Indole derivatives and their applications

Abstract

Belonging to the medical field, an indole derivative, its preparation method and its application, which have a compound structure shown in formula (I). This type of compound has high pharmacological activity and high selectivity for the sigma-1 receptor, and can be used for the treatment and prevention of neuropsychiatric diseases, especially for the preparation of analgesic drugs.

Description

[0001] Cross - reference to related patent applications

[0002] This patent application claims the priority of a prior invention patent application with the application number 202011005230.9 and the invention title "Indole Derivatives and Their Applications", which was filed with the State Intellectual Property Office of China on September 22, 2020. The full text of the prior application is incorporated into this application by reference. Technical field

[0003] The present invention relates to the field of chemical medicine, and particularly to an indole derivative having high affinity for sigma - 1 receptor, a preparation method thereof, a composition containing the compound, and its applications in the medical field. Technical background

[0004] Sigma - 1 receptor (σ1 receptor) is an emerging drug target in recent years and is the binding protein of a variety of specific psychiatric drugs. The Sigma receptor was first proposed in 1976 and was classified into the opioid receptor family. However, later, since the effects caused by Sigma receptor ligands could not be reversed by opioid receptor antagonists (such as naloxone, naltrexone, etc.), the Sigma receptor was distinguished from the opioid receptor. Currently, it is considered that the Sigma receptor has no homology with opioid receptors or other mammalian proteins and is an independent receptor family, which has two subtypes: Sigma - 1 and Sigma - 2.

[0005] Sigma - 1 receptor has unique pharmacological effects. There is evidence that σ1 receptor ligands may be used to treat mental diseases (such as schizophrenia, depression, anxiety, etc.) and neurological diseases (such as Alzheimer's disease, pain, etc.) as well as movement disorders such as dystonia and tardive dyskinesia, withdrawal from addictive drugs, movement disorders related to Huntington's disease or Tourette syndrome, and Parkinson's disease.

[0006] Sigma - 1 receptor is a ligand - regulated protein molecular chaperone that exerts its molecular chaperone function by interacting with receptors such as NMDA (N - methyl - D - aspartic): regulating NMDA, APMA and other ion channels and downstream receptors, thereby regulating mitochondrial function and the release of neurotransmitters such as serotonin and dopamine. Because it is involved in the regulation of multiple nerve conduction systems, this target is expected to become an important target for drugs regulating the neuropsychiatric system.

[0007] Currently, the prior art discloses different Sigma receptor antagonists. Known Sigma receptor antagonists such as BD1047 can significantly inhibit the neuroinflammatory response caused by cocaine; CM156 can improve the adverse reactions caused by methamphetamine; AZ66 has a neuroprotective effect on the neurotoxicity and cognitive impairment caused by methamphetamine; BD-1063 can dose-dependently reduce the alcohol intake of alcoholic rats and acute alcohol-dependent rats; haloperidol can enhance the analgesic effect of opioids; E-52862 can enhance the analgesic effect of morphine and has a good effect on neuropathic pain.

[0008]

[0009] Currently, there are patents that disclose different ligands for sigma receptors. Among them, patents WO2012072791 and WO2011147910 disclose the structures of compounds targeting sigma receptors and their uses for CNS-related diseases. However, these structures are not the same as the structures of this patent.

[0010] CN202011345740.0 discloses a series of sigma-1 receptor inhibitors with linked bicyclic structures, such as 4-((1-(isoquinolin-6-yl)-1 hydrogen-indol-4-yl)methyl)morpholine, 4-((1-(quinolin-6-yl)-1 hydrogen-indol-4-yl)methyl)morpholine, 4-((1-(quinolin-7-yl)-1 hydrogen-indol-4-yl)methyl)morpholine and other compounds. These compounds have good sigma-1 receptor inhibitory activity, and when used in combination with morphine, they can significantly improve the synergistic effect of morphine, and are effective for both phase I and phase II pain induced by formalin model. However, these compounds still have problems such as high dosage, narrow therapeutic window, and safety needs to be improved.

[0011] Considering the potential applications of σ1 receptor antagonists or agonists in neuropsychiatric and other fields, it is of great significance for clinical applications to find compounds that have better selectivity and pharmacological activity for σ1 receptors and have stronger efficacy and better safety. Summary of the invention

[0012] The present invention provides a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

[0013]

[0014] R 1 is a substituted or unsubstituted, five-membered or six-membered, aromatic ring group or a nitrogen-containing heteroaromatic ring group, wherein the nitrogen-containing heteroaromatic ring group contains 1, 2, 3 or 4 nitrogen atoms; the number of the substituent groups is 1, 2, 3, 4 or 5, and the substituent groups are independently selected from hydrogen, -NH 2, halogen, C1-C3 alkoxy, -OH, C1-C3 haloalkyl, C1-C4 straight-chain or branched alkyl, -CHNOCH 3 ; or, R 1 is wherein R 7 is selected from hydrogen, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C4 straight-chain or branched alkyl, -CHNOCH 3 ;

[0015] R 2 is selected from any one of hydrogen, C1-C3 haloalkyl, and C1-C4 straight-chain or branched alkyl;

[0016] R 3 is selected from any one of the following structures:

[0017]

[0018] R 9 is selected from any one of hydrogen, C1-C3 haloalkyl, and C1-C4 straight-chain or branched alkyl;

[0019] R 13 , R 14 are independently selected from any one of hydrogen, C1-C3 haloalkyl, C1-C4 straight-chain or branched alkyl, and C3-C6 cycloalkyl;

[0020] n1 is 0, 1, 2, 3 or 4;

[0021] n2, n3, n4, n5 are each independently 1 or 2.

[0022] In some embodiments of the present invention, in the compound of formula (I) or its pharmaceutically acceptable salt, R 1 is independently selected from any one of the following structures:

[0023] (preferably ),

[0024] wherein, R 4 is selected from hydrogen, -NH 2 , halogen, C1-C3 alkoxy, -OH, C1-C3 haloalkyl, C1-C4 straight-chain or branched alkyl, -CHNOCH 3 ;

[0025] R 5 is selected from hydrogen, -NH 2, halogen, C1-C3 alkoxy, -OH, C1-C3 haloalkyl, C1-C4 straight-chain or branched alkyl, -CHNOCH 3 ;

[0026] R 6 is selected from hydrogen, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C4 straight-chain or branched alkyl, -CHNOCH 3 ;

[0027] R 7 is selected from hydrogen, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C4 straight-chain or branched alkyl, -CHNOCH 3 ;

[0028] R 8 is selected from hydrogen, -NH 2 , halogen, C1-C3 alkoxy, -OH, C1-C3 haloalkyl, C1-C4 straight-chain or branched alkyl, -CHNOCH 3 ;

[0029] R 10 is selected from hydrogen, -NH 2 , halogen, C1-C3 alkoxy, -OH, C1-C3 haloalkyl, C1-C4 straight-chain or branched alkyl, -CHNOCH 3 ;

[0030] R 11 is selected from hydrogen, -NH 2 , halogen, C1-C3 alkoxy, -OH, C1-C3 haloalkyl, C1-C4 straight-chain or branched alkyl, -CHNOCH 3 ;

[0031] R 12 is selected from hydrogen, -NH 2 , halogen, C1-C3 alkoxy, -OH, C1-C3 haloalkyl, C1-C4 straight-chain or branched alkyl, -CHNOCH 3 .

[0032] In some preferred embodiments of the present invention, R 4 is selected from any one of hydrogen, -NH 2 , halogen, C1-C3 alkoxy, -OH, C1-C3 haloalkyl, C1-C4 straight-chain or branched alkyl.

[0033] In some preferred embodiments of the present invention, R 5 is selected from any one of halogen, -CHNOCH 3 .

[0034] In some preferred embodiments of the present invention, R 6 is selected from hydrogen, C1-C4 linear or branched alkyl.

[0035] In some preferred embodiments of the present invention, R 7 is selected from hydrogen, C1-C4 linear or branched alkyl.

[0036] In some preferred embodiments of the present invention, R 8 is selected from any one of hydrogen, C1-C3 haloalkyl, and C1-C4 linear or branched alkyl.

[0037] In some preferred embodiments of the present invention, R 10 is selected from any one of hydrogen, C1-C3 haloalkyl, and C1-C4 linear or branched alkyl.

[0038] In some preferred embodiments of the present invention, R 11 is selected from any one of hydrogen, C1-C3 haloalkyl, and C1-C4 linear or branched alkyl.

[0039] In some preferred embodiments of the present invention, R 12 is selected from any one of hydrogen, C1-C3 haloalkyl, and C1-C4 linear or branched alkyl.

[0040] In some embodiments of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0041]

[0042] Wherein:

[0043] R 1 is selected from any one of the following structures:

[0044]

[0045] R 2 is selected from any one of hydrogen, C1-C4 linear or branched alkyl;

[0046] R 3 is selected from any one of the following structures:

[0047]

[0048] n1 is 0, 1, 2, 3 or 4;

[0049] R 4 is selected from any one of hydrogen, -NH 2 -OH, C1-C3 haloalkyl, and C1-C4 linear or branched alkyl;

[0050] R 5 is selected from any one of halogen, -CHNOCH 3 ;

[0051] R 6 and R 7 are each independently a straight-chain or branched-chain alkyl group having 1 to 4 carbon atoms;

[0052] R 8 is selected from any one of hydrogen and a straight-chain or branched-chain alkyl group having 1 to 4 carbon atoms;

[0053] R 9 is selected from any one of a haloalkyl group having 1 to 3 carbon atoms and a straight-chain or branched-chain alkyl group having 1 to 4 carbon atoms;

[0054] n2, n3, n4, and n5 are each independently 1 or 2.

[0055] In one embodiment of the present invention, in the structure of formula (I), the haloalkyl group having 1 to 3 carbon atoms is independently selected from -(CH 2 ) a CX 3 , -(CH 2 ) a CHX 2 , -(CH 2 ) a CH 2 X, where a is independently 0, 1, or 2, and X is independently any one of F, Cl, Br, and I;

[0056] In one embodiment of the present invention, the straight-chain or branched-chain alkyl group having 1 to 4 carbon atoms in the structure of formula (I) is independently selected from any one of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl;

[0057] In one embodiment of the present invention, the halogen in the structure of formula (I) is independently selected from any one of F, Cl, Br, and I;

[0058] In one embodiment of the present invention, in the structure of formula (I), n1 is preferably 0 or 1; the halogen is preferably F; the haloalkyl group having 1 to 3 carbon atoms is preferably -CF 3 .

[0059] In a preferred embodiment of the present invention, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof:

[0060]

[0061] wherein R 1 is selected from any one of the following structures:

[0062]

[0063] R 4 is any one selected from hydrogen, halogen, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C4 straight-chain or branched alkyl; preferably any one selected from hydrogen, methoxy, ethoxy, trifluoromethyl, methyl, ethyl;

[0064] R 5 is any one selected from hydrogen, halogen; preferably fluorine;

[0065] R 2 is any one selected from hydrogen, C1-C4 straight-chain or branched alkyl; preferably any one selected from hydrogen, methyl, ethyl;

[0066] R 3 is any one selected from the following structures:

[0067]

[0068] R 9 is any one selected from hydrogen, C1-C3 haloalkyl, C1-C4 straight-chain or branched alkyl; preferably hydrogen, methyl, ethyl; more preferably methyl;

[0069] R 13 is any one selected from hydrogen, C1-C4 straight-chain or branched alkyl; preferably hydrogen, methyl, ethyl;

[0070] R 14 is any one selected from hydrogen, C1-C3 haloalkyl; preferably hydrogen, trifluoromethyl;

[0071] n1 is 0 or 1;

[0072] n2, n3, n4, n5 are each independently 1 or 2.

[0073] In a further preferred embodiment of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0074]

[0075] wherein R 1 is any one selected from the following structures: R 4 is any one selected from hydrogen, C1-C3 haloalkyl, C1-C4 straight-chain or branched alkyl; preferably hydrogen, trifluoromethyl, methyl;

[0076] R 2 is selected from hydrogen, methyl;

[0077] R3 Selected from any one of the following structures:

[0078] Preferably

[0079] R 9 Selected from any one of hydrogen, C1-C4 linear or branched alkyl groups; preferably methyl;

[0080] R 13 Selected from any one of hydrogen, C1-C4 linear or branched alkyl groups; preferably selected from hydrogen, ethyl;

[0081] R 14 Selected from hydrogen, trifluoromethyl; preferably hydrogen;

[0082] n1 is 0;

[0083] n2 and n3 are each independently 1 or 2;

[0084] n4 and n5 are each independently 1.

[0085] Specifically, the compounds described in the present invention are selected from any one of the compounds shown in Table 1 below:

[0086] Table 1. Example compounds of the compounds represented by the general formula (I)

[0087]

[0088]

[0089]

[0090]

[0091] The present invention further provides a preparation method of the general formula (I), including:

[0092] Method 1: The compound of formula (II) and the compound of formula (III) are subjected to a C-N cross-coupling reaction to provide the structure shown in formula (IV);

[0093]

[0094] Or,

[0095] Method 2: Intermediate (V) is prepared to obtain Intermediate (VII) through Grignard reaction and substitution reaction; Intermediate (V) is prepared to obtain Intermediate (VI) through Witting reaction; Intermediate (V) and (VI) undergo reductive amination reaction of aldehyde group with R3-H, and Intermediate (VII) undergoes substitution reaction with R3-H to introduce the corresponding structure at the nitrogen end of R3-H, and Structure (I) is prepared.

