MRGPRX2 antagonist, pharmaceutical composition and application thereof

Abstract

MRGPRX2 antagonist, pharmaceutical composition and application of MRGPRX2 antagonist and pharmaceutical composition. The MRGPRX2 antagonist has structural formula as shown in formula I;

Description

A MRGPRX2 antagonist, pharmaceutical composition and use thereof Technical Field

[0001] The present disclosure relates to the field of medicine, and in particular to a MRGPRX2 antagonist, a pharmaceutical composition, and uses thereof. Background Art

[0002] MRGPRX2 is a receptor expressed on mast cells found in barrier tissues (e.g., skin, airways, gastrointestinal tract) that is activated by numerous ligands, including peptides released from sensory neurons and other cell types. In response to MRGPRX2 activation, mast cells degranulate and release histamine, tryptase, chylothin, chemokines, and cytokines, which in turn trigger urticaria, angioedema, type 2 inflammation (through engagement of the adaptive immune system), and chronic itch and pain.

[0003] Mast cells, as one of the key effector cells in the immune response, are a crucial link between the nervous and immune systems. Due to their close proximity to nerve endings, mast cells have a distinct spatial advantage over other innate immune cells, allowing them to be the first to respond to sensory nerve activation. Disturbances in mast cell-nerve interactions are considered a major factor in the pathogenesis of neurogenic inflammation and pain.

[0004] When mast cells are activated, they release a wide range of pro-inflammatory cytokines and chemokines that can act on specific receptors on sensory nerve endings, causing the nerve endings to release neuropeptides such as substance P (SP) and vasoactive intestinal peptide (VIP). These neuropeptides in turn activate receptors on mast cells, inducing further degranulation of mast cells to release a large number of pro-inflammatory factors and chemokines, causing neurogenic inflammation. In addition to this local interaction between mast cells and sensory nerves, pain signals can also be transmitted through nerve endings Ca 2+ The mediated axonal potential amplification causes the excitation of the terminal fibers, and the generated nerve signals can reach the central nervous system along the axons; neurogenic peptide substances such as SP and VIP can activate mast cells through MRGPRX2 receptors, which indicates that MRGPRX2 contributes to the development of neurogenic inflammation and pain.

[0005] In recent years, with the deepening of research on MRGPRX2, it has been found that the function of MRGPRX2 is becoming increasingly important. This receptor is not only widely involved in the body's non-IgE-mediated hypersensitivity reactions, neurogenic inflammation, pain and convulsions, but also can promote the skin and intestines' innate immune response to harmful stimuli or pathogen invasion. Therefore, this receptor is likely to become a potential target for the development of anti-inflammatory and analgesic drugs in the future.

[0006] By blocking MRGPRX2 activation and mast cell degranulation, MRGPRX2 antagonists have the potential to treat a wide range of mast cell-mediated diseases.

[0007] Summary of the Invention

[0008] The present disclosure provides compounds of formula (I)

[0009] or its stereoisomers, tautomers, solvates, hydrates, active metabolites, isotope labels, and pharmaceutically acceptable salts. The compound has the activity of an MRGPRX2 antagonist and can be used to treat diseases mediated by mast cells.

[0010] The present disclosure also provides a pharmaceutical composition comprising the above-mentioned compound of the present disclosure or its stereoisomers, tautomers, solvates, hydrates, active metabolites, isotope-labeled substances or pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier.

[0011] The present disclosure also provides the use of the disclosed compounds or their stereoisomers, tautomers, solvates, hydrates, active metabolites, isotope-labeled substances or pharmaceutically acceptable salts, and pharmaceutical compositions in the preparation of drugs for inhibiting MRGPRX2 activity.

[0012] The present disclosure also provides the use of the disclosed compounds or their stereoisomers, tautomers, solvates, hydrates, active metabolites, isotopically labeled or pharmaceutically acceptable salts, and the disclosed pharmaceutical compositions in the preparation of a medicament for treating an MRGPRX2-mediated disorder in a subject.

[0013] The present disclosure also provides a method for treating inflammatory disorders, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure or its stereoisomers, tautomers, solvates, hydrates, active metabolites, isotopically labeled forms or pharmaceutically acceptable salts, as well as the pharmaceutical compositions of the present disclosure. DETAILED DESCRIPTION

[0014] The present disclosure is further described in detail below through examples, through which the features and advantages of the present disclosure will become more clear and distinct.

[0015] The word “exemplary” is used exclusively herein to mean “serving as an example, example, or illustration.” Any embodiment described herein as “exemplary” is not necessarily to be construed as preferred or advantageous over other embodiments.

[0016] In addition, the technical features involved in different embodiments of the present disclosure described below can be combined with each other as long as they do not conflict with each other.

[0017] definition

[0018] Unless otherwise defined, all technical and scientific terms herein have the same meanings as commonly understood by those skilled in the art to which the claimed subject matter belongs. Unless otherwise indicated, all patents, patent applications, and publications cited herein are incorporated by reference in their entirety. When trade names appear in this document, they are intended to refer to the corresponding commercial products or their active ingredients.

[0019] It should be understood that the foregoing brief description and the following detailed description are exemplary and explanatory only and do not limit the subject matter of the present invention in any way. In this disclosure, it must be noted that, unless otherwise clearly indicated, the singular forms used in this specification and claims include the plural forms of the referents. It should also be noted that, unless otherwise indicated, the use of "or" and "or" means "and / or". In addition, the use of the term "include" and other forms, such as "comprises", "includes" and "comprising" are not limiting.

[0020] Definitions of standard chemical terms can be found in the literature, including Advanced Organic Chemistry by Carey and Sundberg. th Ed, Vol A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods within the skill of the art, such as mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacological methods, are employed. Unless specifically defined, nomenclature and laboratory procedures and techniques in analytical chemistry, organic synthetic chemistry, and medicinal and pharmaceutical chemistry are known to those skilled in the art. Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, drug delivery, and patient treatment. Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipid filtration). For example, reactions and purification techniques can be performed using kits with manufacturer's instructions, or according to methods known in the art, or as described in this disclosure. In general, the aforementioned techniques and steps can be performed by conventional methods well known in the art and described in various general or more specific literature, which are cited and discussed in this disclosure.

[0021] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents that would result if the formula were written from right to left. For example, CH2O is equivalent to OCH2.

[0022] The term "substituted or unsubstituted" includes both "substituted" and "unsubstituted", where "substituted" means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, as long as the valence state of the specific atom is normal and the compound after substitution is stable; "unsubstituted" means that the hydrogen atoms on the specific atom are not replaced by a substituent. For example, "substituted or unsubstituted ethyl" (for example, when the substituent is a halogen) includes unsubstituted (-CH2CH3), monosubstituted (such as -CH2CH2F), polysubstituted (such as -CHFCH2F, -CH2CHF2, etc.) or fully substituted (-CF2CF3). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible to exist and / or cannot be synthesized will be introduced. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms on the same atom are replaced.

[0023] When any variable (e.g., R) occurs more than once in a composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may optionally be substituted with up to two Rs, and each instance of R has independent options. In addition, combinations of substituents and / or their variants are permitted only if such combinations result in stable compounds. The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes both the occurrence of the event or circumstance and the non-occurrence of the event or circumstance.

[0024] The C m～n It means that there are m to n carbon atoms in the part. For example, the “C 1～8 " group means that the part has 1-8 carbon atoms, that is, the group contains 1 carbon atom, 2 carbon atoms, 3 carbon atoms...8 carbon atoms. Therefore, for example, "C 1～8 "Alkyl" refers to an alkyl group containing 1 to 8 carbon atoms, that is, the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl...octyl, etc. The numerical ranges herein, such as "1-8", refer to each integer in the given range, for example, "1-8 carbon atoms" means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms or 8 carbon atoms.

[0025] The term "alkyl" refers to an optionally substituted straight chain or optionally substituted branched saturated aliphatic hydrocarbon group that is attached to the rest of the molecule by a single bond. "Alkyl" herein can have 1 to about 8 carbon atoms, for example, 1 to 6 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms. Examples of "alkyl" herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, and the like, as well as longer alkyl groups such as heptyl and octyl, etc. When a group as defined herein, such as "alkyl" appears in a numerical range, for example, "C 1-8 "Alkyl" refers to an alkyl group consisting of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, or 8 carbon atoms. For example, "C 1-4 The term "alkyl" refers to an alkyl group which may be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. The alkyl group herein also includes the case where no numerical range is specified.

[0026] The term "alkenyl" refers to an optionally substituted straight chain or optionally substituted branched monovalent hydrocarbon group having at least one C=C double bond. The alkenyl group has, but is not limited to, 2 to about 8 carbon atoms, such as 2 to about 6 carbon atoms, 2 to about 4 carbon atoms. The double bonds in these groups can be in cis or trans conformations and should be understood to include both isomers. Examples of alkenyl groups include, but are not limited to, vinyl (CH=CH2), 1-propenyl (CH2CH=CH2), isopropenyl (C(CH3)=CH2), butenyl and 1,3-butadienyl, etc. When a numerical range appears for alkenyl as defined herein, for example, "C 2-8 The term "alkenyl" refers to an alkenyl group which may be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms or 8 carbon atoms. The alkenyl group herein also encompasses the case where no numerical range is specified.

[0027] The term "alkynyl" refers to an optionally substituted linear or branched monovalent hydrocarbon group having at least one C≡C triple bond. The alkynyl group has, but is not limited to, 2 to about 8 carbon atoms, such as 2 to about 6 carbon atoms, or 2 to about 4 carbon atoms. Examples of alkynyl groups herein include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, and 1,3-butadiynyl. When a numerical range appears for an alkynyl group as defined herein, for example, "C2-8 The term "alkynyl" refers to an alkynyl group which may be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, or 8 carbon atoms. The alkynyl group herein also encompasses the case where no numerical range is specified.

[0028] The term "cycloalkyl" refers to a non-aromatic carbon ring, including a saturated carbocyclic ring (such as a cycloalkyl group) or an unsaturated carbocyclic ring (such as a cycloalkenyl group). Carbocyclic rings include monocarbocyclic rings (having one ring), for example, a monocyclic cycloalkyl group; bicarbocyclic rings (having two rings), for example, a bicyclic cycloalkyl group; and polycarbocyclic rings (having more than two rings). The rings may be bridged or spirocyclic. Carbocyclic rings (such as cycloalkyl or cycloalkenyl groups) may have 3 to 8 carbon atoms, for example, 3 to about 6 ring-forming carbon atoms or 3 to about 5 ring-forming carbon atoms.

[0029] The term "aryl" refers to an optionally substituted aromatic hydrocarbon group having 6 to about 20, such as 6 to 12 or 6 to 10, ring-forming carbon atoms, which can be a monocyclic aromatic group, a bicyclic aromatic group, or a polycyclic aromatic group. A bicyclic aromatic group or a polycyclic aromatic group can be a monocyclic aromatic group fused to another independent ring, such as an alicyclic ring, a heterocyclic ring, an aromatic ring, or an aromatic heterocyclic ring. Non-limiting examples of monocyclic aromatic groups include monocyclic aromatic groups having 6 to about 12, 6 to about 10, or 6 to about 8 ring-forming carbon atoms, such as phenyl; bicyclic aromatic groups are exemplified by naphthyl; and polycyclic aromatic groups are exemplified by phenanthrenyl, anthracenyl, and azulenyl.

[0030] The term "heteroaryl" refers to an arbitrarily substituted heteroaryl group comprising from about 5 to about 20, such as 5 to 12 or 5 to 10 skeleton ring atoms, wherein at least one (such as 1-4, 1-3, 1-2) ring atoms is a heteroatom, and the heteroatoms are independently selected from the heteroatoms of oxygen, nitrogen, sulfur, phosphorus, silicon, selenium and tin, but are not limited thereto. Heteroaryl groups include monocyclic heteroaryl groups (having one ring), bicyclic heteroaryl groups (having two rings) or polycyclic heteroaryl groups (having more than two rings). In embodiments where two or more heteroatoms appear in a ring, the two or more heteroatoms may be the same as each other, or some or all of the two or more heteroatoms may be different from each other. Bicyclic heteroaryl groups or polycyclic heteroaryl groups may be a monocyclic heteroaryl group fused to other independent rings, such as alicyclic, heterocyclic, aromatic, or aromatic heterocyclic rings (collectively referred to as fused ring heteroaryl groups). Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, and the like.

