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CN116354923B - A nitrogen-containing heterocyclic compound and its application - Google Patents

A nitrogen-containing heterocyclic compound and its application Download PDF

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CN116354923B
CN116354923B CN202211661648.4A CN202211661648A CN116354923B CN 116354923 B CN116354923 B CN 116354923B CN 202211661648 A CN202211661648 A CN 202211661648A CN 116354923 B CN116354923 B CN 116354923B
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diazaspiro
methylpiperidin
isobutoxybenzyl
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methyl
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CN116354923A (en
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徐祥清
邱印利
郭强
于民权
赵松
窦飞
靖鹏
侯媛媛
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Nhwa Pharmaceutical Corp
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
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    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
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    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract

The application relates to the field of chemical medicines, in particular to a nitrogen-containing heterocyclic compound and application thereof, and the nitrogen-containing heterocyclic compound provided by the application is shown as a formula I, acts on a 5-HT 2A、5-HT2C receptor, and has better selectivity to 5-HT 2A than or similar to pimecrin. Can be used for treating behavior disorder and psychosis associated with schizophrenia or Parkinson's disease and dementia. The antipsychotic activity of the compounds of the application is comparable to pimecroline, sedating side effects, and cardiotoxicity is less than pimecroline.

Description

Nitrogen-containing heterocyclic compound and application thereof
Technical Field
The invention relates to the field of chemical medicines, in particular to a nitrogen-containing heterocyclic compound and application thereof.
Background
The incidence of the schizophrenia (Schizophrenia) is hidden, the recovery rate is low, and the incidence rate of the schizophrenia is higher in the lifetime. About 0.3-0.7% of the world population is affected by schizophrenia in the life of the world, over 2100 ten thousand patients suffering from schizophrenia are estimated worldwide in 2016, and the current anti-schizophrenia drugs mainly comprise typical anti-schizophrenia drugs and atypical anti-schizophrenia drugs, but the current anti-schizophrenia therapeutic drugs block dopamine receptors strongly, so that adverse reactions such as extrapyramidal reaction (EPS), tardive dyskinesia, increase of prolactin and the like are caused. In the medical field, although various types of active compounds acting on different targets are available for the treatment of Sleep disorders (Sleep disorders), adverse reactions such as addiction, drug resistance and sequelae remain unsolved.
Antipsychotics that exert pharmacological effects by blocking the dopamine D 2 receptor have traditionally been termed first-generation antipsychotics, i.e. "typical" antipsychotics (such as haloperidol), which are breakthrough in the treatment of positive symptoms of schizophrenia but fail to treat 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, risperidone (Risperidone) and the like, known as second generation antipsychotics, i.e., novel antipsychotics, have been developed successively, which, although their respective pharmacological actions are not completely identical, share a common pharmacological characteristic, namely, a far higher affinity for the 5-hydroxytryptamine (5-HT 1A、2A、2C) receptor (5-HT 1A、2A、2C) and the Norepinephrine (NA) receptor (α 1、α2) than for the D 2 receptor. Compared with the first-generation antipsychotics, the clinical effect of the traditional Chinese medicine composition has more advantages, is effective on positive symptoms and traditional antipsychotics, is effective on negative symptoms and cognition deficiency symptoms, has a wider action spectrum, and has adverse reactions such as QT interval prolongation, hyperprolactinemia, weight gain and the like. Thus, finding drugs that are effective against positive, negative symptoms and cognitive impairment of schizophrenia with small side effects is a hotspot of current research.
The 5-hydroxytryptamine system plays an important role in the function of the regulated prefrontal cortex (PFC), including mood control, cognitive behavior and working memory. Pyramidal neurons of PFC and GABA interneurons contain several of the serotonin receptor subtypes 5-HT 1A and 5-HT 2A, which have particularly high densities. PFC and NMDA receptor channels have recently been shown to be targets for 5-HT 1A R, both of which modulate cortical excitatory neurons, affecting cognitive function. Indeed, various preclinical data suggest that 5-HT 1A R may be a new target for the development of antipsychotic drugs. The high affinity of atypical antipsychotics (e.g., olanzapine, aripiprazole, etc.) for 5-HT 1A R and its low EPS side effects all suggest that the 5-hydroxytryptamine system plays an important role in the function of the regulated prefrontal cortex (PFC), including mood control, cognitive behavior, and working memory. Pyramidal neurons of PFC and GABA interneurons contain several 5-HT 1A and 5-HT 2A, which have particularly high densities of the 5-hydroxytryptamine receptor subtypes. Recent studies have shown that 5-HT 1A agonists are associated with atypical antipsychotic therapy and improve negative symptoms and cognitive dysfunction. In the treatment of schizophrenia with the atypical antipsychotic clozapine, 5-HT 2A has been found to play an important role therein, involving various aspects of perception, mood regulation and motor control. Blocking the 5-HT 2A receptor normalizes dopamine release and acts as an antipsychotic. In addition, the 5-HT 2C receptor is closely associated with weight gain.
Pimavanserin is an inverse agonist with high affinity for 5-HT 2A, a 5-HT 2C antagonist, and in vitro experimental results show that it has a higher affinity for 5-HT 2A receptor [ inhibition constant (Ki) of 0.4nm ] than 5-HT 2C (ki=16 nm), and no significant affinity (Ki >300 nm) for 5-HT 2B receptor, dopamine receptor (including D 2 receptor), adrenergic receptor, muscarinic receptor or calcium channel receptor. The medicine is approved by the U.S. food and drug administration to be marketed in the 4 th year of 2016, and has the trade name of Nuplazid TM, and is mainly used for treating parkinsonism symptoms such as illusion and illusion.
Thus, there is a need for an anti-schizophrenia agent that is effective against both positive and negative symptoms, improves cognitive dysfunction, prevents extrapyramidal side effects, including tardive dyskinesia, parkinson's disease, and reduces weight gain.
Disclosure of Invention
The present invention aims to solve at least one of the technical problems existing in the prior art, and therefore, an object of the present invention is to provide a nitrogen-containing heterocyclic compound, as shown in formula I:
wherein N7 is 0, 1 or 2, A is C, O or N;
n3, n6 are each independently selected from integers of 0, 1,2,3, and n3, n6 are not simultaneously 0;
n2 is an integer of 1, 2 or 3;
W is O or S;
z, Q, Y are each independently selected from C, N, and Z, Q are not simultaneously C;
R 2 is selected from hydrogen, substituted or unsubstituted C 1-C5 linear or branched alkyl, substituted or unsubstituted C 3-C5 cycloalkyl, said substituents being selected from methyl, ethyl, propyl, butyl, fluoro, C 3-C5 cycloalkyl;
R 3、R4 is selected from H, halogen, C 1-C5 linear or branched alkyl, phenyl, or R 3 and R 4 form C 3-6 cycloalkyl;
r 5 is hydrogen or halogen;
r 1 is selected from the structures of formula II, III, IV:
In the formula III, N5 is an integer of 0-4, R 8、R9 is independently selected from alkyl of C 1-3, or R 8、R9 and N form substituted or unsubstituted 4-6 membered heterocycle, wherein the substituent is selected from methyl, ethyl, propyl, butyl, fluorine and chlorine;
in the formula II, n4 is an integer of 1-4;
r 7 is selected from methyl, ethyl, isopropyl, isobutyl, benzyl, phenyl, halogenated C 1-C5 linear or branched alkyl;
R 6 is halogen, methyl or hydrogen.
In one embodiment, when R 3 and R 4 form a cycloalkyl group of C 3-C6, the compound of formula I is as shown in formula I-1:
Wherein n1 is an integer of 1,2 or 3.
In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
In another aspect, the invention provides application of a compound shown in formula I and a pharmaceutical composition thereof in preparing medicines for treating mental diseases. The mental disease is schizophrenia. The mental diseases are Parkinson's disease, dementia related behavioral disorder and psychosis.
Compounds of formula I
Wherein N7 is 0, 1 or 2, A is C, O or N;
n3, n6 are each independently selected from integers of 0, 1,2,3, and n3, n6 are not simultaneously 0;
n2 is an integer of 1, 2 or 3;
W is O or S;
z, Q, Y are each independently selected from C, N, and Z, Q are not simultaneously C;
R 2 is selected from hydrogen, substituted or unsubstituted C 1-C5 linear or branched alkyl, substituted or unsubstituted C 3-C5 cycloalkyl, said substituents being selected from methyl, ethyl, propyl, butyl, fluoro, C 3-C5 cycloalkyl;
R 3、R4 is selected from H, halogen, C 1-C5 linear or branched alkyl, phenyl, or R 3 and R 4 form C 3-6 cycloalkyl;
r 5 is hydrogen or halogen;
r 1 is selected from the structures of formula II, III, IV:
in the formula III, N5 is an integer of 0-4, R 8、R9 is independently selected from alkyl of C 1-3 or R 8、R9 and N form substituted or unsubstituted 4-6 membered heterocycle, and the substituent is selected from methyl, ethyl, propyl, butyl, fluorine and chlorine;
in the formula II, n4 is an integer of 1-4;
r 7 is selected from methyl, ethyl, isopropyl, isobutyl, benzyl, phenyl, halogenated C 1-C5 linear or branched alkyl;
R 6 is halogen, methyl or hydrogen.
