CN104163813B - Substituted indole compound, and preparation method and use thereof - Google Patents

Abstract

The invention provides a new indole compound, pharmaceutically acceptable salts and medicinal preparations thereof, and a use of the new indole compound in selective inhibition of 5-hydroxytryptamine reuptake and /or excitation of a 5-HT1A receptor. The invention also relates to medicinal compositions comprising the compounds, and a method for treating the central nervous system dysfunction of mammals, especially humans by using the medicinal compositions.

Description

Substituted indole compounds and methods and uses thereof

technical field

The invention belongs to the technical field of medicines, and in particular relates to compounds and compositions for treating central nervous system dysfunction, as well as methods and applications thereof. In particular, the present invention describes piperazine compounds that can act as serotonin reuptake inhibitors or/and 5-HT _1A receptor agonists.

Background technique

Serotonin, a neurotransmitter that transmits signals in the brain and nervous system, plays an important role in central nervous system (CNS) dysfunction, especially anxiety, depression, aggression and impulsive mood. Antagonizing or stimulating certain types of 5-HT receptors can effectively regulate central nervous system dysfunction. To date, at least 14 serotonin receptors have been identified. These receptors can be divided into different families, respectively recorded as 5-HT ₁ , 5-HT ₂ , 5-HT ₃ , 5-HT ₄ , 5-HT ₅ , 5-HT ₆ and 5-HT ₇ , and each family The different subtypes in are distinguished by a, b and c. The serotonergic neurons of the central nervous system are located in the raphe nucleus of the brainstem, and the 5-HT _1A receptor, a G protein-coupled receptor, is widely distributed in the area that can receive serotonin from the raphe nucleus , including: frontal cortex, lateral septum, amygdala, hippocampus, hypothalamus. In these cortical limbic regions, 5-HT _1A is located in the postsynaptic membrane. At the same time, the 5-HT _1A receptor is also a presynaptic membrane autoreceptor on the raphe nucleus, which can reduce the firing rate of neurons (that is, the amount of serotonin released per action potential), as well as the synthesis of neurotransmitters, Thereby reducing the activity of serotonin in the projection area. Activation of 5-HT _1A receptors on the presynaptic membrane can inhibit the synthesis of tyrosine hydroxylase and the activity of glutamate channels (produced in the medial prefrontal cortex, directed to the raphe nucleus), thereby indirectly reducing the output of serotonin. (Jonathan Savitz, Irwin Lucki, Wayne C. Drevets. 5-HT _1A receptor function in major depressive disorder. Prog Neurobiol. 2009, 88(1): 17-31).

Of all the indications associated with serotonin dysfunction, depression is the most important because according to the World Health Organization, depression has become the fourth most burdensome disease in humans. It is estimated that by 2020, the disability-adjusted life years of depression will rank second among all diseases. (Bromet E, Andrade LH, Hwang I, et al., Cross-nationalepidemiology of DSM-IV major depressive episode. BMC Med. 2011, 9:90).

Historically, pharmacological treatment of mood disorders began in the 1950s and included tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), which rely primarily on the response to neurotransmitters (dopamine, norepinephrine, and 5-hydroxytryptamine) to exert its curative effect. However, non-selectivity to the target and undesired side effects limit their use. By the 1980s, the emergence of serotonin selective reuptake inhibitors (SSRIs) changed this situation. Compared with TCAs, these drugs have comparable efficacy, but fewer side effects, and even if overdose, the toxicity is less (SarkoJ. Andidepressant, old and new. A review of their adverse effects and toxicity in overdose. Emerg Med Clin North Am, 2000;18(4):637-54).

Treatment with traditional SSRIs increases serotonin levels by inhibiting serotonin reuptake and modulating its transport. However, after the use of SSRIs, the 5-HT _1A autoreceptors in the presynaptic membrane will also be activated, resulting in a decrease in the release of serotonin and a decrease in the concentration of serotonin in the synapse. However, with the prolongation of medication time, SSRIs will lead to desensitization of 5-HT _1A autoreceptors, and the activation effect will be restrained, so as to play a normal regulatory role. It can be inferred that the activation of 5-HT _1A autoreceptors is an important reason for delaying the efficacy of SSRIs (Celada P, Puig M, Amargos-Bosch M, et al., The therapeutic role of 5-HT _1A and 5- HT _2A receptors in depression. J Psychiatry Neurosci, 2004, 29(4): 252-65). Therefore, overcoming the negative feedback effects of 5-HT _1A autoreceptor antagonists holds the promise of enhancing and speeding up clinical antidepressants.

In contrast to SSRIs, 5-HT _1A receptor agonists or partial agonists act directly on postsynaptic serotonin receptors to increase serotonin neurotransmission during SSRI latency. Feiger and Wilcox demonstrated that buspirone and gepirone are clinically effective 5-HT _1A partial agonists (Feiger, A. Psychopharmacol. Bull. 1996, 32:659-65). Addition of buspirone to standard SSRI therapy caused significant improvement in patients previously unresponsive to standard treatment for depression (Dimitriou, EJ Clin. Psychopharmacol., 1998, 18:465-9). In January 2011, the FDA approved vilazodone (trade name Viibryd), a new antidepressant with dual effects of SSRI and 5-HT _1A receptor partial agonist, for the treatment of major depressive disorder (MDD) . Compared with traditional SSRIs, vilazodone's own 5-HT _1A receptor agonistic activity theoretically speeds up its onset time, but the promoting effect on the overall antidepressant effect is general (FramptonJE.Vilazodone: in major depressive disorder. CNS Drugs 2011,25(7):615-27).

The invention provides some new compounds with serotonin selective reuptake inhibitor and/or 5-HT _1A receptor agonist activity, which have good clinical application prospect. Compared with existing similar compounds, the compound of the present invention has better drug efficacy, pharmacokinetic properties and/or toxicological properties.

Summary of the invention

The following is merely a general illustration of some aspects of the invention, without limitation thereto. These aspects and others are described more fully later. All references in this specification are hereby incorporated by reference in their entirety. When there is a discrepancy between the disclosure content of this specification and the cited documents, the disclosure content of this specification shall prevail.

The present invention provides a new class of compounds, which have selective inhibitory effect on 5-hydroxytryptamine reuptake and/or agonistic effect on 5-HT _1A receptors, and can be used to prepare and treat human central nervous system (CNS) dysfunction, Medications for depression, anxiety, and bipolar disorder.

The invention also provides methods for preparing such compounds and pharmaceutical compositions containing such compounds.

In one aspect, the present invention relates to a compound, which is a compound represented by formula (I) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, A pharmaceutically acceptable salt or a prodrug thereof,

in:

each Y is independently CR ² or N;

when for , X is CH or N;

when for , X is C;

Hy is selected from the following structures:

R ¹ is F, Cl, Br, I, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ Cycloalkyl, heterocyclic group consisting of 3-10 atoms, C ₆ -C ₁₀ aryl, heteroaryl group consisting of 5-10 atoms, -C(=O)R ⁴ , -(CR ⁶ R ^6a ) _p -C(=O)OR ⁴ , -(CR ⁶ R ^6a ) _p -C(=O)NR ⁵ R ^5a , -C(=NR ⁵ )NR ⁵ R ^5a , -O-(CR ⁶ R ^6a ) _p R ⁴ , -(CR ⁶ R ^6a ) _p -OR ⁴ , -OC(=O)R ⁴ , -OC(=O)NR ⁵ R ^5a , -S(=O) _q R ⁴ , -S(= O) ₂ OR ⁴ , -S(=O) ₂ NR ⁵ R ^5a , -N(R ⁵ )C(=O)R ⁴ , -N(R ⁵ )C(=O)OR ⁴ , -N(R ⁵ )C(=O)NR ⁵ R ^5a , -N(R ⁵ )C(=NR ⁵ )NR ⁵ R ^5a , -N(R ⁵ )S(=O) ₂ R ⁴ or -N(R ⁵ ) S(=O) ₂ NR ⁵ R ^5a , wherein the groups represented by R ¹ are optionally substituted by one or more R ⁷ ;

Each R ² is independently H, F, Cl, Br, I, CN, NO ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ Alkynyl, C ₃ -C ₁₀ cycloalkyl, heterocyclic group consisting of 3-10 atoms, C ₆ -C ₁₀ aryl, heteroaryl group consisting of 5-10 atoms, -C(=O)R ⁴ , -(CR ⁶ R ^6a ) _p -C(=O)OR ⁴ , -(CR ⁶ R ^6a ) _p -C(=O)NR ⁵ R ^5a , -C(=NR ⁵ )NR ⁵ R ^5a , - O-(CR ⁶ R ^6a ) _p R ⁴ , -(CR ⁶ R ^6a ) _p -OR ⁴ , -(CR ⁶ R ^6a ) _p -OC(=O)R ⁴ , -OC(=O)NR ⁵ R ^5a , -OC(=O)N(R ⁵ )S(=O) ₂ R ⁴ , -(CR ⁶ R ^6a ) _p -S(=O) _q R ⁴ , -(CR ⁶ R ^6a ) _p -S (=O) ₂ OR ⁴ , -(CR ⁶ R ^6a ) _p -S(=O) ₂ NR ⁵ R ^5a , -S(=O) ₂ N(R ⁵ )C(=O)R ⁴ , -S (=O) ₂ N(R ⁵ )C(=O)OR ⁴ , -S(=O) ₂ N(R ⁵ )C(=O)NR ⁵ R ^5a , -(CR ⁶ R ^6a ) _p -NR ⁵ R ^5a , -(CR ⁶ R ^6a ) _p -N(R ⁵ )C(=O)R ⁴ , -N(R ⁵ )C(=O)OR ⁴ , -N(R ⁵ )C(=O )NR ⁵ R ^5a , -N(R ⁵ )C(=NR ⁵ )NR ⁵ R ^5a , -(CR ⁶ R ^6a ) _p -N(R ⁵ )S(=O) ₂ R ⁴ or -N(R ⁵ ) S(=O) ₂ NR ⁵ R ^5a ;

Each R ³ is independently H, F, Cl, Br, I, CN, NO ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₁₀ cycloalkyl, 3-10 Heterocyclic group composed of atoms, C ₆ -C ₁₀ aryl group, heteroaryl group composed of 5-10 atoms, -C(=O)R ⁴ , -C(=O)OR ⁴ , -(CR ⁶ R ^6a ) _p -C(=O)NR ⁵ R ^5a , -(CR ⁶ R ^6a ) _p -OR ⁴ , -OC(=O)R ⁴ , -OC(=O)NR ⁵ R ^5a , -OC(=O )NR ⁵ S(=O) ₂ R ⁴ , -SR ⁴ , -S(=O)R ⁴ , -S(=O) ₂ R ⁴ , -S(=O) ₂ OR ⁴ , -S(=O) ) ₂ NR ⁵ R ^5a , -S(=O) ₂ N(R ⁵ )C(=O)R ⁴ , -S(=O) ₂ N(R ⁵ )C(=O)OR ⁴ , -S( =O) ₂ N(R ⁵ )C(=O)NR ⁵ R ^5a , -NR ⁵ R ^5a , -N(R ⁵ )C(=O)R ⁴ , -N(R ⁵ )C(=O) OR ⁴ , -N(R ⁵ )C(=O)NR ⁵ R ^5a , -N(R ⁵ )C(=NR ⁵ )NR ⁵ R ^5a , -N(R ⁵ )S(=O) ₂ R ⁴ Or -N(R ⁵ )S(=O) ₂ NR ⁵ R ^5a , or the R ³ groups on two adjacent ring carbon atoms combine to form a C ₃ -C ₁₀ cycloalkyl group or a group consisting of 3-10 atoms Heterocyclyl, wherein the groups represented by each R ³ are optionally substituted by one or more R ⁷ ;

Each R ⁴ is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, heterocyclic group consisting of 3-10 atoms, C ₆ -C ₁₀ aryl or heteroaryl consisting of 5-10 atoms;

Each R ⁵ and R ^5a are independently H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, 3-10 atoms A heterocyclic group composed of C ₆ -C ₁₀ aryl or a heteroaryl group composed of 5-10 atoms, or R ⁵ , R ^5a , together with the nitrogen atom connected to them, form a heteroaryl group composed of 3-10 atoms Cyclic group or heteroaryl group composed of 5-10 atoms;

Each R ⁶ and R ^6a are independently H, F, Cl, Br, I, CN, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, heterocyclic group consisting of 3-10 atoms, C ₆ -C ₁₀ aryl group or heteroaryl group consisting of 5-10 atoms, or R ⁶ , R ^6a , and the carbon atoms connected to them Together, form a C ₃ -C ₁₀ cycloalkyl group or a heterocyclic group consisting of 3-10 atoms;

Each R ⁷ is independently F, Cl, Br, I, CN, OH, NH ₂ , SH, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ - C ₆ alkoxy, C ₁ -C ₆ alkylamino, -(C ₁ -C ₆ alkylene)-SH, C ₃ -C ₁₀ cycloalkyl, heterocyclic group consisting of 3-10 atoms, C ₆ -C ₁₀ aryl or heteroaryl consisting of 5-10 atoms;

m is 3, 4, 5 or 6;

each n is independently 1, 2, 3 or 4;

each p is independently 0, 1, 2, 3 or 4;

each q is independently 0, 1 or 2;

The condition is that when R1 is ^F , Hy cannot be the following structure:

In one embodiment, each R ² is independently H, F, Cl, Br, I, CN, NO ₂ , OH, NH ₂ , C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylamino, C ₁ -C ₄ alkylmercapto, -S(=O)R ⁴ , -S(=O) ₂ R ⁴ , -S(=O) ₂ OR ⁴ or -S(=O) ₂ NR ⁵ R ^5a .

In another embodiment, each Y is independently CH.

In another embodiment, the compound has the structure shown in formula (II):

Or its stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or its prodrug, wherein:

R ¹ is F, Cl, Br, I, CN, -O-(CR ⁶ R ^6a ) _p R ⁴ , -(CR ⁶ R ^6a ) _p -OR ⁴ or -C(=O)NR ⁵ R ^5a ;

Each R ³ is independently H, F, Cl, Br, I, CN, C ₁ -C ₆ alkyl, C ₁ -C ₄ haloalkyl, -O-(CR ⁶ R ^6a ) _p R ⁴ , -(CR ⁶ R ^6a ) _p -OR ⁴ or -(CR ⁶ R ^6a ) _p -C(=O)NR ⁵ R ^5a ;

Each R ⁴ is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, heterocyclic group consisting of 3-10 atoms, C ₆ -C ₁₀ aryl or heteroaryl consisting of 5-10 atoms;

Each R ⁵ and R ^5a are independently H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, 3-10 atoms A heterocyclic group composed of C ₆ -C ₁₀ aryl or a heteroaryl group composed of 5-10 atoms, or R ⁵ , R ^5a , together with the nitrogen atom connected to them, form a heteroaryl group composed of 3-8 atoms Cyclic group or heteroaryl group composed of 5-10 atoms;

Each R ⁶ and R ^6a are independently H, F, Cl, Br, I, CN, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, heterocyclic group consisting of 3-10 atoms, C ₆ -C ₁₀ aryl group or heteroaryl group consisting of 5-10 atoms, or R ⁶ , R ^6a , and the carbon atoms connected to them Together, form a C ₃ -C ₈ cycloalkyl group or a heterocyclic group consisting of 3-8 atoms;

m is 3, 4, 5 or 6;

each n is independently 1, 2, 3 or 4;

each p is independently 0, 1, 2, 3 or 4;

The proviso is that when R1 is ^F , ^R3 cannot be 6- _OCH3 , 3- _OCH3 or 6-Cl.

In another embodiment, each R ⁴ is independently C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, heterocyclyl consisting of 3-6 atoms, phenyl, or 5-6 atoms The heteroaryl.

In another embodiment, each R ⁵ and R ^5a are independently H, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, heterocyclyl consisting of 3-6 atoms, phenyl or A heteroaryl group composed of 5-6 atoms, or R ⁵ , R ^5a , together with the nitrogen atoms connected to them, form a heterocyclic group composed of 3-6 atoms or a heteroaryl group composed of 5-6 atoms.

In another embodiment, R1 is ^F , Cl, Br, CN, _-OCH3 or -C(=O) _NH2 .

In another embodiment, each R ³ is independently H, Cl, CN, CH ₃ , —OCH ₃ , —C(=O)NH ₂ , or —CF ₃ , with the proviso that when R ¹ is F, R ³ cannot be 6-OCH ₃ , 3-OCH ₃ or 6-Cl.

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

In some embodiments, the pharmaceutical composition of the present invention further comprises an additional therapeutic agent selected from antidepressant drugs, anxiolytic drugs, lithium salt drugs as mood stabilizers, atypical anti- Psychotropic drugs, antiepileptic drugs, antiparkinsonian drugs, drugs that act as serotonin selective reuptake inhibitors and/or 5-HT _1A receptor agonists, central nervous system stimulants, nicotinic antagonists, or combinations thereof .

In some other embodiments, the pharmaceutical composition of the present invention, wherein the additional therapeutic agent is amitriptyline (amitriptyline), desipramine (desipramine), mirtazapine (mirtazapine), amphetamine Bupropion, reboxetine, fluoxetine, trazodone, sertraline, duloxetine, fluvoxamine, rice Milnacipran, levomilnacipran, desvenlafaxine, vilazodone, venlafaxine, dapoxetine, Nefazodone, femoxetine, clomipramine, citalopram, escitalopram, paroxetine, lithium carbonate , Eskalith), buspirone (buspirone), olanzapine (olanzapine), quetiapine (quetiapine), risperidone (risperidone), ziprasidone (ziprasidone), aripiprazole (aripiprazole), piperazine Perospirone, clozapine, modafinil, mecamylamine, cabergoline, adamantane, imipramine, pramipexole, thyroxine, or a combination thereof.

On the other hand, the use of the compound or pharmaceutical composition of the present invention in the preparation of medicaments for preventing, treating or alleviating central nervous system dysfunction in mammals, including humans, can be used.

In some embodiments, the central nervous system dysfunction described in the present invention responds to the regulation of serotonin receptors, and is a kind of mental disorder, referring to depression, anxiety, mania, schizophrenia, bipolar Disorders, sleep disorders, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, movement disorders, sexual dysfunction, musculoskeletal pain disorders, cognitive disorders, memory disorders, Parkinson's disease, Huntington's disease, phobias , substance abuse or addiction, drug addiction withdrawal symptoms and PMS.

In another aspect, the present invention relates to processes for the preparation, isolation and purification of compounds encompassed by formula (I).

Biological test results show that the compound provided by the invention can be used as a better 5-hydroxytryptamine selective reuptake inhibitor and/or 5-HT _1A receptor agonist.

Any embodiment of any aspect of the present invention may be combined with other embodiments as long as they do not contradict each other. In addition, in any embodiment of any aspect of the present invention, any technical feature can be applied to the technical feature in other embodiments, as long as there is no contradiction between them.

The preceding description merely outlines certain aspects of the invention, but is not intended to be limiting. These and other aspects will be described in more detail and more fully below.

Detailed Description of the Invention

Definitions and General Terms

Certain embodiments of the invention are now described in detail, examples of which are illustrated by the accompanying Structural and Chemical Formulas. The present invention is intended to cover all alternatives, modifications and equivalent technical solutions, which are included within the scope of the present invention as defined by the claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application (including, but not limited to, defined terms, term usage, described techniques, etc.), this Application shall prevail.

It is further appreciated that certain features of the invention, which, for clarity, have been described in multiple separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

Unless otherwise specified, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications referred to herein are hereby incorporated by reference in their entirety.

As used herein, the following definitions shall apply unless otherwise stated. For the purposes of the present invention, the chemical elements correspond to the Periodic Table of the Elements, CAS Edition, and Handbook of Chemistry and Physics, 75th Edition, 1994. In addition, the general principles of organic chemistry can refer to the descriptions in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, Its entire content is incorporated herein by reference.

As used herein, the articles "a", "an" and "the" are intended to include "at least one" or "one or more" unless otherwise stated or clearly contradicted by context. Therefore, as used herein, these articles refer to articles of one or more than one (ie, at least one) object. For example, "a component" refers to one or more components, ie there may be more than one component contemplated to be employed or used in the practice of the described embodiment.

The term "subject" as used in the present invention refers to an animal. Typically the animal is a mammal. Subjects, for example, also refer to primates (such as humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

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

The term "comprising" is an open expression, that is, it includes the content specified in the present invention, but does not exclude other content.

"Stereoisomers" refer to compounds that have the same chemical structure, but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, etc. .

"Chiral" is a molecule that has the property of being nonsuperimposable to its mirror image; and "achiral" is a molecule that is superimposable to its mirror image.

"Enantiomer" refers to two non-superimposable isomers of a compound that are mirror images of each other.

"Diastereoisomer" refers to stereoisomers that have two or more chiral neutralities and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting points, boiling points, spectral properties and reactivity. Diastereomeric mixtures can be separated by high resolution analytical procedures such as electrophoresis and chromatography, eg HPLC.

The stereochemical definitions and rules used in the present invention generally follow S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

Many organic compounds exist in optically active forms, ie they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to its chiral center or centers. The prefixes d and 1 or (+) and (-) are symbols used to designate rotation of plane polarized light by a compound, where (-) or 1 indicates that the compound is levorotatory. Compounds prefixed with (+) or d are dextrorotatory. A specific stereoisomer is an enantiomer and a mixture of such isomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate and can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

Any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein may exist in racemic or enantiomerically enriched form, such as (R)-, (S)- or (R,S)-configuration exist. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.

Depending on the choice of starting materials and processes, the compounds of the invention can be obtained as one of the possible isomers or as mixtures thereof, such as racemates and diastereomer mixtures (depending on the number of asymmetric carbon atoms) form exists. Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituent of the cycloalkyl group may have the cis or trans configuration.

The resulting mixture of any stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereoisomers on the basis of differences in the physicochemical properties of the components, for example, by chromatography method and/or fractional crystallization.

The racemates of any resulting final products or intermediates can be resolved into the optical antipodes by known methods by methods familiar to those skilled in the art, e.g., by subjecting the obtained diastereomeric salts thereof to separate. Racemic products can also be separated by chiral chromatography, eg, high performance liquid chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers may be prepared by asymmetric synthesis, see for example Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 ^nd Ed. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, ELStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SHTables of Resolving Agents and Optical Resolutions p.268 (ELEliel, Ed., Univ.of Notre Dame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that are interconvertible through a low energy barrier. If tautomerism is possible (eg, in solution), then a chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol isomerization and imine-enol isomerization Amine isomerization. Valence tautomers include interconversions by recombination of some of the bonding electrons. A specific example of keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention. "Pharmaceutically acceptable" means compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with patient tissues without undue toxicity, irritation, allergic The benefit/risk ratio is proportionate to other concerns and complications, and effective for the intended purpose.

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

As described in the present invention, the compounds of the present invention can be optionally substituted by one or more substituents, such as the above general formula compounds, or as specific examples in the examples, subclasses, and included in the present invention A class of compounds.

The term "substituted" or "substituted" means that one or more hydrogen atoms in the structure are replaced by a particular substituent. Unless otherwise indicated, a substituted group may have a substituent at each substitutable position of the group. When more than one position in a given formula can be substituted by one or more substituents selected from a particular group, then the substituents can be substituted at each position the same or differently.

The term "unsubstituted" means that the specified group bears no substituents.

The term "optionally substituted by..." can be used interchangeably with the term "unsubstituted or substituted by...", that is, the structure in question is either unsubstituted or replaced by one or more The substituents described in the present invention are substituted, and the substituents described in the present invention include, but are not limited to, F, Cl, Br, I, CN, OH, NH ₂ , SH, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamino, -(C ₁ -C ₆ alkylene)-OH, -(C ₁ -C ₆ Alkylene)-NH ₂ , -(C ₁ -C ₆ Alkylene) -SH, -(C ₁ -C ₆ Alkylene) -(C ₁ -C ₆ Alkoxy), -(C ₁ - C ₆ alkylene)-(C ₁ -C ₆ alkylamino), -(C ₁ -C ₆ alkylene)-(C ₁ -C ₆ alkylthio), C ₃ -C ₁₀ cycloalkyl, 3 - a heterocyclic group consisting of 10 atoms, a C ₆ -C ₁₀ aryl group or a heteroaryl group consisting of 5-10 atoms, etc.

In addition, it should be noted that, unless otherwise clearly stated, the descriptions used in the present invention are "each...independently" and "...independently" and "...independently " can be interchanged, and should be understood in a broad sense. It can mean that in different groups, the specific options expressed by the same symbols do not affect each other, or it can mean that in the same group, the options between the same symbols The specific options expressed between them do not affect each other.