[0031] The term "heterocyclyl" refers to a non-aromatic heterocycle, including a saturated heterocycle or an unsaturated heterocycle (containing an unsaturated bond), which does not have a completely conjugated π-electron system and can be classified as a monocyclic, fused polycyclic, bridged, or spirocyclic system without aromaticity. One or more (e.g., 1-4, 1-3, 1-2) of the atoms forming the ring are heteroatoms, such as oxygen, nitrogen, or sulfur atoms. The heterocycle can include a monocyclic heterocycle (having one ring), a bicyclic heterocycle (having two bridged rings), or a polycyclic heterocycle (having more than two bridged rings); spirocycles are also included. The heterocyclic group can have 3 to about 20, such as 3 to about 10, 3 to about 8, 4 to 8, 4 to 7, 5 to about 8, or 5 to about 6 ring atoms. Non-limiting examples of heterocyclyl groups include oxiranyl, thioranyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, oxazolidinyl, tetrahydropyrazolyl, pyrrolinyl, dihydrofuranyl, dihydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyranyl, tetrahydropyranyl, dihydrothiopyranyl, azepanyl, oxepanyl, thiepanyl, oxazabicyclo[2.2.1]heptyl, and azaspiro[3.3]heptyl, and the like.

[0032] The term "halo" or "halogen" refers to an optionally substituted group (such as an alkyl, alkenyl, alkynyl, alkoxy group, etc.) in which at least one hydrogen atom is replaced with a halogen (such as fluorine, chlorine, bromine, iodine, or a combination thereof). In some embodiments, two or more hydrogen atoms are replaced with halogen atoms that are identical to each other (e.g., difluoromethyl, trifluoromethyl); in other embodiments, two or more hydrogen atoms are replaced with halogen atoms that are not identical to each other (e.g., 1-chloro-1-fluoro-1-iodoethyl).

[0033] The term "alkoxy" refers to an alkyl ether group (O-alkyl). Non-limiting examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.

[0034] The term "alkyl acyl" refers to a group consisting of an alkyl group connected to a -CO- group. Non-limiting examples of this term include formyl, acetyl, propionyl, butyryl, etc. For example, the term "C 1-6 "Alkyl acyl" refers to C 1-6 An alkyl group connected to -CO-. For example, the term "C 1-4 "Alkyl acyl" refers to C 1-4 A group formed by connecting an alkyl group to a -CO- group.

[0035] The term "alkylsulfonyl" refers to a group consisting of an alkyl group connected to -SO2-, and non-limiting examples of the term include methylsulfonyl, ethylsulfonyl, propanesulfonyl, butanesulfonyl, etc. For example, the term "C 1-6 "Alkylsulfonyl" refers to C1-6 An alkyl group connected to -SO2-. For example, the term "C 1-4 "Alkylsulfonyl" refers to C 1-4 A group formed by connecting an alkyl group to a -SO2- group.

[0036] The term "heteroaryl acyl" refers to a group consisting of a heteroaryl group linked to a -CO- group. For example, the term "C 5～20 "Heteroarylsulfonyl" refers to C 5～20 A group consisting of a heteroaryl group and a -CO- group. 5～20 "Heteroaryl" is as defined above.

[0037] The term "monocycle", "monocyclic group" or "monocyclic ring system" refers to a structure of one ring (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl and / or heterocyclyl). The term "polycyclic group", "polycyclic group" or "polycyclic ring system" refers to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl and / or heterocyclyl) wherein two adjacent rings share one, two or more ring atoms, e.g., the polycyclic rings may be "fused rings", "spiro rings" or bridged ring structures.

[0038] The term "polycyclic carbocycle" includes bicyclic carbocycles and carbocycles with more than one ring. The term "bicyclic carbocycle" refers to an aromatic or non-aromatic ring containing two rings, wherein each atom in the ring is carbon, and wherein the two rings share one, two, or more ring atoms. For example, the rings are "fused rings" or "spirocycles." Rings connected by non-adjacent atoms are called "bridged" rings, for example, C5-C 12 Bridged carbocycles include, but are not limited to, bicyclo[2.2.2]octyl, bicyclo[1.1.1]pentyl, bicyclo[3.2.1]octyl, and bicyclo[2.1.1]hexyl. Each ring of the bicyclic carbocycle may be substituted with substituents as described above, such as halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amide, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclic, aromatic or heteroaromatic moiety, -CF3, -CN, and the like. The term "C5-C 12 "Bicyclic carbocycle" means that the number of carbon atoms in the bicyclic carbocycle ring is 5-12, not including the carbon atoms in its substituents, which may include C5-C 12 Spirocarbon ring, C5-C 12 Fused carbocyclic or C5-C 12 Bridged carbon rings.

[0039] The term "membered" refers to the number of atoms that make up the ring. For example, pyridine is a six-membered ring, and pyrrole is a five-membered ring.

[0040] In the present disclosure, each group may have the following definitions:

[0041] Hydrogen can be represented as -H, or it can be replaced by isotopes such as deuterium and tritium.

[0042] Halogen may include fluorine, chlorine, bromine, and iodine.

[0043] C 1～8 The alkyl group may include methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, heptyl, octyl, and the like.

[0044] Deuterated C 1～8 Alkyl, tritiated C 1～8 Alkyl can represent the C 1～8 One or more or even all hydrogen atoms on the alkyl group are replaced by isotopes such as deuterium and tritium.

[0045] C 1～8 Alkoxy can be represented by -OC 1～8 Alkyl, where C 1～8 Alkyl groups include those defined above; for example, C 1～8 Alkoxy groups may include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.

[0046] C 1～8 Halogenated alkyl can be represented by C 1～8 A group in which any number of hydrogen atoms in an alkyl group are replaced by halogens, wherein C 1～8 The groups included in alkyl and halogen are as defined above; for example, C 1～8 The haloalkyl group may include -CF3 and the like.

[0047] C 3～8 Cycloalkyl can be represented by a non-aromatic saturated carbocyclic ring, including monocarbocyclic rings (having one ring) and bicarbocyclic rings (having two rings), for example, C 3～8 Cycloalkyl groups may include wait.

[0048] C 3～8 Cycloalkyl C 1～8 Alkyl groups can be represented by C 3～8 Cycloalkyl C 1～8 Alkyl, where C3～8 Cycloalkyl and C 1～8 The definition of alkyl is as above, for example, C 3～8 Cycloalkyl C 1～8 The alkyl group may include cyclopropylmethyl, cyclobutylmethyl, cyclohexylethyl, and the like.

[0049] C 3～8 Heterocyclic groups can be represented by C 3～8 A group obtained by replacing any number of ring atoms in a cycloalkyl group with heteroatoms such as O, S, N, P, and Si, wherein C 3～8 The groups included in the cycloalkyl group are as defined above. For example, C 3～8 Heterocyclyl groups can include oxiranyl, thioranyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, oxazolidinyl, tetrahydropyrazolyl, pyrrolinyl, dihydrofuranyl, dihydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyranyl, tetrahydropyranyl, dihydrothiopyranyl, azepanyl, oxepanyl, thiepanyl, oxazabicyclo[2.2.1]heptyl, azaspiro[3.3]heptyl, and the like.

[0050] C 6～20 The aryl group may include a monocyclic aryl group, a bicyclic aryl group, or more cyclic aryl groups, and for example, may include phenyl, biphenyl, naphthyl, phenanthrenyl, anthracenyl, azulenyl, and the like.

[0051] C 5～20 Heteroaryl can represent an unsaturated group containing any number of heteroatoms such as O, S, N, P, Si as ring atoms. 5～20 Heteroaryl groups can include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, and the like.

[0052] The hydroxyl group can be represented as -OH.

[0053] A mercapto group can be represented as -SH.

[0054] The carboxyl group can be represented as -COOH.

[0055] The ester group can be represented by -COOR', where R' can be C 1～8 Alkyl groups, such as C 1～8 Alkyl substituted ester groups can be represented as -COOC 1～8 Alkyl, where C 1～8 Alkyl groups include groups as defined above.

[0056] Acyl can be represented by -COR', R' can be C 1～8Alkyl groups, such as C 1～8 Alkyl substituted acyl can be represented as -COC 1～8 Alkyl, where C 1～8 Alkyl groups include groups as defined above.

[0057] Amino groups can be represented by -NH2, -NHR' or -N(R')2, where R' can be C 1～8 Alkyl groups, such as C 1～8 Alkyl-substituted amino groups can be represented by -NHC 1～8 Alkyl or -N(C 1～8 Alkyl)2, wherein C 1～8 Alkyl groups include groups as defined above.

[0058] The amide group may be represented by -COamino, wherein the amino group is as defined above.

[0059] Sulfonyl can be represented by -S(O)2R', where R' can be C 1～8 Alkyl groups, such as C 1～8 Alkyl substituted sulfonyl can be represented by -S(O)2C 1～8 Alkyl, where C 1～8 Alkyl groups include groups as defined above.

[0060] A cyano group can be represented as -CN.

[0061] Oxo can be represented as (=O).

[0062] Thio can be represented as (=S).

[0063] In the above definition, when the number of carbon atoms changes, the above definition changes only according to the change in the number of carbon atoms and does not affect the definition of the group type; for example, "C 1～5 The "alkyl" may include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, etc. 1～8 The term "alkyl" is defined as any group having 1 to 5 carbon atoms.

[0064] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0065] The term "pharmaceutical composition" refers to a biologically active compound optionally mixed with at least one pharmaceutically acceptable chemical component or agent, namely a "carrier", which facilitates the introduction of the compound into cells or tissues, including but not limited to stabilizers, diluents, suspending agents, thickening agents and / or excipients.

[0066] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological efficacy of the free acid and free base of the specified compound and has no adverse biological or other effects. Unless otherwise indicated, the salts in the present disclosure may refer to metal salts, ammonium salts, salts formed with organic bases, salts formed with inorganic acids, salts formed with organic acids, salts formed with basic or acidic amino acids, and the like. Non-limiting examples of metal salts include, but are not limited to, salts of alkali metals, such as sodium salts, potassium salts, and the like; salts of alkaline earth metals, such as calcium salts, magnesium salts, barium salts, and the like; aluminum salts, and the like. Non-limiting examples of salts formed with organic bases include, but are not limited to, salts formed with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, and the like. Non-limiting examples of salts formed with inorganic acids include, but are not limited to, salts formed with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Non-limiting examples of salts formed with organic acids include, but are not limited to, salts formed with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, malic acid, maleic acid, tartaric acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Non-limiting examples of salts formed with basic amino acids include, but are not limited to, salts formed with arginine, lysine, ornithine, etc. Non-limiting examples of salts formed with acidic amino acids include, but are not limited to, salts formed with aspartic acid, glutamic acid, etc.

[0067] Pharmaceutically acceptable salts can be synthesized from parent compounds containing acid or basic groups by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent, or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.

[0068] The term "solvate" refers to a physical aggregate formed by a compound of the present disclosure and one or more solvent molecules, which includes varying degrees of ionic and covalent bonds, such as hydrogen bonds. It has been shown that such solvates can be isolated, for example, when one or more solvent molecules are mixed in the crystal lattice. A "solvate" includes two parts: a solvent phase and a separable solvate. There are many examples of corresponding solvates, including ethanol solvates, methanol solvates, etc. A "hydrate" is a solvate with water (H2O) molecules as the solvent. One or more compounds of the present disclosure can be prepared as a solvate at will. The preparation of solvates is well known. For example, M. Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004) describes the preparation of a solvate of the antifungal drug fluconazole, which was prepared using ethyl acetate and water. Similar preparation methods for solvates and hydrates are also described in EC van Tonder et al, AAPS Pharm Sci Tech., 5(1), article 12 (2004); and AL Bingham et al, Chem. Commun., 603-604 (2001). A typical, non-limiting preparation process is to dissolve the compound of the invention in a desired amount of an ideal solvent (organic solvent or water or a mixture thereof) at a temperature above room temperature, cool the solution, allow the solution to crystallize, and then separate and select the crystals using standard methods. IR spectroscopy can be used to confirm the presence of the solvent (water) that forms the solvate (hydrate) in the crystals.