[0096]

[0097] The present invention further provides a preparation method of Intermediate (V), including:

[0098]

[0099] 1H-indole-4-carbaldehyde and R 1 -Br undergo C-N cross-coupling reaction to prepare Intermediate (V).

[0100] Wherein: R 1 、R 2 、R 3 、the definitions of n1 are as described above.

[0101] If the obtained compound of general formula (I) itself is in the form of a mixture of stereoisomers, especially enantiomers or diastereomers, the mixture can be separated by standard procedures known to those skilled in the art. If there are chiral centers, the compound can be prepared in racemic form, or can be synthesized enantioselectively separately.

[0102] The solvates of the compound of general formula (I), its corresponding isomers, or its corresponding salts can also be obtained by standard procedures known to those skilled in the art.

[0103] The present invention further provides a pharmaceutical composition, comprising a therapeutically effective amount of the compound of formula (I) or its pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient.

[0104] In one embodiment of the present invention, the pharmaceutical composition can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Therefore, the active compound of the present invention can be formulated into dosage forms for oral, buccal, intranasal, parenteral (such as intravenous, intramuscular, subcutaneous, intra-articular or transdermal) or rectal administration, or dosage forms suitable for administration by inhalation or insufflation. The compound of the present invention or its pharmaceutically acceptable salt can also be formulated into sustained release or controlled release dosage forms.

[0105] In one embodiment of the present invention, for oral administration, the active compounds of the present invention can be formulated into tablets, pills, capsules, granules, drops, syrups or solutions with pharmaceutically acceptable excipients by conventional means. The excipients are conventional excipients known in the art, such as binders, fillers, lubricants, disintegrants or wetting agents.

[0106] Solid oral formulations can be prepared by methods well known in the art such as mixing, filling and tabletting. Liquid preparations for oral administration, such as solutions, syrups or suspensions, or can be volatilized into dry products and regenerated with water or other suitable carriers before use. Such liquid preparations can be prepared by conventional means using pharmaceutical additives, such as suspending agents, emulsifying agents, non-aqueous carriers and preservatives.

[0107] The pharmaceutical composition is also suitable for parenteral administration, such as sterile solutions, suspensions or reconstitutable dry preparations, aerosols or sprays in suitable unit dosage forms. Sufficient excipients can be used, such as fillers, buffers or surfactants.

[0108] The composition of the present invention can be formulated into a dissolved state or an ointment for transdermal administration.

[0109] The active compounds of the present invention can be formulated into rectal compositions, such as suppositories or retention enemas, for example containing conventional suppository bases, such as cocoa butter or other glycerides.

[0110] The compounds and compositions of the present invention can be used together with other drugs to provide combination therapy.

[0111] The compounds of general formula (I) of the present invention, their corresponding isomers, their corresponding salts or corresponding solvates have a high affinity for sigma receptors, especially sigma-1 receptors, that is, they are selective ligands for sigma receptors (especially sigma-1 receptors) and act as regulators of these receptors, such as agonists, antagonists, inverse agonists.

[0112] In one embodiment of the present invention, the present invention provides the use of the compound of formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition in the preparation of a medicament for treating and preventing diseases or disease states related to sigma receptors (especially sigma-1 receptors). Further, the treatment and prevention of sigma-1 receptor-related diseases is pain, and more preferably, the pain is neuropathic pain, neuralgia, cancer pain, inflammatory pain, interstitial cystitis, bladder pain, allodynia, burning pain, hyperalgesia, sensory hypersensitivity, hyperpathia, neuritis or neuropathy secondary to surgery.

[0113] The IASP (Classification of chronic pain, 2nd edition, IASP Press (2002), 210-211) defines "neuropathic pain", "neuralgia", "allodynia", "causalgia", "hyperalgesia", "hyperesthesia", "hyperpathia", "neuritis", "neuropathy / neuritis", and this part of the content is incorporated into the present invention by reference.

[0114] The present invention also provides the use of a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in the preparation of a drug for regulating the sigma receptor (especially the sigma-1 receptor), wherein the drug optionally contains one or more other active agents for regulating the mammalian nervous system or relieving mental diseases.

[0115] According to a specific embodiment, the pharmaceutical composition of the present invention further includes at least one compound described in the present invention (preferably a compound of formula (I)) and at least one pharmaceutical composition of a drug currently used for treating pain related to sigma-1 receptor-related diseases. In particular, a composition containing at least one compound described in the present invention and an opioid receptor ligand, and the composition can be administered simultaneously, separately, or sequentially for treating and / or preventing diseases mediated by the sigma receptor (especially the sigma-1 receptor).

[0116] The composition can be formulated with at least one pharmaceutically acceptable excipient in a form for simultaneous, separate, or sequential administration. Thus, the combination can be administered in the following ways:

[0117] a) As a combination, used as part of the same pharmaceutical composition, and both are always administered simultaneously.

[0118] b) As a combination of two units, wherein each of them may be administered simultaneously, sequentially, or separately. In a specific embodiment, the compound described in the present invention is administered independently of other drugs such as opioid receptor drugs (i.e., in two units), but both are administered simultaneously. In another specific embodiment, the compound described in the present invention is administered first, and then other drugs such as opioid receptor drugs are administered separately or sequentially. In another specific embodiment, other drugs such as opioid receptor drugs are administered first, and then the compound described in the present invention is administered separately or sequentially.

[0119] In one embodiment of the present invention, the compound of formula (I) is used in a therapeutically effective amount. The effective dosage of the compound of the present invention depends on the relative efficacy of the selected compound, the severity of the disease being treated, or factors such as age, body weight, or the mode of administration. The physician will determine the most appropriate dosage of this therapeutic dose, which will vary depending on the form of administration, the patient population, and the specific compound. The active compound is usually administered one to several times a day, with a daily dose of 0.1 - 1000 mg / kg / day.

[0120] The present invention further provides a method for treating and preventing diseases or disease states related to sigma receptors (especially sigma-1 receptors). The method includes administering to a patient in need of treatment a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0121] Term Explanation:

[0122] The terms "optionally", "optionally", or "optionally present" mean that the subsequent described event or situation may or may not occur, and this description includes the cases where the described event or situation occurs and the cases where it does not occur. For example, "an optionally present bond" means that the bond may or may not be present, and this description includes single bonds, double bonds, or triple bonds, etc.

[0123] The term "comprising" is an open-ended expression, that is, it includes the content specified by the present invention, but does not exclude other aspects. It should be understood that the term "comprising" can cover a closed meaning, that is, "consisting of...".

[0124] As described in the present invention, the compounds of the present invention may optionally be substituted by one or more substituents, such as in the general formula compounds above or in specific examples and subclasses such as in the embodiments. It should be understood that the term "optionally substituted" and the term "substituted or unsubstituted" can be used interchangeably. Generally, the term "substituted" means that one or more hydrogen atoms in the given structure are replaced by specific substituents. Unless otherwise indicated, the optionally substituted group can be substituted at each substitutable position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a specific group, then the substituents can be the same or different at each position.

[0125] In addition, it should be noted that unless otherwise explicitly stated, the description method "independently selected from" used in the present invention should be understood in a broad sense. It can either mean that among different groups, the specific options expressed between the same symbols do not affect each other, or it can mean that within the same group, the specific options expressed between the same symbols do not affect each other.

[0126] In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to the group types or ranges. It is specifically pointed out that the present invention includes each independent secondary combination of each member of these group types and ranges. For example, the term "C1-C4 straight-chain or branched-chain alkyl" specifically refers to methyl, ethyl, C3 alkyl, and C4 alkyl independently disclosed. Examples of the C1-C4 straight-chain or branched-chain alkyl group 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 ), etc.

[0127] "Alkoxy" contains one or more (such as 1, 2, 3 or 4) oxygen bonds, and usually contains 1 to about 12, 1 to about 8, 1 to about 6 carbon atoms or 1 to about 3 carbon atoms, such as methoxy, ethoxy, propoxy, etc. In a specific embodiment of the present invention, the "alkoxy" group contains 1 to about 3 carbon atoms, that is, C1-C3 alkoxy, and can be, for example, methoxy, ethoxy, or propoxy.

[0128] "Cycloalkyl" is an alicyclic hydrocarbon. Typical cycloalkyl groups contain 1 to 4 single rings and / or fused rings, and contain 3 to about 18 carbon atoms, preferably 3 to 10 carbon atoms, such as cyclopropyl, cyclohexyl or adamantyl. In a specific embodiment of the present invention, the cycloalkyl group contains 3 to about 6 carbon atoms, and the specifically mentioned "C3-C6 cycloalkyl" is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0129] "Halogenated" or "halo" refers to brominated, chlorinated, iodinated or fluorinated.

[0130] The so-called "C1-C3 haloalkyl" refers to one or more hydrogens on the C1-C3 straight-chain or branched-chain alkyl being replaced by a halogen, and it has "-(CH 2 )a CX 3 、 -(CH 2 ) a CHX 2 、 -(CH 2 ) a CH 2 Any one of the structures shown by "X", wherein a is independently 0, 1 or 2, and X is independently any one of F, Cl, Br, I. In the specific embodiments of the present invention, "haloalkyl of C1-C3" is, for example, difluoromethyl, trifluoromethyl, trifluoroethyl, fluoroethyl, etc.

[0131] The ranges listed herein (such as numerical ranges) can cover each value within the range and each sub-range formed by each value. Therefore, for example, the statement "n2 is any integer between 0 and 3" includes, for example, any integer between 0 and 2, any integer between 2 and 3, etc., such as 1, 2, 3.

[0132] In the present invention, for -(CH 2 ) n1 -R 3 in the structure of formula I, when n1 is 0, it corresponds to -(CH 2 ) n1 - being a bond.

[0133] The term "hydrogen (H)" represents a single hydrogen atom. Such an atomic group can be connected to other groups, for example, connected to an oxygen atom to form a hydroxyl group.

[0134] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0135] The term "aryl" is an aromatic group containing 5 to 15 ring atoms. A typical aromatic group has a single ring (such as phenyl) or multiple fused rings in which at least one ring is aromatic (such as naphthyl). In the present invention, "aryl" is a single-ring aromatic group containing 5 to 6 ring atoms, such as a benzene ring group, etc.

[0136] The term "heteroaryl" refers to an aryl group in which one or more carbon atoms (such as a methylene group (-CH=) or a vinylene group (-CH=CH-)) have been replaced by trivalent or divalent heteroatoms, respectively, in such a way as to maintain aromaticity, such as through the continuous, delocalized π-electron system characteristic of aromatic groups and the number of out-of-plane π electrons corresponding to Hückel's rule (4n + 2). In the present invention, "heteroaryl" is a monocyclic aromatic group containing 5 to 6 ring atoms, in which one or more carbon atoms (such as a methylene group (-CH=) or a vinylene group (-CH=CH-)) have been replaced by nitrogen atoms, such as imidazole, pyrazole, pyridine, pyrimidine, pyridazine, pyrazine, etc.

[0137] The term "salt" should be understood to mean any form of the compounds used in accordance with the present invention, in which the compounds are in ionic form or are charged and coupled with ions of opposite charge (cation or anion) or in solution. This definition also includes quaternary ammonium salts and complexes formed by active molecules with other molecules and ions, in particular, complexes formed by ionic interactions. This definition particularly includes physiologically acceptable salts; the term must be understood as being equivalent to "pharmacologically acceptable salts" or "pharmaceutically acceptable salts".

[0138] In the context of the present invention, the term "pharmaceutically acceptable salt" refers to any salt that is physiologically compatible (usually meaning non-toxic, particularly because of the ions of opposite charge) when used in an appropriate manner for treatment, application, or use, especially in humans and / or mammals. In the present invention, especially when used in humans and / or mammals, these physiologically acceptable salts can be formed by cations or bases and are understood to be salts formed by at least one compound used in accordance with the present invention - usually an acid (deprotonated) - such as an anion and at least one physiologically compatible cation, preferably inorganic ions. These physiologically acceptable salts can also be formed by anions or acids. In the context of the present invention, especially when used in humans and / or mammals, the above-mentioned physiologically acceptable salts should be understood to be salts formed by at least one compound provided by the present invention - usually protonated, such as in nitrogen - such as a cation and at least one physiologically tolerated anion. In the present invention, especially when used in humans and / or mammals, this definition specifically includes salts formed by physiologically compatible acids, that is, salts formed by specific active compounds with physiologically compatible organic or inorganic acids.

[0139] Prodrugs of the compounds of the present invention, in particular any compounds which are prodrugs of the compounds of formula (I), are also within the scope of the present invention. The term "prodrug" is used in its broad sense and includes those derivatives which are converted in vivo into the compounds of the present invention. Examples of prodrugs include, but are not limited to, derivatives and metabolites of formula (I) which contain a biolyzable moiety such as a biolyzable amide, a biolyzable ester, a biolyzable carbamate, a biolyzable carbonate, a biolyzable acylurea and a biolyzable phosphate ester analogue. Preferably, the prodrug of a compound having a hydroxyl functional group is a lower carboxylic acid ester or phosphate ester of the hydroxyl group. The carboxylic acid ester or phosphate ester is readily formed by esterification of any hydroxyl moiety present in the molecule. Prodrugs can generally be prepared using well-known methods, such as those described in Burger "Medicinal Chemistry and Drug Discovery" 6th Edition (Donald J. Abraham ed., 2001, Wiley) and "Design and Applications of Prodrugs" (H. Bundgaard ed., 1985, Harwood Academic Publishers).

