail current was the control current value. Then, the extracellular fluid containing the drug to be tested was perfused and the recording was continued until the inhibitory effect of the drug on the hERG current reached a stable state. At this time, the peak value of the tail current was the current value after drug addition. The standard of the stable state is judged by whether the three most recent consecutive current recording lines overlap. After reaching a stable situation, if the hERG current recovers or approaches the size before the addition of the drug after flushing with extracellular fluid, other concentrations or drugs can be perfused and tested.

[0282] Experimental Results

[0283] Pimasserin hERG assay IC 50 The cardiotoxicity of compound 1, compound 15, compound 24, compound 28, compound 31 and compound 33 is less than that of pimasserin. The results are shown in the table below.

[0284] Table 3 In vitro hERG test results of compounds

[0285] Compound No. hERG(nM) Pimasseline 208 1 2252 15 2045 24 3655 28 1298 31 1809 33 1235

[0286] Animal experiments

[0287] 1. Test methods

[0288] 1.1 Experiment on the effect of MPTP+MK-801 on the Parkinson's disease mouse model (anti-PDP efficacy model)

[0289] The animals were intraperitoneally injected with different doses of MPTP every morning for 5 consecutive days. On the morning of the 5th day, after an interval of 1.5 hours, MPTP was injected and then pimasserin or NS was intraperitoneally injected. After an interval of 0.5 hours, MK-801 0.3 mg / kg (or NS) was intraperitoneally injected. After another interval of 0.25 hours, the mice were placed in a voluntary activity box (a black polyethylene box with a size of 29 cm × 29 cm × 30 cm) for video recording. The video recording time was 20 minutes. At the end of the recording, video analysis was performed to evaluate the activity of the mice.

[0290] 1.2 Effects on MPTP+APO-induced climbing behavior in male mice (DA motor deterioration model)

[0291] The animals were intraperitoneally injected with different doses of MPTP every morning for 5 consecutive days. On the morning of the 5th day, MPTP was injected and then pipemaserine, clozapine, quetiapine or NS was injected intraperitoneally 1.5 hours later. Then 1 mg / kg APO (dosage volume was 0.1 ml / 10 g body weight) was injected subcutaneously 0.5 hours later. The animals were immediately placed in a climbing cage (the climbing cage was homemade by our company and was a cylindrical cage with a diameter of 13 cm and a height of 15 cm. It was made of a stainless steel mesh with a diameter of about 0.1 cm, a translucent polyethylene plate at the bottom, and a stainless steel cage cover) and their behaviors were observed and scored at 10-11, 20-21, and 30-31 minutes after the injection of APO.

[0292] The scoring criteria are: four feet on the floor score 0; two front feet on the net cage score 1; four feet on the net cage score 2.

[0293] 1.3 Experiment on sedation side effects (anti-sedation model)

[0294] Qualified SPF-grade C57BL / 6j mice were randomly divided into 13 groups, 8 mice in each group: blank group, pimasserin 1, 3, 10, 30 mg / kg group, compound 1: 1, 3, 10, 30 mg / kg group. According to the different doses of each group, different concentrations of solutions were prepared for intraperitoneal injection, and the final administration volume was 10 ml / kg.

[0295] All groups were tested for spontaneous activity 45 minutes after the administration of compounds such as pimaselin, and the movement from 0 to 20 minutes was recorded by video. The 20-minute movement distance was analyzed by Top Scan 3.00 software. The inhibition rate of each group after administration relative to the blank group was calculated, and the sedative effect of the compound was comprehensively evaluated in combination with statistical conclusions.

[0296] 2. Test results

[0297] The experiment showed that the PDP efficacy, sedation, and motor exacerbation ED50 of Pimasserin were 0.37, 6.79, and >30 mg / kg, respectively, and its sedation / PDP efficacy ratio was 18.35, and its motor exacerbation / PDP efficacy ratio was >81.08; the PDP efficacy and sedation ED50 of compound 1 were 0.261 and 21.34 mg / kg, respectively, and its sedation / PDP efficacy ratio was 81.76. It can be seen that compound 1 has better efficacy and higher safety than Pimasserin.

