CN107793362B

CN107793362B - Synthesis and application of phenyl pyridazinone derivative

Info

Publication number: CN107793362B
Application number: CN201610788072.6A
Authority: CN
Inventors: 张桂森; 曹旭东; 张译芳; 邱印利; 赵松; 徐祥清; 刘欣; 刘笔锋
Original assignee: Wuhan Jiayu Technology Co ltd; Nhwa Pharmaceutical Corp
Current assignee: Wuhan Jiayu Technology Co ltd; Nhwa Pharmaceutical Corp
Priority date: 2016-08-30
Filing date: 2016-08-30
Publication date: 2022-04-22
Anticipated expiration: 2036-08-30
Also published as: CN107793362A

Abstract

The invention relates to the field of medicines, in particular to a phenylpyridazine derivative and application thereof. In particular, the invention relates to phenyl pyridazinone derivatives, a pharmaceutical composition containing the phenyl pyridazinone derivatives, and applications of the composition and the pyridazinone derivatives in preparation of medicines for preventing or treating mental and neurological diseases. The pyridazinone derivative has a structure shown in a formula (I). Experiments show that the compounds can be used for preventing or treating mental and neurological diseases.

Description

Synthesis and application of phenyl pyridazinone derivative

Technical Field

The invention belongs to the field of medicinal chemistry, and particularly relates to a phenylpyridazine derivative and application thereof in treating mental and neurological diseases.

Background

Schizophrenia is a disease characterized by deep cognitive and emotional divisions that manifest as the most basic human behavior, such as language, thought, perception, and self-perception. The symptoms of the disease are included in a wide range, most commonly mental disorders such as hallucinations, delusions, and delusions.

Schizophrenia is the most serious psychological disorder, with about 1% of people worldwide suffering from schizophrenia, and only 5% of all treated patients eventually recovering completely. In addition, since schizophrenia often causes complications such as anxiety disorder, depression, or psychotropic substance abuse, a research study by Datamonitor has shown that schizophrenia patients exceeding 1/3 suffer from at least one or more concurrent mental diseases or cognitive disorders.

Antipsychotics that exert pharmacological effects by blocking dopamine D2 receptors have traditionally been referred to as the first generation antipsychotics, the "typical" antipsychotics (e.g., haloperidol), which are breakthrough in treating the positive symptoms of schizophrenia but fail to treat the negative symptoms and cognitive disorders. Typical antipsychotics generally have severe EPS side effects and are ineffective in one-third of schizophrenic patients.

After the 60's of the 20 th century, a series of new generation antipsychotics, including Ziprasidone (Ziprasidone), Risperidone (Risperidone), etc., called second generation antipsychotics, i.e., new antipsychotics, were developed in succession, although their respective pharmacological actions were not completely consistent, but had a common pharmacological profile, i.e., affinity for the 5-hydroxytryptamine (5-HT) receptor (5-HT1A, 2A, 2c) and Norepinephrine (NA) receptor (α 1, α 2) was much higher than for the D2 receptor, resulting in a lower ratio of D2/5-HT 2A. The clinical effect of the compound has more advantages compared with the first generation antipsychotic, the compound has the same effect on positive symptoms as the traditional antipsychotic, and has the effects on negative symptoms and cognitive deficiency symptoms and wider action spectrum, but the compounds have the adverse effects of QT gap prolongation, hyperprolactinemia, weight gain and the like. Therefore, the search for drugs effective in treating schizophrenia positive and negative symptoms and cognitive impairment with less side effects is the focus of research.

Aripiprazole is a kind of bendingprazosin compound, which has been approved by FDA to be on the market in 11 months in 2002. The medicine has unique action mechanism with dopamine D₂、D₃、5-HT_1AAnd 5-HT_2AThe receptor has high affinity with D₄、5-HT_2c、5-HT₇、α₁、H₁The receptor and the 5-HT reuptake site have moderate affinity. Aripiprazole is produced by partial agonism of D2 and 5-HT1A receptors and on 5-HT_2AAntagonism of the receptor produces anti-schizophrenia, having the effect of stabilizing the activity of the dopamine system. Clinical trial studies show that aripiprazole is effective on both positive and negative symptoms of schizophrenia, and long-term application can also reduce the recurrence rate of schizophrenia, improve mood and cognitive dysfunction. Its EPS adverse reaction and the effect of raising serum prolactin level are smaller than those of the traditional antipsychotics or the atypical antipsychotics.

The 5-hydroxytryptamine system plays an important role in the regulation of the function of the prefrontal cortex (PFC), including emotional control, cognitive behavior, and working memory. The pyramidal and GABA interneurons of PFC comprise several subtypes of 5-HT with particularly high density of serotonin receptors_1AAnd 5-HT_2A. It has recently been demonstrated that the PFC and NMDA receptor channels are 5-HT_1AR, the two receptors modulate excitatory neurons of the cerebral cortex, thereby affecting cognitive function. Indeed, various preclinical data suggest 5-HT_1AR may be a new target for antipsychotic drug development. Atypical antipsychotics (e.g. ofolanzapine, aripiprazole, etc.) on 5-HT_1ABoth the high affinity of R and its low EPS side effects suggest that the 5-hydroxytryptamine system plays an important role in the regulation of prefrontal cortex (PFC) function, including emotional control, cognitive behavior, and working memory. The pyramidal and GABA interneurons of PFC comprise several subtypes of 5-HT with particularly high density of 5-hydroxytryptamine receptors_1AAnd 5-HT_2A. Recent studies have shown 5-HT_1AAgonists are associated with atypical antipsychotic treatment and improve negative symptoms and cognitive impairment. In the treatment of schizophrenia with the atypical antipsychotic clozapine, 5-HT was found_2APlays an important role in this context, relating to various aspects of perception, mood regulation and motor control. Blocking 5-HT_2AThe receptor normalizes dopamine release and acts as an antipsychotic. In addition, 5-HT_2CThe receptors are closely associated with weight gain.

D₃The distribution of receptors in the brain is mainly and selectively distributed in the limbic system, two main DA neural pathways are arranged in the brain, one pathway is a nigrostriatal pathway for regulating and controlling motor functions, the other pathway is a DA pathway of the nucleus accumbens prefrontal cortex of the ventral tegmental area of the midbrain, which is closely related to learning cognition and emotional activities, the dysfunction of the DA pathway can cause schizophrenia, the DA pathway is also a main pathway of reward effects (rewarded effects) in the brain, and D is a main pathway of reward effects (rewarded effects) in the brain₃R is distributed in both DA neural pathways and has complex interactions with other DA receptor subtypes, and may be a target for antipsychotic therapy, selective D₃Antagonism of the receptor reduces the negative and cognitive symptoms of schizophrenia and additionally prevents extrapyramidal side effects including tardive dyskinesia, parkinson's disease. Therefore, the search for an anti-schizophrenia drug with small multi-receptor binding side effect has important significance for clinical treatment.

The invention content is as follows:

the present invention is directed to solving at least one of the problems of the prior art. To this end, it is an object of the present invention to propose a novel compound which can be used for the treatment of schizophrenia.

In one aspect, the invention provides a compound which is a compound of formula I or a pharmaceutically acceptable salt of a compound of formula I or a prodrug thereof,

wherein:

z is substituted or unsubstituted- (CH)₂)_n-n is an integer of 1 to 6, the substituent is hydroxyl or methyl, or the carbon chain in Z contains double bonds or oxygen atoms;

q is N or CH;

R₁is hydrogen, halogen, C_1-5Alkoxy, substituted or unsubstituted C_1-5One or more of alkyl; r₂Is hydrogen, C_1-5Alkoxy, substituted or unsubstituted C_1-5Alkyl, substituted or unsubstituted C_3-7Cycloalkyl, substituted or unsubstituted aryl, wherein the substituent is selected from one or more of alkyl, cyano, hydroxyl or halogen; or R₁And R₂Together with a cyclic alkyl or phenyl group to which the carbon to which it is attached forms a five to seven membered ring;

R₃is hydrogen, substituted or unsubstituted C_1-5Alkyl, substituted or unsubstituted C_3-7Cycloalkyl, substituted or unsubstituted aryl, wherein the substituent is selected from one or more of alkyl, cyano, hydroxyl or halogen;

R₄is substituted or unsubstituted phenyl, a compound of formula II, a compound of formula III, a compound of formula IV or a compound of formula V, and the substituent is halogen, cyano, substituted or unsubstituted C_1-5Alkyl, carboxamide or hydroxy;

wherein in the formula II, Y is N or CH, and X is O or S; r₅Is H, halogen or formamide.

In the formula I, Z is substituted or unsubstituted- (CH)₂)_nN is an integer of 1-4, and the substituent is one or more of hydroxyl, carbonyl and methyl.

In the formula I, the halogen is fluorine, chlorine, bromine or iodine.

In the formula I, R is₄Is a compound of formula II, X is O, Y is CH, NH, R₅Selected from hydrogen, fluorine, chlorine, bromine, iodine or formamide; x is S, Y is CH, NH, R₅Is hydrogen; r₄Is substituted phenyl, and the substituent is selected from one or more of methoxy, trifluoromethyl, methyl, ethyl fluorine, chlorine, bromine, iodine and cyano.

In the formula I, R is₁、R₂、R₃Each independently is hydrogen, phenyl, halophenyl, C_1-5Alkyl, halogenated C_1-5Alkyl or C_1-5Hydroxyalkyl, or R₁And R₂Together with a cyclic alkyl or phenyl group to which the carbon to which it is attached forms a five to seven membered ring; further, R is₁、R₂、R₃Each independently hydrogen, fluoro, phenyl, methyl, ethyl, propyl, trifluoromethyl or hydroxymethyl, or R₁And R₂Together with the carbon to which it is attached, form cyclohexane or phenyl.

The compound of the present invention is at least one of the following compounds, or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug thereof of at least one of the following compounds:

2- (3, 4-dichlorophenyl) -6- (3- (4- (4-methoxyphenyl) piperazin-1-yl) propoxy) pyridazin-3 (2H) -one;

2- (3, 4-dichlorophenyl) -6- (3- (4- (2-methoxyphenyl) piperazin-1-yl) propoxy) pyridazin-3 (2H) -one;

2- (3, 4-dichlorophenyl) -6- (3- (4- (2, 3-dimethylphenyl) piperazin-1-yl) propoxy) pyridazin-3 (2H) -one;

2- (3, 4-dichlorophenyl) -6- (3- (4- (pyridin-2-yl) piperazin-1-yl) propoxy) pyridazin-3 (2H) -one;

2- (3, 4-dichlorophenyl) -6- (3- (4- (pyrimidin-2 yl) piperazin-1-yl) propoxy) pyridazin-3 (2H) -one;

6- (3- (4- (2-chlorophenyl) piperazin-1-yl) propoxy) -2- (3, 4-dichlorophenyl) pyridazin-3 (2H) -one;

2- (3, 4-dichlorophenyl) -6- (3- (4- (2, 3-dichlorophenyl) piperazin-1-yl) propoxy) pyridazin-3 (2H) -one;

2- (3, 4-dichlorophenyl) -6- (3- (4- (4-fluorophenyl) piperazin-1-yl) propoxy) pyridazin-3 (2H) -one;

2- (3, 4-dichlorophenyl) -6- (3- (4- (2-fluorophenyl) piperazin-1-yl) propoxy) pyridazin-3 (2H) -one;

2- (3, 4-dichlorophenyl) -6- (3- (4- (3-trifluoromethyl) phenyl) piperazin-1-yl) propoxy) pyridazin-3 (2H) -one;

4- (4- (3- ((1- (3, 4-dichlorophenyl) -6-oxo-1, 6-dihydropyridazin-3-yl) oxy) propyl) piperazin-1-yl) benzonitrile;

6- (3- (4-benzylpiperazin-1-yl) propoxy) -2- (3, 4-dichlorophenyl) pyridazin-3 (2H) -one;