[0140] Any compound involved in the present invention is intended to represent such a specific compound and certain variants or certain forms. In particular, the compounds involved herein may have asymmetric centers, and thus the compounds exist in different enantiomeric or diastereomeric forms. Therefore, any given compound involved in the present invention is intended to represent any one or more enantiomeric forms, one or more diastereomeric forms, and mixtures thereof of the racemate. Similarly, stereoisomerism or geometric isomerism of the compounds is also possible. All stereoisomers of the compounds involved, including enantiomers, diastereomers, geometric isomers and atropisomers, and mixtures thereof, are within the scope of the present invention.

[0141] The compounds or their salts, solvates used in the present invention are preferably in a pharmaceutically acceptable form or in a substantially pure form. A pharmaceutically acceptable form means, in particular, having a pharmaceutically acceptable purity level, excluding common pharmaceutical additives such as diluents and carriers, and excluding materials which are considered toxic at normal dosage levels. The purity level of the compound is preferably higher than 50%, more preferably higher than 70%, and most preferably higher than 90%. In a preferred embodiment, the purity of the compound of formula (I) or its pharmaceutically acceptable salt, solvate or prodrug is above 95%.

[0142] The term "prevention" in the present invention refers to the ability, by treatment, to avoid, minimize or make difficult the onset or development of a disease or condition before the onset of a sigma receptor-mediated related disease.

[0143] Thus, by "treatment" and / or "prevention" as a whole, it means at least achieving the inhibition or improvement of the pain associated with the disorder suffered by an individual, where inhibition and improvement, in a broad sense, mean at least including a reduction in the parameter order of magnitude, such as the symptoms associated with the disorder being treated, that is, the pain associated with diseases mediated by the sigma receptor. Thus, the method of the present invention also includes the case where the disorder is completely inhibited, such as prevention or prevention of occurrence, such as termination, so that the subject no longer suffers from the disorder.

[0144] The term "compound capable of binding to the σ receptor" used in this application is preferably defined as a compound having at least Ki < 5000, preferably Ki < 1000, and most preferably Ki < 100 in the σ receptor competitive binding test using 4 nM of the radioligand 3 H]-Pentazocine, and the compound is specific for the σ receptor, where the σ receptor can be any one of the σ receptor subtypes. Preferably, the compound binds to the σ-1 receptor subtype. The above compounds that bind to the σ receptor can be antagonists, inverse agonists, agonists, partial antagonists, and / or partial agonists. The compounds in the present invention are preferably σ receptor antagonists in the form of σ receptor (neutral) antagonists, inverse agonists, or partial antagonists.

[0145] In a preferred embodiment of the present invention, the σ receptor ligand is a selective σ-1 antagonist, preferably a σ-1 antagonist in the form of a (neutral) antagonist, inverse agonist, or partial antagonist, and more preferably a selective σ-1 (neutral) antagonist.

[0146] "Agonist" is defined as a compound that can bind to a receptor, has intrinsic activity, and thus can increase the basal activity of the receptor when it contacts the receptor.

[0147] "Antagonist" is defined as a compound that can compete with an agonist or inverse agonist for binding to a receptor to block the action of the agonist or inverse agonist on the receptor. However, an antagonist (also called a "neutral" antagonist) has no effect on the constitutive receptor activity. The antagonist mediates by binding to the active site or allosteric site of the receptor, or it can interact at a specific binding site, and the specific binding site usually does not participate in the biological regulation of receptor activity. Antagonist activity can be reversible or irreversible, depending on the lifetime of the antagonist-receptor complex, and in turn, the lifetime of the antagonist-receptor complex depends on the nature of the antagonist-receptor binding.

[0148] "Partial antagonist" is defined as a compound that can bind to a receptor and produce an antagonistic response; however, the partial antagonist does not produce a complete antagonistic response. The partial antagonist is a weak antagonist that partially blocks the action of an agonist or inverse agonist on the receptor.

[0149] An "inverse agonist" is defined as a compound that produces an effect opposite to that of an agonist by occupying the same receptor and thus reduces the basal activity of the receptor (i.e., the signal transduction mediated by the receptor). These compounds are also known as negative antagonists. An inverse agonist is a receptor ligand that causes the receptor to adopt an inactive state, which is relative to the basal state of the receptor, which is the state of the receptor in the absence of any ligand. Thus, while an antagonist can inhibit the activity of an agonist, an inverse agonist is a ligand that can change the receptor structure in the absence of an agonist. Examples

[0150] Examples of the present invention are described in detail below. The examples described below are exemplary and are only used to explain the present invention and should not be construed as limiting the present invention. Unless otherwise specified, the ratios, percentages, etc. referred to herein are by weight.

[0151] Synthesis Examples:

[0152] Synthesis Scheme 1: The compounds of Examples 1-8 can be obtained by reductive amination and C-N bond coupling reactions.

[0153]

[0154] Dissolve indole-4-carbaldehyde and morpholine in a suitable solvent (such as DCM), add NaBH(OAc) 3 React to obtain indole-4-methylmorpholine, and then react indole-4-methylmorpholine with R 1 -Br, Pd 2 (dba) 3 and X-phos in a suitable solvent (such as DCM, xylene) to obtain the target compound.

[0155] Example 1 : Synthesis of 4-((1-(pyridin-4-yl)-1H-indol-4-yl)methyl)morpholine

[0156] Step 1. Synthesis of indole-4-methylmorpholine

[0157]

[0158] Dissolve indole-4-carbaldehyde (250 mg, 1.72 mmol) and morpholine (449.5 mg, 5.16 mmol) in DCM (10 mL), react at room temperature for 1 h, and then add NaBH(OAc) 3(729.1 mg, 3.44 mmol), stirred and reacted at 25 °C for 12 h; added water (30 mL) to quench the reaction, extracted with DCM (30 mL x 2), the DCM organic phase was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Through column chromatography (PE / EA = 2 / 1), 300 mg of indole-4-methylmorpholine was obtained, yield: 80.6%

[0159] Step 2. Synthesis of 4-((1-(pyridin-4-yl)-1H-indol-4-yl)methyl)morpholine

[0160]

[0161] Indole-4-methylmorpholine (110 mg, 0.5 mmol), 4-bromopyridine (95 mg, 0.6 mmol), Pd2(dba)3 (15 mg, 0.025 mmol), Xantphos (15 mg, 0.025 mmol), Cs 2 CO 3 (325 mg, 1.0 mmol) and p-xylene (5 mL) were added to the reaction flask and reacted at 100 °C for 8 h. TLC (PE / EA = 1:1) detected that the reaction was complete; cooled to room temperature, added H 2 O (20 mL), extracted with EA (20 mL x 3), dried over anhydrous sodium sulfate, concentrated, and purified by preparative thin-layer chromatography to obtain 4-((1-(pyridin-4-yl)-1H-indol-4-yl)methyl)morpholine as a pale yellow solid (75 mg, yield: 51.1%).

[0162] 1 1H NMR (400 MHz, Methanol-d 4 ) δ: 8.96 - 8.86 (m, 2H), 8.42 - 8.33 (m, 2H), 8.19 (dd, J = 8.3, 1.0 Hz, 1H), 8.09 (d, J = 3.8 Hz, 1H), 7.65 - 7.57 (m, 2H), 7.37 (dd, J = 3.8, 0.8 Hz, 1H), 4.73 (s, 2H), 4.05 (dd, J = 12.6, 3.4 Hz, 2H), 3.88 - 3.74 (m, 2H), 3.49 - 3.33 (m, 4H). MS (ESI) m / z 294.15 ([M+H] + ).

[0163] Example 2 : Synthesis of 4-((1-(4-fluorophenyl)-1H-indol-4-yl)methyl)morpholine

[0164] Replace 4-bromopyridine with 4-fluorobromobenzene, and synthesize the target product according to the scheme of Example 1

[0165]

[0166] 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.68 - 7.51 (m, 4H), 7.46 - 7.30 (m, 4H), 7.02 (dd, J = 3.4, 0.9 Hz, 1H), 4.70 (s, 2H), 4.03 (s, 2H), 3.78 (s, 2H), 3.53 - 3.33 (m, 4H). MS(ESI) m / z 311.2 ([M+H] + )

[0167] Example 3 : Synthesis of 4 - ((1 - (4 - methoxyphenyl)-1H - indol - 4 - yl)methyl)morpholine

[0168] Replace 4 - bromopyridine with (E)-4 - bromobenzaldoxime, and synthesize the target product according to the method of Example 1

[0169]

[0170] 1 H NMR (400 MHz, Chloroform - d) δ 8.18 (s, 1H), 7.85 - 7.81 (m, 2H), 7.74 - 7.72 (m, 1H), 7.69 - 7.68 (m, 1H), 7.60 - 7.57 (m, 2H), 7.40 - 7.34 (m, 2H), 7.04 - 7.03 (m, 1H), 4.69 (s, 2H), 4.06 - 4.03 (m, 2H), 3.97 (s, 3H), 3.79 - 3.72 (m, 2H), 3.46 - 3.30 (m, 4H). MS(ESI) m / z 350.2 ([M+H] + ).

[0171] Example 4 : Synthesis of 5 - (4 - (morpholinomethyl)-1H - indol - 1 - yl)pyridin - 2 - amine

[0172] Replace 4 - bromopyridine with 5 - bromo - 2 - aminopyridine, and synthesize the target product according to the method of Example 1

[0173]

[0174] 11H NMR (400 MHz, Chloroform-d) δ 8.21 (d, J = 2.7 Hz, 1H), 7.55 (dd, J = 8.7, 2.7 Hz, 1H), 7.28 (d, J = 7.4 Hz, 1H), 7.22 (d, J = 3.3 Hz, 1H), 7.19 - 7.11 (m, 2H), 6.86 (dd, J = 3.2, 0.8 Hz, 1H), 6.64 (d, J = 8.8 Hz, 1H), 4.62 (s, 2H), 3.83 (s, 2H), 3.73 (t, J = 4.7 Hz, 4H), 2.54 (t, J = 4.7 Hz, 4H). MS (ESI) m / z 309.2 ([M+H] + ).

[0175] Example 5 : Synthesis of 4 - ((1 - (1 - isopropyl - 1H - pyrazol - 4 - yl) - 1H - indol - 4 - yl)methyl)morpholine

[0176] Replace 4 - bromopyridine with 4 - bromo - 1 - isopropylpyrazole, and synthesize the target product according to the scheme of Example 1.

[0177]

[0178] 1 1H NMR (400 MHz, Methanol - d 4 ) δ 8.10 (s, 1H), 7.77 (s, 1H), 7.63 - 7.56 (m, 1H), 7.54 (d, J = 3.3 Hz, 1H), 7.34 (d, J = 5.4 Hz, 2H), 6.94 (d, J = 4.1 Hz, 1H), 4.67 (s, 2H), 4.65 - 4.56 (m, 1H), 3.88 (d, J = 119.1 Hz, 4H), 3.38 (s, 4H), 1.57 (d, J = 6.7 Hz, 6H).

[0179] Example 6 : Synthesis of 4 - ((1 - (6 - (trifluoromethyl)pyridin - 3 - yl) - 1H - indol - 4 - yl)methyl)morpholine

[0180] Replace 4 - bromopyridine with 5 - bromo - 2 - trifluoromethylpyridine, and synthesize the target product according to the scheme of Example 1.

[0181]

[0182] 11H NMR (400 MHz, Methanol-d4) δ 8.99 (d, J = 2.5 Hz, 1H), 8.28 (dd, J = 8.5, 2.5 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.80 (dd, J = 9.3, 2.5 Hz, 2H), 7.48 - 7.39 (m, 2H), 7.14 (d, J = 3.5 Hz, 1H), 4.70 (s, 2H), 4.03 (s, 2H), 3.77 (s, 2H), 3.40 (s, 4H). MS (ESI) m / z 362 ([M+H] + ).

[0183] Example 7 : Synthesis of 4 - ((1 - (2 - (trifluoromethyl)pyrimidin - 5 - yl)-1H - indol - 4 - yl)methyl)morpholine

[0184] Replace 4 - bromopyridine with 5 - bromo - 2 - (trifluoromethyl)pyrimidine, and synthesize the target product according to the scheme of Example 1.

[0185]

[0186] 1 1H NMR (400 MHz, Methanol-d4) δ 9.30 (s, 2H), 7.87 (q, J = 2.7 Hz, 2H), 7.51 - 7.41 (m, 2H), 7.20 (dd, J = 3.5, 0.9 Hz, 1H), 4.71 (s, 2H), 4.08 - 3.70 (m, 4H), 3.78 - 3.34 (m, 4H). MS (ESI) m / z 363 ([M+H] + ).

[0187] Example 8: Synthesis of 1 - isopropyl - 4 - (4 - (morpholinomethyl)-1H - indol - 1 - yl)pyridin - 2(1H)-one

[0188] Replace 4 - bromopyridine with 4 - bromo - 1 - isopropyl - 1,2 - dihydropyridin - 2 - one, and synthesize the target product according to the scheme of Example 1.

