CN116554145A - Aralkyl-4- (1H) indolylpiperazine derivative, preparation method and application thereof - Google Patents

Aralkyl-4- (1H) indolylpiperazine derivative, preparation method and application thereof Download PDF

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CN116554145A
CN116554145A CN202210113063.2A CN202210113063A CN116554145A CN 116554145 A CN116554145 A CN 116554145A CN 202210113063 A CN202210113063 A CN 202210113063A CN 116554145 A CN116554145 A CN 116554145A
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alkyl
cyano
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hydrogen
halogen
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王冠
胡志京
杜新丽
葛玉强
李建其
马良
解鹏
万泽红
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Shanghai Pharmaceutical Industry Research Institute Co ltd
Nhwa Pharmaceutical Corp
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Abstract

The invention relates to an aralkyl-4- (1H) indolyl piperazine derivative, a preparation method and application thereof. In particular, the present invention relates toA compound shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound and application thereof in preparing medicines for preventing and/or treating central nervous system diseases related to mammal 5-hydroxytryptamine receptor and/or dopamine receptor.

Description

Aralkyl-4- (1H) indolylpiperazine derivative, preparation method and application thereof
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to an aralkyl-4- (1H) indolyl piperazine derivative, a preparation method and application thereof.
Background
Parkinson's Disease (PD) is a neurodegenerative disease of the nervous system characterized mainly by degeneration of the striatal pathway, and is characterized clinically by resting tremors, muscle rigidity, bradykinesia and dysgestion, and can be accompanied by non-motor symptoms such as depression, constipation and sleep disorders.
Parkinson's disease is the second most neurodegenerative disease in the world, which is secondary to Alzheimer's disease, and frequently occurs in the elderly, and the incidence rate of elderly people over 65 years old in China is 1.7% (Zhang Z X.the Lancet,2005,365 (9459):595-597.). According to incomplete statistics, the number of Chinese parkinsonism is about 270 ten thousand, and new patients are increased by 10 ten thousand year, so that the Chinese parkinsonism has become the first major parkinsonism (Pahwa R.American Journal of Managed Care,2010 (4): S94). Parkinson's disease is not only high in incidence, but also a lifelong disease, and no medicine capable of curing is available at present. With the development of the morbidity, patients gradually lose autonomous life and labor capacity, and complications such as sports injury and confusion are generated, so that the life quality is seriously affected. And patients need to take the medicine for a long time, which brings great economic burden to families.
Dopamine receptor agonists are important drugs for the clinical treatment of Parkinson's Disease (PD) and can directly stimulate postsynaptic dopamine in the striatumThe receptor acts, and because the receptor does not compete with amino acid in brain, metabolism does not generate free radical and has no oxidative stress reaction, and the receptor may have the functions of protecting and repairing nerves. The medicine can be independently used for treating patients with lighter PD symptoms, and can also be used in combination with compound levodopa, so that the dosage of the levodopa is reduced, and adverse reactions such as fluctuation of movement symptoms, movement disorder and the like are relieved (Guridi J.Parkinsons Dis,2012, 2012:1-15.). Dopamine receptor agonists are classified by pharmaceutical chemical structure into ergot bases (bromocriptine, pergolide, ergotoximide, etc.) and non-ergot bases (ropinirole, pramipexole, cabergoline, etc.). Because of the relatively serious toxic and side effects of the combination of the original ergot drugs and levodopa, the novel selective dopamine receptor agonists are rarely used and gradually replaced by the novel selective dopamine receptor agonists without ergot. Representative drugs include: bromocriptine, pergolide, ropinirole, pramipexole. Wherein pramipexole is dopamine D 2 、D 3 、D 4 Receptor agonist, ropinirole is dopamine D 2 、D 3 Receptor agonists.
Selective dopamine receptor agonists remain the key direction of Parkinson's drug research, with multiple drugs entering the clinical trial stage, such as CQA-206-291 in clinical phase III, a D developed by North America 2 Receptor agonists; aplindore fumarate, BAM-1110 and Mesdopetam in clinical phase II also act on different dopamine receptors.
5-HT 1A Receptors belong to the transmembrane or G-protein coupled receptor (GPCR) family, the first isolated and fully sequenced subtype of the serotonin receptor subtype, which is predominantly distributed in the central nervous system in the middle suture nucleus, hippocampus, amygdala and cortex, and can control memory, cognition and improve mood, etc.
5-HT in patients with Parkinson's Disease (PD) 1A The receptor is involved in levodopa-induced catabolism (levodopa induced dys-kinesia, LID) and is therefore of interest to researchers. It was found that presynaptic 5-HT on serotonergic fibers 1A Receptors may reduce abnormal dopamine release; postsynaptic membrane 5-HT 1A The receptor can reduce hyperactive cortical-striatal valleyAmino acid neurotransmission.
Studies have shown that: selective 5-HT 1A Receptor agonists are closely related to pharmacological actions such as dyskinesia, improving cognitive impairment, anxiolytic and depression. The new medicine ELtoprazine (etolazine) developed by Elto et al is an oral small molecule 5HT 1A / 1B Partial agonists, once qualified as FDA-issued orphan drugs, are used to treat Parkinson's Disease (PD) levodopa-induced dyskinesia (PD-LID), currently in phase 2b clinical trials. Currently, more than 680 subjects take Eltoprazine, which shows good efficacy and safety in the treatment of cognitive and motor disorders. (Cabedo N.journal of medicinal chemistry,2001,44 (11): 1794-1801.)
Befiradol as selective 5HT 1A Agonists were first used in clinical trials to treat anti-neuralgia and are now used to treat Parkinson's Disease (PD) levodopa-induced dyskinesia (PD-LID). The literature reports (nouridine El aoux. European Journal of Medicinal Chemistry,44 (11): 4616-4621.) that Befiradol exhibits novel therapeutic properties, has a remarkable anti-dyskinesia function without impairing the therapeutic properties of L-DOPA, and has an ameliorating effect on non-motor psychoemotional symptoms such as antidepressant, anxiolytic effect, etc.
5HT 1A The anti-PD therapeutic effect of the agonist is expected to solve the dyskinesia, emotion improvement, cognition restoration and the like of the Parkinson disease, and becomes a hot spot and a difficult point of global anti-PD drug development. With the deep research of PD pathogenesis and the rapid development of transformation medicine, the development of therapeutic drugs aiming at anti-PD etiology and clinical symptoms is increasingly accelerated.
In recent years, research finds that dopamine neurotransmitters and 5-hydroxytryptamine transmitters are involved in the regulation of the brain on the movement system, and that a synergistic effect on the movement regulation exists between the dopamine system and related receptors of the 5-hydroxytryptamine system, and related clinical experiments also prove that multi-target synergy has the advantage of treating PD. (Ricardo. Bioorganic & Medicinal Chemistry, 2003.)
Wherein Brilearoxazine was developed by Reviva pharmaceutical company and acts on dopamine D 2 、D 3 Receptors and 5-HT 1A Receptor multi-target partial agonists, developed clinically for indications including parkinson's disease, anti-schizophrenia, bipolar disorders, etc., are currently in phase I, II of clinical research. Brilearoxazine has an anti-parkinsonism effect by increasing the release of cortical dopamine. Meanwhile, the literature reports that Brilearoxazine has a remarkable improvement effect on the damage of new object identification induced by sub-chronic phencyclidine. These test results show that Brilearoxazine has significant therapeutic anti-Parkinson activity, and cognitive impairment improving and restoring effects. (Grundt P. Bioorganic)&Medicinal Chemistry Letters,2007,17(3):745-749.)
New anti-PD drug Bifeprinox in clinical stage III is 5-HT 1A Receptor agonists, D 2 Receptor partial agonists are shown in clinical trials to improve motor symptoms, alleviate mental symptoms such as depression, anxiety and the like. (Wang, Q.neuropharmacology,2019, 148:1-10.)
Pridopidine, a new anti-PD agent in clinical phase II, acts on D 2 、5-HT 1A Multiple receptor target drugs such as sigma-1 and the like show the characteristic of better improving dyskinesia in a non-human primate model, and have the functions of improving cognition and neuroprotection. (Chen X. Journal of Medicinal Chemistry,2012,55 (16): 7141-7153.)
Pardoplunox (SLV-308) is a D 2 /D 3 Partial agonists, 5-HT 1A A full agonist having anti-parkinsonism, antidepressant and anxiolytic effects. (Jones CA. Eur. Neuropyschopharmacol. 2010 Aug;20 (8): 582-93.) furthermore, it has a lower tendency to cause side effects such as dyskinesia than other dopaminergic drugs. Phase III clinical trials for the treatment of Parkinson's disease have been entered. (Glennon, J.C.Synapse 2006,60,599-608.)
In addition, patent WO2001049680A1 discloses a new class of indole derivatives, wherein the structure of compound (1 a) which is relatively similar to the compound of the present patent is as follows:
the compound has certain 5-HT 1A And D 4 Receptor affinity activity useful in the treatment of affective disorders such as depression, generalized anxiety disorder, panic disorder, obsessive compulsive disorder, social phobia, eating disorders and neurological disorders such as psychosis, which are associated with 5-HT 1A And D 4 Inhibitory Activity of receptor binding IC 50 The values were 12nm and 92nm, respectively.
A novel class of indole derivatives is disclosed in WO2003002552A1, wherein some of the compounds have valuable activity as serotonin reuptake inhibitors and antagonize 5-HT 1A Receptor action, some compounds also have D 3 And D 4 Affinity of the receptor. Wherein the structure of the compound (1 e) which is relatively similar to the compound of the patent is as follows:
the patent does not disclose any relevant activity data for the compound.
Patent WO2007026959A2 discloses a class of 4-piperazin-1-yl-4-benzo [ B ] thiophene derivatives, wherein the structure of a compound (example 40) similar to the structure of the present patent is as follows:
the biological activity of the compound is only shown to D 2 And 5-HT 2A Receptor affinity (receptor function is not disclosed, and may be agonism, antagonism or inverse agonism etc.), the receptor affinity Ki values are 3.1nm and 0.6nm respectively.
In summary, in view of dopamine D 2 、D 3 Receptors and/or 5-HT 1A The receptor has multi-target synergistic effect and has dopamine D 2 、D 3 Receptors and/or 5-HT 1A The receptor-active multi-target chemical small molecule is expected to overcome movement disorder, improve cognitive impairment, resist anxiety, depression and other mental moods while treating the main movement symptom of Parkinson The improvement aspect plays a new clinical treatment characteristic. In particular dopamine D 2 、D 3 And/or 5-HT 1A The multi-target (partial) agonist has become an important direction for developing novel medicines such as novel global anti-parkinsonism, anti-depression and anti-schizophrenia medicines in the aspects of research and application of medicines, and the research in the field has novel, creative and important scientific values.
Disclosure of Invention
The technical problem to be solved by the invention is to provide an aralkyl-4- (1H) indolyl piperazine derivative, a preparation method and application thereof, in particular to a preparation method and application thereof, which can effectively act on dopamine D 2 、D 3 Receptors and/or 5-HT 1A The receptor can improve PD movement symptoms, overcome movement disorder, improve cognitive impairment, and improve anxiety, depression, etc. to overcome the defects of the prior art.