2- (3, 4-dichlorophenyl) -6- (3- (4- (4-fluorobenzoyl) piperidin-1-yl) propoxy) pyridazin-3 (2H) -one;

6- (3- (4- (benzo [ b ] thiophen-3-yl) piperazin-1-yl) propoxy) -2- (3, 4-dichlorophenyl) pyridazin-3 (2H) -one;

3- (4- (3- ((1- (3, 4-dichlorophenyl) -6-oxo-1, 6-dihydropyridazin-3-yl) oxy) propyl) piperazin-1-yl) benzofuran-5-carboxamide;

6- (3- (4- (1H-indol-3-yl) piperidin-1-yl) propoxy) -2- (3, 4-dichlorophenyl) pyridazin-3 (2H) -one;

6- (3- (4- (benzo [ d ] isothiazol-3-yl) piperazin-1-yl) propoxy) -2- (3, 4-dichlorophenyl) pyridazin-3 (2H) -one;

6- (3- (4- (benzo [ d ] thiazol-2-yl) piperidin-1-yl) propoxy) -2- (3, 4-dichlorophenyl) pyridazin-3 (2H) -one;

2- (3, 4-dichlorophenyl) -6- (3- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-1-yl) propoxy) pyridazin-3 (2H) -one;

2- (3, 4-dichlorophenyl) -6- (4- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-1-yl) butoxy) pyridazin-3 (2H) -one;

6- (4- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-1-yl) butoxy) -2- (4-fluorophenyl) pyridazin-3 (2H) -one;

(E) -2- (3, 4-dichlorophenyl) -6- ((4- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-yl) but-2-en-1-yl) oxy) pyridazin-3 (2H) -one;

2- (3, 4-dichlorophenyl) -6- ((5- (4- ((6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-yl)) pentyl) oxy) pyridazin-3 (2H) -one;

2- (3, 4-dichlorophenyl) -6- (3- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-yl) propoxy) -4, 5-dimethylpyridazin-3 (2H) -one;

2- (3, 4-dichlorophenyl) -6- (3- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-yl) propoxy) -5,6,7, 8-tetrahydrophthalazin-1 (2H) -one;

2- (3, 4-dichlorophenyl) -6- (3- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-yl) propoxy) -phthalazin-1 (2H) -one;

6- (3- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-1-yl) propoxy) -2- (4-fluorophenyl) pyridazin-3 (2H) -one;

6- (3- (4- (6-fluorobenzo [ d ] isoxazolyl-3-yl) piperidin-1-yl) propoxy) -2-phenylpyridazin-3 (2H) -one;

6- (3- (4- (6-fluorobenzo [ d ] isoxazolyl-3-yl) piperidin-1-yl) propoxy) -2- (4-methylphenyl) pyridazin-3 (2H) -one;

6- (3- (4- (6-fluorobenzo [ d ] isoxazolyl-3-yl) piperidin-1-yl) propoxy) -2- (naphthalen-2-yl) pyridazin-3 (2H) -one;

2- (4-chlorophenyl) -6- (3- (4- (fluorobenzo [ d ] isoxazol-3-yl) piperidin-1-yl) propoxy) pyridazin-3 (2H) -one;

2- (3-chlorophenyl) -6- (3- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-yl) propoxy) pyridazin-3 (2H) -one;

2- (2-chlorophenyl) -6- (3- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-yl) propoxy) pyridazin-3 (2H) -one;

2- (2, 3-dichlorophenyl) -6- (3- (4- (6-fluoro [ d ] isoxazol-3-yl) piperidin-1-yl) propoxypyridazin-3 (2H) -one;

2- (2, 4-dichlorophenyl) -6- (3- (4- (6-fluoro [ d ] isoxazol-3-yl) piperidin-1-yl) propoxypyridazin-3 (2H) -one;

2- (2, 5-dichlorophenyl) -6- (3- (4- (6-fluoro [ d ] isoxazol-3-yl) piperidin-1-yl) propoxypyridazin-3 (2H) -one;

2- (3, 5-dichlorophenyl) -6- (3- (4- (6-fluoro [ d ] isoxazol-3-yl) piperidin-1-yl) propoxypyridazin-3 (2H) -one;

2- (3, 4-dichlorophenyl) -6- (3- (4- (6-fluoro [ d ] isoxazol-3-yl) piperidin-1-yl) propoxypyridazin-3 (2H) -one;

2- (2, 4-difluorophenyl) -6- (3- (4- (6-fluoro [ d ] isoxazol-3-yl) piperidin-1-yl) propoxypyridazin-3 (2H) -one;

2- (2, 5-difluorophenyl) -6- (3- (4- (6-fluoro [ d ] isoxazol-3-yl) piperidin-1-yl) propoxypyridazin-3 (2H) -one;

2- (2, 6-difluorophenyl) -6- (3- (4- (6-fluoroph-luorophen [ d ] isoxazol-3-yl) piperidin-1-yl) propoxypyridazin-3 (2H) -one;

2- (3, 5-difluorophenyl) -6- (3- (4- (6-fluoro [ d ] isoxazol-3-yl) piperidin-1-yl) propoxypyridazin-3 (2H) -one;

2- (3-chloro-4-fluorophenyl) -6- (3- (4- (6-fluoro-phenyl [ d ] isoxazol-3-yl) piperidin-1-yl) propoxypyridazin-3 (2H) -one;

6- (3- (4- (2, 3-dichlorophenyl) piperazin-1-yl) propoxy) -2- (4-fluorophenyl) pyridazin-3 (2H) -one;

6- (3- (4- (benzo [ d ] isothiazol-3-yl) piperazin-1-yl) propoxy) -2- (4-fluorophenyl) pyridazin-3 (2H) -one.

In another aspect, the invention also relates to a pharmaceutical composition comprising a compound of any of the present invention, optionally further comprising a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or combination thereof.

In another aspect, the pharmaceutical composition of the present invention is used for preparing a medicament for preventing or treating a psychiatric disorder, optionally, schizophrenia.

Detailed Description

The following describes embodiments of the present invention in detail. The following examples are illustrative only and are not to be construed as limiting the invention.

Definitions and general terms

The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of the elements, and with the handbook of chemistry and Physics (75 th edition, 1994). In addition, general principles of Organic Chemistry can be referred to as described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and Jerry March, John Wiley & Sons, New York:2007, the entire contents of which are incorporated herein by reference.

The term "patient" as used herein refers to humans (including adults and children) or other animals. According to some embodiments of the invention, the "patient" refers to a human.

The term "optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, "optional bond" means that the bond may or may not be present, and the description includes single, double, or triple bonds.

The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.

The term "unsaturated" or "unsaturated" means that the moiety contains one or more degrees of unsaturation.

The compounds of the invention may be optionally substituted with one or more substituents, as described herein, in compounds of the general formula above, or as specifically exemplified, sub-classes, and classes of compounds encompassed by the invention. It is understood that the term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted". In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a particular substituent. Unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently.

In addition, it should be noted that, unless otherwise explicitly indicated, the description of the invention as "…" independently means "that the specific items expressed between the same symbols in different groups do not affect each other, and that the specific items expressed between the same symbols in the same groups do not affect each other.

In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C_1-5Alkyl "means in particular independently disclosed methyl, ethyl, C₃Alkyl radical, C₄Alkyl and C₅An alkyl group.

The term "alkyl" or "alkyl group" as used herein, unless specifically described, refers to a saturated, straight or branched chain, monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents described herein. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms. According to one embodiment of the invention, the alkyl group contains 1 to 12 carbon atoms; according to another embodiment of the invention, the alkyl group contains 1 to 6 carbon atoms; according to one embodiment of the invention, the alkyl group contains 1 to 4 carbon atoms; according to another embodiment of the invention, the alkyl group contains 1 to 3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH)₃) Ethyl group (Et, -CH)₂CH₃) N-propyl (n-Pr, -CH)₂CH₂CH₃) Isopropyl group (i-Pr, -CH (CH)₃)₂) N-butyl (n-Bu, -CH)₂CH₂CH₂CH₃) Isobutyl (i-Bu, -CH)₂CH(CH₃)₂) Sec-butyl (s-Bu, -CH (CH)₃)CH₂CH₃) Tert-butyl (t-Bu, -C (CH)₃)₃) N-pentyl (-CH)₂CH₂CH₂CH₂CH₃) 2-pentyl (-CH (CH)₃)CH₂CH₂CH₃) 3-pentyl (-CH (CH)₂CH₃)₂) 2-methyl-2-butyl (-C (CH)₃)₂CH₂CH₃) 3-methyl-2-butyl (-CH (CH)₃)CH(CH₃)₂) 3-methyl-1-butyl (-CH)₂CH₂CH(CH₃)₂) 2-methyl-1-butyl (-CH)₂CH(CH₃)CH₂CH₃) N-hexyl (-CH)₂CH₂CH₂CH₂CH₂CH₃) 2-hexyl (-CH (CH)₃)CH₂CH₂CH₂CH₃) 3-hexyl (-CH (CH)₂CH₃)(CH₂CH₂CH₃) 2-methyl-2-pentyl (-C (CH))₃)₂CH₂CH₂CH₃) 3-methyl-2-pentyl (-CH (CH)₃)CH(CH₃)CH₂CH₃) 4-methyl-2-pentyl (-CH (CH)₃)CH₂CH(CH₃)₂) 3-methyl-3-pentyl (-C (CH)₃)(CH₂CH₃)₂) 2-methyl-3-pentyl (-CH (CH)₂CH₃)CH(CH₃)₂) 2, 3-dimethyl-2-butyl (-C (CH)₃)₂CH(CH₃)₂) 3, 3-dimethyl-2-butyl (-CH (CH)₃)C(CH₃)₃) N-heptyl, n-octyl, and the like.

The term "carbonyl", whether used alone or in combination with other terms, such as "aminocarbonyl" or "acyloxy", denotes- (C ═ O) -.

The term "H" represents a single hydrogen atom. Such radicals may be attached to other groups, such as oxygen atoms, to form hydroxyl groups.

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

The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1 to 12 carbon atoms. According to one embodiment of the invention, the alkoxy group contains 1 to 6 carbon atoms; according to one embodiment of the invention, the alkoxy group contains 1 to 4 carbon atoms; according to one embodiment of the invention, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group is optionally substituted with one or more substituents described herein.

Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH)₃) Ethoxy (EtO, -OCH)₂CH₃) 1-propoxy (n-PrO, n-propoxy, -OCH)₂CH₂CH₃) 2-propoxy (i-PrO, i-propoxy, -OCH (CH)₃)₂) 1-butoxy (n-BuO, n-butoxy, -OCH)₂CH₂CH₂CH₃) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH)₂CH(CH₃)₂) 2-butoxy (s-BuO, s-butoxy, -OCH (CH)₃)CH₂CH₃) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH)₃)₃) 1-pentyloxy (n-pentyloxy, -OCH)₂CH₂CH₂CH₂CH₃) 2-pentyloxy (-OCH (CH)₃)CH₂CH₂CH₃) 3-pentyloxy (-OCH (CH))₂CH₃)₂) 2-methyl-2-butoxy (-OC (CH))₃)₂CH₂CH₃) 3-methyl-2-butoxy (-OCH (CH)₃)CH(CH₃)₂) 3-methyl-l-butoxy (-OCH)₂CH₂CH(CH₃)₂) 2-methyl-l-butoxy (-OCH)₂CH(CH₃)CH₂CH₃) And so on.

The term "ring" includes carbocycles, heterocycles, aromatic rings, heteroaromatic rings, and the like, wherein the carbocycles, heterocycles, aromatic rings, heteroaromatic ring groups have the meaning as described herein.