[0189]

[0190] 11H NMR (400 MHz, Methanol-d4) δ 8.19 (s, 1H), 7.96 (d, J = 8.2 Hz, 1H), 7.84 (t, J = 3.2 Hz, 1H), 7.54 (d, J = 7.5 Hz, 1H), 7.46 (t, J = 7.7 Hz, 1H), 7.21 (d, J = 3.3 Hz, 2H), 6.97 (s, 1H), 5.35 - 5.17 (m, 1H), 4.71 (d, J = 2.3 Hz, 2H), 4.03 (m, J = 13.2, 3.2 Hz, 2H), 3.81 (t, J = 12.2 Hz, 2H), 3.48 - 3.32 (m, 4H), 1.52 (d, J = 6.1 Hz, 6H). MS (ESI) m / z 334. ([M+H] + ).

[0191] Synthesis Scheme 2: The compounds of Examples 9 - 16 can be obtained through C-N bond coupling reaction and reductive amination reaction.

[0192] Reaction Scheme 2, the compounds of Examples 9 - 16 can be obtained through this synthesis scheme

[0193]

[0194] React 4-indolecarboxaldehyde with R 1 -Br, Pd 2 (dba) 3 , X-phos in a suitable solvent (such as DCM, xylene) to obtain Compound V, and then react Compound V with R 3 -H, NaBH(OAc) 3 to obtain Compound a02.

[0195] Example 9 : Synthesis of 2-((1-(pyridin-4-yl)-1H-indol-4-yl)methyl)-7-oxa-2-azaspiro[3.5]nonane

[0196] Step 1. Synthesis of 1-(pyridin-4-yl)-1H-indole-4-carboxaldehyde

[0197]

[0198] React 4-indolecarboxaldehyde (0.45 g, 3.10 mmol), 4-bromopyridine (0.49 g, 3.10 mmol), X-phos (0.07 g, 0.16 mmol), Pd 2 (dba) 3 (0.14 g, 0.16 mmol), Cs 2 CO 3(2.02 g, 6.20 mmol), KI (0.01 g, 0.03 mmol) were successively added into the reaction flask, then xylene (10 mL) was added. The reaction was carried out at 100 °C for 5 hours under nitrogen protection. After the reaction was detected to be complete by TLC, it was cooled to room temperature. The reaction solution was filtered through diatomaceous earth, washed with EA, concentrated, and purified by column chromatography (PE / EA = 10:1 to 1:1) to obtain 300 mg of flocculent yellow solid with a yield of 43%.

[0199] Step 2. Synthesis of 2-((1-(pyridin-4-yl)-1H-indol-4-yl)methyl)-7-oxa-2-azaspiro[3.5]nonane

[0200]

[0201] 1-(Pyridin-4-yl)-1H-indole-4-carbaldehyde (220 mg, 0.99 mmol), 7-oxa-2-azaspiro[3.5]nonane (130 mg, 0.99 mmol), acetic acid (10 mg, 0.10 mmol) and DCM (15 mL) were successively added into the reaction flask and stirred at 20 °C for 20 minutes. The temperature was lowered to -10 °C, and NaBH(OAc) 3 (0.42 g, 1.98 mmol) was added. After the addition, the temperature was slowly raised to 20 °C and the reaction was carried out for 30 minutes. After the reaction was completed, the reaction solution was cooled to -10 °C, and the reaction was quenched with saturated NaHCO 3 solution, the pH was adjusted to ~7, extracted with DCM (20 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by thin-layer chromatography (DCM / MeOH = 15:1) to obtain 250 mg of white solid with a yield of ~75.7%.

[0202] 1 1H NMR (400 MHz, Methanol-d4) δ 8.96 - 8.385 (m, 2H), 8.41 - 8.31 (m, 2H), 8.15 (m, J = 6.2, 3.1 Hz, 1H), 8.08 (d, J = 3.7 Hz, 1H), 7.55 (q, J = 3.8, 3.1 Hz, 2H), 7.36 (d, J = 3.7 Hz, 1H), 4.8 (s, 2H), 4.09 (q, J = 10.6 Hz, 4H), 3.61 (m, J = 17.3, 5.2 Hz, 4H), 1.92 (m, J = 10.8, 5.3 Hz, 4H). MS (ESI) m / z 334 ([M + H] + )

[0203] Example 10 : Synthesis of 1-((1-(pyridin-4-yl)-1H-indol-4-yl)methyl)piperidin-4-one

[0204] Replace 7-oxa-2-azaspiro[3.5]nonane with 4-piperidone, and synthesize the target product according to the scheme of Example 9.

[0205]

[0206] 1 H NMR(400MHz, Methanol-d4)δ8.94 - 8.87(m, 2H), 8.39 - 8.33(m, 2H), 8.16(d, J = 8.0Hz, 1H), 8.07(d, J = 3.7Hz, 1H), 7.63 - 7.51(m, 2H), 7.34(d, J = 3.8Hz, 1H), 4.68(s, 2H), 3.46 - 3.34(m, 4H), 1.88(m, 2H), 1.82 - 1.73(m, 2H), 1.71(s, 3H).MS(ESI)m / z 322.2([M + H] + ).

[0207] Example 11 : Synthesis of 4-methyl-1-((1-(pyridin-4-yl)-1H-indol-4-yl)methyl)piperidin-4-ol

[0208] Replace 7-oxa-2-azaspiro[3.5]nonane with 4-methylpiperidin-4-ol, and synthesize the target product according to the scheme of Example 9.

[0209]

[0210] 1 H NMR(400MHz, Methanol-d4)δ8.94 - 8.87(m, 2H), 8.39 - 8.33(m, 2H), 8.16(d, J = 8.0Hz, 1H), 8.07(d, J = 3.7Hz, 1H), 7.63 - 7.51(m, 2H), 7.34(d, J = 3.8Hz, 1H), 4.68(s, 2H), 3.46 - 3.34(m, 4H), 1.88(m, 2H), 1.82 - 1.73(m, 2H), 1.71(s, 3H).MS(ESI)m / z 322.2([M + H] + ).

[0211] Example 12 : Synthesis of 3-methyl-1-((1-(pyridin-4-yl)-1H-indol-4-yl)methyl)pyrrol-3-ol

[0212] Replace 7-oxa-2-azaspiro[3.5]nonane with 3-methylpyrrol-3-ol, and synthesize the target product according to the scheme of Example 9.

[0213]

[0214] 1 H NMR (400 MHz, Methanol-d4) δ 8.93 - 8.86 (m, 2H), 8.39 - 8.33 (m, 2H), 8.15 (d, J = 8.1 Hz, 1H), 8.06 (d, J = 3.7 Hz, 1H), 7.61 - 7.50 (m, 2H), 7.33 (dd, J = 23.6, 3.7 Hz, 1H), 4.85 - 4.66 (m, 4H), 3.85 - 3.49 (m, 2H), 2.33 - 2.02 (m, 2H), 1.42 (d, J = 6.1 Hz, 3H)..MS(ESI) m / z 308 ([M+H] + ).

[0215] Example 13 Synthesis of 4-methyl-1-((1-(pyridin-3-yl)-1H-indol-4-yl)methyl)piperidin-4-ol

[0216] Replace 7-oxa-2-azaspiro[3.5]nonane with 4-methylpiperidin-4-ol and 4-bromopyridine with 3-bromopyridine, and synthesize the target product according to the scheme of Example 9.

[0217]

[0218] 1H NMR (400 MHz, Methanol-d4) δ 9.25 (d, J = 2.5 Hz, 1H), 8.98 - 8.73 (m, 2H), 8.22 (m, 1H), 7.95 - 7.76 (m, 2H), 7.57 - 7.42 (m, 2H), 7.22 (m, 1H), 4.70 (s, 2H), 3.55 - 3.36 (m, 4H), 2.01 - 1.68 (m, 4H), 1.29 (s, 3H). MS(ESI) m / z 322.2 ([M+H] + ).

[0219] Example 14 : Synthesis of 4-methyl-1-((1-(pyridin-2-yl)-1H-indol-4-yl)methyl)piperidin-4-ol

[0220] Replace 7-oxa-2-azaspiro[3.5]nonane with 4-methylpiperidin-4-ol and 4-bromopyridine with 2-bromopyridine, and synthesize the target product according to the scheme of Example 9.

[0221]

[0222] 1H NMR (400 MHz, Methanol-d4) δ 8.59 (d, J = 4.9 Hz, 1H), 8.38 (s, 1H), 8.07 - 7.98 (m, 2H), 7.72 (s, 1H), 7.41 (s, 3H), 7.06 (s, 1H), 4.71 (s, 0H), 4.65 (s, 2H), 3.40 (s, 4H), 1.82 (d, J = 12.2 Hz, 4H), 1.27 (s, 3H).

[0223] Example 15 : Synthesis of 4-methyl-1-((1-(pyridazin-3-yl)-1H-indol-4-yl)methyl)piperidin-4-ol

[0224] Replace 7-oxa-2-azaspiro[3.5]nonane with 4-methylpiperidin-4-ol and 4-bromopyridine with 3-bromopyridazine, and synthesize the target product according to the method of Example 9.

[0225]

[0226] 1 H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 9.21 (dd, J = 4.7, 1.3 Hz, 1H), 8.55 (d, J = 8.4 Hz, 1H), 8.28 - 8.19 (m, 2H), 7.95 (dd, J = 9.0, 4.8 Hz, 1H), 7.63 (d, J = 7.4 Hz, 1H), 7.46 - 7.32 (m, 2H), 4.59 (d, J = 4.9 Hz, 2H), 3.28 - 3.13 (m, 4H), 1.92 (td, J = 13.4, 12.9, 5.2 Hz, 2H), 1.60 (d, J = 13.9 Hz, 2H), 1.14 (s, 3H). MS (ESI) m / z 323.2 ([M + H]+).

[0227] Example 16 : Synthesis of 3-methyl-1-((1-(pyridin-4-yl)-1H-indol-4-yl)methyl)azetidin-3-ol

[0228] Replace 7-oxa-2-azaspiro[3.5]nonane with 3-methyl-3-azetidinol, and synthesize the target product according to the method of Example 9.

[0229]

[0230] 11H NMR (400 MHz, Methanol-d4) δ 8.97 - 8.82 (m, 2H), 8.44 - 8.30 (m, 2H), 8.15 (d, J = 7.8 Hz, 1H), 8.07 (d, J = 3.7 Hz, 1H), 7.53 (q, J = 8.8, 8.1 Hz, 2H), 7.34 (d, J = 3.9 Hz, 1H), 4.75 (s, 2H), 4.26 - 3.98 (m, 4H), 1.54 (d, J = 3.7 Hz, 3H). MS (ESI) m / z 394.4 ([M+H] + ).

[0231] Synthesis Scheme 3:

[0232] The compounds of Examples 17 - 23 can be obtained by this synthesis scheme.

[0233]

[0234] React 4 - indolecarboxaldehyde with R 1 -Br, Pd 2 (dba) 3 、X - phos in a suitable solvent (such as DCM, xylene), the resulting compound V reacts with a Grignard reagent to obtain compound a03b, compound a03b reacts with thionyl chloride to obtain compound a03a, and compound a03a further reacts with R3 - H to obtain compound a03.

[0235] Example 17 : Synthesis of 4 - (1 - (1 - (pyridin - 4 - yl) - 1H - indol - 4 - yl)ethyl)morpholine

[0236] Step 1. Synthesis of 1 - (pyridin - 4 - yl) - 1H - indole - 4 - carbaldehyde

[0237]

[0238] React 4 - indolecarboxaldehyde (0.45 g, 3.10 mmol), 4 - bromopyridine (0.49 g, 3.10 mmol), X - phos (0.07 g, 0.16 mmol), Pd 2 (dba)3 (0.14 g, 0.16 mmol), Cs 2 CO 3(2.02 g, 6.20 mmol), KI (0.01 g, 0.03 mmol) were successively added into the reaction flask, and xylene (10 mL) was added. The reaction was carried out at 100 °C for 5 hours under nitrogen protection. After the reaction was completed by TLC detection, the temperature was lowered to room temperature. The reaction solution was filtered through diatomaceous earth, washed with EA, concentrated, and purified by column chromatography (PE / EA = 10:1 to 1:1) to obtain 300 mg of flocculent yellow solid with a yield of 43%.

[0239] Step 2. Synthesis of 1-(1-(pyridin-4-yl)-1H-indol-4-yl)ethyl-1-ol

[0240]

[0241] 1-(Pyridin-4-yl)-1H-indole-4-carbaldehyde (620 mg, 2.79 mmol) and THF (20 mL) were successively added into a 100 mL single-necked flask, and the reaction was stirred at -20 °C for 10 min. After adding methylmagnesium bromide (1.0 mL, 3 M in THF), the reaction was stirred at -20 °C for 1.0 h. After the reaction was monitored by TLC and ended, saturated ammonium chloride solution (100 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (80 mL × 2), dried over anhydrous sodium sulfate, and concentrated to obtain 650 mg of crude light yellow solid with a yield of 97.8%. Without purification, the crude product was directly used for the next step of the reaction.