The invention aims to provide a compound shown in a general formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof:
wherein:
m is selected from CR 0 Or N;
R 0 selected from hydrogen, deuterium, halogen, hydroxy, cyano, amino, and C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy, preferably halogen, cyano, C 1-6 Alkyl or C 1-6 Haloalkyl, more preferably halogen, cyano, C 1-3 Alkyl or C 1-3 Haloalkyl, further preferably cyano;
R 1 selected from halogen, hydroxy, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or- (CH) 2 ) n1 NR aa C(O)R bb Preferably halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl or- (CH) 2 ) n1 NR aa C(O)R bb More preferably halogen, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl or-NR aa C(O)R bb Further preferred are fluorine, chlorine, bromine, cyano, methyl, trifluoromethyl or-NHC (O) CH 3 ；
R aa And R is bb Each independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 Haloalkyl, preferably hydrogen or C 1-6 Alkyl, more preferably hydrogen or C 1-3 Alkyl, further preferably hydrogen or methyl;
R 2 selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, - (CH) 2 ) n2 C(O)R AA Or- (CH) 2 ) n2 S(O) 2 R AA Preferably hydrogen, C 1-6 Alkyl, - (CH) 2 ) n2 C(O)R AA Or- (CH) 2 ) n2 S(O) 2 R AA More preferably hydrogen, C 1-3 Alkyl, -C (O) R AA or-S (O) 2 R AA Further preferred are hydrogen, methyl, -C (O) CH 3 or-S (O) 2 -Ph；
R AA Selected from hydrogen, deuterium, halogen, hydroxy, cyano, amino, and C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, preferably C 1-6 Alkyl or C 6-10 Aryl, more preferably C 1-3 Alkyl or phenyl, further preferably methyl or phenyl;
R 3 each selected from hydrogen, deuterium, halogen, hydroxy, cyano, amino, and C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy, preferably hydrogen, halogen, cyano or C 1-6 Alkyl, more preferably hydrogen, halogen, cyano or C 1-3 Alkyl, further preferably hydrogen, fluorine, chlorine, bromine, cyano or methyl;
n is an integer of 0 to 3;
n1 is an integer of 0 to 2; and is also provided with
n2 is an integer of 0 to 2.
In a further preferred embodiment of the present invention, the general formula (I) is further represented by the general formula (II):
wherein:
M、R 1 、R 2 and R is 3 As described above.
In a further preferred embodiment of the present invention, the general formula (I) is further represented by the general formula (III):
wherein:
m is selected from CR 0 Or N;
R 0 selected from halogen, cyano, C 1-3 Alkyl or C 1-3 Haloalkyl, preferably cyano;
R 1 selected from halogen, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl or-NR aa C(O)R bb Preferably fluorine, chlorine, bromine, cyano, methyl, trifluoromethyl or-NHC (O) CH 3 ；
R aa And R is bb Each independently selected from hydrogen or C 1-3 Alkyl, preferably hydrogen or methyl;
R 2 selected from hydrogen, C 1-3 Alkyl, -C (O) R AA or-S (O) 2 R AA Preferably hydrogen, methyl, -C (O) CH 3 or-S (O) 2 -Ph；
R AA Selected from C 1-3 Alkyl or phenyl, preferably methyl or phenyl.
In a further preferred embodiment of the present invention, formula (I) is further represented by formula (IV):
wherein:
m is selected from CR 0 Or N;
R 0 selected from halogen, cyano, C 1-3 Alkyl or C 1-3 Haloalkyl, preferably cyano;
R 1 selected from halogen, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl or-NR aa C(O)R bb Preferably fluorine, chlorine, bromine, cyano, methyl, trifluoromethyl or-NHC (O) CH 3 ；
R aa And R is bb Each independently selected from hydrogen or C 1-3 Alkyl, preferably hydrogen or methyl;
R 2 selected from hydrogen, C 1-3 Alkyl, -C (O) R AA or-S (O) 2 R AA Preferably hydrogen, methyl, -C (O) CH 3 or-S (O) 2 -Ph；
R AA Selected from C 1-3 Alkyl or phenyl, preferably methyl or phenyl.
In a further preferred embodiment of the invention, the general formula (I) is further selected from the following compounds:
in a further preferred embodiment of the present invention, the above-mentioned pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, hydrobromide, sulfate, trifluoroacetate or mesylate, preferably hydrochloride, hydrobromide.
The present invention further provides a process for preparing a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, comprising the steps of:
the compound shown in the general formula (I-1) reacts with the compound shown in the general formula (I-2) to generate a compound shown in the general formula (I-3), and then the compound shown in the general formula (I-4) is subjected to condensation reaction to prepare the compound shown in the general formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof;
Or alternatively, the process may be performed,
the compound shown in the general formula (I-1) and the compound shown in the general formula (I-5) are directly reacted to prepare the compound shown in the general formula (I), the stereoisomer or the pharmaceutically acceptable salt thereof;
wherein:
X 1 and X 2 Is halogen, each independently selected from fluorine, chlorine, bromine or iodine.
M、R 1 、R 2 、R 3 And n is as described above.
The present invention further provides a process for preparing a compound of formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, comprising the steps of:
the compound shown in the general formula (I-1) reacts with the compound shown in the general formula (II-2) to generate a compound shown in the general formula (II-3), and then the compound shown in the general formula (I-4) is subjected to condensation reaction to prepare the compound shown in the general formula (II), a stereoisomer or a pharmaceutically acceptable salt thereof;
or alternatively, the process may be performed,
the compound shown in the general formula (I-1) and the compound shown in the general formula (II-5) are directly reacted to prepare the compound shown in the general formula (II), the stereoisomer or the pharmaceutically acceptable salt thereof;
wherein:
X 3 and X 4 Is halogen, each independently selected from fluorine, chlorine, bromine or iodine.
M、R 1 、R 2 And R is 3 As described above.
The present invention further provides a process for preparing a compound of formula (III), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, comprising the steps of:
The compound shown in the general formula (III-1) reacts with the compound shown in the general formula (II-2) to generate a compound shown in the general formula (III-3), and then the compound shown in the general formula (I-4) is subjected to condensation reaction to prepare the compound shown in the general formula (III), a stereoisomer or a pharmaceutically acceptable salt thereof;
or alternatively, the process may be performed,
the compound shown in the general formula (III-1) and the compound shown in the general formula (II-5) are directly reacted to prepare the compound shown in the general formula (III), the stereoisomer or the pharmaceutically acceptable salt thereof;
wherein:
X 3 and X 4 Is halogen, each independently selected from fluorine, chlorine, bromine or iodine.
M、R 1 And R is 2 As described above.
The present invention further provides a process for preparing a compound of formula (IV), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, comprising the steps of:
the compound shown in the general formula (IV-1) reacts with the compound shown in the general formula (II-2) to generate a compound shown in the general formula (IV-3), and then the compound shown in the general formula (I-4) is subjected to condensation reaction to prepare the compound shown in the general formula (IV), a stereoisomer or a pharmaceutically acceptable salt thereof;
or alternatively, the process may be performed,
the compound shown in the general formula (IV-1) and the compound shown in the general formula (II-5) are directly reacted to prepare the compound shown in the general formula (IV), the stereoisomer or the pharmaceutically acceptable salt thereof;
Wherein:
X 3 and X 4 Is halogen, each independently selected from fluorine, chlorine, bromine or iodine.
M、R 1 And R is 2 As described above.
In the above synthetic routes, all the starting compounds involved are commercially available, and most of the key intermediates are commercially available, and some of the intermediates are prepared by the methods reported in the references (Zhou N.bioorg Med Chem Lett.2009 Mar1;19 (5): 1528-31.) (Kumar, A.S.J Chem Sci.2018,130, 72.) (Gu ZS.bioorg Med Chem Lett.2017 Dec 15;27 (24): 5420-5423.) by two synthetic routes:
route one:
route two:
wherein:
X 5 and X 6 Is halogen, each independently selected from fluorine, chlorine, bromine or iodine.
M、R 1 、R 2 、R 3 And n is as described above.
The invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of any of the compounds shown, stereoisomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers.
In one embodiment of the invention, the pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. The carrier refers to a carrier conventional in the pharmaceutical field, for example: diluents, excipients such as water, and the like; binders such as cellulose derivatives, gelatin, polyvinylpyrrolidone, and the like; fillers such as starch and the like; disintegrating agents such as calcium carbonate, sodium bicarbonate; lubricants such as calcium stearate or magnesium stearate, and the like. In addition, other adjuvants such as flavoring agents and sweeteners may be added to the composition. For oral administration, it can be prepared into conventional solid preparations such as tablet, powder, lozenge, capsule, suspension, syrup, etc.; when used for injection, the composition can be prepared into injection.
In one embodiment of the present invention, various dosage forms of the pharmaceutical composition may be prepared by methods conventional in the medical field, wherein the content of the active ingredient is 0.1% to 99.5% by weight.
In one embodiment of the invention, the pharmaceutical composition is administered orally, by injection, etc., to a patient in need of such treatment. The administration dose is usually 0.02-5 mg/kg (oral administration) or 0.01-2 mg/kg (injection), and can be determined by a doctor according to the clinical test result and the illness state, age and the like of the patient.
The invention further relates to the use of any of the compounds shown, stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for the preparation of a medicament involving or modulating 5-hydroxytryptamine receptors and/or dopamine receptorsPreferably in the preparation of a polypeptide involved in or modulating 5-HT 1A Receptors, dopamine D 2 Receptors and/or dopamine D 3 Use of a receptor drug.
The invention further relates to the use of any of the compounds, stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for the manufacture of a medicament for the treatment of a central nervous system disorder.
The invention further relates to a method for preparing a medicament for treating central nervous system diseases by using any of the compounds, stereoisomers or pharmaceutically acceptable salts thereof or a pharmaceutical composition thereof.
The invention also relates to a method of treating a central nervous system disorder related to a mammalian 5-hydroxytryptamine receptor and/or a dopamine receptor comprising administering to said mammal a therapeutically effective dose of any of the compounds shown, stereoisomers thereof, or pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates or derivatives thereof, or a pharmaceutical composition thereof.
In some embodiments, the central nervous system disorder to which the present invention relates is selected from one or more of parkinson's disease PD, schizophrenia, bipolar disorder, depression, anxiety, mania, huntington's disease HD, alzheimer's disease, senile dementia, dementia of the alzheimer's type, memory impairment, executive function loss, vascular dementia, neuropathic pain and dysfunctional disorders associated with intelligence, learning or memory, preferably parkinson's disease.
In some preferred embodiments, the central nervous system disorder to which the present invention relates is parkinson's disease.
Detailed description of the invention
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. If there is a conflict, the present application provides definitions. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof. All patents, published patent applications, and publications cited herein are incorporated by reference.
The term "hydrocarbon chain" refers to a chain-like group consisting of C and H. The hydrocarbon chain may be saturated or unsaturated, and in a preferred embodiment, the hydrocarbon chain is saturated. The hydrocarbon chain may be linear or branched, and in preferred embodiments, the hydrocarbon chain is linear. The hydrocarbon chain may optionally contain one or more heteroatoms such as N, O and S. In the case of containing a heteroatom, the heteroatom may be located in the backbone. In preferred embodiments, the hydrocarbon chain may be linear or branched and saturated, optionally containing one or more heteroatoms such as N, O and S in the backbone. When describing hydrocarbon chains, whether or not containing heteroatoms, the number of C atoms may be used to describe, and not counting, the number of heteroatoms. For example, C 2 -C 8 Or C 2 -C 6 The hydrocarbon chain referred to comprises a hydrocarbon chain of 2 to 8 or 2 to 6 carbon atoms, which may optionally comprise additional heteroatoms.
The term "alkyl" refers to a straight or branched saturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms, which is attached to the remainder of the molecule by a single bond. "alkyl" may have 1 to 8 carbon atoms, i.e. "C 1 -C 8 Alkyl ", e.g. C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl, C 3 Alkyl, C 4 Alkyl, C 1-6 Alkyl, C 3-6 An alkyl group. Non-limiting examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 2, 3-dimethylbutyl, 1, 3-dimethylbutyl, or 1, 2-dimethylbutyl, and the like, or isomers thereof.
The above alkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents may be substituted at any useful point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxy, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclyl, aryl or heteroaryl.
The term "subunit" refers to a group obtained by removing one more hydrogen atom from a carbon atom containing a free valence electron, and having two attachment sites for attachment to other parts of the molecule. For example, "alkylene" or "alkylsulfinyl" refers to a saturated straight or branched divalent hydrocarbon radical.