[0069] The term "active metabolite" refers to an active derivative of a compound that is formed when the compound is metabolized.

[0070] The term "polymorph" refers to compounds of the present disclosure that exist in different crystal lattice forms.

[0071] The term "isotope-labeled compound" refers to a compound of the present disclosure that is isotopically labeled. For example, the isotopes in the compounds of the present disclosure may include various isotopes of elements such as H, C, N, O, P, F, and S, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 S.

[0072] The term "pharmaceutically acceptable prodrug" or "prodrug" refers to any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of the present disclosure that, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the present disclosure or a pharmaceutically active metabolite or residue thereof. Particularly preferred derivatives or prodrugs are those that increase the bioavailability of a compound of the present disclosure when administered to a patient (e.g., by making an orally administered compound more readily absorbed into the blood), or that promote the delivery of the parent compound to biological organs or sites of action (e.g., the brain or lymphatic system). Prodrugs can be prepared by modifying functional groups present in a compound, either by conventional manipulation or in vivo, in a manner that allows for decomposition to the parent compound. Various prodrug forms are well known in the art. See, for a discussion of prodrugs, T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) Vol. 14 of the ACSSymposium Series, Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and in Pergamon Press. Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol. 42, p. 309-396; Bundgaard, H. "Design and Application of Prodrugs" in A Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, pp. 113-191; and Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38, the above documents are incorporated herein by reference.

[0073] The term "stereoisomer" refers to an isomer resulting from a different arrangement of atoms in a molecule in space. The compounds disclosed herein contain structures such as asymmetric or chiral centers, double bonds, etc. Therefore, the compounds disclosed herein may include multiple isomeric forms such as optical isomers, geometric isomers, tautomers, atropisomers, etc. These isomers and their single isomers, racemates, etc. are all included in the scope of the present disclosure. For example, for optical isomers, optically active (R)- and (S)-isomers as well as D and L isomers can be prepared by chiral resolution, chiral synthesis or chiral reagents or other conventional techniques. For example, diastereomers can be converted into diastereomers by reaction with an appropriate optically active substance (such as chiral alcohol or Mosher's acid chloride), which can be separated and converted (such as hydrolyzed) into the corresponding single isomers. For another example, separation can also be performed by chromatographic column.

[0074] The "pharmaceutical compositions" herein can be prepared in a manner well known in the pharmaceutical art and can be administered or applied by a variety of routes, depending on whether local or systemic treatment is required and the area to be treated. Administration can be topical (e.g., transdermal, skin, eye and mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal), oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, such as intrathecal or intraventricular administration. Parenteral administration can be in the form of a single bolus, or can be administered, for example, by a continuous infusion pump. The pharmaceutical compositions herein include, but are not limited to, the following forms: tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or dissolved in a liquid vehicle); ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0075] The pharmaceutical compositions herein can be formulated in unit dosage form, each dose containing about 0.1 to 1000 mg, usually about 5 to 1000 mg, more usually about 100 to 500 mg of active ingredient. The term "unit dosage form" refers to physically discrete units suitable as single dosage units for human patients and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in admixture with a suitable pharmaceutical carrier.

[0076] The term "subject" refers to an individual suffering from a disease, disorder, condition, etc., including mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals, such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs, etc.

[0077] The term "treat" and other similar synonyms include alleviating, reducing or ameliorating the symptoms of a disease or condition, preventing other symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, such as preventing the development of the disease or condition, alleviating the disease or condition, making the disease or condition better, alleviating the symptoms caused by the disease or condition, or stopping the symptoms of the disease or condition. In addition, the term may also include the purpose of prevention. The term also includes obtaining a therapeutic effect and / or a prophylactic effect. The therapeutic effect refers to curing or improving the underlying disease being treated. In addition, the cure or improvement of one or more physiological symptoms associated with the underlying disease is also a therapeutic effect, for example, although the patient may still be affected by the underlying disease, the patient's condition is observed to improve. In terms of prophylactic effect, the composition or compound can be administered to a patient at risk for a particular disease, or even if a diagnosis of the disease has not yet been made, the composition or compound can be administered to a patient who has one or more physiological symptoms of the disease.

[0078] The term "amount to achieve the necessary therapeutic effect" or "therapeutically effective amount" refers to the amount of at least one pharmaceutical agent or compound that, after administration, is sufficient to relieve to some extent one or more symptoms of the disease or condition being treated. The result can be a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired change in a biological system. Techniques such as dose escalation studies can be used to determine the effective amount appropriate for any individual case. The actual amount of compound, pharmaceutical composition, or medicament administered is generally determined by the physician based on relevant circumstances, including the condition being treated, the route of administration chosen, the actual compound administered; the age, weight, and response of the individual patient; the severity of the patient's symptoms, etc.

[0079] The ratio or concentration of the disclosed compounds in the pharmaceutical composition may not be fixed and depends on a variety of factors, including dosage, chemical properties (e.g., hydrophobicity), route of administration, etc. For example, the disclosed compounds can be provided in a physiologically buffered aqueous solution containing about 0.1 to 10% w / v of the compound for parenteral administration. Some typical dosage ranges are from about 1 μg / kg to about 1 g / kg body weight / day. In certain embodiments, the dosage range is from about 0.01 mg / kg to about 100 mg / kg body weight / day. The dosage is likely to depend on such variables as the type and extent of the disease or condition, the general health status of the particular patient, the relative biological efficacy of the selected compound, the excipient formulation, and its route of administration.

[0080] The term "administering" refers to a method for delivering a compound or composition to a desired site for a biological effect. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical and rectal administration. Those skilled in the art are familiar with administration techniques that can be used for the compounds and methods described herein, such as those discussed in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.

[0081] The term "IC 50 ” refers to a 50% inhibition of the maximal effect in the assay measuring such effect.

[0082] "Atopic dermatitis" refers to a skin condition that involves chronic inflammation, and symptoms of atopic dermatitis include a red, itchy rash. Atopic dermatitis can appear on the skin anywhere on the body, but is most common on the hands, feet, upper chest, and elbows or knees. Other symptoms of atopic dermatitis may include small raised bumps or thickened, scaly skin.

[0083] "Chronic urticaria" (hives) is a common rash that is triggered by a variety of factors, including certain foods, medications, and stress. Symptoms may include itching, bumps, redness, or skin-colored welts on the skin surface. Given the role of mast cells in chronic idiopathic urticaria, MrgprX2 plays a key role in mast cell activation. Antibacterial host defense peptides, neuropeptides, major basic protein, eosinophil peroxidase, and some FDA-approved peptidergic drugs activate human MrgprX2. Unique features of MrgprX2 that distinguish it from other GPCRs include their presence on the plasma membrane and intracellular sites and their selective expression in MCs. In addition, small molecule inhibitors of MrgprX2 may be beneficial in the treatment of MC-dependent allergic and inflammatory conditions, such as chronic urticaria, which are currently treated by targeting the IgE axis of mast cell activity, and targeting MRGPRX2 may indeed be a treatment option for IgE-independent and drug-resistant chronic urticaria.

[0084] "Anaphylactic shock" is an extreme, often life-threatening allergic reaction to an antigen to which the body has become hypersensitized. Mast cell activation via MrgprB2 has attracted attention for its role in IgE-independent mast cell activation and non-histaminergic pruritus. Mast cell-specific MrgprB2 is key to mast cell degranulation and the associated non-histaminergic pruritus.

[0085] "Asthma" refers to a condition in which a person's airways become inflamed, narrowed, and swollen, and produce excess mucus, leading to difficulty breathing. Mast cells (MCs), which also inhabit smooth muscle, T cells, and leukocytes, are important effector cells of the airway hyperresponsiveness and inflammation that characterize asthma. Even though only a small amount of transcript is present in the healthy state, the level of MrgprX2 transcript increases in severe asthma, characterized by a phenotypic switch from MCT to MCTC. Compared to MCT, the mast cell MCTC population in severe asthma is expressing MrgprX2. Given that SP levels are increased in the lungs of severe asthma patients who activate MrgprX2, treatment with small molecule antagonists would be beneficial for severe asthma patients.

[0086] Compound

[0087] The present disclosure relates to compounds of formula (I)

[0088] or its stereoisomers, tautomers, solvates, hydrates, active metabolites, isotope-labeled substances, or pharmaceutically acceptable salts,

[0089] wherein R1 is selected from C1-C 10 Alkyl, substituted with 0-4 R0 C1-C 10 Alkoxy, substituted with 0-4 R0 C3-C 10 Cycloalkyl, substituted with 0-4 R0 C5-C 10 Polycyclic carbocyclic ring, substituted with 0-4 R0 5-8 membered heterocyclic ring, or -NR 11 R 12 ;

[0090] R2 is selected from hydrogen, C1-C substituted with 0-4 R0 10 Alkyl, or substituted with 0-4 R0 C3-C 10 Cycloalkyl;

[0091] Ring A1 is selected from one of the following ring structures:

[0092] in, represents the site where the A1 ring is attached to NR2, and Indicates the site where A1 is connected to Z;

[0093] R3 are each independently selected from hydrogen, halogen, cyano, hydroxyl, C1-C1-substituted with 0-4 R0 10 Alkyl, substituted with 0-4 R0 C1-C 10 Alkoxy, -NR 31 R 32 , replacing C3-C with 0-4 R0 10 Cycloalkyl, substituted with 0-4 R0 C 2-6 Alkenyl, or substituted with 0-4 R0 C 2-6 Alkynyl;

[0094] Z is a covalent bond, -CR 21 R 22 -, -O-, -S-, -S(O)-, -S(O2)- or -NR 23 -;

[0095] A2 ring is C6-C 20 Aryl, C3-C8 cycloalkyl, 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, O or S, or 5-10 membered heterocyclyl having 1-3 heteroatoms selected from N, O or S;

[0096] R4 are each independently selected from hydrogen, halogen, cyano, hydroxy, C1-C2 substituted with 0-4 R0 substituents 10 Alkyl, substituted with 0-4 R0 C1-C 10 Halogenated alkyl, substituted C1-C 10 Alkoxy, substituted with 0-4 R0 C1-C 10 Halogenated alkoxy, substituted C3-C 10 Cycloalkyl, substituted with 0-4 R0 C 2-6 Alkenyl, substituted with 0-4 R0 C 2-6 Alkynyl, -NR 41 R 42 ,-C(=O)NR 41 R 42 ,-C(=O)OR 43 , -S(O2)R 44 , -S(O)R 44 ,-P(O)R 45 R 46 , replacing C6-C with 0-4 R0 20 Aryl, 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, O or S substituted with 0-4 R0, 5-10 membered heterocyclyl having 1-3 heteroatoms selected from N, O or S substituted with 0-4 R0;

[0097] R0 is independently selected from hydrogen, halogen, cyano, hydroxyl, substituted with 0-4 R 00 C1-C6 alkyl, substituted with 0-4 R 00 C1-C6 alkoxy, substituted with 0-4 R 00 C3-C 10 Cycloalkyl, C1-C6 haloalkyl, hydroxy C1-C6 alkyl, -NR 51 R 52 , replaced by 0-4 R 00 A 5-8 membered heterocyclic group;

[0098] R 11 and R 12 Each independently selected from hydrogen, substituted with 0-4 R 00 C1-C 10 Alkyl, substituted with 0-4 R 00 C1-C 10 Haloalkyl, substituted with 0-4 R 00 C 2-6 Alkenyl, substituted with 0-4 R 00 C 2-6 Alkynyl, or substituted with 0-4 R 00 C 3-6 Cycloalkyl; or, R 11 and R 12 Together with the nitrogen atom to which they are attached, they form a substitution with 0-4 R 00 A 5-10 membered heterocyclic group;

