CN113024435B

CN113024435B - Linbicyclic structure sigma-1 receptor inhibitors

Info

Publication number: CN113024435B
Application number: CN202011345740.0A
Authority: CN
Inventors: 陈科; 蒋钰; 季明华; 王小华; 金雪梅; 张长青; 万泽红
Original assignee: Suzhou Enhua Biomedical Technology Co ltd
Current assignee: Suzhou Enhua Biomedical Technology Co ltd
Priority date: 2019-12-09
Filing date: 2020-11-25
Publication date: 2022-06-17
Anticipated expiration: 2040-11-25
Also published as: CN114702428B; CN114702428A; CN117447376A; CN113024435A

Abstract

The invention relates to the field of chemical medicine, in particular to a sigma-1 receptor inhibitor with a double-ring structure. Specifically provided is a compound with a unique structure and a double ring structure, which has good affinity and selectivity of sigma 1 receptor and is a strong selective inhibitor of sigma 1 receptor. The compound with the double-ring structure has a basic group structure with double aromatic rings, and the inclined symmetrical positions of the opposite sides of the middle aromatic double ring are respectively substituted by another double aromatic ring and alkylamine directly connected with the aromatic rings.

Description

Linbicyclic structure sigma-1 receptor inhibitors

Technical Field

The invention relates to the field of chemical medicine, in particular to a sigma-1 receptor inhibitor with a double-ring structure.

Background

The Sigma-1 receptor (Sigma 1 receptor) is an emerging drug target in recent years, is a binding protein of various specific central nervous system drugs, and plays a physiological role as a receptor type molecular chaperone. The main physiological functions of sigma-1 receptors in the central nervous system include analgesia, nerve protection, cognitive regulation, drug addiction improvement, dyskinesia and the like, while peripheral sigma-1 receptors are involved in regulating the immune function of the body.

Sigma 1 receptors are highly expressed in both central nervous system and peripheral nerves, and are mainly distributed in cell membranes, Endoplasmic Reticulum (ER) membranes and mitochondrial membranes in central nerves, and mainly distributed in lymphoid tissues, lung, liver, kidney, pancreas, spleen, adrenal gland, and heart, etc. in peripheral nervous system.

Sigma receptors have no homology with opioid receptors, and there are two subtypes, σ 1 and σ 2. They bind to ligands in a very unique way: the affinity of the sigma 1 receptor to dextrorotatory medicaments is stronger than that of levorotatory medicaments; the affinity of sigma 2 receptors for levorotary drugs is higher than for dextrorotary drugs. SKF10047 has nanomolar affinity for the σ 1 site and micromolar affinity for the σ 2 site.

The sigma-1 receptor (sigma 1 receptor) was successfully cloned in 1996 as a 29-kDa single-chain protein containing 223 amino acid residues with a relative molecular weight of 26000. The active binding site of the Sigma-1 receptor protein is primarily in the amino acid chain from amino acid 116 to amino acid 223, and the hydrophobic portion of the long chain C-terminus often binds the Sigma-1 receptor ligand in conjunction with one or both of the two hydrophobic transmembrane portions.

σ 1 is a ligand-regulated chaperone that exerts its chaperone effects by interacting with NMDA and opioid receptors. Under normal physiological conditions, the sigma-1 receptor is present in an inactive state in the mitochondrially-associated endoplasmic reticulum membrane, which forms Ca with another chaperone glucose regulator protein 78(GRP78), also known as immunoglobulin heavy chain binding protein (Bip)²⁺A sensitive complex. In pathological conditions, σ 1 and Bip segregate, dissociate into the cytoplasm and cell membrane, and bind to other proteins, and participate in the regulation of a variety of physiological functions. When Ca is in ER²⁺When concentration is reduced or a specific agonist acts on the sigma 1 receptor, the sigma 1 receptor is separated from the Bip and activated, redistributed to a cell membrane lipid raft, regulates ion channels, protein kinases and G Protein Coupled Receptors (GPCRs), and starts a plurality of downstream signal transduction pathways. The Sigma-1 receptor may exert its physiological effects by the following mechanisms: after the sigma 1 receptor is separated from the Bip, the receptor becomes an excited state, is redistributed and is combined with the IP3 receptor to stabilize the IP3 receptor and cause intracellular Ca²⁺By means of voltage-gated ion channels into mitochondria, tricarboxylic acid cycle in mitochondria is initiatedThe ring promotes cell metabolism, thereby having neuroprotective and axon growth promoting effects.

The physiological functions of the sigma-1 receptor (sigma 1 receptor) mainly include analgesia, nerve protection, cognitive regulation, drug addiction improvement and dyskinesia improvement. From biological and functional studies of the sigma receptor, there has been evidence that sigma receptor ligands may be useful in the treatment of psychiatric disorders (such as schizophrenia, depression, anxiety, etc.) and neurological disorders (such as alzheimer's disease, pain, etc.) and dyskinesias such as dystonia and tardive dyskinesia, dyskinesias associated with huntington's chorea or tourette's syndrome, and parkinson's disease. The known sigma receptor ligand, lincarbazol, has been reported to show clinical efficacy in the treatment of psychosis. The sigma binding site has preferential affinity for the dextrorotatory isomers of certain opiate benzomorphanes such as SKF10047, (+) -cycloxazine and (+) -tebuconazole and certain narcolepsy such as haloperidol.

Currently, the prior art discloses different ligands for sigma receptors. Wherein patent WO2012072791 discloses the structure of sigma receptor analogues and CNS-related disease uses; however, these structures are not the same as the structures of this patent.

In view of the potential applications of sigma receptor antagonists or agonists in the CNS field of pain, psychic, etc., it is of great importance for clinical applications to find compounds with potent and selective pharmacological activity at the sigma 1 receptor and with good "pharmaceu-tical properties", i.e. good pharmaceutical properties related to administration, distribution, metabolism and excretion.

Summary of The Invention

The present invention has been made to solve at least one of the technical problems occurring in the prior art, and therefore it is an object of the present invention to provide a structurally unique bicyclic structure compound, which has good affinity and selectivity for sigma 1 receptor, and is a strong selective inhibitor of sigma 1 receptor. The compound has a basic group structure of a connected double aromatic ring, and the opposite oblique symmetrical positions of the middle aromatic double ring are respectively substituted by another double aromatic ring and alkylamine directly connected with the aromatic ring.

In one aspect, the invention relates to a compound represented by formula I or a pharmaceutically acceptable salt thereof:

formula I is a structure of formula VI, VI-1, VII, or VIII,

wherein, in the structures VI and VI-1, Z₁、Z₂、Z₃W is independently selected from N or C; VII Structure and VIII Structure in which K₁、K₂、K₃、K₄、K₅、K₆Independently selected from N or C; key with a key body

Is a key

Or none of them;

wherein A is substituted or unsubstituted naphthyl, formula II-1, formula III, formula IV, or formula V, the substituents of the substituted naphthyl being selected from substituted or unsubstituted C1-5 alkyl and halogen; the substituent of the substituted C1-5 alkyl is selected from halogen;

the structures of formulas II-1, III, IV and V are as follows:

in the formula II-1, Q₁、Q₂、Q₃、Q₄、Q₅、Q₆Independently selected from N or C;

in the formula IV, R₄Is alkyl, in the formula V, R₅Is alkyl, in the formula III, R₁₀Is an alkyl group;

b is the IX structure:

in formula IX, n1 is an integer from 0 to 3, n2 is an integer from 0 to 6; z₄C, O, S or N; z₅Is selected from O or CH₂Or CR₈R₉；R₂、R₃Independently selected from hydrogen, haloalkyl, hydroxy, alkyl, cycloalkyl, amide; r is₈And R₉Independently selected from hydrogen, haloalkyl, hydroxy, alkyl, cycloalkyl, and R₈And R₉Not hydrogen at the same time.

Further, the present invention relates to a compound represented by formula I or a pharmaceutically acceptable salt thereof:

formula I is a structure of formula VI, VII, or VIII,

wherein in the structure VI, Z₁、Z₂、Z₃W is independently selected from N or C; VII Structure and VIII Structure in which K₁、 K₂、K₃、K₄、K₅、K₆Independently selected from N or C; key with a key body

Is a key

Or none of them;

wherein A is substituted or unsubstituted naphthyl, formula II, formula IV, or formula V, and the substituent of the substituted naphthyl is selected from C1-5 alkyl or halogen;

the structures of the formulas II, IV and V are as follows:

in the formula II, Q₁、Q₂、Q₃、Q₄、Q₅Independently selected from N or C;

in the formula IV, R₄Is alkyl, in the formula V, R₅Is an alkyl group;

b is the IX structure:

in formula IX, n1 is an integer from 0 to 3, n2 is an integer from 0 to 6, Z₄C, O, S or N; z is a linear or branched member₅Is selected from O or CH₂Or CR₈R₉；R₂、R₃Independently selected from hydrogen, haloalkyl, hydroxy, alkyl, cycloalkyl, amide; r₈And R₉Independently selected from hydrogen, haloalkyl, hydroxy, alkyl, cycloalkyl, and R₈And R₉Not hydrogen at the same time. Preferably, in formula IX, n1 is an integer from 0 to 3, n2 is an integer from 0 to 4, Z₄C, O or S; z₅Is selected from O or CH₂；R₂、R₃Independently selected from hydrogen, haloalkyl, hydroxy, alkyl, amide.

Further, the compound of formula I or a pharmaceutically acceptable salt thereof has the structure of formula VI:

wherein Z is₁、Z₂、Z₃W is independently selected from N or C;

wherein A is substituted or unsubstituted naphthyl, formula II, formula IV or formula V, and the substituent of the substituted naphthyl is C1-5 alkyl or halogen;

the structures of formulas II, IV and V are as follows:

in the formula II, Q₁、Q₂、Q₃、Q₄、Q₅Independently is N or C;

in the formula IV, R₄Is alkyl, in the formula V, R₅Is an alkyl group;

b is IX-1 structure:

in formula IX-1, n1, n2 are independently integers from 0 to 3, Z₄One selected from C, O, S, N; r is₂、R₃Independently selected from hydrogen, haloalkyl, hydroxyl, alkyl, cycloalkyl, amide. Preferably, in formula IX-1, n1, n2 are independently integers from 0 to 3, Z₄One selected from C, O, S; r₂、R₃Independently selected from hydrogen, haloalkyl, hydroxyl, alkyl, amide.

wherein Z is₁、Z₂、Z₃W is independently selected from N or C;

wherein A is a structure of formula II-2:

in the formula II-2, Q₁、Q₂、Q₃、Q₆Independently is N or C;

b is IX-1 structure:

in formula IX-1, n1, n2 are independently integers from 0 to 3, Z₄One selected from C, O, S, N; r₂、R₃Independently selected from hydrogen, haloalkyl, hydroxyl, alkyl, cycloalkyl, amide.

wherein Z is₁、Z₂、Z₃W is independently selected from N or C;

the structures of formulas II, IV and V are as follows:

in the formula II, Q₁、Q₂、Q₃、Q₄、Q₅Independently is N or C;

in the formula IV, R₄Is alkyl, in the formula V, R₅Is an alkyl group;

b is the IX structure:

in formula IX, n1, n2 are independently integers from 0 to 3, Z₄C, O, S or N; z₅Is CR₈R₉；R₂、R₃Independently selected from hydrogen, haloalkyl, hydroxy, alkyl, cycloalkyl, amide; r₈And R₉Independently selected from hydrogen, haloalkyl, hydroxy, alkyl, cycloalkyl, and R₈And R₉Not hydrogen at the same time.

Further, the compound of formula I or a pharmaceutically acceptable salt thereof has the structure of formula VI-1:

wherein Z is₁、Z₂、Z₃W is independently selected from N or C;

the structures of formulas II, IV and V are as follows:

in the formula II, Q₁、Q₂、Q₃、Q₄、Q₅Independently is N or C;

in the formula IV, R₄Is alkyl, in the formula V, R₅Is an alkyl group;

b is IX-1 structure:

in formula IX-1, n1, n2 are independently integers from 0 to 3, Z₄One selected from C, O, S or N; r₂、R₃Independently selected from hydrogen, haloalkyl, hydroxyl, alkyl, cycloalkyl, amide.

