Antagonist of MAS-related g protein-coupled receptor x2 and use thereof

Abstract

Provided are an antagonist of the MAS-related G protein-coupled receptor X2 (MRGPRX2) and the use thereof. The MRGPRX2 antagonist has a structure of formula (I).

Description

Antagonists of MAS-related G protein receptor X2 and uses thereof Technical Field

[0001] The present disclosure relates to the field of medicine, and in particular to an antagonist of MAS-related G protein receptor X2 (MRGPRX2), a composition comprising the antagonist, and a preparation method thereof. Background Art

[0002] MRGPRX2 (Mas-Related G-Protein Coupled Receptor Member X2) is a receptor expressed on mast cells found in barrier tissues (such as the skin, airways, and gastrointestinal tract) that is activated by many ligands, including various peptides and cytokines released from sensory neurons. In response to MRGPRX2 activation, mast cells degranulate and release histamine, tryptase, chylomicron, and related chemokines and cytokines, which in turn trigger urticaria, angioedema, type 2 inflammation (through the engagement of the adaptive immune system), 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 types of innate immune cells, allowing them to be the first to respond to sensory nerve activation. Disturbances in mast cell-nerve interactions are currently considered a major factor in the pathogenesis of neurogenic inflammation and pain.

[0004] When mast cells are activated, they release a wide range of proinflammatory cytokines and chemokines that act on specific receptors on sensory nerve endings. These include, in particular, neuropeptides such as Substance P (SP) and Vasoactive Intestinal Peptide (VIP) that cause nerve endings to release neuropeptides. These neuropeptides can in turn activate receptors on mast cells and induce further degranulation of mast cells, releasing a large number of downstream proinflammatory factors and chemokines, thereby causing neurogenic inflammation. Neurogenic peptides such as SP and VIP can activate mast cells through the MRGPRX2 receptor, suggesting 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 itching, but also can promote the innate immune response of the skin and intestines 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. MRGPRX2 antagonists have the potential to widely treat diseases mediated by mast cells by blocking the activation of MRGPRX2 and the degranulation of mast cells.

[0006] Summary of the Invention

[0007] The present disclosure relates to compounds of formula I or II, or pharmaceutically acceptable salts, hydrates, solvates, active metabolites, polymorphs, isotope labels, isomers or prodrugs thereof.

[0008] The compound has MRGPRX2 antagonist activity and can be used to treat diseases mediated by mast cells.

[0009] The present application also provides a pharmaceutical composition comprising the above-mentioned compound of the present application or its stereoisomers, tautomers, solvates, hydrates, active metabolites, isotope-labeled substances or pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier.

[0010] The present application also provides the use of the compound of the present application or its stereoisomers, tautomers, solvates, hydrates, active metabolites, isotope labels or pharmaceutically acceptable salts, and pharmaceutical compositions in the preparation of drugs for inhibiting MRGPRX2 activity.

[0011] The present application also provides the use of the compound of the present application or its stereoisomers, tautomers, solvates, hydrates, active metabolites, isotope labels or pharmaceutically acceptable salts, as well as the pharmaceutical composition of the present application in the preparation of a medicament for treating MRGPRX2-mediated disorders in a subject.

[0012] The present application also provides a method for treating inflammatory diseases, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present application or its stereoisomers, tautomers, solvates, hydrates, active metabolites, isotope-labeled substances or pharmaceutically acceptable salts, as well as the pharmaceutical composition of the present application. DETAILED DESCRIPTION

[0013] The present invention will be further described in detail below through the following examples, through which the features and advantages of the present invention will become more clearly understood.

[0014] 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.

[0015] In addition, the technical features involved in different embodiments of the present application described below can be combined with each other as long as they do not conflict with each other.

[0016] definition

[0017] 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.

[0018] It should be understood that the above summary 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 application, 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 "including" and other forms, such as "comprising", "including" and "containing" are not limiting.

[0019] 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.

[0020] 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.

[0021] 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.

[0022] 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.

[0023] 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.

[0024] 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.

[0025] 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.

[0026] 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.

[0027] 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.

[0028] 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.

[0029] 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.

[0030] 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.

[0031] 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).

[0032] 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.

[0033] 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.

[0034] 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, propylsulfonyl, butylsulfonyl, 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.

[0035] 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.

[0036] 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.

[0037] 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, amido, 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.

[0038] 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.

[0039] In this application, each group may have the following definitions:

[0040] Hydrogen can be represented as -H, or it can be replaced by isotopes such as deuterium and tritium.

[0041] Halogen may include fluorine, chlorine, bromine, and iodine.

[0042] 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.

[0043] 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.

[0044] 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.

[0045] 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.

[0046] 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.

[0047] 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.

[0048] 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, oxetanyl, thiepanyl, oxazabicyclo[2.2.1]heptyl, azaspiro[3.3]heptyl, and the like.

[0049] C 6～20 The aryl group may include a monocyclic aryl group, a bicyclic aryl group, or a polycyclic aryl group, and may include, for example, phenyl, biphenyl, naphthyl, phenanthrenyl, anthracenyl, azulenyl, and the like.

[0050] 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.

[0051] The hydroxyl group can be represented as -OH.

[0052] A mercapto group can be represented as -SH.

[0053] The carboxyl group can be represented as -COOH.

[0054] 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.

[0055] 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.

[0056] 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.

[0057] The amide group may be represented by -COamino, wherein the amino group is as defined above.

[0058] 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.

[0059] A cyano group can be represented as -CN.

[0060] Oxo can be represented as (=O).

[0061] Thio can be represented as (=S).

[0062] 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.

[0063] 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.

[0064] 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.

[0065] 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.

[0066] 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.

[0067] 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.

[0068] The term "active metabolite" refers to an active derivative of a compound that is formed when the compound is metabolized.

[0069] The term "polymorph" refers to compounds of the present disclosure that exist in different crystal lattice forms.

[0070] 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.

[0071] 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 invention that, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the present invention or a pharmaceutically active metabolite or residue thereof. Particularly preferred derivatives or prodrugs are those that, when administered to a patient, can increase the bioavailability of the compound of the present invention (e.g., by making an orally administered compound more readily absorbed into the blood), or those 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 the compound in a manner that allows for decomposition to the parent compound, either by conventional manipulation or in vivo. 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.

[0072] The term "stereoisomer" refers to an isomer produced by the different spatial arrangement of atoms in a molecule. The disclosed compounds contain structures such as asymmetric or chiral centers, double bonds, etc. Therefore, the disclosed compounds may include multiple isomeric forms such as optical isomers, geometric isomers, tautomers, atropisomers, and 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 and 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 reacting with appropriate optically active substances (such as chiral alcohols or Mosher's acyl chlorides), which are separated and converted (such as hydrolyzed) into corresponding single isomers. For another example, separation can also be carried out by chromatographic column.

[0073] 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.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] 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.

[0078] 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.

[0079] 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.

[0080] The term "IC 50 ” refers to a 50% inhibition of the maximal effect in the assay measuring such effect.

[0081] "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.

[0082] "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.

[0083] "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.

[0084] "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 are characteristic of asthma. Even though only a small amount of transcript is present in the healthy state, the level of MrgprX2 transcripts increases in severe asthma, which is characterized by a phenotypic switch from MCTs to MCTCs. Compared to MCTs, 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. This type of asthma is also known as allergic asthma, when the immune system's response to allergens leads to asthma symptoms.

[0085] A. The first compound

[0086] The present application relates to a compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope label, isomer or prodrug thereof.

[0087] wherein R1 and R2 are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 cycloalkyl, aryl, heteroaryl, or heterocyclyl;

[0088] A1 ring is selected from an aromatic ring or a heteroaromatic ring;

[0089] R3 are each independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 cycloalkyl, aryl, heteroaryl, or heterocyclyl;

[0090] R4 is selected from C substituted with 0-3 R0 1-6Alkyl, substituted with 0-3 R0 C 1-6 Alkoxy, substituted with 0-3 R0 C 2-6 Alkenyl, substituted with 0-3 R0 C 2-6 Alkynyl, substituted with 0-3 R0 C 3-6 Cycloalkyl, substituted with 0-3 R0 C 5-10 Polycyclic carbocycle, aryl substituted with 0-3 R0, heteroaryl substituted with 0-3 R0, or heterocyclyl substituted with 0-3 R0;

[0091] R0 is independently selected from hydroxy, cyano, halogen, guanidinyl, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -NR 11 R 12 , -NR 11 C(O)R 12 , -NR 11 C(O)OR 12 , -NR 11 C(O)NR 11 R 12 , -NR 11 S(O2)R 12 , -NR 11 S(O2)NR 11 R 12 ,-OC(O)R 11 ,-OC(O)NR 11 R 12 , -S(O2)NR 11 R 12 , -S(O2)R 11 , -NR 11 S(O)R 12 ,-B(OR 11 )(OR 12 ), -P(O)R 13 R 14 , -C(O)R 11 ,-C(O)OR 11 , -C(O)NR 11 R 12 , replaced by 0-3 R 00 Aryl, substituted with 0-3 R 00 or substituted with 0-3 R 00 a heterocyclic group;

[0092] R 00 are independently selected from hydroxy, cyano, halogen, C1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, or -NR 11 R 12 ;

[0093] R 11 and R 12 are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, or C 3-6 Cycloalkyl;

[0094] R 13 and R 14 Each independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, or C 3-6 Cycloalkyl;

[0095] m is 0, 1, 2, 3 or 4.

[0096] The inventors of the present disclosure have discovered that the above-mentioned hydrazine compounds disclosed herein have good MRGPRX2 inhibitory activity and can be used as MRGPRX2 antagonists.

[0097] Depending on the position of the substituted amide group on the piperidine ring, the first compound of the present disclosure may have the following structural formula I-1 or I-2:

[0098] wherein R1, R2, R3, R4, A1 ring and m are as defined above.

[0099] In one embodiment of the first compound, the A1 ring can be C 6-10 An aromatic ring, such as a benzene ring or a naphthalene ring.

[0100] In one embodiment of the first compound, the A1 ring can be a 5-10 membered heteroaromatic ring. In particular, the A1 ring can be selected from one of the following structural formulas:

[0101] In one embodiment of the first compound, the A1 ring can be selected from one of the following structural formulas:

[0102] Above A1 ring It indicates the position where the A1 ring is connected to NR2, and m R3 may be substituted thereon.

[0103] In one embodiment of the first compound, R3 can be independently halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, or C 1-6 alkyl halide;

[0104] m is 1, 2 or 3.

[0105] In one embodiment of the first compound, the A1 ring is

[0106] m is 2;

[0107] One R3 is Cl, and the other R3 is CF3. Preferably, Cl is located at the 6-position of quinolin-4-yl, and CF3 is located at the 2-position of quinolin-4-yl.

[0108] In one embodiment of the first compound, R1 and R2 may both be hydrogen.

[0109] In one embodiment of the first compound, R4 is C substituted with 0-3 R0 1-6 Alkyl groups, such as isopropyl;

[0110] Alternatively, R4 is a C substituted with 0-3 R0 3-6 cycloalkyl, such as cyclopropyl or cyclobutyl;

[0111] Alternatively, R4 is a C substituted with 0-3 R0 5-10 polycyclic carbocycles;

[0112] Alternatively, R4 is a heterocyclic group substituted with 0-3 R0;

[0113] Wherein, R0 is independently halogen, or C 1-6 alkyl.

[0114] In one embodiment of the first compound, R4 is one of the following groups:

[0115] Where n is 0, 1 or 2;

[0116] Rq are each independently selected from hydroxy, cyano, halogen, guanidine, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -NR 11 R 12 , -NR 11 C(O)R 12 , -NR 11 C(O)OR 12 , -NR 11 C(O)NR 11 R 12 , -NR 11 S(O2)R 12 , -NR 11 S(O2)NR 11 R 12 ,-OC(O)R 11 ,-OC(O)NR 11 R 12 , -S(O2)NR 11 R 12 , -S(O2)R 11 , -NR 11 S(O)R 12 ,-B(OR 11 )(OR 12 ), -P(O)R 13 R 14 , -C(O)R 11 ,-C(O)OR 11 , -C(O)NR 11 R 12 , substituted with 0 or 1 R 00 aryl, substituted with 0 or 1 R 00 or substituted with 0 or 1 R 00 a heterocyclic group;

[0117] R 00 are independently selected from hydroxy, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, or -NR 11 R 12 ;

[0118] R 11 and R 12 are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C2-6 Alkynyl, or C 3-6 Cycloalkyl;

[0119] R 13 and R 14 Each independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, or C 3-6 Cycloalkyl.

[0120] In R4 above It represents the position where R4 is connected to the carbonyl group (C=O).

