Compound serving as mrgprx2 antagonist

Abstract

The present invention provides a compound. Specifically, the present invention provides a compound having a structure as represented by formula (I) below, or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, and solvate of the compound. The compound can effectively inhibit the activity of MRGPRX2, and is used for treating or preventing diseases or disorders related to MRGPRX2.

Description

Compounds as MRGPRX2 antagonists TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical chemistry; in particular, the present application relates to a class of novel compounds, a synthetic method thereof and application of the compounds as a MRGPRX2 antagonist in the preparation of a medicament for treating various diseases such as tumors and the like. BACKGROUND

[0002] MRGPRX2 (Mas-related G protein-coupled receptor X2) belongs to the family of G protein-coupled receptors (GPCRs). It plays an important role in many physiological processes, especially in the immune system and pain regulation. MRGPRX2 is mainly expressed in eosinophils and mast cells. These cells are part of the immune system and are involved in allergic reactions and inflammation. There are two main pathways for mast cell activation, the immunoglobulin E (IgE)-dependent and the IgE-independent pathway. Although IgE-dependent signaling is the main pathway for mast cell activation, the IgE-independent pathway has been found to play a key role in various pathophysiology such as inflammation. MRGPRX2 is involved in the conduction of the IgE-independent signaling pathway of mast cells.

[0003] The ligands of MRGPRX2 include endogenous or exogenous chemicals, including basic secretagogues, neurokinins, host defense antimicrobial peptides, and small molecule compounds (such as neuromuscular blockers) or other irritants, etc. Ligand binding leads to a change in the conformation of MRGPRX2, thereby activating its downstream signaling pathway. After GPCR activation, the alpha subunit of G protein (such as Gq, Gi, etc.) dissociates from the receptor and interacts with downstream effector molecules. The activated Gq protein stimulates the conversion of phosphatidylinositol-bisphosphate (PIP2) to diacylglycerol (DAG) and inositol triphosphate (IP3). IP3 promotes the release of calcium ions, which plays an important role in various responses of cells (such as depolarization, secretory response). DAG activates protein kinase C (PKC); activation of Gi protein can inhibit adenylate cyclase, reducing cAMP levels.

[0004] In mast cells and eosinophils, activation of MRGPRX2 can trigger the release of histamine, cytokines and other inflammatory mediators, as well as degranulation. This is related to allergic reactions, inflammation and other immune responses. MRGPRX2 also plays a role in the regulation of pain signals, especially in chronic pain and inflammation-related pain states.

[0005] Studies have shown that MRGPRX2 plays a key role in some allergic diseases (such as urticaria) and painful diseases (such as chronic pain syndrome). Drugs targeting MRGPRX2 can help treat these conditions. Currently, there is no drug targeting MRGPRX2 on the market. Therefore, it is of great significance to develop MRGPRX2 antagonists. SUMMARY

[0006] The purpose of the present application is to provide a new type of MRGPRX2 antagonist.

[0007] In a first aspect, the present application provides a compound of the following formula (I), or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate thereof:

[0008] In formula (I), A is selected from substituted or unsubstituted C

[0009] " " represents a chiral center;

[0010] A is selected from substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted 3- to 9-membered heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and said A is substituted with one or more R 9 substituents;

[0011] R 9 is selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, C(O)R g , C(O)OR f , C(O)NR d R d , or S(O)2R g ; the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl in said R 9 are optionally substituted with one or more groups selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, aryl, heteroaryl, CN, OR f , SR f , NR d R d , C(O)R g , C(O)OR f , C(O)NR d R d, NR d C(O)R g , S(O)2R g , or NR d S(O)2R g ; or the cycloalkyl and heterocyclyl in said R 9 are optionally substituted with =Q; Q is selected from O or CR j R k ; R j and R k are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, aryl, heteroaryl, CN, C(O)R g , C(O)OR f , C(O)NR d R d , or S(O)2R g ; the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl in said R j and R k are optionally substituted with one or more groups selected from halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, aryl, heteroaryl, CN, OR f , SR f , NR d R d , C(O)R g , C(O)OR f , OC(O)R g , C(O)NR d R d , NR d C(O)R g , NR d C(O)NR d R d , OC(O)NR d R d , NR d C(O)OR f , OC(O)OR f , S(O)2R g , S(O)2NR d R d , NR d S(O)2R g , or NR d S(O)2NR d R d ;

[0012] B is selected from substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0013] R 1 is selected from hydrogen, C 1-4 alkyl, or C 3-6 cycloalkyl;

[0014] R 2 is selected from hydrogen, C 1-4 alkyl, or C 3-6 cycloalkyl;

[0015] R 3 and R 4 are each independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, aryl, heteroaryl, CN, OR f , SR f , NR d R d , C(O)R g , C(O)OR f , OC(O)R g , C(O)NR d R d , NR d C(O)R g , S(O)2R g , S(O)2NR d R d , or NR d S(O)2R g ; or R 3 and R 4 together with the carbon atom to which they are attached form =M; M is selected from O or CR h R i ; R h and R i are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, C 3- 6cycloalkyl, 3- to 6-membered heterocyclyl, CN, C(O)R g , or C(O)NR d R d ; or R h and R i together with the carbon atom to which they are attached form a 3- to 6-membered cyclic structure, which cyclic structure optionally contains 0 or 1 heteroatom selected from N, O, S; said R h or R ialkyl in the group of R1is optionally substituted with one or more groups selected from the group consisting of halogen, C 1-4 alkyl, CN, OR f , SR f , NR d R d ;

[0016] or R 3 and R 4 together with the carbon atom to which they are attached form a 3- to 6-membered cyclic structure, which cyclic structure optionally contains 0, or 1 heteroatom selected from N, O, S, and is optionally substituted with one or more groups selected from the group consisting of halogen, C 1-4 alkyl;

[0017] each R 5 is each independently selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, aryl, heteroaryl, CN, OR f , SR f , NR d R d , C(O)R g , C(O)OR f , OC(O)R g , C(O)NR d R d , NR d C(O)R g , S(O)2R g , S(O)2NR d R d , or NR d S(O)2R g ; or two R 5 are linked together to form, together with the 6-membered ring in formula (I), a spiro, bridged, or fused ring structure, which spiro, bridged, or fused ring structure optionally contains 0 or 1 heteroatom selected from N, O, S; or two R 5 together with the same carbon atom to which they are attached form =M; M is defined as above;

[0018] each R d is each independently selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, or C 3-6 cycloalkyl;

[0019] each R f is each independently selected from the group consisting of hydrogen, C 1-4 alkyl, C1-4 Halogenated alkyl, or C 3-6 cycloalkyl;

[0020] Each R g Each is independently selected from hydrogen and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl;

[0021] m is selected from 0, 1, 2, 3, or 4;

[0022] In this context, each of the aforementioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, cyclic, aryl, and heteroaryl groups is optionally and independently substituted by 1 to 3 substituents independently selected from the group consisting of: halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3- to 8-membered heterocyclic, aryl, heteroaryl, CN, NO2, OR f SR f NR d R d C(O)R g C(O)OR f C(O)NR d R d NR d C(O)R g S(O)2R g , or NR d S(O)2R g The prerequisite is that the resulting chemical structure is stable and meaningful; among them, R d R f R g The definition is as described above;

[0023] Unless otherwise specified, the aryl group mentioned above is an aromatic group containing 6-12 carbon atoms; the heteroaryl group is a 5- to 15-membered heteroaromatic group; and the cyclic structure is a saturated or unsaturated cyclic group containing heteroatoms or not containing heteroatoms.

[0024] In another preferred embodiment, equation (I) is equivalent to equation (II):

[0025] The definitions of each group in formula (II) are as described in claim 1.

[0026] In another preferred embodiment, equation (I) is equivalent to equation (III):

[0027] X is selected from CR a R b , O, or N; R a and R b are each independently selected from hydrogen, halogen, or C 1-4 alkyl; p and q are each independently selected from 0, 1, 2, or 3;

[0028] the definitions of the remaining groups in formula (III) are as described above.

[0029] In another preferred embodiment, formula (I) is formula (IV):

[0030] each R 6 is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, aryl, heteroaryl, CN, OR f , SR f , NR d R d , C(O)R g , C(O)OR f , C(O)NR d R d , NR d C(O)R g , S(O)2R g , or NR d S(O)2R g ; n is selected from 0, 1, 2, 3, 4, 5, or 6; R d , R f , R g are as described above;

[0031] A is selected from substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0032] the definitions of the remaining groups in formula (IV) are as described above.

[0033] In another preferred embodiment, formula (I) is formula (V):

[0034] A is selected from substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0035] R h and R i are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, C 3-6cycloalkyl, 3- to 6-membered heterocyclyl, or CN; said R h or R i alkyl is optionally substituted with one or more groups selected from halo, C 1-4 alkyl, CN, OR f , SR f , NR d R d ; each R d is independently selected from hydrogen or C 1-4 alkyl; each R f is independently selected from hydrogen or C 1-4 alkyl.

[0036] In another preferred embodiment, formula (I) is formula (VI):

[0037] R 7 and R 8 are each independently selected from hydrogen, halo, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, aryl, heteroaryl, CN, OR f , SR f , NR d R d , C(O)R g , C(O)OR f , C(O)NR d R d , NR d C(O)R g , S(O)2R g , or NR d S(O)2R g ;

[0038] R 9 is selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, C(O)R g , C(O)OR f , C(O)NR d R d , or S(O)2R g ; said alkyl is optionally substituted with one or more groups selected from halo, C 1-4 alkyl, C 1-4haloalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, aryl, heteroaryl, CN, OR f , SR f , NR d R d , C(O)R g , C(O)OR f , C(O)NR d R d , NR d C(O)R g , S(O)2R g , or NR d S(O)2R g ; cycloalkyl and heterocyclyl as described above are optionally substituted with =Q; Q is selected from O or CR j R k ; R j and R k are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, aryl, heteroaryl, CN, C(O)R g , C(O)OR f , C(O)NR d R d , or S(O)2R g ; alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl in said R j and R k are optionally substituted with one or more groups selected from halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, aryl, heteroaryl, CN, OR f , SR f , NR d R d , C(O)R g , C(O)OR f , OC(O)R g , C(O)NR d R d , NR d C(O)R g , NR d C(O)NR d R d , OC(O)NR d R d , NR d C(O)OR f , OC(O)ORf S(O)2R g S(O)2NR d R d NR d S(O)2R g or NR d S(O)2NR d R d ;

[0039] R d R f R g R h and R i are as defined above.

[0040] In another preferred embodiment, formula (I) is formula (VII):

[0041] R 6 n are as defined above;

[0042] the remaining groups in formula (VII) are as defined above.

[0043] In another preferred embodiment, formula (I) is formula (VIII):

[0044] X, p, q are as defined above;

[0045] R 7 R 8 R 9 are as defined above.

[0046] In another preferred embodiment, formula (I) is formula (IX):

[0047] R 1 R 2 R 3 R 4 R 5 m are as defined above;

[0048] R 6 n are as defined above;

[0049] R 7 R 8 are as defined above;

[0050] R j and R k are as defined above;

[0051] x and y are each independently selected from 0, 1, 2, or 3.