In one embodiment, when R 3 and R 4 form a cycloalkyl group of C 3-C6, the compound of formula I is as shown in formula I-1:
Wherein n1 is an integer of 1,2 or 3.
In one embodiment, the compound of formula I is as shown in formula V:
In yet another embodiment, when R 3 and R 4 form a cycloalkyl group of C 3-C6, the compound of formula I is as shown in formula V-1:
wherein n1 is an integer of 1,2 or 3.
In the above formula V-1 compound, when R1 is a structure of formula II, the formula V-1 compound is a structure of formula V-2:
In one embodiment, the compound of formula I is as shown in formula VI:
In yet another embodiment, when R 3 and R 4 form a cycloalkyl group of C 3-C6, the compound of formula I is as defined in formula VI-1:
wherein n1 is an integer of 1,2 or 3.
In the compound of the formula VI-1, when R1 is a structure of the formula II, the compound of the formula VI-1 is a structure of the formula VI-2:
wherein n4 is an integer of 1,2 or 3.
In one embodiment, the halogen is selected from fluorine, chlorine, bromine and iodine, the straight or branched alkyl of C 1-C5 is selected from methyl, ethyl, propyl, isopropyl, isobutyl and neopentyl, the C 3-C5 cycloalkyl is selected from cyclopropyl, cyclobutyl and cyclopentyl, the substituted cycloalkyl of C 3-C5 is selected from methylcyclopropyl and ethylcyclopropyl, the halo in the haloalkyl is selected from fluoroalkyl, chloroalkyl, bromoalkyl and iodoalkyl, and the straight or branched alkyl of C 1-C3 is methyl, ethyl or propyl.
In one embodiment, the 4-6 membered heterocycle is selected from the group consisting of azetidine, piperazine, pyrrolidine.
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.
In one embodiment, n3, n6 are each independently selected from integers of 0, 1,2, 3, and n3 and n6 are not both 0. In a preferred embodiment, n3, n6 are each independently selected from integers of 0, 1,2, and n3 and n6 are not both 0.
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.
In one embodiment, n4 is selected from integers from 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.
In one embodiment, n5 is selected from integers 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.
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.
In one embodiment, a is C, N or O. In a preferred embodiment, a is N or O.
In one embodiment, R 2 is selected from hydrogen, a substituted or unsubstituted C 1-C5 linear or branched alkyl, a substituted or unsubstituted C 3-C5 cycloalkyl, said substituents being selected from methyl, ethyl, propyl, butyl, fluoro, C 3-C5 cycloalkyl. In a preferred embodiment, R 2 is selected from hydrogen, substituted or unsubstituted C 1-C5 straight or branched alkyl, substituted or unsubstituted C 3-C5 cycloalkyl, said substituents being selected from methyl, ethyl, fluoro, cyclopropyl. In a more preferred embodiment, R 2 is selected from hydrogen, methyl, isopropyl, isobutyl, cyclopropyl, cyclopropylmethyl, neopentyl.
The compound shown in the formula I is any one compound selected from the group consisting of 5- (4-isobutoxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octane-6-one, 5- (3-fluoro-1-methylpiperidin-4-yl) -7- (4-isobutoxybenzyl) -5, 7-diazaspiro [2.5] octane-6-one, 5- (4-isobutoxybenzyl) -7- (1-methylpyrrolidin-3-yl) -5, 7-diazaspiro [2.5] octane-6-one, 5- (2- (dimethylamino) ethyl) -7- (4-isobutoxybenzyl) -5, 7-diazaspiro [2.5] octane-6-one, 5- (4-methoxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octane-6-one, 5- (4-cyclopropoxybenzyl) -7- (1-isobutoxybenzyl) -7- (1-methylpiperidin-3-yl) -5, 7-diazaspiro [2.5] octane-6-one, 5- (2- (dimethylamino) ethyl) -7- (4-isobutoxybenzyl) -5, 7-diazaspiro [2.5] octane-6-one, 5- (4-methoxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [ 2.5-5 ] octane-6-one and 5- (4-methoxy-benzyl) one Octan-6-one;
5- (1- (2, 2-difluoroethyl) piperidin-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- (4-isobutoxybenzyl) -7- (2-methyl-2-azaspiro [3.3] heptan-6-yl) -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] non-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] non-6-one, 5- (4-isobutoxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.6] non-6-one, 7- [ (dimethylamino) methyl ] -5- (4-isobutoxybenzyl) -5-azaspiro [2.5] octane-6-one;
7- (dimethylamino) -5- (4-isobutoxybenzyl) -5-azaspiro [2.5] octan-6-one;
7- (azetidin-1-yl) -5- (4-isobutoxybenzyl) -5-azaspiro [2.5] octan-6-one;
1- (4-isobutoxybenzyl) -5-methyl-3- (1-methylpiperidin-4-yl) -5-phenyltetrahydropyrimidin-2 (1H) -one, 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- (4-isobutoxybenzyl) -7- (4-methylpiperazin-1-yl) -5-azaspiro [2.5] octan-6-one;
7- (4-isobutoxybenzyl) -5- (1-methylpiperidin-4-yl) -5-azaspiro [2.5] octan-6-one;
5- ((6-isobutoxybyridin-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-diazaoxazol [2.5] octan-6-one, 5- ((2R) -1, 2-dimethylpiperidin-4-yl) -7- (4-isobutoxybenzyl) -5, 7-diaza [2.5] octan-6-one, 5- ((2S) -1, 2-dimethylpiperidin-4-yl) -7- (1-isobutoxybenzyl) -7-diazaspiro [2.5] octan-6-one, 5- (4-isobutoxybenzyl) -7- (1-isobutoxybenzyl) octan-6-one, 5- (2-isobutoxybenzyl) 7-diazaspiro [ 2.5-5 ] octan-6-one, 5-one 1-methyl-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] heptane-5-one;
6- (4-isobutoxybenzyl) -4- (1-methylpiperidin-4-yl) -4, 6-diazaspiro [2.4] heptane-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.
Term interpretation:
The term "comprising" is an open-ended expression, i.e., including what is indicated by the invention, but not excluding other aspects. It is to be understood that the term "comprising" may cover the closed meaning, i.e. "consisting of.
As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as the compounds of the general formula above or as specified in the examples, subclasses, and examples. It is to be understood that the term "optionally substituted" may be 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. An optionally substituted group may be substituted at each substitutable position of the group, unless otherwise indicated. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, then the substituents may be the same or different at each position.
In addition, unless explicitly stated otherwise, the description as used in this application is to be construed broadly as meaning that the terms "independently of each other" and "independently of each other" may refer to the fact that, in different groups, specific terms expressed between the same symbols do not affect each other, or may mean that, in the same groups, specific terms expressed between the same symbols do not affect each other.
In the various parts of the present specification, substituents of the presently disclosed compounds are disclosed in terms of the type or scope of groups. It is specifically noted that the present invention includes each individual subcombination of the individual members of these group classes and ranges. For example, the term "C 1-C5 alkyl" refers specifically to independently disclosed methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH 3), ethyl (Et, -CH 2CH3), n-propyl (n-Pr, -CH 2CH2CH3), isopropyl (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)), and, N-pentyl (-CH 2CH2CH2CH2CH3), 2-pentyl (-CH (CH 3)CH2CH2CH3), 3-pentyl (-CH (CH 2CH3)2), 2-methyl-2-butyl (-C (CH 3)2CH2CH3)), a catalyst, 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), and the like.
Ranges recited herein (e.g., numerical ranges) can encompass each and every subrange within the range as well as each subrange formed by each value. Thus, for example, the expression "n 2 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, 3.
The expression "one or more" may denote 1,2, 3, 4, 5, 6 or more.
The term "cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of carbon and hydrogen atoms, preferably containing 1 or 2 rings. The cycloalkyl group may be a monocyclic, fused polycyclic, bridged or spiro ring structure. Cycloalkyl groups may have 3 to 6 carbon atoms, i.e. "C 3-C6 cycloalkyl", for example C 6 cycloalkyl, C 5 cycloalkyl, C 4 cycloalkyl, C 3 cycloalkyl. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The term also covers the case where the C atom may be substituted by oxo (=o).