[0242] Step 3. Synthesis of 4-(1-chloroethyl)-1-(pyridin-4-yl)-1H-indole

[0243]

[0244] 1-(1-(Pyridin-4-yl)-1H-indol-4-yl)ethyl-1-ol (238.3 mg, 1 mmol) and dichloromethane (20 mL) were successively added into a 100 mL single-necked flask, and the mixture was stirred at 20 °C for 10 min. Then SOCl 2 (42.8 mg, 1.20 mmol) was added, and the reaction was stirred at 20 °C for 3 h. After the reaction solution ended, it was concentrated to obtain a residue, and the residue was directly used for the next step of the reaction.

[0245] Step 4. Synthesis of 4-(1-(1-(pyridin-4-yl)-1H-indol-4-yl)ethyl)morpholine

[0246]

[0247] Morpholine (174.2 mg, 2.00 mmol), K 2 CO 3(276.4 mg, 2.00 mmol) and DMF (15 mL) were successively added into a 100 mL single-necked flask. The residue obtained in Step 3 was added under stirring, and the mixture was heated to 80 °C and stirred for reaction for 5 h. After the reaction was monitored by TLC to be complete, the reaction solution was quenched by adding saturated ammonium chloride solution (50 mL), extracted with dichloromethane (50 mL × 2), dried over anhydrous sodium sulfate and concentrated to obtain 420 mg of crude product. After purification by pre-TLC (developing solvent: MeOH / DCM = 5%) and preparative Flash (ACN / H2O = 0% - 15%), 85 mg of pale yellow foamy solid was obtained.

[0248] 1 1H NMR (400 MHz, Methanol-d4) δ 8.90 (d, J = 6.7 Hz, 2H), 8.37 (d, J = 6.7 Hz, 2H), 8.15 (d, J = 8.3 Hz, 1H), 8.07 (d, J = 3.7 Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.35 (d, J = 3.7 Hz, 1H), 5.02 (q, J = 6.8 Hz, 1H), 4.16 - 4.04 (m, 1H), 4.02 - 3.80 (m, 3H), 3.80 - 3.67 (m, 1H), 3.29 - 3.24 (m, 1H), 3.12 - 3.01 (m, 2H), 1.89 (d, J = 6.8 Hz, 3H). MS (ESI) m / z 308.2 ([M+H] + ).

[0249] Example 18 Synthesis of 1-(1-(1-(pyridin-4-yl)-1H-indol-4-yl)ethyl-4-(trifluoromethyl)piperidin-4-ol

[0250] Morpholine was replaced with 4-(trifluoromethyl)piperidin-4-ol, and the target product was synthesized according to the scheme of Example 17.

[0251]

[0252] 11H NMR (400 MHz, Methanol-d4) δ 8.85 - 8.77 (m, 2H), 8.31 - 8.23 (m, 2H), 8.07 (d, J = 8.3 Hz, 1H), 7.98 (d, J = 3.8 Hz, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.51 (t, J = 7.9 Hz, 1H), 7.27 (d, J = 3.8 Hz, 1H), 5.01 (q, J = 6.9 Hz, 1H), 3.85 (m, 1H), 3.24 (mz, 2H), 3.06 (m, 1H), 2.20 (m, 1H), 2.01 - 1.91 (m, 2H), 1.82 (m, 4H). MS(ESI) m / z 390.2 ([M+H] + ).

[0253] Example 19 : 2-(1-(1-(Pyridin-4-yl)-1H-indol-4-yl)ethyl-1-)-7-oxa-2-azaspiro[3.5]nonane

[0254] Replace morpholine with 7-oxa-2-azaspiro[3.5]nonane, and the target product was synthesized according to the procedure of Example 17.

[0255]

[0256] 1 1H NMR (400 MHz, Methanol-d4) δ 8.99 - 8.84 (m, 2H), 8.44 - 8.31 (m, 2H), 8.18 - 8.04 (m, 2H), 7.64 (d, J = 7.5 Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.39 (d, J = 3.7 Hz, 1H), 5.20 (q, J = 6.7 Hz, 1H), 4.39 - 4.20 (m, 2H), 3.77 (m, J = 10.9, 2.0 Hz, 1H), 3.73 - 3.44 (m, 5H), 2.01 (d, J = 12.2 Hz, 4H), 1.72 (d, J = 6.7 Hz, 3H). MS(ESI) m / z 348. ([M+H] + ).

[0257] Example 20 : 1-(1-(Pyridin-4-yl)-1H-indol-4-yl)ethyl)piperidin-4-one

[0258] Replace morpholine with 4-piperidone, and the target product was synthesized according to the procedure of Example 17.

[0259]

[0260] 11H NMR (400 MHz, CD 3 OD) δ 8.92 (d, J = 6.8 Hz, 2H), 8.38 (d, J = 6.9 Hz, 2H), 8.18 (d, J = 8.3 Hz, 1H), 8.08 (d, J = 3.4 Hz, 1H), 7.63 (d, J = 7.4 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.36 (d, J = 3.5 Hz, 1H), 4.71 (d, J = 9.3 Hz, 2H), 3.56 - 3.41 (m, 2H), 3.33 (d, J = 11.9 Hz, 1H), 3.30 - 3.20 (m, 1H), 2.20 - 2.04 (m, 2H). 1.99 (s, 2H).

[0261] Example 21 : 4-Methyl-1-(1-(1-(pyridin-4-yl)-1H-indol-4-yl)ethyl)piperidin-4-ol

[0262] Replace morpholine with 4-methylpiperidin-4-ol, and the target product was synthesized according to the procedure of Example 17.

[0263]

[0264] 1 1H NMR (400 MHz, Methanol-d4) δ 8.93 - 8.86 (m, 2H), 8.42 - 8.33 (m, 2H), 8.14 (d, J = 8.3 Hz, 1H), 8.06 (d, J = 3.8 Hz, 1H), 7.68 (d, J = 7.5 Hz, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.35 (d, J = 3.8 Hz, 1H), 5.03 (q, J = 6.9 Hz, 1H), 3.79 - 3.68 (m, 1H), 3.27 - 3.03 (m, 3H), 2.13 - 1.96 (m, 1H), 1.89 (d, J = 6.9 Hz, 3H), 1.86 - 1.76 (m, 2H), 1.68 (dd, J = 14.8, 3.0 Hz, 1H), 1.24 (s, 3H). MS (ESI) m / z 336.2 ([M+H] + ).

[0265] Example 22 : 4-(1-(1-(6-Methylpyridazin-3-yl)-1H-indol-4-yl)ethyl)morpholine

[0266] Replace 4-bromopyridine with 2-methyl-5-bromopyridazine, and the target product was synthesized according to the procedure of Example 17.

[0267]

[0268] 1 1H NMR (400 MHz, Methanol-d 4 ) δ 8.82 (d, J = 9.4 Hz, 1H), 8.61 (d, J = 8.4 Hz, 1H), 8.44 (d, J = 9.3 Hz, 1H), 8.21 (d, J = 3.8 Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.34 (d, J = 3.7 Hz, 1H), 5.03 (q, J = 6.8 Hz, 1H), 4.16 - 4.05 (m, 1H), 4.03 - 3.82 (m, 3H), 3.81 - 3.70 (m, 1H), 3.32 (s, 1H), 3.29 - 3.24 (m, 1H), 3.07 (d, J = 5.2 Hz, 2H), 2.93 (s, 3H), 1.91 (d, J = 6.8 Hz, 3H).

[0269] Example 23 : 4-(1-(1-(Pyrimidin-2-yl)-1H-indol-4-yl)ethyl)morpholine

[0270] Replace 4-bromopyridine with 2-bromopyrimidine and synthesize the target product according to the procedure of Example 17.

[0271]

[0272] 1 1H NMR (400 MHz, Methanol-d4) δ 8.96 (m, J = 6.8, 2.5 Hz, 1H), 8.81 (d, J = 4.8 Hz, 2H), 8.46 (d, J = 3.8 Hz, 1H), 7.47 - 7.40 (m, 2H), 7.27 (t, J = 4.8 Hz, 1H), 7.05 (m, J = 3.8, 0.8 Hz, 1H), 4.64 (s, 2H), 3.39 (d, J = 3.1 Hz, 4H), 1.91 - 1.73 (m, 4H), 1.27 (s, 3H). MS (ESI) m / z 323. ([M+H] + ).

[0273] Synthesis Scheme 4:

[0274] The compounds of Examples 24 - 27 can be obtained by this synthesis scheme.

[0275]

[0276] React 4-indolecarboxaldehyde with R 1 -Br, Pd 2 (dba) 3, X-phos was added to a suitable solvent (such as DCM, xylene) for reaction to obtain Compound V. Compound V was reacted with (methoxymethyl)triphenylphosphonium chloride under basic conditions to obtain Compound a04a. Compound a04a was hydrolyzed under acidic conditions to obtain Compound VI, and Compound VI was then reacted with R 3 -H and sodium triacetoxyborohydride to obtain Compound a04.

[0277] Example 24 : Synthesis of 4-(2-(1-(pyridin-4-yl)-1H-indol-4-yl)ethyl)morpholine

[0278] Step 1. Synthesis of 1-(pyridin-4-yl)-1H-indole-4-carbaldehyde

[0279]

[0280] 4-Indolecarbaldehyde (0.45 g, 3.10 mmol), 4-bromopyridine (0.49 g, 3.10 mmol), X-phos (0.07 g, 0.16 mmol), Pd 2 (dba) 3 (0.14 g, 0.16 mmol), Cs 2 CO 3 (2.02 g, 6.20 mmol), KI (0.01 g, 0.03 mmol) were successively added to the reaction flask, 10 mL of xylene was added, and the reaction was carried out at 100 °C for 5 hours under nitrogen protection. After the reaction was completed as detected by TLC, the temperature was lowered to room temperature, the reaction solution was filtered through diatomaceous earth, washed with EA, concentrated, and purified by column chromatography (PE / EA = 10:1 to 1:1) to obtain 300 mg of a flocculent yellow solid with a yield of 43%.

[0281] Step 2. Synthesis of 4-[(E)-2-methoxyvinyl]-1-(pyridin-4-yl)-1H-indole

[0282]

[0283] Weigh (methoxymethyl)triphenylphosphonium chloride (3.60 g, 10.50 mmol) and THF (130 mL) in a 100 mL three-necked flask. Under nitrogen protection at low temperature, add t-BuOK (1.18 g, 10.50 mmol). After stirring at low temperature for 40 minutes, add 1-(pyridin-4-yl)-1H-indole-4-carbaldehyde (1.56 g, 7 mmol) dissolved in THF (20 mL). After addition, take it out to room temperature (~20 °C) and react for 1 hour. After monitoring the reaction by TLC (PE:EA = 1:1) and completing the reaction, quench the reaction with saturated ammonium chloride. Extract with EA (50 mL x 3), dry over anhydrous magnesium sulfate, concentrate, and purify by column chromatography (PE:EA = 2:1~1:1) to obtain 3.8 g of a pale yellow oily product (containing triphenylphosphine oxide). The crude product was directly used in the next step without further separation.

[0284] Step 3. Synthesis of 2-(1-(pyridin-4-yl)-1H-indol-4-yl)acetaldehyde

[0285]

[0286] Add 4-[(E)-2-methoxyvinyl]-1-(pyridin-4-yl)-1H-indole (2.00 g, 8 mmol), hydrochloric acid (2 mL), THF (60 mL), and H2O (15 mL) to a 50 mL single-necked flask in sequence. Reflux at 70 °C for 30 minutes. After monitoring the reaction by TLC and completing the reaction, quench the reaction solution to neutral with saturated sodium bicarbonate solution. Extract with EA (30 mL x 3), dry over magnesium sulfate, concentrate to obtain 4 g of a yellow oily crude product. The crude product was directly used in the next step.

[0287] Step 4. Synthesis of 4-(2-(1-(pyridin-4-yl)-1H-indol-4-yl)ethyl)morpholine

[0288]

[0289] Add 2-(1-(pyridin-4-yl)-1H-indol-4-yl)acetaldehyde (0.24 g, 1 mmol), morpholine (0.13 g, 1.50 mmol), and TFA (0.01 g, 0.10 mmol) to a 100 mL single-necked flask in sequence. Stir at 0-5 °C for 15 minutes. Add NaBH(OAc)3 (0.85 g, 4.00 mmol) in batches at low temperature. After adding, raise the temperature to room temperature and react for 40 minutes. After monitoring the reaction by TLC and completing the reaction, quench the reaction with saturated sodium bicarbonate. Extract with DCM (20 mL x 3). Dry the organic phase over anhydrous magnesium sulfate, concentrate to obtain a yellow oily crude product, and purify by pre-TLC (DCM:MeOH = 20:1) to obtain 50 mg of a colorless oily product.

[0290] 11H NMR (400 MHz, Methanol-d4) δ 8.79 - 8.70 (m, 2H), 8.26 - 8.19 (m, 2H), 7.91 - 7.82 (m, 2H), 7.32 (t, J = 7.9 Hz, 1H), 7.20 (d, J = 7.4 Hz, 1H), 7.14 (d, J = 3.7 Hz, 1H), 4.00 (dd, J = 13.2, 3.5 Hz, 2H), 3.86 - 3.74 (m, 2H), 3.55 (d, J = 12.5 Hz, 2H), 3.37 (h, J = 1.9 Hz, 4H), 3.15 (dd, J = 12.3, 3.7 Hz, 2H). MS (ESI) m / z 308 ([M+H] + ).