The term "alkylene" as used herein, alone or in combination with other groups, refers to a straight or branched chain saturated divalent hydrocarbon group. For example, the term "C 1-8 Alkylene "means an alkylene group having 1 to 8 carbon atoms, such as methylene, ethylene, propylene, butylene, pentylene, hexylene, 1-methylethylene, 2-methylethylene, methylpropylene, ethylpropylene, or the like. The alkylene group may be optionally substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxy, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclyl, aryl or heteroaryl.
The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl containing 3 to 20 carbon atoms, i.e. "C 3 -C 20 Cycloalkyl ", e.g. C 3-18 Cycloalkyl, C 3-16 Cycloalkyl, C 3-12 Cycloalkyl, C 3-8 Cycloalkyl, C 3-6 Cycloalkyl, C 3-5 Cycloalkyl, C 3-4 Cycloalkyl, C 4-8 Cycloalkyl, C 4-6 Cycloalkyl, C 5-6 Cycloalkyl, preferably C 3-8 Cycloalkyl, C 3-6 Cycloalkyl, C 3-5 Cycloalkyl, C 3-4 Cycloalkyl groups. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the likeThe method comprises the steps of carrying out a first treatment on the surface of the Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
The cycloalkyl groups described above may each be fused to an aryl, heteroaryl or heterocycloalkyl ring, where the ring attached to the parent structure is cycloalkyl. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents may be substituted at any useful point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxy, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclyl, aryl or heteroaryl.
The term "heterocyclyl" refers to a saturated or unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms in which one or more ring atoms are selected from nitrogen, oxygen or S (O) m (wherein m is an integer of 0 to 2), but does not include-O-; a ring moiety of O-S-or-S-S-, the remaining ring atoms are carbon. That is, "3 to 20 membered heterocyclic group", for example, 3 to 18 membered heterocyclic group, 3 to 16 membered heterocyclic group, 3 to 12 membered heterocyclic group, 3 to 8 membered heterocyclic group, 3 to 6 membered heterocyclic group, 3 to 5 membered heterocyclic group, 3 to 4 membered heterocyclic group, 4 to 8 membered heterocyclic group, 4 to 6 membered heterocyclic group, 5 to 6 membered heterocyclic group, preferably 3 to 8 membered heterocyclic group, 3 to 6 membered heterocyclic group, 3 to 5 membered heterocyclic group, 3 to 4 membered heterocyclic group, 4 to 8 membered heterocyclic group, 4 to 6 membered heterocyclic group, 5 to 6 membered heterocyclic group optionally containing 1 to 4 hetero atoms, 1 to 3 hetero atoms or 1 to 2 hetero atoms wherein the hetero atoms are optionally nitrogen, oxygen or S (O) m (wherein m is an integer of 0 to 2). Non-limiting examples of monocyclic heterocyclyl groups include oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, piperidinyl, piperazinyl, morpholinyl, 1, 3-dioxacyclopentyl, 2-difluoro-1, 3-dioxacyclopentyl, azepinyl, and the like. Non-limiting examples of polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups, where the spiro, fused and bridged heterocyclic groups involved are optionally linked to other groups by single bonds, or to other cycloalkyl groups by any two or more atoms on the ringThe heterocyclic, aryl and heteroaryl groups are further joined in a ring.
The heterocyclic groups described above may each be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclic group. The heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxy, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclic, aryl or heteroaryl.
The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic group having a conjugated pi-electron system, preferably 6 to 12 membered, e.g., phenyl or naphthyl, more preferably phenyl.
The aryl groups described above may be fused to heteroaryl, heterocyclyl or cycloalkyl rings wherein the ring attached to the parent structure is an aryl ring, including benzo 5-10 membered heteroaryl, benzo 3-8 membered cycloalkyl and benzo 3-8 membered heterocyclyl, preferably benzo 5-6 membered heteroaryl, benzo 3-6 membered cycloalkyl and benzo 3-6 membered heterocyclyl. Aryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents may be substituted at any useful point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxy, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclyl, aryl or heteroaryl.
The term "heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, nitrogen, and the like. Heteroaryl groups are preferably 5 to 12 membered, more preferably 5 to 6 membered, such as pyrrolyl, imidazolyl, furanyl, pyranyl, thienyl, thiazolyl, thiadiazolyl, pyrazolyl, oxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, and the like.
The heteroaryl groups described above may be fused to an aryl, cycloalkyl or heterocyclyl ring, wherein the ring attached to the parent structure is a heteroaryl ring. Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents may be substituted at any useful point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxy, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclyl, aryl or heteroaryl.
The term "alkoxy" refers to-O- (alkyl) or-O- (unsubstituted cycloalkyl), wherein alkyl, cycloalkyl are as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, and the like. The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxy, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclyl, aryl or heteroaryl.
The term "alkylthio" refers to-S- (alkyl) or-S- (unsubstituted cycloalkyl), wherein alkyl, cycloalkyl are as defined above. Non-limiting examples of alkylthio groups include: methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio and the like. Alkylthio groups may be optionally substituted or unsubstituted, and when substituted, the substituents may be substituted at any useful point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxy, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclyl, aryl or heteroaryl.
The term "alkylamino" refers to-NH- (alkyl or unsubstituted cycloalkyl), or-N- (alkyl or unsubstituted cycloalkyl), wherein alkyl, cycloalkyl are as defined above. Non-limiting examples of alkylamino groups include: methylamino, ethylamino, propylamino, butylamino, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, and the like. The alkylamino group may be optionally substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxy, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclyl, aryl or heteroaryl.
The term "halogen" or "halo" is understood to mean a fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atom, preferably a fluorine, chlorine, bromine atom.
The term "deuterated hydrocarbon chain" refers to a hydrocarbon chain substituted with one or more deuterium wherein the hydrocarbon chain is as defined above.
The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium, wherein alkyl is as defined above.
The term "halocarbon chain" refers to a hydrocarbon chain substituted with one or more halogens, wherein the hydrocarbon chain is as defined above.
The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.
The term "alkenyl" refers to alkenyl groups, also known as alkenyl groups, wherein the alkene may be further substituted with other related groups.
The term "alkynyl" refers to (ch≡c-), wherein said alkynyl may be further substituted with other related groups.
"hydroxy" refers to-OH.
"amino" means-NH 2 。
"cyano" refers to-CN.
"nitro" means-NO 2 。
"mercapto" refers to-SH.
"carbonyl" means-C (O) -.
"carboxy" means-C (O) OH.
"oxo" refers to = O.
The terms "comprising," "including," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps. Those skilled in the art will appreciate that such terms as "comprising" encompass the meaning of "consisting of …".
The term "one or more" or similar expression "at least one" may denote, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more.
When lower and upper limits of a range of values are disclosed, any number and any range encompassed within the range are specifically disclosed. In particular, each numerical range of values disclosed herein is to be understood as meaning every number and range that is encompassed within the broader range.
Herein, "Z" and "-Z-" are both denoted as the same particular group, which may be used interchangeably.
The expression m-n as used herein refers to the range of m to n and the sub-ranges consisting of the individual point values therein as well as the individual point values. For example, the expression "C 2 -C 8 "OR" C 2-8 "ranges from 2 to 8 carbon atoms are intended to encompass any subrange therein as well as every point value, e.g., C 2 -C 5 、C 3 -C 4 、C 2 -C 6 、C 3 -C 6 、C 4 -C 6 、C 4 -C 7 、C 4 -C 8 、C 2 -C 5 Etc. and C 2 、C 3 、C 4 、C 5 、C 6 、C 7 、C 8 Etc. For example, the expression "C 3 -C 10 "OR" C 3-10 "also should be understood in a similar manner, for example, any subrange and point value contained therein, e.g., C 3 -C 9 、C 6 -C 9 、C 6 -C 8 、C 6 -C 7 、C 7 -C 10 、C 7 -C 9 、C 7 -C 8 、C 8 -C 9 Etc. and C 3 、C 4 、C 5 、C 6 、C 7 、C 8 、C 9 、C 10 Etc. Also for example, the expression "C 1 -C 6 "OR" C 1-6 "ranges from 1 to 6 carbon atoms are to be understood as also covering any subrange therein as well as every point value, e.g. C 2 -C 5 、C 3 -C 4 、C 1 -C 2 、C 1 -C 3 、C 1 -C 4 、C 1 -C 5 、C 1 -C 6 Etc. and C 1 、C 2 、C 3 、C 4 、C 5 、C 6 Etc. Also for example, the expression "ternary to tenth member" is understood to encompass any subrange therein as well as every point value, e.g., ternary to penta, ternary to hexa, ternary to hepta, ternary to octa, quaternary to penta, quaternary to hexa, quaternary to hepta, quaternary to octa, penta to hepta, penta to octa, hexa to hepta, hexa to octa, nona to deca, etc., as well as three, four, five, six, seven, eight, nine, deca, etc. Other similar expressions herein should be understood in a similar manner.
The expressions "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C", and the like, as used herein, all express the same meaning, that is, X may be any one or several of A, B, C.
The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, "cycloalkyl optionally substituted with alkyl" means that alkyl may be, but is not necessarily, present, and the description includes both cases where cycloalkyl is substituted with alkyl and cases where cycloalkyl is not substituted with alkyl.
The terms "substituted" and "substituted" refer to the replacement of one or more (e.g., one, two, three, or four) hydrogens on the designated atom with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution forms a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. When it is described that a substituent is absent, it is understood that the substituent may be one or more hydrogen atoms, provided that the structure is such that the compound is stable. When it is described that each carbon atom in a group can optionally be replaced by a heteroatom, provided that the normal valency of all atoms in the group in the current case is not exceeded, and stable compounds are formed.
If a substituent is described as "optionally … substituted," the substituent may be unsubstituted or may be substituted. If an atom or group is described as being optionally substituted with one or more of the list of substituents, then one or more hydrogens on that atom or group may be replaced with an independently selected, optional substituent. When the substituent is oxo (i.e., =o), it means that two hydrogen atoms are replaced. As used herein, unless indicated, the point of attachment of a substituent may be from any suitable position of the substituent.
When the bond of a substituent is shown as a bond through the ring connecting two atoms, then such substituent may be bonded to any ring-forming atom in the substitutable ring.
When any variable (e.g., R), and the variable with a label (e.g., R 0 、R 1 、R 2 、R 3 、R AA 、R aa 、R bb Etc.) are independent in each case when they occur more than once in the composition or structure of the compound. For example, if a group is substituted with 0, 1, 2, 3 or 4R substituents, the group may optionally be substituted with up to four R substituents, and the options for each R substituent in each case are independent of each other.
The term "substituted" means that one or more hydrogen atoms on a compound or group is replaced by another atom or group. Provided that stable valence states or compounds are formed. The expression "unsubstituted" is understood to mean "unsubstituted". It will be appreciated that where the substituent is hydrogen, this may also mean that the corresponding group is "unsubstituted" or "unsubstituted".
The compounds of the invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of the present invention. In certain embodiments, preferred compounds are those isomeric compounds that exhibit more biological activity. Purified or partially purified isomers and stereoisomers, or racemic or diastereomeric mixtures of the compounds of the invention are also included within the scope of the invention. Purification and isolation of such materials can be accomplished by standard techniques known in the art.
The hydrogen atoms of the invention can be replaced by the isotope deuterium, the content of the deuterium isotope is at least larger than that of natural deuterium isotope, and any hydrogen atom in the compound of the embodiment of the invention can be replaced by deuterium atoms.
The term "pharmaceutically acceptable" refers to substances which, within the scope of normal medical judgment, are suitable for use in contact with the tissues of a patient without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit-to-benefit ratio, and effective for their intended use.
The term "pharmaceutically acceptable salts" refers to salts of the compounds of the present invention which are safe and effective when used in a mammal, and which possess the desired biological activity.
The term "pharmaceutical composition" refers to a mixture comprising one or more compounds of the present invention or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as a physiologically/pharmaceutically acceptable carrier or excipient. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.
The term "pharmaceutically acceptable carrier" refers to those substances which have no significant irritating effect on the organism and which do not impair the biological activity and properties of the active compound. "pharmaceutically acceptable carrier" includes, but is not limited to, glidants, sweeteners, diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersing agents, disintegrants, stabilizers, solvents or emulsifiers.