In each part of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to the type or range of the group. It is specifically intended that the invention includes each individual subcombination of individual members of these radical classes and ranges. For example, the term "C ₁ -C ₆ alkyl" specifically refers to independently disclosed methyl, ethyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl and C ₆ alkyl.

In various sections of the invention linking substituents are described. When the structure clearly requires a linking group, the Markush variables recited for that group are to be understood as linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable recites "alkyl" or "aryl," it is understood that "alkyl" or "aryl" respectively represents the linking group. An alkylene group or an arylene group.

The term "alkyl" or "alkyl group" used in the present invention means a saturated linear or branched monovalent hydrocarbon group containing 1-20 carbon atoms, wherein the alkyl group can be optionally substituted by one or more of the substituents described herein. Unless otherwise specified, an alkyl group contains 1-20 carbon atoms. In one embodiment, the alkyl group contains 1-12 carbon atoms; in another embodiment, the alkyl group contains 1-6 carbon atoms; in yet another embodiment, the alkyl group contains 1 - 4 carbon atoms; in yet another embodiment, the alkyl group contains 1-3 carbon atoms.

Examples of alkyl groups include, but are not limited to, methyl (Me, -CH ₃ ), ethyl (Et, -CH ₂ CH ₃ ), n-propyl (n-Pr, -CH ₂ CH ₂ CH ₃ ), isopropyl (i-Pr, -CH(CH ₃ ) ₂ ), n-butyl (n-Bu, -CH ₂ CH ₂ CH ₂ CH ₃ ), isobutyl (i-Bu, -CH ₂ CH (CH ₃ ) ₂ ), sec-butyl (s-Bu, -CH(CH ₃ )CH ₂ CH ₃ ), tert-butyl (t-Bu, -C(CH ₃ ) ₃ ), n-pentyl (-CH 2CH ₂ CH ₂ CH ₂ CH ₃ ), ₂ -pentyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-pentyl (-CH(CH ₂ CH ₃ ) ₂ ), 2-methyl -2-butyl (-C(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl (-CH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-1- Butyl (-CH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1-butyl (-CH ₂ CH(CH ₃ )CH ₂ CH ₃ ), n-hexyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-hexyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl (-CH(CH ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ )), 2-methyl-2-pentyl (-C(CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 3-methyl-2-pentyl (-CH(CH ₃ )CH(CH ₃ )CH ₂ CH ₃ ), 4-methyl-2-pentyl (-CH(CH ₃ )CH ₂ CH(CH ₃ ) ₂ ), 3-methyl-3-pentyl (-C(CH ₃ )(CH ₂ CH ₃ ) ₂ ), 2-methyl-3-pentyl (-CH(CH ₂ CH ₃ ) CH(CH ₃ ) ₂ ), 2,3-dimethyl-2-butyl (-C(CH ₃ ) ₂ CH (CH ₃ ) ₂ ), 3,3-dimethyl-2-butyl (-CH(CH ₃ )C(CH ₃ ) ₃ ), n-heptyl, n-octyl, and the like.

The term "alkylene" means a saturated divalent hydrocarbyl group obtained by removing two hydrogen atoms from a saturated straight or branched chain hydrocarbyl group. Unless otherwise specified, an alkylene group contains 1-12 carbon atoms. In one embodiment, an alkylene group contains 1-6 carbon atoms; in another embodiment, an alkylene group contains 1-4 carbon atoms; in yet another embodiment, an alkylene group The group contains 1-3 carbon atoms; in yet another embodiment, the alkylene group contains 1-2 carbon atoms. Such examples include methylene ( _-CH2- ), ethylene ( _-CH2CH2- ), isopropylidene (-CH( _{CH3 )} CH2- ₎ , and the like.

As used herein, the term "alkyl" and its prefix "alk" include both straight and branched saturated carbon chains.

The term "alkenyl" means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, wherein there is at least one unsaturated site, that is, a carbon-carbon sp ² double bond, wherein the alkenyl group Groups may be optionally substituted with one or more substituents described herein, including the "cis" and "tans" orientation, or the "E" and "Z" orientation. In one embodiment, an alkenyl group contains 2-8 carbon atoms; in another embodiment, an alkenyl group contains 2-6 carbon atoms; in yet another embodiment, an alkenyl group contains 2 - 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl (-CH= _CH2 ), allyl (-CH2CH= _{CH2 )} , and the like.

The term "alkynyl" means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, wherein there is at least one unsaturated site, that is, a carbon-carbon sp triple bond, wherein the alkynyl group Can be optionally substituted with one or more substituents described herein. In one embodiment, the alkynyl group contains 2-8 carbon atoms; in another embodiment, the alkynyl group contains 2-6 carbon atoms; in yet another embodiment, the alkynyl group contains 2 - 4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH2C≡CH), ₁ -propynyl (-C≡C- _CH3 ), and the like .

The term "alkoxy" denotes an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning described herein. Unless specified otherwise, the alkoxy groups contain 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms; in another embodiment, the alkoxy group contains 1-4 carbon atoms; in yet another embodiment, the alkoxy group Groups contain 1-3 carbon atoms. The alkoxy groups may be optionally substituted with one or more substituents described herein.

Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH ₃ ), ethoxy (EtO, -OCH ₂ CH ₃ ), 1-propoxy (n-PrO, n- Propoxy, -OCH ₂ CH ₂ CH ₃ ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH ₃ ) ₂ ), 1-butoxy (n-BuO, n- Butoxy, -OCH ₂ CH ₂ CH ₂ CH ₃ ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH ₂ CH(CH ₃ ) ₂ ), 2-butane Oxygen (s-BuO, s-butoxy, -OCH(CH ₃ )CH ₂ CH ₃ ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH ₃ ) ₃ ), 1-pentyloxy (n-pentyloxy, -OCH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyloxy (-OCH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-pentyloxy (-OCH(CH ₂ CH ₃ ) ₂ ), 2-methyl-2-butoxy (-OC(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butoxy (-OCH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-l-butoxy (-OCH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-l-butoxy ( _-OCH2CH ( _CH3 ) _{CH2CH3 )} , and so on.

The term "haloalkyl" or "haloalkoxy" means an alkyl, or alkoxy group substituted by one or more halogen atoms, wherein alkyl and alkoxy have the meanings described herein, examples of which include , but not limited to, chloromethyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, etc.

The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N,N-dialkylamino", wherein the amino groups are each independently substituted with one or two alkyl groups. In some embodiments, alkylamino is a lower alkylamino group with one or two C _1-6 alkyl groups attached to a nitrogen atom. In some other embodiments, the alkylamino is a C _1-3 lower alkylamino group. Suitable alkylamino groups may be mono- or di-alkylamino, examples of which include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N- -Diethylamino and the like.

The term "aminoalkyl" denotes a C ₁ -C ₁₀ straight or branched chain alkyl group substituted by one or more amino groups. In some embodiments, aminoalkyl is C ₁ -C ₆ "lower aminoalkyl" substituted with one or more amino groups, examples of which include, but are not limited to, aminomethyl, Aminoethyl, aminopropyl, aminobutyl and aminohexyl.

The term "mercaptoalkyl" denotes a C ₁ -C ₁₀ straight or branched chain alkyl group substituted with one or more mercapto groups. In some embodiments, mercaptoalkyl is a C ₁ -C ₆ "lower mercaptoalkyl" substituted with one or more mercapto groups, examples of which include, but are not limited to, mercaptomethyl, Mercaptoethyl.

The term "cycloalkyl" refers to a saturated monocyclic, bicyclic, or tricyclic ring system containing 3 to 12 carbon atoms. Bicyclic or tricyclic ring systems may include fused, bridged and spiro rings. In some embodiments, the cycloalkyl group contains 3-10 carbon atoms, and in other embodiments, the cycloalkyl group contains 3-8 carbon atoms. And the cycloalkyl group can be independently unsubstituted or substituted with one or more substituents described in the present invention.

The term "heteroatom" means one or more of oxygen (O), sulfur (S), nitrogen (N), phosphorus (P) or silicon (Si), including nitrogen (N), sulfur (S) and phosphorus (P) in any oxidation state; in the form of primary, secondary, tertiary amines and quaternary ammonium salts; or in the form in which the hydrogen on the nitrogen atom in a heterocyclic ring is substituted, for example, N (as in 3,4-dihydro-2H-pyrrolyl N), NH (like NH in pyrrolidinyl) or NR (like NR in N-substituted pyrrolidinyl).

The terms "heterocyclyl" and "heterocycle" are used interchangeably herein to refer to a monocyclic, bicyclic or tricyclic ring containing 3-14 ring atoms, at least one of which is selected from nitrogen, sulfur and oxygen atoms . Rings may be fully saturated or contain one or more degrees of unsaturation, but are never aromatic. Unless otherwise stated, a heterocyclyl group can be carbonyl or nitrogenyl, and a _-CH2- group can optionally be replaced by -C(O)-. Ring sulfur atoms can optionally be oxidized to S-oxides. Ring nitrogen atoms can optionally be oxidized to N-oxygen compounds. In one embodiment, the heterocyclic group is a heterocyclic group consisting of 3-10 atoms, which refers to a saturated or partially unsaturated monocyclic or bicyclic ring containing 3-10 ring atoms. In another embodiment, the heterocyclic group is a heterocyclic group consisting of 3-8 atoms, which refers to a saturated or partially unsaturated monocyclic or bicyclic ring containing 3-8 ring atoms. In another embodiment, the heterocyclic group is a heterocyclic group consisting of 3-6 atoms, which refers to a saturated or partially unsaturated monocyclic ring containing 3-6 ring atoms.

Examples of heterocyclic groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl , pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuryl, dihydrofuryl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolyl, disulfide Pentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl , Dioxanyl, Dithianyl, Thioxanyl, Homopiperazinyl, Homopiperidinyl, Oxepanyl, Thiepanyl, Oxazepine base, diazepine base, thiazepine Base, indolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,3-benzodioxolyl, 2-oxa-5-azabicyclo[2.2.1]hept-5 -base. Examples of -CH ₂ - groups in heterocyclic groups substituted with -C(O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinone 3,5-dioxopiperidinyl and pyrimidinedione. Examples of oxidized sulfur atoms in heterocyclic groups include, but are not limited to, sulfolane, 1,1-dioxothiomorpholinyl. Said heterocyclyl groups may be optionally substituted with one or more substituents described herein.

The term "aryl" denotes monocyclic, bicyclic and tricyclic carbocyclic ring systems containing 6-14 ring atoms, or 6-10 ring atoms, or 6 ring atoms, wherein at least one ring system is aromatic , wherein each ring system contains rings composed of 3-7 atoms. The aryl group is usually, but not necessarily, attached to the parent molecule through the aromatic ring of the aryl group. The term "aryl" is used interchangeably with the term "aromatic ring". Examples of aryl groups may include phenyl, naphthyl and anthracene. The aryl groups may be independently optionally substituted with one or more substituents described herein.

The term "heteroaryl" denotes monocyclic, bicyclic and tricyclic ring systems containing 5-14 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring system is aromatic, And at least one ring system contains one or more heteroatoms, wherein each ring system contains a ring composed of 5-7 atoms. The heteroaryl group is usually, but not necessarily, attached to the parent molecule through the aromatic ring of the heteroaryl group. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl" or "heteroaromatic". The heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, the heteroaryl group of 5-10 atoms contains 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.

Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl , 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2- Pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3- Triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5- Triazinyl; also includes, but is by no means limited to, the following bicyclic rings: benzimidazolyl, benzofuryl, benzothienyl, indolyl (eg 2-indolyl), purinyl, quinolinyl (such as 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (such as 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl), imidazole And[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazole And[1,5-a]pyridyl, etc.

The term "carbonyl", which means -(C=O)-, can be used alone or in combination with other terms; the term "acyl" means -(C=O)-R; "amido" means -NH(C=O) -R; "carbamoyl" means -C(=O) _NH2 , where R represents an alkyl group.

The term "azido" means an azide structure (-N ₃ ). This group can be linked with other groups, for example, with a methyl group, it can form azidomethane (methyl azide, MeN ₃ ); and with a phenyl group, it can form a phenyl Azide (PhN ₃ ).

As described in the present invention, substituents drawing a bond to the central ring to form a ring system (shown below) means that substituents can be substituted at any substitutable position on the ring. For example, formula a represents any position that may be substituted on ring B, as shown in formula b.

The term "spirocyclyl", "spiro ring", means that a ring originates from a special ring carbon on another ring, for example, as described in the following formula c, formula d, ring A and ring B in two saturated Ring systems that share one carbon atom are called "spirocycles" or "spirobicycles". Each ring in a spirocycle is independently carbocyclic or heterocyclic. Such examples include, but are not limited to, 4-oxaspiro[2.4]heptan-6-yl, (R)-4-azaspiro[2.4]heptan-6-yl, spirobicyclyl may independently be Substituted or replaced by one or more substituents described herein.

The term "fused bicyclic", "fused ring", "fused bicyclic group" or "fused cyclic group", as shown in formula e-g, means between two five-membered rings (formula e), two six-membered Between rings (formula f), and between a five-membered ring and a six-membered ring (formula g), a bridged ring system sharing a C-C bond. The system may contain isolated or conjugated unsaturated bonds, but the core ring structure does not include aromatic or heteroaromatic rings (substituents may be aromatic). Each ring in the fused bicyclic ring is independently carbocyclic or heterocyclic.

Examples of fused bicyclic rings include, but are not limited to, hexahydrofuro[2,3-b]furan-3-yl, hexahydrofuro[3,2-b]furan-3-yl, octahydrocyclopentane a[c]pyrrol-5-yl, octahydropentalen-2-yl, octahydro-1H-isoindol-5-yl, and the like. Fused bicyclic groups can be independently unsubstituted or substituted with one or more substituents described herein.

Unless otherwise indicated, the structural formulas described in the present invention include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, those containing asymmetric centers R, S configuration, double bond (Z), (E) isomers, and (Z), (E) conformational isomers. Accordingly, individual stereochemical isomers of the compounds of the present invention or mixtures thereof as enantiomers, diastereomers, or geometric isomers (or conformational isomers) are within the scope of the present invention.

The term "tautomer" or "tautomeric form" as used in the present invention means that structural isomers with different energies can cross a low energy barrier and thus interconvert. For example, proton tautomerization (ie, prototropism) includes interconversions via migration of a proton, such as keto-enol tautomerization and imine-enamine isomerization. Valence tautomers include interconversion by recombination of some of the bonding electrons.

Unless otherwise indicated, all tautomeric forms of the compounds of the invention are included within the scope of the invention. In addition, unless otherwise indicated, the structural formulas of the compounds described herein include enriched isotopes of one or more different atoms.

The term "prodrug" used in the present invention means that a compound is transformed into a compound represented by formula (I) in vivo. Such conversion is effected by prodrug hydrolysis in blood or enzymatic conversion in blood or tissue to the parent structure. The prodrug compound of the present invention can be an ester. In the existing invention, the ester can be used as a prodrug with phenyl esters, aliphatic (C _1-24 ) esters, acyloxymethyl esters, and carbonates. , carbamates and amino acid esters. For example, a compound of the present invention contains an OH group, which can be acylated to give the compound in prodrug form. Other prodrug forms include phosphate esters, eg, phosphorylated parent hydroxyl groups. A complete discussion of prodrugs can be found in: Higuchi et al., Pro-drugs as Novel Delivery Systems, Vol. 14, ACSSymposium Series; Roche et al., ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; Rautio et al., Prodrugs: Design and Clinical Applications, Nature Reviews Drug Discovery, 2008, 7, 255-270, and Hecker et al, Prodrugs of Phosphates and Phosphonates, J. Med. Chem., 2008, 51, 2328- 2345, each article is hereby incorporated by reference.

"Metabolite" refers to a product obtained through metabolism of a specific compound or its salt in vivo. Metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized using assays as described herein. Such products can be obtained by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, degreasing, enzymatic cleavage and the like of the administered compound. Accordingly, the invention includes metabolites of the compounds, including metabolites produced by contacting a compound of the invention with a mammal for a substantial period of time.

Definitions of stereochemistry and usage of conventions in the present invention are generally referred to in the following literature: Parker et al., ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York and Eliel et al., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the present invention may contain asymmetric centers or chiral centers and thus exist as different stereoisomers. All stereoisomeric forms of the compounds of the present invention, including but not limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, constitute the present invention part. Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D, L or R, S are used to indicate the absolute configuration of the molecular chiral center. The prefixes d, l or (+), (-) are used to name the symbol of the plane polarized light rotation of the compound, (-) or l means that the compound is left-handed, and the prefix (+) or d means that the compound is right-handed. The chemical structures of these stereoisomers are the same, but their three-dimensional structures are different. A particular stereoisomer may be an enantiomer, and a mixture of isomers is often referred to as an enantiomeric mixture. A 50:50 mixture of enantiomers is known as a racemic mixture or racemate, which can result in no stereoselectivity or stereospecificity during a chemical reaction. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers, devoid of optical activity.

The "pharmaceutically acceptable salt" used in the present invention refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19, 1977. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or other methods such as ion exchange methods recorded in books and literature these salts. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphorate Salt, camphorsulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, Malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3 - Phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts obtained with appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. The present invention also contemplates the quaternary ammonium salts of any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations formed as counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C _{1 -8} sulfonates and aromatic sulfonates.

A "solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association of solvent molecules with water.

The term "protecting group" or "PG" refers to a substituent that reacts with another functional group, usually to block or protect specific functionality. For example, "amino-protecting group" refers to a substituent attached to the amino group to block or protect the functionality of the amino group in the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, a "hydroxyl protecting group" refers to a substituent of a hydroxy group used to block or protect the functionality of the hydroxy group, suitable protecting groups include acetyl and silyl groups. "Carboxyl protecting group" refers to the substituent of carboxyl to block or protect the functionality of carboxyl. General carboxyl protecting groups include -CH ₂ CH ₂ SO ₂ Ph, cyanoethyl, 2-(trimethylsilane base) ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenyl phosphino)ethyl, nitroethyl, etc. A general description of protecting groups can be found in: Greene et al., Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991 and Kocienski et al., Protecting Groups, Thieme, Stuttgart, 2005.

DESCRIPTION OF THE COMPOUNDS OF THE INVENTION

The indole compound involved in the present invention, its pharmaceutically acceptable salt, pharmaceutical preparation and composition thereof, can be used as 5-hydroxytryptamine selective reuptake inhibitor and/or 5-HT _1A receptor agonist, to human central There are potential uses for the treatment of neurological disorders such as depression, anxiety, and bipolar disorder.

In particular, the present invention relates to one aspect, and the present invention relates to a compound, which is a compound represented by formula (I) or a stereoisomer, a tautomer, a nitrogen oxide, or a compound represented by formula (I). Solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof,

in:

each Y is independently CR ² or N;

when for , X is CH or N;

when for , X is C;

Hy is selected from the following structures:

R ¹ is F, Cl, Br, I, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ Cycloalkyl, heterocyclic group consisting of 3-10 atoms, C ₆ -C ₁₀ aryl, heteroaryl group consisting of 5-10 atoms, -C(=O)R ⁴ , -(CR ⁶ R ^6a ) _p -C(=O)OR ⁴ , -(CR ⁶ R ^6a ) _p -C(=O)NR ⁵ R ^5a , -C(=NR ⁵ )NR ⁵ R ^5a , -O-(CR ⁶ R ^6a ) _p R ⁴ , -(CR ⁶ R ^6a ) _p -OR ⁴ , -OC(=O)R ⁴ , -OC(=O)NR ⁵ R ^5a , -S(=O) _q R ⁴ , -S(= O) ₂ OR ⁴ , -S(=O) ₂ NR ⁵ R ^5a , -N(R ⁵ )C(=O)R ⁴ , -N(R ⁵ )C(=O)OR ⁴ , -N(R ⁵ )C(=O)NR ⁵ R ^5a , -N(R ⁵ )C(=NR ⁵ )NR ⁵ R ^5a , -N(R ⁵ )S(=O) ₂ R ⁴ or -N(R ⁵ ) S(=O) ₂ NR ⁵ R ^5a , wherein the groups represented by R ¹ are optionally substituted by one or more R ⁷ ;

Each R ² is independently H, F, Cl, Br, I, CN, NO ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ Alkynyl, C ₃ -C ₁₀ cycloalkyl, heterocyclic group consisting of 3-10 atoms, C ₆ -C ₁₀ aryl, heteroaryl group consisting of 5-10 atoms, -C(=O)R ⁴ , -(CR ⁶ R ^6a ) _p -C(=O)OR ⁴ , -(CR ⁶ R ^6a ) _p -C(=O)NR ⁵ R ^5a , -C(=NR ⁵ )NR ⁵ R ^5a , - O-(CR ⁶ R ^6a ) _p R ⁴ , -(CR ⁶ R ^6a ) _p -OR ⁴ , -(CR ⁶ R ^6a ) _p -OC(=O)R ⁴ , -OC(=O)NR ⁵ R ^5a , -OC(=O)N(R ⁵ )S(=O) ₂ R ⁴ , -(CR ⁶ R ^6a ) _p -S(=O) _q R ⁴ , -(CR ⁶ R ^6a ) _p -S (=O) ₂ OR ⁴ , -(CR ⁶ R ^6a ) _p -S(=O) ₂ NR ⁵ R ^5a , -S(=O) ₂ N(R ⁵ )C(=O)R ⁴ , -S (=O) ₂ N(R ⁵ )C(=O)OR ⁴ , -S(=O) ₂ N(R ⁵ )C(=O)NR ⁵ R ^5a , -(CR ⁶ R ^6a ) _p -NR ⁵ R ^5a , -(CR ⁶ R ^6a ) _p -N(R ⁵ )C(=O)R ⁴ , -N(R ⁵ )C(=O)OR ⁴ , -N(R ⁵ )C(=O )NR ⁵ R ^5a , -N(R ⁵ )C(=NR ⁵ )NR ⁵ R ^5a , -(CR ⁶ R ^6a ) _p -N(R ⁵ )S(=O) ₂ R ⁴ or -N(R ⁵ ) S(=O) ₂ NR ⁵ R ^5a ;

Each R ³ is independently H, F, Cl, Br, I, CN, NO ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₁₀ cycloalkyl, 3-10 Heterocyclic group composed of atoms, C ₆ -C ₁₀ aryl group, heteroaryl group composed of 5-10 atoms, -C(=O)R ⁴ , -C(=O)OR ⁴ , -(CR ⁶ R ^6a ) _p -C(=O)NR ⁵ R ^5a , -(CR ⁶ R ^6a ) _p -OR ⁴ , -OC(=O)R ⁴ , -OC(=O)NR ⁵ R ^5a , -OC(=O )NR ⁵ S(=O) ₂ R ⁴ , -SR ⁴ , -S(=O)R ⁴ , -S(=O) ₂ R ⁴ , -S(=O) ₂ OR ⁴ , -S(=O) ) ₂ NR ⁵ R ^5a , -S(=O) ₂ N(R ⁵ )C(=O)R ⁴ , -S(=O) ₂ N(R ⁵ )C(=O)OR ⁴ , -S( =O) ₂ N(R ⁵ )C(=O)NR ⁵ R ^5a , -NR ⁵ R ^5a , -N(R ⁵ )C(=O)R ⁴ , -N(R ⁵ )C(=O) OR ⁴ , -N(R ⁵ )C(=O)NR ⁵ R ^5a , -N(R ⁵ )C(=NR ⁵ )NR ⁵ R ^5a , -N(R ⁵ )S(=O) ₂ R ⁴ Or -N(R ⁵ )S(=O) ₂ NR ⁵ R ^5a , or the R ³ groups on two adjacent ring carbon atoms combine to form a C ₃ -C ₁₀ cycloalkyl group or a group consisting of 3-10 atoms Heterocyclyl, wherein the groups represented by each R ³ are optionally substituted by one or more R ⁷ ;

Each R ⁴ is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, heterocyclic group consisting of 3-10 atoms, C ₆ -C ₁₀ aryl or heteroaryl consisting of 5-10 atoms;

Each R ⁵ and R ^5a are independently H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, 3-10 atoms A heterocyclic group composed of C ₆ -C ₁₀ aryl or a heteroaryl group composed of 5-10 atoms, or R ⁵ , R ^5a , together with the nitrogen atom connected to them, form a heteroaryl group composed of 3-10 atoms Cyclic group or heteroaryl group composed of 5-10 atoms;

Each R ⁶ and R ^6a are independently H, F, Cl, Br, I, CN, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, heterocyclic group consisting of 3-10 atoms, C ₆ -C ₁₀ aryl group or heteroaryl group consisting of 5-10 atoms, or R ⁶ , R ^6a , and the carbon atoms connected to them Together, form a C ₃ -C ₁₀ cycloalkyl group or a heterocyclic group consisting of 3-10 atoms;

Each R ⁷ is independently F, Cl, Br, I, CN, OH, NH ₂ , SH, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ - C ₆ alkoxy, C ₁ -C ₆ alkylamino, -(C ₁ -C ₆ alkylene)-SH, C ₃ -C ₁₀ cycloalkyl, heterocyclic group consisting of 3-10 atoms, C ₆ -C ₁₀ aryl or heteroaryl consisting of 5-10 atoms;

m is 3, 4, 5 or 6;

each n is independently 1, 2, 3 or 4;

each p is independently 0, 1, 2, 3 or 4;

each q is independently 0, 1 or 2;

The condition is that when R1 is ^F , Hy cannot be the following structure:

In one embodiment, each R ² is independently H, F, Cl, Br, I, CN, NO ₂ , OH, NH ₂ , C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylamino, C ₁ -C ₄ alkylmercapto, -S(=O)R ⁴ , -S(=O) ₂ R ⁴ , -S(=O) ₂ OR ⁴ or -S(=O) ₂ NR ⁵ R ^5a .