The terms "heterocycle" and "heterocyclyl" are used interchangeably to denote a monovalent or polyvalent, monocyclic, bicyclic or tricyclic ring system containing 3 to 12 ring atoms in which one or more atoms in the ring are independently replaced by heteroatoms having the meaning as described herein, and the ring may be fully saturated or contain one or more unsaturations, but none of the aromatic rings. Unless otherwise indicated, the heterocyclyl group may be a carbon or nitrogen group, and the-CH 2 -group may optionally be replaced by-C (=o) -. The sulfur atom of the ring may optionally be oxidized to an S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxide. Examples of heterocyclyl groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxacyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, and the like. Examples of the substitution of the-CH 2 -group in the heterocyclyl by-C (=o) -include, but are not limited to, 2-oxo-pyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidonyl, 3, 5-dioxopiperidyl and pyrimidinedionyl. Examples of sulfur atoms in the heterocyclic group that are oxidized include, but are not limited to, sulfolane, 1-dioxothiomorpholino. The heterocyclyl group may be optionally substituted with one or more substituents described herein.
The term "hydrogen (H)" means a single hydrogen atom. Such radicals may be attached to other groups, such as to an oxygen atom, to form a hydroxyl group.
The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
The term "pharmaceutically acceptable salt" refers to an inorganic or organic salt of a compound of the invention.
The beneficial technical effects of the invention are as follows:
The compounds provided herein act on 5-HT2A, 5-HT2C receptors with selectivity for 5-HT2A over or similar to pimavanserin. Can be used for treating behavior disorder and psychosis associated with schizophrenia or Parkinson's disease and dementia. The antipsychotic activity of the compounds of the application is comparable to pimecroline, sedative side effects are less than pimecroline, and cardiotoxicity is less than pimecroline.
Detailed description of the preferred embodiments
The present invention will be further described by the following examples, however, the scope of the present invention is not limited to the following examples. Those skilled in the art will appreciate that various changes and modifications can be made to the invention without departing from the spirit and scope thereof.
TABLE 1 Structure of Compounds and names of Compounds
Detailed description of the preferred embodiments
The following examples are for illustrative purposes only and are not intended to be limiting of the invention.
Examples of synthetic aspects
Example 1.5- (4-isobutoxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one (1)
Reaction 1
1.1 Preparation of methyl 1- ([ [4- (2-methylpropyloxy) phenyl ] methyl ] carbamoyl) cyclopropane-1-carboxylate
1- [4- (2-Methylpropyloxy) 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) were dissolved in 20ml DMF and stirred at room temperature for 2 hours. After the completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The solvent was distilled off, and the column chromatography was carried out (PE: ea=4:1) to give 1100mg of methyl 1- ([ [4- (2-methylpropyloxy) phenyl ] methyl ] carbamoyl) cyclopropane-1-carboxylate in a yield of 80.72%.
1.2 Preparation of [1- [ ([ [4- (2-methylpropyloxy) phenyl ] methyl ] amino) methyl ] cyclopropyl ] methanol
Methyl 1- ([ [4- (2-methylpropyloxy) phenyl ] methyl ] carbamoyl) cyclopropane-1-carboxylate (1.10 g,3.602 mmol) and BH 3 -THF (10.00 mL,104.490 mmol) were dissolved with 10mL THF and heated at reflux overnight. After the reaction, cooling to room temperature, adding 2N HCl solution to quench the reaction, stirring at room temperature for 1 hour, washing the aqueous phase with ethyl acetate, adjusting the pH of the aqueous phase to 10 with 4N-NaOH solution, extracting with dichloromethane, and evaporating the solvent to obtain 800mg of [1- [ ([ [4- (2-methylpropyloxy) phenyl ] methyl ] amino) methyl ] cyclopropyl ] methanol crude product. 1.3 preparation of benzyl N- [ [1- (hydroxymethyl) cyclopropyl ] methyl ] -N- [ [4- (2-methylpropyloxy) phenyl ] methyl ] carbamate
[1- [ ([ [4- (2-Methylpropyloxy) phenyl ] methyl ] amino) methyl ] cyclopropyl ] methanol (800.00 mg,3.037 mmol) and CbzCl (777.25 mg, 4.552 mmol) were added to a mixed solution of 10ml NaHCO 3 and 10ml THF, and stirred at room temperature for 2 hours. After the completion of the reaction, water was added thereto, followed by extraction with ethyl acetate. Solvent was removed and column chromatography was performed to purify (PE: ea=1:1) to give 800mg of N- [ [1- (hydroxymethyl) cyclopropyl ] methyl ] -N- [ [4- (2-methylpropyloxy) phenyl ] methyl ] carbamate in 66.26% yield.
1.4 Preparation of benzyl N- [ (1-formylcyclopropyl) methyl ] -N- [ [4- (2-methylpropyloxy) phenyl ] methyl ] carbamate
N- [ [1- (hydroxymethyl) cyclopropyl ] methyl ] -N- [ [4- (2-methylpropyloxy) phenyl ] methyl ] carbamate (700.00 mg,1.761 mmol) and PCC (759.16 mg,3.522 mmol) were dissolved with 20ml dichloromethane, stirred at room temperature for 2 hours, and filtered to give a solution. Removal of the solvent afforded benzyl N- [ (1-formylcyclopropyl) methyl ] -N- [ [4- (2-methylpropyloxy) phenyl ] methyl ] carbamate 500mg in 71.79% yield.
1.5 Preparation of benzyl N- [ (1- [ (1-methylpiperidin-4-yl) amino ] methyl ] cyclopropyl) methyl ] -N- [ [4- (2-methylpropyloxy) phenyl ] methyl ] carbamate
Benzyl N- [ (1-formylcyclopropyl) methyl ] -N- [ [4- (2-methylpropyloxy) phenyl ] methyl ] carbamate (500.00 mg,1.264 mmol), 1-methyl-4-piperidinamine (216.55 mg,1.896 mmol), naBH 3 CN (158.89 mg,2.528 mmol) was added to a mixed solution of 10ml ethanol and 1ml acetic acid and stirred at room temperature overnight. After the reaction, the reaction solution was poured into saturated NaHCO 3 solution and extracted with ethyl acetate. The solvent was removed and purified by column chromatography (DCM: meoh=10:1) to give 350mg of benzyl N- [ (1- [ (1-methylpiperidin-4-yl) amino ] methyl ] cyclopropyl) methyl ] -N- [ [4- (2-methylpropyloxy) phenyl ] methyl ] carbamate in 56.08% yield.
1.6 Preparation of 1-methyl-N- ([ 1- [ ([ [4- (2-methylpropyloxy) phenyl ] methyl ] amino) methyl ] cyclopropyl ] methyl) piperidin-4-amine
Benzyl N- [ (1- [ (1-methylpiperidin-4-yl) amino ] methyl ] cyclopropyl) methyl ] -N- [ [4- (2-methylpropyloxy) phenyl ] methyl ] carbamate (100.00 mg,0.203 mmol) and Pd (OH) 2/C (20.00 mg) were added to 10ml of CF 3CH2 OH solution, followed by hydrogen gas and stirring at room temperature overnight. After the reaction, the mixture was filtered to give a filtrate, and the solvent was removed to give 50mg of 1-methyl-N- ([ 1- [ ([ [4- (2-methylpropyloxy) phenyl ] methyl ] amino) methyl ] cyclopropyl ] methyl) piperidin-4-amine in a yield of 68.65%.
1.7 Preparation of 5- (1-methylpiperidin-4-yl) -7- [ [4- (2-methylpropyloxy) phenyl ] methyl ] -5, 7-diazaspiro [2.5] octan-6-one
1-Methyl-N- ([ 1- [ ([ [4- (2-methylpropyloxy) phenyl ] methyl ] amino) methyl ] cyclopropyl ] methyl) piperidin-4-amine (50.00 mg,0.139 mmol) was dissolved in 5ml THF, triphosgene (50.00 mg,0.139 mmol) was added to the solution, and stirred at room temperature for 2 hours. After the reaction, the reaction mixture was poured into saturated NaHCO 3, extracted with ethyl acetate, the solvent was removed, and purified by column chromatography (DCM: meoh=20:1) to give 17mg of 5- (1-methylpiperidin-4-yl) -7- [ [4- (2-methylpropyloxy) phenyl ] methyl ] -5, 7-diazaspiro [2.5] octane-6-one in yield 31.7％.1H-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＝12.2Hz,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]+.
Example 2.5- (3-fluoro-1-methylpiperidin-4-yl) -7- (4-isobutoxybenzyl) -5, 7-diazaspiro [2.5] octan-6-one (2)
The title compound was prepared by the method of example 1 by substituting 1-methylpiperidin-4-amine as the reaction starting material with 3-fluoro-1-methylpiperidin-4-amine, and the structural formula is shown in the number (2) in Table 1 .1H 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]+.