[0099] R 21 and R 22 are independently selected from hydrogen, halogen and C1-C6 alkyl, or R 21 and R 22 Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl;

[0100] R 23 Selected from hydrogen and C1-C6 alkyl;

[0101] R 31 and R 32 Each independently selected from hydrogen, substituted with 0-4 R 00 C1-C 10 Alkyl, substituted with 0-4 R 00 C3-C 10 Cycloalkyl, substituted with 0-4 R 00 C1-C 10 Haloalkyl, substituted with 0-4 R 00 C 2-6 Alkenyl, substituted with 0-4 R 00 C2-6 Alkynyl, or substituted with 0-4 R 00 C 3-6 Cycloalkyl;

[0102] R 41 and R 42 Each independently selected from hydrogen, substituted with 0-4 R 00 C1-C 10 Alkyl, substituted with 0-4 R 00 C3-C 10 Cycloalkyl, substituted with 0-4 R 00 C1-C 10 Haloalkyl, substituted with 0-4 R 00 C 2-6 Alkenyl, substituted with 0-4 R 00 C 2-6 Alkynyl, or substituted with 0-4 R 00 C 3-6 Cycloalkyl;

[0103] R 43 Selected from hydrogen, substituted with 0-4 R 00 C1-C 10 Alkyl, substituted with 0-4 R 00 C 2-6 Alkenyl, substituted with 0-4 R 00 C 2-6 Alkynyl, or substituted with 0-4 R 00 C 3-6 Cycloalkyl;

[0104] R 44 Selected from C1-C 10 Alkyl and -NH2;

[0105] R 45 and R 46 Each independently selected from substituted with 0-4 R 00 C1-C 10 Alkyl, substituted with 0-4 R 00 C3-C 10 Cycloalkyl, substituted with 0-4 R 00 C1-C 10 alkyl halide;

[0106] R 51 and R 52 Each independently selected from hydrogen, substituted with 0-4 R 00 C1-C 10 Alkyl, substituted with 0-4 R 00 C3-C 10 Cycloalkyl, substituted with 0-4 R 00C1-C 10 Haloalkyl, substituted with 0-4 R 00 C 2-6 Alkenyl, substituted with 0-4 R 00 C 2-6 Alkynyl, or substituted with 0-4 R 00 C 3-6 Cycloalkyl;

[0107] R 00 Each is independently selected from hydrogen, halogen, cyano, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, hydroxy C1-C6 alkyl, -NH2;

[0108] m is 0, 1 or 2;

[0109] n is 0, 1, 2 or 3.

[0110] According to different selections of R1, the compound can be a thioamide compound or a thiourea compound.

[0111] In one embodiment, the compound may be a thioamide compound. In one embodiment, R1 is a C1-C6 alkyl substituted with 0-2 R0s, or, R1 is a C3-C6 cycloalkyl substituted with 0-2 R0s, or, R1 is a C5-C6 cycloalkyl substituted with 0-2 R0s. 10 Polycyclic carbocycle, or R1 is a 5-8 membered heterocyclic group substituted with 0-2 R0;

[0112] wherein R0 is independently selected from hydrogen, halogen, cyano, hydroxy, -NH2, C1-C3 alkyl, hydroxy C1-C3 alkyl, substituted with 0-2 R 00 C3-C6 cycloalkyl, or substituted with 0-2 R 00 A 5-8 membered heterocyclic group;

[0113] R 00 Each is independently selected from hydrogen, halogen, cyano, hydroxy, C1-C3 alkyl, or -NH2.

[0114] In one embodiment, the compound may be a thiourea compound. In one embodiment, R1 is -NR 11 R 12 , where R 11 and R 12 Each independently selected from substituted with 0-2 R 00 C1-C6 alkyl, substituted with 0-2 R 00 C3-C6 cycloalkyl, substituted with 0-2 R 00C1-C6 haloalkyl; or, R 11 and R 12 Together with the nitrogen atom to which they are attached, they form a substitution with 0-2 R 00 A 5-10 membered heterocyclic group;

[0115] R 00 Each is independently selected from hydrogen, halogen, cyano, hydroxy, C1-C3 alkyl, or -NH2.

[0116] Further, R1 is -NR 11 R 12 , where R 11 is a C1-C6 alkyl group; R 12 To replace there is 1 R 00 C1-C6 alkyl, or substituted with 1 R 00 C1-C6 haloalkyl; R 00 Each is independently selected from hydroxy, or -NH2.

[0117] Further, R1 is -NR 11 R 12 , where R 11 is methyl or ethyl; R 12 It is 2-hydroxypropyl, 3,3,3-trifluoro-2-hydroxypropyl, 3,3,3-trifluoro-2-hydroxy-2-methylpropyl, or 2-hydroxy-2-methylpropyl.

[0118] Furthermore, R1 is

[0119] or

[0120] wherein R6 are each independently selected from hydrogen, halogen, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C1-C6 haloalkyl, or hydroxy C1-C6 alkyl;

[0121] t is 0, 1, or 2.

[0122] In the above structural formula, R6 may be a hydroxymethyl group.

[0123] In the above structural formula, t may be 2, one R6 may be a methyl group, and one R6 may be a hydroxyl group.

[0124] In one embodiment, R2 is hydrogen.

[0125] In one embodiment, the A1 ring is selected from one of the following ring structures:

[0126] Wherein, R3 is a C1-C3 alkyl group, and m is 0 or 1.

[0127] In one embodiment, the A1 ring is selected from one of the following ring structures:

[0128] In one embodiment, Z is a covalent bond, -CR 21 R 22 -, -O-, -S(O)-, -S(O2)- or -NR 23 -;

[0129] Among them, R 21 and R 22 are each independently selected from hydrogen, fluorine and methyl;

[0130] R 23 is hydrogen or methyl.

[0131] In one embodiment, Z is -CF2-, -CH2-, -CD2-, -C(CH3)2- or

[0132] In one embodiment, Z is -CH2- or -CD2-.

[0133] In one embodiment, Z is -O-.

[0134] In one embodiment, the A2 ring is C6-C 10 An aromatic ring structure, for example, a benzene ring structure, a dihydroindene ring structure or a naphthalene ring structure having the following formula:

[0135] In one embodiment, the A2 ring is a 5-10 membered heteroaromatic ring structure having 1-3 heteroatoms selected from N, O or S, such as a pyrazole ring structure, an oxazole ring structure, or an indoline ring structure having the following formula:

[0136] In one embodiment, the A2 ring is a 5-10 membered heterocyclic ring structure having 1-3 heteroatoms selected from N, O or S, such as the following pyrrolidine ring structure:

[0137] The above ring structure can be connected to the Z group through the corresponding position, and can be substituted with n R4 groups defined in the present disclosure.

[0138] In one embodiment, R4 can be independently selected from halogen, cyano, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C1-C3 haloalkyl, -NR 41 R 42 ,-C(=O)NR 41 R42 , and -S(O2)R 44 ;

[0139] Among them, R 41 and R 42 Each is independently selected from hydrogen or C1-C3 alkyl;

[0140] R 44 Selected from C1-C3 alkyl and -NH2;

[0141] n is 0, 1 or 2.

[0142] In one embodiment, n is 2, and each R4 is independently F or Cl.

[0143] In one embodiment, n is 2 and R4 is F.

[0144] In one embodiment, n is 2, one R4 is F, and one R4 is Cl.

[0145] In one embodiment, n is 1 and R4 is F or cyano.

[0146] In one embodiment, the compound has the structural formula II

[0147] Among them, R 11 and R 12 Each independently selected from substituted with 0-2 R 00 C1-C6 alkyl, substituted with 0-2 R 00 C3-C6 cycloalkyl, substituted with 0-2 R 00 C1-C6 haloalkyl, substituted with 0-2 R 00 C 2-6 Alkenyl, substituted with 0-2 R 00 C 2-6 Alkynyl; or, R 11 and R 12 Together with the nitrogen atom to which they are attached, they form a substitution with 0-2 R 00 5-6 membered heterocyclic group; wherein R 00 Each is independently selected from hydrogen, halogen, cyano, hydroxy, C1-C3 alkyl, hydroxy C1-C3 alkyl or -NH2;

[0148] R2 is selected from hydrogen, or C1-C6 alkyl;

[0149] X is N or CH;

[0150] Z is -CR 21 R 22 -or-O-; where R 21 and R 22are each independently selected from hydrogen, halogen and C 1-6 Alkyl; or R 21 and R 22 Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl;

[0151] R4 are each independently selected from halogen, cyano, and C1-C3 alkyl;

[0152] n is 1 or 2.

[0153] For the compound of formula II, in one embodiment, R 11 is a C1-C6 alkyl group,

[0154] R 12 To replace there is 1 R 00 C1-C6 alkyl;

[0155] Among them, R 00 are each independently selected from hydroxyl groups.

[0156] For the compound of formula II, in one embodiment,

[0157] R 11 is methyl or ethyl,

[0158] R 12 is 2-hydroxypropyl, 3,3,3-trifluoro-2-hydroxypropyl, 3,3,3-trifluoro-2-hydroxy-2-methylpropyl, 1-hydroxy-1-methylcyclopropyl, or 2-hydroxy-2-methylpropyl.

[0159] For the compound of formula II, in one embodiment, R 11 and R 12 Together with the nitrogen atom to which they are attached, they form the following groups

[0160] or

[0161] wherein R6 is each independently selected from hydroxy, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy C1-C6 alkyl;

[0162] t is 0, 1, or 2.

[0163] For the compound of formula II, in one embodiment, R6 is independently selected from hydroxymethyl, and t is 1.

[0164] For the compound of formula II, in one embodiment, R2 is hydrogen.

[0165] For the compound of formula II, in one embodiment, Z is -O-.

[0166] For the compound of formula II, in one embodiment, Z is -CR 21 R 22 -, where R 21 and R 22 are each independently selected from hydrogen, halogen such as fluorine and C 1-6 Alkyl (e.g. C 1-3 alkyl, such as methyl); or R 21 and R 22 Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl (eg, cyclopropyl).

[0167] For the compound of formula II, in one embodiment, Z is -CH2-, -CD2-, -CF2- or

[0168] For the compound of formula II, in one embodiment, n is 1, and R4 is F or cyano.

[0169] For the compound of formula II, in one embodiment, n is 2, and R4 is each independently F or Cl;

[0170] Alternatively, n is 2, and R4 are all F;

[0171] Alternatively, n is 2, one R4 is F, and one R4 is Cl.

[0172] For the compound of formula II, in one embodiment, X is N. For the compound of formula II, in one embodiment, X is CH.

[0173] In one embodiment, the compound has the structure of formula (II-1)

[0174] Among them, R 11 Selected from cyano, substituted with 0-2 R 00 C1-C6 alkyl, a 4-6 membered heterocyclic group containing a heteroatom selected from O, S or N, or NH2COC 1-6 alkyl;

[0175] R 12 Selected from substituted with 0-2 R 00 C1-C6 alkyl, substituted with 0-2 R 00 C3-C6 cycloalkyl, or substituted with 0-2 R 00 C 3-6 Cycloalkyl C 1-6 alkyl;

[0176] R 00Each is independently selected from hydrogen, halogen, cyano, hydroxy, C1-C3 alkyl, hydroxy C1-C3 alkyl or -NH2;

[0177] R2 is selected from hydrogen, or C1-C6 alkyl;

[0178] X is N or CH;

[0179] R4 are each independently selected from halogen, cyano, and C1-C3 alkyl;

[0180] n is 1 or 2.

[0181] For the compound of formula II-1, in one embodiment, R 11 is a C1-C6 alkyl group such as methyl or ethyl,

[0182] R 12 To replace there is 1 R 00 C1-C6 alkyl or substituted with 1 R 00 C 3-6 Cycloalkyl C 1-6 Alkyl, where R 00 are each independently selected from hydroxyl groups.

[0183] For the compound of formula II-1, in one embodiment, R 12 is 2-hydroxypropyl or (1-hydroxycyclopropyl)methyl.