[0291] Example 25 : Synthesis of 1-(2-(1-(pyridin-4-yl)-1H-indol-4-yl)ethyl)-4-(trifluoromethyl)piperidin-4-ol

[0292] Replace morpholine with 4-(trifluoromethyl)piperidin-4-ol and synthesize the target product according to the procedure of Example 24.

[0293]

[0294] 1 1H NMR (400 MHz, Methanol-d4) δ 8.90 - 8.83 (m, 2H), 8.38 - 8.32 (m, 2H), 8.01 - 7.95 (m, 2H), 7.43 (t, J = 7.9 Hz, 1H), 7.36 - 7.23 (m, 2H), 3.82 - 3.68 (m, 2H), 3.49 (s, 4H), 3.39 (td, J = 12.8, 2.8 Hz, 2H), 2.28 (td, J = 14.1, 4.4 Hz, 2H), 2.07 (dd, J = 14.9, 2.6 Hz, 2H). MS (ESI) m / z 390. ([M+H] + ).

[0295] Example 26 : Synthesis of 1-(2-(1-(pyridin-4-yl)-1H-indol-4-yl)ethyl)-3-(trifluoromethyl)pyrrol-3-ol

[0296] Replace morpholine with 3-(trifluoromethyl)pyrrol-3-ol and synthesize the target product according to the procedure of Example 24.

[0297]

[0298] 11H NMR (400 MHz, CD3OD) δ 8.86 (d, J = 7.0 Hz, 2H), 8.34 (d, J = 7.1 Hz, 2H), 8.05 - 7.94 (m, 2H), 7.43 (t, J = 7.9 Hz, 1H), 7.32 (d, J = 7.3 Hz, 1H), 7.25 (d, J = 3.6 Hz, 1H), 4.01 (s, 2H), 3.54 (d, J = 94.7 Hz, 6H), 2.78 - 2.22 (m, 2H).

[0299] MS (ESI) m / z 376.4 ([M+H] + ).

[0300] Example 27 : Synthesis of 4-(2-(1-(6-(trifluoromethyl)pyridin-3-yl)-1H-indol-4-yl)ethyl)morpholine

[0301] Replace 2-bromopyridine with 5-bromo-2-(trifluoromethyl)pyridine and synthesize the target product according to the procedure of Example 24.

[0302]

[0303] 1 1H NMR (400 MHz, Methanol-d4) δ 8.97 (d, J = 2.5 Hz, 1H), 8.26 (dd, J = 8.4, 2.5 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 3.5 Hz.1H), 7.60 (d, J = 8.4 Hz.1H), 7.28 (t, J = 7.8 Hz.1H).7.15 (d, J = 7.2 Hz, 1H), 6.98 (d, J = 3.5 Hz, 1H), 4.09 (s, 2H), 3.83 (s.2H), 3.61 (d, J = 9.6 Hz, 2H), 3.55 - 3.47 (m, 2H), 3.45 - 3.38 (m, 2H). MS (ESI) m / z 334. ([M+H] + ).

[0304] Synthesize other compounds according to the aforementioned method:

[0305] Example 28, 4-((1-(2-methylpyridin-4-yl)-1H-indol-4-yl)methyl)morpholine

[0306]

[0307] 11H NMR (400 MHz, Methanol-d4) δ 8.75 (d, J = 6.8 Hz, 1H), 8.25 - 8.13 (m, 3H), 8.05 (d, J = 3.8 Hz, 1H), 7.64 - 7.62 (m, 1H), 7.58 - 7.54 (m, 1H), 7.36 - 7.34 (m, 1H), 4.73 (s, 2H), 4.62 - 4.02 (m, 2H), 3.86 - 3.79 (m, 2H), 3.49 - 3.41 (m, 2H), 3.39 - 3.36 (m, 2H), 2.87 (s, 3H). MS (ESI) m / z 308.3 ([M + H] + ).

[0308] Example 29, 4 - ((1 - (2 - Trifluoromethylpyridin - 4 - yl) - 1H - indol - 4 - yl)methyl)morpholine

[0309]

[0310] 1 1H NMR (400 MHz, DMSO - d6) δ 8.89 (d, J = 5.4 Hz, 1H), 8.15 - 8.12 (m, 2H), 8.08 - 8.06 (m, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.78 - 7.70 (m, 1H), 7.43 - 7.32 (m, 2H), 4.65 (s, 2H), 3.96 - 3.82 (m, 4H), 3.34 - 3.11 (m, 4H). MS (ESI) m / z 362.4 ([M + H] + ).

[0311] Example 30, 4 - ((1 - (2 - Methoxypyridin - 4 - yl) - 1H - indol - 4 - yl)methyl)morpholine

[0312]

[0313] 1H NMR (400 MHz, DMSO - d6) δ 8.33 (d, J = 5.7 Hz, 1H), 7.96 (d, J = 3.5 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 7.3 Hz, 1H), 7.43 - 7.31 (m, 2H), 7.27 (d, J = 3.5 Hz, 1H), 7.10 (d, J = 1.9 Hz, 1H), 4.63 (s, 2H), 4.06 - 3.76 (m, 7H), 3.28 - 3.19 (m, 4H). MS (ESI) m / z 324.4 ([M + H] + ).

[0314] Example 33: 4-((1-(6-methylpyridin-3-yl)-1H-indol-4-yl)methyl)morpholine

[0315]

[0316] 1H NMR(400MHz, DMSO-d6)δ8.81(d, J = 2.7Hz, 1H), 8.30 - 8.26(m, 1H).7.86 - 7.71(m, 2H), 7.67(d, J = 8.2Hz, 1H), 7.46 - 7.30(m, 2H), 7.12(d, J = 3.5Hz, 1H)4.60(s, 2H), 3.68 - 3.56(m, 4H), 3.34 - 3.18(m, 4H), 2.65(s, 3H).MS(ESI)m / z 308.4([M + H] + ).

[0317] Example 35: 4-((1-(5-methylpyridin-2-yl)-1H-indol-4-yl)methyl)morpholine

[0318]

[0319] 1H NMR(400MHz, Methanol-d4)δ8.51(d, J = 2.1Hz, 1H), 8.20 - 8.08(m, 2H), 7.96 - 7.89(m, 1H), 7.81(d, J = 8.4Hz, 1H), 7.51(d, J = 7.2Hz, 1H), 7.47 - 7.39(m, 1H), 7.17(d, J = 3.5Hz, 1H), 4.71(s, 2H), 4.08 - 3.98(m, 2H), 3.88 - 3.76(m, 2H), 3.44(d, J = 12.3Hz, 2H), 3.40 - 3.32(m, 2H), 2.49(s, 3H).MS(ESI)m / z 308.4([M + H] + ).

[0320] Example 36: 4-((1-(5-trifluoromethylpyridin-2-yl)-1H-indol-4-yl)methyl)morpholine

[0321]

[0322] 1H NMR (400 MHz, Methanol-d4) δ 8.47 (d, J = 2.1 Hz, 1H), 8.20 (d, J = 8.2 Hz, 1H), 8.02 (dd, J = 8.4, 2.2 Hz, 1H), 7.92 (d, J = 3.4 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 7.3 Hz, 1H), 7.41 (t, J = 7.8 Hz, 1H), 7.13 (d, J = 3.4 Hz, 1H), 4.70 (s, 2H), 4.06 - 3.90 (m, 2H), 3.79 - 3.67 (m, 2H), 3.42 - 3.35 (m, 4H). MS(ESI) m / z 362.4 ([M+H] + ).

[0323] Example 37, 4 - ((1-(6 - trifluoromethylpyridazin - 3 - yl)-1H - indol - 4 - yl)methyl)morpholine

[0324]

[0325] 1 1H NMR (400 MHz, Chloroform - d) δ 8.63 (d, J = 8.3 Hz, 1H), 7.98 (d, J = 8.5 Hz, 1H), 7.87 (s, 2H), 7.64 (d, J = 7.1 Hz, 1H), 7.47 (t, J = 7.5 Hz, 1H), 7.19 (s, 1H), 4.53 (s, 2H), 4.41 - 4.21 (m, 2H), 4.02 - 3.86 (m, 2H), 3.48 - 3.28 (m, 2H), 3.04 - 2.88 (m, 2H). MS(ESI) m / z = 363.4 ([M+H]+).

[0326] Example 39, 4 - ((1-(2 - trifluoromethylpyrimidin - 5 - yl)-1H - indol - 4 - yl)methyl)morpholine

[0327]

[0328] 1H NMR (400 MHz, Methanol - d4) δ 9.30 (s, 2H), 7.87 (q, J = 2.7 Hz, 2H), 7.51 - 7.41 (m, 2H), 7.20 (dd, J = 3.5, 0.9 Hz, 1H), 4.71 (s, 2H), 4.08 - 3.72 (m, 4H), 3.48 - 3.32 (m, 4H).. MS(ESI) m / z 363.4 ([M+H] + ).

[0329] Example 42, 2-((1-(6-(trifluoromethyl)pyridin-3-yl)-1H-indol-4-yl)methyl)amino)ethyl)-1-ol

[0330]

[0331] 1 H NMR(400MHz, Methanol-d 4 )δ8.99(d, J = 2.5Hz, 1H), 8.28(dd, J = 8.5, 2.6Hz, 1H), 8.04(d, J = 8.5Hz, 1H), 7.80 - 7.72(m, 2H), 7.44 - 7.36(m, 2H), 7.08(d, J = 3.5Hz, 1H), 4.60(s, 2H), 3.86(dd, J = 6.2, 4.3Hz, 2H), 3.22(dd, J = 6.2, 4.4Hz, 2H). MS(ESI)m / z336.3.([M+H] + ).

[0332] Example 43, 2-(ethyl((1-(6-methylpyridin-3-yl)-1H-indol-4-yl)methyl)amino)ethyl)-1-ol

[0333]

[0334] 1 H NMR(400MHz, Chloroform-d)δ8.69(d, J = 2.6Hz, 1H), 7.72(dd, J = 8.2, 2.6Hz, 1H), 7.39(dd, J = 8.3, 1.0Hz, 1H), 7.33 - 7.28(m, 2H), 7.18(dd, J = 8.2, 7.2Hz, 1H), 7.12(dd, J = 7.1, 0.9Hz, 1H), 6.87(dd, J = 3.3, 0.9Hz, 1H), 3.93(s, 2H), 3.55(t, J = 5.3Hz, 2H), 2.72 - 2.67(m, 4H), 2.65(s, 3H), 1.15(t, J = 7.1Hz, 3H). MS(ESI)m / z = 310.4([M+H] + ).

[0335] Example 45, N-((1-(6-methylpyridin-3-yl)-1H-indol-4-yl)methyl)-2-(trifluoromethoxy)ethyl)-1-amine

[0336]

[0337] 11H NMR (400 MHz, Methanol-d 4 ) δ 9.10 (d, J = 2.5 Hz, 1H), 8.75 (dd, J = 8.7, 2.6 Hz, 1H), 8.10 (dd, J = 9.0, 3.2 Hz, 1H), 7.85 - 7.77 (m, 2H), 7.50 - 7.40 (m, 2H), 7.15 (d, J = 3.4 Hz, 1H), 4.65 (s, 2H), 4.47 - 4.39 (m, 2H), 3.57 - 3.49 (m, 2H), 2.89 (s, 3H). MS (ESI) m / z 350.4 ([M+H] + ).

[0338] Example 46, 2 - ((1 - (6 - methylpyridin - 3 - yl) - 1H - indol - 4 - yl)methyl)amino)ethyl - 1 - ol

[0339]

[0340] 1 1H NMR (400 MHz, Methanol - d4) δ 9.09 (d, J = 2.4 Hz, 1H), 8.76 (dd, J = 8.7, 2.5 Hz, 1H), 8.11 (d, J = 8.7 Hz, 1H), 7.85 - 7.73 (m, 2H), 7.48 - 7.37 (m, 2H), 7.14 (d, J = 3.4 Hz, 1H), 4.60 (s, 2H), 3.92 - 3.79 (m, 2H), 3.32 - 3.18 (m, 2H), 2.89 (s, 3H). MS (ESI) m / z 282.4 ([M+H] + ).

[0341] Example 47 : 4 - methyl - 1 - ((1 - (pyrimidin - 2 - yl) - 1H - indol - 4 - yl)methyl)piperidin - 4 - ol

[0342]

[0343] 1 1H NMR (400 MHz, Methanol - d4) δ 8.99 - 8.94 (m, 1H), 8.81 (d, J = 4.8 Hz, 2H), 8.46 (d, J = 3.8 Hz, 1H), 7.47 - 7.40 (m, 2H), 7.27 (t, J = 4.8 Hz, 1H), 7.08 - 7.03 (m, 1H), 4.64 (s, 2H), 3.50 - 3.34 (m, 4H), 1.91 - 1.73 (m, 4H), 1.27 (s, 3H). MS (ESI) m / z 323. ([M+H] +).