Example 3.5- (4-isobutoxybenzyl) -7- (1-methylpyrrolidin-3-yl) -5, 7-diazaspiro [2.5] octane-6-one (3)
The title compound was prepared by the method of example 1 by substituting 1-methylpiperidin-4-amine for 1-methylpyrrolidine-3-amine as the starting material, and the structural formula is shown in Table 1 under number (3) .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,2H),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]+.
Example 4.5- (2- (dimethylamino) ethyl) -7- (4-isobutoxybenzyl) -5, 7-diazaspiro [2.5] octane-6-one (4)
The title compound was prepared by the method of example 1 by substituting N, N-dimethylethane-1, 2-diamine for 1-methylpiperidin-4-amine as the reaction starting material, and the structural formula is shown in Table 1 under number (4) .1H 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]+.
Example 5.5- (4-methoxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one (5)
The title compound was prepared by the method of example 1 by substituting 4-methoxybenzylamine for 1- [4- (2-methylpropyloxy) phenyl ] methylamine, and the structural formula is shown in Table 1 under number (5) .1H 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]+.
Example 6.5- (4-Cyclopropoxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one (6)
The title compound was prepared by the method of example 1 by substituting 1- [4- (2-methylpropyloxy) phenyl ] methylamine for (4-cyclopropylphenyl) methylamine, and the structural formula is shown in Table 1 as number (6) .1H 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]+.
Example 7.5- (4- (cyclopropylmethoxy) benzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one (7)
The title compound was prepared by the method of example 1 by substituting (4- (cyclopropylmethoxy) phenyl) methylamine for 1- [4- (2-methylpropyloxy) phenyl ] methylamine, the structural formula of which is shown in Table 1 under number (7) .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),1.90(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]+.
Example 8.5- (1-Benzylpiperidin-4-yl) -7- (4-isobutoxybenzyl) -5, 7-diazaspiro [2.5] octan-6-one (8)
The title compound was prepared as in example 1 by substituting 1-methylpiperidin-4-amine for 1-benzylpiperidin-4-amine, having the structural formula shown in Table 1 under number (8) .1H NMR(400MHz,DMSO-d6)δ7.66–7.55(m,2H),7.52–7.42(m,3H),7.16–7.07(m,2H),6.91–6.82(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]+.
Example 9.5- (1- (2, 2-difluoroethyl) piperidin-4-yl) -7- (4-isobutoxybenzyl) -5, 7-diazaspiro [2.5] octan-6-one (9)
The title compound was prepared as in example 1 by substituting 1- (difluoromethyl) piperidin-4-amine for 1-methylpiperidin-4-amine as the reaction starting material, and the structural formula was shown in the number (9) in Table 1 .1H 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＝11.8Hz,1H),0.97(d,J＝6.7Hz,3H),0.51(s,1H),0.40(s,1H).LCMS(ES,m/z):436[M+H]+.
Example 10.5- (4-isobutoxybenzyl) -7- (2-methyl-2-azaspiro [3.3] heptan-6-yl) -5, 7-diazaspiro [2.5] octan-6-one (10)
The title compound was prepared by the method of example 1 by substituting 1-methylpiperidin-4-amine as the reaction starting material with 2-methyl-2-azaspiro [3.3] heptane-6-amine, and the structural formula is shown as number (10) in Table 1 .1H NMR(400MHz,DMSO-d6)δ7.10(d,J＝8.3Hz,2H),6.86(d,J＝8.5Hz,2H),4.71(q,J＝8.8Hz,1H),4.32(s,2H),3.70(d,J＝6.5Hz,2H),3.42(s,2H),3.26(s,2H),2.99(s,2H),2.89(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]+.
Example 11.5- (1-methylpiperidin-4-yl) -7- (4- (neopentyloxy) benzyl) -5, 7-diazaspiro [2.5] octan-6-one (11)
The title compound was prepared by the method of example 1 by substituting (4- (neopentyloxy) phenyl) methylamine for 1- [4- (2-methylpropyloxy) phenyl ] methylamine, the structural formula of which is shown in the number (11) in Table 1 .1H 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),3.00(s,2H),2.89(s,3H),2.03(qd,J＝13.1,3.9Hz,2H),1.96–1.87(m,2H),1.05(s,9H),0.68–0.56(m,2H),0.50(t,J＝3.0Hz,2H).LCMS(ES,m/z):427[M+H]+.
EXAMPLE 12.5- (4-isobutoxybenzyl) -7- (1-isobutylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one (12)
The title compound was prepared as in example 1 by substituting 1-methylpiperidin-4-amine for 1-isobutylpiperidin-4-amine and having the structural formula shown in number (12) in Table 1 .1H 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(dq,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]+.
Example 13.5- (4-isobutoxybenzyl) -7- (1-isopropylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one (13)
The title compound was prepared as in example 1 by substituting 1-methylpiperidin-4-amine for 1-isopropylpiperidin-4-amine, having the structural formula shown in Table 1 under number (13) .1H 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),2.81–2.70(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]+.
EXAMPLE 14.6- (4-isobutoxybenzyl) -8- (1-methylpiperidin-4-yl) -6, 8-diazaspiro [3.5] non-7-one (14)
The title compound was prepared by the method of example 1 by substituting 1- (methoxycarbonyl) cyclopropane-1-carboxylic acid for 1- (ethoxycarbonyl) cyclobutane-1-carboxylic acid, and the structural formula is shown in Table 1 as number (14) .1H 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,2H),1.68(d,J＝11.5Hz,6H),0.97(d,J＝6.7Hz,6H).LCMS(ES,m/z):400[M+H]+.
EXAMPLE 15.5- (4-isobutoxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octane-6-thione (15)
The target compound was prepared as in example 1 by replacing the reaction raw material triphosgene with thiophosgene, and the structural formula is shown as the number (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]+.
EXAMPLE 16.5- (4-hydroxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one (16) reaction scheme 2
5- (4-Methoxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octane-6-one (100 mg,0.0291 mmol) (prepared as in example 5) was taken and mixed with 20ml of dichloromethane, cooled in an ice-water bath, and under nitrogen protection, boron tribromide (7.5 mg,0.0300 mmol) dissolved in dichloromethane was slowly added dropwise thereto, and the mixture was left to react at room temperature after the completion of the dropwise addition. After the reaction, water is added dropwise to perform the hair-quenching reaction, the organic phase is washed by saturated sodium bicarbonate solution, the solvent is removed, and the mixture is separated and purified by column chromatography (DCM: meOH=20:1) to obtain 67mg of 5- (4-hydroxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octane-6-one, and the yield is high 70.0％.1HNMR(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,3H),1.90(t,J＝11.1Hz,2H),1.56(td,J＝13.1,9.3Hz,2H),1.42(d,J＝11.6Hz,2H),0.54–0.47(m,2H),0.40(t,J＝2.9Hz,2H).LCMS(ES,m/z):330[M+H]+.
EXAMPLE 17.7- (4-isobutoxybenzyl) -5- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.6] nonan-6-one (17)
Reaction 3
17.1 Preparation of 2- (1-formylcyclopropyl) acetonitrile
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, nitrogen blanketed, cooled to 0 ℃, PCC (7.27 g,33.727 mmol) was added, stirred for 2 hours, filtered, the filter cake was washed with dichloromethane and the solvent was removed under pressure to give 3g of 2- (1-formylcyclopropyl) acetonitrile in 122.22% yield as a tan oil.
17.2 Preparation of 2- [1- [ (1-methylpiperidin-4-yl) amino ] methyl ] cyclopropylacetonitrile
2- (1-Formyl-cyclopropyl) acetonitrile (2.80 g, 25.618 mmol) and acetic acid (7.70 g,128.222 mmol) were added to 30.00mL of dichloromethane under nitrogen, 1-methylpiperidin-4-amine (3.21 g,28.210 mmol) was added, stirred for 30min, STAB (8.16 g,38.501 mmol) was added, and the temperature was reduced to 0℃for reaction. After the reaction, 30ml of water was added dropwise at room temperature to quench the reaction. The organic phase was extracted with dichloromethane (3×10 ml), washed with saturated brine and dried over anhydrous Na 2SO4. The filtrate was filtered and concentrated to dryness and the next reaction was carried out directly without purification.
17.3 Preparation of benzyl (1- (cyanomethyl) cyclopropyl) methyl) (1-methylpiperidin-4-yl) carbamate
2- [1- [ (1-Methylpiperidin-4-yl) amino ] methyl ] cyclopropylacetonitrile (3.03 g, 14.65mmol) and Na 2CO3 (4.66 g,43.967 mmol) were added to a 50ml THF/H 2 O mixed solution, nitrogen gas was purged, the temperature was lowered to 0℃and benzyl chloroformate (2.75 g,16.121 mmol) was slowly added dropwise thereto, and the reaction was continued at room temperature after completion of the dropwise addition. After the reaction, 20ml of water was added at room temperature to quench the reaction. The organic phase was extracted with ethyl acetate (3×10 ml), washed with saturated brine and dried over anhydrous Na 2SO4. Filtration, concentration of the filtrate to dryness, column chromatography separation and purification (n-hexane/ea=5:1) gave benzyl (1- (cyanomethyl) cyclopropyl) methyl) (1-methylpiperidin-4-yl) carbamate 1.9g, yield 38.1%, yellow oil.