The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 carbon atoms. Bicyclic or tricyclic ring systems may include fused, bridged and spiro rings. According to one embodiment of the invention, the cycloalkyl group contains 3 to 10 carbon atoms; according to one embodiment of the invention, the cycloalkyl group contains 3 to 8 carbon atoms; according to one embodiment of the invention, the cycloalkyl group contains 3 to 6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The cycloalkyl group is optionally substituted with one or more substituents described herein.

The term "aryl" denotes monocyclic, bicyclic and tricyclic carbocyclic ring systems containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, at least one of which is aromatic. The aryl group is typically, but not necessarily, attached to the parent molecule through an aromatic ring of the aryl group. Examples of the aryl group may include phenyl, naphthyl, and anthracene. The aryl group is optionally substituted with one or more substituents described herein.

The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. For a detailed discussion of prodrugs, reference may be made to the following: higuchi et al, Pro-drugs as Novel Delivery Systems, vol.14, a.c.s.symposium Series; roche et al, ed., Bioreversible Cariers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; rautio et al, primers: Design and Clinical Applications, Nature Reviews Drug Discovery,2008,7,255-.

The term "metabolite" as used herein refers to a product obtained by the metabolism of a particular compound or salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.

As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: s.m.berge et al, j.pharmaceutical Sciences, 66: 1-19,1977. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, salts of inorganic acids formed by reaction with amino groups such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and salts of organic acids such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or those obtained by other methods described in the literature above, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, malates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, stearates, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N⁺(C_1-4Alkyl radical)₄A salt. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. AlkaliThe metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C_1-8Sulfonates and aromatic sulfonates.

The invention has the beneficial technical effects that:

the compound provided by the invention has stronger affinity to D2, 5HT1A and 5HT2A, has potential effect of improving the positive symptoms of schizophrenia, and has potential effect of improving the negative symptoms and cognitive disorder; and low affinity for 5HT2C, H1 and alpha 1, thereby not causing weight gain. Animal experiments show that the compound of the invention has small extrapyramidal side effects.

General synthetic schemes

The general synthesis method of the compound is that a pyridazinone parent body is synthesized firstly, then reacts with halogenated alkane to link a carbon chain, and then reacts with a nitrogen end to prepare the compound. For example:

Detailed Description

The following examples are for illustrative purposes only and are not intended to be limiting of the present invention.

A. Examples of synthetic aspects

Example 1, 2- (3, 4-dichlorophenyl) -6- (3- (4- (4-methoxyphenyl) piperazin-1-yl) propoxy) pyridazin-3 (2H) -one

Reaction scheme 1

1) 14.5g of phenylhydrazine hydrochloride and 9.8g of maleic anhydride are dissolved in 200ml of purified water. 40ml of concentrated hydrochloric acid was slowly added thereto with stirring, and after completion of the addition, the mixture was refluxed for 6 hours. After the reaction is finished, cooling in ice-water bath to separate out yellow solid. Suction filtration is carried out, and the filter cake is washed twice by water. Taking out the filter cake and using saturated NaHCO₃Dissolving, filtering insoluble substances, adjusting the pH value of clear liquid to 2-3 by using concentrated hydrochloric acid, precipitating white solid, and performing suction filtration and drying to obtain 17.3g with the yield of 92.0%.

2) And (2) taking 9.4g of the product in the first step, 13.8g of anhydrous potassium carbonate and 18.8g of 1, 3-dibromopropane, adding 100ml of acetone, heating and refluxing for reaction for 4 hours, cooling to room temperature, filtering, evaporating the solvent to dryness to obtain a light yellow oily substance, and performing flash chromatography to obtain 10.5g of a white solid, wherein the melting point is 77-79 ℃, and the yield is 68.2%.

3) Taking 1.40g of the product of the second step, 1.0g of 4-methoxyphenyl piperazine hydrochloride and 2.0g of potassium carbonate, adding 50ml of acetonitrile, heating and refluxing for 6 hours, cooling to room temperature, evaporating the solvent, adding a proper amount of dichloromethane, washing with water, separating a water layer, adding anhydrous magnesium sulfate to dry an organic layer, evaporating the solvent to obtain a yellow oily substance, and performing flash chromatography to obtain 1.76g of a light yellow oily substance with the yield of 82.5%.

¹H NMR(600MHz,CDCl₃)δ7.89(d,J＝2.5Hz,1H),7.66(dd,J＝8.7,2.5Hz,1H),7.52(d,J＝8.7Hz,1H),7.06–6.96(m,2H),6.92–6.90(m,2H),6.89–6.82(m,2H),4.27(t,J＝6.4Hz,2H),3.78(s,3H),3.29–3.09(m,4H),2.77–2.62(m,4H),2.64–2.51(m,2H),2.19–1.86(m,2H).MS(ESI)m/z 489.2([M+H]⁺)

Example 2, 2- (3, 4-dichlorophenyl) -6- (3- (4- (2-methoxyphenyl) piperazin-1-yl) propoxy) pyridazin-3 (2H) -one

The title compound was prepared by the procedure of example 1, substituting 2-methoxyphenylpiperazine hydrochloride for 4-methoxyphenylpiperazine hydrochloride.

¹H NMR(600MHz,CDCl₃)δ7.89(d,J＝2.5Hz,1H),7.65(dd,J＝8.7,2.5Hz,1H),7.51(d,J＝8.7Hz,1H),7.06–6.98(m,3H),6.98–6.89(m,2H),6.87(dd,J＝8.1,1.1Hz,1H),4.26(t,J＝6.4Hz,2H),3.87(s,3H),3.12(s,4H),2.70(s,4H),2.63–2.51(m,2H),2.09–1.94(m,2H).MS(ESI)m/z489.1([M+H]⁺)

Example 3, 2- (3, 4-dichlorophenyl) -6- (3- (4- (2, 3-dimethylphenyl) piperazin-1-yl) propoxy) pyridazin-3 (2H) -one

The title compound was prepared in the same manner as in example 1 using 2, 3-dimethylphenylpiperazine hydrochloride instead of 4-methoxyphenylpiperazine hydrochloride.

¹H NMR(600MHz,CDCl₃)δ7.91(d,J＝2.4Hz,1H),7.68(dd,J＝8.7,2.5Hz,1H),7.53(d,J＝8.7Hz,1H),7.10(t,J＝7.7Hz,1H),7.06–6.99(m,2H),6.94(t,J＝8.2Hz,2H),4.29(t,J＝6.4Hz,2H),2.94(t,J＝4.2Hz,4H),2.62(dd,J＝26.6,19.3Hz,6H),2.29(s,3H),2.25(s,3H),2.14–1.99(m,2H).MS(ESI)m/z487.3([M+H]⁺)

Example 4 2- (3, 4-dichlorophenyl) -6- (3- (4- (pyridin-2-yl) piperazin-1-yl) propoxy) pyridazin-3 (2H) -one

The title compound was prepared by the procedure of example 1, substituting 2-pyridylpiperazine for 4-methoxyphenylpiperazine hydrochloride.

¹H NMR(600MHz,CDCl₃)δ8.24–8.14(m,1H),7.88(d,J＝2.5Hz,1H),7.64(dd,J＝8.7,2.5Hz,1H),7.56–7.45(m,2H),7.05–6.96(m,2H),6.69–6.60(m,2H),4.26(t,J＝6.4Hz,2H),3.64–3.43(m,4H),2.67–2.32(m,6H),2.23–1.90(m,2H).MS(ESI)m/z460.3([M+H]⁺)

Example 5 2- (3, 4-dichlorophenyl) -6- (3- (4- (pyrimidin-2 yl) piperazin-1-yl) propoxy) pyridazin-3 (2H) -one

The title compound was prepared by the procedure of example 1, substituting 2-pyrimidylpiperazine for 4-methoxyphenylpiperazine hydrochloride.

¹H NMR(600MHz,CDCl₃)δ8.30(d,J＝4.7Hz,2H),7.88(d,J＝2.5Hz,1H),7.64(dd,J＝8.7,2.5Hz,1H),7.50(d,J＝8.7Hz,1H),7.08–6.89(m,2H),6.48(t,J＝4.7Hz,1H),4.25(t,J＝6.3Hz,2H),3.90–3.80(m,4H),2.54(dt,J＝7.2,6.2Hz,6H),2.04–1.98(m,2H).MS(ESI)m/z461.5([M+H]⁺)

Example 6, 6- (3- (4- (2-chlorophenyl) piperazin-1-yl) propoxy) -2- (3, 4-dichlorophenyl) pyridazin-3 (2H) -one

The title compound was prepared by the procedure of example 1, substituting 2-chlorophenylpiperazine hydrochloride for 4-methoxyphenylpiperazine hydrochloride.

¹H NMR(600MHz,CDCl₃)δ7.90(d,J＝2.5Hz,1H),7.66(dd,J＝8.7,2.5Hz,1H),7.52(d,J＝8.7Hz,1H),7.37(dd,J＝7.9,1.5Hz,1H),7.23(ddd,J＝8.9,7.7,1.5Hz,1H),7.07–7.03(m,1H),7.03–6.96(m,3H),4.27(t,J＝6.4Hz,2H),3.10(s,4H),2.62(dd,J＝32.5,25.2Hz,6H),2.11–1.91(m,2H).MS(ESI)m/z493.4([M+H]⁺)

Example 7 2- (3, 4-dichlorophenyl) -6- (3- (4- (2, 3-dichlorophenyl) piperazin-1-yl) propoxy) pyridazin-3 (2H) -one

The title compound was prepared as in example 1 using 2, 3-dichlorophenyl piperazine hydrochloride instead of 4-methoxyphenylpiperazine hydrochloride.

¹H NMR(600MHz,CDCl₃)δ7.90(d,J＝2.4Hz,1H),7.67(dd,J＝8.7,2.5Hz,1H),7.53(d,J＝8.7Hz,1H),7.22–7.12(m,2H),7.07–7.00(m,2H),7.01–6.94(m,1H),4.28(t,J＝6.4Hz,2H),3.09(s,4H),2.87–2.44(m,6H),2.18–1.95(m,2H).MS(ESI)m/z527.5([M+H]⁺)

Example 82- (3, 4-dichlorophenyl) -6- (3- (4- (4-fluorophenyl) piperazin-1-yl) propoxy) pyridazin-3 (2H) -one

The title compound was prepared by the procedure of example 1, substituting 4-fluorophenylpiperazine hydrochloride for 4-methoxyphenylpiperazine hydrochloride.

¹H NMR(600MHz,CDCl3)δ7.89(d,J＝2.5Hz,1H),7.66(dd,J＝8.7,2.5Hz,1H),7.52(d,J＝8.7Hz,1H),7.06–6.99(m,2H),6.99–6.95(m,2H),6.90–6.88(m,2H),4.27(t,J＝6.4Hz,2H),3.20–3.07(m,4H),2.74–2.63(m,4H),2.61–2.52(m,2H),2.02(dd,J＝14.2,6.7Hz,2H).

m/z477.6([M+H]⁺)

Example 92- (3, 4-dichlorophenyl) -6- (3- (4- (2-fluorophenyl) piperazin-1-yl) propoxy) pyridazin-3 (2H) -one

The title compound was prepared by the procedure of example 1, substituting 2-fluorophenylpiperazine hydrochloride for 4-methoxyphenylpiperazine hydrochloride.

¹H NMR(600MHz,CDCl₃)δ7.89(d,J＝2.5Hz,1H),7.66(dd,J＝8.7,2.5Hz,1H),7.52(d,J＝8.7Hz,1H),7.11–7.01(m,4H),6.99–6.92(m,2H),4.27(t,J＝6.4Hz,2H),3.13(s,4H),2.68(s,4H),2.62–2.52(m,2H),2.20–1.94(m,2H).m/z 477.7([M+H]⁺)

Example 10

2- (3, 4-dichlorophenyl) -6- (3- (4- (3-trifluoromethyl) phenyl) piperazin-1-yl) propoxy) pyridazin-3 (2H) -one

The title compound was prepared by the procedure of example 1, substituting 3-trifluoromethylphenylpiperazine hydrochloride for 4-methoxyphenylpiperazine hydrochloride.