Further, the compound of formula I or a pharmaceutically acceptable salt thereof has a structure according to formula VII:

wherein, K₁、K₂、K₃、K₄、K₅Independently selected from one of N or C; key with a key body

Is a key

Or none of them;

wherein A is substituted or unsubstituted naphthyl, and the substituent of the substituted naphthyl is selected from C1-5 alkyl or halogen;

b is IX-1 structure:

in formula IX-1, n1, n2 are independently integers from 0 to 3, Z₄Selected from C or O; r₂、R₃Independently selected from hydrogen, halogenated alkyl, hydroxyl and alkyl.

Further, the compound of formula I or a pharmaceutically acceptable salt thereof is of the structure:

K₆is selected from N or C;

wherein A is substituted or unsubstituted naphthyl and a structure shown in formula II, and the substituent of the substituted naphthyl is selected from C1-5 alkyl or halogen;

the structure of formula II is as follows:

in formula II, Q₁、Q₂、Q₃、Q₄、Q₅Independently selected from N or C;

b is an IX structure:

in formula IX, n1, n2 are independently integers from 0 to 3, Z₄C, O, S or N; z₅Is selected from O or CH₂Or CR₈R₉； R₂、R₃Independently selected from hydrogen, haloalkyl, hydroxy, alkyl, cycloalkyl, amide; r₈And R₉Independently selected from hydrogen, haloalkyl, hydroxy, alkyl, cycloalkyl, and R₈And R₉Not hydrogen at the same time. Preferably, in formula IX, n1, n2 are integers from 0 to 3, Z₄C, O or S; z₅Is selected from O or CH₂；R₂、R₃Independently selected from hydrogen, haloalkyl, hydroxyl, alkyl, amide.

Preferably, in the compound of formula I or a pharmaceutically acceptable salt thereof, the number of substituents on the substituted naphthyl group is 1 to 7, such as 1,2, 3, 4, 5, 6, or 7, the substituents being at any substitutable position of the naphthyl group, more preferably the number of substituents is 1; the alkyl is selected from C1-C5 alkyl; the cycloalkyl is selected from C3-C5 cycloalkyl; the halogenated alkyl is selected from halogenated alkyl of C1-C5; the halogen is selected from fluorine, chlorine, bromine or iodine; the amino group is-NH₂-NHRa or-NRaRb, wherein Ra, Rb are alkyl groups selected from C1-5 linear or branched alkyl groups; the amide is selected from acetamide, trifluoroacetamide, propionamide and isobutyramide. Further, the alkyl of C1-C5 is selected from methyl, ethyl, propyl, butyl or pentyl; the cycloalkyl of C3-C5 is selected from cyclopropyl, cyclobutyl and cyclopentyl; the halogenated alkyl of C1-C5 is selected from trifluoromethyl and difluoromethyl.

Further, the compound of formula I or a pharmaceutically acceptable salt thereof has the structure:

the formula I is a structure of formulas VI, VII and VIII,

wherein, in the structure VI, Z₁Is N, Z₂、Z₃W is independently selected from N or C;

in structures VII and VIII, K₁、K₂、K₃、K₄、K₅、K₆Independently selected from N or C;

wherein A is unsubstituted naphthyl, formula II, formula IV, or formula V;

the structures of the formulas II, IV and V are as follows:

in the formula IV, R₄One selected from methyl, ethyl and propyl;

in the formula V, R₅One selected from methyl, ethyl and propyl;

b is the IX structure:

in formula IX, n1, n2 are independently 0, 1,2, 3; z₄One selected from C, O, S; z₅Is selected from CH₂Or O; r is₂、R₃Independently selected from hydrogen, trifluoromethyl, hydroxy, methyl, ethyl, propyl, isobutyramide.

Further, the compound of formula I or a pharmaceutically acceptable salt thereof has the structure of formula XII:

wherein A is a substituted or unsubstituted naphthyl group,

the substituent of the substituted naphthyl is C1-5 alkyl or halogen;

in the formula IV, R₄Is methyl, ethyl or propyl;

in the formula V, R₅Is methyl, ethyl or propyl;

b is IX-1 structure:

in formula IX-1, n1, n2 are independently integers from 0 to 3, Z₄One selected from C, O, S, N; r is₂And R₃Independently selected from hydrogen, haloalkyl, hydroxy, alkyl, cycloalkyl, and amide. Preferably, in formula IX-1, n2 is an integer from 1 to 3, n1 is 2, Z₄One selected from C, O, S, N; r is₂And R₃Independently selected from hydrogen, trifluoromethyl, hydroxyl and methyl.

Further, the compound of formula I or a pharmaceutically acceptable salt thereof has the structure of formula XI:

wherein n3 is an integer of 0 to 3, R₇A substituent selected from hydrogen, substituted or unsubstituted C1-5 alkyl and halogen, said substituted C1-5 alkyl being selected from halogen; the halogen is fluorine, chlorine, bromine or iodine; preferably, the C1-C5 alkyl group is selected from methyl, ethyl, propyl, butyl or pentyl; key with a key body

Is a key

Or is absent;

K₁、K₂、K₃、K₄、K₅is selected from N or C.

Further, the compound of formula I or a pharmaceutically acceptable salt thereof has the following structure:

wherein

Q₃、Q₄Independently selected from N or C; k is₆Is selected from N or C; n4 is an integer selected from 0 to 3, Z₆Is selected from O or CH₂. Preferably, K₆Is C, Z₆Is CH₂。

Further, any of the compounds represented by formula I or the pharmaceutically acceptable salts thereof is selected from any one of the following compounds:

4- ((1- (naphthalen-2-yl) -1H-indol-4-yl) methyl) morpholine or its hydrochloride

4- ((4-methylpiperazin-1-yl) methyl) -1- (naphthalen-2-yl) -1 h-indole or its hydrochloride

4- ((4-cyclopropylpiperazin-1-yl) methyl) -1- (naphthalen-2-yl) -1-hydro-indole or its hydrochloride

2-methyl-1- (4- ((1- (naphthalen-2-yl) -1 h-indol-4-yl) methyl) piperazin-1 yl) propan-1-one or its hydrochloride

4- ((1-isoquinolin-3-yl) -1-hydro-indol-4-yl) methyl) morpholine or its hydrochloride

4- ((1- (quinazolin-2-yl) -1H-indol-4-yl) methyl) morpholine or its hydrochloride

4- ((1- (quinolin-7-yl) -1 h-indol-4-yl) methyl) morpholine or its hydrochloride

4- ((1- (quinolin-6-yl) -1 h-indol-4-yl) methyl) morpholine or a hydrochloride thereof

4- ((1- (isoquinolin-6-yl) -1H-indol-4-yl) methyl) morpholine or its hydrochloride

4- ((1- (quinazolin-6-yl) -1H-indol-4-yl) methyl) morpholine or its hydrochloride

4- ((1- (quinoxalin-6-yl) -1H-indol-4-yl) methyl) morpholine or its hydrochloride

4- ((1- (1-methyl-1-hydro-indazol-5-yl) -1-hydro-indol-4-yl) methyl) morpholine or its hydrochloride

4- ((1- (2-methyl-1-hydro-indazol-5-yl) -1-hydro-indol-4-yl) methyl) morpholine or its hydrochloride

4- ((1- (naphthalen-2-yl) -1-hydro-pyrrolo [2,3] pyridin-4-yl) methyl) morpholine or its hydrochloride

4- ((1- (naphthalen-2-yl) -1H-indazol-4-yl) methyl) morpholine or its hydrochloride

4- ((1- (quinolin-6-yl) -1-hydro-indazol-4-yl) methyl) morpholine or its hydrochloride

4- ((1- (naphthalen-2-yl) -1H-benzimidazol-4-yl) methyl) morpholine or its hydrochloride salt

4- ((1- (quinolin-6-yl) -1-hydro-benzimidazol-4-yl) methyl) morpholine or its hydrochloride salt

4- ((1- (quinolin-6-yl) -1 h-indol-5-yl) methyl) morpholine or its hydrochloride

4- ((1- (quinolin-6-yl) -1 h-indol-4-yl) methyl) thiomorpholine or its hydrochloride

4- ((1- (naphthalen-2-yl) -1H-indol-4-yl) methyl) thiomorpholine or its hydrochloride

4-methyl-1- ((1-naphthalen-2-yl) -1-hydro-indol-4-yl) methyl) piperidin-4-yl or hydrochloride thereof

1- ((1- (quinolin-6-yl) -1 h-indol-4-yl) methyl) -4- (trifluoromethyl) piperidin-4-yl or the hydrochloride thereof

4-methyl-1- ((1- (quinolin-6-yl) -1 h-indol-4-yl) methyl) piperidin-4-yl or the hydrochloride salt thereof

3-methyl-1- ((1- (quinolin-6-yl) -1 h-indol-4-yl) methyl) pyrrolidine-3-hydroxy or its hydrochloride

4- (1- (1- (quinolin-6-yl) -1 h-indol-4-yl) ethyl) morpholine or its hydrochloride

4-methyl-1- (1- (1- (quinolin-6-yl) -1 h-indol-4-yl) ethyl) piperidin-4-ol or the hydrochloride thereof

4- (1- (1- (quinolin-6-yl) -1 h-indazol-4-yl) ethyl) morpholine or its hydrochloride

4- ((7-naphthalen-2-yl) -1H-indol-3-yl) methyl) morpholine or its hydrochloride

4- (([1, 2' -dinaphthalen ] -5-yl) methyl) morpholine or hydrochloride thereof

4- ((5- (quinolin-6-yl) naphthalen-1-yl) methyl) morpholine or its hydrochloride

4- (2- (4-naphthalen-2-yl) -1H-indazol-1-yl) ethyl) morpholine or its hydrochloride salt

4- (2- (4- (naphthalen-2-yl) -1H-benzimidazol-1-yl) ethyl) morpholine or its hydrochloride

4- (2- (4-naphthalen-2-yl) -7-hydro-pyrrolo [2,3-d ] pyrimidin-7-yl) ethyl) morpholine or its hydrochloride salt

4- (2- ((8- (naphthalen-2-yl) quinolin-4-yl) oxy) ethyl) morpholine or its hydrochloride salt

4- (2- (1- (quinolin-6-yl) -1 h-indol-4-yl) ethyl) morpholine or its hydrochloride

1- (2- (1- (quinolin-6-yl) -1 h-indol-4-yl) ethyl) -4 (trifluoromethyl) piperidin-4-ol or the hydrochloride thereof

In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, as described above, and a pharmaceutically acceptable carrier.

In another aspect, the invention provides a compound as described in formula I or a pharmaceutically acceptable salt thereof, and the use of a pharmaceutical composition containing the compound in the preparation of a medicament for the treatment and prevention of a sigma receptor related disease or condition. Further, the treatment and prevention of the sigma receptor related diseases is pain, preferably neuropathic or inflammatory pain, post-operative pain, cancer pain, trigeminal neuralgia, osteoarthritis pain, burn pain, phantom limb pain.

Detailed Description

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

The term "comprising" is open-ended, i.e. including what is specified in the invention, but not excluding other aspects. It should be understood that the term "comprising" may encompass the closed meaning, i.e., "consisting of …".

As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as compounds of the general formula above or as specified in the examples, subclasses. It is understood that the term "optionally substituted" may be used interchangeably with the term "substituted or unsubstituted". In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a particular substituent. Unless otherwise indicated, an optionally substituted group may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, then the substituents may be substituted at each position, identically or differently.

In addition, it should be noted that, unless otherwise explicitly indicated, the description of the present invention as "independently" is to be understood in a broad sense and may mean that specific items expressed between the same symbols in different groups do not affect each other, or that specific items expressed between the same symbols in the same groups do not affect each other.

In each part of this specification, substituents for the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C1-C5 alkyl" refers specifically to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH)₃) Ethyl group (Et, -CH)₂CH₃) N-propyl (n-Pr, -CH)₂CH₂CH₃) Isopropyl (i-Pr, -CH (CH)₃)₂) N-butyl (n-Bu, -CH)₂CH₂CH₂CH₃) Isobutyl (i-Bu, -CH)₂CH(CH₃)₂) Sec-butyl (s-Bu, -CH (CH)₃)CH₂CH₃) T-butyl (t-Bu, -C (CH)₃)₃) N-pentyl (-CH)₂CH₂CH₂CH₂CH₃) 2-pentyl (-CH (CH)₃)CH₂CH₂CH₃) 3-pentyl (-CH (CH)₂CH₃)₂) 2-methyl-2-butyl (-C (CH)₃)₂CH₂CH₃) 3-methyl-2-butyl (-CH (CH)₃)CH(CH₃)₂) 3-methyl-1-butyl (-CH)₂CH₂CH(CH₃)₂) 2-methyl-1-butyl (-CH)₂CH(CH₃)CH₂CH₃) And the like.