[0298] Table 4

[0299]

Claims

1. A compound represented by formula I or a pharmaceutically acceptable salt thereof: in, n7 is 0, 1 or 2; A is C, O or N; n3 and n6 are independently selected from integers of 0, 1, 2, and 3, and n3 and n6 are not 0 at the same time; n2 is 1; W is O or S; Y is selected from C and N, Z and Q are N; R2 is selected from hydrogen, substituted or unsubstituted C1-C5 straight or branched alkyl, substituted or unsubstituted C3-C5 cycloalkyl, and the substituent is selected from methyl, ethyl, propyl, butyl, fluorine, C3-C5 cycloalkyl; R3 and R4 are independently selected from H, halogen, C 1- C5 straight chain or branched alkyl, phenyl, or R3 and R4 form a C 3- C5 cycloalkyl; R5 is hydrogen or halogen; R1 is selected from the structure of formula II: In formula II, n4 is selected from an integer of 1-4; R7 is selected from methyl, ethyl, isopropyl, isobutyl, benzyl, phenyl, halogenated C 1-5 A straight chain or branched alkyl group; R6 is halogen, methyl or hydrogen; When R3 and R4 form a C3-C5 cycloalkyl group, the structure is as shown in Formula I-1: Wherein, n1 is an integer of 1, 2 or 3.

2. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound of formula I is of formula V: When R3 and R4 form a C3-C5 cycloalkyl group, the structure is as shown in Formula V-1: Wherein, n1 is an integer of 1, 2 or 3.

3. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound of formula I is of formula VI structure: When R3 and R4 form a C3-C5 cycloalkyl group, the structure is as shown in Formula VI-1: Wherein, n1 is an integer of 1, 2 or 3.

4. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 or 3, characterized in that: When R1 is a structure of formula II, the compound of formula I is a structure of formula VI-2: Wherein, n4 is an integer of 1, 2 or 3.

5. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that: When R1 is a structure of formula II, the compound is a structure of formula V-2:

6. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The halogen is fluorine, chlorine, bromine or iodine.

7. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The C1-C5 straight or branched alkyl group is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl and neopentyl; the unsubstituted C3-C5 cycloalkyl group is selected from cyclopropyl, cyclobutyl and cyclopentyl; the substituted C3-C5 cycloalkyl group is selected from methylcyclopropyl and ethylcyclopropyl; the halo group is selected from fluoro, chloro, bromo and iodo.

8. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: in, n1 and n4 are independently selected from integers of 1, 2, and 3; R2 is selected from hydrogen, methyl, isopropyl, isobutyl, cyclopropyl, cyclopropylmethyl, neopentyl; R5 is selected from hydrogen, fluorine, chlorine, bromine, iodine; R7 is selected from methyl, ethyl, isopropyl, isobutyl, phenyl, benzyl, difluoroethyl; R6 is selected from fluorine, chlorine, bromine, iodine, hydrogen, and methyl.

9. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that in, R1 is selected from the structure of formula II: In formula II, n4 is an integer from 1 to 4; R7 is selected from methyl, ethyl, isopropyl, isobutyl, phenyl, benzyl, difluoroethyl; R6 is selected from fluorine, chlorine, bromine, iodine, hydrogen, and methyl.