¹H NMR(600MHz,CDCl₃)δ7.89(d,J＝2.5Hz,1H),7.66(dd,J＝8.7,2.5Hz,1H),7.57–7.51(m,1H),7.36(t,J＝8.0Hz,1H),7.13(s,1H),7.11–7.05(m,2H),7.04–6.99(m,2H),4.28(t,J＝6.4Hz,2H),3.30–3.18(m,4H),2.64(dd,J＝20.9,15.9Hz,4H),2.63–2.55(m,2H),2.17–1.92(m,2H).m/z527.5([M+H]⁺)

Example 11, 4- (4- (3- ((1- (3, 4-dichlorophenyl) -6-oxo-1, 6-dihydropyridazin-3-yl) oxy) propyl) piperazin-1-yl) benzonitrile

The title compound was prepared by the procedure of example 1, substituting 4- (piperazin-1-yl) benzonitrile for 4-methoxyphenylpiperazine hydrochloride.

¹H NMR(600MHz,CDCl₃)δ7.88(d,J＝2.5Hz,1H),7.66(dd,J＝8.7,2.5Hz,1H),7.55–7.48(m,3H),7.09–6.96(m,2H),6.87(t,J＝5.8Hz,2H),4.27(t,J＝6.4Hz,2H),3.43–3.24(m,4H),2.70–2.53(m,6H),2.01(dd,J＝13.7,6.9Hz,2H).MS(ESI)m/z484.6([M+H]⁺)

Example 12, 6- (3- (4-Benzylpiperazin-1-yl) propoxy) -2- (3, 4-dichlorophenyl) pyridazin-3 (2H) -one

The title compound was prepared as in example 1, substituting 4-benzylpiperazine for 4-methoxyphenylpiperazine hydrochloride.

¹H NMR(600MHz,CDCl₃)δ7.88(d,J＝2.5Hz,1H),7.65(dd,J＝8.7,2.5Hz,1H),7.52(d,J＝8.7Hz,1H),7.33(d,J＝4.4Hz,4H),7.27(dd,J＝8.6,4.5Hz,1H),7.00(s,2H),4.23(t,J＝6.4Hz,2H),3.53(d,J＝6.1Hz,2H),2.66–2.37(m,8H),2.10–1.78(m,3H).MS(ESI)m/z473.6([M+H]⁺)

Example 13 2- (3, 4-dichlorophenyl) -6- (3- (4- (4-fluorobenzoyl) piperidin-1-yl) propoxy) pyridazin-3 (2H) -one

The title compound was prepared as in example 1 using 4-fluorobenzoylpiperidine hydrochloride instead of 4-methoxyphenylpiperazine hydrochloride.

¹H NMR(600MHz,CDCl₃)δ7.98(dd,J＝8.7,5.5Hz,2H),7.89(d,J＝2.4Hz,1H),7.65(dd,J＝8.7,2.4Hz,1H),7.53(d,J＝8.7Hz,1H),7.16(t,J＝8.6Hz,2H),7.07–6.91(m,2H),4.25(t,J＝6.3Hz,2H),3.25–3.22(m,1H),3.04(d,J＝11.5Hz,2H),2.55(t,J＝7.2Hz,2H),2.17(s,2H),2.03–1.98(m,2H),1.90–1.81(m,4H).MS(ESI)m/z 504.1([M+H]⁺)

Example 14, 6- (3- (4- (benzo [ b ] thiophen-3-yl) piperazin-1-yl) propoxy) -2- (3, 4-dichlorophenyl) pyridazin-3 (2H) -one

The title compound was prepared by the procedure of example 1, substituting 4-benzo [ b ] thiophen-3-ylpiperazine hydrochloride for 4-methoxyphenylpiperazine hydrochloride.

¹H NMR(600MHz,CDCl₃)δ8.00–7.87(m,1H),7.67(ddd,J＝8.8,2.4,0.6Hz,1H),7.57(d,J＝8.0Hz,1H),7.53(d,J＝8.7Hz,1H),7.42(q,J＝5.5Hz,2H),7.33–7.25(m,1H),7.07–7.00(m,2H),6.91(d,J＝7.7Hz,1H),4.29(t,J＝6.3Hz,2H),3.21(s,4H),2.92–2.53(m,6H),2.15–1.97(m,2H).MS(ESI)m/z 514.7([M+H]⁺)

Example 15, 3- (4- (3- ((1- (3, 4-dichlorophenyl) -6-oxo-1, 6-dihydropyridazin-3-yl) oxy) propyl) piperazin-1-yl) benzofuran-5-carboxamide

The title compound was prepared by the procedure of example 1, substituting 3- (piperazin-1-yl) benzofuran-5-carboxamide for 4-methoxyphenylpiperazine hydrochloride.

¹H NMR(600MHz,CDCl₃)δ7.89(d,J＝2.4Hz,1H),7.71–7.64(m,1H),7.56–7.50(m,1H),7.45(s,1H),7.42(d,J＝9.0Hz,1H),7.18–7.13(m,2H),7.07–6.98(m,2H),4.29(t,J＝6.3Hz,2H),3.24(d,J＝4.3Hz,4H),2.66(dd,J＝35.5,28.3Hz,6H),2.07(t,J＝6.9Hz,2H),1.90–1.54(m,2H).m/z 542.8([M+H]⁺)

Example 16 6- (3- (4- (1H-indol-3-yl) piperidin-1-yl) propoxy) -2- (3, 4-dichlorophenyl) pyridazin-3 (2H) -one

The title compound was prepared by the procedure of example 1, substituting 3- (piperidin-4-yl) -1H-indole for 4-methoxyphenylpiperazine hydrochloride.

¹H NMR(600MHz,CDCl₃)δ8.22(s,1H),7.91(t,J＝5.4Hz,2H),7.66(dd,J＝8.7,2.5Hz,1H),7.52(d,J＝8.7Hz,1H),7.40(d,J＝8.1Hz,1H),7.26–7.13(m,3H),7.08–6.97(m,2H),4.31(t,J＝6.4Hz,2H),3.29(d,J＝2.8Hz,2H),2.80(t,J＝5.7Hz,2H),2.74–2.59(m,3H),2.22–1.99(m,2H),1.70(s,4H).MS(ESI)m/z 497.1([M+H]⁺)

Example 17 6- (3- (4- (benzo [ d ] isothiazol-3-yl) piperazin-1-yl) propoxy) -2- (3, 4-dichlorophenyl) pyridazin-3 (2H) -one

The title compound was prepared by the procedure of example 1, substituting benzo [ d ] isothiazolyl-3 piperazine for 4-methoxyphenylpiperazine hydrochloride.

¹H NMR(600MHz,CDCl₃)δ7.96–7.88(m,2H),7.82(d,J＝8.1Hz,1H),7.70–7.64(m,1H),7.52(dd,J＝9.1,3.5Hz,1H),7.50–7.45(m,1H),7.41–7.35(m,1H),7.07–6.92(m,2H),4.28(t,J＝6.4Hz,2H),3.75–3.54(m,4H),2.76–2.69(m,4H),2.65–2.53(m,2H),2.10–1.95(m,2H).MS(ESI)m/z 515.5([M+H]⁺)

Example 18 6- (3- (4- (benzo [ d ] thiazol-2-yl) piperidin-1-yl) propoxy) -2- (3, 4-dichlorophenyl) pyridazin-3 (2H) -one

The title compound was prepared by the procedure of example 1, substituting benzo [ d ] thiazolyl-2-piperidine for 4-methoxyphenylpiperazine hydrochloride.

¹H NMR(600MHz,CDCl₃)δ7.98(d,J＝8.1Hz,1H),7.89(d,J＝2.5Hz,1H),7.88–7.84(m,1H),7.65(dd,J＝8.7,2.5Hz,1H),7.51(d,J＝8.7Hz,1H),7.49–7.42(m,1H),7.38–7.32(m,1H),7.06–6.89(m,2H),4.25(t,J＝6.4Hz,2H),3.16–3.09(m,3H),2.62–2.51(m,2H),2.18(dd,J＝20.0,11.1Hz,4H),2.02–1.93(m,4H).MS(ESI)m/z515.2([M+H]⁺)

Example 19, 2- (3, 4-dichlorophenyl) -6- (3- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-1-yl) propoxy) pyridazin-3 (2H) -one

The title compound was obtained in the same manner as in example 1 except for using 6-fluorobenzo [ d ] isoxazole-3-piperidine hydrochloride instead of 4-methoxyphenylpiperazine hydrochloride.

¹H NMR(600MHz,CDCl₃)δ7.88(d,J＝2.4Hz,1H),7.73–7.60(m,2H),7.56–7.41(m,1H),7.23(dd,J＝8.5,1.6Hz,1H),7.10–6.93(m,3H),4.25(t,J＝6.3Hz,2H),3.08(d,J＝11.8Hz,3H),2.57(t,J＝7.3Hz,2H),2.25–1.89(m,6H),1.25(d,J＝0.6Hz,2H).MS(ESI)m/z517.6([M+H]⁺)

Example 202- (3, 4-dichlorophenyl) -6- (4- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-1-yl) butoxy) pyridazin-3 (2H) -one

Reaction formula 2

1) 21.1g of hydrochloric acid 3, 4-dichlorophenylhydrazine and 9.8g of maleic anhydride are dissolved in 200ml of purified water. 40ml of concentrated hydrochloric acid was slowly added thereto with stirring, and after completion of the addition, the mixture was refluxed for 6 hours. After the reaction, the mixture was cooled in an ice-water bath to precipitate a yellow solid. Suction filtration is carried out, and the filter cake is washed twice by water. Taking out the filter cake and using saturated NaHCO₃Dissolving, filtering to remove insoluble substances, adjusting the pH value of clear liquid to 2-3 with concentrated hydrochloric acid, precipitating white solid, and performing suction filtration and drying to obtain 22.4g with yield of 87.8%.

2) Taking 12.4g of the product in the first step, 13.8g of anhydrous potassium carbonate and 18.8g of 1, 4-dibromobutane, adding 100ml of acetone, heating and refluxing for reaction for 4 hours, cooling to room temperature, filtering, evaporating the solvent to dryness to obtain pale yellow oily matter, and obtaining 13.5g of white solid through a flash chromatography column, wherein the melting point is 73-74 ℃, and the yield is 69.4%.

3) Taking 1.60g of the second-step product, 1.28g of 6-fluorobenzo [ d ] isoxazole-3-piperidine hydrochloride and 2.0g of potassium carbonate, adding 50ml of acetonitrile, heating and refluxing for reaction for 6 hours, cooling to room temperature, evaporating the solvent, adding a proper amount of dichloromethane, washing with water, separating a water layer, drying an organic layer with anhydrous magnesium sulfate, evaporating the solvent to obtain a yellow oily substance, and performing flash chromatography to obtain 2.36g of a light yellow oily substance with the yield of 89.1%.

¹H NMR(600MHz,CDCl₃)δ7.88(d,J＝2.4Hz,1H),7.73–7.60(m,2H),7.56–7.41(m,1H),7.23(dd,J＝8.5,1.6Hz,1H),7.10–6.93(m,3H),4.25(t,J＝6.3Hz,2H),3.08(d,J＝11.8Hz,3H),2.57(t,J＝7.3Hz,2H),2.25–1.89(m,6H),1.25(d,J＝0.6Hz,2H).MS(ESI)m/z531.3([M+H]⁺)

Example 21 6- (4- (4- (6-Fluorobenzo [ d ] isoxazol-3-yl) piperidin-1-yl) butoxy) -2- (4-fluorophenyl) pyridazin-3 (2H) -one

The title compound was prepared in the same manner as in example 20 using 4-fluorophenylhydrazine hydrochloride instead of 3, 4-dichlorohydrazinehydrochloride.