17.4 Preparation of benzyl [ [1- (2-aminoethyl) cyclopropyl ] methyl ] (1-methylpiperidin-4-yl) carbamate
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 a solution of 20.00ml of methanolic amine, hydrogen gas was introduced and stirred at room temperature. After the reaction is finished, filtering, washing a filter cake with methanol, concentrating the filtrate under reduced pressure, and directly carrying out the next reaction without purifying the obtained product.
17.5 Preparation of benzyl [ [1- [2- [ (4-isobutoxybenzyl) amino ] ethyl ] cyclopropyl ] methyl ] (1-methylpiperidin-4-yl) carbamate
Benzyl [ [1- (2-aminoethyl) cyclopropyl ] methyl ] (1-methylpiperidin-4-yl) carbamate (1.92 g, 5.560 mmol) and MgSO 4 (2.68 g,22.265 mmol) were added to 25.00ml ethanol and 4-isobutoxybenzaldehyde (1.09 g,6.116 mmol) was added portionwise under nitrogen. Cooled to 0 ℃, naBH 4 (0.53 g,14.009 mmol) was added and after the addition was completed, the reaction was allowed to proceed at room temperature. After completion of the reaction, the temperature was lowered to 0℃and the reaction was quenched by adding 20ml of water, extracted with ethyl acetate (3X 10 ml), and the organic phase was washed with saturated sodium chloride solution and dried over anhydrous Na 2SO4. Filtration and concentration of the filtrate under reduced pressure gave 1.4g of benzyl [ [1- [2- [ (4-isobutoxybenzyl) amino ] ethyl ] cyclopropyl ] methyl ] (1-methylpiperidin-4-yl) carbamate in 49.6% yield as a yellow oil.
Preparation of 6N- [ [1- [2- [ (4-isobutoxybenzyl) amino ] ethyl ] cyclopropyl ] methyl ] -1-methylpiperidin-4-amine
Benzyl [ [1- [2- [ (4-isobutoxybenzyl) amino ] ethyl ] cyclopropyl ] methyl ] (1-methylpiperidin-4-yl) carbamate (1.40 g,2.358 mmol) was added to 15.00ml of tetrahydrofuran, pd/C (200.00 mg,1.879 mmol) was added thereto in portions, and the reaction was put under a hydrogen atmosphere to react at room temperature. After the reaction, the mixture was filtered and the cake was washed with tetrahydrofuran. The filtrate is concentrated to dryness under reduced pressure, and the obtained product is directly subjected to the next reaction without purification.
17.7 Preparation of 7- (4-isobutoxybenzyl) -5- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.6] non-6-one
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 10.00ml tetrahydrofuran, cooled to-78℃under nitrogen, and triphosgene (0.21 g, 0.514 mmol) was slowly added. After the reaction was completed, 4ml of saturated NaHCO 3 solution was added at room temperature to quench the reaction. The aqueous phase was extracted with ethyl acetate (3 x10 ml), the organic phase was washed with saturated sodium chloride solution and dried over anhydrous Na 2SO4. Filtration, concentration of the filtrate under reduced pressure, purification by column chromatography (DCM: meoh=20:1) afforded 7- (4-isobutoxybenzyl) -5- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.6] non-6-one 0.12g, yield 17.4％.1H 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]+.
EXAMPLE 18.5- (4-isobutoxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.6] non-6-one (18)
The title compound was prepared as in example 17 by substituting 1-methylpiperidin-4-amine for (4-isobutoxyphenyl) methylamine and substituting 1-methyl-4-piperidone for 4-isobutoxybenzaldehyde, and the structural formula was shown in the number (18) of Table 1 .1H NMR(400MHz,DMSO-d6)δ7.24–7.18(m,2H),6.90–6.82(m,2H),4.20(s,2H),3.92(s,1H),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]+.
EXAMPLE 19.7- [ (dimethylamino) methyl ] -5- (4-isobutoxybenzyl) -5-azaspiro [2.5] octan-6-one (19) reaction scheme 4
19.1 Preparation of 5- [ [4- (2-methylpropyloxy) phenyl ] methyl ] -6-oxo-5-azaspiro [2.5] octane-7-carbaldehyde
5- [ [4- (2-Methylpropyloxy) phenyl ] methyl ] -5-azaspiro [2.5] octan-6-one (1.00 g,3.479 mmol) and LiHMDS (5.00 ml) were added to a 5.00ml tetrahydrofuran solution, and the mixture was cooled to-78℃under nitrogen protection, reacted for 1 hour, and DMF (508.65 mg,6.959 mmol) was slowly added dropwise to the reaction mixture, and reacted at-78℃for 1 hour. After the completion of the reaction, 10ml of water was added to quench the reaction, the reaction mixture was extracted with ethyl acetate (3X 10 ml), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to give 600mg of 5- [ [4- (2-methylpropyloxy) phenyl ] methyl ] -6-oxo-5-azaspiro [2.5] octane-7-carbaldehyde in a yield of 54.7%. A light brown oil.
19.2 Preparation of 7- (hydroxymethyl) -5- [ [4- (2-methylpropyloxy) phenyl ] methyl ] -5-azaspiro [2.5] octan-6-one
5- [ [4- (2-Methylpropyloxy) phenyl ] methyl ] -6-oxo-5-azaspiro [2.5] octane-7-carbaldehyde (600.00 mg,1.902 mmol) and 5.00mL methanol were added to a 25mL round-bottomed flask, nitrogen was purged, cooled to 0℃and NaBH 4 (215.91 mg,5.707 mmol) was added, and the mixture was allowed to react at room temperature for 30 minutes after the completion of the addition. After the completion of the reaction, 10ml of water was added to quench the reaction, the reaction mixture was extracted with ethyl acetate (3X 10 ml), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to give 600mg of 7- (hydroxymethyl) -5- [ [4- (2-methylpropyloxy) phenyl ] methyl ] -5-azaspiro [2.5] octan-6-one in a yield of 99.36%.
19.3 (5- [ [4- (2-Methylpropyloxy) phenyl ] methyl ] -6-oxo-5-azaspiro [2.5] oct-7-yl) methyl methanesulfonate
7- (Hydroxymethyl) -5- [ [4- (2-methylpropyloxy) phenyl ] methyl ] -5-azaspiro [2.5] octan-6-one (150.00 mg,0.473 mmol), 2.00mL tetrahydrofuran and triethylamine (95.64 mg,0.945 mmol) were added to an 8mL sealed tube, nitrogen was purged, cooled to 0℃and MsCl (81.20 mg, 0.09 mmol) was added, and the mixture was allowed to react at room temperature for 30 minutes after the completion of the addition. After the completion of the reaction, the reaction mixture was extracted with ethyl acetate (3X 10 ml), and the organic phase was dried over anhydrous sodium sulfate, and the dried filtrate was concentrated under reduced pressure. 110mg of (5- [ [4- (2-methylpropyloxy) phenyl ] methyl ] -6-oxo-5-azaspiro [2.5] oct-7-yl) methylsulfonate was obtained in a yield of 58.86% as a light brown oil.
19.4 Preparation of 7- [ (dimethylamino) methyl ] -5- [ [4- (2-methylpropyloxy) phenyl ] methyl ] -5-azaspiro [2.5] octan-6-one
(5- [ [4- (2-Methylpropyloxy) phenyl ] methyl ] -6-oxo-5-azaspiro [2.5] oct-7-yl) methyl methanesulfonate (110.00 mg, 0.276 mmol), dimethylamine hydrochloride (45.36 mg, 0.554 mmol) and DIEA (107.84 mg, 0.284 mmol) were added to 3.00ml of ethylene glycol, and the mixture was heated to 80℃for 3 hours. The organic phase was dried over anhydrous sodium sulfate, extracted with ethyl acetate (3×10 ml) and the filtrate concentrated under reduced pressure. Column chromatography separation and purification (DCM: meoh=20:1) afforded 7- [ (dimethylamino) methyl ] -5- [ [4- (2-methylpropyloxy) phenyl ] methyl ] -5-azaspiro [2.5] octane-6-one 37.7mg, yield 39.35％.1H NMR(400MHz,Methanol-d4)δ7.28–7.14(m,2H),6.94–6.82(m,2H),4.76(d,J＝14.4Hz,1H),4.32(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),3.10(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]+.