[0121] In one embodiment of the first compound, the first compound may have the structural formula 1-3

[0122] Among them, R 31 and R 32 are each independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, or C 3-6 Cycloalkyl;

[0123] R4 is selected from aryl substituted with 0-3 R0, heteroaryl substituted with 0-3 R0, or heterocyclyl substituted with 0-3 R0;

[0124] R0 are each independently selected from hydroxy, cyano, halogen, guanidine, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -NR 11 R 12 , -NR 11 C(O)R 12 , -NR 11 C(O)OR 12 , -NR 11 C(O)NR 11 R 12 , -NR 11 S(O2)R 12 , -NR11 S(O2)NR 11 R 12 ,-OC(O)R 11 ,-OC(O)NR 11 R 12 , -S(O2)NR 11 R 12 , -S(O2)R 11 , -NR 11 S(O)R 12 ,-B(OR 11 )(OR 12 ), -P(O)R 13 R 14 , -C(O)R 11 ,-C(O)OR 11 , -C(O)NR 11 R 12 , replaced by 0-3 R 00 Aryl, substituted with 0-3 R 00 or substituted with 0-3 R 00 a heterocyclic group;

[0125] R 00 Each independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, or -NR 11 R 12 ;

[0126] R 11 and R 12 are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, or C 3-6 Cycloalkyl;

[0127] R 13 and R 14 Each independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, or C 3-6 Cycloalkyl.

[0128] In one embodiment of the first compound having the structural formula of 1-3, R 31 C1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Haloalkyl, such as -CF3;

[0129] R 32 is halogen, such as Cl or F, especially Cl.

[0130] In one embodiment, the first compound has the structural formula of 1-3,

[0131] R4 is

[0132] Among them, R 42 For hydrogen, halogen, C 1-3 Alkyl or C 1-3 alkyl halide;

[0133] R 41 C 1-3 Alkyl or C 1-3 Halogenated alkyl.

[0134] In particular, in the above embodiments of R4, R 42 is hydrogen, R 41 C 1-3 Alkyl such as methyl, or C 1-3 Haloalkyl groups include difluoromethyl and trifluoroethyl.

[0135] In one embodiment of the first compound having the structural formula of I-3, R4 is

[0136] wherein X1, X2, X3 and X4 are each independently a C atom or a N atom, and not all of X1, X2, X3 and X4 are N atoms;

[0137] R 51 、R 52 、R 53 、R 54 and R 55 are independently hydrogen, halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, -N(R 50 )2, -NHS(O2)R 50 or -P(O)(R 50 )2,

[0138] R 50 are independently hydrogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl.

[0139] In one embodiment of the first compound having the structural formula of I-3, R4 is Among them, R 61 is cyano, halogen (such as F), C 1-3 Alkoxy (e.g., methoxy), NHC(O)R 50 or -P(O)(R 50 )2,R 50 Each independently is C 1-3 an alkyl group (e.g., methyl, ethyl, or propyl);

[0140] Alternatively, R4 is Among them, R 65 For cyano, NHC(O)R 50 or -NHS(O2)R 50 , R 50 Each independently is C 1-3 Alkyl (e.g., methyl, ethyl, n-propyl, or isopropyl);

[0141] Alternatively, R4 is Among them, R 63 For hydrogen, halogen, C 1-3 Alkoxy (e.g., methoxy) or -NH2;

[0142] Alternatively, R4 is Among them, R 62 C 1-3 Alkoxy (e.g., methoxy) or -NH2;

[0143] Alternatively, R4 is Among them, R 64 C 1-3 Alkoxy (e.g., methoxy) or -NH2;

[0144] Alternatively, R4 is where R 66 For hydrogen, C 1-3 Alkoxy (e.g., methoxy) or -NH2;

[0145] Alternatively, R4 is where R 67 and R 68 are independently hydrogen, C 1-3 Alkoxy (e.g., methoxy) or -NH2.

[0146] In one embodiment of the first compound having the structural formula of I-3, R4 is Among them, R 65 -S(O2)NR 11 R 12 , where R 11 and R 12Each independently selected from hydrogen or C 1-6 In particular, R 11 and R 12 One is hydrogen and the other is C 1-6 Alkyl (eg, methyl or ethyl).

[0147] In one embodiment of the first compound having the structural formula of I-3, R4 is

[0148] Wherein, X3 is N or CH, R 65 is hydrogen or C 1-3 Alkyl (eg, methyl).

[0149] In one embodiment of the first compound having the structural formula of I-3, R4 is or

[0150] B. Second compound

[0151] The present disclosure also relates to a compound of formula II or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope label, isomer or prodrug thereof,

[0152] wherein R1 and R2 are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 cycloalkyl, aryl, heteroaryl, or heterocyclyl;

[0153] A1 ring is selected from an aromatic ring or a heteroaromatic ring;

[0154] R3 are each independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 cycloalkyl, aryl, heteroaryl, or heterocyclyl;

[0155] Ring A2 is selected from an aromatic ring or a heteroaromatic ring;

[0156] R 20 are each independently selected from hydrogen, hydroxy, cyano, halogen, guanidinyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-6 Cycloalkyl, -NR 11 R 12 , -NR 11 C(O)R 12 , -NR 11 C(O)OR 12 , -NR 11 C(O)NR 11 R 12 , -NR 11 S(O2)R 12 , -NR 11 S(O2)NR 11 R 12 ,-OC(O)R 11 ,-OC(O)NR 11 R 12 , -S(O2)NR 11 R 12 , -S(O2)R 11 , -NR 11 S(O)R 12 ,-B(OR 11 )(OR 12 ), -P(O)R 13 R 14 , -C(O)R 11 ,-C(O)OR 11 , -C(O)NR 11 R 12 , replaced by 0-3 R 00 Aryl, substituted with 0-3 R 00 or substituted with 0-3 R 00 a heterocyclic group;

[0157] R 21 and R 22 Each independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, or C 3-6 Cycloalkyl; or, R 21 With an R on the A2 ring 20 Together they form a 5-6 membered heterocyclic ring;

[0158] R 00 are independently selected from hydroxy, cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-6 Cycloalkyl, or -NR 11 R 12 ;

[0159] R 11 and R 12 are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, or C 3-6 Cycloalkyl;

[0160] m is 0, 1, 2, 3 or 4;

[0161] t is 0, 1, 2, or 3.

[0162] The second compound has an aminocyclohexyl ring structure and carries a phosphoryl group (-P(=O)R 21 R 22 ). The inventors of the present disclosure have found that by modifying the phosphoryl group, the second compound has good MRGPRX2 inhibitory activity and can be used as a MRGPRX2 antagonist.

[0163] Depending on the position of the substituted amide group on the cyclohexyl ring, the second compound of the present disclosure may have the following structural formula II-1 or II-2:

[0164] Among them, R1, R2, R3, R 20 、R 21 、R 22 , A1 ring, A2 ring, t and m are as defined above.

[0165] In one embodiment of the second compound, the A1 ring is C 6-10 An aromatic ring, such as a benzene ring or a naphthalene ring; or, the A1 ring is a 5-10 membered heteroaromatic ring.

[0166] In one embodiment of the second compound, the A1 ring is selected from one of the following structural formulas:

[0167] Preferably, the A1 ring is selected from one of the following structural formulas:

[0168] Above A1 ring It indicates the position where the A1 ring is connected to NR2, and m R3 may be substituted thereon.

[0169] In one embodiment of the second compound, R3 is each independently halogen, cyano, C 1-6 Alkyl, C1-6 Alkoxy, or C 1-6 alkyl halide;

[0170] m is 1, 2 or 3.

[0171] In one embodiment of the second compound, R1 and R2 are both hydrogen.

[0172] In one embodiment of the second compound, the A2 ring is C 6-10 Aromatic rings, such as benzene or naphthalene;

[0173] Alternatively, the A2 ring is a 5-6 membered heteroaromatic ring;

[0174] Preferably, the A2 ring is selected from

[0175] Above A2 ring It indicates the position where the A2 ring is connected to the nitrogen on the amide (N(=O)R1).

[0176] In one embodiment of the second compound, R 21 and R 22 Each independently selected from C 1-3 Alkyl groups, such as methyl.

[0177] In one embodiment of the second compound, R 20 are each independently selected from hydrogen, halogen, or C 1-3 alkyl;

[0178] t is 0 or 1.

[0179] In one embodiment of the second compound, the second compound has the structural formula II-3

[0180] Among them, R 41 and R 42 are each independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, or C 3-6 Cycloalkyl;

[0181] R 20 are each independently selected from hydrogen, hydroxy, cyano, halogen, guanidinyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -NR 11R 12 , -NR 11 C(O)R 12 , -NR 11 C(O)OR 12 , -NR 11 C(O)NR 11 R 12 , -NR 11 S(O2)R 12 , -NR 11 S(O2)NR 11 R 12 ,-OC(O)R 11 ,-OC(O)NR 11 R 12 , -S(O2)NR 11 R 12 , -S(O2)R 11 , -NR 11 S(O)R 12 ,-B(OR 11 )(OR 12 ), -P(O)R 13 R 14 , -C(O)R 11 ,-C(O)OR 11 , -C(O)NR 11 R 12 , replaced by 0-3 R 00 Aryl, substituted with 0-3 R 00 or substituted with 0-3 R 00 a heterocyclic group;

[0182] R 21 and R 22 Each independently selected from C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkylamino; or, R 21 With R on A2 ring 20 Together they form a 5-6 membered heterocyclic ring;

[0183] Ring A2 is selected from

[0184] In one embodiment of the second compound having the structural formula II-3, R 41 C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Haloalkyl, such as -CF3;

[0185] R 42 is a halogen, such as Cl or F.

[0186] In one embodiment of the second compound having the structural formula II-3, the A2 ring is

[0187] R 21 and R 22 are each independently methyl.

[0188] In one embodiment of the second compound having the structural formula II-3, R 21 and R 22 Each independently selected from C 1-6 Alkyl groups are for example methyl or ethyl, especially methyl.

[0189] In one embodiment, the compounds of the present disclosure (including the first compound and the second compound) are selected from one of the following:

[0190] Composition and application

[0191] The present application provides a pharmaceutical composition comprising the above-mentioned compound of the present application or its stereoisomers, tautomers, solvates, hydrates, active metabolites, isotope-labeled substances or pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier.

[0192] As demonstrated in this application, the above-mentioned compounds of the present application have good inhibitory activity against MRGPRX2, so the above-mentioned compounds of the present application or their stereoisomers, tautomers, solvates, hydrates, active metabolites, isotope labels or pharmaceutically acceptable salts, and the pharmaceutical compositions of the present application can be used as drugs that inhibit MRGPRX2 activity and can be used to prepare drugs for inhibiting MRGPRX2 activity. The present application 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, and the pharmaceutical compositions of the present application in the preparation of drugs for inhibiting MRGPRX2 activity.

[0193] Similarly, the present application also relates to the use of the compounds of the present application or their stereoisomers, tautomers, solvates, hydrates, active metabolites, isotope labels or pharmaceutically acceptable salts, as well as the pharmaceutical compositions of the present application in the preparation of drugs for treating MRGPRX2-mediated disorders in a subject.

[0194] Similarly, the present application also relates to a method for treating inflammatory diseases, comprising administering to a subject in need thereof a therapeutically effective amount of the above-mentioned compound of the present application or its stereoisomers, tautomers, solvates, hydrates, active metabolites, isotope-labeled substances or pharmaceutically acceptable salts, or pharmaceutical compositions.

[0195] In the present application, the MRGPRX2-mediated condition can be an inflammatory condition, such as a skin condition. In one embodiment, the inflammatory condition 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, asthma.

[0196] 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.

[0197] Example 1: N-(3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)piperidin-1-yl)-1-methyl-1H-pyrazole-4-carboxamide

[0198] Step A: tert-Butyl (1-nitrosopiperidin-3-yl)carbamate

[0199] 5.00 g (24.9 mmol, 1.0 eq) of tert-butyl piperidin-3-ylcarbamate was dissolved in a mixture of 12.5 mL of acetic acid and 7.5 mL of water and the temperature was lowered to 0°C. A solution of 3.44 g (49.9 mmol, 2.0 eq) of sodium nitrite in 5 mL of water was added dropwise, maintaining the temperature below 0°C. The reaction system was allowed to warm to room temperature and stirred for 1.5 hours. TLC confirmed complete reaction of the starting material. Saturated sodium bicarbonate solution was added to neutralize the reaction, followed by extraction three times with ethyl acetate, drying over anhydrous sodium sulfate, filtration, and evaporation under reduced pressure to afford a white solid (5.60 g, yield = 98%).

[0200] LC-MS: (M+H-100) + ; m / z = 130.14;

[0201] Step B: tert-Butyl (1-aminopiperidin-3-yl)carbamate

[0202] Dissolve 1.00 g (4.45 mmol, 1.0 eq) of tert-butyl (1-nitrosopiperidin-3-yl)carbamate and 1.45 g (22.2 mmol, 5.0 eq) of zinc powder in 6.0 mL of methanol and cool to -10°C. Add 6.0 mL of glacial acetic acid dropwise and stir at -10°C for 0.5 hours. Allow the reaction to warm to room temperature and stir overnight. Complete reaction of the starting materials was confirmed by TLC. Filter the mixture and evaporate to dryness under reduced pressure. Add 20 mL of water and neutralize with saturated sodium bicarbonate solution. Extract the mixture several times with dichloromethane, dry over anhydrous sodium sulfate, filter, and evaporate to dryness under reduced pressure to obtain a yellow oil (1.20 g, crude product).