[0052] In another preferred embodiment, equation (I) is equation (X):

[0053] R 3 R 4 The definition is as described above;

[0054] R 7 R 8 R j and R k The definition of is as described above.

[0055] In another preferred embodiment, the compound, or an optical isomer thereof, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, or a solvate, is selected from one of the following:

[0056] "*" indicates a chiral center;

[0057] When the above structure contains two R groups, one R group is selected from hydrogen, and the other R group is selected from hydrogen, deuterium, methyl, or fluorine; or one R group is selected from deuterium, and the other R group is selected from hydrogen, deuterium, methyl, or fluorine; or one R group is selected from methyl, and the other R group is selected from hydrogen, deuterium, methyl, or fluorine; or one R group is selected from fluorine, and the other R group is selected from hydrogen, deuterium, methyl, or fluorine.

[0058] A second aspect of the invention provides a pharmaceutical composition comprising the compound described in the first aspect of the invention, or an optical isomer thereof, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate, and a pharmaceutically acceptable carrier.

[0059] A third aspect of the invention provides the use of the compound described in the first aspect of the invention, or an optical isomer thereof, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, or a solvate, characterized in that it is used to prepare a pharmaceutical composition for treating diseases, conditions, or symptoms associated with MRGPRX2.

[0060] In another preferred embodiment, the disease, disorder or condition is selected from the group consisting of urticaria (chronic spontaneous urticaria, acute spontaneous urticaria, and other spontaneous urticarias, cold urticaria, solar urticaria, heat contact urticaria, vibratory urticaria, and other physical urticarias, contact urticaria, aquagenic urticaria, and other non-physical urticarias), mastocytosis, atopic dermatitis, Crohn's disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, cancer pain, chronic pruritus, drug-induced pseudoallergy, metabolic syndrome, gastroesophageal reflux, asthma, cough, migraine, chronic pruritus, acute pruritus, nodular prurigo, pseudoallergy, and allergic and painful diseases. DETAILED DESCRIPTION

[0061] The present inventors have made an unexpected discovery of a class of novel MRGPRX2 antagonists, as well as their preparation methods and uses. The present compounds can be used in the treatment of various diseases related to the MRGPRX2. Based on the above discovery, the present inventors have completed the present application.

[0062] TERMS

[0063] Unless otherwise indicated, the term "or" as used herein is used to mean "and / or" (i.e., "one or the other or both").

[0064] Unless otherwise indicated, each chiral carbon atom (chiral center) in all of the compounds of the present application can optionally be in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.

[0065] As used herein, the term "alkyl," alone or in combination with other substituents, refers to a straight-chain (i.e., unbranched) or branched-chain saturated hydrocarbon groups, or a combination of straight-chain and branched-chain groups. When an alkyl group is specified to have a certain number of carbon atoms, for example, C 1-10 ), it is meant that the alkyl group contains from 1 to 10 carbon atoms. For example, C 1-8 alkyl refers to an alkyl group containing 1 to 8 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, or the like.

[0066] As used herein, the term "alkenyl," alone or in combination with other substituents, refers to a straight-chain or branched-chain carbon-linked group having at least one carbon-carbon double bond. The alkenyl group can be substituted or unsubstituted. When an alkenyl group is specified to have a certain number of carbon atoms, for example, C 2-8 ), it is meant that the alkenyl group contains from 2 to 8 carbon atoms. For example, C 2-8 alkenyl refers to an alkenyl group containing 2 to 8 carbon atoms, including ethenyl, propenyl, 1,2-butenyl, 2,3-butenyl, butadienyl, or the like.

[0067] As used herein, the term "alkynyl," alone or in combination with other substituents, refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond. The alkynyl group can be straight or branched, or a combination thereof. When an alkynyl group is preceded by a carbon atom number limitation (e.g., C 2-8 alkynyl) means that the alkynyl group contains 2 to 8 carbon atoms. For example, the term "C 2-8 alkynyl" means a straight or branched chain alkynyl group having from 2 to 8 carbon atoms, including ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, sec-butynyl, t-butynyl, or the like.

[0068] As used herein, the term "cycloalkyl," alone or as part of another substituent means a monocyclic, bicyclic or polycyclic ring system radical having saturated or partially saturated rings. When a cycloalkyl group is preceded by a carbon atom number limitation (e.g., C 3-10 ) means that the cycloalkyl group contains 3 to 10 carbon atoms. In some preferred embodiments, the term "C 3-8 cycloalkyl" means a saturated or partially unsaturated monocyclic or bicyclic alkyl radical having from 3 to 8 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, or the like. "Spiro cycloalkyl" means a bicyclic or polycyclic radical in which single rings share one carbon atom (termed a spiro atom), which can contain one or more double bonds, but no ring has a fully conjugated pi-electron system. "Fused cycloalkyl" means a fully carbon bicyclic or polycyclic radical in which each ring shares an adjacent pair of carbon atoms with other rings in the system, in which one or more rings can contain one or more double bonds, but no ring has a fully conjugated pi-electron system. "Bridged cycloalkyl" means a fully carbon polycyclic radical in which any two rings share two non-adjacent carbon atoms, which can contain one or more double bonds, but no ring has a fully conjugated pi-electron system. The cycloalkyl group contains only carbon atoms. Some examples of cycloalkyl groups are as follows, although the application is not limited to only the cycloalkyl groups listed below.

[0069] Unless otherwise indicated, the following terms used in the specification and claims have the following meanings. "Aryl" means a fully carbon monocyclic or fused polycyclic (that is, rings that share adjacent pairs of carbon atoms) ring radical having a conjugated pi-electron system, such as phenyl and naphthyl. The aryl ring can be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of attachment to the parent molecule must be at a carbon atom on the ring having the conjugated pi-electron system. The aryl group can be substituted or unsubstituted. Some examples of aryl groups are as follows, although the application is not limited to only the aryl groups listed below.

[0070] "Heteroaryl" refers to a monocyclic or polycyclic group having aromaticity, containing one to several heteroatoms (optionally selected from nitrogen, oxygen, and sulfur), or a polycyclic group formed by the fusion of a heterocyclyl group (containing one to several heteroatoms optionally selected from nitrogen, oxygen, and sulfur) with an aryl group, with the point of attachment being on the aryl group. The heteroaryl group can be optionally substituted or unsubstituted. Some examples of heteroaryl groups are as follows, although the application is not limited to the following described heteroaryl groups.

[0071] "Heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic ring-containing hydrocarbon substituent in which one or more of the ring atoms is selected from nitrogen, oxygen, or sulfur, with the remaining ring atoms being carbon. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl. Polycyclic heterocyclyl groups refer to heterocyclyl groups that include spiro, fused, and bridged ring systems. "Spirocyclyl" refers to a polycyclic heterocyclyl group in which each ring in the system shares one atom (referred to as a spiro atom) with the other ring in the system, in which one or more of the ring atoms is selected from nitrogen, oxygen, or sulfur, with the remaining ring atoms being carbon. "Fused cyclyl" refers to a polycyclic heterocyclyl group in which each ring in the system shares an adjacent pair of atoms with the other ring in the system, one or more of the rings can contain one or more double bonds, but no ring has a fully conjugated pi-electron system, and in which one or more of the ring atoms is selected from nitrogen, oxygen, or sulfur, with the remaining ring atoms being carbon. "Bridged cyclyl" refers to a polycyclic heterocyclyl group in which any two rings share two non-adjacent atoms, which can contain one or more double bonds, but no ring has a fully conjugated pi-electron system, and in which one or more of the ring atoms is selected from nitrogen, oxygen, or sulfur, with the remaining ring atoms being carbon. If both a saturated ring and an aromatic ring are present in a heterocyclyl group (e.g., the saturated ring and the aromatic ring are fused together), the point of attachment to the parent must be on the saturated ring. Note: when the point of attachment to the parent is on the aromatic ring, it is referred to as a heteroaryl group, not a heterocyclyl group. Some examples of heterocyclyl groups are as follows, although the application is not limited to the following described heterocyclyl groups.

[0072] As used herein, the term "halogen" or "halo," either alone or as part of another substituent, refers to F, Cl, Br, and I.

[0073] As used herein, the term "substituted" (with or without the modifier "arbitrarily") means that one or more hydrogen atoms on a particular group are replaced with a particular substituent. The particular substituents are those described in the foregoing, or those substituents that appear in the various embodiments. Unless otherwise specified, an arbitrarily substituted group can have one substituent selected from a particular group at any substitutable position on the group, which substituents can be the same or different at each position. A cyclic substituent, such as a heterocyclyl group, can be attached to another ring, such as a cycloalkyl group, to form a spiro bicyclic ring system, i.e., two rings that share a common carbon atom. It will be understood by those skilled in the art that combinations of substituents contemplated by the present application are those combinations that result in stable or chemically feasible compounds. Such substituents include, but are not limited to: C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3- cycloalkyl, 3- to 12-membered heterocyclyl, aryl, heteroaryl, halogen, hydroxyl, carboxyl (-COOH), C 1-8 formyl, C 2-10 acyl, C 2-10 ester, amino.

[0074] For the sake of convenience and in keeping with common understanding, the terms "arbitrarily substituted" or "optionally substituted" apply only to positions that can be substituted with a substituent, and do not include those substitutions that are chemically infeasible.

[0075] As used herein, unless otherwise specified, the term "pharmaceutically acceptable salt" means a salt that is suitable for contact with the tissues of a subject (e.g., a human) without undue toxicity, side effects, or interact deleteriously with the tissues. In some embodiments, a pharmaceutically acceptable salt of a compound of the present application includes a salt of a compound of the present application that has an acidic group (e.g., potassium salt, sodium salt, magnesium salt, calcium salt) or a salt of a compound of the present application that has a basic group (e.g., sulfate salt, hydrochloride salt, phosphate salt, nitrate salt, carbonate salt).

[0076] Use:

[0077] The present application provides a use of a compound of Formula (I), or a deuterated derivative thereof, a salt, isomer (enantiomer or diastereomer, if present), hydrate, pharmaceutically acceptable carrier or excipient thereof, for inhibiting the activity of MRGPRX2.

[0078] The compounds of the present application can be used as an MRGPRX2 antagonist for the treatment of urticaria (spontaneous urticaria such as chronic spontaneous urticaria, acute spontaneous urticaria, physical urticaria such as cold urticaria, solar urticaria, heat contact urticaria, vibration urticaria, non-physical urticaria such as contact urticaria, aquagenic urticaria), mastocytosis, atopic dermatitis, Crohn's disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, cancer pain, chronic pruritus, drug-induced pseudoallergy, metabolic syndrome, gastroesophageal reflux, asthma, cough, migraine, chronic pruritus, acute pruritus, nodular prurigo, anaphylaxis, and other allergic, inflammatory and painful diseases.