The terms "administration" or "administering" and the like refer to a method that may enable delivery of a compound or composition to a desired biological site of action. These methods include, but are not limited to, oral or parenteral (including intraventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), topical, rectal administration, and the like. In particular for injection or oral administration.
As used herein, the term "treating" includes alleviating, alleviating or ameliorating a disease or symptom, preventing other symptoms, ameliorating or preventing underlying metabolic factors of a symptom, inhibiting a disease or symptom, e.g., preventing the development of a disease or symptom, alleviating a disease or symptom, promoting alleviation of a disease or symptom, or halting signs of a disease or symptom, and extends to including prevention. "treating" also includes achieving therapeutic benefit and/or prophylactic benefit. Therapeutic benefit refers to eradication or amelioration of the condition being treated. In addition, therapeutic benefit is achieved by eradicating or ameliorating one or more physiological symptoms associated with the underlying disease, although the patient may still have the underlying disease, an amelioration of the patient's disease may be observed. Prophylactic benefit means that the patient is using the composition to prevent a risk of a disease, or is taking the patient when one or more physiological conditions of the disease are present, although the disease has not yet been diagnosed.
The term "active ingredient", "therapeutic agent", "active substance" or "active agent" refers to a chemical entity that is effective in treating or preventing a disorder, disease or condition of interest. The term "neuropsychiatric disorders" refers to the collective term of neurological disorders and psychiatric disorders, including neurological disorders and/or psychiatric disorders.
The term "effective amount", "therapeutically effective amount" or "prophylactically effective amount" with respect to a drug, drug unit or active ingredient refers to a sufficient amount of a drug or agent that is acceptable for side effects but achieves the intended effect. Determination of an effective amount varies from person to person, depending on the age and general condition of the individual, and also on the particular active substance, a suitable effective amount in an individual can be determined by one skilled in the art from routine experimentation.
As used herein, "individual" includes human or non-human animals. Exemplary human individuals include human individuals (referred to as patients) or normal individuals suffering from a disease (e.g., a disease described herein). "non-human animals" in the context of the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).
The following detailed description is intended to illustrate non-limiting embodiments so that others skilled in the art may more fully understand the invention's solution, its principles and its practical application, to thereby modify and practice the invention in many forms best suited to the requirements of a particular use.
Advantageous effects
The compound has novel structure and can act on 5-HT 1A Receptors, dopamine D 2 Receptors and/or dopamine D 3 Receptors and exhibit a certain (partial) agonistic activity. Some compounds exhibit 5-HT response 1A Receptors, dopamine D 2 And D 3 At least two of the receptors have (partial) agonism and, in particular, some compounds have also been shown to be 5-HT 1A Receptors, dopamine D 2 And D 3 The triple (partial) agonistic activity of the receptor suggests that the receptor has remarkable curative effect on central nervous system disorder diseases such as Parkinson and can be used for preparing medicines for treating central nervous system disorder diseases.
Detailed Description
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. Further, it is understood that various changes and modifications may be made by those skilled in the art after reading the teachings of the present invention, and such equivalents are intended to fall within the scope of the claims appended hereto.
Examples
Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only for illustrating the present invention and should not be construed as limiting the scope of the present invention. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention. The proportions or percentages used herein are by weight unless otherwise indicated.
The structure of the compounds of the present invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS).
Nuclear magnetic resonance spectroscopy was performed using a Unity Inova 400 or 600 nmr, chemical shifts (δ) given in parts per million (ppm), and the determination solvent was deuterated dimethyl sulfoxide (DMSO-d) 6 ) And heavy water (D) 2 O), internal standard Tetramethylsilane (TMS); the liquid chromatography is measured by an Agilent 1946B ESI-MS mass spectrometer; the high-efficiency thin-layer chromatography silica gel plate is manufactured by Shanghai Haohong biological medicine technology Co., ltd, the product number is C10008, and the specification adopted by TLC is 2.5X5cm 0.25mm.
Synthetic method of examples 1-12:
4- (piperazin-1-yl) -1H-indole compound (6.46 mmol) was dissolved in acetone (20 mL), potassium carbonate (12.92 mmol), 1-bromo-2-chloroethane (or 1-bromo-3-chloropropane) (12.92 mmol) was added and reacted at 60℃for 8H, TLC monitored complete aryl piperazine compound conversion or no reduction of starting material with increasing reaction time, the reaction was stopped, and the remaining potassium carbonate was removed by filtration. The filtrate was distilled off to remove the solvent, water (15 mL) was added, extracted with dichloromethane (30 mL x 3), and the organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=3:1) to give the chloroalkyl 4- (piperazin-1-yl) -1H-indole compound.
Substituted chloroalkyl 4- (piperazin-1-yl) -1H-indole compound (1.80 mmol,1.0 eq), substituted pyridinol (2.16 mmol,1.0 eq), potassium carbonate (4.50 mmol,2.5-3.0 eq), potassium iodide (1.80 mmol,1.0 eq) were dissolved in acetonitrile (15 mL). Heating and refluxing, and stirring and reacting for 5-12h at 85 ℃. TLC monitored the reaction was complete and heating was stopped. Removing insoluble salt by suction filtration after cooling, and removing the solvent by reduced pressure distillation. Water (10 mL) was added, the mixture was extracted with dichloromethane (20 mL. Times.3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. Separating and purifying by silica gel column chromatography (dichloromethane: methanol=50:1) to obtain aralkyl-4- (1H) indolyl piperazine compound, dissolving in ethyl acetate (10 mL), and dropwise adding ethyl acetate hydrochloride (2N) to obtain aralkyl-4- (1H) indolyl piperazine hydrochloride with a yield of 30-80%.
Example 1
Preparation of 4- (4- (3- ((6-fluoropyridin-3-yl) oxy) propyl) piperazin-1-yl) -1H-indole hydrochloride
0.39g (3.40 mmol,1.2 eq) of 2-fluoro-5-hydroxypyridine, 0.78g (2.8 mmol,1.0 eq) of 4- (4- (3-chloropropyl) piperazin-1-yl) -1H-indole, K 2 CO 3 1.2g (8.4 mmol,3 eq) of potassium iodide 0.47g (2.80 mmol,1.0 eq) are dissolved in 20mL of acetonitrile and the reaction is stirred under reflux for 8h. Removing insoluble salt by suction filtration after cooling, and removing the solvent by reduced pressure distillation. Water (10 mL) was added, extracted with dichloromethane (20 mL. Times.3), the organic phases were combined, washed with saturated brine, and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude product. Purifying by column chromatography to obtain yellowish oily substance, dissolving in 6mL ethyl acetate, and adding dropwise 2M HCl/EtOAc to adjust pH <3, separating out solid, filtering, and vacuum drying to obtain the target product with 0.60g and the yield of 55.0%.
ESI-MS[M+H] + :m/z 355.2。
1 H NMR(400MHz,DMSO)δ11.19(s,1H),10.51(s,1H),7.98(dd,J＝3.2,1.8Hz,1H),7.68(ddd,J＝9.5,6.6,3.2Hz,1H),7.33(t,J＝2.8Hz,1H),7.20(dd,J＝8.9,3.4Hz,1H),7.14(d,J＝8.1Hz,1H),7.04(t,J＝7.8Hz,1H),6.56(d,J＝7.4Hz,1H),6.49(t,J＝2.7Hz,1H),4.22(t,J＝6.0Hz,2H),3.76(d,J＝12.8Hz,2H),3.70(d,J＝11.9Hz,2H),3.45-3.30(m,4H),3.17(t,J＝12.3Hz,2H),2.34-2.23(m,2H).
Example 2
Preparation of 7- (4- (3- ((6-fluoropyridin-3-yl) oxy) propyl) piperazin-1-yl) -1H-indole hydrochloride
0.10g (0.87 mmol,1.2 eq) of 2-fluoro-5-hydroxypyridine, 0.20g (0.72 mmol,1.0 eq) of 7- (4- (3-chloropropyl) piperazin-1-yl) -1H-indole, K 2 CO 3 0.30g (2.1 mmol,3 eq) of potassium iodide 0.12g (0.72 mmol,1.0 eq) are dissolved in 10ml acetonitrile and the reaction is stirred under reflux for 8h. Removing insoluble salt by suction filtration after cooling, and removing the solvent by reduced pressure distillation. Water (5 mL) was added, extracted with dichloromethane (15 mL. Times.3), the organic phases were combined, washed with saturated brine and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude product. Purifying by column chromatography to obtain pale yellow oily substance, dissolving in 3mL ethyl acetate, and adding dropwise 2M HCl/EtOAc to adjust pH<3, separating out solid, filtering, and vacuum drying to obtain the target product with 0.15g and the yield of 53.3%.
ESI-MS[M+H] + :m/z 355.1。
1 H NMR(400MHz,DMSO)δ11.09(s,1H),10.51(s,1H),7.98(dd,J＝3.2,1.8Hz,1H),7.68(ddd,J＝9.4,6.6,3.1Hz,1H),7.38(t,J＝2.8Hz,1H),7.31(d,J＝7.9Hz,1H),7.21(dd,J＝8.9,3.4Hz,1H),6.98(t,J＝7.7Hz,1H),6.74(d,J＝7.5Hz,1H),6.48(dd,J＝3.1,1.8Hz,1H),4.23(t,J＝6.0Hz,2H),3.72(d,J＝11.9Hz,2H),3.58(d,J＝12.8Hz,2H),3.47-3.31(m,4H),3.17(t,J＝12.0Hz,2H),2.33-2.23(m,2H)。
Example 3
Preparation of 4- (4- (3- ((6- (trifluoromethyl) pyridin-3-yl) oxy) propyl) piperazin-1-yl) -1H-indole hydrochloride
88mg (0.54 mmol,1.0 eq) of 6- (trifluoromethyl) pyridin-3-ol, 150mg (0.54 mmol,1.0 eq) of 4- (4- (3-chloropropyl) piperazin-1-yl) -1H-indole, K 2 CO 3 224mg (1.62 mmol,3.0 eq) of potassium iodide 90mg (0.54 mmol,1.0 eq) are dissolved in 6mL of acetonitrile and the reaction is stirred under reflux for 8h. Removing insoluble salt by suction filtration after cooling, and removing the dissolved salt by reduced pressure distillationAnd (3) an agent. Water (5 mL) was added, extracted with dichloromethane (15 mL. Times.3), the organic phases were combined, washed with saturated brine and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude product. Purifying by column chromatography to obtain pale yellow oily substance, dissolving in 3mL ethyl acetate, and adding dropwise 2M HCl/EtOAc to adjust pH<3, separating out solid, filtering, and vacuum drying to obtain 81mg of target product with a yield of 34.0%.
ESI-MS[M+H] + :m/z 405.1。
1 H NMR(400MHz,DMSO)δ11.21(s,1H),10.83(s,1H),8.52(d,J＝2.8Hz,1H),7.93(d,J＝8.8Hz,1H),7.68(dd,J＝8.8,2.9Hz,1H),7.34(t,J＝2.8Hz,1H),7.14(d,J＝8.1Hz,1H),7.04(t,J＝7.8Hz,1H),6.57(d,J＝7.4Hz,1H),6.50(d,J＝2.8Hz,1H),4.34-4.21(m,3H),3.71(d,J＝16.5Hz,3H),3.37(d,J＝12.8Hz,3H),3.22(t,J＝12.1Hz,2H),2.43-2.24(m,3H)。
Example 4
Preparation of 5- (3- (4- (1H-indol-4-yl) piperazin-1-yl) propoxy) -2-cyanopyridine hydrochloride
0.48g (3.89 mmol,1.2 eq) of 2-cyano-5-hydroxypyridine, 0.90g (3.24 mmol,1.0 eq) of 4- (4- (3-chloropropyl) piperazin-1-yl) -1H-indole, K 2 CO 3 1.12g (8.10 mmol,2.5 eq) of potassium iodide 0.54g (3.24 mmol,1.0 eq) are dissolved in 20mL of acetonitrile and the reaction is stirred under reflux for 6h. Removing insoluble salt by suction filtration after cooling, and removing the solvent by reduced pressure distillation. Water (10 mL) was added, extracted with dichloromethane (20 mL. Times.3), the organic phases were combined, washed with saturated brine, and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude product. Purifying by column chromatography to obtain yellowish oily substance, dissolving in 6mL ethyl acetate, and adding dropwise 2M HCl/EtOAc to adjust pH <3, separating out solid, filtering, and vacuum drying to obtain the target product with 0.85g and the yield of 65.9%.