Ranges (e.g., numerical ranges) recited herein can encompass each value in the range as well as each subrange formed by each value. Thus, for example, the expression "n₂The "is any integer between 0 and 3" includes, for example, any integer between 0 and 2, any integer between 2 and 3, and the like, for example, 1,2, and 3.

The expression "one or more" may denote 1,2, 3, 4, 5, 6 or more.

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

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

Key with a key body

Is a key

Or none of them.

The term "pharmaceutically acceptable salt" refers to salts prepared by mixing a compound of formula I with an acid, wherein the anion of the acid is generally considered suitable for human use, which is generally prepared by reaction of the free base with a suitable organic or inorganic acid. When used in medicine, the salts of the compounds of the present invention are non-toxic "pharmaceutically acceptable salts". Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention include those derived from inorganic acids, for example hydrochloric, hydrobromic, hydrofluoric, boric, fluoroboric, phosphoric, metaphosphoric, nitric, carbonic, sulfonic and sulfuric acids, and those derived from organic acids, for example acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isothiocarboxylic, lactic, lactobionic, maleic, malic, methanesulfonic, trifluoromethanesulfonic, succinic, toluenesulfonic, tartaric and trifluoroacetic acids, if possible.

Advantageous technical effects of the invention

The compound provided by the invention is a double-ring structure sigma-1 receptor inhibitor, a double-ring structure compound with pharmacological activity and receptor selectivity on sigma-1 receptors, a preparation method of the compounds and application of the compounds in treatment and prevention of central nervous diseases. The series of compounds have good sigma-1 receptor inhibitory activity, can be used in combination with morphine, can remarkably improve the synergistic effect of morphine, and is effective on I-phase pain and II-phase pain induced by a formalin model.

Description of the drawings:

FIG. 1: rate of morphine inhibition of pain

FIG. 2: formalin-phase I pain test results

FIG. 3: formalin-II phase pain test results

Examples

The following describes embodiments of the present invention in detail. The following examples are illustrative only and are not to be construed as limiting the invention. Unless otherwise indicated, all ratios, percentages, and the like referred to herein are by weight.

General scheme of synthesis:

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

Synthesis scheme 1: the compounds of examples 1-19 can be obtained by reductive amination, and C-N bond coupling reactions

Synthesis scheme 2: the compounds of examples 20-25 can be obtained by this synthetic scheme

Synthesis scheme 3:

examples 26 to 28 the target products were obtained by Buckwald coupling reaction, reduction and substitution according to the following synthetic routes

Synthesis scheme 4:

example 29 the desired product was obtained by amidation, Buckwald coupling, reduction according to the following synthetic route

Synthesis scheme 5:

examples 30 and 31 the desired product was obtained by amidation, Buckwald coupling, reduction according to the following synthetic route

Synthesis scheme 6:

examples 32-34 the desired products were obtained by substitution, Buckwald coupling reaction, according to the following synthetic route

Synthesis scheme 7:

example 35 the desired product was obtained by substitution and Buckwald coupling reaction according to the following synthetic route

Synthesis scheme 8:

examples 36 to 37 the target products were obtained by Buckwald coupling, wittig reaction, reductive amination according to the following synthetic route

The resulting reaction product may be purified by a conventional method such as crystallization, chromatography and trituration, if necessary. When the above-described process of the compounds of the present invention produces a mixture of regioisomers, these isomers can be separated by conventional techniques such as preparative chromatography. If chiral centers are present, the compounds may be prepared in racemic form, or individual enantiomers may be prepared by corresponding transfer synthesis or resolution.

The term "pharmacological tool" refers to the property of the compounds of the invention by which they are highly selective ligands of the sigma receptor, which indicates that the compounds of formula I according to the invention can be used as a model for testing other compounds as sigma ligands, e.g. radioligands are substituted, and also for establishing physiological activity related to the sigma receptor.

The invention also provides a pharmaceutical composition for administration to a patient, which comprises a compound of the invention, a pharmaceutically acceptable salt, derivative, prodrug or stereoisomer thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

In a preferred embodiment, the pharmaceutical composition is in solid or liquid oral form. Suitable dosage forms for oral administration may be tablets, capsules, syrups or solutions, and may contain conventional excipients known in the art, such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth or povidone; fillers, for example lactose, sucrose, corn starch, calcium phosphate, sorbitol or glycine; tableting lubricants, such as magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline cellulose; or a pharmaceutically acceptable wetting agent such as sodium lauryl sulfate.

The solid oral compositions can be prepared by conventional methods of mixing, filling, and tableting. Repeated mixing operations can be used to distribute the active agent throughout those compositions that use large amounts of filler. Such operations are conventional in the art. Tablets may be prepared, for example, by wet or dry granulation, optionally coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.

The pharmaceutical compositions may also be adapted for parenteral administration, such as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms. Suitable excipients, such as fillers, buffers or surfactants, may be used.

The formulations mentioned are prepared using standard methods such as those described or indicated in the spanish and united states pharmacopeia and similar references.

Administration of the compounds or compositions of the present invention may be carried out in any suitable manner, such as intravenous injection, oral formulation, intraperitoneal and intravenous administration. Oral administration is preferred because of the convenience of the patient and the chronic nature of the disease to be treated.

Generally, an effective amount of a compound of the invention to be administered will depend on the relative effectiveness of the compound selected, the severity of the condition being treated and the weight of the patient. However, the active compounds are usually administered once or several times daily, for example 1,2, 3 or 4 times daily, in a total daily dose of 0.1-1000 mg/kg/day.

The compounds and compositions of the present invention may be used with other drugs to provide combination therapy. The other agents may form part of the same composition, or as separate compositions for simultaneous or non-simultaneous administration.

The following examples are given solely for the purpose of further illustrating the invention and should not be taken as limiting the scope of the invention.

Synthesis scheme 1:

the compounds of examples 1 to 19 can be obtained by this synthesis scheme

Example 1:4- ((1- (naphthalen-2-yl) -1H-indol-4-yl) methyl) morpholine hydrochloride

¹H NMR(400MHz,CDCl₃)δ：8.00(d,J＝8.8Hz,1H),7.95–7.86(m,3H),7.67(dd,J＝8.7,2.2 Hz,1H),7.60–7.50(m,3H),7.46(d,J＝3.3Hz,1H),7.24–7.15(m,2H),6.95–6.92(m,1H), 3.85(s,2H),3.79–3.70(m,4H),2.65–2.49(m,4H).MS(ESI)m/z 343.2([M+H]⁺).

Step 1. Synthesis of indole-4-methylmorpholine

Indole-4-carbaldehyde (250mg, 1.72mmol) and morpholine (449.54mg, 5.16mmol) were dissolved in DCM (10mL) and reacted at room temperature for 1h before addition of NaBH (OAc)₃(729.07mg, 3.44mmol), stirring at normal temperature and reacting for 12 h; the reaction was quenched with water (30mL), extracted with DCM (30mLx2), the organic phase washed with brine (10mLx3), the organic phase dried over anhydrous sodium sulfate, filtered, concentrated to give crude product, and column chromatographed (PE/EA 2/1) to give indole-4-methylmorpholine 300mg, yield: 80.6 percent

Step 2.4 Synthesis of- ((1- (naphthalen-2-yl) -1H-indol-4-yl) methyl) morpholine

Mixing indole-4-methylmorpholine (250.0mg, 1.16mmol), 2-bromonaphthalene (265.86mg, 1.28mmol), BINAP (143.21mg, 0.23mmol), Pd (dba)₂(69.0mg, 0.12mmol) in p-xylene(10.0mL), potassium tert-butoxide (155.97mg, 1.39mmol) was added and the reaction was carried out at 98 ℃ for 12 h; the reaction was quenched by addition of water (80mL), EA (80mL) extracted, the organic phase washed with brine (30mLx3), dried over anhydrous sodium sulfate, filtered, concentrated to give crude product, which was chromatographed (DCM/MeOH ═ 40:1) to give 150mg of 4- ((1- (naphthalen-2-yl) -1 h-indol-4-yl) methyl) morpholine, yield: 37.8 percent

Step 3.4- ((1- (naphthalen-2-yl) -1H-indol-4-yl) methyl) morpholine hydrochloride Synthesis

1-naphthyl-indole-4-methylmorpholine (140.0mg, 0.4mmol) was dissolved in DCM (2mL) and HCl/EA (5.0mL) was added to precipitate a white solid; after concentration and drying, 1-naphthyl-indole-4-methylmorpholine hydrochloride (140.0mg, yield: 92.4%) was obtained.

Example 2:4- ((4-methylpiperazin-1-yl) methyl) -1- (naphthalen-2-yl) -1 h-indole hydrochloride

The title compound was prepared by substituting morpholine with 4-methylpiperazine according to the procedure of example 1.

¹H NMR(400MHz,CDCl₃)δ：7.99(d,J＝8.7Hz,1H),7.95–7.85(m,3H),7.66(dd,J＝8.7,2.1 Hz,1H),7.58–7.50(m,3H),7.45(d,J＝3.3Hz,1H),7.24–7.14(m,2H),6.92(dd,J＝3.3,0.8Hz, 1H),3.87(s,2H),2.79–2.41(m,8H),2.34(s,3H).MS(ESI)m/z 356.2([M+H]⁺).

Example 3:4- ((4-Cyclopropylpiperazin-1-yl) methyl) -1- (naphthalen-2-yl) -1H-indole hydrochloride

The title compound was prepared by the method of example 1, substituting morpholine for 4-cyclopropylpiperazine.

¹H NMR(400MHz,CDCl₃)δ：8.00(d,J＝8.7Hz,1H),7.95–7.85(m,3H),7.65(dd,J＝8.7,2.2 Hz,1H),7.62–7.49(m,3H),7.47(d,J＝3.3Hz,1H),7.23(d,J＝6.4Hz,2H),6.88(d,J＝3.3Hz, 1H),4.02(s,2H),3.08–2.46(m,9H),0.48(d,J＝6.3Hz,4H).MS(ESI)m/z 382.2([M+H]⁺).

Example 4: 2-methyl-1- (4- ((1- (naphthalen-2-yl) -1 hydro-indol-4-yl) methyl) piperazin-1 yl) propan-1-one hydrochloride

The title compound was prepared by the method of example 1, substituting morpholine for isobutyramidopiperazine.

¹H NMR(400MHz,CDCl₃)δ：8.00(d,J＝8.7Hz,1H),7.97–7.85(m,3H),7.67(dd,J＝8.7,2.2 Hz,1H),7.61–7.50(m,3H),7.46(d,J＝3.3Hz,1H),7.25–7.12(m,2H),6.91(dd,J＝3.3,0.9Hz, 1H),3.87(s,2H),3.74–3.48(m,4H),2.79(hept,J＝6.8Hz,1H),2.59–2.48(m,4H),1.13(d,J＝ 6.7Hz,6H).MS(ESI)m/z 412.25([M+H]⁺).

Example 5:4- ((1-isoquinolin-3-yl) -1-hydro-indol-4-yl) methyl) morpholine hydrochloride

The title compound was prepared by the procedure of example 1, substituting 2-bromonaphthalene for 3-bromoisoquinoline.

¹H NMR(400MHz,CDCl₃)δ：9.26(d,J＝0.9Hz,1H),8.09–8.00(m,2H),7.89–7.83(m,2H), 7.81–7.80(m,1H),7.73(ddd,J＝8.3,6.8,1.2Hz,1H),7.58(ddd,J＝8.1,6.8,1.1Hz,1H),7.29– 7.24(m,1H),7.19(dd,J＝7.2,0.9Hz,1H),6.97(dd,J＝3.4,0.8Hz,1H),3.84(s,2H),3.78–3.69 (m,4H),2.60–2.48(m,4H).MS(ESI)m/z 344.1([M+H]⁺).