In another embodiment, each Y is independently CH.

In another embodiment, the compound has the structure shown in formula (II):

Or its stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or its prodrug, wherein:

R ¹ is F, Cl, Br, I, CN, -O-(CR ⁶ R ^6a ) _p R ⁴ , -(CR ⁶ R ^6a ) _p -OR ⁴ or -C(=O)NR ⁵ R ^5a ;

Each R ³ is independently H, F, Cl, Br, I, CN, C ₁ -C ₆ alkyl, C ₁ -C ₄ haloalkyl, -O-(CR ⁶ R ^6a ) _p R ⁴ , -(CR ⁶ R ^6a ) _p -OR ⁴ or -(CR ⁶ R ^6a ) _p -C(=O)NR ⁵ R ^5a ;

Each R ⁴ is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, heterocyclic group consisting of 3-10 atoms, C ₆ -C ₁₀ aryl or heteroaryl consisting of 5-10 atoms;

Each R ⁵ and R ^5a are independently H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, 3-10 atoms A heterocyclic group composed of C ₆ -C ₁₀ aryl or a heteroaryl group composed of 5-10 atoms, or R ⁵ , R ^5a , together with the nitrogen atom connected to them, form a heteroaryl group composed of 3-8 atoms Cyclic group or heteroaryl group composed of 5-10 atoms;

Each R ⁶ and R ^6a are independently H, F, Cl, Br, I, CN, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, heterocyclic group consisting of 3-10 atoms, C ₆ -C ₁₀ aryl group or heteroaryl group consisting of 5-10 atoms, or R ⁶ , R ^6a , and the carbon atoms connected to them Together, form a C ₃ -C ₈ cycloalkyl group or a heterocyclic group consisting of 3-8 atoms;

m is 3, 4, 5 or 6;

each n is independently 1, 2, 3 or 4;

each p is independently 0, 1, 2, 3 or 4;

The proviso is that when R1 is ^F , ^R3 cannot be 6- _OCH3 , 3- _OCH3 or 6-Cl.

In another embodiment, each R ⁴ is independently C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, heterocyclyl consisting of 3-6 atoms, phenyl, or 5-6 atoms The heteroaryl.

In another embodiment, each R ⁵ and R ^5a are independently H, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, heterocyclyl consisting of 3-6 atoms, phenyl or A heteroaryl group composed of 5-6 atoms, or R ⁵ , R ^5a , together with the nitrogen atoms connected to them, form a heterocyclic group composed of 3-6 atoms or a heteroaryl group composed of 5-6 atoms.

In another embodiment, R1 is ^F , Cl, Br, CN, _-OCH3 or -C(=O) _NH2 .

In another embodiment, each R ³ is independently H, Cl, CN, CH ₃ , —OCH ₃ , —C(=O)NH ₂ , or —CF ₃ , with the proviso that when R ¹ is F, R ³ cannot be 6-OCH ₃ , 3-OCH ₃ or 6-Cl.

In some other embodiments, the present invention relates to one of the following compounds or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or its precursors Drugs, but by no means limited to these compounds:

Unless otherwise specified, stereoisomers, tautomers, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds represented by formula (I) are all included in the scope of the present invention.

The compounds disclosed herein may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. The present invention intends to make all stereoisomer forms of the compound shown in formula (I), including but not limited to diastereoisomers, enantiomers, atropisomers and geometric (or conformational) isomers Identities, as well as mixtures thereof, such as racemic mixtures, form part of the present invention.

In structures disclosed herein, when the stereochemistry of any particular chiral atom is not indicated, then all stereoisomers of the structure are contemplated and included in the invention as disclosed compounds . When stereochemistry is indicated by a solid wedge or a dashed line indicating a particular configuration, then a stereoisomer of that structure is identified and defined.

The compound represented by formula (I) can exist in different tautomer forms, and all these tautomers, as described in the claims, are included in the scope of the present invention.

The compounds represented by formula (I) may exist in the form of salts. In one embodiment, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith. In another embodiment, the salt is not necessarily a pharmaceutically acceptable salt, but may be used for preparing and/or purifying the compound shown in formula (I) and/or for isolating the compound shown in formula (I) intermediates of enantiomers.

Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids such as acetates, aspartates, benzoates, benzenesulfonates, bromides/hydrobromides, bicarbonates/ Carbonate, Bisulfate/Sulfate, Camphorsulfonate, Chloride/HCl, Chlorophylline Salt, Citrate, Ethionate, Fumarate, Glucoheptonate, Glucose Sugarate, Glucuronate, Hippurate, Hydroiodide/Iodide, Isethionate, Lactate, Lactobionate, Lauryl Sulfate, Malate, Malate salt, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate Salt, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalactonate, propionate, stearate, succinate, sulfosalicylate, tartrate , tosylate and trifluoroacetate.

Inorganic acids from which salts can be derived include, for example, hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, and the like.

Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid , Ethansulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid, etc.

Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from Groups I to XII of the Periodic Table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.

Organic bases from which salts can be derived include primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include, for example, isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine .

The pharmaceutically acceptable salts of this invention can be synthesized from the parent compound, a basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (such as Na, Ca, Mg or K hydroxides, carbonates, bicarbonates, etc.), or by They are prepared by reacting the free base forms of these compounds with stoichiometric amounts of the appropriate acid. Such reactions are usually carried out in water or organic solvents or a mixture of both. Generally, non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile will be required where appropriate. In, for example, "Remington's Pharmaceutical Sciences", 20th ed., Mack Publishing Company, Easton, Pa., (1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use )", a further list of suitable salts can be found in Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

In addition, the compounds disclosed in the present invention, including their salts, can also be obtained in the form of their hydrates or in the form of solvents (such as ethanol, DMSO, etc.) containing them for their crystallization. The compounds disclosed herein may inherently or by design form solvates with pharmaceutically acceptable solvents, including water; thus, it is intended that the present invention embrace both solvated and unsolvated forms.

Any structural formulas given herein are also intended to represent non-isotopically enriched as well as isotopically enriched forms of these compounds. Isotopically enriched compounds have structures depicted by the general formulas given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O , ¹⁸ O, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, ³⁶ Cl and ¹²⁵ I.

In another aspect, the compounds of the present invention include isotopically enriched compounds as defined herein, for example, those compounds in which radioactive isotopes such as ³ H, ¹⁴ C and ¹⁸ F are present, or in which non-radioactive isotopes such as ² H and ¹³ C. Such isotopically enriched compounds can be used in metabolic studies (using ¹⁴ C), reaction kinetics studies (using e.g. ² H or ³ H), detection or imaging techniques such as positron emission tomography (PET) or including pharmaceutical or Single-photon emission computed tomography (SPECT) for the determination of substrate tissue distribution may be used in radiation therapy of patients. ¹⁸ F-enriched compounds are particularly ideal for PET or SPECT studies. The isotope-enriched compound represented by formula (I) can be prepared by using a suitable isotope-labeled reagent to replace the previously used unlabeled reagent by conventional techniques familiar to those skilled in the art or as described in the examples and preparation processes of the present invention.

^In addition, substitution with heavier isotopes, particularly deuterium (ie,2H or D), may afford certain therapeutic advantages resulting from greater metabolic stability. For example, due to increased in vivo half-life or reduced dosage requirements or improved therapeutic index. It should be understood that deuterium in the present invention is regarded as a substituent of the compound represented by formula (I). An isotopic enrichment factor can be used to define the concentration of such heavier isotopes, especially deuterium. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent of a compound of the invention is designated as deuterium, the compound has, for each designated deuterium atom, at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), At least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation) Deuterium incorporation), an isotopic enrichment factor of at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates of the present invention include those wherein the solvent of crystallization may be isotopically substituted eg _D2O , acetone _- d6, _DMSO -d6.

In another aspect, the present invention relates to intermediates for the preparation of compounds represented by formula (I).

In another aspect, the present invention relates to methods for the preparation, isolation and purification of compounds represented by formula (I).

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention. In one embodiment, the pharmaceutical composition of the present invention further includes a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle or a combination thereof. In another embodiment, the pharmaceutical composition may be in liquid, solid, semi-solid, gel or spray form.

Compositions, Formulations and Administration of Compounds of the Invention

The present invention provides a pharmaceutical composition, which comprises the compound disclosed in the present invention; and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or a combination thereof. The amount of the compound in the pharmaceutical composition disclosed in the present invention refers to the amount that can effectively detect and inhibit the protein kinase in biological samples or patients.

It will also be recognized that some of the compounds of the invention may exist in free form for use in therapy or, if appropriate, as a pharmaceutically acceptable derivative thereof. Some non-limiting embodiments of pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of these esters, or the ability to directly or indirectly provide the present invention when administered to a patient in need thereof. Any additional adducts or derivatives of the compound or its metabolites or residues.

The pharmaceutical composition disclosed in the present invention can be prepared and packaged in a bulk form, wherein a safe and effective amount of the compound represented by formula (I) can be extracted, and then administered to patients in the form of powder or syrup. Alternatively, the pharmaceutical compositions disclosed herein can be prepared and packaged in unit dosage form, wherein each physically discrete unit contains a safe and effective amount of the compound represented by formula (I). When prepared in unit dosage form, the pharmaceutical compositions disclosed herein may generally contain, for example, 0.5 mg to 1 g, or 1 mg to 700 mg, or 5 mg to 100 mg of a compound disclosed herein.

The "pharmaceutically acceptable excipient" used in the present invention means a pharmaceutically acceptable material, mixture or vehicle related to the consistency of the administered dosage form or pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when mixed to avoid interactions that would substantially reduce the efficacy of the compounds disclosed in this invention when administered to a patient and would result in a pharmaceutical composition that is not pharmaceutically acceptable Interaction. Furthermore, each excipient must be pharmaceutically acceptable, eg, of sufficiently high purity.

Suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form chosen. Furthermore, pharmaceutically acceptable excipients can be selected according to their specific function in the composition. For example, certain pharmaceutically acceptable excipients can be selected to facilitate the production of uniform dosage forms. Certain pharmaceutically acceptable excipients can be selected to aid in the production of stable dosage forms. Certain pharmaceutically acceptable excipients can be selected to aid in the carrying or transport of the disclosed compounds from one organ or part of the body to another organ or part of the body when administered to a patient. Certain pharmaceutically acceptable excipients can be selected to enhance patient compliance.

Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents , solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste-masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, tackifiers, antioxidants, Preservatives, stabilizers, surfactants and buffers. The skilled artisan will recognize that certain pharmaceutically acceptable excipients may serve more than one function, and may serve alternative functions, depending on how much of that excipient and which other excipients are present in the formulation. agent.

The skilled artisan possesses the knowledge and skill in the art to enable them to select appropriate pharmaceutically acceptable excipients in appropriate amounts for use in the present invention. Furthermore, there are numerous resources available to the skilled artisan which describe pharmaceutically acceptable excipients and are useful in selecting suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

Disclosed in Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York Various carriers for formulating pharmaceutically acceptable compositions, and known techniques for their preparation, the contents of each of these documents are incorporated herein by reference. Concerned about the use of any of the compounds disclosed herein, except for any commonly used carriers that are incompatible with the compounds disclosed herein, such as by producing any undesired biological effects, or by interacting in a deleterious manner with any other ingredient in a pharmaceutically acceptable composition scope of the invention.

The pharmaceutical compositions disclosed herein are prepared using techniques and methods known to those skilled in the art. Descriptions of some common methods in the art can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company).

Therefore, in another aspect, the present invention relates to a process for preparing a pharmaceutical composition, said pharmaceutical composition comprising a compound disclosed in the present invention and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or a combination thereof, the process comprising Mix the various ingredients. Pharmaceutical compositions comprising compounds disclosed herein can be prepared by mixing, for example, at ambient temperature and atmospheric pressure.

The compounds disclosed herein are generally formulated in dosage forms suitable for administration to a patient by the desired route. For example, dosage forms include those suitable for the following routes of administration: (1) oral administration, such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration, such as sterile solutions, suspensions, and reconstituted powders; (3) transdermal administration, such as transdermal patches (4) rectal administration, such as suppository; (5) inhalation, such as aerosol, solution and dry powder; and (6) topical administration, such as cream, ointment, lotion, solution, paste , sprays, foams and gels.

In one embodiment, the compounds disclosed herein can be formulated as oral dosage forms. In another embodiment, the compounds disclosed herein may be formulated for inhalation. In another embodiment, the compounds disclosed herein can be formulated for nasal administration. In yet another embodiment, the compounds disclosed herein may be formulated for transdermal administration. In yet another embodiment, the compounds disclosed herein may be formulated for topical administration.

The pharmaceutical composition provided by the present invention can be provided in the form of compressed tablets, triturated tablets, chewable lozenges, quick-dissolving tablets, recompressed tablets, or enteric-coated tablets, sugar-coated or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substance that resists the acidic effects of the stomach but dissolves or disintegrates in the intestine, thus protecting the active ingredient from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac and cellulose acetate phthalate. Dragees are compressed tablets surrounded by a coating of sugar, which helps to mask an unpleasant taste or odor and to protect the tablet from oxidation. Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble substance. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings have the same general characteristics as sugar coatings. Multiple compressed tablets are compressed tablets prepared by more than one compression cycle, including multilayer tablets, and press-coated or dry-coated tablets.

Tablet dosage forms can be prepared from the active ingredient in powder, crystalline or granulated form alone or in combination with one or more carriers or excipients as described herein, including binders, disintegrants, Debonding agents, release-controlling polymers, lubricants, diluents and/or colorants. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges.

The pharmaceutical composition provided by the present invention can be provided in the form of soft capsule or hard capsule, which can be prepared from gelatin, methylcellulose, starch or calcium alginate. The hard gelatin capsules, also known as dry-filled capsules (DFC), consist of two segments, one inserted into the other, thus completely encapsulating the active ingredient. Soft elastic capsules (SEC) are soft, spherical shells, such as gelatin shells, which are plasticized by the addition of glycerol, sorbitol or similar polyols. Soft gelatin shells may contain a preservative to prevent the growth of microorganisms. Suitable preservatives are those described herein, including methyl and parabens, and sorbic acid. Liquid, semi-solid and solid dosage forms provided herein can be encapsulated in capsules. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239 and 4,410,545. The capsules may also be coated, as known to those skilled in the art, to improve or maintain dissolution of the active ingredient.

The pharmaceutical compositions provided herein can be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs and syrups. Emulsions are two-phase systems in which one liquid is completely dispersed in the form of globules in another liquid, which can be either oil-in-water or water-in-oil. Emulsions may include pharmaceutically acceptable non-aqueous liquids and solvents, emulsifying agents and preservatives. Suspensions may contain pharmaceutically acceptable suspending agents and preservatives. The aqueous alcoholic solution may include a pharmaceutically acceptable acetal, such as a di(lower alkyl)acetal of a lower alkylaldehyde, such as acetaldehyde diethyl acetal; and a water-soluble solvent having one or more hydroxyl groups, such as Propylene glycol and ethanol. Elixirs are clear, sweetened hydroalcoholic solutions. A syrup is a concentrated aqueous solution of a sugar such as sucrose, and may also contain a preservative. For liquid dosage forms, for example, a solution in polyethylene glycol can be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, such as water, for precise and convenient administration.

Other useful liquid and semisolid dosage forms include, but are not limited to, those comprising the active ingredients provided herein and secondary mono- or poly-alkylene glycols including: 1,2-Dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-di Methyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of polyethylene glycol. These formulations may further include one or more antioxidants such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin , cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters and dithiocarbamates.

Where appropriate, dosage unit formulations for oral administration can be microencapsulated. They may also be formulated as prolonged or sustained release compositions, for example by coating or embedding the particulate material in polymers, waxes or the like.

The oral pharmaceutical composition provided by the present invention can also be provided in the form of liposomes, micelles, microspheres or nanosystems. Micellar dosage forms can be prepared as described in U.S. Pat. No. 6,350,458.

The pharmaceutical compositions provided herein can be provided as non-effervescent or effervescent granules and powders for reconstitution into liquid dosage forms. Pharmaceutically acceptable carriers and excipients used in non-effervescent granules or powders may include diluents, sweeteners and wetting agents. Pharmaceutically acceptable carriers and excipients used in effervescent granules or powders may include organic acids and carbon dioxide sources.

Coloring and flavoring agents may be used in all of the above dosage forms.

The compounds disclosed in this invention can also be combined with soluble polymers as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyoxyethylene polylysine substituted with palmitoyl residues. In addition, the compounds disclosed in the present invention can be combined with a class of biodegradable polymers used in the controlled release of drugs, such as polylactic acid, polyε-caprolactone, polyhydroxybutyric acid, polyorthoester , polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphiphilic block copolymers of hydrogels.

The pharmaceutical compositions provided herein can be formulated as immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted- and programmed release forms.

The pharmaceutical compositions provided herein can be formulated with other active ingredients that do not impair the intended therapeutic effect, or with substances that supplement the intended effect.

The pharmaceutical compositions provided herein can be administered parenterally by injection, infusion or implantation for local or systemic administration. Parenteral administration as used in the present invention includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.

The pharmaceutical composition provided by the invention can be formulated into any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems and formulations suitable for administration in liquids before injection. Solid forms made into solutions or suspensions. Such dosage forms may be prepared according to conventional methods known to those skilled in the pharmaceutical sciences (see Remington: The Science and Practice of Pharmacy, supra).

Pharmaceutical compositions intended for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous carriers, water-miscible carriers, non-aqueous carriers, anti- Antimicrobial or antimicrobial growth preservatives, stabilizers, dissolution enhancers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, polyvalent Chelating agents or chelating agents, antifreeze agents, cryoprotectants, thickeners, pH regulators and inert gases.

Suitable aqueous vehicles include, but are not limited to: water, saline, normal saline or phosphate buffered saline (PBS), Sodium Chloride Injection, Ringers Injection, Isotonic Dextrose Injection, Sterile Water Injection, Dextrose and Lactated Ringers Injection. Non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil, and coconut oil. chain triglycerides, and palm seed oil. Water miscible carriers include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycols (such as polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N-methyl- 2-pyrrolidone, N,N-dimethylacetamide and dimethylsulfoxide.

Suitable antimicrobials or preservatives include, but are not limited to, phenol, cresol, amalgam, benzyl alcohol, chlorobutanol, methyl and propyl parabens, thimerosal, benzalkonium chloride (such as benzethonium chloride), methyl and propylparabens, and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerol and dextrose. Suitable buffers include, but are not limited to, phosphate and citrate. Suitable antioxidants are those as described herein, including bisulfite and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents are those as described herein, including sodium carboxymethylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone. Suitable emulsifiers include those described herein, including polyoxyethylene sorbitan monolaurate. Polyoxyethylene tax-free sorbitan monooleate 80 and triethanolamine oleate. Suitable sequestering or chelating agents include, but are not limited to EDTA. Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulfobutyl ether-beta-cyclodextrin and sulfo butyl butyl ether 7-β-cyclodextrin ( CyDex, Lenexa, KS).

The pharmaceutical compositions provided herein can be formulated for single or multiple dose administration. The single-dose formulations are packaged in ampoules, vials or syringes. Such multiple dose parenteral formulations must contain the antimicrobial agent in bacteriostatic or fungistatic concentrations. All parenteral formulations must be sterile, as known and practiced in the art.

In one embodiment, the pharmaceutical compositions are provided as ready-to-use sterile solutions. In another embodiment, the pharmaceutical compositions are provided as sterile dry soluble products, including lyophilized powders and hypodermic tablets, which are reconstituted with a vehicle prior to use. In yet another embodiment, the pharmaceutical composition is formulated as a ready-to-use sterile suspension. In yet another embodiment, the pharmaceutical composition is formulated as a sterile dry insoluble product for reconstitution with a vehicle prior to use. In yet another embodiment, the pharmaceutical composition is formulated as a ready-to-use sterile emulsion.

The pharmaceutical compositions disclosed herein can be formulated in immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted- and programmed release forms.

The pharmaceutical composition can be formulated as a suspension, solid, semi-solid or thixotropic liquid for administration as an implanted depot. In one embodiment, the pharmaceutical compositions disclosed herein are dispersed in a solid inner matrix surrounded by an outer polymeric membrane that is insoluble in bodily fluids but allows the active ingredients in the pharmaceutical composition to diffuse through.

Suitable internal matrices include polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, plasticized Polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, silicone Carbonate copolymers, hydrogels of hydrophilic polymers such as esters of acrylic and methacrylic acid, collagen, cross-linked polyvinyl alcohol, and partially hydrolyzed polyvinyl acetate of coaches.

Suitable outer polymeric films include polyethylene, polypropylene, ethylene/propylene copolymer, ethylene/ethyl acrylate copolymer, ethylene/vinyl acetate copolymer, silicone rubber, dimethicone, neoprene Rubber, Chlorinated Polyethylene, Polyvinyl Chloride, Copolymers of Vinyl Chloride and Vinyl Acetate, Vinylidene Chloride, Ethylene and Propylene, Ionomer Polyethylene Terephthalate, Butyl Rubber Chlorohydrin Rubber, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/ethyleneoxyethanol copolymer.

On the other hand, the pharmaceutical composition disclosed in the present invention can be formulated into any dosage form suitable for inhalation administration to patients, such as dry powder, aerosol, suspension or solution composition. In one embodiment, the pharmaceutical composition disclosed in the present invention can be formulated into a dosage form suitable for administration to patients by inhalation of dry powder. In yet another embodiment, the pharmaceutical composition disclosed in the present invention can be formulated into a dosage form suitable for inhalation administration to patients through a nebulizer. Dry powder compositions for delivery to the lung by inhalation generally comprise a compound disclosed herein in fine powder form and one or more finely powdered pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients which are particularly suitable for use as dry powders are known to those skilled in the art and include lactose, starch, mannitol, and mono-, di- and polysaccharides. Fine powders can be prepared, for example, by micronization and grinding. In general, a size-reduced (eg, micronized) compound can be defined by a _D50 value (eg, measured by laser diffraction) of about 1 to 10 microns.

Aerosol formulations can be formulated by suspending or dissolving a compound disclosed herein in a liquefied propellant. Suitable propellants include chlorinated hydrocarbons, hydrocarbons and other liquefied gases. Representative propellants include: trichlorofluoromethane (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetrafluoroethane (propellant 114), tetrafluoroethane (HFA-134a), 1 ,1-difluoroethane (HFA-152a), difluoromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoropropane (HFA-227a), perfluoropropane, perfluorobutane, perfluoro Pentane, Butane, Isobutane and Pentane. Aerosol formulations comprising compounds disclosed herein are typically administered to patients via a metered dose inhaler (MDI). Such devices are known to those skilled in the art

Aerosol formulations may contain additional pharmaceutically acceptable excipients that can be used with MDIs, such as surfactants, lubricants, co-solvents, and other excipients to improve the physical stability of the formulation, improve valve characteristics, Improve solubility, or improve taste.

Pharmaceutical compositions adapted for transdermal administration may be prepared as discrete patches intended to remain in intimate contact with the epidermis of the patient for an extended period of time. For example, the active ingredient can be delivered from a patch by iontophoresis, as generally described in Pharmaceutical Research, 3(6), 318 (1986).

Pharmaceutical compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. For example, ointments, creams and gels may be formulated with an aqueous or oily base, with suitable thickening and/or gelling agents and/or solvents. Such bases may include, water, and/or oils such as liquid liquid paraffin and vegetable oils such as arachis oil or castor oil, or solvents such as polyethylene glycol. Thickeners and gelling agents used according to the nature of the base include soft paraffin, aluminum stearate, cetearyl alcohol, polyethylene glycol, lanolin, beeswax, carbopol and cellulose derivatives, and/or mono Glyceryl stearate and/or nonionic emulsifiers.