[0344] Bioactivity Examples:

[0345] The in vitro affinities of certain representative compounds of the present invention for sigma (σ-1 and σ-2) binding sites were tested. The specific test protocol is as follows:

[0346] Preparation of Test Compound : All test samples were dissolved in DMSO with a final concentration of 1%. If the dissolution was poor or the suspension was uneven, HCl (10%, 10 μL) was appropriately added. The starting concentration was 1.0×10 -5 M (i.e., 10 μM), and then successively 1 μM, 333 nM, 100 nM, 33 nM, 10 nM, 3.3 nM, 1 nM, 0.33 nM, 0.1 nM, 0.01 nM, and stored for use.

[0347] sigma-1 Receptor Binding Activity Test:

[0348] Preparation of Receptor Membrane : Guinea pig whole brain was homogenized with 10 mM Tris-HCl buffer containing 320 mM sucrose at pH = 7.4, the weight was adjusted, centrifuged at 1000 g for 10 min, the supernatant was taken and homogenized with 10 mM Tris-HCl buffer containing 320 mM sucrose at pH = 7.4, then centrifuged at 1000 g at 4 °C for 10 min, the supernatant was taken, centrifuged at 50000 g at 4 °C for 25 min again, the precipitate was taken and homogenized with 10 mM Tris-HC buffer without sucrose at pH = 7.4, centrifuged at 50000 g at 4 °C for 25 min, the precipitate was taken and the above operation was repeated. Finally, the precipitate was stored at -80 °C for use.

[0349] Binding Assay : The prepared receptor membrane was made into a suspension of 220 mg / ml membrane with 10 mM Tris-HCl buffer without sucrose at pH = 7.4 and stored for use. 100 μL of the membrane preparation was added to each reaction tube. 100 μL of 10 mM Tris-HC buffer without sucrose at pH = 7.4 was added to the total binding tube (TB), 100 μL of haloperidol (final concentration 1.0×10 -5 M) was added to the non-specific binding tube (NB), and 100 μL of the test compound was added to each test compound tube (CB). 4 nM of the radioactive ligand was added to all reaction tubes 310 μL of [H]-Pentazocine. Incubate each reaction tube at 25 °C for 135 min. After the reaction is complete, the bound ligand is rapidly filtered under reduced pressure. Whatman GF / C filter paper is pre-soaked in 0.5% PEI for more than 1 h, washed thoroughly with ice-cold assay buffer, the filter is taken out and placed in a 4 mL scintillation vial, 1 mL of toluene scintillation fluid is added and mixed well. Finally, the scintillation vial is placed in a HIDEX liquid scintillation counter for counting.

[0350] sigma-2 receptor binding activity assay

[0351] Preparation of Receptor Membrane : The same as the above method for preparing σ-1 receptor membranes.

[0352] Binding Assay : Prepare the prepared receptor membranes into a 220 mg / mL membrane suspension with 10 mM Tris-HCl buffer without sucrose for standby. Add 100 μL of the membrane preparation to each reaction tube, add 100 μl of 10 mM Tris-HC buffer without sucrose at pH 7.4 to the total binding tube (TB), and add 100 μL of DTG (final concentration 1.0×10 -5 M) to the non-specific binding tube (NB). Add 100 μL of the test compound (final concentration 1.0×10 -5 M) to each test compound binding tube (CB); add 10 μL of the radioactive ligand 3 [H]-DTG to each reaction tube, with a final concentration of 5 nM. Incubate each reaction tube at 25 °C for 135 min. After the reaction is complete, the bound ligand is rapidly filtered under reduced pressure. Whatman GF / C filter paper is soaked in 0.5% PEI for more than 1 h, washed thoroughly with ice-cold assay buffer, the filter is taken out and placed in a 4 mL scintillation vial, 1 mL of toluene scintillation fluid is added and mixed well. Finally, the scintillation vial is placed in a Finnish HIDEX liquid scintillation counter for counting.

[0353] Calculation of Ki value:

[0354] Calculate the IC50 of each compound by the logit method;

[0355] Obtain the Kd value and Bmax of each radioactive ligand by Scatchard plotting;

[0356] Use the Cheng and Prusoff equation (Cheng Y, Prusoff WH, 1973, Biochem Pharmacol. 22(23)) to convert the obtained IC50 value into the Ki value. The experimental results of some compound tests are shown in Table 2. N / A and "--" in the following table indicate not measured:

[0357] Table 2

[0358]

[0359]

[0360] ICR Mouse Morphine Synergistic Test

[0361] Male mice weighing between 18 - 22 g were used. The room temperature was about 25 °C. The hot plate temperature was set at 55 °C, and the maximum thermal pain threshold was set at 60 s. The time from placement until licking the hind paw or jumping was recorded as the pain threshold. All mice were first measured for the basal pain threshold twice. Mice with a basal pain threshold of 5 - 30 s were considered qualified, and unqualified mice were excluded.

[0362] The qualified mice were randomly divided into a vehicle control + morphine group (1.25, 2.5, 5, 10 mg / kg), an E52862 (40 mg / kg) + morphine (1.25, 2.5, 5, 10 mg / kg) group, and a compound 1 (20 m / kg) + morphine (1.25, 2.5, 5, 10 mg / kg) group according to the basal pain threshold. Morphine in all test groups was administered subcutaneously, E52862 (4 - [-2 - [[5 - methyl - 1 - (2 - naphthyl) - 1H - pyrazol - 3 - yl]oxy]ethyl]morpholine synthesized according to reference J.Med.Chem.2012, 55, 8211 - 8224) and compound 1 were administered intraperitoneally (the administration volume was 0.1 ml / 10 g). The pain threshold was measured 0.5 h after drug administration, and the possible maximum analgesic effect (MPE%) of the test compound was calculated: MPE% = (after administration - before administration) / (60 - before administration) × 100%.

[0363] The results are shown in Table 3 below:

[0364] Table 3. Analgesic Results of Mouse Hot Plate Experiment

[0365]

[0366] The results of the ICR mouse hot plate model test showed that when morphine was used in combination with compound 1 or E52862, compared with morphine alone, the ED 50 could be reduced. Compound 1 could significantly reduce the morphine dosage, and the synergistic effect reached 1.5 - fold. The positive compound E - 52862 could significantly reduce the morphine dosage, and the synergistic effect reached 1.9 - fold. It was indicated that in this model, the combination group of compound 1 and morphine could enhance the morphine efficacy, achieving an effect equivalent to that of the positive drug E52862.

[0367] Formalin Test

[0368] The specific operations are as follows: Normal saline was used as the solvent, and intraperitoneal injection was administered respectively. The administration volume of the administration group was 5 ml / kg. The administration time of the test drug was 15 min before the modeling test. Before the experimental test, after administration, the rats had to adapt to the experimental device for 5 - 10 min. After adaptation, 100 μL of 5% formalin solution (containing 1.85% formaldehyde) was subcutaneously injected into the right hind foot dorsum of the rats for modeling. The successful standard of the model was the formation of a skin papule. If the injected foot bled, the animal was discarded. The software automatically recorded the number of times the foot was lifted at 1 - minute intervals between 0 - 60 min after modeling.

[0369] Data analysis: Phase I, 0 - 10 min, Phase II, 10 - 60 min. The t - test was used to detect the statistical differences between groups. The analgesic effect was expressed as the inhibition rate. Inhibition rate % = (licking and biting times of the solvent group - licking and biting times of the administration group) / licking and biting times of the solvent group × 100%. The analgesic effect was the inhibition rate %, and the larger the value, the better the analgesic effect.

[0370] The results are shown in Table 4 below:

[0371] Table 4: Inhibition rate of formalin experiment

[0372]

[0373] The results showed that the positive compound E52862 (160 mpk) and the above - mentioned compound of the present invention (80 mpk) were effective in this model; moreover, the compound of the present invention also showed efficacy in Phase I pain, indicating that the compound had analgesic effects on both acute pain and inflammatory pain.

[0374] Rat sciatic nerve ligation (CCI) - induced neuropathic pain model

[0375] Male SPF - grade SD rats were used in the experiment. 14 days before administration, the sciatic nerve of the rats was ligated surgically to establish a sciatic nerve ligation - induced neuropathic pain model. The test animals were administered intraperitoneally. 30 min and 60 min after administration, the rats were placed in a transparent plexiglass box with a wire mesh at the bottom with a pore size of 0.5 cm × 0.5 cm. They were allowed to adapt for 10 min before the experiment. A stainless - steel wire with a diameter of 0.5 mm was used with a dynamic tactile pain tester to vertically stimulate the middle of the plantar surface of the right hind limb on the surgical side, and pressure was applied slowly until the rat lifted its foot or licked its foot. This force was the mechanical paw withdrawal threshold (PWT). Each stimulation was completed within 10 s, and the maximum value was 40 g. It was measured 2 - 3 times, and the average value was taken to calculate the maximum analgesic effect after administration. The t - test was used to detect the statistical differences between groups. Maximum analgesic effect % = (PWT after administration - PWT before administration) / (PWT of the blank group - PWT before administration) × 100%.

[0376] The results are shown in Table 5, indicating that after a single administration of Compound 1, it has a rapid onset of action. In the medium-dose and high-dose groups, it can significantly relieve the neuropathic pain caused by sciatic nerve ligation in rats at 0.5 and 1 hour after administration. And during the experiment, no side effects such as tremors, lateral recumbency, inability to get up, or excitement were found in the experimental group (Compound 1 group) of mice, indicating that the mice have good tolerance to the test compound.

[0377] Table 5. Inhibition rate of neuropathic pain induced by sciatic nerve ligation (CCI) in rats

[0378]

[0379] The sham operation group means that the skin of the rat is only incised and then sutured, without surgically ligating the sciatic nerve of the rat.

[0380] The blank group means that the solvent is used to replace the drug.

[0381] Using the same test method, the inhibition rates of Compound 28, Compound 33, Compound E52862, and Compound C020 (Compound EP003-D5-C020 described in Example 8 of CN202011345740.0, abbreviated as C020, 4-((1-(quinolin-6-yl)-1H-indol-4-yl)methyl)morpholine hydrochloride ) in the CCI-induced neuropathic pain experiment were tested. The test results showed that Compound 28 and Compound 33 demonstrated good pharmacodynamic effects in the rat sciatic nerve pain (CCI) experiment. At the dosage of 80 mg / kg, the inhibition rates at 1 h were 67% and 81.7% respectively, and there were significant differences. While for E52862 and C020 at the dosage of 80 mg / kg, the inhibition rates at 1 h were only 35.4% and 16.1% respectively.

[0382] Oxaliplatin-induced chemotherapy-induced neuropathic pain (OINP)

[0383] Male SPF-grade SD rats were used in the experiment to establish a chemotherapy-induced neuropathic pain model induced by oxaliplatin. 30 minutes after intraperitoneal administration of the rats, the rats were placed on a cold plate covered with a cylindrical plexiglass with a surface temperature of 5 °C, and the stopwatch was immediately started. The latency of the cold pain threshold of the rats was recorded by the double-blind method. Each rat was measured once in a single test, and the cut-off time was 120 s. The criteria for judging the manifestation of cold-induced pain in rats were obvious foot lifting, foot licking, rapid foot shaking, and jumping. The cold pain threshold 30 minutes after a single administration was recorded. One-way ANOVA test was used to detect the statistical differences between groups. Maximum analgesic effect (MPE)% = (pain threshold of the administration group - pain threshold of the model group) / (pain threshold of the blank group - pain threshold of the model group) * 100%.

[0384] The results are shown in Table 6, indicating that after administration of Compound 1, the low, medium, and high-dose groups can all relieve oxaliplatin-induced chemotherapy-induced neuralgia.

[0385] Table 6. Inhibition rate of oxaliplatin-induced chemotherapy-induced neuralgia experiment

[0386]

[0387] Taking Compound 28 and Compound 33 of the present invention as examples below, the safety of the compounds of the present invention was evaluated.

[0388] Withdrawal test

[0389] Test objective: To establish a mouse physical dependence - mouse jumping experiment model, and at the same time determine the effects of Compound 28 and Compound 33 after multiple administrations and injection of naloxone antagonist on withdrawal symptoms such as mouse jumping and weight loss.

[0390] The specific operation is as follows: ICR mice (SPF grade), male, were randomly divided into 4 groups, with 10 mice in each group. They were intraperitoneally injected (i.p.) with increasing doses continuously for 7 times within 2 days, and the drug doses were administered in sequence as follows: 10, 20, 30, 40, 60, 80, 80 mg / kg; positive control (morphine group), intraperitoneally injected (i.p.) with morphine injection at 5, 10, 20, 30, 40, 50, 50 mg / kg; solvent group (pure water), intraperitoneally injected (i.p.) with an equal volume of pure water. After 2 hours of the last administration, each mouse in the above groups was intraperitoneally injected (i.p.) with 10 mg / kg of naloxone hydrochloride, and then the incidence and number of mouse jumps within 10 minutes and the weight change of the mice after 1 hour were recorded.

[0391] Experimental results:

[0392] Morphine group (5 - 50 mg / kg i.p.): After morphine-dependent mice were urged to withdraw by naloxone, the withdrawal symptoms were obvious, among which the number of jumping reactions was high, and there was a significant difference compared with the solvent group; after being urged to withdraw by naloxone, the weight change was not obvious, and there was no significant difference compared with the solvent group;

[0393] Compound 28 and Compound 33 groups (10 - 80 mg / kg i.p.), after drug-dependent mice were urged to withdraw by naloxone, the withdrawal symptoms were not obvious, the number of jumping reactions had no significant difference compared with the solvent group, and in terms of weight loss, there were no significant changes before and after withdrawal in the solvent group and all drug administration groups.