EXAMPLE 20.7- (dimethylamino) -5- (4-isobutoxybenzyl) -5-azaspiro [2.5] octane-6-one (20)
Reaction 5
Dimethylamine (21.82 mg, 0.284 mmol), DMF (5.00 mL) and DIEA (125.08 mg,0.968 mmol) were added to a 25mL round bottom flask, stirred for 0.5 h, 7-iodo-5- [ [4- (2-methylpropyloxy) phenyl ] methyl ] -5-azaspiro [2.5] octan-6-one (100.00 mg,0.242 mmol) was added, warmed to 60℃and reacted overnight. After the reaction was completed, ethyl acetate was extracted (2×20 ml), the organic phase was washed with water (2×20 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under pressure to dryness. Column chromatography purification (DCM: meoh=20:1) afforded 7- (dimethylamino) -5- (4-isobutoxybenzyl) -5-azaspiro [2.5] octane-6-one 63.6mg, yield 69.82％.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),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]+.
Example 21.7- (azetidin-1-yl) -5- (4-isobutoxybenzyl) -5-azaspiro [2.5] octan-6-one (21)
The target compound was prepared as in example 20 by substituting the reaction starting material dimethylamine with heteroalicyclic butane, and the structural formula is shown in the number (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]+.
EXAMPLE 22.1- (4-isobutoxybenzyl) -5-methyl-3- (1-methylpiperidin-4-yl) -5-phenyltetrahydropyrimidin-2 (1H) -one (22)
The title compound was prepared by the method of example 1 by substituting 3-ethoxy-2-methyl-3-oxo-2-phenylpropionic acid for 1- (methoxycarbonyl) cyclopropane-1-carboxylic acid as the reaction starting material, and the structural formula is shown in the number (22) in Table 1 .1HNMR(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＝12.1Hz,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]+.
Example 23.5,5-difluoro-1- (4-isobutoxybenzyl) -3- (1-methylpiperidin-4-yl) tetrahydropyrimidin-2 (1H) -one (23)
The title compound was prepared by the method of example 1 by substituting 3-ethoxy-2, 2-difluoro-3-oxopropanoic acid for 1- (methoxycarbonyl) cyclopropane-1-carboxylic acid, and the structural formula is shown in Table 1 under number (23) .1H 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]+.
Example 24.5,5-difluoro-1- (4-isobutoxybenzyl) -3- (1-methylpiperidin-4-yl) tetrahydropyrimidin-2 (1H) -one (24)
The title compound was prepared by the method of example 1 by substituting 3-ethoxy-2-methyl-3-oxopropionic acid for 1- (methoxycarbonyl) cyclopropane-1-carboxylic acid, and the structural formula is shown in Table 1 under number (24) .1H 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＝12.8Hz,2H),1.04(d,J＝6.7Hz,6H),0.99(d,J＝6.7Hz,3H).LCMS:(ES,m/z):374[M+H]+.
Example 25 5- (-isobutoxybenzyl) 7- (-methylpiperazin-1-yl) 5-azaspiro [2.5] octan-6-one (25)
The target compound was prepared as in example 20 by substituting N-methylpiperazine for dimethylamine as the reaction material, and the structural formula of the target compound was shown as the number (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＝14.6Hz,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),0.97(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]+.
EXAMPLE 26 5- (-isobutoxybenzyl) 7- (-methylpiperazin-1-yl) 5-azaspiro [2.5] octan-6-one (26)
The procedure of example 20 was followed except that 7-iodo-5- [ [4- (2-methylpropyloxy) phenyl ] methyl ] -5-azaspiro [2.5] octan-6-one as a reaction starting material was replaced with 7-iodo-5- (1-methylpiperidin-4-yl) -5-azaspiro [2.5] octan-6-one and dimethylamine was replaced with 4-isobutoxybenzaldehyde to prepare the target compound having the structural formula shown in the number (26) of 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]+.
EXAMPLE 27 5- [ (6-Isobutoxypyridin-3-yl) methyl ] -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octane-6-one (27)
The title compound was prepared by the method of example 1 by substituting 1- [4- (2-methylpropyloxy) phenyl ] methylamine with (6-isobutoxy pyridin-3-yl) methylamine, and the structural formula is shown in the number (27) in Table 1 .1HNMR(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]+.
Example 28 5- (2-fluoro-4-isobutoxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octane-6-one (28)
The title compound was prepared by the method of example 1 by substituting 1- [4- (2-methylpropyloxy) phenyl ] methylamine with (2-fluoro-4-isobutoxyphenyl) methylamine, and the structural formula is shown in the number (28) in Table 1 .1HNMR(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]+.
Example 29 5- (3-fluoro-4-isobutoxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one (29)
The title compound was prepared by the method of example 1 by substituting 1- [4- (2-methylpropyloxy) phenyl ] methylamine with (3-fluoro-4-isobutoxyphenyl) methylamine, and the structural formula is shown in the number (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),1.47–1.38(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]+.
Example 30 5- (4-isobutoxybenzyl) -7- (1-methylazo-4-yl) -5-7-diazaoxazol [2.5] octan-6-one (30)
The title compound was prepared as in example 1 by substituting 1-methylazepan-4-amine for 1-methyl-4-piperidylamine as the starting material and having the structural formula shown in Table 1 under the number (30) .1H-NMR(400MHz,Methanol-d4):δ7.17(d,J＝8.3Hz,2H),6.87(d,J＝8.2Hz,2H),4.52–4.40(m,3H),3.73(d,J＝6.4Hz,2H),3.58–3.42(m,2H),3.50(s,4H),3.25(dt,J＝14.5,11.0Hz,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]+.
Example 31- ((2R) -1, 2-dimethylpiperidin-4-yl) -7- (4-isobutoxybenzyl) -5, 7-diazaspiro [2.5] octane-6-one (31)
The title compound was prepared as in example 1 by substituting (2R) -1, 2-dimethylpiperidin-4-amine for 1-methyl-4-piperidinamine as the starting material, and the structural formula was shown as number (31) in Table 1 .1H 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]+.
Example 32 5- ((2S) -1, 2-dimethylpiperidin-4-yl) -7- (4-isobutoxybenzyl) -5, 7-diazaspiro [2.5] octan-6-one (32)
The title compound was prepared as in example 1 by substituting (2S) -1, 2-dimethylpiperidin-4-amine for 1-methyl-4-piperidinamine as the starting material, and the structural formula was shown as number (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]+.
Example 33 5- (2-chloro-4-isobutoxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one (33)
The title compound was prepared by substituting (2-chloro-4-isobutoxyphenyl) methylamine for 1- [4- (2-methylpropyloxy) phenyl ] methylamine as the reaction starting material according to the method of example 1 and having the structural formula shown in Table 1 under number (33) in .1HNMR(400MHz,Methanol-d4)δ7.21(d,J＝8.5Hz,1H),6.96(d,J＝2.4Hz,1H),6.88(dd,J＝8.6,2.5Hz,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] octane-6-one (34)
The title compound was prepared by the method of example 1 by substituting 1- [4- (2-methylpropyloxy) phenyl ] methylamine for 1- [3- (2-methylpropyloxy) phenyl ] methylamine, and the structural formula is shown in Table 1 as number (34) .1H 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]+.
Example 35 4- (4-isobutoxybenzyl) -6- (1-methylpiperidin-4-yl) -4, 6-diazaspiro [2.4] heptane-5-one (35)
The title compound was prepared as in example 1 by substituting 1- (methoxycarbonyl) cyclopropane-1-carboxylic acid with 1- [ (tert-butoxycarbonyl) amino ] cyclopropane-1-carboxylic acid, substituting 1- [4- (2-methylpropyloxy) phenyl ] methylamine with 1-methyl-4-piperidinamine, substituting 1-methyl-4-piperidinamine with 4- (2-methylpropyloxy) benzaldehyde, and the structural formula was shown in the number (35) in Table 1 .1H NMR(400MHz,Methanol-d4)δ7.10(d,J＝8.2Hz,2H),6.87(d,J＝8.2Hz,2H),6.33(s,1H),4.83(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]+.
Example 36 6- (4-isobutoxybenzyl) -4- (1-methylpiperidin-4-yl) -4, 6-diazaspiro [2.4] heptane-5-one (36)
The title compound was prepared as in example 1 by substituting 1- (methoxycarbonyl) cyclopropane-1-carboxylic acid with 1- [ (tert-butoxycarbonyl) amino ] cyclopropane-1-carboxylic acid and substituting 1-methyl-4-piperidylamine with 1-methylpiperidine-4-carbaldehyde as the reaction starting material, and the structural formula was shown as number (36) in Table 1 .1H 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),2.57–2.41(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]+.
Example 37 5- (1-ethylpiperidin-4-yl) -7- (4-isobutoxybenzyl) -5, 7-diazaspiro [2.5] octan-6-one (37)
The title compound was prepared as in example 1 by substituting 1-methyl-4-piperidylamine for 1-ethyl-4-piperidylamine, having the structural formula shown in Table 1 under number (37) .1H 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]+.