[0203] LC-MS: (M+H) + ; m / z = 216.20;

[0204] Step C: tert-Butyl (1-(1-methyl-1H-pyrazole-4-carboxamido)piperidin-3-yl)carbamate

[0205] 60.0 mg (476 μmol, 1.0 eq) of 1-methylpyrazole-4-carboxylic acid was dissolved in 1 mL of N,N-dimethylformamide, and then 190 mg (500 μmol, 1.05 eq) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate and 123.0 mg (952 μmol, 2.0 eq) of N,N-diisopropylethylamine were added to the reaction system. After stirring at room temperature for 1 minute, 102 mg (476 μmol, 1.0 eq) of tert-butyl (1-aminopiperidin-3-yl)carbamate was added to the reaction system, and the reaction was continued by stirring for 1 hour. LC-MS results confirmed that the reaction of the starting material was complete. 10 mL of water 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 crude product. 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 (47.0 mg, yield = 36%).

[0206] LC-MS: (M+H) + ; m / z = 324.23;

[0207] Step D: N-(3-aminopiperidin-1-yl)-1-methyl-1H-pyrazole-4-carboxamide hydrochloride

[0208] 47.0 mg (145 μmol, 1.0 eq) of tert-butyl (1-(1-methyl-1H-pyrazole-4-carboxamido)piperidin-3-yl)carbamate was dissolved in 1 mL of anhydrous tetrahydrofuran. 363 μL (1.45 mmol, 10.0 eq) of 4M 1,4-dioxane hydrochloride solution was added to the reaction system. The mixture was stirred at room temperature under nitrogen for 18 hours. LC-MS results confirmed the complete reaction of the starting material. The reaction solution was then concentrated under reduced pressure to afford a pale yellow solid (37.8 mg, yield = 100%).

[0209] LC-MS: (M+Na) + ; m / z = 246.1;

[0210] Step E: N-(3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)piperidin-1-yl)-1-methyl-1H-pyrazole-4-carboxamide

[0211] 30.0 mg (116 μmol, 1.0 eq) of N-(3-aminopiperidin-1-yl)-1-methyl-1H-pyrazole-4-carboxamide hydrochloride was dissolved in 1 mL of N,N-dimethylformamide, and then 46.1 mg (173 μmol, 1.5 eq) of 4,6-dichloro-2-(trifluoromethyl)quinoline and 31.9 mg (231 μmol, 2.0 eq) of potassium carbonate were added to the reaction system. The mixture was stirred at 100°C under nitrogen protection for 4 hours. The reaction of the raw materials was confirmed to be complete by LC-MS, and the temperature was cooled to room temperature. 10 mL of water 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 crude product. 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 (8.40 mg, yield = 16%).

[0212] LC-MS: (M+H) + ; m / z = 453.13;

[0213] 1HNMR (400MHz, CDCl3) δ8.20(s,1H),7.99(d,J=9.0Hz,1H),7.90(s,1H),7.74(s,1H),7.63(d,J=8.9Hz,1H),6.92(s,1H ),6.75(s,1H),6.68(s,1H),4.09-4.02(m,1H),3.95(s,3H),3.35-3.12(m,3H),3.10-2.67(m,2H),2.13-1.87(m,3H).

[0214] 19 F NMR(376MHz, CDCl3)δ-67.77,68.08.

[0215] Example 2: N-(1-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)piperidin-3-yl)-1-methyl-1H-pyrazole-4-carboxamide

[0216] Step A: tert-Butyl (1-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)piperidin-3-yl)carbamate

[0217] 100 mg (376 μmol, 1.0 eq) of 4,6-dichloro-2-(trifluoromethyl)quinoline was dissolved in 5 mL of 1,4-dioxane, and 97.1 mg (451 μmol, 1.2 eq) of tert-butyl (1-aminopiperidin-3-yl)carbamate was added. This was followed by 245 mg (752 μmol, 2.0 eq) of cesium carbonate, 34.4 mg (38.0 μmol, 0.1 eq) of tris(dibenzylideneacetone)dipalladium, and 35.8 mg (75.0 μmol, 0.2 eq) of 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl. The mixture was stirred at 110°C for 3 hours. LC-MS confirmed the formation of the product. 5 mL of water was added, and the mixture was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and purified by preparative TLC to obtain a yellow solid (45.0 mg, yield = 21%).

[0218] LC-MS: (M+H) + ; m / z = 445.15;

[0219] Step B:N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)piperidine-1,3-diamine trihydrochloride

[0220] 95.0 mg (214 μmol, 1.0 eq) tert-butyl (1-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)piperidin-3-yl)carbamate was dissolved in 10 mL of dichloromethane, and 2.2 mL of hydrochloric acid / 1,4-dioxane solution (4.0 mol / L) was added dropwise. The mixture was stirred at 40°C for 8 hours. TLC confirmed that the reaction of the raw materials was complete, and the mixture was evaporated to dryness under reduced pressure to obtain a light yellow oily liquid (93.0 mg).

[0221] Step C: N-(1-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)piperidin-3-yl)-1-methyl-1H-pyrazole-4-carboxamide

[0222] 31.0 mg (246 μmol, 1.2 eq) of 1-methyl-1H-pyrazole-4-carboxylic acid, 0.09 mL of N,N-diisopropylethylamine and 117 mg (307 μmol, 1.5 eq) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate were dissolved in 5 mL of anhydrous tetrahydrofuran and stirred at room temperature for 0.5 hours. 93.0 mg (205 μmol, 1.0 eq) of N 1 -(6-Chloro-2-(trifluoromethyl)quinolin-4-yl)piperidine-1,3-diamine trihydrochloride was stirred at room temperature for 1 hour. LC-MS confirmed the formation of the product, 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 over 55 minutes; flow rate: 70 mL / min) and lyophilized to afford a white solid (31.0 mg, two-step yield = 32%).

[0223] LC-MS: (M+H) + ; m / z = 452.87;

[0224] 1 H NMR (400MHz, CDCl3) δ8.05(d,J=9.0Hz,1H),7.83(s,1H),7.78(s,1H),7.73(d,J=2.2Hz,1H),7.68-7.65(m,1H), 7.36(s,1H),6.49(brs,1H),6.05(s,1H),4.48-4.46(s,1H),3.95(s,3H),3.19-2.79(m,4H),2.11-1.75(m,4H).

[0225] 19 F NMR (376MHz,CDCl3)δ-67.93.

[0226] Example 3: (R)-N-(1-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)piperidin-3-yl)-3-((1-methylethyl)sulfonamido)benzamide

[0227] Step A: Methyl 3-((1-methylethyl)sulfonamido)benzoate

[0228] 200 mg (1.32 mmol, 1.0 eq) of methyl 3-aminobenzoate, 188 mg (1.32 mmol, 1.0 eq) of propane-2-sulfonyl chloride, 209 mg (2.64 mmol, 2.0 eq) of pyridine, and 5 mL of dichloromethane were added to a 100 mL reaction flask. Under nitrogen, the reaction solution was reacted at 45°C for 14 hours. LC-MS confirmed complete reaction of the starting materials. 20 mL of water was added to the reaction solution, and the reaction solution was extracted three times with dichloromethane (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (dichloromethane:methanol = 30:1) to obtain a yellow solid (300 mg, yield = 88%).

[0229] LC-MS:(MH) - ; m / z = 255.97;

[0230] Step B: 3-((1-methylethyl)sulfonamido)benzoic acid

[0231] 300 mg (1.16 mmol, 1.0 eq) of methyl 3-((1-methylethyl)sulfonamido)benzoate, 146 mg (3.49 mmol, 3.0 eq) of lithium hydroxide monohydrate, 2 mL of water, 2 mL of methanol, and 6 mL of tetrahydrofuran were added to a 100 mL reaction flask. Under nitrogen, the reaction solution was allowed to react at room temperature for 14 hours. LC-MS confirmed complete reaction of the starting materials. The reaction solution was concentrated until most of the solvent was removed, and water (20 mL) was added. The pH was adjusted to 5-6 with 1 M dilute hydrochloric acid, and the mixture was extracted three times with dichloromethane (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude yellow solid (270 mg, yield = 95%).

[0232] LC-MS:(MH) - ; m / z = 241.98;

[0233] Step C: (R)-N-(1-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)piperidin-3-yl)-3-((1-methylethyl)sulfonamido)benzamide

[0234] 42.0 mg (174 μmol, 1.2 eq) 3-((1-methylethyl)sulfonamido)benzoic acid, 82.0 mg (218 μmol, 1.5 eq) 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 72.0 μL (435 μmol, 3.0 eq) N,N-diisopropylethylamine, and 5 mL tetrahydrofuran were added to a 100 mL reaction bottle. Under nitrogen protection, the reaction solution was stirred at room temperature for 10 minutes. Then, 50.0 mg (145 μmol, 1.0 eq) (R)-N 1 -(6-Chloro-2-(trifluoromethyl)quinolin-4-yl)piperidine-1,3-diamine was dissolved in 2 mL of tetrahydrofuran, slowly added to the reaction solution, and stirred at room temperature for 1 hour. LC-MS confirmed that the raw material was completely reacted. Water (20 mL) was added and extracted three times with dichloromethane (20 mL). The organic phases were combined, washed twice with saturated brine, 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 minutes; flow rate: 70 mL / min) and lyophilized to obtain a pure white solid (21.0 mg, yield = 25%).

[0235] LC-MS: (M+H) + ; m / z = 570.18;

[0236] 1 H NMR (400MHz, DMSO-d6) δ9.91 (s, 1H), 9.05 (s, 1H), 8.41 (m, 2H), 7.94 (d, J = 9.0 Hz,1H),7.77(dd,J=9.0,1.8Hz,1H),7.70-7.49(m,2H),7.42-7.38(m,2H),7. 28(s,1H),4.12-4.07(m,1H),3.25-3.16(m,2H),3.04(d,J=9.6Hz,1H),2.60( t,J=10.3Hz,2H),1.94-1.64(m,3H),1.49-1.33(m,1H),1.23(d,J=6.8Hz,6H).

[0237] 19 F NMR(376MHz,DMSO-d6)δ-66.68.

[0238] Example 4: (R)-N-(1-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)piperidin-3-yl)-4-((2,2-difluoroethyl)amino)benzamide

[0239] Step A: Ethyl 4-((2,2-difluoroethyl)amino)benzoate

[0240] 1.00 g (5.16 mmol, 1.0 eq) of 4-ethoxycarbonylphenylboronic acid was dissolved in 50 mL of acetonitrile, and then 0.80 g (10.3 mmol, 2.0 eq) of 2,2-difluoroethylamine, 0.20 g (1.03 mmol, 0.2 eq) of copper acetate monohydrate, 1.60 g (15.5 mmol, 3.0 eq) of triethylamine and 2.0 g of Molecular sieves were added to the reaction system, and the reaction was stirred at 80°C under air for 18 hours. LC-MS results confirmed the complete reaction of the starting material. The mixture was cooled to room temperature, filtered through a celite pad, and the filtrate was evaporated to dryness under reduced pressure. 30 mL of 10% aqueous ammonia and 20 mL of ethyl acetate were added, and the mixture was shaken and allowed to stand. The organic phase was separated and washed with brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 0-1:10) to obtain a yellow solid (576 mg, yield = 49%).

[0241] LC-MS: (M+H) + ; m / z = 230.1;

[0242] Step B: 4-((2,2-difluoroethyl)amino)benzoic acid

[0243] 526 mg (2.29 mmol, 1.0 eq) of ethyl 4-((2,2-difluoroethyl)amino)benzoate was dissolved in 9 mL of methanol. 289 mg (6.88 mmol, 3.0 eq) of lithium hydroxide monohydrate in water (4.5 mL) was added to the reaction system. The reaction was stirred at room temperature under nitrogen for 18 hours. LC-MS confirmed the complete reaction of the starting material. The methanol was evaporated under reduced pressure, and the mixture was filtered. The filtrate was adjusted to pH 3 with 2 M hydrochloric acid. After the solid precipitated, it was filtered and the filter cake was vacuum dried to yield a light yellow solid (516 mg, yield = 90%).