ESI-MS[M+H] + :m/z 362.1。
1 H NMR(400MHz,DMSO)δ11.20(s,1H),10.50(s,1H),8.51(d,J＝2.8Hz,1H),8.09(d,J＝8.7Hz,1H),7.67(dd,J＝8.7,2.9Hz,1H),7.34(t,J＝2.8Hz,1H),7.14(d,J＝8.1Hz,1H),7.04(t,J＝7.8Hz,1H),6.56(d,J＝7.5Hz,1H),6.49(t,J＝2.6Hz,1H),4.34(t,J＝5.9Hz,2H),3.77-3.70(m,2H),3.70(d,J＝11.7Hz,2H),3.47-3.29(m,4H),3.17(t,J＝12.2Hz,2H),2.34-2.29(m,2H)。
Example 5
Preparation of N- (5- (3- (4- (1H-indol-4-yl) piperazin-1-yl) propoxy) pyridin-2-yl) acetamide hydrochloride
0.13g (0.87 mmol,1.2 eq) of 2-acetamido-5-hydroxypyridine, 0.20g (0.72 mmol,1.0 eq) of 4- (4- (3-chloropropyl) piperazin-1-yl) -1H-indole, K 2 CO 3 0.03g (2.10 mmol,3 eq) of potassium iodide 0.12g (3.24 mmol,1.0 eq) are dissolved in 6mL of acetonitrile and the reaction is stirred under reflux for 8h. Removing insoluble salt by suction filtration after cooling, and removing the solvent by reduced pressure distillation. Water (6 mL) was added, extracted with dichloromethane (15 mL. Times.3), the organic phases were combined, washed with saturated brine and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude product. Purifying by column chromatography to obtain yellowish oily substance, dissolving in 6mL ethyl acetate, and adding dropwise 2M HCl/EtOAc to adjust pH<3, separating out solid, filtering, and vacuum drying to obtain the target product with 0.17g and the yield of 55.0%.
ESI-MS[M+H] + :m/z 394.2。
1 H NMR(600MHz,D 2 O)δ8.06(d,J＝2.8Hz,1H),7.66-7.58(m,2H),7.42(d,J＝3.2Hz,1H),7.35(d,J＝8.2Hz,1H),7.22(t,J＝7.9Hz,1H),6.78(d,J＝7.5Hz,1H),6.58(dd,J＝3.3,0.9Hz,1H),4.27(t,J＝5.7Hz,2H),3.91(d,J＝13.6Hz,2H),3.84(d,J＝12.2Hz,2H),3.54-3.49(m,2H),3.43(d,J＝13.0Hz,2H),3.21(t,J＝12.6Hz,2H),2.39-2.31(m,2H),2.22(s,3H).
Example 6
Preparation of 4- (4- (3- ((6-chloropyridin-3-yl) oxy) propyl) piperazin-1-yl) -1H-indole hydrochloride
0.28g (2.16 mmol,1.2 eq) of 2-chloro-5-hydroxypyridine, 0.50g (1.80 mmol,1.0 eq) of 4- (4- (3-chloropropyl) piperazin-1-yl) -1H-indole, K 2 CO 3 0.63g (4.50 mmol,2.5 eq) of potassium iodide 0.30g (1.80 mmol,1.0 eq) are dissolved in 10mL of acetonitrile and the reaction is stirred under reflux for 12h. Removing insoluble salt by suction filtration after cooling, and removing the solvent by reduced pressure distillation. Water (5 mL) was added, extracted with dichloromethane (15 mL. Times.3), the organic phases were combined, washed with saturated brine and separated. The organic phase is anhydrousDrying with sodium sulfate, filtering, and concentrating the filtrate to obtain crude product. Purifying by column chromatography to obtain yellowish oily substance, dissolving in 6mL ethyl acetate, and adding dropwise 2M HCl/EtOAc to adjust pH<3, separating out solid, filtering, and vacuum drying to obtain the target product with 0.21g and yield of 28.6%.
ESI-MS[M+H] + :m/z 371.1。
1 H NMR(400MHz,DMSO)δ11.18(s,1H),10.47(s,1H),8.20(d,J＝3.0Hz,1H),7.56(dd,J＝8.7,3.1Hz,1H),7.51(d,J＝8.7Hz,1H),7.33(t,J＝2.8Hz,1H),7.14(d,J＝8.1Hz,1H),7.04(t,J＝7.8Hz,1H),6.56(d,J＝7.4Hz,1H),6.52-6.46(m,1H),4.24(t,J＝5.9Hz,2H),3.80-3.66(m,4H),3.40-3.31(m,4H),3.17(t,J＝12.2Hz,2H),2.33-2.23(m,2H)。
Example 7
Preparation of 4- (4- (3- ((6-methylpyridin-3-yl) oxy) propyl) piperazin-1-yl) -1H-indole hydrochloride
0.38g (3.48 mmol,1.2 eq) of 3-hydroxy-6-methylpyridine, 0.80g (2.90 mmol,1.0 eq) of 4- (4- (3-chloropropyl) piperazin-1-yl) -1H-indole, K 2 CO 3 1.00g (7.25 mmol,2.5 eq) of potassium iodide 0.48g (2.90 mmol,1.0 eq) are dissolved in 20mL of acetonitrile and the reaction is stirred under reflux for 11h. Removing insoluble salt by suction filtration after cooling, and removing the solvent by reduced pressure distillation. Water (10 mL) was added, extracted with dichloromethane (20 mL. Times.3), the organic phases were combined, washed with saturated brine, and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude product. Purifying by column chromatography to obtain yellowish oily substance, dissolving in 6mL ethyl acetate, and adding dropwise 2M HCl/EtOAc to adjust pH <3, separating out solid, filtering, and vacuum drying to obtain target product 313mg with yield of 27.9%.
ESI-MS[M+H] + :m/z 351.1。
1 H NMR(600MHz,D 2 O)δ8.30(d,J＝2.8Hz,1H),8.07(dd,J＝9.0,2.9Hz,1H),7.78(d,J＝9.0Hz,1H),7.42(t,J＝1.6Hz,1H),7.36(d,J＝8.1Hz,1H),7.22(t,J＝7.9Hz,1H),6.79(d,J＝7.6Hz,1H),6.58(dd,J＝3.2,1.0Hz,1H),4.34(t,J＝5.7Hz,2H),3.94-3.78(m,5H),3.56-3.51(m,2H),3.48-3.43(m,2H),3.24-3.21(m,2H),2.69(s,3H),2.44-2.36(m,2H)。
Example 8
Preparation of 4- (4- (3- ((6-bromopyridin-3-yl) oxy) propyl) piperazin-1-yl) -1H-indole hydrochloride
0.61g (3.48 mmol,1.2 eq) of 2-bromo-5-hydroxypyridine, 0.80g (2.90 mmol,1.0 eq) of 4- (4- (3-chloropropyl) piperazin-1-yl) -1H-indole, K 2 CO 3 1.00g (7.25 mmol,2.5 eq) of potassium iodide 0.48g (2.90 mmol,1.0 eq) are dissolved in 20mL of acetonitrile and the reaction is stirred under reflux for 11h. Removing insoluble salt by suction filtration after cooling, and removing the solvent by reduced pressure distillation. Water (10 mL) was added, extracted with dichloromethane (20 mL. Times.3), the organic phases were combined, washed with saturated brine, and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude product. Purifying by column chromatography to obtain yellowish oily substance, dissolving in 6mL ethyl acetate, and adding dropwise 2M HCl/EtOAc to adjust pH<3, separating out solid, filtering, and vacuum drying to obtain the target product with 0.50g and the yield of 38.5%.
ESI-MS[M+H] + :m/z 415.0。
1 H NMR(600MHz,D 2 O)δ8.09(d,J＝3.2Hz,1H),7.59(d,J＝8.8Hz,1H),7.43-7.41(m,2H),7.40(d,J＝3.2Hz,1H),7.38-7.34(m,1H),7.22(t,J＝7.9Hz,1H),6.79(d,J＝7.6Hz,1H),4.25(t,J＝5.7Hz,3H),3.99-3.63(m,3H),3.54-3.48(m,3H),3.35-3.14(m,2H),2.50-2.24(m,3H)。
Example 9
Preparation of 5- (3- (4- (1H-indol-4-yl) piperazin-1-yl) propoxy) -2-fluorobenzonitrile
0.12g (0.87 mmol,1.2 eq) of 2-fluoro-5-hydroxybenzonitrile, 0.20g (0.72 mmol,1.0 eq) of 4- (4- (3-chloropropyl) piperazin-1-yl) -1H-indole, K 2 CO 3 0.30g (2.1 mmol,2.5 eq) of potassium iodide 0.12g (0.72 mmol,1.0 eq) are dissolved in 6mL of acetonitrile and the reaction is stirred under reflux for 8h. Removing insoluble salt by suction filtration after cooling, and removing the solvent by reduced pressure distillation. Water (10 mL) was added, extracted with dichloromethane (20 mL. Times.3), the organic phases were combined, washed with saturated brine, and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude product. The target product is obtained by column chromatography purification, 0.14g, and the yield is 51.5%.
ESI-MS[M+H] + :m/z 423.0。
1 H NMR(400MHz,DMSO)δ11.06(s,1H),7.57(dd,J＝5.1,3.1Hz,1H),7.49(t,J＝9.1Hz,1H),7.40(ddd,J＝9.3,4.5,3.2Hz,1H),7.27(s,1H),7.05(d,J＝8.2Hz,1H),6.99(t,J＝7.7Hz,1H),6.47(d,J＝7.4Hz,1H),6.40(s,1H),4.16-4.12(m,2H),3.21(s,1H),3.20(s,1H),3.18-3.07(m,4H),2.74-2.56(m,4H),1.98-1.94(m,2H)。
Example 10
Preparation of 4- (4- (3- ((6-fluoropyridin-3-yl) oxy) propyl) piperazin-1-yl) -1- (benzenesulfonyl) -1H-indole hydrochloride
Sodium hydride (47 mg,1.90 mmol) was mixed with THF (10 mL), cooled in an ice bath, then a solution of example 1 (230 mg,0.65 mmol) in THF (5 mL) was added and stirred for 15 min. After adding benzenesulfonyl chloride (172 mg,1.00 mmol) dropwise, the mixture was stirred at room temperature for 1h. At the end of the reaction, quench with ice and extract with ethyl acetate (15 ml x 2). The organic phases were combined, washed with saturated brine and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude product. Purifying by column chromatography to obtain yellowish oily substance, adding 3mL ethyl acetate for dissolving, dripping 2M HCl/EtOAc for regulating pH to below 3, separating out solid, filtering, and vacuum drying to obtain target product 0.10g with yield of 29.0%.