[0079] The compounds of the present application, and deuterated derivatives thereof, and pharmaceutically acceptable salts or isomers thereof (if present) or hydrates and / or compositions thereof can be formulated with a pharmaceutically acceptable excipient or carrier and the resulting composition can be administered in vivo to mammals, such as men, women and animals, for the treatment of conditions, symptoms and diseases. The composition can be tablets, pills, suspensions, solutions, emulsions, capsules, aerosols, sterile injection solutions, sterile powders, and the like. In some embodiments, the pharmaceutically acceptable excipient includes microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dicalcium phosphate, mannitol, hydroxypropyl-β-cyclodextrin, β-cyclodextrin (increased), glycine, disintegrants (such as starch, croscarmellose sodium, composite silicate and high molecular polyethylene glycol), granulation binders (such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic) and lubricants (such as magnesium stearate, glycerol and talc). In preferred embodiments, the pharmaceutical composition is a dosage form suitable for oral administration, including but not limited to tablets, solutions, suspensions, capsules, granules, powders. The amount of the compound or pharmaceutical composition of the present application administered to a patient is not fixed and is generally administered in a pharmaceutically effective amount. At the same time, the amount of the compound actually administered can be determined by a physician according to the actual situation, including the condition to be treated, the selected administration route, the actual compound administered, the individual condition of the patient, etc. The dose of the compound of the present application depends on the specific use of treatment, the administration method, the patient's condition, the physician's judgment. The proportion or concentration of the compound of the present application in the pharmaceutical composition depends on various factors, including the dose, the physicochemical properties, the administration route, etc.

[0080] It should be understood that, within the scope of the present application, each of the technical features described above and each of the technical features specifically described below (such as examples) can be combined with each other to form a new or preferred technical solution.

[0081] Pharmaceutical compositions and methods of administration

[0082] Because the compounds of the present invention have excellent inhibitory activity against MRGPRX2, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to treat, prevent and alleviate diseases related to MRGPRX2.

[0083] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably, 5-200 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0084] "Pharmaceutically acceptable carriers" refers to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), and emulsifiers (such as Tween). Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0085] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

[0086] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert excipient (or carrier) such as sodium citrate or dicalcium phosphate, or with such excipients as (a) fillers or extenders, e.g., starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, e.g., hydroxymethylcellulose, alginic acid, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, e.g., glycerol; (d) disintegrating agents, e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solution retarders, e.g., paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) moisturizing agents, e.g., glycerol and sorbitol; (h) respiration accelerators, e.g., high-oleic acid cottonseed oil; and (i) lubricants, e.g., magnesium stearate, calcium stearate, stearic acid, glyceryl monostearate, sodium stearyl fumarate, and talc. In the case of capsules, tablets, and pills, the dosage forms can also comprise buffering agents.

[0087] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, e.g., enteric coatings and other coatings and shells well known in the art. They can optionally contain opacifying agents, and can also be of a composition that they release the active compound or compounds in a certain part of the digestive tract. Examples of embedding compositions that can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0088] Liquid dosage forms for oral administration include pharmaceutically-acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and the like, as well as mixtures thereof.

[0089] Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0090] Suspensions, in addition to the active compounds, can contain suspending agents, as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, and sodium carbromel, and the like.

[0091] Compositions for parenteral injection can contain physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.

[0092] Dosage forms for topical administration of a compound of this application include ointments, powders, sprays, and inhalants. The active component is admixed with a carrier, which can be a sterile, physiologically acceptable carrier, and any buffers, preservatives, or propellants as can be required.

[0093] A compound of this application can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0094] In using the pharmaceutical compositions, therapeutically effective amounts of a compound of this application are administered to a mammal (e.g., human) in need of such treatment in dosages suitable to produce the desired effects in that mammal. Typically, the dosage ranges from about 1 to 2000 mg, preferably 5 to 500 mg, per day for a 60 kg individual. Of course, the specific dosage will vary with the route of administration, the particular drug formulation, the indication for which it is used, and the age, body weight, and general health of the patient.

[0095] The principal advantages of the present application include:

[0096] 1. A compound of Formula I is provided.

[0097] 2. A novel MRGPRX2 antagonist is provided, as well as its preparation and use. The inhibitor inhibits the activity of MRGPRX2 at very low concentrations.

[0098] 3. A well-absorbed orally MRGPRX2 antagonist is provided.

[0099] 4. A pharmaceutical composition for treating diseases associated with MRGPRX2 is provided.

[0100] The application is further illustrated by the following examples. It is to be understood that these examples are merely illustrative of the present application and do not in any way limit the scope of the application. Unless otherwise indicated, the methods of the following examples were carried out in accordance with conventional procedures, or as otherwise described by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0101] Some representative compounds of the present application can be prepared by the following synthetic methods. In each of the following reaction schemes, the reagents and conditions for each step can be selected from those conventionally used in the art for such preparations. After the structure of the compounds of the present application is disclosed, the above selection can be made by one skilled in the art based on the knowledge in the art

[0102] Abbreviations Boc = tert-butyloxycarbonyl CN = cyano DCM = dichloromethane DIPEA or DIEA = N,N-diisopropylethylamine DMF = N,N-dimethylformamide DMSO = dimethyl sulfoxide EtOAc or EA = ethyl acetate Et = ethyl HATU = N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl)uronium hexafluorophosphate LiHMDS = lithium bis(trimethylsilyl)amide Me = methyl MeOH = methanol MeCN = acetonitrile Ph = phenyl PySO3 = pyridine sulfur trioxide TEA = triethylamine THF = tetrahydrofuran TsCl = p-toluenesulfonyl chloride TBDPS = tert-butyldiphenylsilyl TBAF = tetrabutylammonium fluoride

[0103] Example 1: Preparation of Compound 1

[0104] Compound la (200 mg, 0.73 mmol), 3-chloro-lH-pyrazole-4-carboxylic acid ethyl ester (127 mg, 0.73 mmol), cesium carbonate (595 mg, 1.83 mmol) were dissolved in acetonitrile (4 mL). The reaction mixture was heated at 90 °C with stirring overnight. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography on silica gel to give Compound lb (141 mg, yield 70%) as a yellow solid. MS m / z 277.0 [M+H] + .

[0105] Compound lb (130 mg, 0.47 mmol) was dissolved in a mixture of tetrahydrofuran / methanol / water (2 mL / 2 mL / 2 mL), and lithium hydroxide monohydrate (30 mg, 0.71 mmol) was added. The reaction was stirred at room temperature overnight. The reaction was concentrated under reduced pressure, and the resulting crude product Compound lc was used directly in the next step.

[0106] Compound lc (117 mg, 0.47 mmol), tert-butyl ((lS,3R)-3-aminocyclohexyl)carbamate (100 mg, 0.47 mmol), N,N-diisopropylethylamine (182 mg, 1.41 mmol) were dissolved in DMF (3 mL), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl)uronium hexafluorophosphate (563 mg, 1.48 mmol) was added. The reaction was stirred at room temperature for 0.5 h. The reaction was diluted with water, and the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by preparative thin layer chromatography to give Compound Id (33 mg, yield 16%) as a yellow oil solid. MS m / z 445.1 [M+H] + .

[0107] Compound 1d (33 mg, 0.07 mmol) was dissolved in dichloromethane (2 mL), and hydrogen chloride dioxane solution (4 M, 0.5 mL) was added dropwise. The reaction was heated at 40 °C and stirred for 3 h. The reaction was concentrated under reduced pressure, and the obtained crude compound 1e was used directly in the next step.

[0108] Compound 1e (28 mg, 0.07 mmol), 4,6-dichloro-2-(trifluoromethyl)quinoline (20 mg, 0.07 mmol) was dissolved in dimethyl sulfoxide (1 mL), and N,N-diisopropylethylamine (28 mg, 0.22 mmol) was added dropwise. The reaction was heated at 130 °C and stirred overnight. The reaction was diluted with water, and the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude was purified by preparative thin layer plate to give compound 1 (5 mg, yield 12%) as a white solid. 1 H NMR (500 MHz, DMSO-d) δ 8.60 (d, J = 2.2 Hz, 1H), 8.38 (s, 1H), 7.88 (dd, J = 12.9, 8.4 Hz, 2H), 7.74 (dd, J = 9.0, 2.2 Hz, 1H), 7.49 (d, J = 8.1 Hz, 1H), 6.94 (s, 1H), 5.08-4.98 (m, 1H), 4.00-3.84 (m, 2H), 3.26-3.11 (m, 4H), 2.20-2.13 (m, 1H), 2.00-1.94 (m, 1H), 1.91-1.87 (m, 1H), 1.84-1.78 (m, 1H), 1.57-1.43 (m, 2H), 1.41-1.29 (m, 2H). MS m / z 573.8 [M+H] + .

[0109] Example 2: Preparation of compound 2

[0110] Compound 1a (153 mg, 0.56 mmol), ethyl 3-iodopyrazole-4-carboxylate (150 mg, 0.56 mmol), cesium carbonate (456 mg, 1.40 mmol) were dissolved in acetonitrile (3 mL). The reaction mixture was heated at 90 °C and stirred overnight. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained crude was purified by silica gel column chromatography to give compound 2a (73 mg, yield 35%) as a yellow solid. MS m / z 368.9 [M+H] + .

[0111] Compound 2a (73 mg, 0.20 mmol), cuprous cyanide (36 mg, 0.40 mmol) were dissolved in DMF (2 mL). The reaction was heated at 140 °C overnight. The reaction was diluted with water and the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude was purified by preparative thin layer plate to give compound 2b (48 mg, yield 91%) as a yellow solid. MS m / z 268.1 [M+H] + .

[0112] Compound 2b (48 mg, 0.18 mmol) was dissolved in a mixture of tetrahydrofuran / methanol / water (1 mL / 1 mL / 1 mL), and lithium hydroxide monohydrate (11 mg, 0.27 mmol) was added. The reaction was stirred at room temperature overnight. The reaction was concentrated under reduced pressure and the resulting crude compound 2c was used directly in the next step.

[0113] Compound 2c (43 mg, 0.18 mmol), compound 2d (62 mg, 0.18 mmol), N,N- diisopropylethylamine (70 mg, 0.54 mmol) were dissolved in DMF (2 mL), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (216 mg, 0.57 mmol) was added. The reaction was stirred at room temperature for 0.5 h. The reaction was diluted with water and the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude was purified by preparative thin layer plate to give compound 2 (32 mg, yield 32%) as a white solid. 1 H NMR (500 MHz, DMSO-d) δ 8.61-8.55 (m, 2H), 8.26 (d, J = 7.7 Hz, 1H), 7.90 (d, J = 9.0 Hz, 1H), 7.75 (dd, J = 9.0, 2.2 Hz, 1H), 7.49 (d, J = 8.1 Hz, 1H), 6.96 (s, 1H), 5.24-5.15 (m, 1H), 4.02-3.86 (m, 2H), 3.32-3.25 (m, 2H), 3.22-3.14 (m, 2H), 2.20-2.15 (m, 1H), 2.01-1.95 (m, 1H), 1.94-1.89 (m, 1H), 1.86-1.80 (m, 1H), 1.60-1.43 (m, 2H), 1.42-1.25 (m, 2H). MS m / z 564.8 [M+H] + .