Lotions may be formulated with an aqueous or oily base, and generally also contain one or more emulsifying, stabilizing, dispersing, suspending or thickening agents.

Powders for external use may be formed in the presence of any suitable powder base such as talc, lactose or starch. Drops may be formulated with an aqueous or non-aqueous base containing one or more dispersing agents, solubilizers, suspending agents or preservatives.

Topical formulations may be administered by application to the affected area one or more times daily; occlusive dressings covering the skin are preferably used. Adhesive depot systems allow for continuous or prolonged drug delivery.

For the treatment of the eyes, or other organs such as the mouth and skin, the compositions may be applied as topical ointments or creams. When formulated in an ointment, the compounds disclosed herein may be employed with either a paraffinic or a water soluble ointment base. Alternatively, the compounds disclosed herein may be formulated in a cream with an oil-in-water cream base or with an oil-in-water base.

Uses of the compounds and compositions of the invention

The above-mentioned compounds and pharmaceutical compositions provided by the present invention can be used for the preparation of medicines for preventing, treating or alleviating central nervous system dysfunction in mammals, including humans, and can also be used for preparing medicines for inhibiting serotonin reuptake and/or Drugs that agonize 5-HT _1A receptors.

Specifically, the amount of the compound in the composition of the present invention can effectively and detectably selectively inhibit the reuptake of serotonin and have an agonistic effect on the 5-HT _1A receptor, and the compound of the present invention can be used as a therapeutic agent for human CNS Drugs for nervous system (CNS) disorders such as depression and anxiety.

The compounds of the present invention can be used, but not limited to, to prevent, treat or alleviate central nervous system dysfunction diseases in mammals, including humans, by administering an effective amount of the compounds or compositions of the present invention to patients. The human central nervous system dysfunction diseases that respond to the regulation of serotonin receptors further include, but are not limited to, depression, anxiety, mania, schizophrenia, sleep disorders, bipolar disorder, Obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, movement disorder, sexual dysfunction, musculoskeletal pain disorder, cognitive impairment, memory impairment, Parkinson's disease, Huntington's disease, phobias, substance abuse or adulthood Addiction, drug addiction withdrawal symptoms, and PMS, among others.

In addition to being useful in human therapy, the compounds and pharmaceutical compositions of the present invention are also useful in the veterinary treatment of mammals in pets, imported breeds and farm animals. Examples of additional animals include horses, dogs and cats. Here, the compounds of the present invention include their pharmaceutically acceptable derivatives.

treatment method

In one embodiment, the methods of treatment disclosed herein comprise administering a safe and effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention to a patient in need thereof. Various embodiments disclosed herein include methods of treating the above-mentioned diseases by administering a safe and effective amount of a compound disclosed herein or a pharmaceutical composition comprising a compound disclosed herein to a patient in need thereof.

In one embodiment, a compound disclosed herein or a pharmaceutical composition comprising a compound disclosed herein may be administered by any suitable route of administration, including systemic and topical administration. Systemic administration includes oral, parenteral, transdermal, and rectal administration. Typical parenteral administration refers to administration by injection or infusion, including intravenous, intramuscular and subcutaneous injection or infusion. Topical administration includes application to the skin as well as ocular, otic, intravaginal, inhalational and intranasal administration. In one embodiment, a compound disclosed herein or a pharmaceutical composition comprising a compound disclosed herein may be administered orally. In another embodiment, a compound disclosed herein or a pharmaceutical composition comprising a compound disclosed herein may be administered by inhalation. In yet another embodiment, a compound disclosed herein or comprising a compound disclosed herein may be administered intranasally.

In one embodiment, the compound disclosed in the present invention or the pharmaceutical composition comprising the compound disclosed in the present invention can be administered at one time, or several times at different time intervals within a specified period of time according to the dosing regimen. For example, once, twice, three or four times per day. In one embodiment, the administration is once daily. In yet another embodiment, the administration is twice daily. Administration can be until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for compounds disclosed herein or pharmaceutical compositions comprising compounds disclosed herein depend on the compound's pharmacokinetic properties, such as dilution, distribution and half-life, which can be determined by the skilled artisan. In addition, suitable dosing regimens for compounds disclosed herein or pharmaceutical compositions comprising compounds disclosed herein, including the duration for which such regimens are carried out, depend on the disease being treated, the severity of the disease being treated, the age and The physical condition, the medical history of the patient being treated, the nature of the concomitant therapy, the desired effect of the treatment, etc. are factors within the knowledge and experience of the skilled person. Such skilled artisans will also appreciate that adjustments to the dosing regimen may be required as an individual patient's response to the dosing regimen, or as individual patient needs change over time.

A compound disclosed herein may be administered simultaneously with, or preceded or followed by, one or more other therapeutic agents. The compound of the present invention may be administered separately from other therapeutic agents by the same or different routes of administration, or may be administered together with them in the form of a pharmaceutical composition.

For an individual of about 50-70 kg, the pharmaceutical compositions and combinations disclosed in the present invention may contain about 1-1000 mg, or about 1-500 mg, or about 1-250 mg, or about 1-150 mg, or about 0.5-100 mg, or Unit dosage forms of about 1-50 mg active ingredient. The therapeutically effective amount of the compound, pharmaceutical composition or combination thereof depends on the species, body weight, age and individual condition of the individual, the disorder or disease being treated or its severity. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each active ingredient required to prevent, treat or inhibit a disorder or the progression of a disease.

The dosage properties cited above have been demonstrated in in vitro and in vivo tests using advantageously mammals (eg mice, rats, dogs, monkeys) or isolated organs, tissues and specimens thereof. The compounds disclosed herein are used in vitro as solutions, eg, aqueous solutions, and in vivo, eg, as suspensions or aqueous solutions, enterally, parenterally, especially intravenously.

In one embodiment, the therapeutically effective dose of a compound disclosed herein is from about 0.1 mg to about 2,000 mg per day. Pharmaceutical compositions thereof should provide a dosage of about 0.1 mg to about 2,000 mg of the compound. In a specific embodiment, pharmaceutical dosage unit forms are prepared to provide from about 1 mg to about 2,000 mg, from about 10 mg to about 1,000 mg, from about 20 mg to about 500 mg, or from about 25 mg to about 250 mg of the principal active ingredient or per dosage unit form Combinations of the main ingredients. In a particular embodiment, pharmaceutical dosage unit forms are prepared to provide about 10 mg, 20 mg, 25 mg, 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg or 2000 mg of the principal active ingredient.

In addition, the compounds disclosed herein may be administered as prodrugs. In the present invention, the "prodrug" of the compound disclosed in the present invention is a functional derivative that can finally release the compound disclosed in the present invention in vivo when administered to a patient. When administering the compounds disclosed in the present invention in the form of prodrugs, those skilled in the art can implement one or more of the following methods: (a) change the in vivo onset time of the compound; (b) change the in vivo effect duration of the compound; (c) ) alter the in vivo delivery or distribution of the compound; (d) alter the in vivo solubility of the compound; and (e) overcome side effects or other difficulties faced by the compound. Typical functional derivatives used to prepare prodrugs include variants of the compound that are chemically or enzymatically cleaved in vivo. These variations, including the preparation of phosphates, amides, esters, thioesters, carbonates and carbamates, are well known to those skilled in the art.

Compound Synthesis Method

In order to describe the present invention, examples are listed below. However, it should be understood that the present invention is not limited to these examples, but only provides a method of practicing the present invention.

Generally, the compounds of the present invention can be prepared by the methods described in the present invention, and unless otherwise specified, the definitions of the substituents are as shown in formula (I). The following reaction schemes and examples serve to further illustrate the present invention.

Those skilled in the art will recognize that the chemical reactions described herein can be used to suitably prepare many other compounds of the invention and that other methods for preparing the compounds of the invention are considered to be within the scope of the invention Inside. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art through modification methods, such as appropriate protection of interfering groups, by using other known reagents in addition to those described in the present invention, or by incorporating Reaction conditions with some routine modifications. In addition, reactions disclosed herein or known reaction conditions are also recognized to be applicable to the preparation of other compounds of this invention.

In the examples described below, unless indicated otherwise, all temperatures are in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. General reagents from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Tianjin Fuchen Chemical Reagent Factory, Wuhan Xinhuayuan Technology Development Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd. and Qingdao Ocean Chemical Factory can be purchased.

Anhydrous tetrahydrofuran, dioxane, toluene, and ether were obtained by reflux drying over sodium metal. Anhydrous dichloromethane and chloroform were obtained by refluxing and drying over calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide were dried over anhydrous sodium sulfate before use.

The following reactions were generally carried out under a positive pressure of nitrogen or argon or over anhydrous solvents with a drying tube (unless otherwise indicated), the reaction vials were fitted with suitable rubber stoppers, and the substrate was introduced by syringe. Glassware is dried.

The chromatographic column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Factory. NMR spectra were performed using CDCl ₃ , d ₆ -DMSO, CD ₃ OD or d ₆ -acetone as solvents (reported in ppm), and TMS (0 ppm) or chloroform (7.25 ppm) as reference standards. When multiplets appear, the following abbreviations will be used: s (singlet, singlet), d (doublet, doublet), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broadened) peak), dd (doublet of doublets, quartet), dt (doublet of triplets, double triplet). Coupling constants are expressed in Hertz (Hz).

The conditions for low-resolution mass spectrometry (MS) data are: Agilent 1200 or Agilent 6120Series LCMS (column model: Zorbax SB-C18, 2.1 × 30mm, 3.5 microns, 6min, flow rate is 0.6mL/min. Mobile phase: 5-95% The ratio of (CH ₃ CN with 0.1% formic acid) in (H ₂ O with 0.1% formic acid) was detected by UV at 210/254 nm, using low-response electrospray mode (ESI).

Pure compounds were characterized by Agilent 1100 Series High Performance Liquid Chromatography (HPLC) with UV detection at 210 nm and 254 nm. Columns are typically operated at 40°C.

The following abbreviations are used throughout this disclosure:

aq. aqueous solution

ascorbic acid ascorbic acid

_CH2Cl2 , _DCM dichloromethane

CDCl ₃ deuterated chloroform

DIEA, DIPEA Diisopropylethylamine

DMF N,N-Dimethylformamide

DMAP 4-Dimethylaminopyridine

DMSO dimethyl sulfoxide

EtOAc, EA ethyl acetate

Et ₃ N, TEA Triethylamine

EDTA ethylenediaminetetraacetic acid

EGTA Ethylene glycol diethyl ether diamine tetraacetic acid

g grams

glucose

hours

H ₂ SO ₄ sulfuric acid

HBTU Benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate

_{K2CO3potassium carbonate}

KI potassium iodide

KCl potassium chloride

MeOH, _CH3OH Methanol

MgSO ₄ magnesium sulfate

mL, ml milliliter

min minute

N ₂ Nitrogen

RT, rt, r.t. room temperature

NaBH ₄ sodium borohydride

NH ₄ Cl Ammonium Chloride

NaHCO ₃ sodium bicarbonate

NaH ₂ PO ₄ sodium dihydrogen phosphate

NaCl sodium chloride

Sodium Na ₂ SO ₄ Sulfate

PCC pyridinium chlorochromate

PE petroleum ether (60-90℃)

THF Tetrahydrofuran

Tri-HCl Tris Hydroxymethylaminomethane Hydrochloride

TsCl p-toluenesulfonyl chloride

The following synthetic schemes describe the steps involved in preparing the compounds disclosed in this invention. Unless otherwise stated, each ^R1 and ^R3 has the definition as described in the present invention.

Synthetic Scheme 1

The compound fragment shown in the general structure of formula ( 3 ) can be prepared by synthesis scheme 1: anhydrous piperazine ( 1 ) and 2-chloropyridine ( 2 ) react under the action of potassium carbonate to produce the compound of formula ( 3 ) intermediates shown.

Synthetic scheme 2

The compounds disclosed in the present invention can be prepared by the general synthesis method described in Synthesis Scheme 2, and the specific steps can be referred to the examples. In Synthesis Scheme 2, first, 6-caprolactone ( 4 ) undergoes alcoholysis under the catalysis of sulfuric acid, and the resulting intermediate is oxidized by PCC to obtain compound ( 5 ). Afterwards, compound ( 5 ) and phenylhydrazine compound ( 6 ) are subjected to Fischer indole ring closure in alcoholic solvents such as ethanol, isopropanol, and tert-butanol to generate compound ( 7 ). Compound ( 7 ) is reacted with a reducing agent, such as lithium aluminum hydride, at a suitable temperature, such as 40-120°C, to obtain compound ( 8 ). Finally, convert the hydroxyl group in compound ( 8 ) into p-toluenesulfonic acid group, and then combine with compound ( 3 ) under the action of inorganic base, such as potassium carbonate, sodium carbonate, or organic base, such as triethylamine, in a suitable solvent , such as nucleophilic substitution in acetonitrile, tetrahydrofuran, ethanol, and DMF to obtain the target compound ( 10 ).

Synthetic Scheme 3

The compounds disclosed in the present invention can be prepared by the general synthesis method described in Synthesis Scheme 3, and the specific steps can be referred to the examples. In Synthetic Scheme 3,

First, compound ( 11 ) was subjected to Friedel-Crafts acylation with chlorobutyryl chloride to generate compound ( 12 ). Compound ( 12 ) is reacted with a reducing agent such as sodium borohydride or lithium aluminum tetrahydride in a suitable solvent, such as tert-butanol, isopropanol, to obtain compound ( 8 ). Afterwards, the hydroxyl group in the compound ( 8 ) is converted into a p-toluenesulfonic acid group, and then the compound ( 3 ) is reacted with an inorganic base such as potassium carbonate, sodium carbonate, or an organic base such as triethylamine in a suitable solvent , such as nucleophilic substitution in acetonitrile, tetrahydrofuran, ethanol, DMF, to obtain the target compound ( 10 )

Synthetic Scheme 4

The compounds disclosed in the present invention can be prepared by the general synthesis method described in Synthesis Scheme 4, and the specific steps can be referred to the examples. In Synthesis Scheme 4, firstly, tetrahydropyran ( 13 ) and phenylhydrazine compound ( 14 ) are subjected to Fisher indole ring closure at a suitable temperature, such as 40-120° C., to generate compound ( 15 ). Then, the hydroxyl group in the compound ( 15 ) is converted into a p-toluenesulfonic acid group, and then with the compound (3) under the action of an inorganic base, such as potassium carbonate, sodium carbonate, or an organic base, such as triethylamine, in a suitable solvent , such as nucleophilic substitution in acetonitrile, tetrahydrofuran, ethanol, DMF, to obtain the target compound ( 17 ).

The compounds, pharmaceutical compositions and applications provided by the present invention will be further described below in conjunction with the examples.

Example 1 5-methoxy-3-(4-(4-(pyridin-2-yl)piperazin-1-yl)butyl)-1H-indole

Step 1) Ethyl 6-oxohexanoate

6-Caprolactone (15.0 g, 0.13 mol) was dissolved in ethanol (125 mL), and heated at 80° C. for 24 hours. Then the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, then ice water (150 mL) was added successively, ethyl acetate (150 mL) was extracted three times, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and dried to obtain ethyl- 6-Hydroxycaproic acid 10.3 g. Then ethyl-6-hydroxyhexanoic acid (10.3g, 68.6mmol) was dissolved in dichloromethane (20mL), and at 0°C, the above solution was added dropwise into a dichloromethane solution of PCC (16.2g, 75.5mmol) ( 140mL), the dropwise addition was completed, and the reaction was continued at room temperature for 2h. Then the reaction mixture was cooled to room temperature, ethyl acetate (100 mL) was added, suction filtered, the filtrate was concentrated, and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=10/1) to obtain the title compound as white Solid (9.28 g, 45.2%).

LC-MS (ESI, pos.ion) m/z: 159.3[M+H] ⁺ ;

¹ H NMR (CDCl ₃ , 400MHz) δ(ppm): 9.77(t, J=1.4Hz, 1H), 4.16-4.11(m, 2H), 2.49-2.46(m, 2H), 2.35-2.32(m, 2H), 1.69-1.65 (m, 4H), 1.26 (t, J=7.1Hz, 3H).

Step 2) Ethyl 4-(5-methoxy-1H-indol-3-yl)butanoate

At room temperature, ethyl 6-oxohexanoate (0.33g, 1.27mmol) was added to ethanol (125mL), then p-methoxyphenylhydrazine hydrochloride (1.2g, 6.8mmol) was added, and the temperature was raised to 80 ℃ for 20 h, then the reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure, then ice water (100 mL) was added successively, ethyl acetate (150 mL×3) was extracted, the organic phase was dried with anhydrous sodium sulfate, filtered, concentrated, Purification by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=4/1) gave the title compound as a white solid (0.49 g, 30.0%).

LC-MS (ESI, pos.ion) m/z: 262.2[M+H] ⁺ ;

¹ H NMR(CDCl ₃ ,400MHz)δ(ppm):7.89(br s,1H),7.25-7.22(m,1H),7.22(s,1H),7.03(d,J=2.2Hz,1H), 6.96(d, J=1.9Hz, 1H), 6.84(dd, J=8.8, 4.8Hz, 1H), 4.15-4.10(m, 2H), 3.86(s, 3H), 2.77(t, J=7.4Hz , 2H), 2.38(t, J=7.4Hz, 2H), 2.07-2.00(m, 2H), 1.25(t, J=7.1Hz, 3H).

Step 3) 4-(5-methoxy-1H-indol-3-yl)butan-1-ol

Ethyl 4-(5-methoxy-1H-indol-3-yl)butanoate (0.33 g, 1.27 mmol) was dissolved in anhydrous tetrahydrofuran (25 mL). Lithium aluminum tetrahydride (0.19 g, 5.08 mmol) was added in batches at 0° C. After the addition was completed, the mixture was reacted at room temperature for 1 h, and then heated to 80° C. for 20 h. After the reaction was completed, the reaction mixture was cooled to 0° C., slowly added saturated sodium sulfate solution (1 mL) to quench the reaction, then added ethyl acetate (150 mL), filtered, concentrated the filtrate, and purified by silica gel column chromatography (petroleum ether/ethyl acetate Ester (v/v)=2/1), the title compound was obtained as a white solid (0.21 g, 75.0%). LC-MS (ESI, pos.ion) m/z: 220.2[M+H] ⁺ ;

¹ H NMR(CDCl ₃ ,400MHz)δ(ppm):7.90(br s,1H),7.25-7.21(m,1H),7.02(d,J=2.2Hz,1H),6.94(d,J=1.7 Hz,1H),6.83(dd,J=8.8,2.4Hz,1H),3.86(s,3H),3.68(t,J=6.5Hz,2H),2.75(t,J=7.3Hz,2H), 1.81-1.74 (m, 2H), 1.70-1.63 (m, 2H).

Step 4) 4-(5-methoxy-1H-indol-3-yl)butyl 4-methylbenzenesulfonate

4-(5-Methoxy-1H-indol-3-yl)butan-1-ol (0.42g, 1.9mmol) was dissolved in dichloromethane (20mL), and triethylamine (0.3mL , 2.28mmol) and p-toluenesulfonyl chloride (0.43g, 2.28mmol), react at room temperature for 4h. After the reaction was completed, add water (100 mL) to quench, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=4/1) to obtain the title The compound was a white solid (0.46 g, 65.0%).

LC-MS (ESI, pos.ion) m/z: 374.1[M+H] ⁺ ;

¹ H NMR (CDCl ₃ , 400MHz) δ(ppm): 7.87(br s, 1H), 7.58(d, J=8.2Hz, 2H), 7.30(d, J=8.0Hz, 2H), 7.22(d, J＝8.8Hz, 1H), 6.96(d, J＝2.2Hz, 1H), 6.90(s, 1H), 6.83(dd, J＝8.8, 2.3Hz, 1H), 4.15-4.04(m, 2H), 3.86(s, 3H), 2.66(d, J=6.4Hz, 2H), 2.45-2.42(m, 2H), 1.73(t, J=3.0Hz, 2H).

Step 5) 1-(pyridin-2-yl)piperazine

2-Chloropyridine (0.8g, 7.2mmol) was dissolved in N,N-dimethylformamide (10mL), and potassium carbonate (1.0g, 7.2mmol) and anhydrous piperazine (1.2g, 14.4mmol), heated to 120°C for reaction. After 20 hours, cool to room temperature, pour the reaction solution into 10 mL of water, extract with ethyl acetate (20 mL x 3), combine the organic phases, dry the organic phases over anhydrous sodium sulfate, filter, concentrate the filtrate, and purify by silica gel column chromatography (dichloromethane/methanol (v/v)=20/1), the title compound was obtained as a yellow oil (0.38 g, 32.0%).

LC-MS (ESI, pos.ion) m/z: 164.3[M+H] ⁺ ;

¹ H NMR (CDCl ₃ , 400MHz) δ (ppm): 8.18 (dd, J=4.8, 1.1 Hz, 1H), 7.50-7.46 (m, 1H), 6.65-6.61 (m, 2H), 3.51 (t, J=5.1Hz, 4H), 2.99(t, J=5.1Hz, 4H).

Step 6) 5-methoxy-3-(4-(4-(pyridin-2-yl)piperazin-1-yl)butyl)-1H-indole

Under nitrogen protection, 4-(5-methoxy-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (0.22g, 0.58mmol) and 1-(pyridin-2-yl) Piperazine (95mg, 0.58mmol) was dissolved in acetonitrile (15mL), then potassium carbonate (120mg, 0.87mmol) and catalytic amount of potassium iodide (20mg, 0.12mmol) were added thereto, heated to 80°C for reaction. After 20 hours, cool to room temperature, evaporate the solvent under reduced pressure, and purify by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a white solid (0.09g, 45.0% ).

LC-MS (ESI, pos.ion) m/z: 365.3[M+H] ⁺ ;

¹ H NMR(CDCl ₃ ,400MHz)δ(ppm):8.19-8.18(m,1H),7.93(br s,1H),7.49-7.45(m,1H),7.22(d,J＝8.8Hz,1H ), 7.03(d, J=2.1Hz, 1H), 6.96(s, 1H), 6.83(dd, J=8.8, 2.3Hz, 1H), 6.65-6.60(m, 2H), 3.87(s, 3H) ,3.54(t,J=5.0Hz,4H),2.76(t,J=7.3Hz,2H),2.55(t,J=5.0Hz,2H),2.43(t,J=7.6Hz,2H),1.79 -1.71(m,2H),1.68-1.62(m,2H).

Example 2 5-Chloro-3-(4-(4-(pyridin-2-yl)piperazin-1-yl)butyl)-1H-indole

Step 1) Ethyl 4-(5-chloro-1H-indol-3-yl)butanoate

The title compound of this step was prepared by referring to the method described in step 2 of Example 1, that is, ethyl 6-oxohexanoate (2.0 g, 12.6 mmol) and p-chlorophenylhydrazine hydrochloride (2.4 g, 13.6 mmol) were suspended Prepared by reaction in ethanol (125mL). The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=4/1) to obtain the title compound as a white solid (1.16 g, 35.0%).

LC-MS (ESI, pos.ion) m/z: 266.2[M+H] ⁺ ;

¹ H NMR (CDCl ₃ , 400MHz) δ (ppm): 8.06 (br s, 1H), 7.55 (d, J = 1.4Hz, 1H), 7.26-7.24 (m, 1H), 7.11 (dd, J = 8.6 ,1.8Hz,1H),7.00(s,1H),4.15-4.10(m,2H),2.75(t,J＝7.4Hz,2H),2.36(t,J＝7.4Hz,2H),2.05-2.00 (m,2H),1.27-1.24(m,3H).

Step 2) 4-(5-Chloro-1H-indol-3-yl)butan-1-ol

The title compound of this step was prepared by referring to the method described in step 3 of Example 1, that is, ethyl 4-(5-chloro-1H-indol-3-yl)butanoate (0.68g, 2.54mmol) and lithium aluminum hydride (0.38g, 10.16mmol) was prepared by suspending in tetrahydrofuran (25mL). The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) to obtain the title compound as a white solid (0.42 g, 75.0%).

LC-MS (ESI, pos.ion) m/z: 224.2[M+H] ⁺ ;

¹ H NMR (CDCl ₃ , 400MHz) δ (ppm): 8.07 (br s, 1H), 7.55 (d, J = 1.8Hz, 2H), 2.74 (t, J = 7.3Hz, 2H), 1.78-1.73 ( m,2H), 1.69-1.63(m,2H).