Example 38 5- (4-Isopentylbenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one (38)
The title compound was prepared as in example 1 by substituting 1- [4- (2-methylpropyloxy) phenyl ] methylamine with (4-isopentylphenyl) methylamine, and the structural formula is shown in Table 1 under number (38) .1H NMR(400MHz,Methanol-d4):δ7.16(s,4H),4.51(s,2H),4.49–4.41(m,1H),3.59(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]+.
Example 39 5- (4- (isobutylamino) benzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octane-6-one (39)
The title compound was prepared by substituting 4- (aminomethyl) -N-isobutylaniline for 1- [4- (2-methylpropyloxy) phenyl ] methylamine as the reaction starting material according to the method of example 1, having the structural formula shown in Table 1 under the number (39) in example .1H 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]+. - (4- (isobutylamino) benzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octane-6-one (40)
The title compound was prepared by the method of example 1 by substituting 1- [4- (2-methylpropyloxy) phenyl ] methylamine with [4- (methylisopropyloxy) phenyl ] methylamine, and the structural formula is shown in the number (40) in Table 1 .1HNMR(400MHz,Methanol-d4)δ7.32(d,J＝8.2Hz,2H),7.25(d,J＝8.0Hz,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]+.
Pharmacological examples:
In vitro receptor binding assay
1. Experimental method
1.1 Preparation of solutions required for experiments
A (for preparing 5-HT 2C receptor film) 50mM Tris-HCl buffer, 96.8g Tris was dissolved in double distilled water to a total volume of 4000ml, pH was adjusted to 7.5 with HCl, diluted to 16000mL, pH=7.4
B (for preparation of 5-HT 2A receptor film) 11.7mg EDTA,380.84mg MgCl 2 was weighed and added to 50mM Tris-HCl buffer in a total volume of 400mL, adjusting pH=7.4. The final concentrations were EDTA 0.1mM and MgCl 2 mM, respectively.
For preparing Dopamine acceptor membranes 2.978g HEPES,1.17g NaCl,0.119g MgCl 2, 36.5mg EDTA was weighed to a total volume of 250ml pure water and pH=7.4 was adjusted. The final concentrations were 50mM HEPES,50mM NaCl,5mM MgCl 2 and 0.5mM EDTA,pH 7.4, respectively.
1.2 Preparation of receptor membranes
1) Preparation of CHO-5-HT 2A receptor membranes
CHO-5-HT 2A cells were thawed naturally after removal from the-80℃refrigerator and centrifuged at 2000g at 4℃for 15 minutes. Taking the precipitate, and discarding the supernatant. Adding solution B into the sediment. The cells were mixed for 20-30 seconds and then centrifuged at 50000g,4℃for 25min. Carefully discarding the supernatant, adding the solution B again, mixing well, centrifuging at 4 ℃ for 25min and 50000 g. The precipitate was stored at-80 ℃.
2) Preparation of 5-HT 2C membranes
Taking out rat cortex at-80deg.C, naturally thawing, adding solution A, homogenizing for 4 times at 4 th gear for 3-4s, centrifuging at-80deg.C for 25min, discarding supernatant, adding solution A, mixing with vortex mixer, centrifuging at-00g for 25min at 4deg.C, repeating the centrifugation twice, discarding supernatant, and storing at-80deg.C.
3) Preparation of CHO-D 2 receptor membranes
Taking out cell CHO-D 2 by a refrigerator at-80 ℃, naturally thawing, centrifuging 2000g for 15min, adding homogenate C into the precipitate, uniformly mixing by a vortex mixer, centrifuging at 50000g for 25min at 4 ℃, discarding the supernatant, taking the precipitate, adding a buffer solution C again for washing, resuspending and centrifuging, after centrifuging, discarding the supernatant, and storing the precipitate at-80 ℃ for later use.
1.3 Receptor competitive binding assay
1) 5-HT 2A receptor competitive binding assay
The first step is to prepare a suspension of 10mg/mL membrane for later use by homogenate B for the prepared membrane.
In the second step, 100. Mu.L of the membrane preparation was added to each reaction tube.
In the third step, 100. Mu. L B solution was added to the total binding Tube (TB), METHYSERGIDE. Mu.L (final concentration 1.0X10 -5 M) was added to the non-specific binding tube (NB), and 100. Mu.L of the test compound was added to each test compound tube (CB).
In the fourth step, the radioligand 3 H-KETANSERIN. Mu.L was added to each reaction tube at a final concentration of 2.98nM.
And fifthly, incubating each reaction tube for 25min at 37 ℃, after the reaction is finished, quickly filtering the Whatman test paper GF/C plate by decompression, soaking the Whatman test paper GF/C plate for more than 1h in advance by using 0.5% PEI, drying a filter membrane at 60 ℃ after filtering, attaching a bottom membrane, adding 40 mu L of scintillation liquid, sealing the upper membrane, and standing.
And sixthly, putting the scintillation cup into a liquid scintillation counter for counting.
2) 5-HT 2C receptor competitive binding assay
The first step is to prepare a suspension of 210mg/mL membrane for later use by homogenate B for the prepared membrane.
In the second step, 100. Mu.L of the membrane preparation was added to each reaction tube.
In the third step, 100. Mu. L B solution was added to the total binding Tube (TB), KETANSERIN (final concentration 1.0X10 -5 M) was added to the nonspecific binding tube (NB) and 100. Mu.L of the test compound was added to each test compound tube (CB).
In the fourth step, the radioligand 3 H-Mesulergine. Mu.L was added to each reaction tube at a final concentration of 3nM.
And fifthly, incubating each reaction tube for 25min at 37 ℃, after the reaction is finished, rapidly filtering the combined ligand through decompression, saturating Whatman test paper GF/C by using 0.5% PEI solution 1h in advance, fully washing with ice-cold Tris buffer solution, taking out a filter disc, putting the filter disc into a 4mL scintillation cup, adding 1mL toluene scintillation liquid, and uniformly mixing.
And sixthly, putting the scintillation cup into a liquid scintillation counter for counting.
3) CHO-D 2 receptor competitive binding assay
The first step is to prepare 8mg/mL membrane suspension for later use by homogenate C.
In the second step, 100. Mu.L of the membrane preparation was added to each reaction tube.
In the third step, 100. Mu. L C of liquid was added to the total binding Tube (TB), 100. Mu. L Haloperidol (final concentration 1.0X10 -5 M) was added to the non-specific binding tube (NB), and 100. Mu.L of the test compound was added to each test compound binding tube (CB).
In the fourth step, the radioligand 3 H-Spiperone. Mu.L was added to each reaction tube at a final concentration of 1.176nM.
And fifthly, incubating each reaction tube for 25min at 37 ℃, after the reaction is finished, quickly filtering the Whatman test paper GF/B plate by decompression, soaking the Whatman test paper GF/B plate for more than 1h in advance by using 0.5% PEI, drying a filter membrane at 60 ℃ after filtering, attaching a bottom membrane, adding 40 mu L of scintillation liquid, sealing the upper membrane, and standing.
And sixthly, placing the filter plate into a liquid flash counter for counting.
2. Experimental results
Pimavanserin and 5-HT 2A、5-HT2C receptor Ki values were 0.036 and 2.94nM, respectively, and Compound 1 and 5-HT 2A、5-HT2C receptor Ki values were 0.0002 and 3.54nM, respectively, superior to pimavanserin. The details are given in the following table:
table 2 in vitro receptor binding Activity (Ki value, nM) of the compounds
Numbering of compounds 5-HT 2A (Ki value, nM) 5-HT 2C (Ki value, nM) 2C/2A
Pimavanserin 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
In vitro hERG assay
Cells were seeded onto slides with cell densities below 50% and cultured overnight. The experimental cells were transferred to a bath of about 1ml embedded in an inverted microscope platform, and the extracellular fluid was perfused at a perfusion rate of 2.7 ml/min. After 5 minutes of stabilization, the experiment was started. Membrane current was recorded using a HEKA EPC-10 patch clamp amplifier and PATCHMASTER acquisition system (HEKA Instruments inc. D-67466lambrecht, pfalz, germany). All experiments were completed at room temperature (22-24 ℃).
A P-97 microelectrode drawing instrument (Sutter Instrument Company, one DIGITAL DRIVE, novato, CA 94949) was used in the experiments to straighten the electrodes (BF 150-110-10). The inner diameter of the electrode is 1-1.5mm, and the water inlet resistance after being filled with the internal liquid is 2-4MΩ.
The electrophysiological stimulation scheme of hERG potassium channel is that first, the membrane voltage is clamped at-80 mV, the cell is stimulated for 2s, +20mV voltage, the hERG potassium channel is activated, and then repolarized to-50 mV for 5s, so as to generate outward tail current, and the stimulation frequency is once every 15 s. The current value is the peak value of the tail current.