¹H NMR(600MHz,CDCl₃)δ7.73–7.64(m,3H),7.26(dd,J＝8.5,2.1Hz,1H),7.19–7.13(m,2H),7.07(td,J＝8.8,2.1Hz,1H),7.04–6.98(m,2H),4.21(t,J＝6.4Hz,2H),3.09(d,J＝10.5Hz,3H),2.58–2.42(m,2H),2.21–2.01(m,6H),1.87–1.77(m,2H),1.70(dt,J＝9.5,7.5Hz,2H).MS(ESI)m/z＝481.3([M+H]⁺)

Example 22, (E) -2- (3, 4-dichlorophenyl) -6- ((4- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-yl) but-2-en-1-yl) oxy) pyridazin-3 (2H) -one

The title compound was prepared in the same manner as in example 20 except that (E) -1, 4-dibromobut-2-ene was used instead of 1, 4-dibromobutane.

¹H NMR(600MHz,CDCl₃)δ7.89(d,J＝2.5Hz,1H),7.70(dd,J＝8.7,5.1Hz,1H),7.66(dd,J＝8.7,2.5Hz,1H),7.51(d,J＝8.7Hz,1H),7.25(dd,J＝8.5,2.1Hz,1H),7.06(td,J＝8.8,2.1Hz,1H),7.04–6.99(m,2H),6.08–5.79(m,2H),4.72(d,J＝5.6Hz,2H),3.11(dd,J＝33.4,9.0Hz,5H),2.19-2.07(m,6H).MS(ESI)m/z＝545.3([M+H]⁺)

Example 23, 2- (3, 4-dichlorophenyl) -6- ((5- (4- ((6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-yl)) pentyl) oxy) pyridazin-3 (2H) -one

The title compound was prepared as in example 20, substituting 1, 5-dibromopentane for 1, 4-dibromobutane.

¹H NMR(600MHz,CDCl₃)δ7.89(d,J＝2.1Hz,1H),7.73(dd,J＝8.6,5.1Hz,1H),7.66(dd,J＝8.7,2.1Hz,1H),7.52(d,J＝8.7Hz,1H),7.26(d,J＝8.4Hz,1H),7.07(t,J＝8.8Hz,1H),7.04–6.99(m,2H),4.20(t,J＝6.5Hz,2H),3.11(d,J＝10.4Hz,3H),2.57–2.42(m,2H),2.14(dt,J＝47.0,27.2Hz,4H),1.89–1.73(m,2H),1.77–1.58(m,2H),1.54–1.47(m,2H),1.34–1.20(m,2H).

m/z＝480.2([M+H]⁺)

Example 24, 2- (3, 4-dichlorophenyl) -6- (3- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-yl) propoxy) -4, 5-dimethylpyridazin-3 (2H) -one

Reaction formula 3

1) 21.1g of hydrochloric acid 3, 4-dichlorophenylhydrazine and 12.6g of 3, 4-dimethylmaleic anhydride are dissolved in 200ml of purified water. 40ml of concentrated hydrochloric acid was slowly added thereto with stirring, and after completion of the addition, the mixture was refluxed for 6 hours. After the reaction, the mixture was cooled in an ice-water bath to precipitate a yellow solid. Suction filtration is carried out, and the filter cake is washed twice by water. Taking out the filter cake and using saturated NaHCO₃Dissolving, filtering insoluble substances, adjusting the pH value of clear liquid to 2-3 by using concentrated hydrochloric acid, precipitating white solid, and performing suction filtration and drying to obtain 26.3g with the yield of 92.6%.

2) Taking 14.2g of the product in the first step, 13.8g of anhydrous potassium carbonate and 18.8g of 1, 3-dibromopropane, adding 100ml of acetone, heating and refluxing for reaction for 4 hours, cooling to room temperature, filtering, evaporating the solvent to dryness to obtain a pale yellow oily substance, and obtaining 16.8g of a white solid through a flash chromatography column, wherein the melting point is 68-69 ℃, and the yield is 83.3%.

3) Taking 2.1g of the second-step product, 1.28g of 6-fluorobenzo [ d ] isoxazole-3-piperidine hydrochloride and 2.0g of potassium carbonate, adding 50ml of acetonitrile, heating and refluxing for reaction for 6 hours, cooling to room temperature, evaporating the solvent, adding a proper amount of dichloromethane, washing with water, separating a water layer, drying an organic layer with anhydrous magnesium sulfate, evaporating the solvent to obtain a yellow oily substance, and performing flash chromatography to obtain 2.16g of a light yellow oily substance with the yield of 84.4%.

¹H NMR(600MHz,CDCl₃)δ7.92(d,J＝2.5Hz,1H),7.71(dd,J＝8.7,5.1Hz,1H),7.67(dd,J＝8.7,2.5Hz,1H),7.54–7.46(m,1H),7.25(dd,J＝8.3,2.1Hz,1H),7.06(td,J＝8.8,2.1Hz,1H),4.26(t,J＝6.3Hz,2H),3.18–2.93(m,3H),2.65–2.52(m,2H),2.26–2.16(m,8H),2.16–1.97(m,6H).MS(ESI)m/z545.3([M+H]⁺)

EXAMPLE 25 2- (3, 4-dichlorophenyl) -6- (3- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-yl) propoxy) -5,6,7, 8-tetrahydrodaizin-1 (2H) -one

The title compound was prepared in the same manner as in example 24 using 5,6,7, 8-tetrahydrophthalic anhydride in place of 3, 4-dimethylmaleic anhydride.

¹H NMR(600MHz,CDCl₃)δ8.23(d,J＝4.0Hz,1H),7.73(s,1H),7.71(s,1H),7.58(t,J＝7.8Hz,1H),6.79(dd,J＝6.8,5.2Hz,1H),6.71(d,J＝8.5Hz,1H),4.26–3.99(m,4H),3.95–3.84(m,4H),3.57(t,J＝6.4Hz,2H),3.46-3.26(m,4H),3.05–2.94(m,2H),2.87(t,J＝6.0Hz,2H),2.75–2.65(m,2H),2.03–1.93(m,2H).MS(ESI)m/z405.6([M+H]⁺)

EXAMPLE 26 2- (3, 4-dichlorophenyl) -6- (3- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-yl) propoxy) -phthalazin-1 (2H) -one

The title compound was prepared in the same manner as in example 24 except that phthalic anhydride was used instead of 3, 4-dimethylmaleic anhydride.

¹H NMR(600MHz,CDCl₃)δ8.54–8.46(m,1H),8.08–8.01(m,1H),8.00(d,J＝2.5Hz,1H),7.91–7.81(m,2H),7.77–7.54(m,2H),7.55(d,J＝8.7Hz,1H),7.27(dd,J＝8.5,2.1Hz,1H),7.08(td,J＝8.8,2.1Hz,1H),4.46(t,J＝6.3Hz,2H),3.16(d,J＝11.1Hz,3H),2.69(t,J＝6.9Hz,2H),2.43–1.94(m,8H).MS(ESI)m/z 567.5([M+H]⁺)

Example 27 6- (3- (4- (6-Fluorobenzo [ d ] isoxazol-3-yl) piperidin-1-yl) propoxy) -2- (4-fluorophenyl) pyridazin-3 (2H) -one

Reaction formula 4

1) 16.2g of para-fluorophenylhydrazine hydrochloride and 9.8g of maleic anhydride are dissolved in 200ml of purified water. Slowly adding 40ml of concentrated hydrochloric acid under stirring, heating and refluxing after adding,the reaction was carried out for 6 hours. After the reaction, the mixture was cooled in an ice-water bath to precipitate a yellow solid. Suction filtration is carried out, and the filter cake is washed twice by water. Taking out the filter cake and using saturated NaHCO₃Dissolving, filtering insoluble substances, adjusting the pH value of clear liquid to 2-3 by using concentrated hydrochloric acid, precipitating white solid, and performing suction filtration and drying to obtain 15.8g with the yield of 76.7%.

2) 10.4g of the product in the first step, 13.8g of anhydrous potassium carbonate and 18.8g of 1, 3-dibromopropane are taken, 100ml of acetone is added, the mixture is heated and refluxed for reaction for 4 hours, the mixture is cooled to room temperature, the solvent is filtered and evaporated to dryness to obtain pale yellow oily substance, 9.8g of brown oily substance is obtained through a flash chromatography column, and the yield is 60.2%.

3) Taking 1.60g of the second-step product, 1.0g of 6-fluorobenzo [ d ] isoxazole-3-piperidine hydrochloride and 2.0g of potassium carbonate, adding 50ml of acetonitrile, heating and refluxing for reaction for 6 hours, cooling to room temperature, evaporating the solvent, adding a proper amount of dichloromethane, washing with water, separating a water layer, drying an organic layer with anhydrous magnesium sulfate, evaporating the solvent to obtain a yellow oily substance, and performing flash chromatography to obtain 1.77g of a light yellow oily substance with the yield of 76.0%.

¹H NMR(600MHz,CDCl₃)δ7.70(dd,J＝8.7,5.1Hz,1H),7.68–7.65(m,2H),7.27–7.23(m,1H),7.18–7.12(m,2H),7.09–7.04(m,1H),7.03–6.97(m,2H),4.25(t,J＝6.4Hz,2H),3.16–2.99(m,3H),2.76–2.48(m,2H),2.29–1.93(m,6H),1.26(s,2H).MS(ESI)

m/z467.3[M+H]⁺)

Example 28, 6- (3- (4- (6-fluorobenzo [ d ] isoxazolyl-3-yl) piperidin-1-yl) propoxy) -2-phenylpyridazin-3 (2H) -one

The title compound was prepared in the same manner as in example 28 using phenylhydrazine hydrochloride instead of 4-fluorophenylhydrazine hydrochloride.

¹H NMR(600MHz,CDCl₃)δ7.75–7.66(m,3H),7.51–7.44(m,2H),7.40–7.33(m,1H),7.26(dd,J＝8.5,2.1Hz,1H),7.11–6.97(m,3H),4.26(t,J＝6.4Hz,2H),3.09(dd,J＝13.4,5.3Hz,3H),2.61–2.47(m,2H),2.24–1.94(m,8H).MS(ESI)m/z 449.4([M+H]⁺)

Example 29, 6- (3- (4- (6-fluorobenzo [ d ] isoxazolyl-3-yl) piperidin-1-yl) propoxy) -2- (4-methylphenyl) pyridazin-3 (2H) -one

The title compound was obtained in the same manner as in example 28 except for using 4-methylphenylhydrazine hydrochloride in place of 4-fluorophenylhydrazine hydrochloride.¹H NMR(600MHz,CDCl₃)δ7.71(dd,J＝8.7,5.1Hz,1H),7.55(d,J＝8.4Hz,2H),7.31–7.19(m,3H),7.07(td,J＝8.8,2.1Hz,1H),7.04–6.98(m,2H),4.25(t,J＝6.4Hz,2H),3.09(d,J＝11.2Hz,3H),2.65–2.53(m,2H),2.40(s,3H),2.18(t,J＝12.3Hz,2H),2.12–2.04(m,4H),2.04–1.97(m,2H).MS(ESI)m/z463.6([M+H]⁺)

Example 30, 6- (3- (4- (6-fluorobenzo [ d ] isoxazolyl-3-yl) piperidin-1-yl) propoxy) -2- (naphthalen-2-yl) pyridazin-3 (2H) -one

The title compound was obtained in the same manner as in example 28 except for using 2-naphthylhydrazine hydrochloride in place of 4-fluorophenylhydrazine hydrochloride.