Step 3) 4-(5-Chloro-1H-indol-3-yl)butyl 4-methylbenzenesulfonate

The title compound of this step was prepared by referring to the method described in Step 4 of Example 1, that is, 4-(5-chloro-1H-indol-3-yl)butan-1-ol (0.42g, 1.9mmol), triethyl Prepared by dissolving amine (0.3mL, 2.28mmol) and p-toluenesulfonyl chloride (0.43g, 2.28mmol) in dichloromethane (20mL). The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=4/1) to obtain the title compound as a white solid (0.57 g, 80.0%).

LC-MS (ESI, pos.ion) m/z: 378.1[M+H] ⁺ ;

¹ H NMR (CDCl ₃ , 400MHz) δ(ppm): 8.04(br s, 1H), 7.76(d, J=8.3Hz, 2H), 7.46(d, J=1.8Hz, 1H), 7.31(d, J＝8.0Hz, 2H), 7.27-7.24(m, 1H), 7.11(dd, J＝8.6, 2.0Hz, 1H), 6.96(d, J＝2.0Hz, 1H), 4.04(t, J＝5.9 Hz, 2H), 2.65(t, J=6.6Hz, 2H), 2.44(t, J=5.4Hz, 3H), 1.71-1.66(m, 4H).

Step 4) 5-Chloro-3-(4-(4-(pyridin-2-yl)piperazin-1-yl)butyl)-1H-indole

The title compound of this step was prepared by referring to the method described in step 6 of Example 1, that is, 4-(5-chloro-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (0.22g, 0.58mmol ), 1-(pyridin-2-yl)piperazine (0.10g, 0.58mmol), potassium carbonate (120mg, 0.87mmol) and a catalytic amount of potassium iodide (20mg, 0.12mmol) were dissolved in acetonitrile (15mL) to obtain . The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1), concentrated and dried to obtain the title compound as a white solid (0.13 g, 62.0%).

LC-MS (ESI, pos.ion) m/z: 369.2[M+H] ⁺ ;

¹ H NMR (CDCl ₃ , 400MHz) δ (ppm): 8.19-8.18 (m, 1H), 8.15 (br s, 1H), 7.56 (d, J=1.5Hz, 1H), 7.49-7.45 (m, 1H ),7.24(s,1H),7.11(dd,J=8.6,1.8Hz,1H),6.99(s,1H),6.65-6.60(m,2H),3.54(t,J=5.0Hz,4H) ,2.74(t,J=7.3Hz,4H),2.55(t,J=5.0Hz,2H),2.43(t,J=7.6Hz,2H),1.75-1.71(m,2H),1.66-1.60( m,2H).

Example 3 5-fluoro-3-(4-(4-(pyridin-2-yl)piperazin-1-yl)butyl)-1H-indole

Step 1) Ethyl 4-(5-fluoro-1H-indol-3-yl)butanoate

The title compound of this step was prepared by referring to the method described in step 2 of Example 1, that is, ethyl 6-oxohexanoate (1.0 g, 6.3 mmol) and p-fluorophenylhydrazine hydrochloride (0.86 g, 6.8 mmol) were suspended Prepared by reaction in ethanol (125mL). The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=4/1) to obtain the title compound as a white solid (0.94 g, 60.0%).

LC-MS (ESI, pos.ion) m/z: 250.2[M+H] ⁺ ;

¹ H NMR (CDCl ₃ , 400MHz) δ (ppm): 8.04 (br s, 1H), 7.27-7.22 (m, 2H), 7.02 (d, J = 2.0Hz, 1H), 6.93 (td, J = 9.1 ,2.6Hz,1H),4.15-4.10(m,2H),2.76(t,J=7.4Hz,2H),2.37(t,J=7.4Hz,2H),2.06-1.99(m,2H),1.25 (t, J = 7.1 Hz, 3H).

Step 2) 4-(5-fluoro-1H-indol-3-yl)butan-1-ol

The title compound of this step was prepared by referring to the method described in step 3 of Example 1, that is, ethyl 4-(5-fluoro-1H-indol-3-yl)butanoate (0.32g, 1.27mmol) and lithium aluminum hydride (0.19g, 5.08mmol) was prepared by suspending in tetrahydrofuran (25mL). The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) to obtain the title compound as a white solid (0.20 g, 75.0%).

LC-MS (ESI, pos.ion) m/z: 208.2[M+H] ⁺ ;

¹ H NMR(CDCl ₃ ,400MHz)δ(ppm):8.07(br s,1H),7.25-7.20(m,2H),6.99(s,1H),6.91(td,J＝9.1,2.4Hz,1H ), 3.67(t, J=6.4Hz, 2H), 2.72(t, J=7.4Hz, 2H), 1.79-1.72(m, 2H), 1.68-1.53(m, 2H).

Step 3) 4-(5-fluoro-1H-indol-3-yl)butyl 4-methylbenzenesulfonate

The title compound of this step was prepared by referring to the method described in step 4 of Example 1, that is, 4-(5-fluoro-1H-indol-3-yl)butan-1-ol (0.39g, 1.9mmol), triethyl Prepared by dissolving amine (0.3mL, 2.28mmol) and p-toluenesulfonyl chloride (0.43g, 2.28mmol) in dichloromethane (20mL). The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=4/1) to obtain the title compound as a white solid (0.45 g, 65.0%).

LC-MS (ESI, pos.ion) m/z: 362.2[M+H] ⁺ ;

¹ H NMR (CDCl ₃ , 400MHz) δ (ppm): 7.99 (br s, 1H), 7.76 (d, J = 8.2Hz, 2H), 7.31 (d, J = 8.0Hz, 2H), 7.26-7.23 ( m,1H),7.11(dd,J=9.6,2.3Hz,1H),6.92(td,J=9.1,2.4Hz,1H),4.03(d,J=5.8Hz,2H),2.65(t,J =6.5Hz, 2H), 2.43(s, 3H), 1.71(t, J=3.2Hz, 4H).

Step 4) 5-fluoro-3-(4-(4-(pyridin-2-yl)piperazin-1-yl)butyl)-1H-indole

The title compound of this step was prepared by referring to the method described in step 6 of Example 1, that is, 4-(5-fluoro-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (0.20g, 0.58mmol ), 1-(pyridin-2-yl)piperazine (0.10g, 0.58mmol), potassium carbonate (120mg, 0.87mmol) and a catalytic amount of potassium iodide (20mg, 0.12mmol) were dissolved in acetonitrile (15mL) to obtain . The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a white solid (0.14 g, 67.0%).

LC-MS (ESI, pos.ion) m/z: 353.2[M+H] ⁺ ;

¹ H NMR(CDCl ₃ ,400MHz)δ(ppm):8.18(dd,J=4.8,1.2Hz,1H),8.09(br s,1H),7.49-7.45(m,1H),7.25-7.22(m ,2H),7.01(d,J=1.7Hz,1H),6.91(td,J=9.1,2.3Hz,1H),6.65-6.60(m,2H),3.54(t,J=5.0Hz,4H) ,2.74(t,J=7.3Hz,2H),2.54(t,J=5.1Hz,4H),2.42(t,J=7.6Hz,2H),1.77-1.69(m,2H),1.66-1.61( m,2H).

Example 4 3-(4-(4-(pyridin-2-yl)piperazin-1-yl)butyl)-1H-indole-5-carbonitrile

Step 1) 3-(4-chlorobutyryl)-1H-indole-5-carbonitrile

At 0°C, 4-chlorobutyryl chloride (9.6g, 68.0mmol) was added dropwise to dichloromethane (90mL) containing aluminum chloride (9.0g, 68.0mmol), the dropwise addition was completed, and the reaction was continued for 0.5h, then A dichloromethane solution (800 mL) of 5-cyanindole (8.1 g, 57.0 mmol) was added dropwise, and after the addition was complete, the reaction was carried out at room temperature for 2 h. Then, the reaction solution was added into a mixed solvent of ice water (50 g) and concentrated hydrochloric acid (50 mL), and the reaction was continued at room temperature for 20 h. After the reaction was completed, suction filtered, washed the filter cake with water and ethyl acetate, and dried to obtain a yellow solid (8.9 g, 64%).

LC-MS (ESI, pos.ion) m/z: 247.1[M+H] ⁺ ;

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 8.63 (d, J = 0.7Hz, 1H), 8.35 (s, 1H), 7.62-7.60 (m, 1H), 7.52 (dd, J = 8.4 , 1.5Hz, 1H), 3.69(t, J=6.5Hz, 2H), 3.11(t, J=7.2Hz, 2H), 2.24-2.17(m, 2H).

Step 2) 3-(4-Hydroxybutyl)-1H-indole-5-carbonitrile

Dissolve 3-(4-chlorobutyryl)-1H-indole-5-carbonitrile (490mg, 2.0mmol) in isopropanol (20mL), add sodium borohydride (230mg, 6.0mmol) in batches at 0°C ). The reaction solution was heated to 80°C and stirred for 6h, then cooled to 0°C, saturated sodium carbonate solution (1 mL) was added dropwise, filtered with suction, the filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/ v)=2/1), a white solid (343 mg, 80%) was obtained.

LC-MS (ESI, pos.ion) m/z: 215.2[M+H] ⁺ ;

¹ H NMR (CDCl ₃ , 400MHz) δ(ppm): 7.96(d, J=0.8Hz, 1H), 7.46-7.44(m, 1H), 7.34(dd, J=8.4, 1.4Hz, 1H), 7.20 (s,1H),4.58(s,1H),3.59(t,J=6.5Hz,2H),2.79(t,J=7.5Hz,2H),1.79-1.73(m,2H),1.65-1.60( m,2H).

Step 3) 4-(5-cyano-1H-indol-3-yl)butyl 4-methylbenzenesulfonate

The title compound of this step was prepared by referring to the method described in step 4 of Example 1, that is, 3-(4-hydroxybutyl)-1H-indole-5-carbonitrile (0.41g, 1.9mmol), triethylamine (0.3 mL, 2.28mmol) and p-toluenesulfonyl chloride (0.43g, 2.28mmol) were dissolved in dichloromethane (20mL) and prepared by reacting. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=4/1) to obtain the title compound as a white solid (0.56 g, 80.0%).

LC-MS (ESI, pos.ion) m/z: 369.2[M+H] ⁺ ;

¹ H NMR(CDCl ₃ ,400MHz)δ(ppm):8.32(br s,1H),7.89(s,1H),7.79(d,J=8.3Hz,2H),7.40(s,2H),7.43- 7.41(m, 2H), 7.35(d, J=8.1Hz, 2H), 7.10(d, J=1.9Hz, 2H), 4.08(t, J=5.5Hz, 2H), 2.74(t, J=6.6 Hz, 2H), 2.46(s, 3H), 1.78-1.74(m, 2H), 1.31-1.26(m, 2H).

Step 4) 3-(4-(4-(pyridin-2-yl)piperazin-1-yl)butyl)-1H-indole-5-carbonitrile

The title compound was prepared by referring to the method described in step 6 of Example 1, that is, 4-(5-cyano-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (0.21g, 0.58mmol) , 1-(pyridin-2-yl)piperazine (0.01g, 0.58mmol), potassium carbonate (120mg, 0.87mmol) and a catalytic amount of potassium iodide (20mg, 0.12mmol) were dissolved in acetonitrile (15mL). The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a white solid (0.14 g, 68.0%).

LC-MS (ESI, pos.ion) m/z: 360.1[M+H] ⁺ ;

¹ H NMR(CDCl ₃ ,400MHz)δ(ppm):8.46(br s,1H),8.19-8.17(m,1H),8.00(s,1H),7.95(s,1H),7.49-7.45(m ,1H),7.40-7.37(m,2H),7.11-7.10(m,1H),6.65-6.60(m,2H),3.55(t,J=5.1Hz,4H),2.78(t,J=7.3 Hz, 2H), 2.56(t, J=5.1Hz, 4H), 2.44(t, J=7.6Hz, 2H), 1.75-1.73(m, 2H), 1.65-1.63(m, 2H).

Example 5 3-(4-(4-(3-chloropyridin-2-yl)piperazin-1-yl)butyl)-5-methoxy-1H-indole

Step 1) 1-(3-chloropyridin-2-yl)piperazine

The title compound of this step was prepared by referring to the method described in step 5 of Example 1, that is, 2,3-dichloropyridine (1.1g, 7.2mmol), potassium carbonate (1.0g, 7.2mmol) and anhydrous piperazine (1.2g , 14.4mmol) were mixed in N,N-dimethylformamide (10mL). Purification by silica gel column chromatography (dichloromethane/methanol (v/v)=20/1) gave the title compound as a yellow oil (0.50 g, 35.0%).

LC-MS (ESI, pos.ion) m/z: 198.2[M+H] ⁺ ;

¹ H NMR (CDCl ₃ , 400MHz) δ (ppm): 8.18 (dd, J=4.8, 1.6Hz, 1H), 7.57 (dd, J=7.7, 1.6Hz, 1H), 6.82 (dd, J=7.8, 4.8Hz, 1H), 3.32(t, J=4.8Hz, 4H), 3.04(t, J=4.9Hz, 4H).

Step 2) 3-(4-(4-(3-chloropyridin-2-yl)piperazin-1-yl)butyl)-5-methoxy-1H-indole

The title compound of this step was prepared by referring to the method described in step 6 of Example 1, that is, 4-(5-methoxy-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (0.22g, 0.58mmol), 1-(3-chloropyridin-2-yl)piperazine (0.11g, 0.58mmol), potassium carbonate (120mg, 0.87mmol) and a catalytic amount of potassium iodide (20mg, 0.12mmol) were dissolved in acetonitrile (15mL ) prepared by reaction. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a white solid (0.12 g, 50.0%).

LC-MS (ESI, pos.ion) m/z: 399.1[M+H] ⁺ ;

¹ H NMR (CDCl ₃ , 400MHz) δ (ppm): 8.17 (dd, J = 4.7, 1.5 Hz, 1 H), 7.87 (br s, 1 H), 7.56 (dd, J = 7.7, 1.6 Hz, 1 H)) ,7.23(d,J=8.8Hz,1H),7.03(d,J=2.3Hz,1H),6.96(t,J=1.9Hz,1H),6.86-6.80(m,2H),6.65-6.60( m,2H),3.87(s,3H),3.40(s,4H),2.76(t,J=7.3Hz,2H),2.63(t,J=4.3Hz,4H),2.47(t,J=7.6 Hz, 2H), 1.77-1.73(m, 2H), 1.68-1.63(m, 2H).

Example 6 2-(4-(4-(5-methoxy-1H-indol-3-yl)butyl)piperazin-1-yl)nicotinecarbonitrile

Step 1) 2-(piperazin-1-yl)nicotinecarbonitrile

The title compound of this step was prepared with reference to the method described in Example 1 step 5, that is, 2-chloro-3-cyanopyridine (1.0g, 7.2mmol), potassium carbonate (1.0g, 7.2mmol) and anhydrous piperazine ( 1.2 g, 14.4 mmol) were mixed in N,N-dimethylformamide (10 mL). The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a yellow solid (0.51 g, 38.0%).

LC-MS (ESI, pos.ion) m/z: 189.2[M+H] ⁺ ;

¹ H NMR (CDCl ₃ , 400MHz) δ (ppm): 8.34 (dd, J = 4.8, 1.9 Hz, 1H), 7.76 (dd, J = 7.6, 2.0 Hz, 1H), 6.73 (dd, J = 7.6, 4.8Hz, 1H), 3.69(t, J=5.0Hz, 4H), 3.04(t, J=5.0Hz, 4H).

Step 2) 2-(4-(4-(5-methoxy-1H-indol-3-yl)butyl)piperazin-1-yl)nicotinecarbonitrile

The title compound of this step was prepared by referring to the method described in step 6 of Example 1, that is, 4-(5-methoxy-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (0.22g, 0.58mmol), 2-(piperazin-1-yl)nicotinecarbonitrile (0.11g, 0.58mmol), potassium carbonate (120mg, 0.87mmol) and a catalytic amount of potassium iodide (20mg, 0.12mmol) were dissolved in acetonitrile (15mL ) prepared by reaction. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a white solid (0.12 g, 53.0%).

LC-MS (ESI, pos.ion) m/z: 391.3[M+H] ⁺ ;

¹ H NMR (CDCl ₃ , 400MHz) δ (ppm): 8.32 (dd, J = 4.7, 1.8 Hz, 1H), 7.85 (br s, 1H), 7.74 (dd, J = 7.6, 1.8 Hz, 1H), 7.23(d, J=8.9Hz, 1H), 7.03(d, J=2.3Hz, 1H), 7.03(t, J=2.1Hz, 1H), 6.97(s, 1H), 6.84(dd, J=8.8 ,2.3Hz,1H),6.71(dd,J=7.6,4.8Hz,1H),3.87(s,3H),3.75(t,J=4.8Hz,4H),2.76(t,J=7.3Hz,2H ), 2.60(t, J=4.8Hz, 4H), 2.46(t, J=7.6Hz, 2H), 1.75-1.73(m, 2H), 1.66-1.62(m, 2H).

Example 7 5-methoxy-3-(4-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)butyl)-1H-ind indole

step 1) 1-(5-(trifluoromethyl)pyridin-2-yl)piperazine

The title compound of this step was prepared by referring to the method described in step 5 of Example 1, that is, 2-chloro-5-(trifluoromethyl)pyridine (1.3g, 7.2mmol), potassium carbonate (1.0g, 7.2mmol) and Water piperazine (1.2 g, 14.4 mmol) was prepared by mixing in N,N-dimethylformamide (10 mL). The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a yellow oil (1.00 g, 60.0%).

LC-MS (ESI, pos.ion) m/z: 232.2[M+H] ⁺ ;

¹ H NMR (CDCl ₃ , 400MHz) δ(ppm): 8.39(s, 1H), 7.61(dd, J=9.0, 2.4Hz, 1H), 6.62(d, J=9.0Hz, 1H), 3.62(t , J=5.1Hz, 4H), 2.97(t, J=5.1Hz, 4H).

Step 2) 5-methoxy-3-(4-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)butyl)-1H-ind indole

The title compound of this step was prepared by referring to the method described in step 6 of Example 1, that is, 4-(5-methoxy-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (0.22g, 0.58mmol), 1-(5-(trifluoromethyl)pyridin-2-yl)piperazine (0.13g, 0.58mmol), potassium carbonate (120mg, 0.87mmol) and a catalytic amount of potassium iodide (20mg, 0.12mmol) Prepared by dissolving in acetonitrile (15mL). The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a white solid (0.18 g, 71.0%).

LC-MS (ESI, pos.ion) m/z: 433.1[M+H] ⁺ ;

¹ H NMR (CDCl ₃ , 400MHz) δ (ppm): 8.39 (s, 1H), 7.83 (br s, 1H), 7.60 (dd, J=9.0, 2.4Hz, 1H), 7.23 (s, 1H), 7.03(d, J=2.4Hz, 1H), 6.96(d, J=2.0Hz, 1H), 6.84(dd, J=8.7, 2.4Hz, 1H), 6.61(d, J=9.0Hz, 1H), 3.87(s, 3H), 3.64(t, J=5.1Hz, 4H), 2.76(t, J=7.4Hz, 2H), 2.53(t, J=5.1Hz, 4H), 2.43(t, J=7.6 Hz, 2H), 1.77-1.74(m, 2H), 1.66-1.64(m, 2H).

Example 8 3-(4-(4-(3-chloropyridin-2-yl)piperazin-1-yl)butyl)-5-fluoro-1H-indole

The title compound of this step was prepared by referring to the method described in step 6 of Example 1, that is, 4-(5-fluoro-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (0.20g, 0.58mmol ), 1-(3-chloropyridin-2-yl)piperazine (0.11g, 0.58mmol), potassium carbonate (120mg, 0.87mmol) and catalytic amount of potassium iodide (20mg, 0.12mmol) were dissolved in acetonitrile (15mL) The reaction is prepared. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a white solid (0.15 g, 67.0%).

LC-MS (ESI, pos.ion) m/z: 388.1[M+H] ⁺ ;

¹ H NMR (CDCl ₃ , 400MHz) δ (ppm): 8.16 (dd, J = 4.8, 1.6 Hz, 1H), 8.11 (br s, 1H), 7.55 (dd, J = 7.8, 1.6 Hz, 1H), 7.26-7.22(m,2H),7.00(d,J=2.0Hz,1H),6.91(td,J=9.1,2.4Hz,1H),6.81(dd,J=7.7,4.8Hz,1H),3.40 (s,4H),2.74(t,J=7.3Hz,2H),2.62(t,J=4.5Hz,4H),2.46(t,J=7.6Hz,2H),1.77-1.70(m,2H) ,1.67-1.59(m,2H).

Example 9 2-(4-(4-(5-fluoro-1H-indol-3-yl)butyl)piperazin-1-yl)nicotinecarbonitrile

Step 1) 2-(piperazin-1-yl)nicotinecarbonitrile

The title compound of this step was prepared by referring to the method described in step 5 of Example 1, that is, 2-chloronicotine carbonitrile (1.0g, 7.2mmol), potassium carbonate (1.0g, 7.2mmol) and anhydrous piperazine (1.2g , 14.4 mmol) were mixed in N,N-dimethylformamide (10 mL) to give the title compound as a yellow solid (0.51 g, 38.0%).

MS(ESI,pos.ion)m/z:189.2[M+H] ⁺ ;

¹ H NMR (CDCl ₃ , 400MHz) δ (ppm): 8.34 (dd, J = 4.8, 1.9 Hz, 1H), 7.76 (dd, J = 7.6, 2.0 Hz, 1H), 6.73 (dd, J = 7.6, 4.8Hz, 1H), 3.69(t, J=5.0Hz, 4H), 3.04(t, J=5.0Hz, 4H).

Step 2) 2-(4-(4-(5-fluoro-1H-indol-3-yl)butyl)piperazin-1-yl)nicotinecarbonitrile

The title compound of this step was prepared by referring to the method described in step 6 of Example 1, that is, 4-(5-fluoro-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (0.20g, 0.58mmol ), 2-(piperazin-1-yl)nicotinecarbonitrile (0.11g, 0.58mmol), potassium carbonate (120mg, 0.87mmol) and a catalytic amount of potassium iodide (20mg, 0.12mmol) were dissolved in acetonitrile (15mL) The reaction is prepared. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a white solid (0.15 g, 70.0%).

LC-MS (ESI, pos.ion) m/z: 378.3[M+H] ⁺ ;

¹ H NMR (CDCl ₃ , 400MHz) δ (ppm): 8.32 (dd, J = 4.8, 1.9 Hz, 1H), 8.02 (br s, 1H), 7.74 (dd, J = 7.6, 1.9 Hz, 1H), 7.27-7.22(m,2H),7.02(d,J=1.8Hz,1H),6.92(td,J=9.0,2.5Hz,1H),6.72(dd,J=7.6,4.8Hz,1H),3.74 (t, J=4.9Hz, 4H), 2.73(t, J=7.4Hz, 2H), 2.58(t, J=4.9Hz, 4H), 2.44(t, J=7.6Hz, 2H), 1.77-1.70 (m,2H),1.65-1.58(m,2H).

Example 10 2-(4-(4-(5-fluoro-1H-indol-3-yl)butyl)piperazin-1-yl)nicotinamide

Step 1) 2-(piperazin-1-yl)nicotinamide

The title compound of this step was prepared by referring to the method described in step 5 of Example 1, that is, 2-chloronicotinamide (1.1g, 7.2mmol), potassium carbonate (1.0g, 7.2mmol) and anhydrous piperazine (1.2g, 14.4 mmol) were prepared by mixing in N,N-dimethylformamide (10 mL). Purification by silica gel column chromatography (dichloromethane/methanol (v/v)=20/1) gave the title compound as a yellow solid (0.71 g, 48.0%).

LC-MS (ESI, pos.ion) m/z: 207.2[M+H] ⁺ ;

¹ H NMR (CDCl ₃ , 400MHz) δ (ppm): 8.55 (br s, 1H), 8.40 (dd, J=4.8, 1.9Hz, 1H), 8.30 (dd, J=7.6, 1.9Hz, 1H), 7.08 (dd, J = 7.6, 4.8Hz, 1H), 6.0 (s, 1H), 3.22-3.19 (m, 4H), 3.05 (t, J = 4.8Hz, 4H).

Step 2) 2-(4-(4-(5-fluoro-1H-indol-3-yl)butyl)piperazin-1-yl)nicotinamide

The title compound of this step was prepared by referring to the method described in step 6 of Example 1, that is, 4-(5-fluoro-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (0.20g, 0.58mmol ), 2-(piperazin-1-yl) nicotinamide (0.12g, 0.58mmol), potassium carbonate (120mg, 0.87mmol) and a catalytic amount of potassium iodide (20mg, 0.12mmol) were dissolved in acetonitrile (15mL) and prepared by reaction get. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a white solid (0.09 g, 40.0%).