[0184] For the compound of formula II-1, in one embodiment, n is 1 and R4 is F.

[0185] For the compound of formula II-1, in one embodiment, X is CH.

[0186] For the compound of formula II-1, in one embodiment, R2 is hydrogen.

[0187] In one embodiment, the compound is selected from one of the following compounds:

[0188] Composition and application

[0189] The present disclosure provides a pharmaceutical composition comprising the above-mentioned compound of the present disclosure or its stereoisomers, tautomers, solvates, hydrates, active metabolites, isotope-labeled substances or pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier.

[0190] As demonstrated in the present disclosure, the above-mentioned compounds of the present disclosure have good inhibitory activity against MRGPRX2. Therefore, the above-mentioned compounds of the present disclosure or their stereoisomers, tautomers, solvates, hydrates, active metabolites, isotope labels or pharmaceutically acceptable salts, as well as the pharmaceutical compositions of the present disclosure can be used as drugs for inhibiting MRGPRX2 activity and can be used to prepare drugs for inhibiting MRGPRX2 activity. The present disclosure therefore relates to the use of the above-mentioned compounds of the application or their stereoisomers, tautomers, solvates, hydrates, active metabolites, isotope labels or pharmaceutically acceptable salts, as well as the pharmaceutical compositions of the present disclosure, in the preparation of drugs for inhibiting MRGPRX2 activity.

[0191] Likewise, the present disclosure also relates to the use of the disclosed compounds or their stereoisomers, tautomers, solvates, hydrates, active metabolites, isotopically labeled or pharmaceutically acceptable salts, and the disclosed pharmaceutical compositions in the preparation of a medicament for treating an MRGPRX2-mediated disorder in a subject.

[0192] Similarly, the present disclosure also relates to a method for treating MRGPRX2-mediated disorders, comprising administering to a subject in need thereof a therapeutically effective amount of the above-mentioned compound of the present disclosure or its stereoisomers, tautomers, solvates, hydrates, active metabolites, isotope-labeled substances or pharmaceutically acceptable salts, or pharmaceutical compositions.

[0193] In the present disclosure, the MRGPRX2-mediated disorder can be an inflammatory disorder, such as a skin disorder. In one embodiment, the inflammatory disorder is atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis), urticaria, pseudoallergic reactions triggered by small molecules, such as anaphylactoid drug reactions, anaphylactic shock, rosacea, asthma, systemic pruritus, such as cholestatic or uremic pruritus, chronic pruritus triggered by systemic diseases, or adverse drug reactions; in particular, urticaria.

[0194] The disclosed compounds also have excellent ability to penetrate the blood-brain barrier and thus have the potential to treat MRGPRX2-mediated central nervous system diseases. MRGPRX2-mediated conditions can also be central nervous system-related diseases, including neuroinflammation such as neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease) and central nervous system injuries (such as brain trauma, spinal cord injury, traumatic brain injury (TBI), stroke), neuropathic pain (such as chronic pain syndrome, postherpetic neuralgia, fibromyalgia), mental illness (such as anxiety, depression, post-traumatic stress disorder (PTSD)), autoimmune encephalopathy such as multiple sclerosis (MS) (such as autoimmune encephalomyelitis), glial cell-related diseases (such as glioma), infectious encephalopathy (such as encephalitis).

[0195] In order to make the purpose, technical solutions and advantages of the present disclosure more clear, the technical solutions of exemplary embodiments of the present disclosure will be further described below.

[0196] Specific implementation plan

[0197] Example 1 N-(5-(3,5-difluorobenzyl)thiazol-2-yl)-2-methylpropanesulfamide

[0198] Step A: N-(5-(3,5-difluorobenzyl)thiazol-2-yl)isobutyramide

[0199] 100 mg (442 μmol, 1.0 eq) of 5-(3,5-difluorobenzyl)thiazol-2-amine was dissolved in 1 mL of dichloromethane. 5.40 mg (44.2 μmol, 0.1 eq) of 4-dimethylaminopyridine, 51.8 mg (486 μmol, 1.1 eq) of isobutyryl chloride, and 114 mg (884 μmol, 2.0 eq) of N,N-diisopropylethylamine were added sequentially to the reaction system under an ice-water bath. After returning to room temperature, the reaction was stirred for 2 hours. LC-MS confirmed the complete reaction of the starting materials. 5 mL of saturated aqueous sodium bicarbonate and 10 mL of ethyl acetate were added, and the organic phase was separated. The aqueous phase was extracted twice with ethyl acetate (10 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated to yield a yellow solid (131 mg, yield = 100%).

[0200] LC-MS: (M+H) + ; m / z = 297.1;

[0201] Step B: N-(5-(3,5-difluorobenzyl)thiazol-2-yl)-2-methylpropanethioamide

[0202] 130 mg (439 μmol, 1.0 eq) of N-(5-(3,5-difluorobenzyl)thiazol-2-yl)isobutyramide was dissolved in 6 mL of diphenyl ether, and 177 mg (439 μmol, 1.0 eq) of Lawesson's reagent was added to the reaction system. The reaction was stirred at 140°C under nitrogen for 4 hours. LC-MS results confirmed the complete reaction of the starting material. The solvent was evaporated under reduced pressure to obtain the crude product, which was purified by preparative chromatography (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30% to 70% B over 55 minutes; flow rate: 70 mL / min) and lyophilized to obtain a yellow solid (19.5 mg, yield = 14%).

[0203] LC-MS: (M+H) +; m / z = 313.22;

[0204] 1 HNMR (400MHz, CDCl3) δ12.85(s,1H),7.28(s,1H),6.78-6.74(m,2H),6.72-6.67(m,1H),4.10(s,2H),3.17-3.10(m,1H),1.34(d,J=6.7Hz,6H).

[0205] 19 FNMR (376MHz,CDCl3)δ-109.35.

[0206] Example 2 N-(5-(3,5-difluorobenzyl)thiazol-2-yl)tetrahydrofuran-3-methylsulfamide

[0207] Step A: N-(5-(3,5-difluorobenzyl)thiazol-2-yl)tetrahydrofuran-3-carboxamide

[0208] 103 mg (884 μmol, 2.0 eq) of tetrahydrofuran-3-carboxylic acid was dissolved in 1 mL of dichloromethane, and 128 μL (1.77 mmol, 4.0 eq) of thionyl chloride was added to the reaction system. The reaction was stirred at 40°C under nitrogen for 2 hours. The solvent was evaporated to dryness under reduced pressure, and the residue was dissolved in 1 mL of dichloromethane. 100 mg (442 μmol, 1.0 eq) of 5-(3,5-difluorobenzyl)thiazol-2-amine, 5.4 mg (44.2 μmol, 0.eq) of 4-dimethylaminopyridine, and 114 mg (884 μmol, 2.0 eq) of N,N-diisopropylethylamine were added to the reaction system in sequence under an ice-water bath. After returning to room temperature, the reaction was stirred for another 2 hours. LC-MS results confirmed that the reaction of the raw materials was complete. 5 mL of saturated aqueous sodium bicarbonate solution and 10 mL of ethyl acetate were added to separate the organic phase. The aqueous phase was extracted twice with ethyl acetate (10 mL). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated to give a light red solid (143 mg, yield = 100%).

[0209] LC-MS: (M+H) + ; m / z = 325.1;

[0210] Step B: N-(5-(3,5-difluorobenzyl)thiazol-2-yl)tetrahydrofuran-3-methylsulfamide

[0211] 140 mg (432 μmol, 1.0 eq) of N-(5-(3,5-difluorobenzyl)thiazol-2-yl)tetrahydrofuran-3-carboxamide was dissolved in 3 mL of o-xylene, and 177 mg (432 μmol, 1.0 eq) of Lawesson's reagent was added to the reaction system. The reaction was stirred at 138°C under nitrogen for 6 hours. LC-MS results confirmed the complete reaction of the starting material. The solvent was evaporated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (methanol / dichloromethane = 0-1:30) and preparative chromatography (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30% to 70% B over 55 minutes; flow rate: 70 mL / min). The product was lyophilized to obtain a yellow solid (27.2 mg, yield = 19%).

[0212] LC-MS: (M+H) + ; m / z = 341.10;

[0213] 1 HNMR(400MHz, CDCl3)δ12.42(brs,1H),7.29(s,1H),6.79-6.72(m,2H),6.72-6.66( m,1H),4.13-4.02(m,5H),3.93-3.87(m,1H),3.69-3.62(m,1H),2.42-2.30(m,2H).

[0214] 19 FNMR (376MHz,CDCl3)δ-109.28.

[0215] The examples in Table 1 were prepared by the method described above for Example 2, by substituting different starting substrate carboxylic acids.

[0216] Table 1: Examples 3 to 6

[0217] Example 7 (S)-1-ethyl-3-(5-(4-fluorophenoxy)thiazol-2-yl)-1-(2-hydroxypropyl)thiourea

[0218] Step A: 5-(4-fluorophenoxy)thiazol-2-amine

[0219] 431 mg (3.84 mmol, 2.0 eq) of 4-fluorophenol, 9 mL of tetrahydrofuran, and 1 mL of DMF were added to a 100 mL reaction flask. The temperature was cooled to 0°C. 169 mg (4.23 mmol, 2.2 eq, 60%) of sodium hydride was added to the reaction mixture and stirred at room temperature for 10 minutes. 500 mg (1.92 mmol, 1.0 eq) of 5-bromo-1,3-thiazol-2-amine was added to the reaction mixture and stirred at room temperature for 30 minutes. LCMS showed complete reaction of the starting material. The reaction mixture was added with 20 mL of water and extracted three times with ethyl acetate (50 mL). The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (dichloromethane:methanol = 30:1) to afford a brown oil (220 mg, yield = 54%).

[0220] LC-MS: (M+H) + ; m / z = 211.02;

[0221] Step B: (S)-1-(Ethylamino)propan-2-ol

[0222] 500 mg (6.65 mmol, 1.0 eq) of S-1-amino-2-propanol, 322 mg (7.32 mmol, 1.1 eq) of acetaldehyde, and 10 mL of ethanol were added to a 100 mL reaction flask. The atmosphere was purged with nitrogen three times, and the temperature was lowered to 0°C. 503 mg (13.3 mmol, 2.0 eq) of sodium borohydride was slowly added to the reaction mixture, and the temperature was maintained at 0°C for 1 hour. TLC indicated complete reaction of the starting materials. The reaction mixture was quenched by adding 0.5 mL of water and then concentrated to dryness (avoid high temperatures as the product has a low boiling point), yielding 300 mg of a light yellow oily liquid.

[0223] LC-MS: (M+H) + ; m / z = 104.10;

[0224] Step C: (S)-1-ethyl-3-(5-(4-fluorophenoxy)thiazol-2-yl)-1-(2-hydroxypropyl)thiourea

[0225] A 25 mL reaction flask was charged with 200 mg (951 μmol, 1.0 eq) of 5-(4-fluorophenoxy)thiazol-2-amine, 196 mg (1.90 mmol, 2.0 eq) of (S)-1-(ethylamino)propan-2-ol, 169 mg (951 μmol, 1.0 eq) of N,N'-thiocarbonyldiimidazole, 288 mg (2.85 mmol, 3.0 eq) of triethylamine, and 5 mL of dichloromethane. The atmosphere was purged with nitrogen three times and the reaction mixture was incubated at 45°C for 3 hours. LC-MS confirmed complete reaction of the starting materials. 20 mL of water was added to the reaction system, and the mixture was extracted three times with dichloromethane (20 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative chromatography (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 min; flow rate: 70 mL / min) and lyophilized to give a white solid (34.0 mg, yield = 10%).

[0226] LC-MS: (M+H) + ; m / z = 356.09;

[0227] 1 H NMR(400MHz, CDCl3)δ7.08-6.96(m,4H),6.94(s,1H),4.22-4.19(m,1H),3 .99-3.88(m,1H),3.85-3.71(m,2H),3.45-3.41(m,1H),1.34-1.26(m,6H).

[0228] 19 F NMR (376MHz,CDCl3)δ-119.80.