[0394] Specifically as shown in the following table:

[0395]

[0396] Conclusion: According to the results of this experiment, neither compound 28 nor compound 33 produced obvious somatic withdrawal reactions in mice.

[0397] Rotarod test

[0398] Purpose of the test: The rotarod test is often used to examine the effects of drugs on the motor coordination ability and muscle relaxation of animals, reflect the inhibitory effect of drugs on the central nervous system, preliminarily evaluate the safety of drugs, and provide reference for the development of long-term toxicity tests of drugs.

[0399] The specific operation is as follows: One day before the experiment, a preliminary screening of the rotarod test was carried out. The rotation speed of the rotarod for ICR mice (SPF grade) was set at a constant speed of 25 rpm / min. Five mice were placed on a rotarod with a diameter of 3 cm. The rotarod was started. If a mouse fell during the experiment, it was placed on the rod again. Each training lasted for 5 minutes, and the training was carried out continuously for 3 times. The interval between two trainings was more than 20 minutes as the fatigue recovery time. After the 3rd time the mouse was placed on the rod, the time the mouse stayed on the rod was recorded. Mice with a stay time of less than 5 minutes, holding the axis motionless, jumping, and poor body coordination ability were excluded. After screening, the qualified mice were re-grouped. The experiment was carried out under the air-conditioned room temperature conditions of 22 - 24 °C. After each group of mice was administered the drug, the drop latency within 4 minutes at 0.5 h, 1 h, and 2 h after administration was measured;

[0400] The experimental results are shown in the following table

[0401]

[0402] Conclusion: Compound 28 at a high dose (128 mpk) had motor disorders at 0.5 h and 1 h after administration and returned to normal at 2 h after administration; compound 33 at a high dose (128 mpk) had slight motor disorders at 0.5 h and 1 h after administration, but there was no significant difference compared with the blank group; it returned to normal at 2 h after administration; after compound 28 and compound 33 were administered at medium dose (64 mpk) and low dose (32 mpk), there were no obvious motor disorders and no significant difference compared with the blank group.

[0403] Compound C020 and compound E52862 were tested in the same way. The test results showed that in the high-dose groups of compound E52862 and compound C020, motor disorders occurred in the rotarod test after administration; among them, in the medium-dose and high-dose groups (64 & 128 mpk) of compound C020, the motor function was affected in the rotarod test within 0.5 - 3 h after administration.

[0404] The above test results show that the compounds provided by the present invention have less side effects on the motor coordination of mice and have good safety.

Claims

1. A compound of the general formula (I) or a pharmaceutically acceptable salt thereof: R 2 selected from any one of hydrogen, C1-C3 haloalkyl, and C1-C4 straight-chain or branched alkyl; R 3 selected from any one of the following structures: R 9 any one selected from hydrogen, C1-C3 haloalkyl, and C1-C4 straight-chain or branched alkyl; R 13 、R 14 are independently selected from any one of hydrogen, C1-C3 haloalkyl, C1-C4 straight-chain or branched alkyl, and C3-C6 cycloalkyl; n1 is 0, 1, 2, 3 or 4; n2, n3, n4, n5 are each independently 1 or 2; R 1 Independently selected from any one of the following structures: wherein, R 4 selected from hydrogen, -NH 2 , halogen, C1-C3 alkoxy, -OH, C1-C3 haloalkyl, C1-C4 straight or branched alkyl, -CHNOCH 3 ; any one of them R 5 selected from hydrogen, -NH 2 , halogen, C1-C3 alkoxy, -OH, C1-C3 haloalkyl, C1-C4 straight or branched alkyl, -CHNOCH 3 ; any one of them R 6 selected from any one of hydrogen, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C4 straight-chain or branched alkyl, -CHNOCH 3 ; R 7 selected from any one of hydrogen, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C4 straight-chain or branched alkyl, -CHNOCH 3 ; R 8 selected from hydrogen, -NH 2 , halogen, C1-C3 alkoxy, -OH, C1-C3 haloalkyl, C1-C4 straight-chain or branched alkyl, -CHNOCH 3 ; any one of them R 10 Selected from hydrogen, -NH 2 , halogen, C1-C3 alkoxy, -OH, C1-C3 haloalkyl, C1-C4 straight-chain or branched alkyl, -CHNOCH 3 ; any one of them R 11 selected from hydrogen, -NH 2 , halogen, C1-C3 alkoxy, -OH, C1-C3 haloalkyl, C1-C4 straight-chain or branched alkyl, -CHNOCH 3 ; any one of them R 12 selected from hydrogen, -NH 2 , halogen, C1-C3 alkoxy, -OH, C1-C3 haloalkyl, C1-C4 straight-chain or branched alkyl, -CHNOCH 3 any one of them.

2. The compound of the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein, R 4 independently selected from hydrogen, -NH 2 , halogen, C1-C3 alkoxy, -OH, C1-C3 haloalkyl, C1-C4 straight or branched alkyl 3. The compound of the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein, R 5 independently selected from halogen, -CHNOCH 3 any one of them.

4. The compound of the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein, R 6 independently selected from hydrogen, C1-C4 straight-chain or branched alkyl groups.

5. The compound of the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein, R 7 independently selected from hydrogen, C1-C4 linear or branched alkyl groups.

6. The compound of the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein, R 8 Any one selected from hydrogen, haloalkyl having 1 to 3 carbon atoms, and linear or branched alkyl having 1 to 4 carbon atoms.

7. The compound of the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein, R 10 Any one selected from hydrogen, haloalkyl having 1 to 3 carbon atoms, and linear or branched alkyl having 1 to 4 carbon atoms.

8. The compound of the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein, R 11 Any one selected from hydrogen, haloalkyl having 1 to 3 carbon atoms, and linear or branched alkyl having 1 to 4 carbon atoms.

9. The compound of the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein, R 12 Any one selected from hydrogen, C1-C3 haloalkyl, and C1-C4 straight-chain or branched alkyl.

10. A compound of the general formula (I) or a pharmaceutically acceptable salt thereof: wherein: R 1 selected from any one of the following structures: R 2 Any one selected from hydrogen, C1-C4 straight-chain or branched alkyl; R 3 selected from any one of the following structures: n1 is 0, 1, 2, 3 or 4; R 4 selected from any one of hydrogen, -NH 2 , -OH, haloalkyl having 1 to 3 carbon atoms, and linear or branched alkyl having 1 to 4 carbon atoms; R 5 selected from any one of halogen, -CHNOCH 3 ; R 6 、R 7 each independently represents a C1-C4 straight-chain or branched-chain alkyl group; R 8 Any one selected from hydrogen, C1-C4 straight-chain or branched alkyl; R 9 Any one selected from haloalkyl groups having 1 to 3 carbon atoms and linear or branched alkyl groups having 1 to 4 carbon atoms; n2, n3, n4, n5 are each independently 1 or 2.

11. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein: wherein R 1 is selected from any one of the following structures: R 4 any one selected from hydrogen, halogen, C1-C3 alkoxy, C1-C3 haloalkyl, and C1-C4 straight-chain or branched alkyl; R 5 Any one selected from hydrogen and halogen; R 2 Any one selected from hydrogen, C1-C4 linear or branched alkyl; R 3 selected from any one of the following structures: R 9 any one selected from hydrogen, C1-C3 haloalkyl, and C1-C4 straight-chain or branched alkyl; R 13 Selected from any one of hydrogen, C1-C4 straight-chain or branched alkyl groups; R 14 any one selected from hydrogen and haloalkyl having 1 to 3 carbon atoms; n1 is 0 or 1; n2, n3, n4, n5 are each independently 1 or 2.

12. The compound of the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 11, wherein, R 4 Any one selected from hydrogen, methoxy, ethoxy, trifluoromethyl, methyl, and ethyl.

13. The compound of the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 11, wherein, R 5 Selected from fluorine.

14. The compound of the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 11, wherein, R 2 Any one selected from hydrogen, methyl, and ethyl.

15. The compound of the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 11, wherein, R 9 Selected from hydrogen, methyl or ethyl.

16. The compound of the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 11, wherein, R 9 Selected from methyl.

17. The compound of the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 11, wherein, R 13 Selected from hydrogen, methyl or ethyl.

18. The compound of the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 11, wherein, R 14 Selected from hydrogen or trifluoromethyl.

19. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein: wherein R 1 is selected from any one of the following structures: R 4 is selected from any one of hydrogen, C1-C3 haloalkyl, and C1-C4 linear or branched alkyl; R 2 selected from hydrogen or methyl; R 3 selected from any one of the following structures: R 9 selected from any one of hydrogen, C1-C4 straight-chain or branched alkyl groups; R 13 Selected from any one of hydrogen, C1-C4 straight-chain or branched alkyl groups; R 14 selected from hydrogen, trifluoromethyl; n1 is 0; n2, n3 are each independently 1 or 2; n4, n5 are each independently 1.

20. The compound of the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 19, wherein, R 4 Selected from hydrogen, trifluoromethyl or methyl.

21. The compound of the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 19, wherein, R 3 For 22. The compound of the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 19, wherein, R 9 Selected from methyl.

23. The compound of general formula (I) as defined in claim 19 or 21, or a pharmaceutically acceptable salt thereof, characterized in that, R 13 selected from hydrogen or ethyl.

24. The compound of general formula (I) as defined in claim 19 or 21, or a pharmaceutically acceptable salt thereof, characterized in that, R 14 Selected from hydrogen.

25. The compound or a pharmaceutically acceptable salt thereof as defined in any one of claims 1-2, 6-11 or 19, characterized in that: The C1-C3 haloalkyl groups are independently selected from -(CH 2 ) a CX 3 , -(CH 2 ) a CHX 2 , -(CH 2 ) a CH 2 X, where a is independently 0, 1 or 2, and X is independently any one of F, Cl, Br, I; The C1-C4 straight-chain or branched-chain alkyl group is independently selected from any one of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl; The halogen is independently selected from any one of F, Cl, Br, I; n1 is 0 or 1.

26. The compound or a pharmaceutically acceptable salt thereof as defined in any one of claims 1-2, 6-11 or 19, characterized in that, The halogen is F; the C1-C3 haloalkyl group is -CF 3 .

27. The compound or a pharmaceutically acceptable salt thereof as defined in claim 25, characterized in that, The halogen is F; the C1-C3 haloalkyl group is -CF 3 .

28. The compound or a pharmaceutically acceptable salt thereof as defined in claim 11, characterized in that, selected from any one of the following compounds:

29. The compound or a pharmaceutically acceptable salt thereof as defined in claim 1, characterized in that, selected from any one of the following compounds:

30. A method for preparing the compound of general formula (I) as defined in claim 10 or a pharmaceutically acceptable salt thereof, which is selected from one of the following methods: a) A method comprising subjecting a compound of formula (II) and a compound of formula (III) to a C-N coupling reaction to provide the structure shown in formula (IV), wherein R1 is as defined in claim 10; b) A method comprising introducing a general formula compound (V), (VI) or (VII) at the nitrogen terminus of R 3 -H through reductive amination or substitution reaction wherein R 1 、R 2 、R 3 、n1 are as defined in claim 10.

31. A method for preparing the compound or a pharmaceutically acceptable salt thereof as defined in claim 1, said method comprises: Reacting compound V with (methoxymethyl)triphenylphosphonium chloride under basic conditions to obtain compound a04a, and subjecting compound a04a to a hydrolysis reaction under acidic conditions to obtain compound VI: Or reacting compound V with a Grignard reagent first, and then reacting with thionyl chloride to obtain compound VII: Introduce the general formula compounds (V), (VI) or (VII) at the nitrogen terminus of R-H through reductive amination or substitution reaction: 3 ​ wherein, R 1 , R 2 , R 3 , and n1 are as defined in claim 1.

32. A pharmaceutical composition, characterized in that, comprises a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof as defined in any one of claims 1-29 and a pharmaceutically acceptable carrier.

33. Use of the compound or a pharmaceutically acceptable salt thereof as defined in any one of claims 1-29 or the pharmaceutical composition as defined in claim 32 in the manufacture of a medicament for the treatment and / or prevention of diseases mediated by sigma receptors.

34. The use as defined in claim 33, characterized in that, the diseases mediated by sigma receptors are selected from pain.

35. The use as defined in claim 34, characterized in that, the pain is neuropathic pain, neuralgia, cancer pain, inflammatory pain, interstitial cystitis, bladder pain, allodynia, burning pain, hyperalgesia, sensory hypersensitivity, hyperpathia, neuritis or neuropathy secondary to surgery.

36. A composition comprising at least one compound as described in any one of claims 1-29 or a pharmaceutically acceptable salt thereof and an opioid receptor drug, said composition being administrable simultaneously, separately or sequentially for treating and / or preventing sigma receptor-mediated related diseases.

37. The composition according to claim 36, wherein, the sigma receptor-mediated related diseases are selected from pain.

38. The composition according to claim 37, wherein, the pain is neuropathic pain, neuralgia, cancer pain, inflammatory pain, interstitial cystitis, bladder pain, allodynia, burning pain, hyperalgesia, sensory hypersensitivity, hyperpathia, neuritis or neuropathy secondary to surgery.

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