The channel current was recorded using a whole cell recording mode in the experiment. Extracellular fluid (approximately 2 ml per minute) was first perfused and recorded continuously, and current stabilization was awaited (current decay (Run-Down) less than 5% in 5 minutes), at which point the tail current peak was the control current value. And then, the extracellular fluid containing the drug to be detected is perfused and continuously recorded until the inhibition effect of the drug on hERG current reaches a stable state, and at the moment, the tail current peak value is the current value after drug addition. The steady state criteria is determined by whether the nearest 3 consecutive current traces overlap. After reaching the steady state, if hERG current reverts to or approaches the magnitude prior to drug administration after rinsing with extracellular fluid perfusion, then perfusion testing may continue for other concentrations or drugs.
Experimental results
Pimaricin hERG assay IC 50 is 208nM, compound 1, compound 15, compound 24, compound 28, compound 31, compound 33 have less cardiotoxicity than pimaricin. The results are shown in the following table.
Table 3 in vitro hERG test results of compounds
Numbering of compounds hERG(nM)
Pimavanserin 208
1 2252
15 2045
24 3655
28 1298
31 1809
33 1235
Animal experiment
1. Test method
1.1 Experiment of influence on MPTP+MK-801 Parkinson's psychosis mouse model (anti-PDP drug efficacy model)
Animals received intraperitoneal injections at each morning to administer different doses of MPTP, and were continuously administered for 5 days, after the interval of 1.5h after the MPTP injection on the 5 th morning, pimaline or NS was intraperitoneally injected, after the interval of 0.5h, MK-801 was intraperitoneally injected for 0.3mg/kg (or NS), after the interval of 0.25h, the mice were placed in an autonomous incubator (a black polyethylene incubator with the specification of 29cm×29cm×30 cm) for video recording for 20min, and video analysis was performed after video recording was completed to evaluate the activity of the mice.
1.2 Influence on MPTP+APO-induced climbing behavior in Male mice (DA motor deterioration model)
Animals received intraperitoneal injections at each morning to administer different doses of MPTP for 5 days, after the injection of MPTP at 5 morning, pimapine, clozapine, quetiapine or NS were intraperitoneally injected at 1.5h intervals, 1mg/kg of APO (administration volume 0.1ml/10g body weight) was injected subcutaneously at 0.5h intervals, and immediately after the subcutaneous injection, the animals were placed in climbing cages (climbing cages made of stainless steel wire mesh with a diameter of about 0.1cm, semi-transparent polyethylene plates at the bottom, stainless steel cage covers) and the behaviors of 10-11,20-21,30-31 minutes after APO injection were observed and scored.
The scoring criteria were four feet scoring 0 on the floor, two front feet scoring 1 on the netpen, four feet scoring 2 on the netpen.
1.3 Study of sedative side Effect (anti-sedative model)
Qualified SPF grade C57BL/6j mice are randomly divided into 13 groups, 8 blank groups, pimavanserin 1, 3, 10 and 30mg/kg groups and compound 1:1, 3, 10 and 30mg/kg groups. Solutions with different concentrations are prepared according to different dosages of each group for intraperitoneal injection administration, and the final administration volume is 10ml/kg.
All groups were tested for autonomous activity 45min after administration of pimavanserin and the like, video recorded for 0-20min movement, and Top Scan3.00 software analyzed for 20min movement path. The inhibition rate of each group was calculated relative to the blank group after administration, and the sedation of the compound was comprehensively evaluated in combination with the statistical conclusion.
2. Test results
Experiments show that the drug effect, the sedative and exercise deterioration ED50 of pimavanserin PDP are respectively 0.37 mg/kg, 6.79 mg/kg, the sedative/PDP drug effect ratio is 18.35, the exercise deterioration/PDP drug effect ratio is >81.08, the PDP drug effect and sedative ED50 of the compound 1 are respectively 0.261 mg/kg and 21.34mg/kg, and the sedative/PDP drug effect ratio is 81.76. Compound 1 was found to have better efficacy and higher safety than pimavanserin.
TABLE 4 Table 4

Claims (14)

1. Compounds of formula I or a pharmaceutically acceptable salt:
wherein N7 is 0, 1 or 2;A is C, O or N;
n3, n6 are each independently selected from integers of 0, 1,2,3, and n3, n6 are not simultaneously 0;
n2 is 1;
W is O or S;
Y is C, N and Z, Q is N;
R 2 is selected from hydrogen, substituted or unsubstituted C 1-C5 linear or branched alkyl, substituted or unsubstituted C 3-C5 cycloalkyl, and the substituent is selected from methyl, ethyl, propyl, butyl, fluorine and C 3-C5 cycloalkyl;
R 3、R4 is independently selected from H, halogen, C 1-C5 straight or branched alkyl, phenyl, or R 3 and R 4 form C 3-C5 cycloalkyl;
r 5 is hydrogen or halogen;
r 1 is selected from the structures of formula II:
in the formula II, n4 is selected from integers of 1-4;
R 7 is selected from methyl, ethyl, isopropyl, isobutyl, benzyl, phenyl, halogenated C 1-5 linear or branched alkyl;
R 6 is halogen, methyl or hydrogen;
When R 3 and R 4 form a cycloalkyl group of C 3-C5, the structure is as in formula I-1:
Wherein n1 is an integer of 1,2 or 3.
2. The compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is of formula V:
When R 3 and R 4 form a cycloalkyl group of C 3-C5, the structure is as defined 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, wherein the compound of formula I is of formula VI:
When R 3 and R 4 form a cycloalkyl group of C 3-C5, the structure is as shown in formula VI-1:
wherein n1 is an integer of 1,2 or 3.
4. A compound of formula I according to claim 1 or 3, or a pharmaceutically acceptable salt thereof, wherein when R 1 is of formula II, the compound of formula I is 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, wherein when R 1 is of formula II, the compound is of formula V-2:
6. the compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein the halogen is fluorine, chlorine, bromine or iodine.
7. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein the C 1-C5 straight or branched alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, neopentyl, the unsubstituted C 3-C5 cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, the substituted C 3-C5 cycloalkyl is selected from methylcyclopropyl, ethylcyclopropyl, and the halo is selected from fluoro, chloro, bromo, iodo.
8. A compound of formula I according to claim 1, wherein n1, n4 are independently selected from integers of 1,2, 3;
R 2 is selected from hydrogen, methyl, isopropyl, isobutyl, cyclopropyl, cyclopropylmethyl, neopentyl;
R 5 is selected from hydrogen, fluorine, chlorine, bromine, iodine;
r 7 is selected from methyl, ethyl, isopropyl, isobutyl, phenyl, benzyl, difluoroethyl;
r 6 is selected from fluorine, chlorine, bromine, iodine, hydrogen, methyl.
9. A compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein,
R 1 is selected from the structures of formula II:
in the formula II, n4 is an integer of 1-4;
r 7 is selected from methyl, ethyl, isopropyl, isobutyl, phenyl, benzyl, difluoroethyl;
r 6 is selected from fluorine, chlorine, bromine, iodine, hydrogen, methyl.
10. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from any one of the following:
5- (4-isobutoxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octane-6-one, 5- (3-fluoro-1-methylpiperidin-4-yl) -7- (4-isobutoxybenzyl) -5, 7-diazaspiro [2.5] octane-6-one, 5- (4-isobutoxybenzyl) -7- (1-methylpyrrolidin-3-yl) -5, 7-diazaspiro [2.5] octane-6-one;
5- (4-methoxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octan-6-one;
5- (4- (cyclopropoxybenzyl) -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- (2, 2-difluoroethyl) piperidin-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] non-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] non-6-one;
5- (4-isobutoxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.6] non-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-diazaoxazol [2.5] octan-6-one;
5- ((2R) -1, 2-dimethylpiperidin-4-yl) -7- (4-isobutoxybenzyl) -5, 7-diazaspiro [2.5] octane-6-one, 5- ((2S) -1, 2-dimethylpiperidin-4-yl) -7- (4-isobutoxybenzyl) -5, 7-diazaspiro [2.5] octane-6-one, 5- (2-chloro-4-isobutoxybenzyl) -7- (1-methylpiperidin-4-yl) -5, 7-diazaspiro [2.5] octane-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] heptane-5-one;
6- (4-isobutoxybenzyl) -4- (1-methylpiperidin-4-yl) -4, 6-diazaspiro [2.4] heptane-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 comprising a 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, vehicle, or combination thereof.
12. Use of a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 11 in the manufacture of a medicament for the treatment of psychotic disorders.
13. The use according to claim 12, wherein the psychotic disorder is schizophrenia.
14. The use according to claim 12, wherein the psychotic disorder is parkinson's disease, dementia-related behavioral disorders and psychoses.
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