¹H NMR(600MHz,CDCl₃)δ8.20(d,J＝1.9Hz,1H),7.95–7.84(m,3H),7.79(dd,J＝8.8,2.1Hz,1H),7.68(dd,J＝8.7,5.1Hz,1H),7.54–7.48(m,2H),7.25(dd,J＝8.5,2.1Hz,1H),7.11–6.99(m,3H),4.30(t,J＝6.4Hz,2H),3.23–3.03(m,3H),2.66–2.50(m,2H),2.23–1.92(m,8H).MS(ESI)m/z499.7([M+H]⁺)

Example 31 2- (4-chlorophenyl) -6- (3- (4- (fluorobenzo [ d ] isoxazol-3-yl) piperidin-1-yl) propoxy) pyridazin-3 (2H) -one

The title compound was obtained in the same manner as in example 28 except for using 4-chlorophenylhydrazine hydrochloride in place of 4-fluorophenylhydrazine hydrochloride.¹H NMR(600MHz,CDCl₃)δ7.74–7.64(m,3H),7.46–7.40(m,2H),7.26(dd,J＝8.5,2.0Hz,1H),7.07(td,J＝8.9,2.2Hz,1H),7.04–6.97(m,2H),4.26(t,J＝6.4Hz,2H),3.09(d,J＝10.7Hz,3H),2.57(t,J＝7.4Hz,2H),2.34–1.91(m,6H),1.27(s,2H).MS(ESI)m/z483.6([M+H]⁺)

Example 32 2- (3-chlorophenyl) -6- (3- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-yl) propoxy) pyridazin-3 (2H) -one

The title compound was obtained in the same manner as in example 28 except for using 3-chlorophenylhydrazine hydrochloride in place of 4-fluorophenylhydrazine hydrochloride.

¹H NMR(600MHz,CDCl₃)δ7.71(dd,J＝8.7,5.1Hz,1H),7.57–7.53(m,1H),7.47–7.43(m,1H),7.43–7.36(m,2H),7.26(dd,J＝8.5,2.1Hz,1H),7.09–7.01(m,3H),4.20(t,J＝6.4Hz,2H),3.08(d,J＝11.6Hz,3H),2.56(t,J＝7.3Hz,2H),2.32–1.88(m,8H).MS(ESI)

m/z483.5([M+H]⁺)

Example 33 2- (2-chlorophenyl) -6- (3- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-yl) propoxy) pyridazin-3 (2H) -one

The title compound was obtained in the same manner as in example 28 except for using 2-chlorophenylhydrazine hydrochloride in place of 4-fluorophenylhydrazine hydrochloride.

¹H NMR(600MHz,CDCl₃)δ7.75–7.69(m,2H),7.68–7.63(m,1H),7.40(t,J＝8.1Hz,1H),7.38–7.30(m,1H),7.26(dd,J＝8.5,2.1Hz,1H),7.07(td,J＝8.8,2.1Hz,1H),7.05–6.99(m,2H),4.28(t,J＝6.4Hz,2H),3.20–3.06(m,3H),2.58(t,J＝7.3Hz,2H),2.38–1.86(m,8H).MS(ESI)m/z483.7([M+H]⁺)

Example 34 2- (2, 3-dichlorophenyl) -6- (3- (4- (6-fluoro [ d ] isoxazol-3-yl) piperidin-1-yl) propoxypyridazin-3 (2H) -one

The title compound was obtained in the same manner as in example 28 except for using 2, 3-dichlorophenylhydrazine hydrochloride in place of 4-fluorophenylhydrazine hydrochloride.

¹H NMR(600MHz,CDCl₃)δ7.69(dd,J＝8.7,5.1Hz,1H),7.53(dd,J＝7.7,1.9Hz,1H),7.39–7.31(m,2H),7.24(dd,J＝8.5,2.1Hz,1H),7.10–6.99(m,3H),4.30–3.99(m,2H),3.16–2.98(m,3H),2.54–2.44(m,2H),2.20–1.85(m,8H).MS(ESI)m/z 517.5([M+H]⁺)

Example 35 2- (2, 4-dichlorophenyl) -6- (3- (4- (6-fluoro [ d ] isoxazol-3-yl) piperidin-1-yl) propoxypyridazin-3 (2H) -one

The title compound was obtained in the same manner as in example 28 except for using 2, 4-dichlorophenylhydrazine hydrochloride in place of 4-fluorophenylhydrazine hydrochloride.

1H NMR(600MHz,CDCl3)δ7.70(dd,J＝8.7,5.1Hz,1H),7.55(s,1H),7.39(d,J＝1.0Hz,2H),7.26(dd,J＝8.5,2.0Hz,1H),7.12–6.91(m,3H),4.28–4.11(m,2H),3.24–2.94(m,3H),2.54(t,J＝7.3Hz,2H),2.28–1.91(m,8H).MS(ESI)m/z 517.4([M+H]⁺)

Example 36 2- (2, 5-dichlorophenyl) -6- (3- (4- (6-fluoro [ d ] isoxazol-3-yl) piperidin-1-yl) propoxypyridazin-3 (2H) -one

The title compound was obtained in the same manner as in example 28 except for using 2, 5-dichlorophenylhydrazine hydrochloride in place of 4-fluorophenylhydrazine hydrochloride.

¹H NMR(600MHz,CDCl₃)δ7.69(dd,J＝8.7,5.1Hz,1H),7.47(s,1H),7.46–7.43(m,2H),7.35(dd,J＝8.6,2.5Hz,1H),7.24(dd,J＝8.5,2.1Hz,1H),7.08–6.99(m,3H),4.19(t,J＝6.4Hz,2H),3.17–3.00(m,3H),2.58–2.47(m,2H),2.23–1.87(m,8H).MS(ESI)m/z517.5([M+H]⁺)

Example 37, 2- (3, 5-dichlorophenyl) -6- (3- (4- (6-fluoro [ d ] isoxazol-3-yl) piperidin-1-yl) propoxypyridazin-3 (2H) -one

The title compound was obtained in the same manner as in example 28 except for using 3, 5-dichlorophenylhydrazine hydrochloride in place of 4-fluorophenylhydrazine hydrochloride.

¹H NMR(600MHz,CDCl₃)δ7.76–7.63(m,3H),7.33(t,J＝1.8Hz,1H),7.25(dd,J＝8.5,2.1Hz,1H),7.06(td,J＝8.8,2.1Hz,1H),7.04–6.99(m,2H),4.28(t,J＝6.4Hz,2H),3.49–2.92(m,3H),2.72–2.48(m,2H),2.20(dd,J＝16.2,9.0Hz,2H),2.12–1.94(m,6H).MS(ESI)m/z517.5([M+H]⁺)

Example 38 2- (3, 4-difluorophenyl) -6- (3- (4- (6-fluorophenyl [ d ] isoxazol-3-yl) piperidin-1-yl) propoxypyridazin-3 (2H) -one

The title compound was obtained in the same manner as in example 28 except for using 3, 4-difluorophenylhydrazine hydrochloride in place of 4-fluorophenylhydrazine hydrochloride.

¹H NMR(600MHz,CDCl₃)δ7.70(dd,J＝8.7,5.1Hz,1H),7.64(ddd,J＝11.5,7.2,2.6Hz,1H),7.57–7.51(m,1H),7.27–7.21(m,2H),7.07(td,J＝8.8,2.1Hz,1H),7.04–6.97(m,2H),4.27(t,J＝6.4Hz,2H),3.27–3.03(m,3H),2.71–2.45(m,2H),2.20(dd,J＝16.1,9.3Hz,2H),2.14–1.95(m,6H).MS(ESI)m/z485.6([M+H]⁺)

Example 39 2- (2, 4-difluorophenyl) -6- (3- (4- (6-fluorophenyl [ d ] isoxazol-3-yl) piperidin-1-yl) propoxypyridazin-3 (2H) -one

2, 4-difluorophenylhydrazine hydrochloride is used to replace 4-fluorophenylhydrazine hydrochloride,the title compound was prepared by the method of example 28¹H NMR(600MHz,CDCl₃)δ7.69(dd,J＝8.7,5.1Hz,1H),7.44(td,J＝8.5,5.9Hz,1H),7.24(dd,J＝8.5,2.1Hz,1H),7.09–6.93(m,5H),4.19(t,J＝6.4Hz,2H),3.16–2.90(m,3H),2.59–2.46(m,2H),2.24–2.13(m,2H),2.09–1.92(m,6H).MS(ESI)m/z485.4([M+H]⁺)

EXAMPLE 40 2- (2, 5-difluorophenyl) -6- (3- (4- (6-fluorophenyl [ d ] isoxazol-3-yl) piperidin-1-yl) propoxypyridazin-3 (2H) -one

The preparation of the title compound was carried out in the same manner as in example 28 using 2, 5-difluorophenylhydrazine hydrochloride in place of 4-fluorophenylhydrazine hydrochloride¹H NMR(600MHz,CDCl₃)δ7.69(dd,J＝8.7,5.1Hz,1H),7.26–7.16(m,3H),7.13–7.08(m,1H),7.07–6.97(m,3H),4.20(t,J＝6.4Hz,2H),3.08(dd,J＝17.3,9.5Hz,3H),2.58–2.47(m,2H),2.25–2.10(m,2H),2.13–1.93(m,6H).MS(ESI)m/z485.6([M+H]⁺)

Example 41 2- (2, 6-difluorophenyl) -6- (3- (4- (6-fluoro [ d ] isoxazol-3-yl) piperidin-1-yl) propoxypyridazin-3 (2H) -one

The preparation of the title compound was carried out in the same manner as in example 28 using 2, 6-difluorophenylhydrazine hydrochloride in place of 4-fluorophenylhydrazine hydrochloride¹H NMR(600MHz,CDCl₃)δ7.70(dd,J＝8.7,5.1Hz,1H),7.40(tt,J＝8.5,6.1Hz,1H),7.25(dd,J＝8.5,2.1Hz,1H),7.09–7.00(m,5H),4.19(t,J＝6.4Hz,2H),3.15–2.99(m,3H),2.58–2.48(m,2H),2.17(td,J＝11.4,4.7Hz,2H),2.13–1.94(m,6H)..MS(ESI)m/z485.5([M+H]⁺)

Example 42 2- (3, 5-difluorophenyl) -6- (3- (4- (6-fluoro [ d ] isoxazol-3-yl) piperidin-1-yl) propoxypyridazin-3 (2H) -one

The title compound was prepared in the same manner as in example 28 using 3, 5-difluorophenylhydrazine hydrochloride in place of 4-fluorophenylhydrazine hydrochloride¹H NMR(600MHz,CDCl₃)δ7.81(dd,J＝6.6,2.6Hz,1H),7.70(dd,J＝8.7,5.1Hz,1H),7.65(ddd,J＝8.9,4.2,2.6Hz,1H),7.27–7.19(m,2H),7.07(td,J＝8.8,2.1Hz,1H),7.04–6.97(m,2H),4.26(t,J＝6.4Hz,2H),3.12–3.03(m,3H),2.66–2.48(m,2H),2.20(dd,J＝16.2,8.9Hz,2H),2.13–1.93(m,6H).MS(ESI)m/z485.2([M+H]⁺)

Example 43 2- (3-chloro-4-fluorophenyl) -6- (3- (4- (6-fluoro-phenyl [ d ] isoxazol-3-yl) piperidin-1-yl) propoxypyridazin-3 (2H) -one

The title compound was obtained by the same procedure as in example 28 except for using 3-chloro-4-fluorophenylhydrazine hydrochloride in place of 4-fluorophenylhydrazine hydrochloride.

¹H NMR(600MHz,CDCl₃)δ7.70(dd,J＝8.7,5.1Hz,1H),7.49–7.41(m,2H),7.25(dd,J＝8.5,1.9Hz,1H),7.07–7.03(m,1H),7.03–6.97(m,2H),6.85–6.74(m,1H),4.29(t,J＝6.3Hz,2H),3.20–2.98(m,3H),2.57(t,J＝7.3Hz,2H),2.19(dd,J＝16.3,9.1Hz,2H),2.14–1.98(m,6H).MS(ESI)m/z501.4([M+H]⁺)

Example 44 6- (3- (4- (2, 3-dichlorophenyl) piperazin-1-yl) propoxy) -2- (4-fluorophenyl) pyridazin-3 (2H) -one

The title compound was obtained by the procedure of example 28 using 2, 3-dichlorophenyl piperazine hydrochloride instead of 6-fluoro [ d ] isoxazole-3-piperidine hydrochloride.