[0244] LC-MS: (M+H) + ; m / z = 202.1;

[0245] Step C: (R)-N-(1-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)piperidin-3-yl)-4-((2,2-difluoroethyl)amino)benzamide

[0246] 24.5 mg (122 μmol, 1.05 eq) of 4-((2,2-difluoroethyl)amino)benzoic acid was dissolved in 0.5 mL of N,N-dimethylformamide, and then 46.3 mg (122 μmol, 1.05 eq) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate and 30.0 mg (232 μmol, 2.0 eq) of N,N-diisopropylethylamine were added to the reaction system. After stirring at room temperature for 1 minute, 40.0 mg (116 μmol, 1.0 eq) of (R)-N 1 6-Chloro-2-(trifluoromethyl)quinolin-4-yl)piperidine-1,3-diamine was added to the reaction system, and the reaction was stirred for 30 minutes. LC-MS results confirmed the complete reaction of the starting material. 10 mL of water and 10 mL of ethyl acetate were added, and the organic phase was separated. The aqueous phase was extracted twice with 10 mL of ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by preparative chromatography (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% B over 55 minutes; flow rate: 70 mL / min) and lyophilized to obtain a light yellow solid (13.4 mg, yield = 22%).

[0247] LC-MS: (M+H) + ; m / z = 527.95;

[0248] 1 H NMR(400MHz,DMSO-d6)δ9.03(s,1H),8.42(s,1H),7.99-7.92(m,2H),7.77(dd, J=9.0,2.1Hz,1H),7.64(d,J=8.5Hz,2H),7.27(s,1H),6.69-6.67(m,2H),6.48- 6.45(m,1H),6.10(tt,J=55.9,3.5Hz,1H),4.09-4.05(m,1H),3.60-3.51(m,2H),3.34-3 .02(m,2H),2.82-2.55(m,2H),2.02-1.78(m,2H),1.75-1.65(m,1H),1.48-1.31(m,1H).

[0249] 19 F NMR(376MHz,DMSO-d6)δ-66.68,-121.38.

[0250] Example 5: (S)-N-(1-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)piperidin-3-yl)-1-methyl-1H-pyrazole-4-carboxamide

[0251] Step A: tert-Butyl (S)-(1-nitrosopiperidin-3-yl)carbamate

[0252] 5.00 g (24.9 mmol, 1.0 eq) of tert-butyl (S)-piperidin-3-ylcarbamate was dissolved in a mixture of 12.5 mL of acetic acid and 7.5 mL of water and the temperature was lowered to 0°C. A solution of 3.44 g (49.9 mmol, 2.0 eq) of sodium nitrite in 5.0 mL of water was added dropwise, maintaining the temperature below 0°C. The reaction system was allowed to warm to room temperature and stirred for 1.5 hours. TLC confirmed complete reaction of the starting material. Saturated sodium bicarbonate solution was added to neutralize the reaction, and the mixture was extracted three times with ethyl acetate (50 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure to obtain a white solid (6.20 g, crude product).

[0253] LC-MS: (M+H-100) + ; m / z = 130.06;

[0254] Step B: tert-Butyl (S)-(1-aminopiperidin-3-yl)carbamate

[0255] Dissolve 1.00 g (4.02 mmol, 1.0 eq) of tert-butyl (S)-(1-nitrosopiperidin-3-yl)carbamate and 1.32 g (20.1 mmol, 5.0 eq) of zinc powder in 30.0 mL of methanol and cool to -10°C. Add 11.0 mL of glacial acetic acid dropwise, and stir at -10°C for 0.5 hours. Allow the reaction system to warm to room temperature and stir overnight. Complete reaction of the starting materials was confirmed by TLC. Filter the mixture and evaporate to dryness under reduced pressure. Add 20 mL of water and neutralize with saturated sodium bicarbonate solution. Extract the mixture several times with dichloromethane (20 mL), dry over anhydrous sodium sulfate, filter, and evaporate to dryness under reduced pressure to obtain a brown oil (1.40 g, crude product).

[0256] LC-MS: (M+H) + ; m / z = 216.18;

[0257] Step C: (S)-tert-Butyl(1-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)piperidin-3-yl)carbamate

[0258] 100 mg (376 μmol, 1.0 eq) of 4,6-dichloro-2-(trifluoromethyl)quinoline was dissolved in 5.0 mL of 1,4-dioxane, and 97.1 mg (451 μmol, 1.2 eq) of tert-butyl (S)-(1-aminopiperidin-3-yl)carbamate was added. This was followed by the addition of 72.2 mg (1.50 mmol, 2.0 eq) of sodium tert-butoxide, 34.4 mg (75.0 μmol, 0.1 eq) of tris(dibenzylideneacetone)dipalladium, and 35.8 mg (150 μmol, 0.2 eq) of 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl. The mixture was evacuated three times, purged with nitrogen, and stirred at 110°C for 2.0 hours. LC-MS confirmed the formation of the product. 5 mL of water was added, and the mixture was extracted three times with ethyl acetate (5 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 50:1 to 5:1) to give a yellow solid (65.0 mg, yield = 36%).

[0259] LC-MS: (M+H) + ; m / z = 445.17;

[0260] Step D: (S)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)piperidine-1,3-diamine hydrochloride

[0261] 65.0 mg (146 μmol, 1.0 eq) of tert-butyl (S)-(1-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)piperidin-3-yl)carbamate was dissolved in 10 mL of dichloromethane, and 1.5 mL of hydrochloric acid / 1,4-dioxane solution (4.0 mol / L) was added dropwise. The mixture was stirred at 40°C for 7.0 hours. TLC confirmed that the reaction of the raw materials was complete, and the mixture was evaporated to dryness under reduced pressure to give a white solid (140 mg, crude product).

[0262] Step E: (S)-N-(1-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)piperidin-3-yl)-1-methyl-1H-pyrazole-4-carboxamide

[0263] 22.1 mg (175 μmol, 1.2 eq) of 1-methyl-1H-pyrazole-4-carboxylic acid, 0.05 mL of N,N-diisopropylethylamine and 83.4 mg (219 μmol, 1.5 eq) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate were dissolved in 5.0 mL of anhydrous tetrahydrofuran and stirred at room temperature for 0.5 hours. 140 mg (146 μmol, 1.0 eq) of (S)-N 1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)piperidine-1,3-diamine hydrochloride was stirred at room temperature for 1 hour. LC-MS confirmed the formation of the product. 3 mL of water and 5 mL of ethyl acetate were added, and the organic phase was separated. The aqueous phase was extracted twice with ethyl acetate (5 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by preparative chromatography (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% B over 55 minutes; flow rate: 70 mL / min) and lyophilized to obtain a white solid (15.0 mg, two-step yield = 22%).

[0264] LC-MS: (M+H) + ; m / z = 453.14;

[0265] 1 H NMR(400MHz,DMSO-d6)δ9.02(s,1H),8.41(s,1H),8.12(s,1H),7.98-7.91(m,2H),7.84(s,1H),7.79-7.77(m,1H),7.2 6(s,1H),4.06-4.04(m,1H),3.84(s,3H),3.16-3.02(m,2H),2.70-2.54(m,2H),1.88-1.81(m,2H),1.75-1.65(m,2H).

[0266] 19 F NMR(376MHz,DMSO-d6)δ-66.69.

[0267] Example 6: (R)-N-(1-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)piperidin-3-yl)-1-methyl-1H-pyrazole-4-carboxamide

[0268] Step A: tert-Butyl (R)-(1-nitrosopiperidin-3-yl)carbamate

[0269] 5.00 g (24.9 mmol, 1.0 eq) of tert-butyl (R)-piperidin-3-ylcarbamate was dissolved in a mixture of 12.5 mL of acetic acid and 7.5 mL of water and the temperature was lowered to 0°C. A solution of 3.44 g (49.9 mmol, 2.0 eq) of sodium nitrite in 5.0 mL of water was added dropwise, maintaining the temperature below 0°C. The reaction system was allowed to warm to room temperature and stirred for 1.5 hours. TLC confirmed complete reaction of the starting material. Saturated sodium bicarbonate solution was added to neutralize the reaction, followed by extraction with ethyl acetate (50 mL) three times, drying over anhydrous sodium sulfate, filtration, and evaporation under reduced pressure to obtain a white solid (6.70 g, crude product).

[0270] LC-MS: (M+H-100) + ; m / z = 130.07;

[0271] Step B: (R)-tert-Butyl (1-aminopiperidin-3-yl)carbamate

[0272] 1.00 g (3.71 mmol, 1.0 eq) of tert-butyl (R)-(1-nitrosopiperidin-3-yl)carbamate and 1.21 g (18.6 mmol, 5.0 eq) of zinc powder were dissolved in 30.0 mL of methanol and cooled to -10°C. 10.0 mL of glacial acetic acid was added dropwise, and the mixture was stirred at -10°C for 0.5 hours. The reaction system was allowed to warm to room temperature and stirred overnight. TLC confirmed complete reaction of the starting materials, and the mixture was filtered and evaporated to dryness under reduced pressure. 20 mL of water was added, and the mixture was neutralized with saturated sodium bicarbonate solution. The mixture was then extracted several times with dichloromethane (20 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure to obtain a brown oil (1.30 g, crude product).

[0273] LC-MS: (M+H) + ; m / z = 216.18;

[0274] Step C: (R)-tert-Butyl(1-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)piperidin-3-yl)carbamate

[0275] 200 mg (752 μmol, 1.0 eq) of 4,6-dichloro-2-(trifluoromethyl)quinoline was dissolved in 5.0 mL of 1,4-dioxane, and 194 mg (902 μmol, 1.2 eq) of tert-butyl (R)-(1-aminopiperidin-3-yl)carbamate was added. This was followed by the addition of 144 mg (1.50 mmol, 2.0 eq) of sodium tert-butoxide, 68.8 mg (75.0 μmol, 0.1 eq) of tris(dibenzylideneacetone)dipalladium, and 71.7 mg (150 μmol, 0.2 eq) of 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl. The mixture was stirred at 110°C for 2 hours. LC-MS confirmed the formation of the product. 10 mL of water was added, and the mixture was extracted three times with ethyl acetate (10 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50:1 to 5:1) to give a yellow solid (113 mg, yield = 33%).

[0276] LC-MS: (M+H) + ; m / z = 445.18;

[0277] Step D: (R)-N 1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)piperidine-1,3-diamine hydrochloride

[0278] 113 mg (254 μmol, 1.0 eq) of tert-butyl (R)-(1-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)piperidin-3-yl)carbamate was dissolved in 10 mL of dichloromethane, and 2.5 mL of hydrochloric acid / 1,4-dioxane solution (4.0 mol / L) was added dropwise. The mixture was stirred at 40°C for 7 hours. TLC confirmed that the reaction of the raw materials was complete, and the mixture was evaporated to dryness under reduced pressure to give a white solid (220 mg, crude product).

[0279] Step E: (R)-N-(1-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)piperidin-3-yl)-1-methyl-1H-pyrazole-4-carboxamide

[0280] 38.6 mg (306 μmol, 1.2 eq) of 1-methyl-1H-pyrazole-4-carboxylic acid, 0.08 mL of N,N-diisopropylethylamine and 145 mg (383 μmol, 1.5 eq) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate were dissolved in 5.0 mL of anhydrous tetrahydrofuran and stirred at room temperature for 0.5 hours. 220 mg (254 μmol, 1.0 eq.) (R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)piperidine-1,3-diamine hydrochloride was stirred at room temperature for 1 hour. LC-MS confirmed the formation of the product. 3 mL of water and 5 mL of ethyl acetate were added, and the organic phase was separated. The aqueous phase was extracted twice with ethyl acetate (5 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by preparative chromatography (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% B over 55 minutes; flow rate: 70 mL / min) and lyophilized to obtain a white solid (45.0 mg, two-step yield = 39%).

[0281] LC-MS: (M+H) + ; m / z = 453.11;

[0282] 1H NMR(400MHz,DMSO-d6)δ9.03(s,1H),8.41(s,1H),8.12(s,1H),7.98-7.93(m,2H),7.84(s,1H),7.79-7.76(m,1H),7.2 6(s,1H),4.12-3.98(m,1H),3.84(s,3H),3.18-2.99(m,2H),2.81-2.55(m,2H),1.88-1.81(m,2H),1.75-1.65(m,2H).

[0283] 19 F NMR(376MHz,DMSO-d6)δ-66.69.

[0284] Example 7: N-(1-((4-cyano-3-(trifluoromethyl)phenyl)amino)piperidin-4-yl)-1-methyl-1H-pyrazole-4-carboxamide

[0285] Step A: tert-Butyl (1-nitrosopiperidin-4-yl)carbamate

[0286] 5.00 g (24.9 mmol, 1.0 eq) of tert-butyl piperidin-4-ylcarbamate was dissolved in a mixture of 12.5 mL of acetic acid and 7.5 mL of water and the temperature was lowered to 0°C. A solution of 3.44 g (49.9 mmol, 2.0 eq) of sodium nitrite in 5.0 mL of water was added dropwise, maintaining the temperature below 0°C. The reaction system was allowed to warm to room temperature and stirred for 1.5 hours. TLC confirmed complete reaction of the starting material. Saturated sodium bicarbonate solution was added to neutralize the reaction, followed by extraction with ethyl acetate (50 mL) three times, drying over anhydrous sodium sulfate, filtration, and evaporation under reduced pressure to yield a white solid (5.70 g, crude product).