[0114] Example 3: Preparation of compound 3

[0115] Compound 3a (1.50 g, 4.05 mmol) (synthesis of 3a can be found in Adv. Synth. Catal. 2023, 365, 201) and triphenylphosphine (2.65 g, 10.13 mmol) were dissolved in tetrahydrofuran (50 mL) and added dropwise under ice bath.

[0116] Diisopropyl azodicarbonate (2.17 g, 10.53 mmol). The reaction mixture was stirred in an ice bath for 0.5 hours, followed by the dropwise addition of diphenyl azidophosphate (2.90 g, 10.53 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give a yellow oily compound 3b (1.30 g, 76% yield).

[0117] Compound 3b (1.30 g, 3.10 mmol) was dissolved in methanol (30 mL), and palladium on carbon (10%, 130 mg) was added. The reaction mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The resulting crude compound 3c was used directly in the next reaction step.

[0118] Compound 3c (1.00 g, 2.72 mmol) and 4,6-dichloro-2-(trifluoromethyl)quinoline (721 mg, 2.72 mmol) were dissolved in dimethyl sulfoxide (15 mL), and N,N-diisopropylethylamine (1.05 g, 8.16 mmol) was added dropwise. The reaction mixture was heated and stirred overnight at 130 °C. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate (3 × 40 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography to obtain a mixture of off-white solids 3d and 3d' (640 mg, yield 39%). MS m / z 598.2 [M+H] + .

[0119] A mixture of compounds 3d and 3d' (640 mg, 1.07 mmol), 1-methylpyrazol-4-carboxylic acid (135 mg, 1.07 mmol), and N,N-diisopropylethylamine (414 mg, 3.21 mmol) were dissolved in DMF (10 mL), followed by the addition of N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (427 mg, 1.12 mmol). The reaction mixture was stirred at room temperature for 0.5 hours. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give a white solid compound 3e (639 mg, 85% yield). MS m / z 706.2 [M+H] + .

[0120] Compound 3e (639 mg, 0.91 mmol) was dissolved in tetrahydrofuran (15 mL), and a solution of tetrabutylammonium fluoride in tetrahydrofuran (1 M, 2 mL) was added dropwise. The reaction was heated at 50 °C overnight. The reaction was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography on silica gel to give compound 3 (385 mg, 91% yield) as a white solid (compound 3 is a mixture of 1S,3R (3A) and 1R,3S (3B)). 1 H NMR (500 MHz, DMSO-d) δ 8.59 (d, J = 2.0 Hz, 1H), 8.11 (s, 1H), 7.94-7.88 (m, 2H), 7.83 (s, 1H), 7.75 (dd, J = 9.0, 2.1 Hz, 1H), 7.53 (d, J = 7.9 Hz, 1H), 6.79 (s, 1H), 4.89 (d, J = 3.5 Hz, 1H), 4.40-4.29 (m, 1H), 4.18 (s, 1H), 4.10-4.01 (m, 1H), 3.84 (s, 3H), 2.17 (d, J = 11.4 Hz, 1H), 2.04 (d, J = 12.6 Hz, 1H), 1.89 (d, J = 12.4 Hz, 1H), 1.57-1.48 (m, 3H). MS m / z 467.9 [M+H] + Compound 3 can be chiral resolution by SFC to give 3A and 3B.

[0121] Example 4: Preparation of compound 4

[0122] Compound 3 (320 mg, 0.69 mmol) was dissolved in dichloromethane / dimethyl sulfoxide (5 mL / 5 mL), and N,N-diisopropylethylamine (445 mg, 3.45 mmol) was added dropwise. Sulfur trioxide pyridine (329 mg, 2.07 mmol) was added under ice bath. The reaction was stirred at ice bath for 2 hours. The reaction was diluted with water, and the mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography on silica gel to give compound 4 (204 mg, 64% yield) as a white solid (compound 4 is a mixture of 1S,3R (4A) and 1R,3S (4B)). 1H NMR (500 MHz, DMSO-d) δ 8.55 (d, J = 2.0 Hz, 1H), 8.17 - 8.10 (m, 2H), 7.92 (d, J = 9.0 Hz, 1H), 7.84 (s, 1H), 7.77 (dd, J = 9.0, 2.1 Hz, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.04 (s, 1H), 4.43 - 4.28 (m, 2H), 3.85 (s, 3H), 2.68 - 2.53 (m, 4H), 2.30 (d, J = 12.2 Hz, 1H), 2.01 - 1.94 (m, 1H). MS m / z 465.9 [M+H] + .

[0123] 4A and 4B synthesis:

[0124] The synthesis of compounds 3d and 3d’ was achieved by resolution with L-tartaric acid and D-tartaric acid (the method is referenced to the resolution with tartaric acid in patent WO2018119395A1). Compound 3d (352 mg) and 3d’ (332 mg) were obtained. The optical purity of compound 3d was 65.28% by chiral HPLC (AS column_15% MeOH / C02 mobile phase, flow rate 2 mL / min) and the optical purity of compound 3d’ was 66.20%. The chiral configuration of 3d and 3d’ was provisionally assigned.

[0125] The resolution of the mixture of second batch of 3d and 3d’ was achieved by adding D-tartaric acid, slow precipitation (longer time), and then using water and dichloromethane to rinse several times to obtain compound 3d (224 mg) with an optical purity (chiral test method is the same as above) of 99.16%.

[0126] Compound 3d was converted to compound 4A (238 mg) by condensation, deprotection and oxidation (the synthesis method is referenced to the synthesis of compounds 3 and 4). Compound 3d’ was converted to compound 4B (216 mg) by the same method.

[0127] Example 5: Preparation of compound 5

[0128] Methyltriphenylphosphonium bromide (107 mg, 0.30 mmol) was dissolved in tetrahydrofuran (3 mL) and LiHMDS (1 M, 0.3 mL) was added dropwise under ice bath. The reaction was stirred at ice bath for 0.5 h, and then a solution of compound 4 (70 mg, 0.15 mmol) in tetrahydrofuran (2 mL) was added dropwise. The reaction was stirred at room temperature for 2 h. The reaction was quenched with saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude was separated and purified by column chromatography on silica gel to give compound 5 (18 mg, yield 26%) as a white solid. (Compound 5 is a mixture of 1S,3R (5B) and 1R,3S (5A)). 1 H NMR (500 MHz, DMSO-d) δ 8.60 (d, J = 1.4 Hz, 1H), 8.12 (s, 1H), 8.00 (d, J = 7.9 Hz, 1H), 7.91 (d, J = 9.0 Hz, 1H), 7.83 (s, 1H), 7.76 (dd, J = 8.9, 1.8 Hz, 1H), 7.55 (d, J = 8.2 Hz, 1H), 6.93 (s, 1H), 4.89 (s, 2H), 4.01 - 3.94 (m, 1H), 3.88 - 3.76 (m, 4H), 2.65 - 2.56 (m, 2H), 2.26 - 2.17 (m, 2H), 2.08 - 2.02 (m, 1H), 1.69 - 1.60 (m, 1H). MS m / z 463.9 [M+H] + Compound 5 can be chiral separated by SFC to give 5A and 5B.

[0129] Example 6: Preparation of compound 6

[0130] Compound 5 (8 mg, 0.017 mmol), zinc copper reagent (11 mg, 0.09 mmol), diiodomethane (23 mg, 0.09 mmol) were dissolved in ether (2 mL). The reaction mixture was stirred at room temperature under nitrogen atmosphere overnight. The reaction was filtered through celite, the filter cake was rinsed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The resulting crude was separated and purified by preparative thin layer plate to give compound 6 (1 mg, yield 12%) (Compound 6 is a mixture of 1S,3R (6B) and 1R,3S (6A)). MS m / z 477.9 [M+H] + Compound 6 can be chiral separated by SFC to give 6A and 6B.

[0131] Example 7: Preparation of compound 7

[0132] Compound 1a (147 mg, 0.54 mmol), ethyl 4-pyrazolecarboxylate (75 mg, 0.54 mmol), cesium carbonate (440 mg, 1.35 mmol) were dissolved in acetonitrile (3 mL). The reaction mixture was heated at 90 °C with stirring overnight. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography on silica gel to give compound 7a (28 mg, yield 22%) as a yellow oil.

[0133] Compound 7a (28 mg, 0.12 mmol) was dissolved in a mixture of tetrahydrofuran / methanol / water (1 mL / 1 mL / 1 mL), and lithium hydroxide monohydrate (8 mg, 0.18 mmol) was added. The reaction was stirred at room temperature overnight. The reaction was concentrated under reduced pressure, and the resulting crude compound 7b was used directly in the next step.

[0134] Compound 7b (25 mg, 0.12 mmol), compound 2d (41 mg, 0.12 mmol), N,N- diisopropylethylamine (46 mg, 0.36 mmol) were dissolved in DMF (1 mL), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urem hexafluorophosphate (48 mg, 0.13 mmol) was added. The reaction was stirred at room temperature for 0.5 hours. The reaction was diluted with water, and the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by preparative thin layer chromatography to give compound 7 (22 mg, yield 35%) as a white solid. 1 H NMR (500 MHz, DMSO-d) δ 8.60 (d, J = 2.2 Hz, 1H), 8.30 (s, 1H), 8.01-7.85 (m, 3H), 7.74 (dd, J = 9.0, 2.2 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 6.93 (s, 1H), 5.14-5.01 (m, 1H), 4.02-3.83 (m, 2H), 3.22-3.16 (m, 4H), 2.19-2.13 (m, 1H), 2.00-1.94 (m, 1H), 1.90-1.79 (m, 2H), 1.59-1.43 (m, 2H), 1.41-1.27 (m, 2H). MS m / z 539.8 [M+H] + .

[0135] Example 8: Preparation of compound 8

[0136] Compound 8a (1.50 g, 4.52 mmol) was dissolved in dichloromethane (30 mL), and boron tribromide in dichloromethane (1 M, 7 mL) was added dropwise under ice bath. The reaction was stirred under ice bath for 0.5 h. The reaction was quenched with saturated aqueous sodium bicarbonate solution, and the mixture was extracted with dichloromethane (3 x 30 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude compound 8b was used directly in the next step.

[0137] Compound 8b (1.00 g, 4.13 mmol), p-toluenesulfonyl chloride (789 mg, 4.13 mmol) was dissolved in dichloromethane (20 mL), and sodium hydride (60%, 330 mg, 8.26 mmol) was added under ice bath. The reaction was stirred under ice bath for 0.5 h. The reaction was quenched with saturated aqueous ammonium chloride solution, and the mixture was extracted with dichloromethane (3 x 20 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude was purified by column chromatography on silica gel to give compound 8c (912 mg, 56% yield) as a yellow oil.

[0138] Compound 8c (500 mg, 1.26 mmol), ethyl 4-pyrazolecarboxylate (176 mg, 1.26 mmol), and cesium carbonate (1.03 g, 3.15 mmol) were dissolved in acetonitrile (10 mL). The reaction mixture was heated and stirred at 90 °C overnight. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude was purified by column chromatography on silica gel to give compound 8d (86 mg, 19% yield) as a yellow oil.