Example 6:4- ((1- (quinazolin-2-yl) -1H-indol-4-yl) methyl) morpholine hydrochloride

Preparation of the title Compound by substituting 2-Bromonaphthalene for 2-bromoquinazoline

¹H NMR(400MHz,CDCl₃)δ：9.37(s,1H),9.00(d,J＝8.3Hz,1H),8.45(d,J＝3.7Hz,1H),8.02 (d,J＝8.6Hz,1H),7.95–7.85(m,2H),7.59–7.49(m,1H),7.35(t,J＝7.8Hz,1H),7.24(d,J＝ 7.4Hz,1H),6.96(d,J＝3.7Hz,1H),3.83(s,2H),3.78–3.65(m,4H),2.61–2.46(m,4H).MS (ESI)m/z 345.1([M+H]⁺).

Example 7:4- ((1- (quinolin-7-yl) -1H-indol-4-yl) methyl) morpholine hydrochloride

The title compound was prepared by substituting 2-bromonaphthalene for 7-bromoquinoline as in example 1

¹H NMR(400MHz,CDCl₃)δ：8.98(dd,J＝4.2,1.7Hz,1H),8.23(dt,J＝6.9,1.1Hz,2H),7.97(d, J＝8.7Hz,1H),7.78(dd,J＝8.7,2.2Hz,1H),7.66(dt,J＝7.9,1.0Hz,1H),7.50(d,J＝3.3Hz, 1H),7.45(dd,J＝8.3,4.3Hz,1H),7.25-7.16(m,2H),6.97(dd,J＝3.3,0.8Hz,1H),3.84(s,2H), 3.80-3.69(m,4H),2.65-2.47(m,4H).MS(ESI)m/z 442.2([M+H]⁺).

Example 8:4- ((1- (quinolin-6-yl) -1-hydro-indol-4-yl) methyl) morpholine hydrochloride

The title compound was prepared by substituting 6-bromoquinoline for 2-bromonaphthalene as in example 1

¹H NMR(400MHz,CDCl₃)δ：8.96(dd,J＝4.2,1.7Hz,1H),8.30–8.24(m,1H),8.20(dd,J＝8.3, 1.0Hz,1H),7.95–7.88(m,2H),7.57(dt,J＝7.9,1.1Hz,1H),7.51–7.43(m,2H),7.25–7.16(m, 2H),6.96(dd,J＝3.3,0.9Hz,1H),3.85(s,2H),3.78–3.70(m,4H),2.56(t,J＝4.7Hz,4H).MS (ESI)m/z 344.1([M+H]⁺).

Example 9: 4- ((1- (isoquinolin-6-yl) -1-hydro-indol-4-yl) methyl) morpholine hydrochloride

The title compound was prepared by substituting 6-bromoisoquinoline with 2-bromonaphthalene according to the procedure of example 1

¹H NMR(400MHz,CDCl₃)δ：9.31(t,J＝1.0Hz,1H),8.59(d,J＝5.8Hz,1H),8.14(d,J＝8.7Hz, 1H),7.91(d,J＝2.0Hz,1H),7.82(dd,J＝8.7,2.1Hz,1H),7.73-7.66(m,1H),7.61(dt,J＝7.9,1.0 Hz,1H),7.47(d,J＝3.4Hz,1H),7.26-7.17(m,2H),6.99(dd,J＝3.4,0.8Hz,1H),3.84(s,2H), 3.77-3.71(m,4H),2.55(t,J＝4.6Hz,4H).MS(ESI)m/z 344.2([M+H]⁺).

Example 10:4- ((1- (quinazolin-6-yl) -1H-indol-4-yl) methyl) morpholine hydrochloride

Preparation of the title Compound by substituting 6-bromoquinazoline with 2-bromonaphthalene

1H NMR(400MHz,CDCl3)δ：9.47(d,J＝0.8Hz,1H),9.38(s,1H),8.23(d,J＝8.9Hz,1H),8.15 (dd,J＝9.0,2.4Hz,1H),8.02(d,J＝2.3Hz,1H),7.61–7.52(m,1H),7.45(d,J＝3.3Hz,1H),7.25 –7.18(m,2H),7.00(dd,J＝3.3,0.9Hz,1H),3.84(s,2H),3.77–3.71(m,4H),2.58–2.50(m,4H). MS(ESI)m/z 345.15([M+H]⁺).

Example 11:4- ((1- (quinoxalin-6-yl) -1H-indol-4-yl) methyl) morpholine hydrochloride

The title compound was prepared by substituting 6-bromoquinoxaline for 2-bromonaphthalene in the same manner as in example 1

¹H NMR(400MHz,CDCl₃)δ：8.90(d,J＝1.9Hz,1H),8.88(d,J＝1.8Hz,1H),8.27(d,J＝9.0Hz, 1H),8.23(d,J＝2.4Hz,1H),8.02(dd,J＝9.0,2.5Hz,1H),7.67(dt,J＝8.2,1.0Hz,1H),7.50(d,J ＝3.3Hz,1H),7.27–7.16(m,2H),7.01(dd,J＝3.5,0.9Hz,1H),3.84(s,2H),3.78–3.71(m,4H), 2.59–2.51(m,4H).MS(ESI)m/z 345.2([M+H]⁺).

Example 12:4- ((1- (1-methyl-1-hydro-indazol-5-yl) -1-hydro-indol-4-yl) methyl) morpholine hydrochloride

The title compound was prepared by substituting 2-bromonaphthalene for 1-methyl-5-bromoindazole, according to the method of example 1

¹H NMR(400MHz,CDCl3)δ：8.05(s,1H),7.80(t,J＝1.3Hz,1H),7.53(d,J＝1.4Hz,2H), 7.44-7.33(m,2H),7.23-7.12(m,2H),6.89(dd,J＝3.2,0.8Hz,1H),4.15(s,3H),3.87(s,2H),3.76 (t,J＝4.7Hz,4H),2.58(t,J＝4.6Hz,4H).MS(ESI)m/z 347.2([M+H]⁺).

Example 13:4- ((1- (2-methyl-1-hydro-indazol-5-yl) -1-hydro-indol-4-yl) methyl) morpholine hydrochloride

The title compound was prepared by substituting 2-bromonaphthalene for 2-methyl-5-bromoindazole, according to the method of example 1

¹H NMR(400MHz,CDCl3)δ：7.97(s,1H),7.82(dt,J＝9.1,0.9Hz,1H),7.70(dd,J＝2.1,0.8Hz, 1H),7.43(dd,J＝9.1,2.0Hz,2H),7.37(d,J＝3.2Hz,1H),7.20–7.11(m,2H),6.87(dd,J＝3.2, 0.9Hz,1H),4.27(s,3H),3.84(s,2H),3.78–3.70(m,4H),2.55(dd,J＝5.8,3.5Hz,4H).MS(ESI) m/z 347.2([M+H]⁺).

Example 144- ((1- (naphthalen-2-yl) -1-hydro-pyrrolo [2, 3)]Pyridin-4-yl) methyl) morpholine hydrochloride

The title compound was prepared by substituting indole-4-carbaldehyde for pyrrolo [2,3] pyridine-4 carbaldehyde in the same manner as in example 1

¹H NMR(400MHz,CDCl3)δ：8.35(d,J＝4.8Hz,1H),8.16(d,J＝2.0Hz,1H),8.03–7.86(m, 4H),7.62(d,J＝3.6Hz,1H),7.57–7.46(m,2H),7.18(d,J＝4.8Hz,1H),6.88(d,J＝3.6Hz,1H), 3.85(s,2H),3.78–3.73(m,4H),2.56(t,J＝4.7Hz,4H).MS(ESI)m/z 344.2([M+H]⁺).

Example 15:4- ((1- (naphthalen-2-yl) -1H-indazol-4-yl) methyl) morpholine hydrochloride

The title compound was prepared by substituting indole-4-carbaldehyde for indazole-4-carbaldehyde in the same manner as in example 1

¹H NMR(400MHz,CDCl3)δ：8.55(s,1H),8.15(d,J＝2.0Hz,1H),8.02(d,J＝8.8Hz,1H),7.97 –7.87(m,3H),7.77(d,J＝8.4Hz,1H),7.61–7.48(m,2H),7.39(t,J＝7.8Hz,1H),7.18(d,J＝ 6.9Hz,1H),3.87(s,2H),3.76(t,J＝4.6Hz,4H),2.54(t,J＝4.6Hz,4H).

MS(ESI)m/z 344.2([M+H]⁺).

Example 16:4- ((1- (quinolin-6-yl) -1-hydro-indazol-4-yl) methyl) morpholine hydrochloride

The title compound was prepared by substituting 2-bromonaphthalene for 6-bromoquinoline and indole-4-carbaldehyde for indazole-4-carbaldehyde in the same manner as in example 1

¹H NMR(400MHz,Methanol-d₄)δ9.48-9.16(m,2H),8.95-8.63(m,3H),8.49(d,J＝9.1Hz, 1H),8.32(d,J＝8.5Hz,1H),8.18(dd,J＝8.5,5.4Hz,1H),7.84-7.59(m,2H),4.85(s,2H),4.15- 4.00(m,2H),3.83(t,J＝12.4Hz,2H),3.55-3.34(m,4H).MS(ESI)m/z 345.2([M+H]⁺).

Example 17:4- ((1- (naphthalen-2-yl) -1H-benzimidazol-4-yl) methyl) morpholine hydrochloride

The title compound was prepared by substituting indole-4-carbaldehyde for benzimidazole-4-carbaldehyde in the same manner as in example 1

¹H NMR(400MHz,CDCl3)δ：8.05-7.82(m,6H),7.64-7.53(m,3H),7.29-7.23(m,1H),7.13(d,J ＝7.2Hz,1H),3.29(s,2H),3.26-3.10(m,4H),1.73(t,J＝4.6Hz,4H).MS(ESI)m/z 344.2 ([M+H]⁺)

Example 18:4- ((1- (quinolin-6-yl) -1-hydro-benzimidazol-4-yl) methyl) morpholine hydrochloride

The title compound was prepared by substituting 2-bromonaphthalene for 6-bromoquinoline and indole-4-carbaldehyde for benzimidazole-4-carbaldehyde in example 1

¹H NMR(400MHz,Chloroform-d)δ9.02(dd,J＝4.3,1.7Hz,1H),8.40-8.20(m,3H),8.05-7.84 (m,2H),7.54(dd,J＝8.4,4.5Hz,2H),7.47-7.31(m,2H),4.10(s,2H),3.77(t,J＝4.6Hz,4H), 2.64(t,J＝4.6Hz,4H).MS(ESI)m/z 345.2([M+H]⁺).

Example 19:4- ((1- (quinolin-6-yl) -1-hydro-indol-5-yl) methyl) morpholine hydrochloride

The title compound was prepared by substituting 2-bromonaphthalene for 6-bromoquinoline and indole-4-carbaldehyde for indole-5-carbaldehyde in example 1

¹H NMR(400MHz,CDCl3)δ：8.96(dd,J＝4.3,1.7Hz,1H),8.26(d,J＝9.7Hz,1H),8.21(dd,J＝ 8.4,1.7Hz,1H),7.96–7.89(m,2H),7.57(d,J＝8.0Hz,1H),7.52–7.43(m,2H),7.27–7.15(m, 2H),6.96(d,J＝3.4Hz,1H),3.85(s,2H),3.77–3.71(m,4H),2.56(t,J＝4.6Hz,4H).MS(ESI) m/z 344.2([M+H]⁺).

Synthesis scheme 2:

the compounds of examples 20-25 can be obtained by this synthetic scheme

Example 20:4- ((1- (quinolin-6-yl) -1-hydro-indol-4-yl) methyl) thiomorpholine hydrochloride

¹H NMR(400MHz,Methanol-d₄)δ:9.26(d,J＝6.8Hz,2H),8.56(d,J＝1.6Hz,1H),8.47(d,J＝ 1.4Hz,2H),8.19-8.13(m,1H),7.97-7.90(m,2H),7.52-7.42(m,2H),7.18(d,J＝3.4Hz,1H), 4.74(s,2H),3.93-3.78(m,2H),3.41(t,J＝11.8Hz,2H),3.14(td,J＝13.8,12.5,2.4Hz,2H),2.88 (t,J＝14.5Hz,2H).MS(ESI)m/z 360.2([M+H]⁺).