[0287] LC-MS: (M+H) + ; m / z = 230.19;

[0288] Step B: tert-Butyl (1-aminopiperidin-4-yl)carbamate

[0289] 1.00 g (4.36 mmol, 1.0 eq) of tert-butyl (1-nitrosopiperidin-4-yl)carbamate and 1.43 g (21.8 mmol, 5.0 eq) of zinc powder were dissolved in 30.0 mL of methanol and cooled to -10°C. 12.0 mL of glacial acetic acid was added dropwise, and the mixture was stirred at -10°C for 0.5 hours. The reaction system was allowed to warm to room temperature and stirred overnight. TLC confirmed complete reaction of the starting materials, and the mixture was filtered and evaporated to dryness under reduced pressure. 20 mL of water was added, and the mixture was neutralized with saturated sodium bicarbonate solution. The mixture was then extracted several times with dichloromethane (20 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure to obtain a yellow oil (1.80 g, crude product).

[0290] LC-MS: (M+H) + ; m / z = 216.20;

[0291] Step C: tert-Butyl (1-(4-cyano-3-(trifluoromethyl)phenyl)amino)piperidin-4-yl)carbamate

[0292] 220 mg (880 μmol, 1.0 eq) of 4-bromo-2-(trifluoromethyl)benzonitrile was dissolved in 10.0 mL of 1,4-dioxane, and 227 mg (1.05 mmol, 1.2 eq) of tert-butyl (1-aminopiperidin-4-yl)carbamate was added. This was followed by the addition of 573 mg (1.76 mmol, 2.0 eq) of cesium carbonate, 80.6 mg (88.0 μmol, 0.1 eq) of tris(dibenzylideneacetone)dipalladium, and 83.9 mg (176 μmol, 0.2 eq) of 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl. The mixture was stirred at 110°C for 1 hour. LC-MS confirmed the formation of the product. 10 mL of water was added, and the mixture was extracted three times with ethyl acetate (10 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 50:1 to 5:1) to give a light yellow solid (250 mg, yield = 74%).

[0293] LC-MS: (M+H) + ; m / z = 385.14;

[0294] Step D: 4-(4-aminopiperidin-1-yl)amino)-2-(trifluoromethyl)benzonitrile hydrochloride

[0295] 250 mg (650 μmol, 1.0 eq) tert-butyl (1-(4-cyano-3-(trifluoromethyl)phenyl)amino)piperidin-4-yl)carbamate was dissolved in 10 mL of dichloromethane, and 6.5 mL of hydrochloric acid / 1,4-dioxane solution (4.0 mol / L) was added dropwise. The mixture was stirred at 40°C for 3 hours. TLC confirmed that the reaction of the raw materials was complete, and the mixture was evaporated to dryness under reduced pressure to obtain a light yellow solid (210 mg, crude product).

[0296] Step E: N-(1-((4-cyano-3-(trifluoromethyl)phenyl)amino)piperidin-4-yl)-1-methyl-1H-pyrazole-4-carboxamide

[0297] 98.4 mg (780 μmol, 1.2 eq) of 1-methyl-1H-pyrazole-4-carboxylic acid, 0.21 mL of N,N-diisopropylethylamine, and 370 mg (975 μmol, 1.5 eq) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate were dissolved in 5.0 mL of anhydrous tetrahydrofuran and stirred at room temperature for 0.5 hour. 220 mg (650 μmol, 1.0 eq) of 4-(4-aminopiperidin-1-yl)amino)-2-(trifluoromethyl)benzonitrile hydrochloride was added, and the mixture was stirred at room temperature for 1 hour. The formation of the product was confirmed by LC-MS, and 3 mL of water and 5 mL of ethyl acetate were added to separate the organic phase. The aqueous phase was extracted twice with ethyl acetate (5 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 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 (65.0 mg, two-step yield = 25%).

[0298] LC-MS: (M+H) + ; m / z = 393.14;

[0299] 1 H NMR (400MHz, DMSO-d6) δ8.30(d,J=6.8Hz,1H),8.11(s,1H),7.90-7.80(m,2H),7.75(d,J=8.6Hz,1H),7.17(s,1 H),6.99(s,1H),3.84(s,3H),3.81-3.71(m,1H),2.98-2.96(m,2H),2.58-2.55(m,2H),1.87-1.84(m,2H),1.69 -1.66(m,2H).

[0300] 19 F NMR(376MHz,DMSO-d6)δ-61.48.

[0301] Example 8: 1-Methyl-N-(1-((2-(trifluoromethyl)pyridin-4-yl)amino)piperidin-4-yl)-1H-pyrazole-4-carboxamide

[0302] Step A: tert-Butyl (1-((2-(trifluoromethyl)pyridin-4-yl)amino)piperidin-4-yl)carbamate

[0303] 120 mg (531 μmol, 1.0 eq) of 4-bromo-2-(trifluoromethyl)pyridine was dissolved in 5.0 mL of 1,4-dioxane, and 137 mg (637 μmol, 1.2 eq) of tert-butyl (1-aminopiperidin-4-yl)carbamate was added. This was followed by 346 mg (1.06 mmol, 2.0 eq) of cesium carbonate, 48.6 mg (53.0 μmol, 0.1 eq) of tris(dibenzylideneacetone)dipalladium, and 50.6 mg (106 μmol, 0.2 eq) of 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl. The mixture was stirred at 110°C for 1 hour. LC-MS confirmed the formation of the product. 10 mL of water was added, and the mixture was extracted three times with ethyl acetate (10 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 50:1 to 5:1) to give a light yellow solid (151 mg, yield = 79%).

[0304] LC-MS: (M+H) + ; m / z = 361.18;

[0305] Step B:N 1 -(2-(Trifluoromethyl)pyridin-4-yl)piperidine-1,4-diamine hydrochloride

[0306] 151 mg (419 μmol, 1.0 eq) tert-butyl (1-((2-(trifluoromethyl)pyridin-4-yl)amino)piperidin-4-yl)carbamate was dissolved in 10 mL of dichloromethane, and 4.2 mL of hydrochloric acid / 1,4-dioxane solution (4.0 mol / L) was added dropwise. The mixture was stirred at 40°C for 3 hours. TLC confirmed that the reaction of the raw materials was complete, and the mixture was evaporated to dryness under reduced pressure to give a light yellow solid (212 mg, crude product).

[0307] Step C: 1-methyl-N-(1-((2-(trifluoromethyl)pyridin-4-yl)amino)piperidin-4-yl)-1H-pyrazole-4-carboxamide

[0308] 63.3 mg (502 μmol, 1.2 eq) of 1-methyl-1H-pyrazole-4-carboxylic acid, 0.14 mL of N,N-diisopropylethylamine and 238 mg (628 μmol, 1.5 eq) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate were dissolved in 5.0 mL of anhydrous tetrahydrofuran and stirred at room temperature for 0.5 hours. 212 mg (419 μmol, 1.0 eq) of N 1 -(2-(Trifluoromethyl)pyridin-4-yl)piperidine-1,4-diamine hydrochloride was stirred at room temperature for 1 hour. LC-MS confirmed the formation of the product. 3 mL of water and 5 mL of ethyl acetate were added, and the organic phase was separated. The aqueous phase was extracted twice with ethyl acetate (5 mL). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by preparative chromatography (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% B over 55 minutes; flow rate: 70 mL / min) and lyophilized to obtain a white solid (56.0 mg, two-step yield = 36%).

[0309] LC-MS: (M+H) + ; m / z = 369.15;

[0310] 1 H NMR (400MHz, DMSO-d6) δ8.31 (s, 1H), 8.20 (d, J = 5.8Hz, 1H), 8.11 (s, 1H), 7.86-7.83 (m, 2H), 7.06 (s, 1H), 6.83 (s, 1H),3.84(s,3H),3.80-3.73(m,1H),2.98-3.95(m,2H),2.58-2.55(m,2H),1.87-1.84(m,2H),1.72-1.64(m,2H).

[0311] 19 F NMR(376MHz,DMSO-d6)δ-66.99.

[0312] Example 9: 1-Methyl-N-(1-((2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)amino)piperidin-4-yl)-1H-pyrazole-4-carboxamide

[0313] Step A: 5-bromo-2-(trifluoromethyl)imidazo[1,2-a]pyridine

[0314] 2.00 g (11.6 mmol, 1.0 eq) of 6-bromopyridin-2-amine and 4.41 g (23.1 mmol, 2.0 eq) of tert-butyl (1-aminopiperidin-4-yl)carbamate were dissolved in 30 mL of ethanol and heated under reflux overnight. LC-MS confirmed the formation of the product, and the mixture was evaporated to dryness under reduced pressure. The mixture was slurried in 5.0 mL of ethanol, filtered, and evaporated to dryness under reduced pressure to obtain a white solid (3.05 g, yield = 99%).

[0315] LC-MS: (M+H) + ;m / z=264.98,266.98;

[0316] Step B: tert-Butyl (1-((2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)amino)piperidin-4-yl)carbamate

[0317] 500 mg (1.89 mmol, 1.0 eq) of 5-bromo-2-(trifluoromethyl)imidazo[1,2-a]pyridine was dissolved in 10 mL of 1,4-dioxane, and 528 mg (2.45 mmol, 1.3 eq) of tert-butyl (1-aminopiperidin-4-yl)carbamate was added. This was followed by 1.23 g (3.77 mmol, 2.0 eq) of cesium carbonate, 42.0 mg (189 μmol, 0.1 eq) of palladium acetate, and 117 mg (189 μmol, 0.1 eq) of 1,1'-binaphthyl-2,2'-bisdiphenylphosphine. The mixture was stirred at 100°C for 1 hour. LC-MS confirmed the formation of the product. 10 mL of water was added, and the mixture was extracted three times with ethyl acetate (10 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure to obtain the crude product. The crude product was purified by preparative chromatography (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 minutes; flow rate: 70 mL / min) and lyophilized to give a white solid (60.0 mg, yield = 7.9%).

[0318] LC-MS: (M+H) + ;m / z=400.25;

[0319] Step C:N 1 -(2-(Trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)piperidine-1,4-diamine hydrochloride

[0320] 60.0 mg (150 μmol, 1.0 eq) tert-butyl (1-((2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)amino)piperidin-4-yl)carbamate was dissolved in 10 mL of dichloromethane, and 1.31 mL of hydrochloric acid / 1,4-dioxane solution (4.0 mol / L) was added dropwise. The mixture was stirred at 40°C for 3 hours. LC-MS confirmed that the reaction of the raw materials was complete, and the mixture was evaporated to dryness under reduced pressure to give a white solid (73 mg, crude product).

[0321] Step D: 1-methyl-N-(1-((2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)amino)piperidin-4-yl)-1H-pyrazole-4-carboxamide

[0322] 22.7 mg (180 μmol, 1.2 eq) of 1-methyl-1H-pyrazole-4-carboxylic acid, 0.05 mL of N,N-diisopropylethylamine and 85.5 mg (225 μmol, 1.5 eq) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate were dissolved in 5.0 mL of anhydrous tetrahydrofuran and stirred at room temperature for 0.5 hours. 73.0 mg (150 μmol, 1.0 eq) of N 1 -(2-(Trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)piperidine-1,4-diamine hydrochloride was stirred at room temperature for 1 hour. LC-MS confirmed the formation of the product. 3 mL of water and 5 mL of ethyl acetate were added, and the organic phase was separated. The aqueous phase was extracted twice with ethyl acetate (5 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by preparative chromatography (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% B over 55 minutes; flow rate: 70 mL / min) and lyophilized to obtain a white solid (29.0 mg, two-step yield = 47%).

[0323] LC-MS: (M+H) + ; m / z = 408.16;

[0324] 1H NMR (400MHz, DMSO-d6) δ8.41(s,1H),8.13(s,1H),7.98(s,1H),7.90(d,J=7.6Hz,1H),7.85(s,1H),7.41(dd,J=8.9,7.6Hz,1H),7.02(d,J=8.9H z,1H),6.46(d,J=7.5Hz,1H),3.85(s,3H),3.83-3.75(m,1H),3.15-3.1 2(m,2H),2.72(t,J=10.9Hz,2H),1.92-1.89(m,2H),1.76-1.67(m,2H).

[0325] 19 F NMR(376MHz,DMSO-d6)δ-61.40.

[0326] The examples in Table 1 were prepared by referring to the methods of Examples 2 to 9 described above, by substituting different starting substrates or intermediates as required.