LC-MS (ESI, pos.ion) m/z: 396.1[M+H] ⁺ ;

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 8.27 (dd, J = 4.9, 1.9 Hz, 1 H), 7.93 (dd, J = 7.5, 1.9 Hz, 1 H), 7.28-7.25 (m, 1 H ), 7.16(dd, J=9.9, 2.4Hz, 1H), 6.99(dd, J=7.5, 4.9Hz, 1H), 6.82(td, J=9.2, 2.4Hz, 1H), 3.38(t, J= 4.8Hz, 4H), 2.81-2.75(m, 6H), 2.63(t, J=7.6Hz, 2H), 1.76-1.70(m, 2H), 1.68-1.66(m, 2H).

Example 11 5-fluoro-3-(4-(4-(4-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)butyl)-1H-indole

Step 1) 1-(4-(trifluoromethyl)pyridin-2-yl)piperazine

The title compound of this step was prepared by referring to the method described in step 5 of Example 1, that is, 2-chloro-4-(trifluoromethyl)pyridine (1.3g, 7.2mmol), potassium carbonate (1.0g, 7.2mmol) and Water piperazine (1.2g, 14.4mmol) was prepared by mixing in N,N-dimethylformamide (10mL). The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a yellow oil (1.00 g, 60.0%).

LC-MS (ESI, pos.ion) m/z: 232.2[M+H] ⁺ ;

¹ H NMR (CDCl ₃ , 400MHz) δ (ppm): 8.29 (d, J = 5.0Hz, 1H), 6.77 (d, J = 5.8Hz, 1H), 3.59 (t, J = 5.1Hz, 4H), 3.00 (t, J = 5.1 Hz, 4H).

Step 2) 5-fluoro-3-(4-(4-(4-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)butyl)-1H-indole

The title compound of this step was prepared by referring to the method described in step 6 of Example 1, that is, 4-(5-fluoro-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (0.20g, 0.58mmol ), 1-(4-(trifluoromethyl)pyridin-2-yl)piperazine (0.13g, 0.58mmol), potassium carbonate (120mg, 0.87mmol) and catalytic amount of potassium iodide (20mg, 0.12mmol) were dissolved in Prepared by reaction in acetonitrile (15 mL). The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a white solid (0.19 g, 80.0%).

LC-MS (ESI, pos.ion) m/z: 421.2[M+H] ⁺ ;

¹ H NMR (CDCl ₃ , 400MHz) δ(ppm): 8.28(d, J=5.1Hz, 1H), 7.98(br s, 1H), 7.27-7.22(m, 2H), 7.02(d, J=2.0 Hz, 1H), 6.92(td, J=9.0, 2.5Hz, 1H), 6.78-6.76(m, 2H), 3.61(t, J=5.1Hz, 4H), 2.74(t, J=7.4Hz, 2H ), 2.55(t, J=5.1Hz, 4H), 2.44(t, J=7.6Hz, 2H), 1.76-1.70(m, 2H), 1.67-1.61(m, 2H).

Example 12 5-fluoro-3-(4-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)butyl)-1H-indole

The title compound of this step was prepared by referring to the method described in step 6 of Example 1, that is, 4-(5-fluoro-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (0.20g, 0.58mmol ), 1-(5-(trifluoromethyl)pyridin-2-yl)piperazine (0.13g, 0.58mmol), potassium carbonate (120mg, 0.87mmol) and catalytic amount of potassium iodide (20mg, 0.12mmol) were dissolved in Prepared by reaction in acetonitrile (15 mL). The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a white solid (0.17 g, 70.0%).

LC-MS (ESI, pos.ion) m/z: 421.2[M+H] ⁺ ;

¹ H NMR(CDCl ₃ ,400MHz)δ(ppm):8.39(s,1H),7.96(br s,1H),7.60(dd,J=9.0,2.3Hz,1H),7.27-7.22(m,2H ), 7.02(d, J=1.5Hz, 1H), 6.92(td, J=9.0, 2.4Hz, 1H), 6.61(d, J=9.0Hz, 1H), 3.64(t, J=5.0Hz, 4H ), 2.74(t, J=7.4Hz, 2H), 2.52(t, J=5.1Hz, 4H), 2.42(t, J=7.5Hz, 2H), 1.78-1.72(m, 2H), 1.66-1.58 (m,2H).

Example 13 3-(4-(4-(3-chloropyridin-2-yl)piperazin-1-yl)butyl)-1H-indole-5-carbonitrile

The title compound was prepared by referring to the method described in step 6 of Example 1, that is, 4-(5-cyano-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (0.21g, 0.58mmol) , 1-(3-chloropyridin-2-yl)piperazine (0.11g, 0.58mmol), potassium carbonate (120mg, 0.87mmol) and catalytic amount of potassium iodide (20mg, 0.12mmol) were dissolved in acetonitrile (15mL) for reaction prepared. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a white solid (0.15 g, 68.0%).

LC-MS (ESI, pos.ion) m/z: 394.1[M+H] ⁺ ;

¹ H NMR (CDCl ₃ , 400MHz) δ (ppm): 8.46 (br s, 1H), 8.16 (dd, J = 4.8, 1.6 Hz, 1H), 7.95 (s, 1H), 7.56 (dd, J = 7.8 ,1.6Hz,1H),7.42-7.37(m,2H),7.11(s,1H),6.81(dd,J=7.7,4.8Hz,1H),3.41(s,4H),2.78(t,J= 7.3Hz, 2H), 2.48(t, J=7.6Hz, 2H), 1.76-1.71(m, 2H), 1.68-1.62(m, 2H).

Example 14 3-(4-(4-(3-cyanopyridin-2-yl)piperazin-1-yl)butyl)-1H-indole-5-carbonitrile

The title compound was prepared by referring to the method described in step 6 of Example 1, that is, 4-(5-cyano-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (0.21g, 0.58mmol) , 2-(piperazin-1-yl) nicotine carbonitrile (0.11g, 0.58mmol), potassium carbonate (120mg, 0.87mmol) and catalytic amount of potassium iodide (20mg, 0.12mmol) were dissolved in acetonitrile (15mL) for reaction prepared. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a white solid (0.13 g, 60.0%).

LC-MS (ESI, pos.ion) m/z: 385.2[M+H] ⁺ ;

¹ H NMR(CDCl ₃ ,400MHz)δ(ppm):8.38-8.35(m,1H),7.97(s,1H),7.95(s,1H),7.77(dd,J＝7.6,1.9Hz,1H) ,7.4(s,2H),7.13(d,J=1.7Hz,1H),6.76(dd,J=7.6,4.8Hz,1H),3.78(t,J=4.8Hz,4H),2.81(t, J=7.3Hz, 2H), 2.65(t, J=4.8Hz, 4H), 2.50(t, J=7.5Hz, 2H), 1.79-1.73(m, 2H), 1.70-1.62(m, 2H).

Example 15 2-(4-(4-(5-cyano-1H-indol-3-yl)butyl)piperazin-1-yl)nicotinamide

The title compound was prepared by referring to the method described in step 6 of Example 1, that is, 4-(5-cyano-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (0.21g, 0.58mmol) , 2-(piperazin-1-yl)nicotinamide (0.12g, 0.58mmol), potassium carbonate (120mg, 0.87mmol) and a catalytic amount of potassium iodide (20mg, 0.12mmol) were dissolved in acetonitrile (15mL) and prepared by reacting . The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a white solid (0.12 g, 53.0%).

LC-MS (ESI, pos.ion) m/z: 403.2[M+H] ⁺ ;

¹ H NMR(DMSO-d ₆ ,400MHz)δ(ppm):11.37(s,1H),8.22(dd,J＝4.7,1.7Hz,1H),8.08(s,1H),7.87(s,1H) ,7.74(dd,J=7.4,1.7Hz,1H),7.51-7.49(m,2H),7.41-7.39(m,1H),7.34(s,1H),6.89(dd,J=7.4,4.8Hz , 1H), 3.25(s, 4H), 2.74(t, J=7.3Hz, 2H), 2.46(s, 4H), 1.69-1.65(m, 2H), 1.54-1.50(m, 2H).

Example 16 3-(4-(4-(4-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)butyl)-1H-indole-5-methyl Nitrile

The title compound was prepared by referring to the method described in step 6 of Example 1, that is, 4-(5-cyano-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (0.21g, 0.58mmol) , 1-(4-(trifluoromethyl)pyridin-2-yl)piperazine (0.13g, 0.58mmol), potassium carbonate (120mg, 0.87mmol) and a catalytic amount of potassium iodide (20mg, 0.12mmol) were dissolved in acetonitrile (15 mL) was prepared by reaction. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a white solid (0.17 g, 69.0%).

LC-MS (ESI, pos.ion) m/z: 428.2[M+H] ⁺ ;

¹ H NMR (CDCl ₃ , 400MHz) δ (ppm): 8.36 (br s, 1H), 8.28 (d, J = 5.0Hz, 1H), 7.96 (s, 1H), 7.43-7.38 (m, 2H), 7.4(s, 2H), 7.10(d, J=1.8Hz, 1H), 6.78-6.76(m, 2H), 3.61(t, J=5.0Hz, 4H), 2.79(t, J=7.4Hz, 2H ), 2.55(t, J=5.0Hz, 4H), 2.44(t, J=7.5Hz, 2H), 1.79-1.72(m, 2H), 1.67-1.61(m, 2H).

Example 17 3-(4-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)butyl)-1H-indole-5-methyl Nitrile

The title compound was prepared by referring to the method described in step 6 of Example 1, that is, 4-(5-cyano-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (0.21g, 0.58mmol) , 1-(5-(trifluoromethyl)pyridin-2-yl)piperazine (0.13g, 0.58mmol), potassium carbonate (120mg, 0.87mmol) and a catalytic amount of potassium iodide (20mg, 0.12mmol) were dissolved in acetonitrile (15 mL) was prepared by reaction. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a white solid (0.17 g, 67.0%).

LC-MS (ESI, pos.ion) m/z: 428.1[M+H] ⁺ ;

¹ H NMR(CDCl ₃ ,400MHz)δ(ppm):8.41-8.39(m,1H),7.97(s,1H),7.63(dd,J=9.0,2.3Hz,1H),7.43(s,2H) ,7.28(s,1H),7.13(s,1H),6.64(d,J=9.0Hz,1H),3.69(t,J=5.0Hz,4H),2.81(t,J=7.4Hz,2H) , 2.59 (t, J = 5.0Hz, 4H), 2.50 (t, J = 7.5Hz, 2H), 1.79-1.74 (m, 2H), 1.70-1.64 (m, 2H).

Example 18 3-(4-(4-(3-methoxypyridin-2-yl)piperazin-1-yl)butyl)-1H-indole-5-carbonitrile

Step 1) 1-(3-methoxypyridin-2-yl)piperazine

The title compound of this step was prepared by referring to the method described in step 5 of Example 1, that is, 2-chloro-3-methoxypyridine (1.0g, 7.2mmol), potassium carbonate (1.0g, 7.2mmol) and anhydrous piperazine (1.2g, 14.4mmol) were prepared by mixing in N,N-dimethylformamide (10mL). The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a white solid (0.17 g, 12.0%).

LC-MS (ESI, pos.ion) m/z: 194.2[M+H] ⁺ ;

¹ H NMR(CDCl ₃ ,400MHz)δ(ppm):7.75-7.76(m,1H),7.24-7.26(m,1H),6.91-6.95(m,1H),3.85(s,3H),3.29- 3.33 (m, 4H), 2.99 (t, 4H, J=5.16Hz).

Step 2) 3-(4-(4-(3-methoxypyridin-2-yl)piperazin-1-yl)butyl)-1H-indole-5-carbonitrile

The title compound was prepared by referring to the method described in step 6 of Example 1, that is, 4-(5-cyano-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (0.21g, 0.58mmol) , 1-(3-methoxypyridin-2-yl)piperazine (0.11g, 0.58mmol), potassium carbonate (120mg, 0.87mmol) and a catalytic amount of potassium iodide (20mg, 0.12mmol) were dissolved in acetonitrile (15mL) Prepared by reaction. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a white solid (0.17 g, 67.0%).

LC-MS (ESI, pos.ion) m/z: 389.1[M+H] ⁺ ;

¹ H NMR (CDCl ₃ , 400MHz) δ (ppm): 8.57 (s, 1H), 7.93 (s, 1H), 7.86-7.85 (m, 1H), 7.43 (s, 2H), 7.12 (d, J= 7.0Hz, 1H), 7.03(s, 1H), 6.83(dd, J＝7.9, 4.9Hz, 1H), 3.84(s, 3H), 3.51(s, 4H), 2.78(t, J＝6.9Hz, 2H), 2.73-2.72 (m, 4H), 2.53 (t, J=7.3Hz, 2H), 1.74-1.69 (m, 4H).

Example 19 3-(4-(4-(3-methylpyridin-2-yl)piperazin-1-yl)butyl)-1H-indole-5-carbonitrile

Step 1) 1-(3-Methylpyridin-2-yl)piperazine

The title compound of this step was prepared according to the method described in step 5 of Example 1, that is, 2-chloro-3-picoline (0.9g, 7.2mmol), potassium carbonate (1.0g, 7.2mmol) and anhydrous piperazine ( 1.2g, 14.4mmol) were prepared by mixing in N,N-dimethylformamide (10mL). The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a white solid (0.14 g, 11.0%).

LC-MS (ESI, pos.ion) m/z: 178.2[M+H] ⁺ ;

¹ H NMR (CDCl ₃ , 400MHz) δ(ppm): 8.09(d, J=4.8Hz, 1H), 7.55(d, J=7.3Hz, 1H), 6.95(dd, J=7.3, 4.8Hz, 1H ), 3.15-3.17(m,4H), 3.06-3.09(m,4H), 2.32(s,3H).

Step 2) 3-(4-(4-(3-methylpyridin-2-yl)piperazin-1-yl)butyl)-1H-indole-5-carbonitrile

The title compound was prepared by referring to the method described in step 6 of Example 1, that is, 4-(5-cyano-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (0.21g, 0.58mmol) , 1-(3-methylpyridin-2-yl)piperazine (0.10g, 0.58mmol), potassium carbonate (120mg, 0.87mmol) and a catalytic amount of potassium iodide (20mg, 0.12mmol) were dissolved in acetonitrile (15mL) The reaction is prepared. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a white solid (0.13 g, 60.0%).

LC-MS (ESI, pos.ion) m/z: 373.1[M+H] ⁺ ;

¹ H NMR (CDCl ₃ , 400MHz): δ(ppm) 8.46(s, 1H), 8.13(d, J=3.6Hz, 1H), 7.94(s, 1H), 7.40(s, 2H), 7.38(s ,1H),7.14(s,1H),6.84(dd,J=7.2,5.0Hz,1H),3.27(t,J=4.5Hz,3H),3.51(s,4H),2.79(t,J= 7.0Hz, 2H), 2.71(s, 4H), 2.54(t, J=7.4Hz, 2H), 2.26(s, 3H), 1.80-1.69(m, 4H).

Example 20 5-methoxy-3-(3-(4-(pyridin-2-yl)piperazin-1-yl)propyl)-1H-indole

Step 1) 3-(5-methoxy-1H-indol-3-yl)propan-1-ol

Dissolve 4-methoxyphenylhydrazine hydrochloride (3.63g, 20.8mmol) in a mixed solution of dilute sulfuric acid (4%, 50mL) and N,N-dimethylacetamide (10mL), and heat up to 100°C , and then dropwise added 1,4-dihydropyran (1.9mL, 20.8mmol), and reacted at this temperature for 20h. After the reaction was complete, the reaction mixture was cooled to room temperature, extracted with ethyl acetate (50 mL x 3), and washed with water (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) to obtain the title compound as a white solid (1.5 g, 35%) .

LC-MS (ESI, pos.ion) m/z: 206.0[M+H] ⁺ ;

¹ H NMR(CDCl ₃ ,400MHz)δ(ppm):7.89(br s,1H),7.25-7.23(m,1H),7.04(d,J=2.2Hz,1H),6.97(d,J=1.9 Hz,1H),6.84(dd,J=8.7,2.3Hz,1H),3.86(s,3H),3.73(t,J=6.4Hz,2H),2.82(t,J=7.5Hz,2H), 2.02-1.96 (m, 2H).

Step 2) 3-(5-Methoxy-1H-indol-3-yl)propyl 4-methylbenzenesulfonate

The title compound of this step was prepared by referring to the method described in step 4 of Example 1, that is, 3-(5-methoxy-1H-indol-3-yl)propan-1-ol (1.03g, 5.0mmol), tri Prepared by reacting ethylamine (0.8mL, 6.0mmol) and p-toluenesulfonyl chloride (1.14g, 6.0mmol) in dichloromethane (20mL). The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=4/1) to obtain the title compound as a white solid (1.26 g, 70.0%).

LC-MS (ESI, pos.ion) m/z: 360.1[M+H] ⁺ ;

¹ H NMR (CDCl ₃ , 400MHz) δ(ppm): 7.84(br s, 1H), 7.76(d, J=8.2Hz, 2H), 7.30(d, J=8.1Hz, 2H), 7.22(d, J＝8.8Hz, 1H), 6.94(d, J＝8.8Hz, 1H), 6.89(s, 1H), 6.83(dd, J＝8.8, 2.3Hz, 1H), 4.08(t, J＝6.2Hz, 2H), 3.85(s, 3H), 2.78(t, J=7.2Hz, 2H), 2.43(s 3H), 2.06-2.00(m, 2H).

Step 3) 5-methoxy-3-(3-(4-(pyridin-2-yl)piperazin-1-yl)propyl)-1H-indole

The title compound of this step was prepared by referring to the method described in step 6 of Example 1, that is, 3-(5-methoxy-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (0.21g, 0.58mmol), 1-(pyridin-2-yl)piperazine (0.10g, 0.58mmol), potassium carbonate (120mg, 0.87mmol) and catalytic amount of potassium iodide (20mg, 0.12mmol) were dissolved in acetonitrile (15mL) for reaction prepared. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a white solid (0.11 g, 56.0%).

LC-MS (ESI, pos.ion) m/z: 351.3[M+H] ⁺ ;

¹ H NMR (CDCl ₃ , 400MHz) δ (ppm): 8.18 (dd, J = 4.9, 1.2 Hz, 1 H), 7.96 (br s, 1 H), 7.49-7.45 (m, 1 H), 7.22 (d, J =8.8Hz,1H),7.04(d,J=2.3Hz,1H),6.97(d,J=2.0Hz,1H),6.84(dd,J=8.8,2.4Hz,1H),6.65-6.60(m ,2H),3.87(s,3H),3.56(t,J=5.1Hz,4H),2.77(t,J=7.5Hz,2H),2.58(t,J=5.1Hz,2H),2.50(t , J=3.9Hz, 2H), 2.00-1.92 (m, 2H).

Example 21 5-Chloro-3-(3-(4-(pyridin-2-yl)piperazin-1-yl)propyl)-1H-indole

Step 1) 3-(5-Chloro-1H-indol-3-yl)propan-1-ol

The title compound of this step was prepared by referring to the method described in step 1 of Example 20, that is, p-chlorophenylhydrazine hydrochloride (3.72g, 20.8mmol) and 1,4-dihydropyran (1.9mL, 20.8mmol) were dissolved in Prepared by reacting in a mixed solution of dilute sulfuric acid (4%, 50mL) and N,N-dimethylacetamide (10mL). The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) to obtain the title compound as a white solid (2.35 g, 54%).

LC-MS (ESI, pos.ion) m/z: 210.2[M+H] ⁺ ;

¹ H NMR (CDCl ₃ , 400MHz) δ (ppm): 8.10 (br s, 1H), 7.56 (d, J = 1.8Hz, 1H), 7.26-7.24 (m, 2H), 7.11 (dd, J = 8.6 , 1.9Hz, 1H), 6.99(s, 1H), 3.71(t, J=6.4Hz, 2H), 2.80(t, J=7.5Hz, 2H), 1.99-1.92(m, 2H).

Step 2) 3-(5-Chloro-1H-indol-3-yl)propyl 4-methylbenzenesulfonate

The title compound of this step was prepared by referring to the method described in step 4 of Example 1, that is, 3-(5-chloro-1H-indol-3-yl)propan-1-ol (1.05g, 5.0mmol), triethylamine (0.8mL, 6.0mmol) and p-toluenesulfonyl chloride (1.14g, 6.0mmol) were prepared by dissolving in dichloromethane (20mL). The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=4/1) to obtain the title compound as a white solid (1.09 g, 60.0%).

LC-MS (ESI, pos.ion) m/z: 364.1[M+H] ⁺ ;

¹ H NMR (CDCl ₃ , 400MHz) δ(ppm): 8.03(br s, 1H), 7.76(d, J=8.3Hz, 2H), 7.44(d, J=2.0Hz, 1H), 7.31(d, J＝8.0Hz, 2H), 7.26-7.24(m 1H), 7.11(dd, J＝8.6, 2.0Hz, 1H), 6.95(d, J＝2.2Hz, 1H), 4.07(t, J＝6.2Hz , 2H), 2.75 (t, J=7.3Hz, 2H), 2.44 (s, 3H), 2.04-1.97 (m, 2H).

Step 3) 5-Chloro-3-(3-(4-(pyridin-2-yl)piperazin-1-yl)propyl)-1H-indole

The title compound of this step was prepared by referring to the method described in step 6 of Example 1, that is, 3-(5-chloro-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (0.21g, 0.58mmol ), 1-(pyridin-2-yl)piperazine (0.10g, 0.58mmol), potassium carbonate (120mg, 0.87mmol) and a catalytic amount of potassium iodide (20mg, 0.12mmol) were dissolved in acetonitrile (15mL) to obtain . The crude product was subjected to silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1), concentrated and dried to obtain the title compound as a white solid (0.15 g, 72.0%).

LC-MS (ESI, pos.ion) m/z: 355.1[M+H] ⁺ ;

¹ H NMR(CDCl ₃ ,400MHz)δ(ppm):8.18(dd,J=4.8,1.2Hz,1H),8.13(br s,1H),7.58(m,1H),7.50-7.45(m,1H ),7.24(s,1H),7.11(dd,J=8.6,1.9Hz,1H),7.01(d,J=1.7Hz,1H),6.66-6.60(m,2H),3.57(t,J= 5.0Hz, 4H), 2.76(t, J=7.5Hz, 2H), 2.58(t, J=5.1, 4H), 2.48(t, J=7.6Hz, 2H), 1.97-1.90(m, 2H).

Example 22 5-fluoro-3-(3-(4-(pyridin-2-yl)piperazin-1-yl)propyl)-1H-indole

Step 1) 3-(5-fluoro-1H-indol-3-yl)propan-1-ol

The title compound of this step was prepared by referring to the method described in step 1 of Example 20, that is, dissolving 4-fluorophenylhydrazine hydrochloride (3.37g, 20.8mmol) and 1,4-dihydropyran (1.9mL, 20.8mmol) Prepared by reacting in a mixed solution of dilute sulfuric acid (4%, 50mL) and N,N-dimethylacetamide (10mL). The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) to obtain the title compound as a white solid (3.53 g, 88%).

LC-MS (ESI, pos.ion) m/z: 194.2[M+H] ⁺ ;

¹ H NMR(CDCl ₃ ,400MHz)δ(ppm):8.05(br s,1H),7.27-7.23(m,1H),7.03(d,J=2.0Hz,1H),6.96-6.91(m,1H ), 3.72(t, J=6.4Hz, 2H), 2.81(t, J=7.5Hz, 2H), 2.00-1.93(m, 2H).

Step 2) 3-(5-fluoro-1H-indol-3-yl)propyl 4-methylbenzenesulfonate

The title compound of this step was prepared by referring to the method described in step 4 of Example 1, that is, 3-(5-fluoro-1H-indol-3-yl)propan-1-ol (0.97g, 5.0mmol), triethylamine (0.8mL, 6.0mmol) and p-toluenesulfonyl chloride (1.14g, 6.0mmol) were prepared by dissolving in dichloromethane (20mL). The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=4/1) to obtain the title compound as a white solid (1.28 g, 74.0%).

LC-MS (ESI, pos.ion) m/z: 348.1[M+H] ⁺ ;

¹ H NMR(CDCl ₃ ,400MHz)δ(ppm):8.00(br s,1H),7.79(s,1H),7.77(s,1H),7.33(s,1H),7.31(s,1H), 7.27-7.24(m,1H),7.09(dd,J=9.6,2.4Hz,1H),6.96(d,J=2.1Hz,1H),6.92(dd,J=9.1,2.5Hz,1H),4.07 (t, J=6.2Hz, 2H), 2.75(t, J=7.3Hz, 2H), 2.44(s, 3H), 2.05-1.97(m, 2H).