[0139] Compound 8d (80 mg, 0.22 mmol) was dissolved in a mixture of tetrahydrofuran / methanol / water (2 mL / 2 mL / 2 mL), and lithium hydroxide monohydrate (14 mg, 0.33 mmol) was added. The reaction was stirred at room temperature overnight. The reaction was concentrated under reduced pressure, and the crude compound 8e was used directly in the next step.

[0140] Compound 8e (74 mg, 0.22 mmol), compound 2d (76 mg, 0.22 mmol), and N,N- diisopropylethylamine (85 mg, 0.66 mmol) were dissolved in DMF (2 mL), and N,N,N',N'- tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (88 mg, 0.23 mmol) was added. The reaction was stirred at room temperature for 0.5 h. The reaction was diluted with water, and the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude was purified by preparative thin layer plate to give compound 8f (21 mg, 14% yield) as a white solid. MS m / z 661.9 [M+H] + .

[0141] Cuprous iodide (29 mg, 0.15 mmol) was mixed with tetrahydrofuran (2 mL) and methyl lithium ethyl ether solution (1.6 M, 0.14 mL) was added dropwise under ice bath and nitrogen atmosphere. The reaction was stirred at ice bath for 10 minutes and then a solution of compound 8f (10 mg, 0.015 mmol) in tetrahydrofuran (0.5 mL) was added dropwise. The reaction was stirred at room temperature overnight and iodomethane (43 mg, 0.30 mmol) was added dropwise under ice bath. The reaction was stirred at ice bath for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride solution and the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative thin layer plate to give compound 8 (2 mg, yield 24%) as a white solid. 1 H NMR (500 MHz, DMSO-d) δ 8.60 (d, J = 2.2 Hz, 1H), 8.27 (s, 1H), 7.99-7.85 (m, 3H), 7.74 (dd, J = 9.0, 2.2 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 6.93 (s, 1H), 4.91-4.83 (m, 1H), 4.01-3.84 (m, 2H), 3.14-3.08 (m, 2H), 3.01-2.96 (m, 2H), 2.18-2.13 (m, 1H), 1.98-1.95 (m, 1H), 1.89-1.79 (m, 2H), 1.54 (s, 6H), 1.47-1.39 (m, 2H), 1.34 (d, J = 7.7 Hz, 2H). MS m / z 532.0 [M+H] + .

[0142] Example 9: Preparation of compound 9

[0143] Cuprous iodide (29 mg, 0.15 mmol) was mixed with tetrahydrofuran (2 mL) and methyl lithium ethyl ether solution (1.6 M, 0.14 mL) was added dropwise under ice bath and nitrogen atmosphere. The reaction was stirred at ice bath for 10 minutes and then a solution of compound 8f (10 mg, 0.015 mmol) in tetrahydrofuran (0.5 mL) was added dropwise. The reaction was stirred at room temperature overnight and iodomethane (43 mg, 0.30 mmol) was added dropwise under ice bath. The reaction was stirred at ice bath for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride solution and the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative thin layer plate to give compound 8 (2 mg, yield 24%) as a white solid. 1H NMR (500 MHz, DMSO-d) δ 8.60 (d, J = 2.2 Hz, 1H), 8.28 (s, 1H), 7.94-7.86 (m, 3H), 7.74 (dd, J = 9.0, 2.2 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 6.93 (s, 1H), 5.33-5.27 (m, 1H), 4.95-4.87 (m, 1H), 4.01-3.85 (m, 2H), 3.17-2.99 (m, 4H), 2.18-2.13 (m, 1H), 1.99-1.94 (m, 1H), 1.90-1.79 (m, 2H), 1.55-1.51 (m, 3H), 1.49-1.41 (m, 2H), 1.39-1.30 (m, 2H). MS m / z 518.0 [M+H] + .

[0144] Example 10: Preparation of compound 10

[0145] Compound 4 (10 mg, 0.02 mmol), compound 10-a (5 mg, 0.02 mmol) were dissolved in DMF (1 mL) and cooled to -60 °C under nitrogen atmosphere. A solution of potassium tert-butoxide (5 mg, 0.04 mmol) in DMF (1 mL) was added dropwise. The reaction was stirred at -60 °C for 0.5 h, and then diluted with dilute hydrochloric acid (1 M, 1 mL). The mixture was stirred at room temperature for 0.5 h, extracted with ethyl acetate (3 x 5 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer plate to give compound 10 (5 mg, yield 46%) as a white solid (compound 10 is a mixture of 1S, 3R (10B) and 1R, 3S (10A)). Compound 10 can be chiral separated by SFC to give 10A and 10B. 1 H NMR (500 MHz, DMSO-d) δ 8.58 (d, J = 2.2 Hz, 1H), 8.13 (s, 1H), 8.07 (d, J = 7.8 Hz, 1H), 7.92 (d, J = 9.0 Hz, 1H), 7.84 (s, 1H), 7.76 (dd, J = 9.0, 2.2 Hz, 1H), 7.59 (d, J = 8.2 Hz, 1H), 7.01 (s, 1H), 4.07-3.95 (m, 2H), 3.85 (s, 3H), 2.71-2.62 (m, 2H), 2.20-2.14 (m, 1H), 2.03-1.96 (m, 1H), 1.88-1.81 (m, 1H), 1.68-1.60 (m, 1H). MS m / z 499.8 [M+H] + .

[0146] Example 11: Preparation of compound 11

[0147] Compound 4B (20 mg, 0.04 mmol) (4B was prepared using 3d’ synthesis from the first batch resolution in Example 4), compound 11-a (14 mg, 0.06 mmol) were dissolved in tetrahydrofuran (1 mL) and cooled to -70 °C under nitrogen atmosphere. LiHMDS tetrahydrofuran solution (1 M, 0.1 mL) was added dropwise. The reaction was stirred at -70 °C for 0.5 h. The reaction was quenched with saturated aqueous ammonium chloride solution and the mixture was extracted with ethyl acetate (3 x 5 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude was purified by preparative thin layer plate to give compound 11 (7 mg, yield 33%) as a white solid. 1 H NMR (500 MHz, DMSO-d) δ 8.62 (d, J = 2.1 Hz, 1H), 8.13 (s, 1H), 8.02 (d, J = 7.9 Hz, 1H), 7.91 (d, J = 9.0 Hz, 1H), 7.85 (s, 1H), 7.76 (dd, J = 9.0, 2.2 Hz, 1H), 7.62 (d, J = 7.7 Hz, 1H), 6.87 (s, 1H), 3.90 - 3.78 (m, 4H), 3.70 - 3.61 (m, 1H), 3.05 - 2.98 (m, 1H), 2.94 - 2.86 (m, 1H), 2.26 - 2.20 (m, 1H), 1.85 - 1.69 (m, 9H). MS m / z 492.0 [M+H] + .

[0148] Example 12: Preparation of compound 12

[0149] Compound 4A (20 mg, 0.04 mmol) (4A was prepared using 3d synthesis from the first batch resolution in Example 4), compound 11-a (14 mg, 0.06 mmol) were dissolved in tetrahydrofuran (1 mL) and cooled to -70 °C under nitrogen atmosphere. LiHMDS tetrahydrofuran solution (1 M, 0.1 mL) was added dropwise. The reaction was stirred at -70 °C for 0.5 h. The reaction was quenched with saturated aqueous ammonium chloride solution and the mixture was extracted with ethyl acetate (3 x 5 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude was purified by preparative thin layer plate to give compound 12 (8 mg, yield 38%) as a white solid. 1H NMR (500 MHz, DMSO-d) δ 8.62 (d, J = 2.2 Hz, 1H), 8.13 (s, 1H), 8.02 (d, J = 7.9 Hz, 1H), 7.91 (d, J = 9.0 Hz, 1H), 7.85 (s, 1H), 7.76 (dd, J = 9.0, 2.2 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 6.87 (s, 1H), 3.88 - 3.79 (m, 4H), 3.69 - 3.62 (m, 1H), 3.04 - 2.99 (m, 1H), 2.91 - 2.88 (m, 1H), 2.24 - 2.20 (m, 1H), 1.85 - 1.68 (m, 9H). MS m / z 491.9 [M+H] + .

[0150] Example 13: Preparation of compounds 13 and 14

[0151] Compound 13-a (21 mg, 0.05 mmol) was dissolved in tetrahydrofuran (1 mL) and cooled to -70 °C under nitrogen atmosphere. LiHMDS tetrahydrofuran solution (1 M, 0.06 mL) was added dropwise. The reaction was stirred at -70 °C for 0.5 h, and then tetrahydrofuran solution (0.5 mL) of compound 4B (20 mg, 0.04 mmol) (4B was synthesized using 3d’ from the first batch of resolution in Example 4) was added dropwise. The reaction was quenched with saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate (3 x 5 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude was purified by preparative thin layer plate to give compound 13 (2 mg, 10% yield) as a white solid (the double bond configuration was tentatively assigned as E) and compound 14 (3 mg, 14% yield) as a white solid (the double bond configuration was tentatively assigned as Z).

[0152] Compound 13: 1H NMR (500 MHz, DMSO) δ 8.59 (d, J = 2.2 Hz, 1H), 8.13 (s, 1H), 8.05 (d, J = 7.9 Hz, 1H), 7.91 (d, J = 9.0 Hz, 1H), 7.84 (d, J = 0.5 Hz, 1H), 7.76 (dd, J = 9.0, 2.2 Hz, 1H), 7.56 (d, J = 8.3 Hz, 1H), 6.98 (s, 1H), 6.86 (d, J = 86.7 Hz, 1H), 4.00 - 3.86 (m, 2H), 3.84 (s, 3H), 2.97 (dd, J = 13.0, 3.8 Hz, 1H), 2.47 - 2.45 (m, 1H), 2.20 - 2.16 (m, 1H), 2.09 - 2.03 (m, 1H), 1.75 - 1.69 (m, 1H), 1.69 - 1.62 (m, 1H). MS m / z 482.2 [M+H] + .

[0153] Compound 14: 1 H NMR (500 MHz, DMSO-d) δ 8.59 (d, J = 2.2 Hz, 1H), 8.12 (s, 1H), 8.03 (d, J = 7.9 Hz, 1H), 7.92 (d, J = 9.0 Hz, 1H), 7.83 (s, 1H), 7.76 (dd, J = 9.0, 2.2 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 6.96 (s, 1H), 6.86 (d, J = 86.5 Hz, 1H), 3.99 - 3.86 (m, 2H), 3.84 (s, 3H), 3.06 - 3.02 (m, 1H), 2.45 - 2.41 (m, 1H), 2.22 - 2.18 (m, 1H), 1.91 - 1.84 (m, 2H), 1.70 - 1.62 (m, 1H). MS m / z 482.0 [M+H] + .