[0327] Table 1: Examples 10-87

[0328] Example 88: N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-4-(dimethylphosphoryl)benzamide

[0329] Step A: Methyl 4-(dimethylphosphoryl)benzoate

[0330] 500 mg (2.18 mmol, 1.0 eq) of methyl 3-bromobenzoate, 204 mg (2.61 mmol, 1.2 eq) of dimethylphosphine oxide, 1.39 g (6.54 mmol, 3.0 eq) of potassium phosphate, 151 mg (262 μmol, 0.12 eq) of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 99.0 mg (109 μmol, 0.05 eq) of tris(dibenzylideneacetone)dipalladium, and 10 mL of 1,4-dioxane were added to a reaction flask, and the atmosphere was replaced with nitrogen three times. Under nitrogen protection, the reaction system was stirred at 100 ° C for 12 hours. The formation of the target product was confirmed by LC-MS results. After cooling, 20 mL of water was added to the reaction system, and the mixture was extracted three times with 20 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (dichloromethane:methanol=30:1) to give a yellow oily product (300 mg, yield = 60%).

[0331] LC-MS: (M+H) + ; m / z = 227.13;

[0332] Step B: 4-(Dimethylphosphoryl)benzoic acid

[0333] 280 mg (1.23 mmol, 1.0 eq) of methyl 3-(dimethylphosphoryl)benzoate, 5 mL of a 4M hydrochloric acid solution in 1,4-dioxane, and 5 mL of purified water were added to a reaction flask and stirred overnight at 100°C. LC-MS confirmed complete reaction of the starting materials. After cooling, 20 mL of water was added to the reaction system, and the mixture was extracted three times with 20 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (dichloromethane:methanol = 30:1) to afford the product as a yellow oil (180 mg, yield = 73%).

[0334] LC-MS: (M+H) + ; m / z = 199.07;

[0335] Step C: N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-4-(dimethylphosphoryl)benzamide

[0336] A 25 mL reaction flask was charged with 27.0 mg (136 μmol, 1.0 eq) of 4-(dimethylphosphoryl)benzoic acid, 68.0 mg (164 μmol, 1.2 eq) of (1S,3R)-N1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine, 62.0 mg (164 μmol, 1.2 eq) of N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate, 105 mg (818 μmol, 1.2 eq) of N,N-diisopropylethylamine, and 5 mL of tetrahydrofuran. The atmosphere was purged with nitrogen three times, and the reaction mixture was stirred at room temperature for 2 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 20 mL of ethyl acetate. The organic phases were combined, 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 (27.0 mg, yield = 37%).

[0337] LC-MS: (M+H) + ; m / z = 524.07;

[0338] 1 H NMR (400MHz, DMSO-d6) δ8.62(d,J=2.3Hz,1H),8.49(d,J=7.9Hz,1H),7.98-7.82(m,5H),7.75(dd,J=9.0,2.2Hz,1H),7.53 (d,J=8.0Hz,1H),6.97(s,1H),4.10-4.03(m,1H),3.99-3.84(m,1H),2.20-2.17(m,1H),1.99-1.96(m,1H),1.89-1.82(m, 2H),1.69(s,3H),1.65(s,3H),1.61-1.49(m,2H),1.46-1.29(m,2H).

[0339] 19 F NMR(376MHz,DMSO-d6)δ-66.45.

[0340] 31 P NMR (162 MHz, DMSO-d6) δ 32.50.

[0341] Example 89: N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-6-(dimethylphosphoryl)nicotinamide

[0342] Step A: Ethyl 6-(dimethylphosphoryl)nicotinate

[0343] Dissolve 100 mg (0.44 mmol, 1.0 eq) of ethyl 6-bromonicotinate in 5 mL of 1,4-dioxane, then add 185 mg (0.87 mmol, 2.0 eq) of potassium phosphate, 30.2 mg (0.05 mmol, 0.12 eq) of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, and 19.9 mg (0.02 mmol, 0.05 eq) of tris(dibenzylideneacetone)dipalladium. After addition, replace the atmosphere with nitrogen three times. Finally, inject 50.9 mg (0.65 mmol, 1.5 eq) of dimethylphosphine oxide in 1 mL of 1,4-dioxane into the system with a syringe. After addition, heat to 110°C and stir for 18 hours. LC-MS confirmed the complete reaction of the starting materials and the formation of the desired product. The reaction was quenched by adding 10 mL of water, followed by extraction three times with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The resulting residue was purified by column chromatography (DCM:MeOH = 30:1) to give ethyl 6-(dimethylphosphoryl)nicotinate (60.0 mg, yield = 60%) as a light yellow solid.

[0344] LC-MS: (M+H) + ; m / z = 228.11;

[0345] Step B: 6-(dimethylphosphoryl)nicotinic acid

[0346] To a 50 mL Shrek tube, add 60.0 mg (0.26 mmol, 1.0 eq) of ethyl 6-(dimethylphosphoryl)nicotinate, 2 mL of water, and 10 mL of a 4 M solution of hydrochloric acid in 1,4-dioxane. Under nitrogen, raise the temperature to 80°C for 18 hours. LC-MS confirmed complete reaction of the starting material, and the mixture was evaporated to dryness under reduced pressure to afford crude 6-(dimethylphosphoryl)nicotinic acid (50.0 mg, 94% yield).

[0347] LC-MS: (M+H) + ;m / z=200.25;

[0348] Step C: N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-6-(dimethylphosphoryl)nicotinamide

[0349] 50.0 mg (0.25 mmol, 1.0 eq) of 6-(dimethylphosphoryl)nicotinic acid, 115 mg (0.30 mmol, 1.2 eq) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate and 97.3 mg (0.75 mmol, 3.0 eq) of N,N-diisopropylethylamine were dissolved in 8 mL of anhydrous tetrahydrofuran, and the atmosphere was replaced with nitrogen three times and stirred at room temperature for 10 minutes. Then, 115 mg (0.28 mmol, 1.1 eq) of (1S,3R)-N 1 6-Chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine was added to the reaction mixture, and stirring was continued at room temperature for 2 hours. LC-MS analysis confirmed the complete reaction of the starting material. 20 mL of water was added, and the mixture was extracted three times with 40 mL of ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The organic phases were concentrated under reduced pressure to obtain the crude product, which was purified by preparative chromatography (mobile phase A: 0.1% trifluoroacetic acid; mobile phase B: acetonitrile; gradient: 30%-70% B over 55 minutes; flow rate: 70 mL / min) and lyophilized to afford N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-6-(dimethylphosphoryl)nicotinamide (43.0 mg, yield = 33%) as a white solid.

[0350] LC-MS: (M+H) + ; m / z = 525.3;

[0351] 1 H NMR (400MHz, DMSO-d6) δ9.11(d,J=2.1Hz,1H),8.69(d,J=8.0Hz,1H),8.61(d,J=2.3Hz,1H ),8.35-8.31(m,1H),8.06-8.03(m,1H),7.90(d,J=9.0Hz,1H),7.76-7.73(m,1H),7.52(d, J=8.0Hz,1H),6.97(s,1H),4.10-4.06(m,1H),3.94-3.91(m,1H),2.22-2.19(m,1H),2.00 -1.92(m,2H),1.86-1.83(m,1H),1.70-1.67(m,6H),1.59-1.50(m,2H),1.44-1.29(m,2H).

[0352] 19 F NMR(376MHz,DMSO-d6)δ-66.45.

[0353] Example 90: N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-3-(dimethylphosphoryl)benzamide

[0354] Step A: Methyl 3-(dimethylphosphoryl)benzoate

[0355] 500 mg (2.32 mmol, 1.0 eq) of methyl 3-bromobenzoate, 217 mg (2.79 mmol, 1.2 eq) of dimethylphosphine oxide, 1.48 g (6.97 mmol, 3.0 eq) of potassium phosphate, 161 mg (279 μmol, 0.12 eq) of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 106 mg (116 μmol, 0.05 eq) of tris(dibenzylideneacetone)dipalladium, and 10 mL of 1,4-dioxane were added to the reaction flask, and the atmosphere was replaced with nitrogen three times. Under nitrogen protection, the reaction system was stirred at 100 °C for 12 h. The formation of the target product was confirmed by LC-MS results. Subsequently, 20 mL of water was added to the reaction system, and the mixture was extracted three times with 20 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (dichloromethane:methanol=30:1) to give a yellow oily product (280 mg, yield = 56%).

[0356] LC-MS: (M+H) + ; m / z = 213.03;

[0357] Step B: 3-(Dimethylphosphoryl)benzoic acid

[0358] 280 mg (1.32 mmol, 1.0 eq) of methyl 3-(dimethylphosphoryl)benzoate, 5 mL of a 4M hydrochloric acid solution in 1,4-dioxane, and 5 mL of purified water were added to a reaction flask and stirred overnight at 100°C. LC-MS confirmed the complete reaction of the starting materials. Subsequently, 20 mL of water was added to the reaction system, and the mixture was extracted three times with 20 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (dichloromethane:methanol = 30:1) to afford the product as a yellow oil (150 mg, yield = 57%).

[0359] LC-MS: (M+H) + ; m / z = 199.13;

[0360] Step C: N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-3-(dimethylphosphoryl)benzamide

[0361] 27.0 mg (136 μmol, 1.0 eq) 3-(dimethylphosphoryl)benzoic acid, 68.0 mg (164 μmol, 1.2 eq) (1S, 3R)-N 1 A 25 mL reaction flask was charged with 62.0 mg (164 μmol, 1.2 eq) of N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (N-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine, 105 mg (818 μmol, 1.2 eq) of N,N-diisopropylethylamine, and 5 mL of tetrahydrofuran. The atmosphere was purged with nitrogen three times, and the reaction mixture was stirred at room temperature for 2 hours. LC-MS confirmed complete reaction of the starting materials. Subsequently, 20 mL of water was added to the reaction system, and the mixture was extracted three times with 20 mL of ethyl acetate. The organic phases were combined, 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 (30.0 mg, yield = 42%).

[0362] LC-MS: (M+H) + ; m / z = 524.06;

[0363] 1 H NMR (400MHz, DMSO-d6) δ8.62(d,J=2.3Hz,1H),8.53(d,J=7.9Hz,1H),8.20(dt,J= 11.9,1.6Hz,1H),8.00(dq,J=7.8,1.4Hz,1H),7.94-7.86(m,2H),7.75(dd,J=9.0, 2.2Hz,1H),7.61(td,J=7.7,2.6Hz,1H),7.52(d,J=8.0Hz,1H),6.96(s,1H),4.14-4.02(m,1H),3.95-3.8 7(m,1H),2.20-2.11(m,1H),2.02-1.80(m,3H),1.70-1.67(m,6H),1.58-1.55(m,2H),1.41-1.35(m,2H).

[0364] 19 F NMR(376MHz,DMSO-d6)δ-66.46.

[0365] 31 P NMR (162 MHz, DMSO-d6) δ 32.68.

[0366] Example 91: N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-2-(dimethylphosphoryl)isonicotinamide

[0367] 55.0 mg (0.28 mmol, 1.0 eq) of 2-(dimethylphosphoryl)isonicotinic acid, 126 mg (0.33 mmol, 1.2 eq) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate and 107 mg (0.83 mmol, 3.0 eq) of N,N-diisopropylethylamine were dissolved in 8 mL of anhydrous tetrahydrofuran, and the atmosphere was replaced with nitrogen three times and stirred at room temperature for 10 minutes. Then, 127 mg (0.30 mmol, 1.1 eq) (1S,3R)-N 1 1,3-diamine was added to the reaction mixture, and stirring was continued at room temperature for 2 hours. LC-MS analysis confirmed the complete reaction of the starting material. 20 mL of water was added, and the mixture was extracted three times with 40 mL of ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The organic phases were concentrated under reduced pressure to obtain the crude product, which was purified by preparative chromatography (mobile phase A: 0.1% trifluoroacetic acid; mobile phase B: acetonitrile; gradient: 30%-70% B over 55 minutes; flow rate: 70 mL / min) and lyophilized to obtain N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-2-(dimethylphosphoryl)isonicotinamide (41.0 mg, yield = 28%) as a white solid.

[0368] LC-MS: (M+H) + ; m / z = 525.08;

[0369] 1 H NMR (400MHz, DMSO-d6) δ8.91-8.89(m,2H),8.61(d,J=2.3Hz,1H),8.34(d,J= 8.0Hz,1H),7.91-7.89(m,2H),7.75(dd,J=9.1,2.2Hz,1H),7.52(d,J=8.0Hz ,1H),6.97(s,1H),4.12-4.08(m,1H),3.97-3.91(m,1H),2.21-2.18(m,1H), 2.00-1.83(m,3H),1.70-1.67(m,6H),1.61-1.51(m,2H),1.42-1.33(m,2H).

[0370] 19 F NMR(376MHz,DMSO-d6)δ-66.46.