[0229] Example 8 (S)-3-(5-(3,5-difluorobenzyl)thiazol-2-yl)-1-ethyl-1-(2-hydroxypropyl)thiourea

[0230] Step A: tert-Butyl (5-((3,5-difluorophenyl)(hydroxy)methyl)thiazol-2-yl)carbamate

[0231] In a 250 mL three-necked flask, dissolve 1.50 g (7.49 mmol, 1.0 eq) of tert-butyl thiazole-2-carbamate in 30 mL of anhydrous tetrahydrofuran. Cool to -78°C in a dry ice bath under nitrogen. Add 6.7 mL (16.7 mmol, 2.2 eq) of n-butyllithium solution dropwise to the reaction system, stirring for 30 minutes. Then, add 1.60 g (11.2 mmol, 1.5 eq) of 3,5-difluorobenzaldehyde in 5 mL of tetrahydrofuran dropwise to the reaction mixture. Allow the mixture to rise to room temperature and stir for 2 hours. LC-MS indicated complete reaction. The reaction solution was poured into 50 mL of ice water, and the pH value was adjusted to 6-7 with 6 mol / L hydrochloric acid. The mixture was extracted three times with ethyl acetate (50 mL). The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was slurried with petroleum ether to obtain a white solid (1.80 g, yield = 70%).

[0232] LC-MS:(M-56+H) + ; m / z = 287.06;

[0233] Step B: 5-(3,5-difluorobenzyl)thiazol-2-amine

[0234] In a 100 mL reaction flask, 5.90 g (17.2 mmol, 1.0 eq) of tert-butyl (5-((3,5-difluorophenyl)(hydroxy)methyl)thiazol-2-yl)carbamate was dissolved in 26 mL of trifluoroacetic acid. The atmosphere was purged with nitrogen three times, and the temperature was lowered to 0°C. 8.02 g (68.9 mmol, 4.0 eq) of triethylsilane was then added to the reaction solution, which was naturally warmed to room temperature and stirred for 3 hours. TLC indicated complete reaction of the starting material. The reaction solution was concentrated under reduced pressure to remove most of the trifluoroacetic acid, and saturated sodium bicarbonate solution was added to adjust the pH to 6-8. The solution was extracted three times with ethyl acetate (100 mL). The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (DCM:MeOH = 20:1) to obtain a light yellow solid (2.10 g, yield = 54%).

[0235] LC-MS: (M+H) + ; m / z = 227.03;

[0236] Step C: N-(5-(3,5-difluorobenzyl)thiazol-2-yl)-1H-imidazole-1-carboxylic acid amide

[0237] In a 25 mL reaction flask, 100 mg (442 μmol, 1.0 eq) of 5-(3,5-difluorobenzyl)thiazol-2-amine and 184 μL (1.33 mmol, 3.0 eq) of triethylamine were dissolved in 5 mL of anhydrous N,N-dimethylformamide. Then, 94.52 mg (530 μmol, 1.2 eq) of di(1H-imidazol-1-yl)thiomethanone was added. The atmosphere was purged with nitrogen three times, and the temperature was raised to 65°C and stirred for 16 hours. TLC confirmed complete reaction of the starting material. The mixture was extracted three times with ethyl acetate (30 mL). The combined organic phases were washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to yield the crude product (95.0 mg, yield = 63%).

[0238] LC-MS:(MH) - ; m / z = 334.97;

[0239] Step D: (S)-3-(5-(3,5-difluorobenzyl)thiazol-2-yl)-1-ethyl-1-(2-hydroxypropyl)thiourea

[0240] In a 10 mL Shrek tube, 60.0 mg (178 μmol, 1.0 eq) of N-(5-(3,5-difluorobenzyl)thiazol-2-yl)-1H-imidazole-1-carboxylic acid amide, 92.0 mg (892 μmol, 5.0 eq) (S)-1-(ethylamino)propan-2-ol, and 124 μL (892 μmol, 5 eq) of triethylamine were dissolved in 6 mL of anhydrous N,N-dimethylformamide and stirred at 65°C for 16 hours. LC-MS indicated complete reaction. The reaction mixture was concentrated to dryness, and the crude product was purified by preparative chromatography (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30% to 70% B over 55 minutes; flow rate: 70 mL / min) and lyophilized to afford a white solid (30.0 mg, yield = 43%).

[0241] LC-MS: (M+H) + ; m / z = 372.05;

[0242] 1 H NMR(400MHz, CDCl3)δ6.96(s,1H),6.79-6.74(m,2H),6.72-6.67(m,1H), 4.23-4.16(m,1H),4.05-3.98(m,1H),3.98(s,2H),3.90-3.76(m,2H),3.41(d,J=15.2Hz,1H),1.31-1.28(m,,6H).

[0243] 19F NMR (376MHz, CDCl3) δ-109.60.

[0244] Example 9 3-(5-(3,5-difluorobenzyl)thiazol-2-yl)-1-ethyl-1-(2-hydroxy-2-methylpropyl)thiourea

[0245] Step A: 1-(Ethylamino)-2-methylpropan-2-ol

[0246] After placing 45 mL (89.4 mmol, 3.0 eq) of 2M ethylamine in tetrahydrofuran in an ice-water bath, 2.20 g (29.8 mmol, 1.0 eq) of methyl propylene oxide dissolved in 40 mL of anhydrous methanol was slowly added to the reaction system. The mixture was then heated and stirred at 100°C under sealed conditions for 18 hours. LC-MS results confirmed the complete reaction of the starting material. The solvent was evaporated under reduced pressure to dryness, yielding a pale yellow liquid (2.7 g, yield = 77%).

[0247] LC-MS: (M+H) + ; m / z = 118.2;

[0248] Step B: 3-(5-(3,5-difluorobenzyl)thiazol-2-yl)-1-ethyl-1-(2-hydroxy-2-methylpropyl)thiourea

[0249] 100 mg (442 μmol, 1.0 eq) of 5-(3,5-difluorobenzyl)thiazole-2-amine was dissolved in 8 mL of tetrahydrofuran, and then 126 mg (707 μmol, 1.6 eq) of N,N'-thiocarbonyldiimidazole and 134 mg (1.33 mmol, 3.0 eq) of triethylamine were added to the reaction system. After stirring at 60°C under nitrogen for 2.5 hours, 104 mg (884 μmol, 2.0 eq) of 1-(ethylamino)-2-methylpropan-2-ol was added to the reaction system and the reaction was continued to stir at 60°C for 18 hours. LC-MS results confirmed that the reaction of the starting material was complete, and the solvent was evaporated under reduced pressure to give a crude product, which was purified by preparative chromatography (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 min; flow rate: 70 mL / min) and lyophilized to give a yellow solid (24.2 mg, yield = 14%).

[0250] LC-MS: (M+H) + ; m / z = 386.13;

[0251] 1H NMR (400MHz, CDCl3) δ6.95(s,1H),6.76-6.71(m,2H),6.69-6.64(m,1H),3.96(s,2H),3.90(s,2H),3.59(s,2H),1.34(s,6H),1.27(t,J=6.9Hz,3H).

[0252] 19 F NMR (376MHz, CDCl3) δ-109.66.

[0253] Example 10 (S)-3-(5-(3,5-difluorobenzyl)-1,3,4-thiadiazol-2-yl)-1-ethyl-1-(2-hydroxypropyl)thiourea

[0254] Step A: 5-(3,5-difluorobenzyl)-1,3,4-thiadiazol-2-amine

[0255] 1.00 g (5.81 mmol, 1.0 eq) (3,5-difluorophenyl)acetic acid and 0.53 g (5.81 mmol, 1.0 eq) thiosemicarbazide were added to 3.0 mL of phosphorus oxychloride and stirred at 80°C for 3 hours. LC-MS confirmed the formation of the product. The reaction mixture was cooled to room temperature and then added dropwise to ice water. 50% wt sodium hydroxide solution was added dropwise to adjust the pH of the mixture to 9-10, and the solid was filtered off. The solid was dissolved in dichloromethane, filtered, and dried over anhydrous sodium sulfate. After filtering again, it was evaporated to dryness under reduced pressure to obtain a white solid (1.20 g, yield = 91%).

[0256] LC-MS: (M+H) + ; m / z = 228.04;

[0257] Step B: (S)-3-(5-(3,5-difluorobenzyl)-1,3,4-thiadiazol-2-yl)-1-ethyl-1-(2-hydroxypropyl)thiourea

[0258] 100 mg (440 umol, 1.0 eq) of 5-(3,5-difluorobenzyl)-1,3,4-thiadiazol-2-amine and 60.1 mg (660 umol, 1.5 eq) of 1,1-thiocarbonyldiimidazole were dissolved in 5.0 mL of anhydrous tetrahydrofuran. 0.18 mL (1.32 mmol, 3.0 eq) of triethylamine was added. The atmosphere was purged with nitrogen three times and stirred at 60°C for 3 hours. 90.8 mg (880 umol, 2.0 eq) of (S)-1-(ethylamino)propan-2-ol was added and the mixture was stirred at 60°C for 18 hours. The formation of the product was confirmed by LC-MS, and the product was evaporated to dryness under reduced pressure. The crude product was purified by preparative chromatography (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 min; flow rate: 70 mL / min) and lyophilized to give a light yellow solid (5.0 mg, yield = 3.0%).

[0259] LC-MS: (M+H) + ; m / z = 373.07;

[0260] 1 H NMR (400MHz, CDCl3) δ6.83-6.78(m,2H),6.74-6.68(m,1H),4.34-4.27(m,1H),4.18(s, 2H),3.98-3.81(m,3H),3.45-3.42(m,1H),1.33(d,J=6.3Hz,3H),1.27(t,J=7.0Hz,3H).

[0261] 19 F NMR (376MHz, CDCl3) δ-109.02.

[0262] Example 11 (S)-3-(5-(3,5-difluorobenzyl)pyridin-2-yl)-1-ethyl-1-(2-hydroxypropyl)thiourea

[0263] Step A: 5-(3,5-difluorobenzyl)pyridin-2-amine

[0264] 1.00 g (4.54 mmol, 1.0 eq) of 2-aminopyridine-5-boronic acid pinacol ester was dissolved in 12 mL of 1,4-dioxane. 1.00 g (5.00 mmol, 1.1 eq) of 3,5-difluorobenzyl bromide, 0.17 g (227 μmol, 0.05 eq) of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, 1.30 g (9.09 mmol, 2.0 eq) of potassium carbonate, and 4 mL of water were added to the reaction system. The mixture was stirred at 100°C under nitrogen for 3 hours. LC-MS results confirmed that the reaction of the raw materials was complete. The temperature was cooled to room temperature, 20 mL of water and 20 mL of ethyl acetate were added, and the organic phase was separated. The aqueous phase was extracted twice with ethyl acetate (20 mL). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated to give a crude product. The crude product was purified by column chromatography (methanol / dichloromethane = 0-1:30) to give a brown solid (738.8 mg, yield = 74%).

[0265] LC-MS: (M+H) + ; m / z = 221.1;

[0266] Step B: (S)-3-(5-(3,5-difluorobenzyl)pyridin-2-yl)-1-ethyl-1-(2-hydroxypropyl)thiourea

[0267] 100 mg (454 μmol, 1.0 eq) of 5-(3,5-difluorobenzyl)pyridin-2-amine was dissolved in 5 mL of dichloromethane, and then 80.9 mg (454 μmol, 1.0 eq) of N,N'-thiocarbonyldiimidazole and 138 mg (1.36 mmol, 3.0 eq) of triethylamine were added to the reaction system. After stirring at 40°C for 1.5 hours under nitrogen protection, 93.7 mg (908 μmol, 2.0 eq) of (S)-1-(ethylamino)propan-2-ol was added to the reaction system and the reaction was continued to stir at 40°C for 18 hours. LC-MS results confirmed that the reaction of the starting material was complete, and the solvent was evaporated under reduced pressure to give a crude product, which was purified by preparative chromatography (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 min; flow rate: 70 mL / min) and lyophilized to give an orange solid (16.0 mg, yield = 10%).