Step 1.1 Synthesis of 1- (quinolin-6-yl) -1-hydro-indole-carbaldehyde

In a 200mL single-neck flask were added in the order indole-4-carbaldehyde (100%, 1.45g, 10mmol), 6-bromoquinoline (2.08g, 10.00mmol), and Cs₂CO₃(6.52g，20.00mmol)、Pd₂(dba)₃(0.92g, 1.00mmol), X-Phos (0.48g, 1.00mmol), KI (0.17g, 1.00mmol) and xylene (40mL), N₂The oil bath is protected and heated to 90 ℃ to stir for 4 h. After the completion of the TLC monitoring reaction, the reaction solution was cooled to room temperature, filtered, concentrated to give 2.2g of crude product, and column chromatography (eluent: EA/PE + DCM ═ 10% to 50%) gave 1- (quinolin-6-yl) -1 h-indole-carbaldehyde (820mg) as a pale yellow foamy solid, yield: 30.1 percent.

Step 2.4 Synthesis of- ((1- (quinolin-6-yl) -1H-indol-4-yl) methyl) thiomorpholine

1- (Quinolin-6-yl) -1H-indole-carbaldehyde (272mg, 1.0mmol) and mercaptomorpholine (309.5mg, 3.0mmol) were combined, dissolved in DCM (10.0mL), reacted at room temperature for 1h and NaBH (OAc) added₃(423.9mg, 2.0mmol), stirring at normal temperature and reacting for 12 h; the reaction was quenched by addition of water (30mL), extracted with DCM (30mL), washed with brine (10mL), dried over anhydrous sodium sulfate, filtered, concentrated to give crude product, which was chromatographed (PE/EA-2/1) to give 300mg product, yield: 83.4 percent

Step 3.4 Synthesis of- ((1- (quinolin-6-yl) -1H-indol-4-yl) methyl) thiomorpholine hydrochloride

4- ((1- (quinolin-6-yl) -1 h-indol-4-yl) methyl) thiomorpholine (300mg, 0.83mmol) was dissolved in dichloromethane (10mL), and an ethyl acetate hydrochloride solution (1mL,1M) was added and reacted at room temperature for 10 minutes; vacuum concentrating, and drying to obtain 325mg of 4- ((1- (quinolin-6-yl) -1 h-indol-4-yl) methyl) thiomorpholine hydrochloride as a yellow solid with a yield of 98.4%.

Example 21:4- ((1- (naphthalen-2-yl) -1H-indol-4-yl) methyl) thiomorpholine hydrochloride

The title compound was prepared by substituting 6-bromoquinoline with 2-bromonaphthalene according to the procedure in example 20.

¹H NMR(400MHz,CDCl₃)δ：7.99(d,J＝8.7Hz,1H),7.95–7.86(m,3H),7.66(dd,J＝8.7,2.2 Hz,1H),7.59–7.52(m,3H),7.46(d,J＝3.3Hz,1H),7.24–7.15(m,2H),6.90(dd,J＝3.4,0.8Hz, 1H),3.91(s,2H),2.95–2.67(m,8H).MS(ESI)m/z 359.15([M+H]⁺).

Example 22: 4-methyl-1- ((1-naphthalen-2-yl) -1-hydro-indol-4-yl) methyl) piperidin-4-yl hydrochloride

The title compound was prepared by substituting thiomorpholine for 4-methyl-4-hydroxypiperidine and 6-bromoquinoline for 2-bromonaphthalene as in example 20

¹H NMR(400MHz,CDCl3)δ：8.00(d,J＝8.7Hz,1H),7.96–7.84(m,3H),7.67-7.60(m,2H), 7.60-7.45(m,4H),7.32-7.26(m,1H),6.88(dd,J＝3.4,0.9Hz,1H),4.40(s,2H),3.33-2.99(m,4H), 2.32(s,2H),1.72(d,J＝14.3Hz,3H),1.33(s,3H).MS(ESI)m/z 371.2([M+H]⁺).

Example 23: 1- ((1- (quinolin-6-yl) -1-hydro-indol-4-yl) methyl) -4- (trifluoromethyl) piperidin-4-yl hydrochloride

The title compound was prepared by substituting thiomorpholine for 4-trifluoromethyl-4-hydroxypiperidine and using the method of example 20

¹H NMR(400MHz,Methanol-d₄)δ9.27(t,J＝6.0Hz,2H),8.57(s,1H),8.52-8.45(m,2H),8.17 (dd,J＝8.4,5.4Hz,1H),7.93(dd,J＝8.2,5.7Hz,2H),7.55-7.41(m,2H),7.21(d,J＝3.4Hz,1H), 4.76(s,2H),3.65-3.55(m,2H),3.54-3.39(m,2H),2.15(td,J＝14.0,4.2Hz,2H),2.07-1.96(m, 2H).MS(ESI)m/z 426.2([M+H]⁺).

Example 24: 4-methyl-1- ((1- (quinolin-6-yl) -1 h-indol-4-yl) methyl) piperidin-4-yl hydrochloride

The title compound was prepared by substituting 4-methyl-4-hydroxypiperidine for thiomorpholine in the same manner as in example 20

¹H NMR(400MHz,Methanol-d₄)δ9.39-9.23(m,2H),8.59(t,J＝1.4Hz,1H),8.50(d,J＝1.4Hz, 2H),8.20(dd,J＝8.4,5.4Hz,1H),8.00-7.87(m,2H),7.57-7.37(m,2H),7.19(d,J＝3.4Hz,1H), 4.70(s,2H),3.42(dd,J＝7.5,3.1Hz,4H),1.97-1.73(m,4H),1.28(s,3H).MS(ESI)m/z 372.2 ([M+H]⁺).

Example 25: 3-methyl-1- ((1- (quinolin-6-yl) -1 h-indol-4-yl) methyl) pyrrolidine-3-hydroxy hydrochloride

The title compound was prepared by substituting thiomorpholine for 3-methyl-3-hydroxypyrrolidine as in example 20

¹H NMR(400MHz,Methanol-d₄)δ9.38-9.20(m,2H),8.57(d,J＝1.7Hz,1H),8.48(d,J＝2.0Hz, 2H),8.17(dd,J＝8.4,5.4Hz,1H),7.90(q,J＝2.8Hz,2H),7.58-7.36(m,2H),7.18(dd,J＝20.4, 3.4Hz,1H),4.84-4.69(m,2H),3.90-3.49(m,2H),3.42-3.34(m,1H),3.29-3.23(m,1H),2.33- 2.01(m,2H),1.44(d,J＝7.3Hz,3H).MS(ESI)m/z 358.2([M+H]⁺).

Synthesis scheme 3:

examples 26 to 28 the target products were obtained by Buckwald coupling, reduction and substitution according to the following synthetic routes

Example 26: synthesis of 4- (1- (1- (quinolin-6-yl) -1 h-indol-4-yl) ethyl) morpholine hydrochloride

¹H NMR(400MHz,Methanol-d4)δ9.40–9.21(m,2H),8.55(dd,J＝35.3,1.5Hz,3H),8.20(dd,J ＝8.4,5.4Hz,1H),7.99–7.86(m,2H),7.66–7.44(m,2H),7.22(dd,J＝3.6,0.9Hz,1H),5.06(m, 1H),4.19–4.08(m,1H),3.95(m,3H),3.82–3.69(m,1H),3.32(s,1H),3.19–3.05(m,2H),1.94 (d,J＝6.9Hz,3H).MS:[M+1]＝358.2

Step 1.1 Synthesis of 1- (quinolin-6-yl) -1H-indole-carbaldehyde

In a 200mL single-neck flask were added in this order indole-4-carbaldehyde (1.45g, 10mmol), 6-bromoquinoline (2.08g, 10.00mmol), and Cs₂CO₃(6.52g，20.00mmol)、Pd₂(dba)₃(0.92g, 1.00mmol), X-Phos (0.48g, 1.00mmol), KI (0.17g, 1.00mmol) and xylene (40mL), N₂The reaction is stirred for 4 hours at 90 ℃ under protection. After TLC monitoring reaction, cooling to room temperature, filtering reaction liquid, concentrating to obtain 2.2g crude product, and performing column chromatography (eluent: EA/PE + DCM is 10% -50%) to obtain light yellow foam solid 1- (quinoline-6-yl) -1 hydrogen-indole-formaldehyde (820 mg); yield: 30.1 percent.

Step 2.1 Synthesis of 1- (1- (quinolin-6-yl) -1H-indol-4-yl) ethan-1-ol

1- (quinolin-6-yl) -1-hydro-indole-carbaldehyde (820mg, 3.01mmol) was dissolved in THF (20mL), cooled to-20 ℃ and stirred for 10min, bromo (methyl) magnesium (1.0mL,3M in THF) was added, and stirred for 1.0h at-20 ℃. After the completion of the reaction was monitored by TLC, the reaction was quenched by addition of saturated ammonium chloride solution (80mL), extracted with ethyl acetate (80mLx2), the organic phase was collected, dried and concentrated to give 1- (1- (quinolin-6-yl) -1 h-indol-4-yl) ethan-1-ol as a pale yellow foamy solid (910mg), which was used in the next reaction without purification.

Step 3.1 Synthesis of 1- (1- (quinolin-6-yl) -1H-indol-4-yl) ethyl methanesulfonate

1- (1- (quinolin-6-yl) -1 h-indol-4-yl) ethan-1-ol (288.3mg, 1mmol), TEA (151.8mg, 1.50mmol) and acetonitrile (30mL) were charged to a 100mL reaction flask, chloromethylsulfonic acid (137.5mg, 1.20mmol) was added at 0-20 deg.C, and the reaction stirred at 20 deg.C for 2 h. After the reaction, the reaction solution was used directly for the next reaction.

Step 4.4 Synthesis of (1- (1- (quinolin-6-yl) -1H-indol-4-yl) ethyl) morpholine

4-morpholine (230.4mg, 2.00mmol) was added to the reaction mixture, and the mixture was heated to 75 ℃ in an oil bath, and the reaction was stirred at this temperature overnight. After TLC detection, the reaction was quenched by addition of saturated sodium chloride solution (80mL), extracted with ethyl acetate (50mLx2), dried over anhydrous sodium sulfate, concentrated to give 420mg of crude product, and purified by pre-TLC (developing solvent: MeOH/DCM-8% to give 61mg of 4- (1- (1- (quinolin-6-yl) -1 h-indol-4-yl) ethyl) morpholine, 15.8% yield.

Step 5.4 Synthesis of 1- (1- (quinolin-6-yl) -1H-indol-4-yl) ethyl) morpholine hydrochloride

4- (1- (1- (quinolin-6-yl) -1 h-indol-4-yl) ethyl) morpholine (61mg, 0.16mmol) was dissolved in dichloromethane (8mL), a solution of ethyl acetate hydrochloride (0.1mL,0.16mmol) was added and the reaction was allowed to complete by sonication for 10min at room temperature. Concentrated under reduced pressure and dried to give 4- (1- (1- (quinolin-6-yl) -1 h-indol-4-yl) ethyl) morpholine hydrochloride (68mg) as a yellow solid with a yield of 97.7%.

Example 27: 4-methyl-1- (1- (1- (quinolin-6-yl) -1 h-indol-4-yl) ethyl) piperidin-4-ol hydrochloride

Morpholine is replaced by 4-methylpiperidine-4-ol, and the target product is synthesized according to the scheme 3

1H NMR(400MHz,Methanol-d4)δ9.29–9.25(m,2H),8.57(d,J＝1.5Hz,1H),8.47(d,J＝1.4 Hz,2H),8.17(dd,J＝8.4,5.4Hz,1H),7.92–7.87(m,2H),7.55–7.43(m,2H),7.18(d,J＝3.5Hz, 1H),5.04(q,J＝6.9Hz,1H),2.08–1.99(m,1H),1.92(d,J＝6.9Hz,3H),1.88–1.77(m,2H), 1.74–1.67(m,1H),1.36(m,4H),1.26(s,3H).MS:[M+1]＝386.2

Example 28:4- (1- (1- (quinolin-6-yl) -1 h-indazol-4-yl) ethyl) morpholine hydrochloride

Indole-4-formaldehyde is replaced by indazole-4-formaldehyde, and the target product is synthesized according to the scheme 3

1H NMR(400MHz,Methanol-d4)δ9.34(d,J＝8.5Hz,1H),9.25(dd,J＝5.4,1.3Hz,1H),8.83– 8.71(m,3H),8.47(d,J＝9.2Hz,1H),8.28(d,J＝8.4Hz,1H),8.21–8.14(m,1H),7.78(t,J＝7.9 Hz,1H),7.74–7.68(m,1H),4.15–4.06(m,1H),3.92(q,J＝16.6,15.3Hz,3H),3.74(t,J＝12.1 Hz,1H),3.19–3.05(m,2H),2.03–1.96(m,1H),1.94(d,J＝6.9Hz,3H),1.27(d,J＝3.8Hz,1H).