[0154] Example 14: Preparation of compounds 15 and 16

[0155] Compound 13-a (21 mg, 0.05 mmol) was dissolved in tetrahydrofuran (1 mL) and cooled to -70 °C under nitrogen atmosphere. LiHMDS tetrahydrofuran solution (1 M, 0.06 mL) was added dropwise. The reaction was stirred at -70 °C for 0.5 h, and then tetrahydrofuran solution (0.5 mL) of compound 4A (20 mg, 0.04 mmol) (4A was synthesized using 3d from the first batch of resolution in Example 4) was added dropwise. The reaction was quenched with saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate (3 x 5 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude was purified by preparative thin layer plate to give compound 15 (3 mg, 14% yield) as a white solid (the double bond configuration was tentatively assigned as E) and compound 16 (3 mg, 14% yield) as a white solid (the double bond configuration was tentatively assigned as Z).

[0156] Compound 15: 1 H NMR (500 MHz, DMSO-d) δ 8.59 (d, J = 2.2 Hz, 1H), 8.13 (s, 1H), 8.05 (d, J = 7.9 Hz, 1H), 7.91 (d, J = 9.0 Hz, 1H), 7.84 (s, 1H), 7.76 (dd, J = 9.0, 2.2 Hz, 1H), 7.56 (d, J = 8.2 Hz, 1H), 6.98 (s, 1H), 6.86 (d, J = 86.7 Hz, 1H), 3.97 - 3.87 (m, 2H), 3.84 (s, 3H), 2.97 (dd, J = 12.7, 3.9 Hz, 1H), 2.47 - 2.46 (m, 1H), 2.20 - 2.16 (m, 1H), 2.09 - 2.03 (m, 1H), 1.75 - 1.69 (m, 1H), 1.69 - 1.62 (m, 1H). MS m / z 481.9 [M+H] + .

[0157] Compound 16: 1H NMR (500 MHz, DMSO-d) δ 8.59 (d, J = 2.2 Hz, 1H), 8.12 (s, 1H), 8.03 (d, J = 7.9 Hz, 1H), 7.92 (d, J = 9.0 Hz, 1H), 7.84 (s, 1H), 7.76 (dd, J = 9.0, 2.2 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 6.96 (s, 1H), 6.86 (d, J = 86.5 Hz, 1H), 3.98 - 3.87 (m, 2H), 3.84 (s, 3H), 3.04 (dd, J = 12.9, 3.1 Hz, 1H), 2.45 - 2.41 (m, 1H), 2.21 (s, 1H), 1.92 - 1.83 (m, 2H), 1.71 - 1.63 (m, 1H). MS m / z 481.9 [M+H] + .

[0158] Example 15: Preparation of compound 17

[0159] Compound 4B (20 mg, 0.04 mmol) (4B was synthesized using 3d’ from the first batch of resolution in Example 4), compound 17-a (14 mg, 0.06 mmol) were dissolved in tetrahydrofuran (1 mL) and cooled to -70 °C under nitrogen atmosphere. LiHMDS tetrahydrofuran solution (1 M, 0.1 mL) was added dropwise. The reaction was stirred at -70 °C for 0.5 h. The reaction was quenched with saturated aqueous ammonium chloride solution and the mixture was extracted with ethyl acetate (3 x 5 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude was purified by preparative thin layer plate to give compound 17 (7 mg, yield 34%) as a white solid (the configuration of the double bond Z / E was not determined). 1H NMR (500 MHz, DMSO-d) δ 8.61 (dd, J = 7.6, 2.2 Hz, 1H), 8.12 (d, J = 3.8 Hz, 1H), 8.01 (dd, J = 24.0, 7.9 Hz, 1H), 7.91 (dd, J = 9.0, 6.3 Hz, 1H), 7.84 (dd, J = 4.6, 0.4 Hz, 1H), 7.78 - 7.73 (m, 1H), 7.58 (dd, J = 42.4, 7.9 Hz, 1H), 6.90 (d, J = 4.3 Hz, 1H), 5.44 - 5.34 (m, 1H), 4.00 - 3.83 (m, 4H), 3.79 - 3.68 (m, 1H), 3.00 - 2.83 (m, 1H), 2.44 (d, J = 12.8 Hz, 1H), 2.25 - 2.19 (m, 1H), 2.09 - 1.80 (m, 1H), 1.79 - 1.65 (m, 2H), 1.63 (d, J = 5.9 Hz, 3H). MS m / z 478.1 [M+H] + .

[0160] Example 16: Preparation of compound 18

[0161] Compound 4A (20 mg, 0.04 mmol) (4A was prepared from 3d synthesis using the first batch of resolution in Example 4), compound 17-a (14 mg, 0.06 mmol) were dissolved in tetrahydrofuran (1 mL) and cooled to -70 °C under nitrogen atmosphere. LiHMDS tetrahydrofuran solution (1 M, 0.1 mL) was added dropwise. The reaction was stirred at -70 °C for 0.5 h. The reaction was quenched with saturated aqueous ammonium chloride solution and the mixture was extracted with ethyl acetate (3 x 5 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude was purified by preparative thin layer plate to give compound 17 as a white solid (7.2 mg, 35% yield) (the configuration of the double bond Z / E is not determined). 1H NMR (500 MHz, DMSO-d) δ 8.61 (dd, J = 7.6, 2.2 Hz, 1H), 8.12 (d, J = 3.7 Hz, 1H), 8.01 (dd, J = 23.9, 7.9 Hz, 1H), 7.91 (dd, J = 9.0, 6.3 Hz, 1H), 7.84 (d, J = 4.5 Hz, 1H), 7.78 - 7.73 (m, 1H), 7.58 (dd, J = 42.3, 7.9 Hz, 1H), 6.90 (d, J = 4.3 Hz, 1H), 5.40 (q, J = 6.3 Hz, 1H), 3.96 - 3.83 (m, 4H), 3.79 - 3.68 (m, 1H), 3.01 - 2.84 (m, 1H), 2.44 (dd, J = 12.7, 3.7 Hz, 1H), 2.25 - 2.19 (m, 1H), 2.07 - 1.80 (m, 1H), 1.77 - 1.65 (m, 2H), 1.63 (d, J = 6.5 Hz, 3H). MS m / z 477.9 [M+H] + .

[0162] Example 17: Preparation of compound 19

[0163] Compound 4A (8 mg, 0.06 mmol) (4A was prepared from 3d synthesis using the first batch of resolution in Example 4) was dissolved in tetrahydrofuran (1 mL) and LiHMDS tetrahydrofuran solution (1 M, 0.1 mL) was added dropwise under nitrogen atmosphere in ice bath. The reaction was stirred at room temperature for 0.5 hour, and then compound 19-a (20 mg, 0.04 mmol) in tetrahydrofuran was added dropwise. The reaction was stirred at room temperature for 0.5 hour. The reaction was quenched with saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate (3 x 5 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude was purified by preparative thin layer plate to give compound 19 (8 mg, 38% yield) as a white solid (the configuration of the double bond Z / E was not determined). 1H NMR (500 MHz, DMSO-d) δ 8.57 (dd, J = 9.7, 2.1 Hz, 1H), 8.18 - 8.07 (m, 2H), 7.92 (dd, J = 8.9, 7.2 Hz, 1H), 7.84 (d, J = 6.0 Hz, 1H), 7.79 - 7.74 (m, 1H), 7.62 (dd, J = 26.2, 8.2 Hz, 1H), 7.04 (d, J = 12.8 Hz, 1H), 5.71 (d, J = 6.3 Hz, 1H), 4.12 - 4.01 (m, 2H), 3.85 (d, J = 3.0 Hz, 3H), 3.10 - 2.99 (m, 1H), 2.81 - 2.72 (m, 1H), 2.46 - 2.38 (m, 1H), 2.29 - 2.17 (m, 2H), 1.82 - 1.70 (m, 1H). MS m / z 488.9 [M+H] + .

[0164] Example 18: Preparation of compound 20

[0165] Compound 20-a (23 mg, 0.06 mmol) was dissolved in tetrahydrofuran (1 mL) and cooled to -60 °C under nitrogen atmosphere, NaHMDS tetrahydrofuran solution (1 M, 0.1 mL) was added dropwise. The reaction was stirred at room temperature for 0.5 h, and then tetrahydrofuran solution of compound 4A (20 mg, 0.04 mmol) (4A was prepared from 3d synthesis using the first batch of resolution in example 4) was added dropwise. The reaction was heated at 50 °C and stirred for 0.5 h. The reaction was quenched with saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate (3 x 5 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude was purified by preparative thin layer plate to give compound 20 (7 mg, yield 33%) as a white solid. 1 H NMR (500 MHz, DMSO-d) δ 8.61 (d, J = 2.2 Hz, 1H), 8.12 (s, 1H), 8.03 (d, J = 7.9 Hz, 1H), 7.91 (d, J = 9.0 Hz, 1H), 7.84 (s, 1H), 7.76 (dd, J = 9.0, 2.2 Hz, 1H), 7.62 (d, J = 7.9 Hz, 1H), 6.90 (s, 1H), 4.02 - 3.95 (m, 1H), 3.87 - 3.77 (m, 4H), 2.83 - 2.78 (m, 1H), 2.74 - 2.70 (m, 1H), 2.28 - 2.20 (m, 2H), 2.15 - 2.09 (m, 1H), 1.76 - 1.67 (m, 1H), 1.14 - 1.02 (m, 4H). MS m / z 490.0 [M+H] + .

[0166] Example 19: Preparation of compound 21

[0167] Compound 3d (220 mg, 0.37 mmol) (3d used the product after the second batch split in Example 4) was dissolved in methanol (5 mL), and di-tert-butyl dicarbonate (85 mg, 0.39 mmol) was added dropwise. The reaction was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure, and the resulting crude compound 21-a (285 mg, 111% yield) was used directly in the next step. MS m / z 467.9 [M+H] + .

[0168] Compound 21-a (285 mg, 0.37 mmol) was dissolved in tetrahydrofuran (5 mL), and a solution of tetrabutylammonium fluoride in tetrahydrofuran (1 M, 2 mL) was added dropwise. The reaction was heated at 50 °C and stirred overnight. The reaction was concentrated under reduced pressure, and the resulting crude was purified by column chromatography on silica gel to give compound 21-b (171 mg, 100% yield) as a white solid. MS m / z 459.9 [M+H] + .

[0169] Compound 21-b (171 mg, 0.37 mmol) was dissolved in dichloromethane / dimethyl sulfoxide (2 mL / 2 mL), and N,N-diisopropylethylamine (239 mg, 1.85 mmol) was added dropwise. Sulfur trioxide pyridine (176 mg, 1.11 mmol) was added under ice bath. The reaction was stirred under ice bath for 1 h. The reaction was diluted with water, and the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude was purified by column chromatography on silica gel to give compound 21-c (163 mg, 96% yield) as a white solid. MS m / z 457.9 [M+H] + .

[0170] Methyl triphenylphosphonium iodide (267 mg, 0.66 mmol) was dissolved in tetrahydrofuran (5 mL), and LiHMDS (1 M, 0.7 mL) was added dropwise under ice bath. The reaction was stirred under ice bath for 0.5 h, and a solution of compound 21-c (150 mg, 0.33 mmol) in tetrahydrofuran (2 mL) was added dropwise. The reaction was stirred at room temperature for 2 h. The reaction was quenched with saturated aqueous ammonium chloride, and the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude was purified by column chromatography on silica gel to give compound 21-d (31 mg, 21% yield) as a white solid. MS m / z 455.9 [M+H] + .