ESI-MS[M+H] + :m/z 495.1。
1 H NMR(400MHz,DMSO)δ10.50(s,1H),8.05-7.99(m,2H),7.96(dd,J＝3.2,1.8Hz,1H),7.86(d,J＝3.8Hz,1H),7.77-7.69(m,1H),7.69-7.60(m,4H),7.31(t,J＝8.1Hz,1H),7.19(dd,J＝8.9,3.4Hz,1H),6.97(d,J＝3.8Hz,1H),6.85(d,J＝7.8Hz,1H),4.20(t,J＝6.0Hz,2H),3.63(t,J＝13.5Hz,4H),3.44-3.26(m,4H),3.17(t,J＝11.9Hz,2H),2.27-2.23(m,2H)。
Example 11
Preparation of 1- (4- (4- (3- ((6-fluoropyridin-3-yl) oxy) propyl) piperazin-1-yl) -1H-indol-1-yl) ethan-1-one hydrochloride
Sodium hydride (37 mg,0.92 mmol) was mixed with THF (10 mL), cooled in an ice bath, then a solution of example 1 (120 mg,0.31 mmol) in THF (5 mL) was added and stirred for 15 min. After dropwise addition of acetyl chloride (36 mg,0.46 mmol), the mixture was stirred at room temperature for 1h. At the end of the reaction, quench with ice and extract with ethyl acetate (15 ml x 2). The organic phases were combined, washed with saturated brine and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude product. Purifying by column chromatography to obtain yellowish oily substance, adding 3mL ethyl acetate for dissolving, dripping 2M HCl/EtOAc for regulating pH to below 3, separating out solid, filtering, and vacuum drying to obtain target product 0.05g with yield of 37.3%.
ESI-MS[M+H] + :m/z 397.1。
1 H NMR(600MHz,D 2 O)δ8.15(d,J＝8.3Hz,1H),7.87(dd,J＝3.2,1.4Hz,1H),7.73(d,J＝3.9Hz,1H),7.62(ddd,J＝9.3,6.4,3.2Hz,1H),7.41(t,J＝8.1Hz,1H),7.09(dd,J＝9.0,2.6Hz,1H),7.04(d,J＝7.8Hz,1H),6.83(dd,J＝3.9,0.8Hz,1H),4.26(t,J＝5.7Hz,2H),3.91-3.70(m,4H),3.59-3.48(m,2H),3.48-3.15(m,4H),2.70(s,3H),2.42-2.26(m,2H)。
Example 12
Preparation of 4- (4- (3- ((6-fluoropyridin-3-yl) oxy) propyl) piperazin-1-yl) -1-methyl-1H-indole hydrochloride
1-methyl-4- (piperazin-1-yl) -1H-indole 0.32g (1.50 mmol,1.0 eq), 3- ((6-fluoropyridin-3-yl) oxy) propyl 4-methylbenzenesulfonate 0.50g (1.5 mmol,1.0 eq), K 2 CO 3 0.60g (4.5 mmol,3.0 eq) are dissolved in 10ml acetonitrile and the reaction is stirred under reflux for 8h. Removing insoluble salt by suction filtration after cooling, and removing the solvent by reduced pressure distillation. Water (10 mL) was added, extracted with dichloromethane (20 mL. Times.3), the organic phases were combined, washed with saturated brine, and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude product. Purifying by column chromatography to obtain pale yellow oily substance, dissolving in 3ml ethyl acetate, and adding dropwise 2M HCl/EtOAc to adjust pH<3, separating out solid, filtering, and vacuum drying to obtain white solid 0.18g with 29.6% yield.
ESI-MS[M+H] + :m/z 369.2。
1 H NMR(600MHz,D 2 O)δ7.87(dd,J＝3.2,1.4Hz,1H),7.62(ddd,J＝9.3,6.4,3.2Hz,1H),7.33-7.25(m,3H),7.09(dd,J＝9.0,2.6Hz,1H),6.80(dd,J＝7.4,1.0Hz,1H),6.55(dd,J＝3.1,0.8Hz,1H),4.24(t,J＝5.7Hz,2H),3.91(d,J＝25.3Hz,3H),3.82(s,3H),3.52-3.45(m,2H),3.46-3.32(m,3H),3.30-3.11(m,2H),2.37-2.29(m,2H)。
Comparative example 1 (refer to patent WO2001049680A1 Compound 1 a)
Preparation of 4- (4- (3- (2, 4-difluorophenoxy) propyl) piperazin-1-yl) -1H-indole hydrochloride
75mg (0.58 mmol,1.0 eq) of 2, 4-difluorophenol, 0.16g (0.58 mmol,1.0 eq) of 4- (4- (3-chloropropyl) piperazin-1-yl) -1H-indole, K 2 CO 3 0.24g (1.7 mmol,3 eq) of potassium iodide 96mg (0.58 mmol,1.0 eq) are dissolved in 6mL acetonitrile and the reaction is stirred under reflux for 8h. Removing insoluble salt by suction filtration after cooling, and removing the solvent by reduced pressure distillation. Water (5 mL) was added, extracted with dichloromethane (15 mL. Times.3), the organic phases were combined, washed with saturated brine and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude product. Purifying by column chromatography to obtain pale yellow oily substance, dissolving in 3mL ethyl acetate, and adding dropwise 2M HCl/EtOAc to adjust pH <3, separating out solid, filtering, and vacuum drying to obtain 124mg of target product with a yield of 52.4%.
ESI-MS[M+H] + :m/z 372.2。
1 H NMR(600MHz,DMSO-d6)δ11.21(s,1H),11.13(s,1H),7.31(tt,J＝8.0,4.1Hz,2H),7.25(td,J＝9.4,5.4Hz,1H),7.13(d,J＝8.1Hz,1H),7.08-6.98(m,2H),6.56(d,J＝7.5Hz,1H),6.49(s,1H),4.17(t,J＝6.0Hz,2H),3.71(d,J＝12.6Hz,2H),3.66(d,J＝11.8Hz,2H),3.39-3.31(m,4H),3.30-3.23(m,2H),2.32-2.24(m,2H)。
Comparative example 2 (refer to patent WO2003002552A1 Compound 1 e)
Preparation of 4- (4- (2- ((2-chloropyridin-3-yl) oxy) ethyl) piperazin-1-yl) -1H-indole hydrochloride
3.5mL of 1-bromo-2-chloroethane, 0.55g of 4- (piperazin-1-yl) -1H-indole and 0.5mL of DIPEA were dissolved in 6mL of acetone and stirred at 60℃for 5H. The reaction was completed, cooled to room temperature, 10mL of water was added, extracted with dichloromethane (15 mL x 3), the organic phases were combined, washed with saturated brine and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude product. Purification by column chromatography gave 360mg of 4- (4- (3-chloroethyl) piperazin-1-yl) -1H-indole in 26.1% yield.
180mg (1.4 mmol,1.0 eq) of 2-chloro-3-hydroxypyridine, 0.36g (1.4 mmol,1.0 eq) of 4- (4- (3-chloroethyl) piperazin-1-yl) -1H-indole, K 2 CO 3 0.58g (4.2 mmol,3 eq) of potassium iodide 0.23g (1.4 mmol,1.0 eq) are dissolved in 6mL of acetonitrile and the reaction is stirred under reflux for 12h. Removing insoluble salt by suction filtration after cooling, and removing the solvent by reduced pressure distillation. Water (10 mL) was added, extracted with dichloromethane (20 mL. Times.3), the organic phases were combined, washed with saturated brine, and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude product. Purifying by column chromatography to obtain pale yellow oily substance, dissolving in 3mL ethyl acetate, and adding dropwise 2M HCl/EtOAc to adjust pH <3, separating out solid, filtering, and vacuum drying to obtain 92mg of target product with the yield of 16.7%.
ESI-MS[M+H] + :m/z 357.1。
1 H NMR(600MHz,DMSO-d6)δ11.75(s,1H),11.24(s,1H),8.05(dd,J＝4.7,1.4Hz,1H),7.71(dd,J＝8.2,1.5Hz,1H),7.46(dd,J＝8.2,4.6Hz,1H),7.32(t,J＝2.8Hz,1H),7.14(d,J＝8.0Hz,1H),7.02(t,J＝7.8Hz,1H),6.61(d,J＝7.6Hz,1H),6.52(s,1H),4.68(t,J＝5.0Hz,2H),3.77(d,J＝12.0Hz,2H),3.76-3.74(m,3H),3.74-3.70(m,3H),3.62-3.46(m,2H)。
Comparative example 3 (example 40 of reference patent WO2007026959A 2)
Preparation of 1- (benzo [ b ] thiophen-4-yl) -4- (3- ((6-methylpyridin-3-yl) oxy) propyl) piperazine hydrochloride
After 1- (benzo [ b ] thiophen-4-yl) piperazine hydrochloride was released in methylene chloride solution, 1-bromo-3-chloropropane was added to give 1- (benzo [ b ] thiophen-4-yl) -4- (3-chloropropyl) piperazine as a white solid in 61% yield.
371mg of 1- (benzo [ b ] thiophen-4-yl) -4- (3-chloropropyl) piperazine (3.4 mmol,1 eq) and 1g of 2-methyl-5-hydroxypyridine (3.4 mmol,1 eq) were dissolved in acetonitrile (50 mL). 1.4g of potassium carbonate (10.2 mmol,3 eq) and 564mg of potassium iodide (3.4 mmol,1 eq) were added and the reaction stirred under reflux for 8h. Removing insoluble salt by suction filtration after cooling, and removing the solvent by reduced pressure distillation. Water (15 mL) was added, extracted with dichloromethane (25 mL. Times.3), the organic phases were combined, washed with saturated brine and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude product. Purifying by column chromatography to obtain pale yellow oily substance, adding 3mL ethyl acetate for dissolving, dripping 2M HCl/EtOAc for regulating pH to be less than 3, separating out solid, filtering, and vacuum drying to obtain 530mg of target product with a yield of 38.6%.
ESI-MS[M+H] + :m/z 368.2。
1 H NMR(400MHz,DMSO)δ10.96(s,1H),8.47(s,1H),7.92(s,1H),7.82(d,J＝5.6Hz,1H),7.75(d,J＝8.1Hz,1H),7.69(d,J＝8.6Hz,1H),7.54(d,J＝5.6Hz,1H),7.37(t,J＝7.9Hz,1H),7.02(d,J＝7.5Hz,1H),4.32(t,J＝6.0Hz,2H),3.70(d,J＝11.7Hz,2H),3.64-3.59(m,1H),3.59-3.56(m,1H),3.41-3.37(m,4H),3.29(t,J＝12.1Hz,2H),2.62(s,3H),2.37-2.29(m,2H)。
Biological test evaluation
The invention is further illustrated below in conjunction with test examples, which are not meant to limit the scope of the invention.
Test example 1 5-HT in vitro of the inventive Compounds 1A Receptor function test
1.1 Experimental materials
1.1.1 cell information: HEK293/5HT 1A And (5) internal construction.
1.1.2 Experimental reagent consumables:
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1.1.3 laboratory apparatus:
name of the name Suppliers (suppliers) Model number
Cell counter Countstar BioTech
EnVision multifunctional board reader PerkinElmer 2105
Milli-Q ultra-pure water instrument Millipore IQ 7000
Centrifugal machine Cence TDZ5-WS
Leather upgrading micro-liquid adding device Tecan D300e
1.2 Experimental methods
(1) Compound preparation: test compound and 5HT were diluted to 0.1mM using stimulation buffer for use.
(2) Experiment buffer solution preparation: with ddH 2 O5X stimulation buffer was diluted to 1X and IBMX was added to a final concentration of 0.5mM and mixed well for use.
(3) Cells were digested with pancreatin, centrifuged after termination, cell pellet resuspended with 10mL of pre-warmed HBSS, centrifuged, resuspended with 1mL stimulation buffer added and 20 μl counted.
(4) Diluting appropriate amount of cell suspension to 0.6X10 6 mu.L of cell suspension was added to each well of the cell plate per mL, and centrifuged at 1000rpm for 1 minute.
(5) Dilution and transfer of compounds using bravo: compounds were diluted 4-fold at 8 points in the compound plate; the diluted compound was then transferred to 384 white plates using bravo and centrifuged at 1000rpm for 1 min.
(6) Assay plates were blocked and incubated at room temperature for 15 minutes.
(7) Tecan D300e was used to add forskolin in DMSO at a final concentration of 1. Mu.M in a stock solution of 0.2mM and centrifuged at 1000rpm for 1 min.
(8) The plates were incubated for 45 minutes at room temperature.
(9) cAMP standard curve preparation: the initial concentration was 2848nM and the 8 spots were serially diluted 4-fold. mu.L was added to the assay plate at a peak concentration of 712nM.