¹H NMR(600MHz,CDCl₃)δ7.69–7.64(m,2H),7.20–7.13(m,4H),7.06–6.98(m,2H),6.97(dd,J＝7.1,2.4Hz,1H),4.26(t,J＝6.4Hz,2H),3.08(s,4H),2.67–2.58(m,6H),2.10–1.94(m,2H).MS(ESI)m/z477.6([M+H]⁺)

Example 45, 6- (3- (4- (benzo [ d ] isothiazol-3-yl) piperazin-1-yl) propoxy) -2- (4-fluorophenyl) pyridazin-3 (2H) -one

The title compound was prepared by the method of example 28 substituting benzo [ d ] isothiazole-3-piperazine-for 6-fluorobenzo [ d ] isoxazole-3-piperidine hydrochloride

¹H NMR(600MHz,CDCl₃)δ7.92(d,J＝8.2Hz,1H),7.83(d,J＝8.1Hz,1H),7.73–7.63(m,2H),7.48(ddd,J＝8.1,7.0,1.0Hz,1H),7.37(ddd,J＝8.0,7.0,0.9Hz,1H),7.20–7.12(m,2H),7.06–6.98(m,2H),4.27(t,J＝6.4Hz,2H),3.70–3.52(m,4H),2.81–2.67(m,4H),2.63–2.56(m,2H),2.13–1.92(m,2H).MS(ESI)m/z466.6([M+H]⁺)

TABLE 1 preferred compound numbers and structural formulas prepared in the examples

Pharmacological examples

In the following embodiment, the adopted homogenate includes three kinds of homogenate of a homogenate, a homogenate B and a homogenate C, and the configuration methods are respectively as follows:

a homogenate contained Tris-HCl buffer at a final concentration of 0.01M and sucrose solution at a final concentration of 0.32M, pH 7.4.

The B homogenate was 0.01M Tris-HCl buffer, pH 7.4.

The C homogenate was 50mM Tris buffer, pH 7.4.

Example 46

5HT_1APreparation of the film

Rat decapitation, ice-based procedure, rapidly taking brain striatum, combining 2 striatums into a centrifugal tube, adding 3ml buffer (0.05M Tris-HCl buffer containing 0.1% ascorbic acid, 10um eugenine and 4mM CaCl)₂) Homogenizing in 4 grades of 3-4s for 4 times, and adding 5ml buffer (0.05M Tris-HCl buffer containing 0.1% ascorbic acid, 10um eugenol and 4 mM) CaCl₂) Incubating at 37 deg.C for 10min, adjusting weight of the tube with balance, centrifuging at 12000r and 4 deg.C for 20min, discarding supernatant, adding 3ml of solution B, mixing with vortex mixer, adding 5ml of solution C, centrifuging, repeating for three times, discarding supernatant, and storing at-80 deg.C.

Receptor binding assay materials:

isotopic ligands³H-8-OH-DPAT (67.0Ci/mmol) available from Perkinelmer; 5-HT, available from RBI; GF/C glass fiber filter paper from Whatman; subpackaging a Tris inlet; PPO and POPOPOP are purchased from Shanghai reagent I factory; fat-soluble scintillation liquid. Beckman LS-6500 model multifunctional liquid scintillation counter.

The experimental method comprises the following steps:

(1) the prepared membrane is firstly dispersed evenly by a homogenizer by using a proper amount of homogenate, 15 test tubes are mixed into a 100ml container, and a proper amount of homogenate is added to form a 50ml membrane suspension for later use.

(2) Each reaction tube was filled with 100. mu.L of the membrane preparation and 100. mu.L of the homogenate.

(3) 100 μ L of the homogenate was added to total bound Tubes (TB) and 100 μ L of 5-HT (final concentration 10) was added to non-specific bound tubes (NB)^-5M), test Compound specific binding tube (SB) 100. mu.L of test Compound (final concentration 10)^-5M)；

(4) Adding radioactive ligand into each reaction tube³10 μ L of H-8-OH-DPAT (each reaction tube is provided with 2 parallel tubes, and each tube is placed on ice during sample loading).

(5) Incubating each reaction tube at 37 ℃ for 10min, after the reaction is finished, rapidly filtering the combined ligand through decompression, fully washing the ligand by using ice-cold test buffer solution, taking out the filter disc, putting the filter disc into a 3ml scintillation cup, adding 2ml of toluene scintillation solution, and uniformly mixing;

(6) putting the scintillation vial into a liquid scintillation counter for counting

The inhibition ratio (I%) (total binding tube cpm-compound cpm)/(total binding tube cpm-non-specific binding tube cpm) × 100%

Compounds were run in duplicate for each experiment and two separate experiments were run.

The results are shown in Table 2

Example 47

5HT_2APreparation of the film

Rat decapitation, ice operation, rapidly taking brain striatum, combining 2 striatums into a centrifugal test tube, adding 3ml buffer solution (0.05M Tris-HCl buffer solution: 6.05g Tris is dissolved in 1000ml double distilled water, adjusting pH to 7.5 with concentrated HCl) into 4 grades of 3-4s for homogenate, homogenizing for 4 times, then adding 5ml buffer solution, incubating for 10min at 37 ℃, adjusting weight of the test tube with a balance after incubation, centrifuging for 20min at 12000r and 4 ℃, discarding supernatant, adding 3ml A solution, mixing uniformly with a vortex mixer, adding 5ml buffer solution, centrifuging, discarding supernatant, and storing the precipitate at-80 ℃ for later use.

Receptor binding assay materials:

isotope ligand [ alpha ], [ alpha ] an³H]Ketanserin (67.0Ci/mmol) from PerkinElmer; methysergide, available from RBI; GF/C glass fiber filter paper from Whatman; subpackaging a Tris inlet; PPO and POPOPOP are purchased from Shanghai reagent I factory; fat-soluble scintillation liquid. Beckman LS-6500 model multifunctional liquid scintillation counter.

The experimental method comprises the following steps:

(2) mu.L of the membrane preparation and 100. mu.L of the buffer were added to each reaction tube.

(3) Add 100. mu.L of homogenate to total bound Tube (TB) and 100. mu.L of methylserine to non-specific bound tube (NB) (final concentration 10)^-5M), test Compound specific binding tube (SB) 100. mu.L of test Compound (final concentration 10)^-5M)；

(4) Adding radioactive ligand into each reaction tube³H-Ketanserin 10u L (each reaction tube is provided with 2 parallel tubes, each tube is placed on ice when the sample is added).

(5) Incubating each reaction tube at 37 ℃ for 15min, after the reaction is finished, rapidly filtering the combined ligand through decompression, fully washing the ligand by using ice-cold test buffer solution, taking out the filter disc, putting the filter disc into a 3ml scintillation cup, adding 2ml of toluene scintillation solution, and uniformly mixing;

The results are shown in Table 2

Example 48

D₂Preparation of the film

Rat decapitation, ice operation, taking brain striatum rapidly, combining 2 striatums into a centrifugal test tube, adding 3ml buffer solution (0.05M Tris-HCl buffer solution containing NaCl 120mM, KCl 5mM, MgCl21mM and CaCl 21 mM), homogenizing at 4 grades for 3-4s, homogenizing for 4 times, then adding 5ml buffer solution, adjusting the weight of the homogenized test tube with a balance, centrifuging at 12000r and 4 ℃ for 20min, discarding supernatant, adding 3mlB solution, mixing uniformly with a vortex mixer, adding 5ml B solution, centrifuging, discarding supernatant, and storing the precipitate at-80 ℃ for later use.

Receptor binding assay materials:

isotopic ligands³H-Spiperone (67.0Ci/mmol) from Perkinelmer; butalclamol, available from RBI corporation; GF/C glass fiber filter paper from Whatman; subpackaging a Tris inlet; PPO and POPOPOP are purchased from Shanghai reagent I factory; fat-soluble scintillation liquid. Beckman LS-6500 model multifunctional liquid scintillation counter.

The experimental method comprises the following steps:

(3) Add 100. mu.L of the homogenate to the total binding Tube (TB) and 100. mu.L of Butalclamol to the non-specific binding tube (NB) (final concentration 10)^-5M), test Compound specific binding tube (SB) 100. mu.L of test Compound (final concentration 10)^-5M)；

(4) Adding radioactive ligand into each reaction tube³H-Spiperone 10u L (each reaction tube is provided with 2 parallel tube, the sample loading each tube placed on ice).

(5) Incubating each reaction tube at 37 ℃ for 20min, after the reaction is finished, rapidly filtering the combined ligand through decompression, fully washing the ligand by using ice-cold test buffer solution, taking out the filter disc, putting the filter disc into a 3ml scintillation cup, adding 2ml of toluene scintillation solution, and uniformly mixing;

The results are shown in Table 2.

Examples 49 and 5HT_2CPreparation of the film

Rat decapitation, ice operation, rapidly taking brain striatum, combining 2 striatum into a centrifugal test tube, adding 3ml buffer solution (0.05M Tris-HCl buffer solution: 6.05g Tris is dissolved in 1000ml double distilled water, adjusting pH to 7.5 with concentrated HCl) into 4 grades of 3-4s for homogenate, homogenizing for 4 times, then adding 5ml buffer solution, incubating for 10min at 37 ℃, adjusting weight of the test tube with a balance after incubation, centrifuging for 20min at 12000r and 4 ℃, discarding supernatant, adding 3ml A solution, mixing uniformly with a vortex mixer, adding 5ml buffer solution, centrifuging, discarding supernatant, and storing the precipitate at-80 ℃ for later use.

Receptor binding assay materials:

isotope ligand [ alpha ], [ alpha ] an³H]-mesulergine (67.0Ci/mmol) from PerkinElmer; mianserin, available from RBI corporation; GF/C glass fiber filter paper from Whatman; subpackaging a Tris inlet; PPO and POPOPOP are purchased from Shanghai reagent I factory; fat-soluble scintillation liquid. Beckman LS-6500 model multifunctional liquid scintillation counter.

The experimental method comprises the following steps:

(3) 100 μ L of the homogenate was added to the total bound Tubes (TB) and 100 μ L of mianserin (final concentration 10) was added to the non-specific bound tubes (NB)^-5M), test Compound specific binding tube (SB) 100. mu.L of test Compound (final concentration 10)^-5M)；

(4) The radioactive ligand is added into each reaction tube³H]10 μ L of mesulergine (2 parallel channels for each reaction channel and ice for each channel when loading).

Example 50 Histamine H₁Preparation of acceptor membranes

Cutting rat head, operating on ice, rapidly taking guinea pig cerebellum, adding homogenate F, mixing uniformly by a vortex mixer, centrifuging at 48000g and 4 ℃ for 10min, removing supernatant, taking precipitate, adding homogenate F for washing, repeating the centrifugation for three times, removing supernatant after centrifugation, and storing the precipitate at-80 ℃ for later use.

H₁Receptor affinity assay:

the first step is as follows: the prepared membrane is uniformly dispersed by a homogenizer by using a proper amount of homogenate F, 15 test tubes are mixed into a 100ml container, and a proper amount of homogenate is added to form a 50ml membrane suspension for later use.

The second step is that: each reaction tube was charged with 100. mu.L of the membrane preparation.

The third step: add 100. mu.L of homogenate F to total binding Tube (TB) and 100. mu.L of promethazine to non-specific binding tube (NB) (final concentration 10)^-5M), test Compound specific binding tube (SB) 100. mu.L of test Compound (final concentration 10)^-5M)；

The fourth step: adding radioactive ligand into each reaction tube³H-pyrilamine 10. mu.L (each reaction tube has 2 parallel channels, and each channel is placed on ice when loading sample).