[0171] Compound 21-d (30 mg, 0.07 mmol) was dissolved in methanol (3 mL), p-toluenesulfonic acid (60 mg, 0.35 mmol) was added. The reaction was heated at 50 °C and stirred overnight. The reaction was concentrated under reduced pressure. The resulting crude was purified by preparative thin layer plate to give compound 21-e (22 mg, yield 96%). MS m / z 355.9 [M+H] + .

[0172] Compound 21-e (3 mg, 0.008 mmol), compound 21-f (2 mg, 0.01 mmol), N,N- diisopropylethylamine (4 mg, 0.03 mmol) were dissolved in acetonitrile (1 mL), and then N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (4 mg, 0.01 mmol) was added. The reaction was stirred at room temperature for 0.5 h. The reaction was concentrated under reduced pressure. The resulting crude was purified by preparative thin layer plate to give compound 21 (1.5 mg, yield 38%) as a white solid. 1 H NMR (500 MHz, DMSO-d) d 8.60 (d, J = 2.2 Hz, 1H), 8.17 (s, 1H), 7.99 (d, J = 7.9 Hz, 1H), 7.91 (d, J = 9.0 Hz, 1H), 7.85 (s, 1H), 7.76 (dd, J = 9.0, 2.2 Hz, 1H), 7.55 (d, J = 8.1 Hz, 1H), 6.93 (s, 1H), 4.90-4.88 (m, 2H), 4.16-4.10 (m, 2H), 4.00-3.93 (m, 1H), 3.87-3.80 (m, 1H), 2.61-2.53 (m, 2H), 2.25-2.18 (m, 2H), 2.03-1.95 (m, 2H), 1.40-1.33 (m, 3H). MS m / z 477.9 [M+H] + .

[0173] Example 20: Preparation of compound 22

[0174] Compound 21-e (3 mg, 0.008 mmol), compound 22-a (2 mg, 0.01 mmol), N,N- diisopropylethylamine (4 mg, 0.03 mmol) were dissolved in acetonitrile (1 mL), and then N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (4 mg, 0.01 mmol) was added. The reaction was stirred at room temperature for 0.5 h. The reaction was concentrated under reduced pressure. The resulting crude was purified by preparative thin layer plate to give compound 22 (1.4 mg, yield 31%) as a white solid. 1H NMR (500 MHz, DMSO-d) δ 8.59 (d, J = 2.2 Hz, 1H), 8.30 (s, 1H), 8.18 (d, J = 7.9 Hz, 1H), 7.99 (s, 1H), 7.91 (d, J = 9.0 Hz, 1H), 7.76 (dd, J = 9.0, 2.2 Hz, 1H), 7.55 (d, J = 8.1 Hz, 1H), 6.94 (s, 1H), 5.23 - 5.17 (m, 2H), 4.93 - 4.87 (m, 2H), 4.01 - 3.96 (m, 1H), 3.87 - 3.82 (m, 1H), 2.61 - 2.57 (m, 2H), 2.25 - 2.19 (m, 2H), 2.01 - 1.96 (m, 2H). MS m / z 531.9 [M+H] + .

[0175] Example 21: Preparation of compound 23 (IGP-20024-01) (A057-130)

[0176] Compound 21-e (3 mg, 0.008 mmol), compound 23-a (2 mg, 0.01 mmol), N,N- diisopropylethylamine (4 mg, 0.03 mmol) were dissolved in acetonitrile (1 mL), and then N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urem hexafluorophosphate (4 mg, 0.01 mmol) was added. The reaction was stirred at room temperature for 0.5 h. The reaction was concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer plate to give compound 23 (1.3 mg, yield 31%) as a white solid. 1 H NMR (500 MHz, DMSO-d) δ 8.59 (d, J = 2.2 Hz, 1H), 8.30 (s, 1H), 8.18 (d, J = 7.9 Hz, 1H), 7.99 (s, 1H), 7.91 (d, J = 9.0 Hz, 1H), 7.76 (dd, J = 9.0, 2.2 Hz, 1H), 7.55 (d, J = 8.1 Hz, 1H), 6.94 (s, 1H), 5.23 - 5.17 (m, 2H), 4.93 - 4.87 (m, 2H), 4.01 - 3.96 (m, 1H), 3.87 - 3.82 (m, 1H), 2.61 - 2.57 (m, 2H), 2.25 - 2.18 (m, 2H), 2.06 - 1.97 (m, 2H). MS m / z 497.9 [M+H] + .

[0177] Example 22: Preparation of compound 24

[0178] Compound 21-e (3 mg, 0.008 mmol), compound 24-a (2 mg, 0.01 mmol), N,N- diisopropylethylamine (4 mg, 0.03 mmol) were dissolved in acetonitrile (1 mL), and then N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl) uronium hexafluorophosphate (4 mg, 0.01 mmol) was added. The reaction was stirred at room temperature for 0.5 h. The reaction was concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer plate to give compound 24 (1.3 mg, yield 32%) as a white solid. 1 H NMR (500 MHz, DMSO-d) δ 8.59 (d, J = 2.2 Hz, 1H), 8.39 (s, 1H), 8.35 (d, J = 7.2 Hz, 1H), 7.91 (d, J = 9.0 Hz, 1H), 7.76 (dd, J = 9.0, 2.2 Hz, 1H), 7.55 (d, J = 8.2 Hz, 1H), 6.96 (s, 1H), 4.91 (s, 2H), 3.98-3.94 (m, 4H), 3.88-3.85 (m, 1H), 2.63-2.54 (m, 2H), 2.26-2.19 (m, 2H), 2.01-1.96 (m, 2H). MS m / z 489.0 [M+H] + .

[0179] Example 23: Preparation of compound 25

[0180] Compound 21-e (3 mg, 0.008 mmol), compound 25-a (2 mg, 0.01 mmol), N,N- diisopropylethylamine (4 mg, 0.03 mmol) were dissolved in acetonitrile (1 mL), and then N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl) uronium hexafluorophosphate (4 mg, 0.01 mmol) was added. The reaction was stirred at room temperature for 0.5 h. The reaction was concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer plate to give compound 25 (1.4 mg, yield 32%) as a white solid. 1H NMR (500 MHz, DMSO-d) δ 8.60 (d, J = 2.2 Hz, 1H), 8.12 (s, 1H), 8.04 (d, J = 7.9 Hz, 1H), 7.91 (d, J = 9.0 Hz, 1H), 7.83 (s, 1H), 7.76 (dd, J = 9.0, 2.2 Hz, 1H), 7.56 (d, J = 8.1 Hz, 1H), 6.93 (s, 1H), 4.91 - 4.86 (m, 2H), 4.75 (s, 1H), 4.01 (s, 1H), 3.99 - 3.95 (m, 1H), 3.85 - 3.80 (m, 1H), 2.62 - 2.54 (m, 2H), 2.25 - 2.19 (m, 2H), 2.04 - 1.96 (m, 2H), 1.05 (s, 6H). MS m / z 521.8 [M+H] + .

[0181] Example 24: Preparation of compound 26

[0182] Compound 21-e (3 mg, 0.008 mmol), compound 26-a (2 mg, 0.01 mmol), N,N- diisopropylethylamine (4 mg, 0.03 mmol) were dissolved in acetonitrile (1 mL), and then N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl) uronium hexafluorophosphate (4 mg, 0.01 mmol) was added. The reaction was stirred at room temperature for 0.5 h. The reaction was concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer plate separation to give compound 26 (1.8 mg, yield 38%) as a white solid. MS m / z 555.8 [M+H] + .

[0183] Example 25: Preparation of compound 27

[0184] Compound 21-e (3 mg, 0.008 mmol), compound 27-a (2 mg, 0.01 mmol), N,N- diisopropylethylamine (4 mg, 0.03 mmol) were dissolved in acetonitrile (1 mL), and then N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl) uronium hexafluorophosphate (4 mg, 0.01 mmol) was added. The reaction was stirred at room temperature for 0.5 h. The reaction was concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer plate separation to give compound 27 (1.1 mg, yield 23%) as a white solid. 1H NMR (500 MHz, DMSO-d) δ 8.61-8.56 (m, 3H), 7.91 (d, J = 9.0 Hz, 1H), 7.76 (dd, J = 9.0, 2.2 Hz, 1H), 7.56 (d, J = 8.2 Hz, 1H), 6.97 (s, 1H), 5.48-5.42 (m, 2H), 4.91 (s, 2H), 3.99-3.95 (m, 1H), 3.89-3.84 (m, 1H), 2.62-2.53 (m, 2H), 2.26-2.21 (m, 2H), 2.03-1.96 (m, 2H). MS m / z 556.9 [M+H] + .

[0185] Example 26: Preparation of compound 28

[0186] Compound 4A (20 mg, 0.04 mmol) (4A was prepared from 3d synthesis using the first batch of resolution in Example 4), compound 28-a (16 mg, 0.06 mmol) were dissolved in tetrahydrofuran (1 mL) and cooled to -70 °C under nitrogen atmosphere. LiHMDS tetrahydrofuran solution (1 M, 0.1 mL) was added dropwise. The reaction was stirred at -70 °C for 0.5 h. The reaction was quenched with saturated aqueous ammonium chloride solution and the mixture was extracted with ethyl acetate (3 x 5 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude was purified by preparative thin layer plate to give compound 28 (0.88 mg, yield 40%) as a white solid (the double bond configuration Z / E was not determined). MS m / z 507.9 [M+H] + .

[0187] Example 27: Inhibition activity of compounds on MRGPRX2 receptor

[0188] The inhibition of MRGPRX2 receptor by the compounds was determined by HTRF kit to measure IP-1 (inositol monophosphate) after adding different concentrations of test compounds using CHO cell line stably expressing MRGPRX2. The CHO cell line stably expressing MRGPRX2 was cultured in F-12 medium containing 10% fetal bovine serum and 0.2 mg / mL Hygromycin B at 37 °C with 5% carbon dioxide. The old medium was removed and washed once with PBS, and 1 mL TrypLE Express was added to the well for 5 min. The cells were collected and resuspended in F-12 medium containing 10% fetal bovine serum and 0.2 mg / mL Hygromycin B. The cells were seeded in 384-well plates at a density of 5,000 cells per well. After 24 h, the old medium was removed and 30 μL of test compound solution was added to the well. The final concentration of the test compound was 10 μM. After 1 h, 30 μL of IP-1 solution was added to the well. After 30 min, 30 μL of HTRF solution was added to the well. After 1 h, the fluorescence intensity was measured at 615 nm and 495 nm. The inhibition of MRGPRX2 receptor by the compounds was calculated according to the following formula: Inhibition (%) = (1 - (test compound - background) / (DMSO - background)) x 100 TMIncubate the cells in Express solution at 37°C for about 2 minutes. When the cells are detached from the dish bottom, add about 5 mL of 37°C pre-warmed complete medium. Gently pipette the cell suspension to dissociate the aggregated cells. Transfer the cell suspension to a sterile centrifuge tube and centrifuge at 1000 rpm for 5 minutes. Remove the supernatant and re-suspend the cells in medium. Count the cells and seed 10 μL per well (20000 cells per well) in a 384-well plate. Prepare 1x stimulation buffer according to the kit instruction; use DMSO to dilute the positive compound and the test compound in gradient. Use Echo to dispense 10 nL per well, and place the cell culture plate in a 37°C incubator for 10 minutes. Dispense 10 nL of 1 mM Cortistatin-14 stimulation solution, centrifuge and place in a 37°C incubator for 60 minutes. Dilute d2-IP1 and Anti-IP1-Cryptate to working concentration with Lysis & Detection Buffer; after incubation, add 3 μL d2-IP1 to all experimental wells; then add 3 μL Anti-IP1-Cryptate to all experimental wells, centrifuge and place at room temperature for 1 hour; after incubation, detect the fluorescence reading at 665 nm and 620 nm. Use GraphPad to perform nonlinear regression fitting to calculate the IC 50 values of each compound. The experimental results are shown in Table 1.