(10) mu.L of cAMP-d2 solution (stock solution diluted 1:20 with lysis buffer) was added to the plate and centrifuged at 1000rpm for 1 min.
(11) Then, 5. Mu.L of Anti-cAMP-Cryptate solution (stock solution diluted 1:20 with lysis buffer) was added to the plate and centrifuged at 1000rpm for 1 min.
(12) The plates were incubated at room temperature for 1 hour and centrifuged at 1000rpm for 1 minute before reading.
(13) The plate was read using Envision. Excitation light 320nm, emission 620nm and 665nm. Analyzing the derived data to calculate the maximum activation rate E of the compound max EC (EC) 50 。
1.3 experimental results: see table 1.
TABLE 1 Compound of the invention against 5-HT 1A Results of receptor function experiments
1.4 experimental conclusion:
as can be seen from the results of Table 1 above, the compounds of the present invention act on 5-HT 1A Receptors and exhibit good 5-HT 1A Receptor (partial) agonistic activity.
Test example 2 in vitro dopamine D of the inventive Compounds 2L Receptor function assay
2.1 Experimental materials
2.1.1 cell information:
cell name Suppliers (suppliers)
HEK293/D 2L Kinsrui biosciences Co Ltd
2.1.2 experimental reagent consumable:
2.1.3 laboratory apparatus:
name of the name Suppliers (suppliers) Model number
Cell counter Countstar BioTech
EnVision multifunctional board reader PerkinElmer 2105
Milli-Q ultra-pure water instrument Millipore IQ 7000
Centrifugal machine Cence TDZ5-WS
Leather upgrading micro-liquid adding device Tecan D300e
2.2 Experimental methods
(1) Compound preparation: the test compound and Dopamine were diluted to 200nM for use.
(2) Experiment buffer solution preparation: with ddH 2 O5X stimulation buffer was diluted to 1X and IBMX was added to a final concentration of 0.5mM and mixed well for use.
(3) Cells were digested with pancreatin, centrifuged after termination, cell pellet resuspended with 10mL of pre-warmed HBSS, centrifuged, and added
1mL stimulation buffer, 20. Mu.L was resuspended and counted.
(4) Diluting appropriate amount of cell suspension to 0.4X10 6 mu.L of cell suspension was added to each well of the cell plate per mL, and centrifuged at 1000rpm for 1 minute.
(5) Dilution and transfer of compounds using bravo: compounds were diluted 4-fold at 8 points in the compound plate; the diluted compound was then transferred to 384 white plates using bravo and centrifuged at 1000rpm for 1 min.
(6) Assay plates were blocked and incubated at room temperature for 15 minutes.
(7) Tecan D300e was used to add forskolin in DMSO at a stock solution of 0.2mM and a final concentration of 0.25. Mu.M, and centrifuged at 25.1nL forskolin,1000rpm for 1 min per well.
(8) The plates were incubated for 45 minutes at room temperature.
(9) cAMP standard curve preparation: the initial concentration was 2848nM and the 8 spots were serially diluted 4-fold. mu.L was added to the assay plate at a peak concentration of 712nM.
(10) mu.L of cAMP-d2 solution (stock solution diluted 1:20 with lysis buffer) was added to the plate and centrifuged at 1000rpm for 1 min.
(11) Then, 5. Mu.L of Anti-cAMP-Cryptate solution (stock solution diluted 1:20 with lysis buffer) was added to the plate and centrifuged at 1000rpm for 1 min.
(12) The plates were incubated at room temperature for 45 minutes and centrifuged at 1000rpm for 1 minute before reading.
(13) The plate was read using Envision. Excitation light 320nm, emission 620nm and 665nm. Analysis of the derived data, calculation of maximum activation rate Emax and EC of the compound 50 。
2.3 experimental results: see table 2.
TABLE 2 Compound pair D of the invention 2 Results of receptor function experiments
2.4 experimental conclusion:
as can be seen from the results of Table 2 above, the compounds of the present invention can be used asFor dopamine D 2 Receptors and exhibit good dopamine D 2 Receptor (partial) agonistic activity.
Test example 3 in vitro dopamine D of the Compounds of the invention 3 Receptor function assay
3.1 Experimental materials
3.1.1 cell information: CHO-K1/D 3 CRE, built-in.
3.1.2 experimental reagent consumable:
3.1.3 laboratory apparatus:
name of the name Suppliers (suppliers) Model number
Cell counter Countstar BioTech
EnVision multifunctional board reader PerkinElmer 2105
Milli-Q ultra-pure water instrument Millipore IQ 7000
Centrifugal machine Cence TDZ5-WS
Leather upgrading micro-liquid adding device Tecan D300e
3.2 Experimental methods
The first day: cell plating
(1) The cultured cells were digested with pancreatin, and after termination of the digestion of the medium, the cell suspension was transferred to a centrifuge tube, 750
Centrifuge at rpm for 5 minutes.
(2) The supernatant was discarded, and the pellet was resuspended in an appropriate amount of plating medium and 20. Mu.L was counted using a cytometer.
(3) Diluting appropriate amount of cell suspension to 0.5X10 6 mu.L of cell suspension (cell density 10000 cells/well) was added per well to each cell plate per mL.
(4) Cell plates were exposed to 5% CO 2 Culture at 37℃overnight.
The following day: experimental detection
(1) Test compounds were diluted to 0.2mM using DMSO and reference compound, dopamine, was diluted to 0.02mM.
(2) Compound dilution (4-fold dilution at 8 concentration points) was performed using Bravo with an initial concentration of 5 μm for the test compound and 500nM for the reference compound; then 5. Mu.L of the sample was added to the cell plate, and the final concentration of the test compound was 1. Mu.M, and the final concentration of the reference compound was 100nM. Positive control wells were 100nM Dopamine and negative control wells were equal volumes of DMSO.
(3) Centrifugation at 1000rpm for 1 min, 5% CO 2 Incubation was carried out at 37℃for 30 minutes.
(4) 40nL of 0.2. 0.2mM Forskolin DMSO solution was transferred to the cell plate using Tecan-D300e at a final concentration of 0.4. Mu.M. Blank plus cells did not add Forskolin.
(5) Centrifugation at 1000rpm for 1 min, 5% CO 2 Incubation was carried out at 37℃for 4 hours.
(6) Taking out the lysate 30 minutes in advance, melting in a normal-temperature water bath, and recovering to the room temperature. And taking out a proper amount of substrate, diluting the substrate with the lysate according to the proportion of 1:50, and uniformly mixing for later use.
(7) 20. Mu.L of detection reagent was added and centrifuged at 1000rpm for 1 minute.
(8) After incubation for 3 minutes at room temperature, plates were read using Envision. The procedure selected was a hypersensitivity chemiluminescent detection procedure. Analyzing the derived data to calculate the maximum activation rate E of the compound max EC (EC) 50 。
3.3. Experimental results: see table 3.
TABLE 3 Compound pair D of the invention 3 Results of receptor function experiments
3.4 experimental conclusion:
as can be seen from the results of Table 3 above, the compounds of the present invention act on dopamine D 3 Receptors and exhibit good dopamine D 3 Receptor (partial) agonistic activity.
As a result of in vitro experiments in which the above tables 1 to 3 are combined, the compounds of the present invention have an effect on D 2 、D 3 And/or 5-HT 1A Characteristics of multiple targets, and for D 2 、D 3 And/or 5-HT 1A The receptor showed (partial) agonistic activity at the receptor, examples 1, 3-4, 6-9, 11-12 vs D 2 、D 3 And/or 5-HT 1A In particular, examples 1, 4 and 11 show more potent agonism on 5-HT 1A Receptors, dopamine D 2 And D 3 Triple (partial) agonistic activity of the receptor.
Test example 4 in vitro liver microsome assay of the Compounds of the invention
4.1 purpose of experiment
The compounds of the invention were evaluated for one-phase metabolic stability in CD-1 mice, SD rats and human liver microsomes.
4.2 Experimental materials
(1) Experimental reagent:
reagent(s) Suppliers (suppliers) Model number
Dibasic potassium phosphate trihydrate Greagent 01031670
Monopotassium phosphate Greagent 01115129
Phosphoric acid Greagent 01113527
Testosterone (Testosterone) Dr.E 01279087
Dimethyl sulfoxide Sigma D8418
Buspirone TRC B689850
Acetonitrile Fisher A9984
CD-1 mouse liver microsome RILD LQDL LM-XS-02M
SD rat liver microsome RILD DMXD LM-DS-02M
Human liver microsome Corning 452117
NADP Aladdin N113163
G6P Shanghai source leaf S11024
MgCl 2 Greagent 01115966
G6PDH Shanghai source leaf S10078
(2) Experimental instrument:
name of the name Suppliers (suppliers) Model number
Liquid phase SCIEX Exion LC tm
Mass spectrometry SCIEX Triple Qvad 5500
Centrifugal machine Thermo Fisher 75009915
Plate rocking machine Thermo Scientific 88882006
4.3 Experimental methods
(1) Preparing a buffer solution: 73.21g of dibasic potassium phosphate trihydrate and 10.78g of monobasic potassium phosphate were dissolved in 4000mL of ultrapure water. The pH of the solution was adjusted to 7.40.+ -. 0.10 using 10% phosphoric acid or 1M potassium hydroxide to a final concentration of 100mM.
(2) Preparing and diluting a solution: stock solutions of test compounds were prepared with a concentration of 10mM using dimethyl sulfoxide (DMSO), stored at 4℃and diluted with neat acetonitrile to a working solution concentration of 100. Mu.M when used. A control compound testosterone stock solution at a concentration of 10mM was prepared with DMSO and stored at-20 ℃. In use, the solution is diluted to a working solution concentration of 400 mu M with pure acetonitrile.
(3) Preparation of the stop solution: the stop solution was acetonitrile containing the internal standard buspirone. The prepared stop solution is stored in a refrigerator at the temperature of 2-8 ℃.
(4) Preparation of liver microsome solution: microsomes of various species (CD-1 mice, SD rats and humans) were diluted with 100mM potassium phosphate buffer to 20 Xworking solution. The final concentration of microsomes in the reaction system was 0.5mg/mL.
(5) Preparation of a reduced Nicotinamide Adenine Dinucleotide Phosphate (NADPH) regeneration system: weighing appropriate amount of Nicotinamide Adenine Dinucleotide Phosphate (NADP), glucose-6-phosphate (G6P), magnesium chloride (MgCl) 2 ) And glucose-6-phosphate dehydrogenase (G6 PDH) were prepared as stock solutions at concentrations of 65.33mM, 330mM, 300mM and 250Units/mL, respectively. The four stock solutions are added into a proper amount of buffer solution, and the mixture is gently mixed upside down. The final concentrations in the NADPH regeneration system were respectively: 2.65mM NADP, 10.2mM G6P, 6.12mM MgCl 2 And 2.45Units/mL G6PDH.
(6) Incubation process: incubation was completed in 96-well plates. Several incubation plates were prepared, designated T0, T5, T10, T20, T40, T60, PB60 and NCF60, respectively. The first 6 plates correspond to reaction time points of 0, 5, 10, 20, 40 and 60 minutes, respectively. The NCF60 plates were incubated with potassium phosphate buffer instead of NADPH regeneration system solution for 60 min. PB60 plates were incubated with potassium phosphate buffer instead of liver microsomes for 60 min. All conditional samples were three in parallel.
2. Mu.L of the test compound or control compound and 100. Mu.L of microsomal working solution (containing 1mg/mL of liver microsomal protein) were added to the T0, T5, T10, T20, T40, T60 and NCF60 plates, respectively, 2. Mu.L of the test compound and 100. Mu.L of potassium phosphate buffer were added to the PB60 plates, and the above incubation plates were placed in a 37℃water bath for pre-incubation for about 5 minutes.