[0268] LC-MS: (M+H) + ; m / z = 366.15;

[0269] 1H NMR (400MHz, CDCl3) δ10.48(brs,1H),8.17-7.85(m,2H),7.46(d,J=7.5Hz,1H),6.72-6.59(m,3H),4.24-4.08(m,2H) ,3.89(s,2H),3.80-3.72(m,1H),3.62-3.50(m,1H),3.28-3.24(m,1H),1.28(t,J=6.9Hz,3H),1.13(d,J=6.1Hz,3H).

[0270] 19 F NMR (376MHz,CDCl3)δ-109.70.

[0271] The examples in Table 2 were prepared by referring to the methods of Examples 7 to 11 described above, by substituting different starting substrates or intermediates as required.

[0272] Table 2: Examples 12 to 100

[0273] Inhibitory activity test of the disclosed compounds

[0274] Cell Information

[0275] 1. This study used a CHO cell line stably expressing the MRGPRX2 receptor, incubated with different concentrations of test compounds, and measured the inhibitory effect of the compounds on the MRGPRX2 receptor using the HTRF IP1 kit.

[0276] 2. The CHO cell line stably expressing MRGPRX2 was cultured in F-12 medium containing 10% fetal bovine serum and 0.2 mg / mL HygRomycin B at a temperature of 37°C and a carbon dioxide concentration of 5%.

[0277] 3. Cell passaging: Remove old culture medium and wash once with PBS, then add 1 mL TRypLE TMIncubate the ExpReSS solution at 37°C for approximately 2 minutes. Once the cells have detached from the bottom of the dish, add approximately 5 mL of complete medium preheated to 37°C. Gently pipette the cell suspension to dissociate any aggregated cells. Transfer the cell suspension to a sterile centrifuge tube and centrifuge at 1000 rpm for 5 minutes.

[0278] 4. To maintain the physiological activity of cells, the cell confluence was controlled at around 80%.

[0279] 5. Cell passaging, thawing and freezing should be carried out according to conventional methods.

[0280] Determination of the inhibitory activity of compounds on MRGPRX2 receptor

[0281] 1. Prepare 1×Stimulation Buffer according to the kit instructions for use. 2. Use DMSO to serially dilute the positive compound and the test compound to 10 concentrations, then dilute the compound to 10× with 1×Stimulation Buffer, shake and mix until ready for use. 3. After cell counting, inoculate the cells in a 384-well plate at a density of 20,000 cells / well / 9.1μL. 4. Take 1.4μL of the 10× compound diluted in step 3 and add it to the corresponding experimental wells (the compound is 10×, 10 concentrations, 2 replicates), among which 1.4μL of the 10× first concentration positive compound is added to the PC well, and 1.4μL of 10×DMSO buffer (1%) is added to the VC well. After centrifugation, incubate at 37°C for 10 minutes. 5. Prepare a 1μM CoRtiStatin-14 solution with 1× Stimulation Buffer, add 3.5μL to each experimental well, centrifuge, and incubate at 37°C for 60 minutes. 6. Dilute d2-IP1 and Anti-IP1-CRyptate to working concentrations using LySiS & Detection Buffer. 7. After incubation, add 3μL d2-IP1 to all experimental wells. 8. Then add 3μL Anti-IP1-CRyptate to all experimental wells, centrifuge, and let stand at room temperature for 1 hour. 9. After incubation, use a microplate reader to detect the values ​​at 665nm and 620nm under excitation at a wavelength of 330nm.

[0282] Each compound prepared was tested using the above analytical procedure and the results obtained are shown in Table 3. For selected examples, the activity range is shown as follows: "A" represents the antagonist activity IC 50 <50nM; "B" indicates antagonist activity IC 50 Between 50 and 300 nM; "C" represents the IC of antagonist activity 50 Between 301 and 1000 nM; "D" indicates antagonist activity IC50 ≥1000nM, “NE” means not detected.

[0283] Table 3: Inhibitory activity of the compounds disclosed herein on MRGPRX2 receptor (IC 50 )

[0284] E154 is the compound of Example E154 reported in patent CN114845709A, and serves as a positive reference molecule. Its structure is as follows:

[0285] Conclusion: The compounds disclosed in Examples 7, 8, 9 and 13 showed stronger MRGPRX2 receptor inhibitory activity than the positive control compound E154.

[0286] Pharmacokinetic experiments

[0287] Male SD rats were divided into groups of 3 per group and were administered the example compound (10 mg / kg) orally ...

[0288] Table 4: Pharmacokinetic parameters of different compounds after oral administration to rats at 10 mg / kg

[0289] Table 5: Pharmacokinetic parameters of the compound after intravenous administration of 2 mg / kg to rats

[0290] The pharmacokinetic test results show that the disclosed example compounds have excellent pharmacokinetic properties and a bioavailability of greater than 85%.

[0291] Blood-brain distribution experiment

[0292] Male Sprague-Dawley rats were divided into groups of three and injected intravenously with the example compound (2 mg / kg). The animals were fasted overnight, from 10 hours before dosing to 4 hours after dosing. Rats were sacrificed 0.5 hours after dosing, and blood and brain tissue were collected. After processing, the samples were centrifuged at 4000 rpm for 20 minutes at 4°C. 300 μl of the supernatant was transferred to a new 96-well plate and mixed with 300 μl of 0.1% FA water. Analysis was performed by LC / MS / MS. The results are shown in Table 6.

[0293] Table 6: Results of the blood-brain distribution experiment in rats

[0294] The results of the blood-brain distribution experiment showed that the compound of Example 84 of the present disclosure can penetrate the blood-brain barrier, and the blood-brain ratio of the drug is better than that of E154, indicating that it has the potential to treat central nervous system diseases.

[0295] Comparison of physical stability

[0296] Example 7 and the positive control compound E154 were both solid after synthesis and lyophilization. After 10 days of sealed storage at room temperature, E154 transformed from a solid to an adherent colloid, while Example 7 remained unchanged, indicating that Example 7 had superior physical stability to Compound E154.

[0297] In addition, most of the compounds synthesized as described in Chinese invention patent application CN114845709A are in colloidal state, while the compounds of the embodiments of the present disclosure are all in solid state, which also shows that the compounds of the embodiments of the present disclosure are superior to the compounds in Chinese invention patent application CN114845709A in terms of physical state.

[0298] The present disclosure has been described above in conjunction with preferred embodiments, but these embodiments are merely exemplary and serve only as an illustration. On this basis, various replacements and improvements can be made to the present disclosure, all of which fall within the scope of protection of the present disclosure.

Claims

1. Compounds of formula (I) or its stereoisomers, tautomers, solvates, hydrates, active metabolites, isotope-labeled substances, pharmaceutically acceptable salts, in, R1 is selected from C1-C 10 Alkyl, substituted with 0-4 R0 C1-C 10 Alkoxy, substituted with 0-4 R0 C3-C 10 Cycloalkyl, substituted with 0-4 R0 C5-C 10 Polycyclic carbocyclic ring, substituted with 0-4 R0 5-8 membered heterocyclic ring, or -NR 11 R 12 ; R2 is selected from hydrogen, C1-C substituted with 0-4 R0 10 Alkyl, or substituted with 0-4 R0 C3-C 10 Cycloalkyl; The A1 ring is selected from one of the following ring structures: in, represents the site where the A1 ring is attached to NR2, and indicates the site where the A1 ring is attached to Z; R3 is independently selected from hydrogen, halogen, cyano, hydroxyl, C1-C2 substituted with 0-4 R0 10 Alkyl, substituted with 0-4 R0 C1-C 10 Alkoxy, -NR 31 R 32 , replace C3-C with 0-4 R0 10 Cycloalkyl, substituted with 0-4 R0 2-6 Alkenyl, or substituted with 0-4 R0 C 2-6 Alkynyl; Z is a covalent bond, -CR 21 R 22 -, -O-, -S-, -S(O)-, -S(O2)- or -NR 23 -; A2 ring is C6-C 20 Aryl, C3-C8 cycloalkyl, 5-10 membered heteroaryl, or a 5-10 membered heterocyclic group having 1-3 heteroatoms selected from N, O or S; R4 is independently selected from hydrogen, halogen, cyano, hydroxyl, C1-C2-substituted with 0-4 R0 substituents. 10 Alkyl, substituted with 0-4 R0 C1-C 10 Halogenated alkyl, substituted C1-C 10 Alkoxy, substituted with 0-4 R0 C1-C 10 Halogenated alkoxy, substituted with 0-4 R0 C3-C 10 Cycloalkyl, substituted with 0-4 R0 2-6 Alkenyl, substituted with 0-4 R0 2-6 Alkynyl, -NR 41 R 42 , -C(=O)NR 41 R 42 , -C(=O)OR 43 , -S(O2)R 44 , -S(O)R 44 , -P(O)R 45 R 46 , replace C6-C with 0-4 R0 20 Aryl, 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, O or S substituted with 0-4 R0, 5-10 membered heterocyclyl having 1-3 heteroatoms selected from N, O or S substituted with 0-4 R0; R0 is independently selected from hydrogen, halogen, cyano, hydroxyl, substituted with 0-4 R 00 C1-C6 alkyl, substituted with 0-4 R 00 C1-C6 alkoxy, substituted with 0-4 R 00 C3-C 10 Cycloalkyl, C1-C6 haloalkyl, hydroxy C1-C6 alkyl, -NR 51 R 52 , replaced by 0-4 R 00 A 5-8 membered heterocyclic group; R 11 and R 12 Each independently selected from hydrogen, substituted with 0-4 R 00 C1-C 10 Alkyl, substituted with 0-4 R 00 C1-C 10 Haloalkyl, substituted with 0-4 R 00 C 2-6 Alkenyl, substituted with 0-4 R 00 C 2-6 Alkynyl, or substituted with 0-4 R 00 C 3-6 Cycloalkyl; or, R 11 and R 12 Together with the N atom to which they are attached, they form a substitution with 0-4 R 00 A 5-10 membered heterocyclic group; R 21 and R 22 are each independently selected from hydrogen, halogen and C1-C6 alkyl, or R 21 and R 22 Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl; R 23 is selected from hydrogen and C1-C6 alkyl; R 31 and R 32 Each independently selected from hydrogen, substituted with 0-4 R 00 C1-C 10 Alkyl, substituted with 0-4 R 00 C3-C 10 Cycloalkyl, substituted with 0-4 R 00 C1-C 10 Haloalkyl, substituted with 0-4 R 00 C 2-6 Alkenyl, substituted with 0-4 R 00 C 2-6 Alkynyl, or substituted with 0-4 R 00 C 3-6 Cycloalkyl; R 41 and R 42 Each independently selected from hydrogen, substituted with 0-4 R 00 C1-C 10 Alkyl, substituted with 0-4 R 00 C3-C 10 Cycloalkyl, substituted with 0-4 R 00 C1-C 10 Haloalkyl, substituted with 0-4 R 00 C 2-6 Alkenyl, substituted with 0-4 R 00 C 2-6 Alkynyl, or substituted with 0-4 R 00 C 3-6 Cycloalkyl; R 43 Selected from hydrogen, substituted with 0-4 R 00 C1-C 10 Alkyl, substituted with 0-4 R 00 C 2-6 Alkenyl, substituted with 0-4 R 00 C 2-6 Alkynyl, or substituted with 0-4 R 00 C 3-6 Cycloalkyl; R 44 Selected from C1-C 10 Alkyl and -NH2; R 45 and R 46 Each independently selected from 0-4 R 00 C1-C 10 Alkyl, substituted with 0-4 R 00 C3-C 10 Cycloalkyl, substituted with 0-4 R 00 C1-C 10 Haloalkyl; R 51 and R 52 Each independently selected from hydrogen, substituted with 0-4 R 00 C1-C 10 Alkyl, substituted with 0-4 R 00 C3-C 10 Cycloalkyl, substituted with 0-4 R 00 C1-C 10 Haloalkyl, substituted with 0-4 R 00 C 2-6 Alkenyl, Generation has 0-4 R 00 C 2-6 Alkynyl, or substituted with 0-4 R 00 C 3-6 Cycloalkyl; R 00 Each is independently selected from hydrogen, halogen, cyano, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, hydroxy C1-C6 alkyl, -NH2; m is 0, 1 or 2; n is 0, 1, 2 or 3.