10. A compound or a pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from any one of the following compounds: 5-(4-isobutoxybenzyl)-7-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.5]octan-6-one; 5-(3-fluoro-1-methylpiperidin-4-yl)-7-(4-isobutoxybenzyl)-5,7-diazaspiro[2.5]octan-6-one; 5-(4-isobutoxybenzyl)-7-(1-methylpyrrolidin-3-yl)-5,7-diazaspiro[2.5]octan-6-one; 5-(4-methoxybenzyl)-7-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.5]octan-6-one; 5-(4-Cyclopropyloxybenzyl)-7-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.5]octan-6-one; 5-(4-(cyclopropylmethoxy)benzyl)-7-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.5]octan-6-one; 5-(1-benzylpiperidin-4-yl)-7-(4-isobutoxybenzyl)-5,7-diazaspiro[2.5]octan-6-one; 5-(1-(2,2-difluoroethyl)piperidin-4-yl)-7-(4-isobutoxybenzyl)-5,7-diazaspiro[2.5]octan-6-one; 5-(1-methylpiperidin-4-yl)-7-(4-(neopentyloxy)benzyl)-5,7-diazaspiro[2.5]octan-6-one; 5-(4-isobutoxybenzyl)-7-(1-isobutylpiperidin-4-yl)-5,7-diazaspiro[2.5]octan-6-one; 5-(4-isobutoxybenzyl)-7-(1-isopropylpiperidin-4-yl)-5,7-diazaspiro[2.5]octan-6-one; 6-(4-isobutoxybenzyl)-8-(1-methylpiperidin-4-yl)-6,8-diazaspiro[3.5]nonan-7-one; 5-(4-isobutoxybenzyl)-7-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.5]octane-6-thione; 5-(4-hydroxybenzyl)-7-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.5]octane-6-one; 7-(4-isobutoxybenzyl)-5-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.6]nonan-6-one; 5-(4-isobutoxybenzyl)-7-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.6]nonan-6-one; 1-(4-isobutoxybenzyl)-5-methyl-3-(1-methylpiperidin-4-yl)-5-phenyltetrahydropyrimidin-2(1H)-one; 5,5-difluoro-1-(4-isobutoxybenzyl)-3-(1-methylpiperidin-4-yl)tetrahydropyrimidin-2(1H)-one; 1-(4-isobutoxybenzyl)-5-methyl-3-(1-methylpiperidin-4-yl)tetrahydropyrimidin-2(1H)-one; 5-((6-isobutoxypyridin-3-yl)methyl)-7-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.5]octan-6-one; 5-(2-fluoro-4-isobutoxybenzyl)-7-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.5]octan-6-one; 5-(3-fluoro-4-isobutoxybenzyl)-7-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.5]octan-6-one; 5-(4-isobutoxybenzyl)-7-(1-methylazo-4-yl)-5-(7-diazaoxazolo[2.5]octan-6-one; 5-((2R)-1,2-dimethylpiperidin-4-yl)-7-(4-isobutoxybenzyl)-5,7-diazaspiro[2.5]octan-6-one; 5-((2S)-1,2-dimethylpiperidin-4-yl)-7-(4-isobutoxybenzyl)-5,7-diazaspiro[2.5]octan-6-one; 5-(2-chloro-4-isobutoxybenzyl)-7-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.5]octan-6-one; 5-(3-isobutoxybenzyl)-7-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.5]octan-6-one; 4-(4-isobutoxybenzyl)-6-(1-methylpiperidin-4-yl)-4,6-diazaspiro[2.4]heptan-5-one; 6-(4-isobutoxybenzyl)-4-(1-methylpiperidin-4-yl)-4,6-diazaspiro[2.4]heptan-5-one; 5-(1-ethylpiperidin-4-yl)-7-(4-isobutoxybenzyl)-5,7-diazaspiro[2.5]octan-6-one; 5-(4-isopentylbenzyl)-7-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.5]octan-6-one; 5-(4-(isobutylamino)benzyl)-7-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.5]octan-6-one; 5-(4-(Isopropoxymethyl)benzyl)-7-(1-methylpiperidin-4-yl)-5,7-diazaspiro[2.5]octan-6-one.

11. A pharmaceutical composition, characterized in that Containing the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, optionally further comprising a pharmaceutically acceptable excipient, carrier, adjuvant, solvent or a combination thereof.

12. Use of the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 11 in the preparation of a drug for treating mental illness.

13. The use according to claim 12, characterized in that: The mental illness is schizophrenia.

14. The use according to claim 12, characterized in that: The mental illnesses are Parkinson's disease, dementia-related behavioral disorders and psychosis.

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