Synthesis scheme 4:

example 29 Buckwald coupling, reduction and substitution gave the title product according to the following synthetic route

Example 29:4- ((7-Naphthalen-2-yl) -1H-indol-3-yl) methyl) morpholine hydrochloride

¹H NMR(400MHz,CDCl₃)δ：8.09(d,J＝1.5Hz,1H),7.99(d,J＝8.5Hz,1H),7.94–7.87(m, 2H),7.80–7.73(m,2H),7.57–7.50(m,2H),7.35(dd,J＝7.3,1.1Hz,1H),7.31–7.26(m,2H), 3.82(s,2H),3.76(t,J＝4.7Hz,4H),2.66–2.53(m,4H).MS(ESI)m/z 343.2([M+H]⁺).

Step 1. Synthesis of (7-chloro-1-hydro-indol-3-yl) (morpholinyl) methanone

Dissolving 7-chloro-1-hydro-indole-3-carboxylic acid (700.0mg, 3.58mmol) and oxalyl chloride (1.36g, 10.74mmol) in DCM (10.0mL) and a catalytic amount of DMF, reacting for 1h under nitrogen protection at room temperature, and concentrating; morpholine (623.78mg, 7.16mmol) and Et₃Dissolving N (724.52mg, 7.16mmol) in DCM (10.0mL), diluting the above acyl chloride in DCM (20mL) and slowly adding dropwise into the reaction flask, and reacting for 2h at normal temperature; after completion of the reaction, a saturated ammonium chloride solution (20mL) was added, DCM was extracted (20mLx3), the combined organic phases were washed with saturated brine (20mLx2), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude 700.0mg, which was subjected to column chromatography (PE/EtOAc ═ 15/1) to give (7-chloro-1-hydro-indol-3-yl) (morpholinyl) methanone (400mg, yield: 42.2%).

Step 2. Synthesis of morpholine (7- (naphthalen-2-yl) -1H-indol-3-yl) methanone

Prepared from (7-chloro-1H-indol-3-yl) (morpholinyl) methanone (400.0mg, 1.51mmol), 2-naphthaleneboronic acid (519.41mg, 3.02mmol), caesium fluoride (688.11mg,4.53mmol), TEBA (68.79mg,0.30mmol) and Pd (dppf)₂Cl₂(123.31mg, 0.15mmol) in 40.0mL Toluene/H₂In O, stirring and reacting for 12 hours at 100 ℃ under the protection of nitrogen; after the reaction, water (40mL) was added, EA was extracted (30mLx3), the organic phase was washed with saturated brine (20mLx2), dried over anhydrous sodium sulfate, filtered, concentrated to obtain a crude product, and column chromatography (PE/EA 3/1) was performed to obtain morpholine (7- (naphthalen-2-yl) -1 h-indol-3-yl) methanone (400.0mg, yield: 74.3%).

Step 3.4 Synthesis of- ((7- (naphthalen-2-yl) -1H-indol-3-yl) methyl) morpholine

Dissolving morpholine (7- (naphthalene-2-yl) -1H-indol-3-yl) methanone (200.0mg, 0.56mmol) in THF (10mL), adding LAH (85.0mg, 1.12mmol), and stirring under nitrogen at 60 ℃ for reaction for 12 h; after the reaction, 40mL of water was added, EA extraction was performed (30mLx3), the organic phases were combined, washed with saturated brine (30mLx2), dried over anhydrous sodium sulfate, filtered, concentrated to give a crude product, and column chromatography was performed (PE/EA 1/1) to give 4- ((7- (naphthalen-2-yl) -1 h-indol-3-yl) methyl) morpholine (90.0mg, yield: 46.9%).

Step 4.4- ((7- (naphthalen-2-yl) -1H-indol-3-yl) methyl) morpholine hydrochloride Synthesis

Adding 4- ((7- (naphthalene-2-yl) -1H-indol-3-yl) methyl) morpholine (60.0mg, 0.18mmol) into DCM (2mL), magnetically stirring to dissolve and clarify, adding HCl/EA solution (4.0mL), and carrying out ultrasonic reaction for 5 mins; concentration and drying gave 4- ((7- (naphthalen-2-yl) -1-hydro-indol-3-yl) methyl) morpholine hydrochloride (67.0mg, yield: 98.2%).

Synthesis scheme 5:

examples 30 and 31 the desired products were obtained by Buckwald coupling, reduction and substitution according to the following synthetic route

Example 30:4- (([1, 2' -binaphthyl)]-5-yl) methyl) morpholine hydrochloride

¹H NMR(400MHz,CDCl3)δ：8.39(dt,J＝8.5,1.2Hz,1H),7.98–7.84(m,5H),7.66–7.58(m, 2H),7.57–7.50(m,3H),7.48–7.42(m,1H),7.34(dd,J＝8.5,6.8Hz,1H),3.96(s,2H),3.78–3.67(m,4H),2.56(t,J＝4.7Hz,4H).MS(ESI)m/z 354.2([M+H]⁺).

Step 1 Synthesis of (5-bromonaphthalen-1-yl) (morpholine) methyl ketone

5-bromo-1-naphthoic acid (300.0mg, 1.19mmol) and oxalyl chloride (453.14mg, 3.57mmol) were dissolved in DCM (10.0mL) and reacted for 2h at ambient temperature, concentrated, morpholine (124.58mg, 1.43mmol) and Et were added₃Reacting N (240.83mg,2.38 mmol) in DCM (10.0mL) at normal temperature for 12 h; after the reaction, water (80mL) was added to quench, EA extraction (50mLx3) was performed, the organic phases were combined, washed with saturated brine (50mLx3), dried over anhydrous sodium sulfate, filtered, concentrated to give crude oil, and column chromatography was performed to give (5-bromonaphthalen-1-yl) (morpholine) methyl ketone (50mg, yield: 13.1%).

Step 2 Synthesis of [1, 2' -Binaphthalen ] -5-Yl (Morpholino) methyl Ketone

(5-Bromomaphthalen-1-yl) - (morpholine) methyl ketone (50.0mg, 0.16mmol), 2-naphthalene boronic acid (55.04mg, 0.32mmol) were added) Cesium fluoride (72.91 mg,0.48mmol), TEBA (3.64mg, 0.016mmol) and Pd (dppf)₂Cl₂(13.07mg, 0.016mmol), Toluene/H was added₂O (10.0mL) is dissolved and stirred to react for 12h at the temperature of 98 ℃; after the reaction is finished, EA is extracted (50mLx3), organic phases are combined, the organic phases are washed by saturated saline (50mLx3), dried by anhydrous sodium sulfate, filtered and concentrated to obtain oily crude products, and the oily crude products are obtained by column chromatography to obtain the [1, 2' -dinaphthalene]-5-yl (morpholine) methyl ketone (50mg, yield: 85.0%).

Step 3.4 Synthesis of- [1, 2' -Binaphthalen ] -5-ylmethylmorpholine

Dissolve [1, 2' -dinaphthalen ] -5-yl (morpholine) methyl ketone (220.0mg, 0.60mmol) and CAH (56.93mg, 1.5mmol) in THF (10.0mL) and stir at 60 ℃ for 12 h; after completion of the reaction, water (80mL) was added to quench, EA extraction (50mLx3) was performed, the organic phases were combined, washed with saturated brine (50mLx3), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to give crude oil, and column chromatography (PE/EA 5/1) was performed to give 4- [1, 2' -binaphthyl ] -5-ylmethyl morpholine (40.0mg, yield: 18.9%).

Step 4.4 salification of- [1, 2' -Binaphthalen ] -5-ylmethyl ] -morpholine hydrochloride

Adding HCl/EA (4.0mL) into DCM (2mL) solution of 4- [1, 2' -dinaphthalene ] -5-ylmethyl morpholine (45.0mg, 0.13mmol), stirring to dissolve and clarify, and performing ultrasonic reaction for 5 min; after concentration and drying, 4- [1, 2' -binaphthyl ] -5-ylmethyl-morpholine hydrochloride (50mg, yield: 98.7%) was obtained.

Example 31:4- ((5- (quinolin-6-yl) naphthalen-1-yl) methyl) morpholine hydrochloride

The title compound was prepared by substituting 2-naphthaleneboronic acid for 6-quinolineboronic acid in the same manner as in example 30.

¹H NMR(400MHz,Methanol-d₄)δ9.39-9.23(m,2H),8.54-8.45(m,2H),8.45-8.25(m,2H), 8.24-8.14(m,1H),7.99(dt,J＝8.6,1.1Hz,1H),7.94-7.83(m,2H),7.80-7.55(m,2H),5.01(s, 2H),4.16-3.99(m,3H),3.80(td,J＝13.1,11.8,3.7Hz,2H),3.46(dd,J＝10.6,3.4Hz,4H).MS (ESI)m/z 355.2([M+H]⁺)。

Synthesis scheme 6:

examples 32 to 34 the target products were obtained by Buckwald coupling, reduction and substitution according to the following synthetic routes

Example 32:4- (2- (4-naphthalen-2-yl) -1H-indazol-1-yl) ethyl) morpholine hydrochloride

¹H NMR(400MHz,CDCl₃)δ：8.20(d,J＝0.9Hz,1H),8.16(d,J＝1.6Hz,1H),7.99(d,J＝8.5Hz, 1H),7.92(td,J＝8.3,7.9,3.0Hz,2H),7.84(dd,J＝8.5,1.8Hz,1H),7.57–7.42(m,4H),7.35(dd, J＝6.9,1.1Hz,1H),4.58(t,J＝7.0Hz,2H),3.74–3.65(m,4H),2.93(t,J＝7.0Hz,2H),2.61– 2.48(m,4H).MS(ESI)m/z 358.15([M+H]⁺).

Step 1.4- (2- (4-bromo-1-hydro-indazol-1-yl) ethyl) morpholine synthesis

4-bromoindazole (300.0mg, 1.52mmol), 4- (2-chloroethyl) morpholine hydrochloride (339.9mg, 1.83mmol), and K₂CO₃(631.3mg,4.56mmol) and KI (252.7mg, 1.52mmol) were dissolved in DMF (5.0mL) and the reaction was stirred at 78 ℃ for 12-18 h; after the reaction is finished, EA is extracted (50mLx3), organic phases are combined and saturated common salt is used for the organic phasesWashed with water (50mLx3), dried over anhydrous sodium sulfate, filtered, concentrated to give crude oil, which was purified by column chromatography (EA/PE 1/2-1/1) to give 4- (2- (4-bromo-1-hydro-indazol-1-yl) ethyl) morpholine (240.0mg, yield: 50.9%).

Step 2.4 Synthesis of (2- (4- (naphthalen-2-yl) -1H-indazol-1-yl) ethyl) morpholine

4- (2- (4-bromo-1-hydro-indazol-1-yl) ethyl) morpholine (240.0mg,0.77mmol), 2-naphthalene boronic acid (266.6mg,1.55 mmol), K₂CO₃(268.12mg,1.94mmol) and Pd (dppf)₂Cl₂(20.0mg,0.077mmol) was dissolved in 10.0mL of 1,4-dioxane/H₂O, stirring and reacting for 12-18h at 90 ℃; EA extraction (50mLx3), organic phases were combined, the organic phase was washed with saturated brine (50mLx3), dried over anhydrous sodium sulfate, filtered, concentrated to give crude oil, and column chromatography (EA/PE 1/2-1/1) gave 4- (2- (4- (naphthalen-2-yl) -1 h-indazol-1-yl) ethyl) morpholine (80.0mg, yield: 29.1%).