Step 3) 5-fluoro-3-(3-(4-(pyridin-2-yl)piperazin-1-yl)propyl)-1H-indole

The title compound of this step was prepared by referring to the method described in step 6 of Example 1, that is, 3-(5-fluoro-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (0.20g, 0.58mmol ), 1-(pyridin-2-yl)piperazine (0.10g, 0.58mmol), potassium carbonate (120mg, 0.87mmol) and a catalytic amount of potassium iodide (20mg, 0.12mmol) were dissolved in acetonitrile (15mL) to obtain . The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a white solid (0.13 g, 65.0%).

LC-MS (ESI, pos.ion) m/z: 339.2[M+H] ⁺ ;

¹ H NMR(CDCl ₃ ,400MHz)δ(ppm):8.18(s,1H),8.10(br s,1H),7.50-7.45(m,1H),7.24-7.24(m,1H),7.03(d ,J=1.4Hz,1H),6.91(dd,J=9.1,1.8Hz,1H),6.66-6.60(m,2H),3.56(t,J=5.0Hz,4H),2.76(t,J= 7.5Hz, 2H), 2.56 (t, J = 5.0, 4H), 2.47 (t, J = 7.6, 2H), 1.97-1.90 (m, 2H).

Example 23 3-(3-(4-(pyridin-2-yl)piperazin-1-yl)propyl)-1H-indole-5-carbonitrile

Step 1) 3-(3-Hydroxypropyl)-1H-indole-5-carbonitrile

The title compound of this step was prepared by referring to the method described in step 1 of Example 20, that is, 4-cyanophenylhydrazine hydrochloride (3.52g, 20.8mmol) and 1,4-dihydropyran (1.9mL, 20.8mmol) Prepared by dissolving in a mixed solution of dilute sulfuric acid (4%, 50mL) and N,N-dimethylacetamide (10mL). The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) to obtain the title compound as a white solid (1.46 g, 35%).

LC-MS (ESI, pos.ion) m/z: 201.1 [M+H] ⁺ ;

¹ H NMR (DMSO-d ₆ , 400MHz) δ(ppm): 11.36(s, 1H), 7.50-7.48(m, 1H), 7.38(dd, J=8.4, 1.5Hz, 1H), 7.31(d, J=2.0Hz, 1H), 4.46(t, J=5.1, 1H), 3.47-3.43(m, 2H), 2.74(d, J=7.6Hz, 2H), 1.81-1.74(m, 2H).

Step 2) 3-(5-cyano-1H-indol-3-yl)propyl 4-methylbenzenesulfonate

The title compound of this step was prepared by referring to the method described in step 4 of Example 1, that is, 3-(3-hydroxypropyl)-1H-indole-5-carbonitrile (1.00 g, 5.0 mmol), triethylamine (0.8 mL, 6.0mmol) and p-toluenesulfonyl chloride (1.14g, 6.0mmol) were dissolved in dichloromethane (20mL) and prepared by reacting. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=4/1) to obtain the title compound as a white solid (1.33 g, 7.0%).

LC-MS (ESI, pos.ion) m/z: 355.1[M+H] ⁺ ;

¹ H NMR (CDCl ₃ , 400MHz) δ (ppm): 8.51 (br s, 1H), 7.83 (s, 1H), 7.77 (d, J=8.3Hz, 2H), 7.40 (s, 2H), 7.33 ( d,J=8.1Hz,2H),7.08(d,J=2.2Hz,1H),4.08(t,J=6.1Hz,2H),2.81(t,J=7.3Hz,2H),2.45(s, 3H), 2.06-1.99 (m, 2H).

Step 3) 3-(3-(4-(pyridin-2-yl)piperazin-1-yl)propyl)-1H-indole-5-carbonitrile

The title compound of this step was prepared by referring to the method described in step 6 of Example 1, that is, 3-(5-cyano-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (0.21g, 0.58 mmol), 1-(pyridin-2-yl)piperazine (0.10g, 0.58mmol), potassium carbonate (120mg, 0.87mmol) and a catalytic amount of potassium iodide (20mg, 0.12mmol) were dissolved in acetonitrile (15mL) and reacted to prepare get. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a white solid (0.14 g, 68.0%).

LC-MS (ESI, pos.ion) m/z: 346.1[M+H] ⁺ ;

¹ H NMR(CDCl ₃ ,400MHz)δ(ppm):8.51(br s,1H),8.20(dd,J=4.9,1.2Hz,1H),8.00(s,1H),7.52-7.48(m,1H ), 7.45-7.40(m, 2H), 7.15(d, J=2.1Hz, 1H), 6.69-6.63(m, 2H), 3.61(t, J=5.1Hz, 2H), 2.62(t, J= 5.1Hz, 4H), 2.52(t, J=3.7Hz, 2H), 2.02-1.95(m, 2H).

Example 24 3-(3-(4-(3-chloropyridin-2-yl)piperazin-1-yl)propyl)-5-methoxy-1H-indole

The title compound of this step was prepared by referring to the method described in step 6 of Example 1, that is, 3-(5-methoxy-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (0.21g, 0.58mmol), 1-(3-chloropyridin-2-yl)piperazine (0.11g, 0.58mmol), potassium carbonate (120mg, 0.87mmol) and a catalytic amount of potassium iodide (20mg, 0.12mmol) were dissolved in acetonitrile (15mL ) prepared by reaction. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a white solid (0.12 g, 55.0%).

LC-MS (ESI, pos.ion) m/z: 385.2[M+H] ⁺ ;

¹ H NMR (CDCl ₃ , 400MHz) δ (ppm): 8.17 (dd, J = 4.8, 1.6 Hz, 1 H), 7.87 (dd, J = 7.7, 1.6 Hz, 1 H), 7.23 (d, J = 8.8 Hz ,1H),7.05(d,J=2.3Hz,1H),6.98(d,J=2.1Hz,1H),6.87-6.80(m,2H),3.87(s,3H),3.41(s,4H) , 2.76 (t, J = 7.5Hz, 2H), 2.64 (t, J = 4.5Hz, 4H), 2.54-2.51 (m, 2H), 2.00-1.95 (m, 2H).

Example 25 2-(4-(3-(5-methoxy-1H-indol-3-yl)propyl)piperazin-1-yl)nicotinecarbonitrile

The title compound of this step was prepared by referring to the method described in step 6 of Example 1, that is, 3-(5-methoxy-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (0.21g, 0.58mmol), 2-(piperazin-1-yl)nicotinecarbonitrile (0.11g, 0.58mmol), potassium carbonate (120mg, 0.87mmol) and a catalytic amount of potassium iodide (20mg, 0.12mmol) were dissolved in acetonitrile (15mL ) prepared by reaction. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a white solid (0.13 g, 60.0%).

LC-MS (ESI, pos.ion) m/z: 376.2[M+H] ⁺ ;

¹ H NMR (CDCl ₃ , 400MHz) δ (ppm): 8.32 (dd, J=4.8, 2.0Hz, 1H), 7.86 (br s, 1.6Hz, 1H), 7.74 (dd, J=7.6, 2.0Hz, 1H), 7.23(s, 1H), 7.03(d, J=2.4Hz, 1H), 6.97(d, J=2.1Hz, 1H), 6.84(dd, J=8.8, 2.4Hz, 1H), 6.71( dd, J=7.6, 4.8Hz, 1H), 3.87(s, 3H), 3.76(t, J=4.9Hz, 4H), 2.77(t, J=7.5Hz, 2H), 2.61(t, J=5.0 Hz, 4H), 2.53-2.50(m, 2H), 1.99-1.91(m, 2H).

Example 26 5-methoxy-3-(3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)propyl)-1H- indole

The title compound of this step was prepared by referring to the method described in step 6 of Example 1, that is, 3-(5-methoxy-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (0.21g, 0.58mmol), 1-(5-(trifluoromethyl)pyridin-2-yl)piperazine (0.13g, 0.58mmol), potassium carbonate (120mg, 0.87mmol) and a catalytic amount of potassium iodide (20mg, 0.12mmol) Prepared by dissolving in acetonitrile (15mL). The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a white solid (0.17 g, 70.0%).

LC-MS (ESI, pos.ion) m/z: 420.2[M+H] ⁺ ;

¹ H NMR (CDCl ₃ , 400MHz) δ (ppm): 8.39 (d, J = 0.78Hz, 1H), 7.87 (br s, 1H), 7.60 (dd, J = 9.0, 2.4Hz, 1H), 7.23 ( s,1H),7.04(d,J=2.4Hz,1H),6.97(d,J=2.1Hz,1H),6.84(dd,J=8.8,2.4Hz,1H),6.11(d,J=9.0 Hz, 1H), 3.87(s, 3H), 3.66(t, J=5.1Hz, 4H), 2.78(t, J=7.5Hz, 2H), 2.55(t, J=5.1Hz, 4H), 2.51- 2.47(m,2H),1.99-1.93(m,2H).

Example 27 3-(3-(4-(3-chloropyridin-2-yl)piperazin-1-yl)propyl)-5-fluoro-1H-indole

The title compound of this step was prepared by referring to the method described in step 6 of Example 1, that is, 3-(5-fluoro-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (0.20g, 0.58mmol ), 1-(3-chloropyridin-2-yl)piperazine (0.11g, 0.58mmol), potassium carbonate (120mg, 0.87mmol) and catalytic amount of potassium iodide (20mg, 0.12mmol) were dissolved in acetonitrile (15mL) The reaction is prepared. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a white solid (0.13 g, 60.0%).

LC-MS (ESI, pos.ion) m/z: 373.2[M+H] ⁺ ;

¹ H NMR (CDCl ₃ , 400MHz) δ (ppm): 8.17 (dd, J=4.7, 1.4Hz, 1H), 8.04 (br s, 1H), 7.56 (dd, J=7.7, 1.4Hz, 1H), 7.26-7.23(m,2H),7.03(d,J=1.4Hz,1H),6.92(td,J=9.0,2.4Hz,1H),6.80(dd,J=7.7,4.8Hz,1H),3.41 (s,4H),2.76(t,J=7.5Hz,2H),2.64(t,J=4.3Hz,4H),2.50(t,J=7.6Hz,2H),1.97-1.90(m,2H) .

Example 28 2-(4-(3-(5-fluoro-1H-indol-3-yl)propyl)piperazin-1-yl)nicotinecarbonitrile

The title compound of this step was prepared by referring to the method described in step 6 of Example 1, that is, 3-(5-fluoro-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (0.20g, 0.58mmol ), 2-(piperazin-1-yl)nicotinecarbonitrile (0.11g, 0.58mmol), potassium carbonate (120mg, 0.87mmol) and a catalytic amount of potassium iodide (20mg, 0.12mmol) were dissolved in acetonitrile (15mL) The reaction is prepared. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a white solid (0.13 g, 62.0%).

LC-MS (ESI, pos.ion) m/z: 364.3[M+H] ⁺ ;

¹ H NMR (CDCl ₃ , 400MHz) δ (ppm): 8.33 (dd, J = 4.8, 1.9 Hz, 1H), 8.10 (br s, 1H), 7.74 (dd, J = 7.6, 1.9 Hz, 1H), 7.27-7.22(m,2H),7.04(d,J=1.8Hz,1H),6.92(td,J=9.0,2.5Hz,1H),6.73(dd,J=7.6,4.8Hz,1H),3.77 (t, J=4.9Hz, 4H), 2.76(t, J=7.4Hz, 2H), 2.63(t, J=4.9Hz, 4H), 2.51(t, J=7.6Hz, 2H), 1.98-1.91 (m,2H).

Example 29 2-(4-(3-(5-fluoro-1H-indol-3-yl)propyl)piperazin-1-yl)nicotinamide

The title compound of this step was prepared by referring to the method described in step 6 of Example 1, that is, 3-(5-fluoro-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (0.20g, 0.58mmol ), 2-(piperazin-1-yl) nicotinamide (0.12g, 0.58mmol), potassium carbonate (120mg, 0.87mmol) and a catalytic amount of potassium iodide (20mg, 0.12mmol) were dissolved in acetonitrile (15mL) and prepared by reaction get. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a white solid (0.15 g, 67.0%).

LC-MS (ESI, pos.ion) m/z: 382.2[M+H] ⁺ ;

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 8.27 (dd, J = 4.9, 1.9 Hz, 1H), 7.92 (dd, J = 7.6, 1.9 Hz, 1H), 7.38-7.35 (m, 1H ),7.30-7.26(m,1H),7.19(dd,J=9.9,2.4Hz,1H),7.12(s,1H),6.99(dd,J=7.5,4.9Hz,1H),6.84(td, J＝9.2, 2.5Hz, 1H), 3.41(d, J＝4.8Hz, 4H), 2.87(t, J＝4.7Hz, 4H), 2.78(t, J＝7.3Hz, 2H), 2.72-2.69( m,2H), 2.02-1.98(m,2H).

Example 30 5-fluoro-3-(3-(4-(4-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)propyl)-1H-indole

The title compound of this step was prepared by referring to the method described in step 6 of Example 1, that is, 3-(5-fluoro-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (0.20g, 0.58mmol ), 1-(4-(trifluoromethyl)pyridin-2-yl)piperazine (0.13g, 0.58mmol), potassium carbonate (120mg, 0.87mmol) and catalytic amount of potassium iodide (20mg, 0.12mmol) were dissolved in Prepared by reaction in acetonitrile (15 mL). The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a white solid (0.17 g, 70.0%).

LC-MS (ESI, pos.ion) m/z: 407.2[M+H] ⁺ ;

¹ H NMR(CDCl ₃ ,400MHz)δ(ppm):8.29(d,J=5.1Hz,1H),8.00(br s,1H),7.27-7.24(m,2H),7.04(d,J=2.0 Hz,1H),6.93(td,J=9.1,2.4Hz,1H),6.79-6.76(m,1H),3.62(t,J=5.1Hz,4H),2.76(t,J=7.5Hz,2H ), 2.56(t, J=5.1Hz, 4H), 2.47(t, J=7.5Hz, 2H), 1.97-1.89(m, 2H).

Example 31 5-fluoro-3-(3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)propyl)-1H-indole

The title compound of this step was prepared by referring to the method described in step 6 of Example 1, that is, 3-(5-fluoro-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (0.20g, 0.58mmol ), 1-(5-(trifluoromethyl)pyridin-2-yl)piperazine (0.13g, 0.58mmol), potassium carbonate (120mg, 0.87mmol) and catalytic amount of potassium iodide (20mg, 0.12mmol) were dissolved in Prepared by reaction in acetonitrile (15 mL). The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a white solid (0.16 g, 68.0%).

LC-MS (ESI, pos.ion) m/z: 407.2[M+H] ⁺ ;

¹ H NMR(CDCl ₃ ,400MHz)δ(ppm):8.39(s,1H),8.09(br s,1H),7.62(dd,J=9.0,2.4Hz,1H),7.28-7.21(m,2H ), 7.07(d, J=2.0Hz, 1H), 6.93(td, J=9.1, 2.5Hz, 1H), 6.62(d, J=9.0Hz, 1H), 3.76(t, J=4.9Hz, 4H ), 2.77(t, J=7.4Hz, 2H), 2.67(t, J=5.1Hz, 4H), 2.58(t, J=7.7Hz, 2H), 2.04-2.00(m, 2H).

Example 32 3-(3-(4-(3-chloropyridin-2-yl)piperazin-1-yl)propyl)-1H-indole-5-carbonitrile

The title compound of this step was prepared by referring to the method described in step 6 of Example 1, that is, 3-(5-cyano-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (0.21g, 0.58 mmol), 1-(3-chloropyridin-2-yl)piperazine (0.11g, 0.58mmol), potassium carbonate (120mg, 0.87mmol) and a catalytic amount of potassium iodide (20mg, 0.12mmol) were dissolved in acetonitrile (15mL) Prepared by reaction. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a white solid (0.14 g, 62.0%).

LC-MS (ESI, pos.ion) m/z: 380.2[M+H] ⁺ ;

¹ H NMR (CDCl ₃ , 400MHz) δ (ppm): 8.44 (br s, 1H), 8.17 (dd, J = 4.8, 1.6 Hz, 1H), 7.98 (s, 1H), 7.56 (dd, J = 7.7 ,1.6Hz,1H),7.43-7.38(m,2H),7.12(d,J=1.8Hz,1H),6.82(dd,J=7.7,4.8Hz,1H),3.4(s,4H),2.81 (t, J = 7.5Hz, 2H), 2.65 (t, J = 4.4Hz, 4H), 2.51 (t, J = 7.6Hz, 2H), 1.98-1.94 (m, 2H).

Example 33 3-(3-(4-(3-cyanopyridin-2-yl)piperazin-1-yl)propyl)-1H-indole-5-carbonitrile

The title compound of this step was prepared by referring to the method described in step 6 of Example 1, that is, 3-(5-cyano-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (0.21g, 0.58 mmol), 2-(piperazin-1-yl)nicotinecarbonitrile (0.11g, 0.58mmol), potassium carbonate (120mg, 0.87mmol) and a catalytic amount of potassium iodide (20mg, 0.12mmol) were dissolved in acetonitrile (15mL) Prepared by reaction. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a white solid (0.12 g, 55.0%).

LC-MS (ESI, pos.ion) m/z: 371.2[M+H] ⁺ ;

¹ H NMR (CDCl ₃ , 400MHz) δ (ppm): 8.43 (br s, 1H), 8.35 (dd, J = 4.8, 2.0 Hz, 1H), 8.00 (s, 1H), 7.77 (dd, J = 7.6 ,1.9Hz,1H),7.43(s,2H),7.14(d,J=2.0Hz,1H),6.74(dd,J=7.6,4.8Hz,1H),3.78(t,J=4.9Hz,4H ), 2.83(t, J=7.5Hz, 2H), 2.62(t, J=4.9Hz, 4H), 2.49(t, J=7.5Hz, 2H), 1.99-1.92(m, 2H).

Example 34 2-(4-(3-(5-cyano-1H-indol-3-yl)propyl)piperazin-1-yl)nicotinamide

The title compound of this step was prepared by referring to the method described in step 6 of Example 1, that is, 3-(5-cyano-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (0.21g, 0.58 mmol), 2-(piperazin-1-yl)nicotinamide (0.12g, 0.58mmol), potassium carbonate (120mg, 0.87mmol) and catalytic amount of potassium iodide (20mg, 0.12mmol) were dissolved in acetonitrile (15mL) and reacted prepared. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a white solid (0.11 g, 50.0%).

LC-MS (ESI, pos.ion) m/z: 389.2[M+H] ⁺ ;

¹ H NMR (CD ₃ OD, 400MHz): δ (ppm) 8.27 (dd, J = 4.9, 1.9 Hz, 1H), 8.01 (d, J = 0.9 Hz, 1H), 7.93 (dd, J = 7.5, 1.9 Hz,1H),7.47-7.45(m,1H),7.35(dd,J=8.4,2.3Hz,1H),7.24(s,1H),6.97(dd,J=7.5,4.9Hz,1H),3.36 -3.34 (m, 4H), 2.83 (d, J=7.3Hz, 4H), 2.66 (d, J=4.8Hz, 4H), 2.54-2.50 (m, 2H), 2.00-1.93 (m, 2H).

Example 35 3-(3-(4-(4-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)propyl)-1H-indole-5-methyl Nitrile

The title compound of this step was prepared by referring to the method described in step 6 of Example 1, that is, 3-(5-cyano-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (0.21g, 0.58 mmol), 1-(4-(trifluoromethyl)pyridin-2-yl)piperazine (0.13g, 0.58mmol), potassium carbonate (120mg, 0.87mmol) and a catalytic amount of potassium iodide (20mg, 0.12mmol) Prepared by reaction in acetonitrile (15 mL). The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a white solid (0.18 g, 75%).

LC-MS (ESI, pos.ion) m/z: 414.2[M+H] ⁺ ;

¹ H NMR(CDCl ₃ ,400MHz)δ(ppm)8.40(br s,1H),8.31(d,J=5.1Hz,1H),8.01(s,1H),7.46-7.41(m,1H),7.28 (s,2H),7.14(d,J=2.0Hz,1H),6.81(s,1H),6.79(d,J=5.2Hz,1H),3.65(d,J=5.1Hz,4H),2.84 (d, J=7.5Hz, 2H), 2.59 (d, J=5.1Hz, 4H), 2.49 (d, J=7.5Hz, 2H), 2.00-1.93 (m, 2H).

Example 36 3-(3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)propyl)-1H-indole-5-methanol Nitrile

The title compound of this step was prepared by referring to the method described in step 6 of Example 1, that is, 3-(5-cyano-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (0.21g, 0.58 mmol), 1-(5-(trifluoromethyl)pyridin-2-yl)piperazine (0.13g, 0.58mmol), potassium carbonate (120mg, 0.87mmol) and a catalytic amount of potassium iodide (20mg, 0.12mmol) Prepared by reaction in acetonitrile (15 mL). The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1), concentrated and dried to obtain the title compound as a white solid (0.17 g, 70%).

LC-MS (ESI, pos.ion) m/z: 414.2[M+H] ⁺ ;

¹ H NMR(CDCl ₃ ,400MHz)δ(ppm):8.39(s,1H),8.35(br s,1H),8.01(s,1H),7.99(s,1H),7.61(dd,J=9.0 ,2.3Hz,1H),7.44-7.39(m,1H),7.13(d,J=1.8Hz,1H),6.28(d,J=9.0Hz,1H),3.68(t,J=5.0Hz,4H ), 2.82(t, J=7.5Hz, 2H), 2.55(t, J=5.1Hz, 4H), 2.47(t, J=7.4Hz, 2H), 1.98-1.90(m, 2H).

Example 37 3-(3-(4-(3-methoxypyridin-2-yl)piperazin-1-yl)propyl)-1H-indole-5-carbonitrile

The title compound of this step was prepared by referring to the method described in step 6 of Example 1, that is, 3-(5-cyano-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (0.21g, 0.58 mmol), 1-(3-methoxypyridin-2-yl)piperazine (0.11g, 0.58mmol), potassium carbonate (120mg, 0.87mmol) and a catalytic amount of potassium iodide (20mg, 0.12mmol) were dissolved in acetonitrile ( 15mL) was prepared by reaction. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a white solid (0.11 g, 50%).

LC-MS (ESI, pos.ion) m/z: 376.1[M+H] ⁺ ;

¹ H NMR (CDCl ₃ , 400MHz) δ (ppm): 8.45 (br s, 1H), 7.96 (s, 1H), 7.86 (d, J=4.3Hz, 1H), 7.40 (s, 2H), 7.15 ( s,1H),7.03(d,J=7.8Hz,1H),6.83(dd,J=7.4,4.9Hz,1H),3.84(s,3H),3.50(s,4H),2.81(t,J =7.44Hz, 2H), 2.70(s, 4H), 2.55(t, J=7.4Hz, 2H), 1.95-2.01(m, 2H).

Example 38 3-(3-(4-(3-methylpyridin-2-yl)piperazin-1-yl)propyl)-1H-indole-5-carbonitrile

The title compound of this step was prepared by referring to the method described in step 6 of Example 1, that is, 3-(5-cyano-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (0.21g, 0.58 mmol), 1-(3-methylpyridin-2-yl)piperazine (0.10g, 0.58mmol), potassium carbonate (120mg, 0.87mmol) and a catalytic amount of potassium iodide (20mg, 0.12mmol) were dissolved in acetonitrile (15mL ) prepared by reaction. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a white solid (0.10 g, 48%).

LC-MS (ESI, pos.ion) m/z: 360.3[M+H] ⁺ ;

¹ H NMR(CDCl ₃ ,400MHz)δ(ppm):8.53(s,1H),8.14(d,J=3.7Hz,1H),7.95(s,1H),7.41(s,2H),7.39(s ,1H),7.21(s,1H),6.84-6.87(dd,J=4.9,7.2Hz,1H),3.35(t,J=4.4Hz,4H),2.83(m,6H),2.66(t, J=7.4Hz, 2H), 2.26(s, 3H), 2.08(t, J=7.8Hz, 2H).

Example 39 3-(3-(4-(pyridin-2-yl)piperazin-1-yl)propyl)-1H-indole-5-carboxamide

Step 1) 3-(3-Hydroxypropyl)-1H-indole-5-carboxylic acid

The title compound of this step was prepared by referring to the method described in step 1 of Example 20, that is, dissolving 4-carboxyphenylhydrazine hydrochloride (3.91g, 20.8mmol) and 1,4-dihydropyran (1.9mL, 20.8mmol) Prepared by reacting in a mixed solution of dilute sulfuric acid (4%, 50mL) and N,N-dimethylacetamide (10mL). The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2/1), concentrated and dried to obtain the title compound as a white solid (1.59 g, 35%).