[0371] Example 92: N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-2-(dimethylphosphoryl)benzamide

[0372] Step A: 2-(Dimethylphosphoryl)benzonitrile

[0373] 1.00 g (5.49 mmol, 1.0 eq) of 2-bromobenzylacetonitrile, 471 mg (6.04 mmol, 1.2 eq) of dimethylphosphine oxide, 1.28 g (6.97 mmol, 1.2 eq) of potassium phosphate, 190 mg (330 μmol, 0.06 eq) of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 150 mg (165 μmol, 0.03 eq) of tris(dibenzylideneacetone)dipalladium, and 10 mL of 1,4-dioxane were added to a reaction flask, and the atmosphere was replaced with nitrogen three times. Under nitrogen protection, the reaction system was stirred at 100 ° C for 12 hours. The formation of the target product was confirmed by LC-MS results. Subsequently, 20 mL of water was added to the reaction system, and the mixture was extracted three times with 50 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (dichloromethane:methanol=30:1) to give a yellow oily product (280 mg, yield = 58%).

[0374] LC-MS: (M+H) + ; m / z = 180.04;

[0375] Step B: 2-(Dimethylphosphoryl)benzoic acid

[0376] 100 mg (0.56 mmol, 1 eq) of 2-(dimethylphosphoryl)benzonitrile and 187 mg (5.96 mmol, 6.0 eq) of potassium hydroxide were added to a 25 mL Shrek tube. 1 mL of water was then added, and the mixture was heated to 90°C with stirring for 4 hours. LC-MS confirmed the complete reaction of the starting materials. 20 mL of water was added to the system, and the mixture was extracted three times with 50 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to yield the product as a pale yellow solid (56.0 mg, yield = 51%).

[0377] LC-MS:(MH) + ; m / z = 196.96;

[0378] Step C: N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-2-(dimethylphosphoryl)benzamide

[0379] In a 25 mL reaction bottle, 30.0 mg (0.15 mmol, 1.0 eq) of 2-(dimethylphosphoryl)benzoic acid and 76.0 mg (0.18 mmol, 1.2 eq) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate were dissolved in 5 mL of tetrahydrofuran. Under nitrogen protection, 130 mg (0.90 mmol, 6.0 eq) of N,N-diisopropylethylamine was added and stirred at room temperature for 10 minutes. Then, 62.4 mg (0.18 mmol, 1.2 eq) of (1S,3R)-N 1 6-Chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine was added to the reaction system, and the reaction solution was stirred at room temperature for 2 hours. LC-MS confirmed complete reaction of the starting material. The reaction solution 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%-70% B over 55 minutes; flow rate: 70 mL / min) and lyophilized to obtain a white solid (16.0 mg, yield = 20%).

[0380] LC-MS: (M+H) + ; m / z = 524.13;

[0381] 1 H NMR (400MHz, CDCl3) δ8.04-8.01(m,2H),7.95-7.90(m,1H),7.71-7.67(m,1H),7.66-7.61(m,3H),6.99(d,J=8.1Hz,1H),6.75(s,1H),4.22-4.1 4(m,1H),3.78-3.75(m,1H),2.60-2.57(m,1H),2.23-2.16(m,2H),2.06 -2.02(m,4H),2.00-1.96(m,3H),1.68-1.54(m,2H),1.48-1.28(m,3H).

[0382] 19 F NMR (376 MHz, CDCl3) δ-75.96.

[0383] 31 P NMR (162 MHz, CDCl3) δ 44.71.

[0384] The examples in Table 2 were prepared by referring to the methods described above for Examples 88 to 92, by substituting different starting substrates or intermediates as required.

[0385] Table 2: Examples 93-116

[0386] Inhibitory activity test of the disclosed compounds

[0387] Cell Information

[0388] 1. This study used a CHO cell line stably expressing the MRGPRX2 receptor. The cells were incubated with various concentrations of the test compounds, and the inhibitory activity of the compounds on the MRGPRX2 receptor was determined using the HTRF IP1 kit. 2. The CHO cell line stably expressing MRGPRX2 was cultured in F-12 medium supplemented with 10% fetal bovine serum and 0.2 mg / mL Hygromycin B at 37°C and 5% CO2. 3. Cell passage: Remove the old medium and wash once with PBS, then add 1 mL of TripLE TM Express solution and incubate at 37°C for approximately 2 minutes. When cells detach from the bottom of the dish, add approximately 5 mL of complete medium preheated at 37°C. Gently pipette the cell suspension to dissociate aggregated cells. Transfer the cell suspension to a sterile centrifuge tube and centrifuge at 1000 rpm for 5 minutes. 4. To maintain cell viability, control the cell confluency at approximately 80%. 5. Cell passaging, thawing, and cryopreservation should be performed according to conventional methods.

[0389] Determination of the inhibitory activity of compounds on MRGPRX2 receptor

[0390] 1. Prepare 1× Stimulation Buffer according to the kit instructions. 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, vortex and mix thoroughly. 3. After cell counting, seed the cells in a 384-well plate at a density of 20,000 cells / well / 9.1μL. 4. Add 1.4μL of the 10× compound diluted in step 3 to the corresponding experimental wells (10× compound, 10 concentrations, 2 replicates). Add 1.4μL of the 10× first concentration of positive compound to the PC well and 1.4μL of 10× DMSO buffer (1%) to the VC well. Centrifuge and 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 in Lysis & Detection Buffer. 7. After incubation, add 3 μL of d2-IP1 to all experimental wells. 8. Then, add 3 μL of Anti-IP1-Cryptate to all experimental wells, centrifuge, and incubate at room temperature for 1 hour. 9. After incubation, read the concentrations at 665 nm and 620 nm using a microplate reader under 330 nm excitation.

[0391] 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 indicated as follows: "A" indicates antagonist activity <100 nM; "B" indicates antagonist activity between 100 and 500 nM; "C" indicates antagonist activity between 501 and 1000 nM; "D" indicates activity between 1001 and 2500 nM; "E" indicates activity above 2500 nM, and "NE" indicates not detected.

[0392] Table 3: Inhibitory activity of the compounds disclosed herein on MRGPRX2 receptor (IC 50 )

[0393] EP400 is the compound of Example 4-400 reported in WO2022067094A1, which serves as a positive reference molecule and has the following structure:

[0394] Conclusion: Multiple compounds disclosed in Examples 2, 3, 6, 29, 32 and 34 of the present invention showed stronger MRGPRX2 receptor inhibitory activity than the positive control compound EP400.

[0395] CYP Inhibition Evaluation Test in Human Liver Microsomes

[0396] Add 150 μL of liver microsome solution / well and 2 μL of 1 mM inhibitor solution / well to a 96-well plate and mix. Preincubate in a 37°C water bath for 10 minutes. After the preincubation period, add 50 μL of NADPH / substrate working solution to the sample and mix to start the reaction. Incubate the P450 enzymes at 37°C. Add 200 μL of stop solution to the sample to quench the reaction and mix. Centrifuge the reaction mixture at 4000 rpm for 20 minutes at 4°C. While centrifuging, load a new 96-well plate with 300 μL / well of 50% acetonitrile, then transfer 150 μL / well of the supernatant, mix, and transfer to a bioanalytical service for LC-MS / MS analysis.

[0397] Table 4: IC analysis results of CYP450 inhibition in human liver microsomes 50 (μM)

[0398] The results of the CYP450 inhibition test showed that Example 6 had an inhibitory effect on each subtype of P450 (except 2C9) greater than 10 μM, which was relatively clean, while EP400 was less than 10 μM (except 3A4 (testosterone)). It can be inferred that under the same conditions, the effect of the compound of this example on CYP450 inhibition is superior to the positive control compound EP400.

[0399] Equilibrium dialysis test for plasma protein binding

[0400] 1. Soak the dialysis membrane (water: 60 min, 20% ethanol: 20 min, dialysis buffer: 20 min). 2. Dilute the test compound to 200 μM in dimethyl sulfoxide (working solution). 3. Thaw the plasma in a 37°C water bath and centrifuge the plasma at 3220g for 10 minutes to clear blood clots. 4. Transfer the supernatant to a new tube and preheat in a 37°C water bath for 10 minutes. 5. Assemble the HTD dialysis device according to the manufacturer's guidelines. 6. Add 3 μL of 200 μM test compound to 597 μL of plasma and spin at 1000 rpm for 2 minutes. 7. Transfer 50 μL of spiked plasma to a 96-well plate, then add 50 μL of dialysis buffer and 200 μL of methanol, with IS* as the T0 sample. 8. Add 120 μL of spiked plasma and 120 μL of dialysis buffer to the chamber of the HTD dialysis device in duplicate. 9. Cover the dialysis apparatus with a breathable cap and incubate the dialysis apparatus and the remaining spiked plasma at 37°C (100 rpm, 5% CO2) for 6 hours. 10. Transfer 50 μL of the dialyzed sample from the dialysis buffer and plasma compartments to separate 96-well plates, then add 50 μL of blank plasma or dialysis buffer and 200 μL of methanol, IS* as B and P samples. 11. Transfer 50 μL of the remaining spiked plasma (as described in step 9) to a 96-well plate, then add 50 μL of dialysis buffer and 200 μL of methanol, IS* as the T6 sample. 12. Centrifuge the sample plate at 3220 g for 40 minutes. 13. Transfer 100 μL of the supernatant to an analytical plate containing an appropriate volume of water for LC-MS / MS. 14. Data analysis.

[0401] Table 5: Plasma protein binding test results

[0402] The results of the plasma protein binding test showed that the plasma protein binding rate of EP400 was as high as 99.52%. When the two drugs are used in combination, they will occupy the binding sites, which will prevent other drugs from being fully bound, resulting in an increase in the free portion of other drugs and enhanced efficacy. This often has certain risks and is not conducive to combined use. The plasma binding rate of Example 6 of the present invention is lower than that of EP400, and the risk of combined use is lower than that of EP400.

[0403] Effect of manual patch clamp technique on hERG channel current

[0404] Whole-cell tail currents from HEK-293 cells stably expressing hERG channels were recorded using a gravity-controlled dosing system, with Example 6 and EP400 administered at 3 μM concentrations. Data were acquired and analyzed using SutterPatch software. The current measured in extracellular fluid without compound served as the control for each cell, and the data were normalized to calculate the inhibition rate for each concentration.

[0405] Table 6: Test results of the effect on hERG channel current

[0406] The results of the hERG channel inhibition test showed that at the same concentration, Example 6 of the present invention had little effect on the hERG channel current, a lower inhibition rate, and was better than EP400.

[0407] Thermodynamic solubility determination

[0408] 1. Weigh approximately 1.0 mg of compound into each of three separate 1.5 mL glass vials (one vial for preparing the standard solution and two vials for measuring solubility in duplicate). 2. Add an appropriate volume (approximately 1000 μL) of assay buffer to each vial of solubility sample to a final concentration of 1 mg / mL. 3. Place a Teflon-encapsulated stainless steel rod stirrer into each vial and seal the vials using molded PTDE / SIL silicone stoppers. 4. Transfer the solubility sample plate to a Thermomixer Comfort plate shaker at 1100 rpm and 25°C for 24 hours. 5. Use a vacuum manifold to transfer the solubility plate sample to the filter plate. 6. Use a vacuum manifold to transfer the solubility plate sample to the filter plate. 7. Transfer 10 μL of the filtered sample and 10 μL of DMSO to 980 μL of methanol with IS* and further dilute 10-fold with methanol:water (1:1) as the filtered sample for LC-MS / MS analysis. 8. For the standard sample, add dimethyl sulfoxide to a final concentration of 1.0 mg / mL. Shake at 1100 rpm, 25°C for 5 minutes. 9. Transfer 10 μL of the 1 mg / mL dimethyl sulfoxide sample and 10 μL of assay buffer to 980 μL of methanol with IS*, then dilute 10-fold with methanol:water (1:1) to serve as the standard sample for LC-MS / MS analysis.

[0409] Table 7: Thermodynamic Solubility Determination

[0410] The results of thermodynamic solubility determination show that under the same conditions, the solubility of Example 6 of the present invention is better than that of EP400.

[0411] Pharmacokinetic experiments

[0412] Male SD rats were divided into groups of 3 rats per group and were administered the example compound (10 mg / kg) orally ...

[0413] Table 8: Pharmacokinetic parameters of different compounds after oral administration to rats at 10 mg / kg

[0414] Table 9: Pharmacokinetic parameters of the compound after intravenous administration of 2 mg / kg in rats

[0415] The results of the pharmacokinetic experiments showed that the example compounds of the present invention had excellent pharmacokinetic properties, with a bioavailability of up to 80%.