After the pre-incubation, the T0 sample is firstly added with 600 mu L of stop solution, then with 98 mu L of NADPH regeneration system working solution, the plate is sealed, and the sample is shaken and then is waited for processing with the subsequent sample. Incubation plates in addition to 98 μl of potassium phosphate buffer per sample well of NCF60, 98 μl of NADPH regeneration system working fluid per sample well of other incubation plates was added to initiate the reaction. The final concentrations of the test compound and the control compound in the reaction system were 1. Mu.M and 4. Mu.M, respectively, the concentrations of the liver microsomes were 0.5mg/mL, and the final concentrations of DMSO and acetonitrile in the reaction system were 0.01% (v/v) and 0.99% (v/v), respectively.
After incubation for a suitable period of time (e.g., 5, 10, 20, 40 and 60 minutes), 600. Mu.L of stop solution containing an internal standard was added to each of the test compound sample and control compound wells, respectively, to terminate the reaction, the plates were closed, shaken and centrifuged at 4000 Xg for 15 minutes at 4 ℃. The supernatant was taken in a 96-well sample receiving plate, diluted with an appropriate amount of pure water, shaken well for LC-MS/MS analysis, and subjected to data processing using software analysis 7.1 (Sciex, frangham, massachusetts, USA). 4.4 experimental results: the results of the in vitro liver microsome stability test are shown in table 4.
TABLE 4 in vitro liver microsome stability test results
Remarks: the clearance classification criteria are shown in the following table:
4.5 experimental conclusion:
the above data shows that inventive example 1 is a moderate rate clearance in SD rats and CD-1 mice liver microsomes and a low constant rate clearance in human liver microsomes; whereas comparative example 3 was associated with high rate clearance in all three species of liver microsomes. Based on the pharmacodynamic activity and pharmacological mechanism of the series of compounds, the slower metabolic rate is favorable for the compounds to exert the pharmacodynamic activity, so that the effect of the compounds of the invention is obviously better than that of the compounds of the comparative examples in the aspect of metabolic rate.
Test example 5 test of the effect of the Compounds of the invention on Tacrine (Tacrine) induced behavior of rat mandibular tremor
5.1 Experimental purposes:
the efficacy of the compounds of the invention was evaluated by intraperitoneal injection of tacrine-induced rat mandibular tremor model.
5.2 experimental protocol:
(1) Experimental materials:
test compounds: the compound of the embodiment of the invention is self-made.
Positive control compound: rotigotine (rotigotine), targetMoI,153266.
And (3) molding medicine: tacrine (tacrine), SIGMA, a3773-1G.
A solvent: normal saline, chenxin pharmaceutical industry, inc, 2111060723.
DMSO：SIGMA，D2650-100ML。
(2) The main experimental instrument comprises:
(3) Experimental animals:
experimental animals: sprague Dawley rats, male, 6 animals/group, shanghai Laek laboratory animal Limited.
(4) Drug administration information:
preparing the medicine: the test compound was taken, added to the vehicle and sonicated.
Route of administration and method: the medicine is injected into the abdominal cavity.
Frequency and duration of dosing: single administration.
Animals were randomly divided into model, dosing and control groups after weight stratification, and detailed dosing information is given in the following table:
(5) The experimental method comprises the following steps:
rats were randomly divided into model groups, dosing groups and control groups after stratification according to body weight. Rats were habituated three days prior to the experiment. On the day of the experiment, firstly injecting solvent or medicine into the abdominal cavity, injecting tacrine into the abdominal cavity according to the weight of 5mg/kg after 30min, putting the rat into a transparent observation box after administration, starting to count mandibular tremors after 10min, continuously counting for 5min, and recording the times of mandibular tremors of the rat within 5 min.
(6) Data processing and statistics:
for experimental dataExpressed, inhibition ratio%100%times (number of model group rat mandibular tremors-number of dosing group rat mandibular tremors)/number of model group rat mandibular tremors
5.3 experimental results: as shown in table 5.
TABLE 5 test results of the effect of the compounds of the invention on the behavior of tacrine-induced mandibular tremor in rats
Group of Inhibition ratio @3mg/kg Inhibition ratio @10mg/kg
Example 1-A 99.9％ -
Rotigotine - 80.2％
5.4 experimental conclusion:
according to the scheme, the example 1 of the invention can obviously inhibit the rat mandibular tremor induced by tacrine, and compared with rotigotine, the compound of the invention has stronger drug effect and potential anti-parkinsonism effect.

Claims (11)

1. A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein:
m is selected from CR 0 Or N;
R 0 selected from hydrogen, deuterium, halogen, hydroxy, cyano, amino, and C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy, preferably halogen, cyano, C 1-6 Alkyl or C 1-6 Haloalkyl, more preferably halogen, cyano, C 1-3 Alkyl or C 1-3 Haloalkyl, further preferably cyano;
R 1 selected from halogen, hydroxy, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or- (CH) 2 ) n1 NR aa C(O)R bb Preferably halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl or- (CH) 2 ) n1 NR aa C(O)R bb More preferably halogen, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl or-NR aa C(O)R bb Further preferred are fluorine, chlorine, bromine, cyano, methyl, trifluoromethyl or-NHC (O) CH 3 ；
R aa And R is bb Each independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 Haloalkyl, preferably hydrogen or C 1-6 Alkyl, more preferably hydrogen or C 1-3 Alkyl, further preferably hydrogen or methyl;
R 2 selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, - (CH) 2 ) n2 C(O)R AA Or- (CH) 2 ) n2 S(O) 2 R AA Preferably hydrogen, C 1-6 Alkyl, - (CH) 2 ) n2 C(O)R AA Or- (CH) 2 ) n2 S(O) 2 R AA More preferably hydrogen, C 1-3 Alkyl, -C (O) R AA or-S (O) 2 R AA Further preferred are hydrogen, methyl, -C (O) CH 3 or-S (O) 2 -Ph；
R AA Selected from hydrogen, deuterium, halogen, hydroxy, cyano, amino, and C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, preferably C 1-6 Alkyl or C 6-10 Aryl, more preferably C 1-3 Alkyl or phenyl, further preferably methyl or phenyl;
R 3 selected from hydrogen, deuterium, halogen, hydroxy, cyano, amino, and C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy, preferably hydrogen, halogen, cyano or C 1-6 Alkyl, more preferably hydrogen, halogen, cyano or C 1-3 Alkyl, further preferably hydrogen, fluorine, chlorine, bromine, cyano or methyl;
n is an integer of 0 to 3;
n1 is an integer of 0 to 2; and is also provided with
n2 is an integer of 0 to 2.
2. The compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein formula (I) is further as shown in formula (II):
Wherein:
M、R 1 、R 2 and R is 3 The method of claim 1.
3. The compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 1 or 2, wherein formula (I) is further as shown in formula (III):
wherein:
m is selected from CR 0 Or N;
R 0 selected from halogen, cyano, C 1-3 Alkyl or C 1-3 Haloalkyl, preferably cyano;
R 1 selected from halogen, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl or-NR aa C(O)R bb Preferably fluorine, chlorine, bromine, cyano, methyl, trifluoromethyl or-NHC (O) CH 3 ；
R aa And R is bb Each independently selected from hydrogen or C 1-3 Alkyl, preferably hydrogen or methyl;
R 2 selected from hydrogen, C 1-3 Alkyl, -C (O) R AA or-S (O) 2 R AA Preferably hydrogen, methyl, -C (O) CH 3 or-S (O) 2 -Ph；
R AA Selected from C 1-3 Alkyl or phenyl, preferably methyl or phenyl.
4. The compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 1 or 2, wherein formula (I) is further as shown in formula (IV):
wherein:
m is selected from CR 0 Or N;
R 0 selected from halogen, cyano, C 1-3 Alkyl or C 1-3 Haloalkyl, preferably cyano;
R 1 selected from halogen, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl or-NR aa C(O)R bb Preferably fluorine, chlorine, bromine, cyano, methyl, trifluoromethyl or-NHC (O) CH 3 ；
R aa And R is bb Each independently selected from hydrogen or C 1-3 Alkyl, preferably hydrogen or methyl;
R 2 selected from hydrogen, C 1-3 Alkyl, -C (O) R AA or-S (O) 2 R AA Preferably hydrogen, methyl, -C (O) CH 3 or-S (O) 2 -Ph；
R AA Selected from C 1-3 Alkyl or phenyl, preferably methyl or phenyl.
5. A compound of general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, selected from the group consisting of:
4- (4- (3- ((6-fluoropyridin-3-yl) oxy) propyl) piperazin-1-yl) -1H-indole,
7- (4- (3- ((6-fluoropyridin-3-yl) oxy) propyl) piperazin-1-yl) -1H-indole,
4- (4- (3- ((6- (trifluoromethyl) pyridin-3-yl) oxy) propyl) piperazin-1-yl) -1H-indole,
5- (3- (4- (1H-indol-4-yl) piperazin-1-yl) propoxy) -2-cyanopyridine,
N- (5- (3- (4- (1H-indol-4-yl) piperazin-1-yl) propoxy) pyridin-2-yl) acetamide,
4- (4- (3- ((6-chloropyridin-3-yl) oxy) propyl) piperazin-1-yl) -1H-indole,
4- (4- (3- ((6-methylpyridin-3-yl) oxy) propyl) piperazin-1-yl) -1H-indole,
4- (4- (3- ((6-bromopyridin-3-yl) oxy) propyl) piperazin-1-yl) -1H-indole,
5- (3- (4- (1H-indol-4-yl) piperazin-1-yl) propoxy) -2-fluorobenzonitrile,
4- (4- (3- ((6-fluoropyridin-3-yl) oxy) propyl) piperazin-1-yl) -1- (benzenesulfonyl) -1H-indole,
1- (4- (4- (3- ((6-fluoropyridin-3-yl) oxy) propyl) piperazin-1-yl) -1H-indol-1-yl) ethan-1-one or
4- (4- (3- ((6-fluoropyridin-3-yl) oxy) propyl) piperazin-1-yl) -1-methyl-1H-indole.
6. A compound of general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, hydrobromide, sulfate, trifluoroacetate or mesylate, preferably hydrochloride or hydrobromide.
7. A process for preparing a compound of general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 6, comprising the steps of:
the compound shown in the general formula (I-1) reacts with the compound shown in the general formula (I-2) to generate a compound shown in the general formula (I-3), and then the compound shown in the general formula (I-4) is subjected to condensation reaction to prepare the compound shown in the general formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof;
or alternatively, the process may be performed,
the compound shown in the general formula (I-1) and the compound shown in the general formula (I-5) are directly reacted to prepare the compound shown in the general formula (I), the stereoisomer or the pharmaceutically acceptable salt thereof;
Wherein:
X 1 and X 2 Is halogen, each independently selected from fluorine, chlorine, bromine or iodine.
M、R 1 、R 2 、R 3 And n is as defined in claim 1.
8. A pharmaceutical composition comprising a therapeutically effective amount of a compound of general formula (I), stereoisomer or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 6, together with one or more pharmaceutically acceptable carriers.
9. Use of a compound of general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, or a pharmaceutical composition according to claim 8 for the preparation of a medicament for the involvement or modulation of the 5-hydroxytryptamine receptor and/or of the dopamine receptor, preferably for the preparation of a medicament for the involvement or modulation of 5-HT 1A Receptors, dopamine D 2 Receptors and/or dopamine D 3 Use of a receptor drug.
10. Use of a compound of general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, or a pharmaceutical composition according to claim 8 for the manufacture of a medicament for the treatment of a central nervous system disorder.
11. The use according to claim 10, wherein the central nervous system disorder is selected from one or more of parkinson's disease PD, schizophrenia, bipolar disorder, depression, anxiety, mania, huntington's disease HD, alzheimer's disease, senile dementia, dementia of the alzheimer's type, memory disorders, loss of executive function, vascular dementia, neuropathic pain and dysfunctional disorders related to intelligence, learning or memory, preferably parkinson's disease.
CN202210113063.2A 2022-01-29 2022-01-29 Aralkyl-4- (1H) indolylpiperazine derivative, preparation method and application thereof Pending CN116554145A (en)

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