The fifth step: incubating each reaction tube at 30 ℃ for 60min, after the reaction is finished, rapidly filtering the combined ligand through decompression, fully washing the ligand by using ice-cold test buffer solution, taking out the filter disc, putting the filter disc into a 3ml scintillation cup, adding 2ml of toluene scintillation solution, and uniformly mixing;

and a sixth step: putting the scintillation vial into a liquid scintillation counter for counting

Example 51 preparation of noradrenaline receptor membranes

Cutting rat head, operating on ice, rapidly taking cerebral cortex, adding homogenate E, mixing uniformly by vortex mixer, centrifuging at 48000g and 4 deg.C for 15min, removing supernatant, taking irrigation sediment, adding 0.05M Tris-HCl buffer solution (PH7.7) for washing, repeating centrifugation for three times, removing supernatant after centrifugation, and storing the sediment at-80 deg.C for later use.

α₁Noradrenaline receptor affinity assay:

the first step is as follows: the prepared membrane is uniformly dispersed by a homogenizer by using a proper amount of homogenate E, 15 test tubes are mixed into a 100ml container, and a proper amount of homogenate is added to form a 50ml membrane suspension for later use.

The second step is that: each reaction tube was charged with 100. mu.L of the membrane preparation and 100. mu.L of the homogenate.

The third step: 100 μ L of the homogenate was added to the total binding Tube (TB) and 100 μ L of prazosin (final concentration 10) was added to the non-specific binding tube (NB)^-5M), test Compound specific binding tube (SB) 100. mu.L of test Compound (final concentration 10)^-5M)；

The fourth step: -releasing agent is added into each reaction tube respectivelyLigands³10 μ L of H-prazosin (each reaction tube has 2 parallel tubes, and each tube is placed on ice during sample application).

The fifth step: incubating each reaction tube at 25 ℃ for 60min, after the reaction is finished, rapidly filtering the combined ligand through decompression, fully washing the ligand by using ice-cold test buffer solution, taking out the filter disc, putting the filter disc into a 3ml scintillation cup, adding 2ml of toluene scintillation solution, and uniformly mixing;

The results are shown in Table 2

The results of in vitro experiments showed that compounds 5,6, 12, 13, 14, 16 and 17 are at three receptors (D)₂,5HT_1A,5HT_2A) Stronger affinity, but for 5HT_2C,H₁,α₁The affinity of (a) is low.

Example 52 MK-801 induced high Activity Compounds anti-schizophrenia Activity in vivo

Laboratory animal and reagent

Healthy Kunming mice, each half male and female, with a weight of 20 + -2 g, were provided by Nanjing Qinglong mountain animal cultivation center.

Ascorbic acid, chemical agents of national drug group, ltd;

MK-801, manufactured by Sigma, USA, is prepared according to the following method: preparing 1mg/ml solution by using 0.1% of vitamin C;

test positive drugs: haloperidol, risperidone, olanzapine, aripiprazole, ziprasidone, quetiapine;

tween 80, concentration 10%.

Experimental methods

Selecting mice with qualified body weight, and randomly dividing the mice into a blank group, a model group, a positive control group (risperidone group) and a drug group. The blank group and the model group are intragastrically administered with 0.1ml/10g of 10% Tween, the positive control group is intragastrically administered with 0.1mg/kg of risperidone, and the drug groups are separately intragastrically administered with the corresponding dose of drugs. After administration, the blank group is intraperitoneally injected with 0.1% ascorbic acid 0.1ml/10g 1h, and the model group, the positive control group (30min), and the drug group are intraperitoneally injected with MK-801 solution 0.1 mg/kg. Thereafter, spontaneous activity was measured in 90 minutes for each group of mice. The results are shown in Table 3.

The experimental result shows that: compared with a model group, risperidone, the compounds 19 and 23 can obviously improve MK-801 induced high activity and apomorphine induced climbing symptoms, and EPS is not caused under effective dose, which indicates that the risperidone has obvious anti-schizophrenia effect.

Example 53 apomorphine-induced mouse climbing experiment

Laboratory animal

Healthy KM mice, male, with a weight of 18-22 g, were provided by Nanjing Qinglongshan animal breeding center.

Primary reagent

Test positive drugs: risperidone, olanzapine, aripiprazole;

apomorphine, supplied by Sigma, dissolved in 0.9% NaCl (containing 0.1% vitamin C) just before use, ready for use;

vitamin C, F20061113, national drug group chemical agents limited;

sodium chloride injection, H32026305, xuzhou city, fifth pharmaceutical factory, ltd.

The instrument is a self-made climbing cage and a stopwatch.

Experimental method, apomorphine induced mouse climbing experiment

The KM mice are male, the weight is 18-22 g, the KM mice are randomly divided into a negative control group, a model group, positive drug dose groups (risperidone, aripiprazole, ziprasidone, quetiapine, olanzapine, haloperidol and clozapine) and compound dose groups (the specific administration dose is shown in the following table), and 10 mice are in each group. And (3) performing intragastric administration on the negative control group and the model group by using corresponding solvent double distilled water, performing intragastric administration on the positive medicine group by using corresponding positive medicine (trace acetic acid is added when dissolved, and double distilled water is added), and performing intragastric administration on each dosage group of the compound by using corresponding dosage of compound, wherein the intragastric administration volume is 0.1ml/10 g. Apomorphine (1mg/kg) was injected subcutaneously 1 hour after gavage in a volume of 0.1ml/10 g. Immediately placing the apomorphine injection product into a climbing cage, adapting for 5 minutes, observing behaviors of 10-11 minutes, 20-21 minutes and 30-31 minutes after the apomorphine injection, and grading according to a grading standard: four feet scored 0 on the floor; the two forefoot scored 1 on the netpen; four feet scored 2 on the netpen.

Example 54 Stiff disease test method

Laboratory animal

The healthy Kunming mouse is female and male half, and the weight is (22 +/-2) g, which is provided by Nanjing Qinglong mountain animal breeding center.

The main reagents are as follows:

a test agent, haloperidol, clozapine, risperidone, olanzapine, aripiprazole, ziprasidone

The instrument comprises the following steps:

self-made rod grabbing equipment: a stainless steel bar with the diameter of 0.3cm and 5cm higher than the workbench is placed in the mouse box.

The experimental method comprises the following steps:

the method comprises the following steps of (1) randomly dividing a KM mouse into a negative control group, a model group, positive drug dose groups (risperidone, aripiprazole, ziprasidone, quetiapine, olanzapine, haloperidol and clozapine) and compound dose groups, wherein the weight of the KM mouse is 20-24 g for each male and female half, and each group contains 10 positive drugs. And (3) performing intragastric administration on the negative control group and the model group by using corresponding solvent double distilled water, performing intragastric administration on the positive medicine group by using corresponding positive medicine (trace acetic acid is added when dissolved, and double distilled water is added), and performing intragastric administration on each dosage group of the compound by using corresponding dosage of compound, wherein the intragastric administration volume is 0.1ml/10 g. After 30min, 60min and 90min of gavage, the two forepaws of the mouse are gently placed on a small rod with the length of 20cm, the diameter of 0.3cm and the height of 5.5cm higher than a workbench, the hind limbs of the animal are gently placed on the bottom surface of the box, the duration of the posture of the two forepaws of the mouse on the rod is recorded, and 30s of rigor and stillness is taken as a positive reaction. If the mouse forepaw has not been lowered, the observation is terminated at 60 s. The number of positive-reacting animals in each compound dose group was counted.

Example 55 acute toxicity study

In the limit experiment of the sequential method, KM mice are taken, male and female are respectively divided into a plurality of groups at random, each group comprises 2-5, and each group comprises 2000mg/kg of compound and solvent group, and the administration is performed by intragastric administration according to 0.2ml/10 g. Animals were observed for mortality within 3 days. (if 3 or more than 3 animals survive within three days and the life status is not obviously abnormal, the observation is continued until the experiment is ended after 7 days; if 3 or more than 3 animals die within three days, the LD50 is measured by a median lethality method.)

Half of the lethal dose method is used for pre-testing KM mice, each half of male and female, are randomly divided into a plurality of groups, 4 mice in each group are respectively a group of 1500mg/kg, 1000mg/kg and 500mg/kg compounds and a solvent group, the mice are subjected to intragastric administration according to 0.2ml/10g, and the death condition of the animals within 1-3 days is observed.

As a result: LD for single drenching of mouse₅₀More than 2000mg/kg, which is far higher than risperidone (82.1mg/kg), has smaller acute toxicity.

TABLE 2 inhibition of the respective receptors by the compounds or IC50

TABLE 3 in vivo animal model test results for preferred compounds

Formulation examples

Example 56 pharmaceutical compositions according to the invention were prepared according to the following formulation, using the compounds prepared in examples 1-45, respectively, as active ingredient, in the form of tablets:

sieving raw materials with a 80-mesh sieve for later use, weighing the active ingredients, microcrystalline cellulose, lactose and povidone K30 according to the prescription amount, adding into a high-speed mixing preparation machine, stirring and mixing uniformly at low speed, adding a proper amount of purified water, stirring at low speed, cutting and granulating at high speed, drying the wet granules at 60 ℃ for 3h, granulating with a 24-mesh sieve, adding carboxymethyl starch sodium, silicon dioxide and magnesium stearate according to the prescription amount, mixing totally, and tabletting by using a rotary tablet press to obtain the pharmaceutical composition of the tablet dosage form.

In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.

Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.

Claims

1. A compound, which is a compound represented by formula I or a pharmaceutically acceptable salt of the compound represented by formula I,

wherein:

z is unsubstituted-(CH₂)_n-n is an integer of 1 to 6, or the carbon chain in Z contains a double bond;

q is N or CH;

R₁selected from hydrogen, C_1-5Alkyl groups of (a); r₂Selected from hydrogen, C_1-5Alkyl groups of (a);

R₃selected from substituted or unsubstituted phenyl, wherein said substituents are selected from halogen;

R₄selected from substituted phenyl, formula II, formula III, formula IV or formula V, said substituents being selected from halogen, cyano, C_1-5The alkyl group, trifluoromethyl group, methoxy group of (a),

wherein in the formula II, Y is selected from N or CH, and X is selected from O or S; r₅Selected from H, halogen or carboxamide group.

2. The compound of claim 1, wherein: z is unsubstituted- (CH)₂)_nAnd n is an integer of 1 to 4.

3. The compound of claim 1, wherein: the halogen is selected from fluorine, chlorine, bromine and iodine.

4. A compound of claim 1, wherein R is₄Selected from formula II, X is O, Y is CH, N, R₅Selected from hydrogen, fluoro, chloro, bromo, iodo or carboxamido; or X is S, Y is CH, N, R₅Selected from hydrogen; or R₄Is substituted phenyl, and the substituent is selected from one or more of methyl, ethyl, fluorine, chlorine, bromine, iodine and cyano.

5. The compound of claim 4, wherein: the R is₁、R₂Each independently selected from hydrogen, methyl, ethyl, propyl, R₃Selected from phenyl。

6. A compound, wherein the compound is at least one of the following compounds, or a pharmaceutically acceptable salt of at least one of the following compounds:

6- (3- (4- (benzo [ d ] thiazolyl-2-yl) piperidin-1-yl) propoxy) -2- (3, 4-dichlorophenyl) pyridazine

-3(2H) -one;

7. A pharmaceutical composition comprising a compound of any one of claims 1 to 6, and a pharmaceutically acceptable excipient, carrier, adjuvant, or combination thereof.

8. Use of a compound according to any one of claims 1 to 6 or a pharmaceutical composition according to claim 7 for the manufacture of a medicament for the treatment of neuropsychiatric disorders.

9. The use according to claim 8, wherein the neuropsychiatric disease is schizophrenia.