[0416] The present application has been described above in conjunction with preferred embodiments, but these embodiments are merely exemplary and serve only as an illustrative example. On this basis, various replacements and improvements can be made to the present application, all of which fall within the scope of protection of the present application.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, in, R1 and R2 are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, aryl, heteroaryl, or heterocyclyl; A1 ring is selected from aromatic rings or heteroaromatic rings; R3 are each independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, aryl, heteroaryl, or heterocyclyl; R4 is selected from C substituted with 0-3 R0 1-6 Alkyl, substituted with 0-3 R0 1-6 Alkoxy, substituted with 0-3 R0 2-6 Alkenyl, substituted with 0-3 R0 2-6 Alkynyl, substituted with 0-3 R0 3-6 Cycloalkyl, substituted with 0-3 R0 5-10 Polycyclic carbocyclic ring, aryl substituted with 0-3 R0, heteroaryl substituted with 0-3 R0, or heterocyclyl substituted with 0-3 R0; R0 is independently selected from hydroxy, cyano, halogen, guanidinyl, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -NR 11 R 12 , -NR 11 C(O)R 12 , -NR 11 C(O)OR 12 , -NR 11 C(O)NR 11 R 12 , -NR 11 S(O2)R 12 , -NR 11 S(O2)NR 11 R 12 , -OC(O)R 11 , -OC(O)NR 11 R 12 , -S(O2)NR 11 R 12 , -S(O2)R 11 , -NR 11 S(O)R 12 , -B(OR 11 )(OR 12 ), -P(O)R 13 R 14 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 11 R 12 , replaced by 0-3 R 00 Aryl, substituted with 0-3 R 00 or substituted with 0-3 R 00 A heterocyclic group; R 00 are independently selected from hydroxy, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, or -NR 11 R 12 ; R 11 and R 12 are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, or C 3-6 Cycloalkyl; R 13 and R 14 Each independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, or C 3-6 Cycloalkyl; m is 0, 1, 2, 3 or 4.

2. The compound according to claim 1 or its pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug, wherein: The compound has the structural formula of I-1 or I-2 wherein R1, R2, R3, R4, A1 ring and m are as defined in claim 1.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, wherein: A1 ring is C 6-10 An aromatic ring, such as a benzene ring or a naphthalene ring.

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, wherein: The A1 ring is a 5-10 membered heteroaromatic ring.

5. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, wherein: Ring A1 is selected from one of the following structural formulas:

6. The compound according to claim 5 or its pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug, wherein: Ring A1 is selected from one of the following structural formulas:

7. The compound according to claim 5, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, wherein: R3 are each independently halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, or C 1-6 Haloalkyl; m is 1, 2 or 3.

8. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, wherein: Ring A1 is m is 2; One R3 is Cl and the other R3 is CF3.

9. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, wherein: R1 and R2 are both hydrogen.

10. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, wherein: R4 is a C that replaces 0-3 R0 1-6 Alkyl, such as isopropyl; Alternatively, R4 is a C substituted with 0-3 R0 3-6 cycloalkyl, such as cyclopropyl or cyclobutyl; Alternatively, R4 is a C substituted with 0-3 R0 5-10 polycyclic carbocycles; Alternatively, R4 is a heterocyclic group substituted with 0-3 R0; Wherein, R0 is independently halogen, or C 1-6 alkyl.

11. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, wherein: R4 is one of the following groups: Where n is 0, 1 or 2; Rq is independently selected from hydroxy, cyano, halogen, guanidine, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -NR 11 R 12 , -NR 11 C(O)R 12 , -NR 11 C(O)OR 12 , -NR 11 C(O)NR 11 R 12 , -NR 11 S(O2)R 12 , -NR 11 S(O2)NR 11 R 12 , -OC(O)R 11 , -OC(O)NR 11 R 12 , -S(O2)NR 11 R 12 , -S(O2)R 11 , -NR 11 S(O)R 12 , -B(OR 11 )(OR 12 ), -P(O)R 13 R 14 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 11 R 12 , substituted with 0 or 1 R 00 aryl, substituted with 0 or 1 R 00 or substituted with 0 or 1 R 00 A heterocyclic group; R 00 are independently selected from hydroxy, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, or -NR 11 R 12 ; R 11 and R 12 are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, or C 3-6 Cycloalkyl; R 13 and R 14 Each independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, or C 3-6 Cycloalkyl.

12. The compound according to claim 2, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, wherein: The compound has the structural formula 1-3 Among them, R 31 and R 32 are each independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, or C 3-6 Cycloalkyl; R4 is selected from aryl substituted with 0-3 R0, heteroaryl substituted with 0-3 R0, or heterocyclyl substituted with 0-3 R0; R0 is independently selected from hydroxyl, cyano, halogen, guanidine, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -NR 11 R 12 , -NR 11 C(O)R 12 , -NR 11 C(O)OR 12 , -NR 11 C(O)NR 11 R 12 , -NR 11 S(O2)R 12 , -NR 11 S(O2)NR 11 R 12 , -OC(O)R 11 , -OC(O)NR 11 R 12 , -S(O2)NR 11 R 12 , -S(O2)R 11 , -NR 11 S(O)R 12 , -B(OR 11 )(OR 12 ), -P(O)R 13 R 14 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 11 R 12 , replaced by 0-3 R 00 Aryl, substituted with 0-3 R 00 or substituted with 0-3 R 00 A heterocyclic group; R 00 Each independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, or -NR 11 R 12 ; R 11 and R 12 are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, or C 3-6 Cycloalkyl; R 13 and R 14 Each independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, or C 3-6 Cycloalkyl.

13. The compound according to claim 12, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, wherein: R 31 C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Haloalkyl, such as -CF3; R 32 is a halogen, such as Cl or F.

14. The compound according to claim 12, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, wherein: R4 is Among them, R 42 For hydrogen, halogen, C 1-3 Alkyl or C 1-3 Haloalkyl; R 41 C 1-3 Alkyl or C 1-3 Halogenated alkyl.

15. The compound according to claim 14 or its pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug, wherein: R 42 is hydrogen, R 41 C 1-3 Alkyl such as methyl, or C 1-3 Haloalkyl is for example difluoromethyl or trifluoroethyl.

16. The compound according to claim 12, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, wherein: R4 is wherein X1, X2, X3 and X4 are each independently a C atom or a N atom, and X1, X2, X3 and X4 are not all N atoms; R 51 , R 52 , R 53 , R 54 and R 55 are independently hydrogen, halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, -N(R 50 )2, -NHS(O2)R 50 or -P(O)(R 50 )2, R 50 are independently hydrogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl.

17. The compound according to claim 16 or its pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug, wherein: R4 is Among them, R 61 is cyano, halogen (such as F), C 1-3 Alkoxy (e.g. methoxy), NHC(O)R 50 or -P(O)(R 50 )2,R 50 Each independently is C 1-3 Alkyl (e.g., methyl, ethyl or propyl); Alternatively, R4 is Among them, R 65 Cyano, -NHC(O)R 50 or -NHS(O2)R 50 , R 50 Each independently is C 1-3 Alkyl (e.g., methyl, ethyl, n-propyl or isopropyl); Alternatively, R4 is Among them, R 63 For hydrogen, halogen, C 1-3 Alkoxy (e.g. methoxy) or -NH2; Alternatively, R4 is Among them, R 62 C 1-3 Alkoxy (e.g. methoxy) or -NH2; Alternatively, R4 is Among them, R 64 C 1-3 Alkoxy (e.g. methoxy) or -NH2; Alternatively, R4 is Where R 66 For hydrogen, C 1-3 Alkoxy (e.g. methoxy) or -NH2; Alternatively, R4 is Where R 67 and R 68 are independently hydrogen, C 1-3 Alkoxy (eg, methoxy) or -NH2.

18. The compound according to claim 12, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, wherein: R4 is Among them, R 65 -S(O2)NR 11 R 12 , Among them, R 11 and R 12 are each independently selected from hydrogen or C 1-6 Alkyl (eg, methyl or ethyl).

19. The compound according to claim 12, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, wherein: R4 is Where X3 is N or CH, R 65 is hydrogen or C 1-3 Alkyl (eg, methyl).

20. The compound according to claim 19, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, wherein: R4 is or 21. A compound of formula II or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, in, R1 and R2 are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, aryl, heteroaryl, or heterocyclyl; A1 ring is selected from aromatic rings or heteroaromatic rings; R3 are each independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, aryl, heteroaryl, or heterocyclyl; A2 ring is selected from aromatic rings or heteroaromatic rings; R 20 are each independently selected from hydrogen, hydroxy, cyano, halogen, guanidinyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -NR 11 R 12 , -NR 11 C(O)R 12 , -NR 11 C(O)OR 12 , -NR 11 C(O)NR 11 R 12 , -NR 11 S(O2)R 12 , -NR 11 S(O2)NR 11 R 12 , -OC(O)R 11 , -OC(O)NR 11 R 12 , -S(O2)NR 11 R 12 , -S(O2)R 11 , -NR 11 S(O)R 12 , -B(OR 11 )(OR 12 ), -P(O)R 13 R 14 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 11 R 12 , replaced by 0-3 R 00 Aryl, substituted with 0-3 R 00 or substituted with 0-3 R 00 A heterocyclic group; R 21 and R 22 Each independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, or C 3-6 Cycloalkyl; or, R 21 With an R on the A2 ring 20 Together they form a 5-6 membered heterocyclic ring; R 00 are independently selected from hydroxy, cyano, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, or -NR 11 R 12 ; R 11 and R 12 are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, or C 3-6 Cycloalkyl; m is 0, 1, 2, 3 or 4; t is 0, 1, 2, or 3.

22. The compound according to claim 21 or its pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug, wherein: The compound has the structural formula II-1 or II-2 Among them, R1, R2, R3, R 20 , R 21 , R 22 , A1 ring, A2 ring, t and m are as defined in claim 19.

23. The compound according to claim 21 or 22, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, wherein: A1 ring is C 6-10 Aromatic rings, such as benzene or naphthalene; Alternatively, the A1 ring is a 5-10 membered heteroaromatic ring.

24. The compound according to claim 21 or 22, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, wherein: Ring A1 is selected from one of the following structural formulas: Preferably, the A1 ring is selected from one of the following structural formulas:

25. The compound according to claim 21 or 22, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, wherein: R3 are each independently halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, or C 1-6 Haloalkyl; m is 1, 2 or 3.

26. The compound according to claim 21 or 22, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, wherein: R1 and R2 are both hydrogen.

27. The compound according to claim 21 or 22, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, wherein: A2 ring is C 6-10 Aromatic rings, such as benzene or naphthalene; Alternatively, the A2 ring is a 5-6 membered heteroaromatic ring; Preferably, the A2 ring is selected from 28. The compound according to claim 21 or 22, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, wherein: R 21 and R 22 Each independently selected from C 1-3 An alkyl group, such as a methyl group.

29. The compound according to claim 21 or 22, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, wherein: R 20 are each independently selected from hydrogen, halogen, or C 1-3 alkyl; t is 0 or 1.

30. The compound according to claim 21 or 22, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, wherein: The compound has the structural formula II-3 Among them, R 41 and R 42 are each independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, or C 3-6 Cycloalkyl; R 20 are each independently selected from hydrogen, hydroxy, cyano, halogen, guanidinyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -NR 11 R 12 , -NR 11 C(O)R 12 , -NR 11 C(O)OR 12 , -NR 11 C(O)NR 11 R 12 , -NR 11 S(O2)R 12 , -NR 11 S(O2)NR 11 R 12 , -OC(O)R 11 , -OC(O)NR 11 R 12 , -S(O2)NR 11 R 12 , -S(O2)R 11 , -NR 11 S(O)R 12 , -B(OR 11 )(OR 12 ), -P(O)R 13 R 14 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 11 R 12 , replaced by 0-3 R 00 Aryl, substituted with 0-3 R 00 or substituted with 0-3 R 00 A heterocyclic group; R 21 and R 22 Each independently selected from C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkylamino; or, R 21 R on the A2 ring 20 Together they form a 5-6 membered heterocyclic ring; The A2 ring is selected from 31. The compound according to claim 30, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, wherein: R 41 C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Haloalkyl, such as -CF3; R 42 is a halogen, such as Cl or F.

32. The compound according to claim 30, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, wherein: A2 ring is R 21 and R 22 are each independently methyl.

33. The compound according to claim 1 or 21, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, wherein: The compound is selected from one of the following:

34. A pharmaceutical composition comprising a compound according to any one of claims 1 to 33 or a stereoisomer, tautomer, solvate, hydrate, active metabolite, isotope-labeled substance or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

35. Use of a compound according to any one of claims 1 to 33 or its stereoisomers, tautomers, solvates, hydrates, active metabolites, isotope-labeled substances or pharmaceutically acceptable salts, and the pharmaceutical composition according to claim 34 in the preparation of a medicament for inhibiting MRGPRX2 activity.

36. Use of a compound of any one of claims 1 to 33 or a stereoisomer, tautomer, solvate, hydrate, active metabolite, isotopically labeled or pharmaceutically acceptable salt thereof, and the pharmaceutical composition of claim 34 in the preparation of a medicament for treating a MRGPRX2-mediated disorder in a subject.

37. The use according to claim 36, wherein The disorder is an inflammatory disorder, such as a skin disorder.

38. The use according to claim 37, wherein Inflammatory disorders 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, asthma.

39. A method for treating an inflammatory disorder comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 33 or a stereoisomer, tautomer, solvate, hydrate, active metabolite, isotopically labeled form or pharmaceutically acceptable salt thereof, and a pharmaceutical composition of claim 34.

40. The method according to claim 39, wherein: Inflammatory disorders 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, asthma.

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