2. The compound according to claim 1, wherein R1 is a C1-C6 alkyl group substituted with 0-2 R0, Alternatively, R1 is a C3-C6 cycloalkyl substituted with 0-2 R0, Alternatively, R1 is a C5-C substituted with 0-2 R0 10 Polycyclic carbocyclic rings, Alternatively, R1 is a 5-8 membered heterocyclic group substituted with 0-2 R0; R0 is independently selected from hydrogen, halogen, cyano, hydroxy, -NH2, C1-C3 alkyl, hydroxy C1-C3 alkyl, substituted with 0-2 R 00 C3-C6 cycloalkyl, or substituted with 0-2 R 00 A 5- to 8-membered heterocyclic group; R 00 Each is independently selected from hydrogen, halogen, cyano, hydroxy, C1-C3 alkyl, or -NH2.

3. The compound according to claim 1, wherein R1 is -NR 11 R 12 , Among them, R 11 and R 12 Each independently selected from substituted with 0-2 R 00 C1-C6 alkyl, substituted with 0-2 R 00 C3-C6 cycloalkyl, substituted with 0-2 R 00 C1-C6 haloalkyl; or, R 11 and R 12 Together with the nitrogen atom to which they are attached, they form a substitution with 0-2 R 00 A 5-10 membered heterocyclic group; R 00 Each is independently selected from hydrogen, halogen, cyano, hydroxy, C1-C3 alkyl, or -NH2.

4. The compound according to claim 3, wherein R1 is -NR 11 R 12 , Among them, R 11 is a C1-C6 alkyl group, R 12 To replace there is 1 R 00 C1-C6 alkyl, or substituted with 1 R 00 C1-C6 haloalkyl; R 00 Each is independently selected from hydroxy, or -NH2.

5. The compound according to claim 3, wherein R1 is -NR 11 R 12 , Among them, R 11 Methyl, ethyl, R 12 It is 2-hydroxypropyl, 3,3,3-trifluoro-2-hydroxypropyl, 3,3,3-trifluoro-2-hydroxy-2-methylpropyl, or 2-hydroxy-2-methylpropyl.

6. The compound according to claim 3, wherein R1 is wherein R6 is independently selected from hydrogen, halogen, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C1-C6 haloalkyl, or hydroxyC1-C6 alkyl; t is 0, 1 or 2.

7. The compound according to claim 6, wherein R6 is hydroxymethyl.

8. The compound according to claim 6, wherein t is 2, one R6 is a methyl group, and one R6 is a hydroxyl group.

9. The compound according to claim 1, wherein R2 is hydrogen.

10. The compound according to claim 1, wherein R3 is a C1-C3 alkyl group, and m is 0 or 1.

11. The compound according to claim 1, wherein The A1 ring is selected from one of the following ring structures:

12. The compound according to claim 1, wherein Z is a covalent bond, -CR 21 R 22 -, -O-, -S(O)-, -S(O2)- or -NR 23 -; Among them, R 21 and R 22 are each independently selected from hydrogen, fluorine and methyl; R 23 It is hydrogen or methyl.

13. The compound according to claim 12, wherein Z is -CF2-, -CH2-, -CD2- or -C(CH3)2-.

14. The compound according to claim 12, wherein Z is -CH2-.

15. The compound according to claim 12, wherein Z is -O-.

16. The compound according to claim 1, wherein A2 ring is C6-C 10 An aromatic ring structure, such as a benzene ring, an indane ring structure or a naphthalene ring structure.

17. The compound according to claim 1, wherein The A2 ring is a 5-10 membered heteroaromatic ring structure having 1-3 heteroatoms selected from N, O or S, such as a pyrazole ring structure, an oxazole ring structure, or an indoline ring structure.

18. The compound according to claim 1, wherein The A2 ring is a 5-10 membered heterocyclic ring structure having 1-3 heteroatoms selected from N, O or S, for example a pyrrolidine ring structure.

19. The compound according to claim 1, wherein R4 is independently selected from halogen, cyano, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C1-C3 haloalkyl, -NR 41 R 42 , -C(=O)NR 41 R 42 , and -S(O2)R 44 ; Among them, R 41 and R 42 Each is independently selected from hydrogen or C1-C3 alkyl; R 44 Selected from C1-C3 alkyl and -NH2; n is 0, 1 or 2.

20. The compound according to claim 1, wherein n is 2, and R4 is each independently F or Cl.

21. The compound according to claim 1, wherein n is 2, and R4 is F.

22. The compound according to claim 1, wherein n is 2, one R4 is F, and one R4 is Cl.

23. The compound according to claim 1, wherein n is 1, and R4 is F or cyano.

24. The compound according to claim 1, wherein The compound has the structural formula II Among them, R 11 and R 12 Each independently selected from substituted with 0-2 R 00 C1-C6 alkyl, substituted with 0-2 R 00 C3-C6 cycloalkyl, substituted with 0-2 R 00 C1-C6 haloalkyl, substituted with 0-2 R 00 C 2-6 Alkenyl, substituted with 0-2 R 00 C 2-6 Alkynyl; or, R 11 and R 12 Together with the nitrogen atom to which they are attached, they form a substitution with 0-2 R 00 5-6 membered heterocyclic group; wherein R 00 Each is independently selected from hydrogen, halogen, cyano, hydroxy, C1-C3 alkyl, hydroxyC1-C3 alkyl or -NH2; R2 is selected from hydrogen, or C1-C6 alkyl; X is N or CH; Z is -CR 21 R 22 -or-O-; where R 21 and R 22 are each independently selected from hydrogen, halogen and C 1-6 Alkyl; or R 21 and R 22 Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl; R4 are each independently selected from halogen, cyano, and C1-C3 alkyl; n is 1 or 2.

25. The compound according to claim 24, wherein R 11 is a C1-C6 alkyl group, R 12 To replace there is 1 R 00 C1-C6 alkyl; Among them, R 00 are each independently selected from hydroxyl.

26. The compound according to claim 24, wherein R 11 is methyl or ethyl, R 12 It is 2-hydroxypropyl, 3,3,3-trifluoro-2-hydroxypropyl, 3,3,3-trifluoro-2-hydroxy-2-methylpropyl, 1-hydroxy-1-methylcyclopropyl, or 2-hydroxy-2-methylpropyl.

27. The compound according to claim 24, wherein R 11 and R 12 Together with the N atom to which they are attached they form the following group wherein R6 is each independently selected from hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy C1-C6 alkyl; t is 0, 1 or 2.

28. The compound according to claim 27, wherein R6 are each independently selected from hydroxymethyl, and t is 1.

29. The compound according to claim 24, wherein R2 is hydrogen.

30. The compound according to claim 24, wherein Z is -O-.

31. The compound according to claim 24, wherein Z is -CR 21 R 22 -, where R 21 and R 22 are independently selected from hydrogen, fluorine and C 1-3 Alkyl groups such as methyl.

32. The compound according to claim 24, wherein Z is -CR 21 R 22 -, where R 21 and R 22 Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl groups include cyclopropyl.

33. The compound according to claim 24, wherein n is 1, and R4 is F or cyano.

34. The compound according to claim 24, wherein n is 2, and R4 is each independently F or Cl; Alternatively, n is 2, and R4 is all F; Alternatively, n is 2, one R4 is F, and one R4 is Cl.

35. Compound of formula (II-1) or its stereoisomers, tautomers, solvates, hydrates, active metabolites, isotope-labeled substances, pharmaceutically acceptable salts, in, R 11 Selected from cyano, substituted with 0-2 R 00 C1-C6 alkyl, a 4-6 membered heterocyclic group containing a heteroatom selected from O, S or N, or NH2COC 1-6 alkyl; R 12 Selected from substituted with 0-2 R 00 C1-C6 alkyl, substituted with 0-2 R 00 C3-C6 cycloalkyl, or substituted with 0-2 R 00 C 3-6 Cycloalkyl C 1-6 alkyl; R 00 Each is independently selected from hydrogen, halogen, cyano, hydroxy, C1-C3 alkyl, hydroxyC1-C3 alkyl or -NH2; R2 is selected from hydrogen, or C1-C6 alkyl; X is N or CH; R4 are each independently selected from halogen, cyano, and C1-C3 alkyl; n is 1 or 2.

36. The compound according to claim 35, wherein R 11 is C1-C6 alkyl such as methyl, ethyl, R 12 To replace there is 1 R 00 C1-C6 alkyl or substituted with 1 R 00 C 3-6 Cycloalkyl C 1-6 Alkyl, where R 00 are each independently selected from hydroxyl.

37. The compound according to claim 36, wherein R 12 It is 2-hydroxypropyl or (1-hydroxycyclopropyl)methyl.

38. The compound according to claim 35, wherein n is 1 and R4 is F.

39. The compound according to claim 35, wherein X is CH.

40. The compound according to claim 35, wherein R2 is hydrogen.

41. The compound according to claim 1, wherein The compound is selected from one of the following compounds:

42. A pharmaceutical composition comprising a compound according to any one of claims 1 to 41 or a stereoisomer, tautomer, solvate, hydrate, active metabolite, isotope-labeled substance or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

43. Use of a compound according to any one of claims 1 to 41 or its stereoisomers, tautomers, solvates, hydrates, active metabolites, isotope-labeled substances or pharmaceutically acceptable salts, and the pharmaceutical composition according to claim 42 in the preparation of a medicament for inhibiting MRGPRX2 activity.

44. Use of a compound of any one of claims 1 to 41 or a stereoisomer, tautomer, solvate, hydrate, active metabolite, isotopically labeled or pharmaceutically acceptable salt thereof, and the pharmaceutical composition of claim 42 in the preparation of a medicament for treating a MRGPRX2-mediated disorder in a subject.

45. The use according to claim 44, wherein The disorder is an inflammatory disorder, such as a skin disorder.

46. ​​The use according to claim 45, wherein MRGPRX2-mediated conditions are atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis), urticaria, pseudoallergic reactions triggered by small molecules, such as anaphylactoid drug reactions, anaphylactic shock, rosacea, asthma, systemic pruritus, such as cholestatic or uremic pruritus, chronic pruritus triggered by systemic diseases or adverse drug reactions; in particular, urticaria; central nervous system related diseases, including neuroinflammation such as neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease) and central nervous system injuries (such as brain trauma, spinal cord injury, traumatic brain injury (TBI), stroke), neuropathic pain (such as chronic pain syndrome, postherpetic neuralgia, fibromyalgia), psychiatric disorders (such as anxiety, depression, post-traumatic stress disorder (PTSD)), autoimmune brain diseases such as multiple sclerosis (MS) (such as autoimmune encephalomyelitis), glial cell-related diseases (such as glioma), infectious brain diseases (such as encephalitis).

47. A method for treating a MRGPRX2-mediated disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-41 or a stereoisomer, tautomer, solvate, hydrate, active metabolite, isotopically labeled, or pharmaceutically acceptable salt thereof, and the pharmaceutical composition of claim 42.

48. The method according to claim 47, wherein: MRGPRX2-mediated conditions are atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis), urticaria, pseudoallergic reactions triggered by small molecules, such as anaphylactoid drug reactions, anaphylactic shock, rosacea, asthma, systemic pruritus, such as cholestatic or uremic pruritus, chronic pruritus triggered by systemic diseases or adverse drug reactions; in particular, urticaria; central nervous system related diseases, including neuroinflammation such as neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease) and central nervous system injuries (such as brain trauma, spinal cord injury, traumatic brain injury (TBI), stroke), neuropathic pain (such as chronic pain syndrome, postherpetic neuralgia, fibromyalgia), psychiatric disorders (such as anxiety, depression, post-traumatic stress disorder (PTSD)), autoimmune brain diseases such as multiple sclerosis (MS) (such as autoimmune encephalomyelitis), glial cell-related diseases (such as glioma), infectious brain diseases (such as encephalitis).

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