[0189] Table 1: Inhibition activity of compounds on MRGPRX2 receptor

[0190] All documents referred to in this disclosure are incorporated by reference herein as if each were individually incorporated by reference. In addition, it is to be understood that various alterations and modifications will become apparent to the skilled artisan after reviewing the above teachings of the present disclosure and that the same are intended to be encompassed by the present disclosure.

Claims

1. A compound of the following formula (I), or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate thereof: in formula (I): "*" represents a chiral center; A is selected from substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted 3- to 9-membered heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and said A is substituted with one or more R 9 substituted with one or more substituents; R 9 selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, C(O)R g , C(O)OR f , C(O)NR d R d , or S(O)2R g ; said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl in R 9 are optionally substituted with one or more groups selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, aryl, heteroaryl, CN, OR f , SR f , NR d R d , C(O)R g , C(O)OR f , C(O)NR d R d , NR d C(O)R g , S(O)2R g , or NR d S(O)2R g ; or said cycloalkyl and heterocyclyl in R 9 are optionally substituted with =Q; Q is selected from O or CR j R k ; R j and R k are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, aryl, heteroaryl, CN, C(O)R g , C(O)OR f , C(O)NR d R d , or S(O)2R g ; said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl in R j and R k are optionally substituted with one or more groups selected from halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, aryl, heteroaryl, CN, OR f SR f NR d R d C(O)R g C(O)OR f OC(O)R g C(O)NR d R d NR d C(O)R g NR d C(O)NR d R d OC(O)NR d R d NR d C(O)OR f OC(O)OR f S(O)2R g S(O)2NR d R d NR d S(O)2R g NR d S(O)2NR d R d ; B is selected from substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 1 selected from hydrogen, C 1-4 alkyl, or C 3-6 cycloalkyl; R 2 selected from hydrogen, C 1-4 alkyl, or C 3-6 cycloalkyl; R 3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, aryl, heteroaryl, CN, OR f , SR f , NR d R d , C(O)R g , C(O)OR f , OC(O)R g , C(O)NR d R d , NR d C(O)R g , S(O)2R g , S(O)2NR d R d , or NR d S(O)2R g ; or R 3 and R 4 together with the carbon atom to which they are attached form =M; M is selected from O or CR h R i ; R h and R i are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-4 alkyl, C 3- 6cycloalkyl, 3- to 6-membered heterocyclyl, CN, C(O)R g , or C(O)NR d R d ; or R h and R i together with the carbon atom to which they are attached form a 3- to 6-membered ring structure, which optionally contains 0 or 1 heteroatom selected from N, O, S; said alkyl in R h or R i is optionally substituted with one or more groups selected from halogen, C 1-4 alkyl, CN, OR f , SR f , NR d R d ; or R 3 and R 4 together with the carbon atom to which they are attached form a 3- to 6-membered cyclic structure, which cyclic structure optionally contains 0, or 1 heteroatom selected from N, O, S, and is optionally substituted with one or more groups selected from halo, C 1-4 alkyl; each R 5 is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, aryl, heteroaryl, CN, OR f , SR f , NR d R d , C(O)R g , C(O)OR f , OC(O)R g , C(O)NR d R d , NR d C(O)R g , S(O)2R g , S(O)2NR d R d , or NR d S(O)2R g ; or two R 5 groups are joined together to form a spiro, bridged, or fused ring structure with the 6-membered ring in Formula (I), which spiro, bridged, or fused ring structure optionally contains 0 or 1 heteroatoms selected from N, O, S; or two R 5 groups, together with the same carbon atom to which they are attached, form =M; M is as defined above. each R is independently selected from hydrogen, C d each R is independently selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, or C 3-6 cycloalkyl; each R is independently selected from hydrogen, C f each R is independently selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, or C 3-6 cycloalkyl; each R g are each independently selected from hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, aryl, heteroaryl; m is selected from 0, 1, 2, 3, or 4; wherein each of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cyclic structure, aryl and heteroaryl is optionally and independently substituted with 1-3 substituents each independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, CN, NO2, OR f , SR f , NR d R d , C(O)R g , C(O)OR f , C(O)NR d R d , NR d C(O)R g , S(O)2R g , or NR d S(O)2R g , provided that the resulting chemical structure is stable and meaningful; wherein R d , R f , R g are as defined above; Unless otherwise specified, the aryl group is an aromatic group containing 6-12 carbon atoms; the heteroaryl group is a 5- to 15-membered heteroaromatic group; and the cyclic structure is a cyclic group that is saturated or unsaturated, and that contains or does not contain a heteroatom.

2. The compound of claim 1, wherein Formula (I) is Formula (II): The definitions of the groups in formula (II) are as described in claim 1.

3. The compound of claim 1, wherein Formula (I) is Formula (III): X is selected from CR a R b , O, or N; R a and R b are each independently selected from hydrogen, halogen, or C 1-4 alkyl; p and q are each independently selected from 0, 1, 2, or 3; The definitions of the remaining groups in formula (III) are as described in claim 1.

4. The compound of any one of claims 1-2, wherein Formula (I) is Formula (IV): each R 6 is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, aryl, heteroaryl, CN, OR f , SR f , NR d R d , C(O)R g , C(O)OR f , C(O)NR d R d , NR d C(O)R g , S(O)2R g , or NR d S(O)2R g ; n is selected from 0, 1, 2, 3, 4, 5, or 6; R d , R f , R g are as defined in claim 1; A is selected from substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; The definitions of the remaining groups in formula (IV) are as described in claim 1.

5. The compound of any one of claims 1-2 and 4, wherein Formula (I) is Formula (V): A is selected from substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R h and R i are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, or CN; the alkyl in R h or R i is optionally substituted with one or more groups selected from halogen, C 1-4 alkyl, CN, OR f , SR f , NR d R d ; each R d is independently selected from hydrogen or C 1-4 alkyl; each R f is independently selected from hydrogen or C 1-4 alkyl.

6. The compound of any one of claims 1-2 and 4-5, wherein Formula (I) is Formula (VI): R 7 and R 8 are each independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, aryl, heteroaryl, CN, OR f , SR f , NR d R d , C(O)R g , C(O)OR f , C(O)NR d R d , NR d C(O)R g , S(O)2R g , or NR d S(O)2R g ; R 9 is selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, C(O)R g , C(O)OR f , C(O)NR d R d , or S(O)2R g ; said alkyl is optionally substituted with one or more groups selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, aryl, heteroaryl, CN, OR f , SR f , NR d R d , C(O)R g , C(O)OR f , C(O)NR d R d , NR d C(O)R g , S(O)2R g , or NR d S(O)2R g ; the cycloalkyl and heterocyclyl mentioned above are optionally substituted with =Q; Q is selected from O or CR j R k ; R j and R k are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, aryl, heteroaryl, CN, C(O)R g , C(O)OR f , C(O)NR d R d , or S(O)2R g ; the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl in said R j and R k are optionally substituted with one or more groups selected from halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, aryl, heteroaryl, CN, OR f , SR f , NR d R d , C(O)R g , C(O)OR f , OC(O)R g , C(O)NR d R d , NR d C(O)R g , NR d C(O)NR d R d , OC(O)NR d R d , NR d C(O)OR f , OC(O)OR f , S(O)2R g , S(O)2NR d R d , NR d S(O)2R g , or NR d S(O)2NR d R d ; R d , R f , R g , R h , and R i are as defined in claim 1.

7. The compound of any one of claims 1 and 3, wherein Formula (I) is Formula (VII): R 6 , n is as defined in claim 4; The definitions of the remaining groups in formula (VII) are as described in claim 3.

8. The compound of any one of claims 1, 3, and 7, wherein Formula (I) is Formula (VIII): The definitions of X, p, and q are as described in claim 3. R 7 , R 8 , R 9 are as defined in claim 6.

9. The compound of claim 1, wherein Formula (I) is Formula (IX): R 1 , R 2 , R 3 , R 4 , R 5 , m is as defined in claim 1 ; R 6 , n is as defined in claim 4; R 7 R 8 The definition is as described in claim 6; R j and R k are as defined in claim 6; x and y are each independently selected from 0, 1, 2, or 3.

10. The compound of any one of claims 1 and 9, wherein Formula (I) is Formula (X): R 3 , R 4 are as defined in claim 1 ; R 7 , R 8 , R j , and R k are as defined in claim 6.

11. The compound of claim 1, or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate thereof, selected from one of the following groups: "*" represents a chiral center; When two R groups are present in the above structure, one R group is selected from hydrogen, and the other R group is selected from hydrogen, deuterium, methyl, or fluorine; or one R group is selected from deuterium, and the other R group is selected from hydrogen, deuterium, methyl, or fluorine; or one R group is selected from methyl, and the other R group is selected from hydrogen, deuterium, methyl, or fluorine; or one R group is selected from fluorine, and the other R group is selected from hydrogen, deuterium, methyl, or fluorine.

12. A pharmaceutical composition, characterized by, A pharmaceutical composition for treating a disease, disorder, or condition associated with MRGPRX2 comprising a compound of any one of claims 1-11, or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate, and a pharmaceutically acceptable carrier thereof.

13. Use of a compound of any one of claims 1 to 11, or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate thereof, characterized in that, A pharmaceutical composition for treating a disease, disorder, or condition associated with MRGPRX2.

14. The use according to claim 13, characterized in that, The disease, disorder, or condition is selected from the group consisting of urticaria (chronic spontaneous urticaria, acute spontaneous urticaria, and other spontaneous urticaria, cold urticaria, solar urticaria, heat contact urticaria, vibration urticaria, and other physical urticaria, contact urticaria, aquagenic urticaria, and other non-physical urticaria), mastocytosis, atopic dermatitis, Crohn's disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, cancer pain, chronic pruritus, drug-induced pseudoallergy, metabolic syndrome, esophageal reflux, asthma, cough, migraine, chronic pruritus, acute pruritus, nodular prurigo, pseudoallergy, and allergic and painful diseases.

Images