LC-MS (ESI, pos.ion) m/z: 220.2[M+H] ⁺ ;

¹ H NMR (CD ₃ OD, 400MHz) δ(ppm): 8.33(s, 1H), 7.79(dd, J=8.4, 1.6Hz, 1H), 7.35(d, J=8.4Hz, 1H), 7.12( s, 1H), 3.63 (t, J = 6.4Hz, 2H), 2.85 (t, J = 7.6Hz, 2H), 1.91-1.98 (m, 2H).

Step 2) 3-(3-Hydroxypropyl)-1H-indole-5-carboxamide

3-(3-Hydroxypropyl)-1H-indole-5-carboxylic acid (1.18g, 5.4mmol) was dissolved in anhydrous N,N-dimethylformamide (24mL), and HBTU ( 3.07g, 8.1mmol), ammonium chloride (1.45g, 27mmol) and triethylamine (3.6mL, 27mmol). After the addition, the reaction was moved to room temperature and reacted at room temperature for 15h. After the reaction was finished, extract with ethyl acetate (50mL x 3), then wash with water (50mL x 3), dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate, and purify by silica gel column chromatography (dichloromethane methanol (v/v )=15/1), the title compound was obtained as a white solid (0.70 g, 60%).

LC-MS (ESI, pos.ion) m/z: 219.2[M+H] ⁺ ;

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 8.19 (s, 1H), 7.65 (dd, J=8.4, 1.6Hz, 1H), 7.35 (dd, J=8.4, 0.4Hz, 1H), 7.11 (s, 1H), 3.63 (t, J = 6.4Hz, 2H), 2.85 (t, J = 7.6Hz, 2H), 1.91-1.98 (m, 2H).

Step 3) 3-(5-carbamoyl-1H-indol-3-yl)propyl 4-methylbenzenesulfonate

The title compound of this step was prepared by referring to the method described in step 4 of Example 1, that is, 3-(3-hydroxypropyl)-1H-indole-5-carboxamide (0.70g, 3.2mmol), triethylamine (0.5 mL, 3.8mmol) and p-toluenesulfonyl chloride (0.73g, 3.8mmol) were dissolved in dichloromethane (20mL) and prepared by reacting. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=4/1) to obtain the title compound as a white solid (0.83 g, 70.0%).

LC-MS (ESI, pos.ion) m/z: 373.0 [M+H] ⁺ ;

¹ H NMR (CD ₃ OD, 400MHz) δ(ppm): 8.12(d, J=1.2Hz, 1H), 7.65-7.73(m, 3H), 7.37(d, J=8.4Hz, 1H), 7.29( d, J=8.0Hz, 2H), 6.96(s, 1H), 4.01(t, J=6.0Hz, 2H), 2.76(t, 2H, J=7.2Hz), 2.37(s, 3H), 1.93- 2.00(m,2H).

Step 4) 3-(3-(4-(pyridin-2-yl)piperazin-1-yl)propyl)-1H-indole-5-carboxamide

The title compound of this step was prepared by referring to the method described in step 6 of Example 1, that is, 3-(5-carbamoyl-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (0.15g, 0.40mmol), 1-(pyridin-2-yl)piperazine (0.06g, 0.40mmol), potassium carbonate (120mg, 0.87mmol) and catalytic amount of potassium iodide (20mg, 0.12mmol) were dissolved in acetonitrile (15mL) for reaction prepared. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a white solid (0.10 g, 75.0%).

LC-MS (ESI, pos.ion) m/z: 364.2[M+H] ⁺ ;

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 8.21 (d, J = 1.2Hz, 1H), 8.06 (dd, J = 4.8, 1.6Hz, 1H), 7.66 (dd, J = 4.8, 1.6 Hz,1H),7.52-7.56(m,1H),7.37(d,J=8.8Hz,1H),7.14(s,1H),6.80(d,J=8.8Hz,2H),6.66(dd,J =6.8,5.2Hz,1H),3.50-3.52(m,4H),2.85(t,J=7.2Hz,2H),2.58-2.61(m,4H),2.49-2.52(m,2H),1.96- 2.03(m,2H).

Example 40 3-(3-(4-(4-chloropyridin-2-yl)piperazin-1-yl)propyl)-1H-indole-5-carboxamide

The title compound of this step was prepared by referring to the method described in step 6 of Example 1, that is, 3-(5-carbamoyl-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (0.15g, 0.40mmol), 1-(3-chloropyridin-2-yl)piperazine (0.08g, 0.40mmol), potassium carbonate (120mg, 0.87mmol) and a catalytic amount of potassium iodide (20mg, 0.12mmol) were dissolved in acetonitrile (15mL ) prepared by reaction. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a white solid (0.10 g, 65.0%).

LC-MS (ESI, pos.ion) m/z: 398.0[M+H] ⁺ ;

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 8.22 (d, J = 1.2Hz, 1H), 8.19 (dd, J = 8.8, 1.6Hz, 1H), 7.74 (dd, J = 7.6, 1.6 Hz,1H),7.67(dd,J=8.4,1.6Hz,1H),7.39(d,J=8.4Hz,1H),7.20(s,1H),6.99(dd,J=7.6,4.8Hz,1H ), 3.50 (m, 4H), 3.15 (m, 4H), 2.96-3.00 (m, 2H), 2.91 (t, J=7.2Hz, 2H), 1.96-2.04 (m, 2H).

Example 41 3-(3-(4-(3-cyanopyridin-2-yl)piperazin-1-yl)propyl)-1H-indole-5-carboxamide

The title compound of this step was prepared by referring to the method described in step 6 of Example 1, that is, 3-(5-carbamoyl-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (0.15g, 0.40mmol), 2-(piperazin-1-yl)nicotinecarbonitrile (0.08g, 0.40mmol), potassium carbonate (120mg, 0.87mmol) and a catalytic amount of potassium iodide (20mg, 0.12mmol) were dissolved in acetonitrile (15mL ) prepared by reaction. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a white solid (0.11 g, 70%).

LC-MS (ESI, pos.ion) m/z: 389.3[M+H] ⁺ ;

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 8.35 (dd, J = 4.8, 1.6 Hz, 1H), 8.21 (s, 1H), 7.92 (dd, J = 7.6, 1.6 Hz, 1H), 7.66(d, J=7.6Hz, 1H), 7.37(d, J=8.4Hz, 1H), 7.15(s, 1H), 6.88(dd, J=7.6, 0.8Hz, 1H), 3.68-3.71(m , 4H), 2.86 (t, J = 7.2Hz, 2H), 2.67-2.69 (m, 4H), 2.54-2.58 (m, 2H), 1.99-2.05 (m, 2H).

Example 42 3-(3-(4-(3-carbamoylpyridin-2-yl)piperazin-1-yl)propyl)-1H-indole-5-methyl Amide

The title compound of this step was prepared by referring to the method described in step 6 of Example 1, that is, 3-(5-carbamoyl-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (0.15g, 0.40mmol), 2-(piperazin-1-yl)nicotinamide (0.08g, 0.40mmol), potassium carbonate (120mg, 0.87mmol) and a catalytic amount of potassium iodide (20mg, 0.12mmol) were dissolved in acetonitrile (15mL) The reaction is prepared. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a white solid (0.10 g, 60%).

LC-MS (ESI, pos.ion) m/z: 407.2[M+H] ⁺ ;

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 8.31 (dd, J = 4.8, 1.6 Hz, 1H), 8.24 (d, J = 1.2 Hz, 1H), 7.93 (dd, J = 7.6, 1.6 Hz,1H),7.67(dd,J=4.8,1.6Hz,1H),7.40(d,J=8.4Hz,1H),7.24(s,1H),7.05(dd,J=7.6,4.8Hz,1H ), 3.55-3.56 (m, 4H), 3.37 (m, 4H), 3.18-3.22 (m, 2H), 2.95 (t, J=7.2Hz, 2H), 2.17-2.25 (m, 2H).

Example 43 3-(3-(4-(4-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)propyl)-1H-indole-5-methanol Amide

The title compound of this step was prepared by referring to the method described in step 6 of Example 1, that is, 3-(5-carbamoyl-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (0.15g, 0.40mmol), 1-(4-(trifluoromethyl)pyridin-2-yl)piperazine (0.09g, 0.40mmol), potassium carbonate (120mg, 0.87mmol) and a catalytic amount of potassium iodide (20mg, 0.12mmol) Prepared by dissolving in acetonitrile (15mL). The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a white solid (0.12 g, 70%).

LC-MS (ESI, pos.ion) m/z: 432.2[M+H] ⁺ ;

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 8.27 (d, J = 5.2Hz, 1H), 8.21 (d, J = 1.2Hz, 1H), 7.66 (dd, J = 8.4, 1.6Hz, 1H), 7.37(dd, J=8.4, 0.4Hz, 1H), 7.14(s, 1H), 6.98(s, 1H), 6.83(d, J=4.8Hz, 1H), 3.61-3.64(m, 4H ), 2.85 (t, J=7.2Hz, 2H), 2.59-2.61 (m, 4H), 2.50-2.54 (m, 2H), 1.96-2.04 (m, 2H).

Example 44 3-(3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)propyl)-1H-indole-5-methanol Amide

The title compound of this step was prepared by referring to the method described in step 6 of Example 1, that is, 3-(5-carbamoyl-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (0.15g, 0.40mmol), 1-(5-(trifluoromethyl)pyridin-2-yl)piperazine (0.09g, 0.40mmol), potassium carbonate (120mg, 0.87mmol) and a catalytic amount of potassium iodide (20mg, 0.12mmol) Prepared by dissolving in acetonitrile (15mL). The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a white solid (0.12 g, 68%).

LC-MS (ESI, pos.ion) m/z: 432.2[M+H] ⁺ ;

¹ H NMR (CD ₃ OD, 400MHz) δ(ppm): 8.32(s, 1H), 8.21(d, J=1.2Hz, 1H), 7.65-7.71(m, 2H), 7.37(d, J=8.4 Hz, 1H), 7.14(s, 1H), 6.85(d, J=8.8Hz, 1H), 3.65-3.69(m, 4H), 2.85(t, J=7.2Hz, 2H), 2.56-2.58(m ,4H), 2.48-2.52(m,2H), 1.95-2.03(m,2H).

Example 45 2-(4-(4-(5-bromo-1H-indol-3-yl)butyl)piperazin-1-yl)nicotinecarbonitrile

Step 1) Ethyl 4-(5-bromo-1H-indol-3-yl)butanoate

The title compound of this step was prepared by referring to the method described in step 2 of Example 1, that is, ethyl 6-oxohexanoate (1.0 g, 6.3 mmol) and p-bromophenylhydrazine hydrochloride (1.50 g, 6.8 mmol) were suspended Prepared by reaction in ethanol (125mL). The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=4/1) to obtain the title compound as a white solid (1.17 g, 60.0%).

LC-MS (ESI, pos.ion) m/z: 310.1[M+H] ⁺ ;

¹ H NMR(CDCl ₃ ,400MHz)δ(ppm):8.03(br s,1H),7.71(s,1H),7.21-7.27(m,2H),6.99(d,J=2.0Hz,1H), 4.12(q, J=7.2Hz, 2H), 2.76(t, J=7.2Hz, 2H), 2.36(t, J=7.2Hz, 2H), 2.00-2.06(m, 2H), 1.26(t, J =7.2Hz, 3H).

Step 2) 4-(5-Bromo-1H-indol-3-yl)butan-1-ol

The title compound of this step was prepared by referring to the method described in step 3 of Example 1, that is, ethyl 4-(5-bromo-1H-indol-3-yl)butanoate (0.98g, 3.17mmo) and lithium aluminum hydride (0.48g, 12.7mmol) was prepared by suspending in anhydrous tetrahydrofuran (25mL). The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) to obtain the title compound as a white solid (0.60 g, 70.0%).

LC-MS (ESI, pos.ion) m/z: 268.2[M+H] ⁺ ;

¹ H NMR (CDCl ₃ , 400MHz) δ (ppm): 8.22 (br s, 1H), 7.73 (d, J = 1.6Hz, 1H), 7.27 (dd, J = 8.4, 1.6Hz, 1H), 7.21 ( d, J=8.4Hz, 1H), 6.96(d, J=2.0Hz, 1H), 3.69(t, J=6.4Hz, 2H), 2.74(t, J=7.2Hz, 2H), 1.73-1.79( m,2H), 1.66-1.70(m,2H).

Step 3) 4-(5-Bromo-1H-indol-3-yl)butyl 4-methylbenzenesulfonate

The title compound of this step was prepared by referring to the method described in Step 4 of Example 1, that is, 4-(5-bromo-1H-indol-3-yl)butan-1-ol (0.36g, 1.9mmol), triethyl Prepared by dissolving amine (0.3mL, 2.28mmol) and p-toluenesulfonyl chloride (0.43g, 2.28mmol) in dichloromethane (20mL). The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=4/1) to obtain the title compound as a white solid (0.64 g, 80.0%).

LC-MS (ESI, pos.ion) m/z: 421.9[M+H] ⁺ ;

¹ H NMR (CDCl ₃ , 400MHz) δ (ppm): 8.13 (br s, 1H), 7.80 (d, J = 8.0Hz, 2H), 7.65 (d, J = 1.2Hz, 1H), 7.34 (d, J＝8.0Hz, 2H), 7.22-7.28(m, 2H), 6.94(s, 1H), 4.07(t, J＝6.0Hz, 2H), 2.66(t, J＝6.4Hz, 2H), 2.45( s,3H), 1.71-1.73(m,4H).

Step 4) 2-(4-(4-(5-bromo-1H-indol-3-yl)butyl)piperazin-1-yl)nicotinecarbonitrile

The title compound of this step was prepared by referring to the method described in step 6 of Example 1, that is, 4-(5-bromo-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (0.24g, 0.58mmol ), 2-(piperazin-1-yl)nicotine carbonitrile (0.11g, 0.58mmol) was dissolved in acetonitrile (15mL) and prepared by reaction. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a white solid (0.13 g, 51.0%).

LC-MS (ESI, pos.ion) m/z: 439.2[M+H] ⁺ ;

¹ H NMR (CDCl ₃ , 400MHz) δ (ppm): 8.33 (dd, J=4.8, 2.0Hz, 1H), 8.01 (br s, 1H), 7.78 (dd, J=7.6, 2.0Hz, 1H), 7.70(s,1H),7.21-7.26(m,2H),7.03(d,J＝1.6Hz,1H),6.78-6.81(m,1H),3.88(m,4H),2.82(m,4H) ,2.76(m,2H),2.64(m,2H),2.45-2.49(m,2H),1.75(m,4H).

Example 46 2-(4-(3-(5-bromo-1H-indol-3-yl)propyl)piperazin-1-yl)nicotinecarbonitrile

Step 1) 3-(5-Bromo-1H-indol-3-yl)propan-1-ol

The title compound of this step was prepared by referring to the method described in step 1 of Example 20, that is, dissolving 4-bromophenylhydrazine hydrochloride (4.64g, 20.8mmol) and 1,4-dihydropyran (1.9mL, 20.8mmol) Prepared by reacting in a mixed solution of dilute sulfuric acid (4%, 50mL) and N,N-dimethylacetamide (10mL). The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) to obtain the title compound as a white solid (1.59 g, 30%).

LC-MS (ESI, pos.ion) m/z: 256.0[M+H] ⁺ ;

¹ H NMR (CDCl ₃ , 400MHz) δ (ppm): 8.34 (br s, 1H), 7.74 (d, J = 1.6Hz, 1H), 7.27 (dd, J = 8.4, 1.6Hz, 1H), 7.19 ( d, J＝8.4Hz, 1H), 6.92-6.93(m, 1H), 3.71(t, J＝6.4Hz, 2H), 2.79(t, J＝7.2Hz, 2H), 1.92-1.99(m, 2H ).

Step 2) 3-(5-Bromo-1H-indol-3-yl)propyl 4-methylbenzenesulfonate

The title compound of this step was prepared by referring to the method described in step 4 of Example 1, that is, 3-(5-bromo-1H-indol-3-yl)propan-1-ol (1.28g, 5.0mmol), triethylamine (0.8mL, 6.0mmol) and p-toluenesulfonyl chloride (1.14g, 6.0mmol) were prepared by dissolving in dichloromethane (20mL). The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=4/1) to obtain the title compound as a white solid (1.32 g, 63.0%).

LC-MS (ESI, pos.ion) m/z: 408.0[M+H] ⁺ ;

¹ H NMR (CDCl ₃ , 400MHz) δ (ppm) δ (ppm): 8.26 (br s, 1H), 7.80 (d, J = 8.0Hz, 2H), 7.62 (d, J = 0.8Hz, 1H), 7.34(d, J=8.0Hz, 2H), 7.21-7.28(m, 2H), 6.91(d, J=1.6Hz, 1H), 4.09(t, J=6.0Hz, 2H), 2.75(t, J =7.2Hz, 2H), 2.46(s, 3H), 1.99-2.02(m, 2H).

Step 3) 2-(4-(3-(5-bromo-1H-indol-3-yl)propyl)piperazin-1-yl)nicotinecarbonitrile

The title compound of this step was prepared by referring to the method described in step 6 of Example 1, that is, 3-(5-bromo-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (0.24g, 0.58mmol ), 2-(piperazin-1-yl)nicotinecarbonitrile (0.10g, 0.58mmol), potassium carbonate (120mg, 0.87mmol) and a catalytic amount of potassium iodide (20mg, 0.12mmol) were dissolved in acetonitrile (15mL) The reaction is prepared. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a white solid (0.14 g, 56.0%).

LC-MS (ESI, pos.ion) m/z: 425.1[M+H] ⁺ ;

¹ H NMR(CDCl ₃ ,400MHz)δ(ppm):8.33(dd,J=4.8,2.0Hz,1H),8.00(br s,1H),7.71-7.76(m,2H),7.21-7.27(m ,2H),7.00(d,J=2.0Hz,1H),6.72(dd,J=7.6,4.8Hz,1H),3.76-3.78(m,4H),2.76(t,J=7.2Hz,2H) ,2.59-2.61(m,4H),2.45-2.49(m,2H),1.88-1.95(m,2H).

biological test

Example A: Compounds in rat synaptosomes on [ ³ Analysis of the inhibitory effect of H]5-HT uptake

experiment method

At 37°C, to the buffer solution (6.2mM NaCl, 4.5mM KCl, 2.25mM MgSO ₄ , 1.08mMNaH ₂ PO ₄ , 2.5mM NaHCO ₃ , 9.9mM glucose, 9μM EGTA and 45μM ascorbic acid(pH 7.4)), In the mixed system formed by synaptosomes (150 μg) and 0.1 μCi [ ³ H] 5-HT, test compounds or positive drugs or negative controls were added and incubated for 15 minutes.

Imipramine is used as a standard positive compound for inhibiting the uptake of serotonin. Add 10 μM imipramine to the same mixed system as above to block the uptake of serotonin, and incubate at 4°C for 15 minutes to measure the activity value of the basic control . Through experiments, the uptake inhibition value of different concentrations of imipramine on rat brain synaptosomes was tested, and an inhibition curve was made.

After incubation, the sample was quickly filtered through a glass fiber filter membrane (GF/B, Packard) with a 96-sample cell harvester (Unifilter, Packard) under vacuum, and washed twice in ice-cold incubation buffer to eliminate free cells. [ ³ H]5-hydroxytryptamine. Filters were dried and residual radioactivity was counted with scintillation fluid (Microscint 0, Packard) in a scintillation counter (Topcount, Packard). The experimental results are expressed as the inhibition percentage of [ ³ H]serotonin uptake relative to the control group.

data analysis

SERT transporter inhibition in rat synaptosomes was measured by the concentration of [ ³ H]5-HT. The test compound needs to be tested at least twice when the concentration exceeds 6log, and the data is subjected to nonlinear regression analysis through the Hill equation curve to obtain the IC ₅₀ value. See Table 1 for the results. Table 1 shows the experimental results of the inhibitory effect of the compounds of the present invention on [ ³ H]5-HT uptake in rat synaptosomes.

Table 1 The results of the inhibitory effect on [ ³ H]5-HT uptake in rat synaptosomes provided by the examples of the present invention

Experimental results show that the compounds provided in the examples of the present invention have better inhibitory activity on the reuptake of [ ³ H]5-HT.

Example B: h5-HT _1A binding affinity test

experiment method

Homogenate to human HEK-293 cell membrane at 22°C, 36 μg protein, 0.3 nM [ ³ H]8-OH-DPAT (Perkin-Elmer) and buffer (50 mM Tris-HCl (pH 7.4), 10 mM MgSO ₄ , 0.5mM EDTA, 2μg/mlaprotinine) in the mixed system formed, with or without adding the test compound, and incubated for 60 minutes.

The standard reference compound is 8-OH-DPAT, and 10 μM 8-OH-DPAT is added to the mixed system under the above conditions to measure the non-specific binding value. The data of series concentrations of 8-OH-DPAT were tested in different experiments to obtain the competition curve.

After incubation, the sample was quickly filtered through a glass fiber filter (GF/B, Packard) pre-soaked with 0.3% PEI using a 96-sample cell harvester (Unifilter, Packard) under vacuum, and repeatedly washed with ice-cold 50mM Tris-HCl. Rinse several times. Filters were dried and residual radioactivity was counted with scintillation fluid (Microscint 0, Packard) in a scintillation counter (Topcount, Packard). The experimental results are expressed as the percentage of inhibition of specific binding of radioligand relative to the control group.

data analysis

The binding assay of [ ³ H]8-OH-DPAT (0.3 nM) to 5-HT _1A receptor in human HEK-293 cells was done by membrane scintillation proximity assay. The test compound needs to be tested at least three times when the concentration exceeds 6log. The data is subjected to nonlinear regression analysis through the Hill equation curve to obtain the IC ₅₀ value, and then calculated by the ChengPrusoff equation to obtain the Ki value. See Table 2 for the results. Table 2 shows the experimental results of the binding affinity of the compounds of the examples of the present invention to the 5-HT _1A receptor.

Table 2 The binding affinity results for 5-HT _1A receptors provided by the examples of the present invention

The experimental results show that the compound of the present invention has a strong binding affinity to the 5-HT _1A receptor.

Finally, it should be noted that there are other ways to implement the invention. Accordingly, the embodiments of the present invention will be described as illustrations, but are not limited to the content described in the present invention, and may be modified within the scope of the present invention or equivalent content added in the claims. All publications or patents cited in the present invention shall be regarded as reference documents of the present invention.

Claims (6)

1. the compound of structure as shown below, or the tautomer of described compound or pharmaceutically acceptable salt:

2. a kind of pharmaceutical composition, comprises the compound described in claim 1 any one and pharmaceutically acceptable carrier, tax Shape agent or combinations thereof.

3. pharmaceutical composition according to claim 2, also comprises additional therapeutic agent, and described additional therapeutic agent is selected from antidepressant Medicine, anxiolytic drugs, the salts medicine as mood stabilizers, atypical antipsychotic drug, antiepileptic, anti- Anti-parkinson drug, as 5-hydroxy tryptamine selectivity reuptake inhibitor and/or 5-ht_1aThe medicine of receptor stimulating agent, maincenter god Through analeptic drug, nicotinic antagonists or combinations thereof.

4. pharmaceutical composition according to claim 3, wherein, described additional therapeutic agent be amitriptyline, desipramine, Mirtazapine, amfebutamone, reboxetine, fluoxetine, trazodone, Sertraline, duloxetine, fluvoxamine, midalcipran, left-handed Midalcipran, desmethylvenlafaxine, vilazodone, venlafaxine, dapoxetine, nefazodone, femoxetine, Clomipramine, Citalopram, escitalopram, paroxetine, lithium carbonate, buspirone, olanzapine, Quetiapine, Risperidone, Ziprasidone, Aripiprazole, cis-N-[4-[4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl, clozapine, modafinil, mecamylamine, cabergoline, diamantane (obsolete), imipramine, pramipexole, first Shape parathyrine or combinations thereof.

5. a kind of usage right requires compound described in 1 any one or the drug regimen described in claim 2-4 any one Purposes in preparing medicine for the thing, described medicine is used for preventing, treat or mitigate the central nervous system dysfunction of the mankind.

6. the purposes of compound or pharmaceutical composition according to claim 5, wherein, described central nervous system function barrier Hinder the regulation and control in response to 5-hydroxytryptamine receptor, be a kind of mental disorder, refer to depression, anxiety neurosis, mania, schizophrenia Disease, bipolar disorders, sleep disorder, obsessive idea and behavior disorder, panic disorder, posttraumatic stress disorder, the dyskinesia, property work( Energy obstacle, musculoskeletal pain obstacle, cognitive disorder, dysmnesia, parkinson, Huntington's disease, phobia, material are indiscriminate With or addiction, drug addiction withdrawal symptom and premenstrualtension syndrome.