Step 3.4- (2- (4- (naphthalen-2-yl) -1H-indazol-1-yl) ethyl) morpholine hydrochloride Synthesis

4- (2- (4- (naphthalen-2-yl) -1 h-indazol-1-yl) ethyl) morpholine (80.0mg, 0.22mol) was dissolved in 2mL DCM and 4.0mL HCl/EA was added to precipitate a white solid; after concentration and drying, 4- (2- (4- (naphthalen-2-yl) -1 h-indazol-1-yl) ethyl) morpholine hydrochloride (65.0mg, yield: 75.0%) was obtained.

Example 33:4- (2- (4- (naphthalen-2-yl) -1H-benzimidazol-1-yl) ethyl) morpholine hydrochloride

The title compound was prepared as in example 32 substituting 4-bromoindazole for 4-bromobenzimidazole.

1H NMR(400MHz,CDCl3)δ：8.46(d,J＝1.7Hz,1H),8.17(dd,J＝8.6,1.8Hz,1H),8.11(s,1H), 7.99–7.93(m,2H),7.90–7.85(m,1H),7.57(dd,J＝5.1,3.4Hz,1H),7.52–7.46(m,2H),7.45– 7.40(m,2H),4.33(t,J＝6.3Hz,2H),3.76–3.66(m,4H),2.83(t,J＝6.3Hz,2H),2.58–2.47(m, 4H).MS(ESI)m/z 358.2([M+H]⁺)。

Example 34:4- (2- (4-naphthalen-2-yl) -7 hydro-pyrrolo [2, 3-d)]Pyrimidin-7-yl) ethyl) morpholine hydrochloride

The title compound was prepared by the method of example 32 substituting 4-bromoindazole for 4-bromo-7 hydro-pyrrolo [2,3-d ] pyrimidine.

¹H NMR(400MHz,Chloroform-d)δ：9.00(s,1H),8.72–8.60(m,1H),8.26(dd,J＝8.5,1.8Hz, 1H),8.00(t,J＝8.9Hz,2H),7.92(d,J＝9.7Hz,1H),7.61–7.50(m,2H),7.41(d,J＝3.6Hz,1H), 6.92(d,J＝3.6Hz,1H),4.46(t,J＝6.4Hz,2H),3.76–3.64(m,4H),2.83(t,J＝6.4Hz,2H),2.55 (dd,J＝5.7,3.7Hz,4H).MS(ESI)m/z 359.2([M+H]⁺).

Synthesis scheme 7:

example 35 the target product was obtained by Buckwald coupling, reduction and substitution according to the following synthetic route

Example 35:4- (2- ((8- (naphthalen-2-yl) quinolin-4-yl) oxy) ethyl) morpholine hydrochloride

¹H NMR(400MHz,CDCl3)δ：8.78(d,J＝5.1Hz,1H),8.26(dd,J＝8.3,1.5Hz,1H),8.09(d,J＝1.6Hz,1H),7.96–7.79(m,5H),7.60(dd,J＝8.3,7.1Hz,1H),7.49(dt,J＝6.2,3.4Hz,2H),6.77 (d,J＝5.2Hz,1H),4.39(t,J＝5.6Hz,2H),3.82–3.73(m,4H),3.02(t,J＝5.6Hz,2H),2.70(t,J＝ 4.7Hz,4H).MS(ESI)m/z 385.2([M+H]⁺).

Step 1.4 Synthesis of (2- ((8-bromoquinolin-4-yl) oxy) ethyl) morpholine

8-bromo-4-hydroxyquinoline (300.0mg, 1.34mmol), 4- (2-chloroethyl) morpholine hydrochloride (299.59mg, 1.61mmol), K₂CO₃(463.0mg, 3.35mmol) and KI (222.44mg, 1.34mmol) were dissolved in DMF (5.0mL) and reacted at 78 ℃ for 12 h; after the reaction was completed, EA extraction (50mLx3), organic phases were combined, the organic phase was washed with saturated brine (50mLx3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude oil 355.8mg, which was subjected to column chromatography (DCM/MeOH ═ 20:1) to obtain 4- (2-) ((8-bromoquinolin-4-yl) oxy) ethyl) morpholine (160.0mg, yield: 35.4%).

Step 2.4 Synthesis of- (2- ((8-naphthalen-2-yl) quinolin-4-yl) oxy) ethyl) morpholine

A mixture of 4- (2- ((8-bromoquinolin-4-yl) oxy) ethyl) morpholine (160.0mg, 0.47mmol), 2-naphthaleneboronic acid (161.67mg, 0.94 mmol), cesium fluoride (214.18mg,1.41mmol), TEBA (11.39mg, 0.05mmol) and Pd (dppf)₂Cl₂(40.83 mg, 0.05mmol) in Toluene/H₂O (20.0mL), stirring and reacting for 15h at 98 ℃; after the reaction was completed, EA extraction (50mLx3), organic phases were combined, the organic phase was washed with saturated brine (50mLx3), dried over anhydrous sodium sulfate, filtered, concentrated to give crude oil, and column chromatography (DCM/MeOH ═ 40/1) was performed to give 4- (2- ((8-naphthalen-2-yl) quinolin-4-yl) oxy) ethyl) morpholine (88.0mg, yield: 48.7%).

Step 3.4 Synthesis of 4- (2- ((8-Naphthalen-2-yl) quinolin-4-yl) oxy) ethyl) morpholine hydrochloride

Dissolving 4- (2- ((8-naphthalen-2-yl) quinolin-4-yl) oxy) ethyl) morpholine (75.0mg, 0.19mol) in DCM (2mL), adding HCl/EA (1.0mL), and carrying out ultrasonic reaction for 5 mins; after concentration and drying, 4- (2- ((8-naphthalen-2-yl) quinolin-4-yl) oxy) ethyl) morpholine hydrochloride (77.6mg, yield: 94.6%).

Synthesis scheme 8:

Example 36:4- (2- (1- (quinolin-6-yl) -1 h-indol-4-yl) ethyl) morpholine hydrochloride

¹H NMR(400MHz,Methanol-d4)δ9.34–9.17(m,2H),8.53(d,J＝2.1Hz,1H),8.50–8.41 (m,2H),8.15(dd,J＝8.4,5.4Hz,1H),7.80(d,J＝3.5Hz,1H),7.73(d,J＝8.3Hz,1H),7.30(dd,J ＝8.4,7.3Hz,1H),7.18(d,J＝7.2Hz,1H),7.06(m,1H),4.11(m,2H),3.87(m,2H),3.66(d,J＝ 12.6Hz,2H),3.49(m,2.9Hz,4H),3.26(m,2H).MS(ESI)m/z 358.2([M+H]⁺).

Step 1.1 Synthesis of 1- (quinolin-6-yl) -1H-indole-4-carbaldehyde

In a 200mL single-neck flask were added in this order indole-4-carbaldehyde (1.45g, 10mmol), 6-bromoquinoline (2.08g, 10.00mmol), and Cs₂CO₃(6.52g，20.00mmol)、Pd₂(dba)₃(0.92g, 1.00mmol), X-Phos (0.48g, 1.00mmol), KI (0.17g, 1.00mmol) and xylene (40 m)L)，N₂The reaction is stirred for 4 hours at 90 ℃ under protection. After TLC monitoring reaction, cooling to room temperature, filtering reaction liquid, concentrating to obtain 2.2g crude product, and performing column chromatography (eluent: EA/PE + DCM is 10% -50%) to obtain light yellow foam solid 1- (quinoline-6-yl) -1 hydrogen-indole-formaldehyde (820 mg); yield: 30.1 percent.

Step 2.6 Synthesis of- (4- [ (E) -2-methoxyvinyl) -1H-indol-1-yl ] quinoline

A100 ml three-necked flask was charged with (methoxymethyl) triphenylphosphonium chloride (4.34g, 12.67mmol), t-BuONa (1.42g, 12.67mmol) and ACN (40ml), stirred at-30 ℃ for 1.0h under nitrogen protection, added with 1- (quinolin-6-yl) -1-hydro-indole-carbaldehyde (2.3g, 8.45mmol) and stirred at 20 ℃ for 3.0. TLC monitored the reaction completion, quenched with saturated ammonium chloride (100mL), extracted with ethyl acetate (80mL), dried, and concentrated to give a crude brown oil. Column chromatography (Ea/Pe ═ 0% to 50%) afforded 6- (4- [ (E) -2-methoxyvinyl) -1 h-indol-1-yl ] quinoline (4.4g) as a brown oil which contained triphenylphosphine oxide and was used directly in the next reaction.

Step 3.2 Synthesis of (1- (quinolin-6-yl) -1H-indol-yl) acetaldehyde

Crude 6- (4- [ (E) -2-methoxyvinyl) -1 h-indol-1-yl]Quinoline (2.2g, 8mmol), hydrochloric acid (0.58g, 16.00mmol), THF (60mL), H₂O (15mL) is added into a 100mL reaction bottle in sequence, reflux reaction is carried out for 30 minutes at 70 ℃, TLC (PE: EA is 1:1+ 2% MeOH) detects that the reaction is completed, a large amount of saturated sodium bicarbonate (20mL) is added to quench the reaction liquid to be neutral, EA is extracted (30mLx3), an organic phase is separated, anhydrous magnesium sulfate is dried, and the mixture is concentrated to obtain 4g of a yellow oily crude product, and the crude product is directly subjected to the next reaction.

Step 4.4 Synthesis of 4- (2 (morpholin-4-yl) ethyl) -1- (quinolin-6-yl) -1H-indole

The crude 2- (1- (quinolin-6-yl) -1 h-indol-yl) acetaldehyde (0.24g, 1mmol), morpholine (0.13g, 1.50mmol) and TFA (0.01g, 0.10mmol) were weighed out and stirred at room temperature for 15 minutes, then NaHB (OAc) was added thereto at low temperature (0-5 ℃ C.)₃(0.85g, 4.00mmol), and after 10 minutes, the temperature was naturally raised to room temperature, and the reaction was carried out at this temperature for 40 minutes. After completion of the reaction, the reaction was quenched with saturated sodium bicarbonate (10mL), extracted with DCM (20mLx2), the organic phase was separated, dried over anhydrous magnesium sulfate, concentrated to give crude yellow oil, which was purified by pre-TLC (DCM: MeOH ═ 20:1) to give 50mg of colorless oily product.

Step 5.4 Synthesis of 4- (2 (morpholin-4-yl) ethyl) -1- (quinolin-6-yl) -1H-indole hydrochloride

4- (2 (morpholin-4-yl) ethyl) -1- (quinolin-6-yl) -1 h-indole (50mg, 0.16mmol) was dissolved in EA, dissolved well and then ethyl acetate hydrochloride solution (0.03g, 0.32mmol) was added, concentrated and dried in vacuo. 65mg of light yellow solid is obtained with a purity yield of 100%.

Example 37: 1- (2- (1- (quinolin-6-yl) -1H-indol-4 yl) ethyl) -4 (trifluoromethyl) piperidin-4-ol hydrochloride substitution of morpholine for 4- (trifluoromethyl) piperidin-4-ol the title compound was synthesized according to the procedure for example 36

¹H NMR(400MHz,Methanol-d4)δ9.38–9.12(m,2H),8.53(d,J＝2.1Hz,1H),8.51–8.36 (m,2H),8.15(dd,J＝8.5,5.4Hz,1H),7.78(d,J＝3.5Hz,1H),7.72(d,J＝8.3Hz,1H),7.28(m, 1H),7.17(m,1H),7.06(m,1H),3.81–3.64(m,2H),3.59–3.31(m,6H),2.22(m,2H),2.12–1.97 (m,2H).MS(ESI)m/z 440.2([M+H]⁺).

Watch (I)

Examples of biological activity:

certain representative compounds of the invention were tested for their activity as sigma (sigma-1 and sigma-2) inhibitors, and the specific protocol was as follows:

test Compound preparation: all the samples were dissolved in DMSO with a final concentration of 1%, e.g., poor dissolution or suspension, HCl (10%, 10. mu.L) was added as appropriate, starting at a concentration of 1.0X 10^-5M (i.e., 10. mu.M), then 1. mu.M, 333nM, 100nM, 33nM, 10nM, 3.3nM, 1nM, 0.33nM, 0.1nM, 0.01nM in that order for use.

Sigma-1 inhibitor activity assay:

receptor membrane preparation: homogenizing guinea pig whole brain with 10mM Tris-HCl buffer solution containing 320mM sucrose pH 7.4, adjusting weight, centrifuging for 10min at 1000g, collecting supernatant, adding 10mM Tris-HCl buffer solution containing sucrose pH 7.4, homogenizing, centrifuging for 10min at 1000g and 4 deg.C, collecting supernatant, centrifuging for 25min at 50000g and 4 deg.C, collecting precipitate, adding 10mM Tris-HC buffer solution containing no sucrose pH 7.4, homogenizing, 50000g, 4 deg.CCentrifuging for 25min, collecting precipitate, repeating the above operation, and storing the precipitate at-80 deg.C.

Binding assay: the prepared acceptor membrane was suspended in 10mM Tris-HCl buffer without sucrose pH 7.4 to prepare a 220mg/ml membrane suspension for use. Each reaction tube was filled with 100. mu.L of the membrane preparation. Total binding tubes 100. mu.L of 10mM Tris-HC buffer without sucrose pH 7.4 was added to binding Tubes (TB) and 100. mu.L haloperidol (final concentration 1.0X 10) was added to non-specific binding tubes (NSB)^-5M), 100 μ L of test compound was added to each test compound tube (CB). All reaction tubes were each charged with radioligand 4nM [ sic ], [ solution ] respectively³H]10. mu.L of Pentazocine. Incubating each reaction tube at 25 ℃ for 135min, after the reaction is finished, rapidly filtering the combined ligand through decompression, soaking Whatman GF/C test paper in 0.5% PEI for more than 1h in advance, fully washing the PEI with ice-cold test buffer solution, taking out a filter disc, putting the filter disc into a 4mL scintillation cup, adding 1mL toluene scintillation solution, uniformly mixing, and finally putting the scintillation bottle into an HIDEX liquid scintillation counter for counting.

Sigma-2 inhibitor activity assay

Receptor membrane preparation: the same as the preparation method of the sigma-1 receptor membrane.

Binding assay: the prepared acceptor membrane is prepared into a membrane suspension of 220mg/mL by using 10mM Tris-HCl buffer solution without sucrose for later use. mu.L of the membrane preparation was added to each reaction tube, 100. mu.L of 10mM Tris-HC buffer solution containing no sucrose and having pH 7.4 was added to the total binding Tube (TB), and 100. mu.L of DTG (final concentration: 1.0X 10) was added to the non-specific binding tube (NSB)^-5M), 100. mu.L of test compound (final concentration 1.0X 10) was added to each test compound binding tube (CB)^-5M) and 100nM (+) -NANM is added to screen sigma-1 receptors; adding radioactive ligand into each reaction tube³H-DTG 10. mu.L, final concentration 5 nM. Incubating each reaction tube at 25 ℃ for 135min, after the reaction is finished, rapidly filtering the combined ligand through decompression, soaking Whatman GF/C test paper in 0.5% PEI for more than 1h, fully washing the PEI with ice-cold test buffer solution, taking out the filter disc, putting the filter disc into a 4mL scintillation cup, adding 1mL toluene scintillation solution, and uniformly mixing. Finally, the scintillation cup was placed in a HIDEX scintillation counter in finland for counting.

And (3) calculating a Ki value:

logic method calculates each compound IC 50;

kd values and Bmax of each radioactive ligand were obtained by Scatchard plot;

table (II) shows some of the results obtained:

watch (II)

Examples of the drug efficacy test:

ICR mouse Hot plate test

Male mice were used with a weight of 18-22g, a room temperature of about 25 ℃, a hotplate temperature of 55 ℃ and a maximum hot pain threshold of 60s, and the time from resting until licking the hindpaw or jumping was recorded as the pain threshold. All mice are firstly tested for 2 times of basic pain threshold values, the basic pain threshold values are qualified within 5-30s, and unqualified mice are eliminated.

Eligible mice were randomly assigned to vehicle control, morphine (1.25, 2.5, 5, 10mg/kg) and E5286240 mg/kg + morphine (1.25, 2.5, 5, 10mg/kg) groups based on basal pain threshold. All test groups morphine were SC, E52862 (ref j.med. chem.2012,55,8211-8224 synthesis) were IP administered vehicle or test compound (dose 0.1ml/10g), pain threshold was measured at 0.5, 2h post-drug, and the maximum possible analgesic effect (MPE%) of the test compound was calculated: MPE% (post-dose-pre-dose) 100/(60-pre-dose).

Results

An ICR mouse hot plate model test result shows that the morphine dosage can be obviously reduced in example 8(EP003-D5-C020 is abbreviated as C020), and the synergistic effect reaches 2.5 times.

An ICR mouse hot plate model test result shows that the positive compound E-52862 can obviously reduce the dosage of morphine, and the synergistic effect reaches 1.9 times.

The details are shown in the following table and fig. 1:

the above table results show that: the combination of morphine and the compound to be tested and the combination of morphine and E52862 both reduce ED50 compared with the single morphine, which indicates that in the model, the combination group of the compound to be tested and the morphine and the combination group of the morphine and E52862 both enhance the drug effect of the morphine. Wherein the combined use of morphine and E52862 results in a 1.9-fold decrease in ED50 compared to morphine alone; the combined use of morphine and test compound reduced the ED50 by a factor of 2.5 when compared to morphine alone. The synergistic effect of the compound to be tested is better than that of E52862.

Formalin test

The specific operation is as follows: IP administration was performed using physiological saline as a vehicle. The administration volume of the model group was 1.3 ml/body, and the administration volume of each of the other administration groups was 5 ml/kg. The administration time of the test drug is 15min before the molding test. Before experimental testing, rats are adapted in the experimental device for 5-10min after administration. The right hind paw of the acclimatized rat was subcutaneously injected with 100. mu.L of 5% formalin solution (containing 1.85% formaldehyde) to form a skin dome as a standard for successful modeling, and if the paw was injected, the animal was discarded. And the software automatically records the foot lifting times within 1min as a time period between 0 and 60min after the molding.

And (3) data analysis: phase I, 0-10min, phase II, 10-60min, phase II-a, 10-40min, phase II-b, 40-60 min. Statistical differences between groups were detected using the t-test. Analgesic effect% (% licking number in vehicle group-licking number in dosing group) × 100%/licking number in vehicle group.

Results

The positive drug E52862(160mpk) and example 8(EP003-D5-C020 for C020) (160mpk) were both effective in the high dose group of this model; the C020 drug is effective to I, II phase pain, and the drug effect results are shown in figures 2 and 3. Wherein, FIG. 2 is the pharmacodynamic diagram of phase I pain, and FIG. 3 is the pharmacodynamic diagram of phase II pain.

Claims

1. A compound represented by formula XII:

wherein A is a substituted or unsubstituted naphthyl group,

the substituent of the substituted naphthyl is C1-5 alkyl or halogen;

in the formula IV, R₄Is methyl, ethyl or propyl;

in the formula V, R₅Is methyl, ethyl or propyl;

b is IX-1 structure:

in formula IX-1, n1, n2 are independently integers from 0 to 3, Z₄One selected from C, O, S, N; r is₂And R₃Independently selected from hydrogen, haloalkyl, hydroxy, alkyl, cycloalkyl, and amide;

the halogenated alkyl is C1-5 halogenated alkyl; the alkyl is C1-5 alkyl; the cycloalkyl is C3-5 cycloalkyl; the amide is acetamide, trifluoroacetamide, propionamide or isobutyramide.

2. A compound of formula XII, or a pharmaceutically acceptable salt thereof, as in claim 1 wherein in formula IX-1 n2 is an integer from 1 to 3, n1 is 2, Z is₄One selected from C, O, S, N; r₂And R₃Independently selected from hydrogen, trifluoromethyl, hydroxyl and methyl.

3. A compound represented by formula XI:

wherein n3 is an integer of 0 to 3, R₇A substituent selected from hydrogen, substituted or unsubstituted C1-5 alkyl and halogen, said substituted C1-5 alkyl being selected from halogen; the halogen is fluorine, chlorine, bromine or iodine; key with a key body

Is any one of a bond "-" or is absent;

K₁、K₂、K₃、K₄、K₅is selected from N or C.

4. The compound of formula XI according to claim 3, wherein the alkyl group from C1 to C5 is selected from methyl, ethyl, propyl, butyl or pentyl.

5. A compound represented by formula X:

wherein the content of the first and second substances,

Q₃、Q₄independently selected from N or C; k₆Is selected from N or C; n4 is an integer selected from 0 to 3, Z₆Selected from O or CH₂。

6. Such as the rightA compound of formula X according to claim 5 or a pharmaceutically acceptable salt thereof, K₆Is C, Z₆Is CH₂。

7. A compound or a pharmaceutically acceptable salt thereof, selected from any one of the compounds shown below:

4- ((1- (naphthalen-2-yl) -1H-indol-4-yl) methyl) morpholine or its hydrochloride,

4- ((4-methylpiperazin-1-yl) methyl) -1- (naphthalen-2-yl) -1 h-indole or its hydrochloride,

4- ((4-cyclopropylpiperazin-1-yl) methyl) -1- (naphthalen-2-yl) -1-hydro-indole or its hydrochloride,

2-methyl-1- (4- ((1- (naphthalen-2-yl) -1 h-indol-4-yl) methyl) piperazin-1 yl) propan-1-one or its hydrochloride,

4- ((1- (quinolin-7-yl) -1 h-indol-4-yl) methyl) morpholine or the hydrochloride thereof,

4- ((1- (quinolin-6-yl) -1 h-indol-4-yl) methyl) morpholine or the hydrochloride thereof,

4- ((1- (isoquinolin-6-yl) -1H-indol-4-yl) methyl) morpholine or its hydrochloride,

4- ((1- (1-methyl-1-hydro-indazol-5-yl) -1-hydro-indol-4-yl) methyl) morpholine or its hydrochloride,

4- ((1- (2-methyl-1H-indazol-5-yl) -1H-indol-4-yl) methyl) morpholine or its hydrochloride,

4- ((1- (quinolin-6-yl) -1 h-indol-4-yl) methyl) thiomorpholine or a hydrochloride thereof,

4- ((1- (naphthalen-2-yl) -1H-indol-4-yl) methyl) thiomorpholine or its hydrochloride,

4-methyl-1- ((1-naphthalen-2-yl) -1 h-indol-4-yl) methyl) piperidin-4-yl or its hydrochloride,

1- ((1- (quinolin-6-yl) -1 h-indol-4-yl) methyl) -4- (trifluoromethyl) piperidin-4-yl or the hydrochloride thereof,

4-methyl-1- ((1- (quinolin-6-yl) -1 h-indol-4-yl) methyl) piperidin-4-yl or the hydrochloride thereof,

3-methyl-1- ((1- (quinolin-6-yl) -1 h-indol-4-yl) methyl) pyrrolidin-3-yl or its hydrochloride,

4- ((7-naphthalen-2-yl) -1-hydro-indol-3-yl) methyl) morpholine or its hydrochloride,

4- (([1, 2' -dinaphthalen ] -5-yl) methyl) morpholine or a hydrochloride thereof,

4- ((5- (quinolin-6-yl) naphthalen-1-yl) methyl) morpholine or the hydrochloride salt thereof,

4- (2- (4-naphthalen-2-yl) -1-hydro-indazol-1-yl) ethyl) morpholine or its hydrochloride salt,

4- (2- (4- (naphthalen-2-yl) -1H-benzimidazol-1-yl) ethyl) morpholine or its hydrochloride,

4- (2- (4-naphthalen-2-yl) -7-hydro-pyrrolo [2,3-d ] pyrimidin-7-yl) ethyl) morpholine or its hydrochloride salt,

4- (2- ((8- (naphthalen-2-yl) quinolin-4-yl) oxy) ethyl) morpholine or its hydrochloride salt,

4- (2- (1- (quinolin-6-yl) -1 h-indol-4-yl) ethyl) morpholine or its hydrochloride,

1- (2- (1- (quinolin-6-yl) -1 h-indol-4-yl) ethyl) -4 (trifluoromethyl) piperidin-4-ol or the hydrochloride salt thereof.

8. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

9. Use of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 8, for the manufacture of a medicament for the treatment and prevention of a sigma receptor associated disease or condition.

10. The use according to claim 9, wherein the sigma receptor related disease is pain.

11. Use according to claim 10, wherein the pain is selected from neuropathic or inflammatory pain, post-operative pain, cancer pain, burn pain, phantom limb pain.

12. The use according to claim 10, wherein the pain is selected from trigeminal neuralgia, osteoarthritis pain.