Mrgprx2 antagonist and use thereof

Abstract

NOT VISIBLE DUE TO STATUS OF PATENT

Description

MRGPRX2 antagonists and uses

[0001] This application requires the applicant to:

[0002] Priority benefit of the prior application, patent application number 202311693381.1, filed with the State Intellectual Property Office of China on December 8, 2023, entitled “MRGPRX2 antagonists and uses thereof”;

[0003] Priority benefit of the prior application, patent application number 202410166370.6, filed with the State Intellectual Property Office of China on February 5, 2024, entitled “MRGPRX2 antagonists and uses thereof”;

[0004] Priority benefit of the prior application, patent application number 202411392820.X, filed with the State Intellectual Property Office of China on September 30, 2024, entitled “MRGPRX2 antagonists and uses thereof”;

[0005] Priority benefit of the prior application, patent application number 202411507978.7, filed with the State Intellectual Property Office of China on October 25, 2024, entitled “MRGPRX2 antagonists and uses thereof”;

[0006] Priority benefit of the prior application, patent application number 202411754629.5, filed with the State Intellectual Property Office of China on November 29, 2024, entitled “MRGPRX2 antagonists and uses thereof”;

[0007] The entire contents of said prior application are incorporated into the present application by reference. Technical Field

[0008] The present invention belongs to the field of medicine. Specifically, the present invention relates to an MRGPRX2 antagonist and its use. Background Art

[0009] Mast cells (MCs) are tissue-resident immune cells that originate from the hematopoietic lineage. MCs reside within various connective tissues and vascularized organs. They are found in greatest numbers and density at the interface between the internal and external milieu, responding to foreign organisms and antigens and acting as sentinels. These sites include the dermis, skeletal muscle, oral mucosa, gastrointestinal mucosa and submucosa, conjunctiva, alveoli and airways, and auricles. Dermal MCs are often in close proximity to blood vessels, nerves, and lymphatic vessels. Activation of MCs through the human high-affinity immunoglobulin E (IgE) receptor (FcεRI) and Mas-related G protein-coupled receptor X2 (MRGPRX2) leads to degranulation, the release of various bioactive substances (such as histamine and proteases), and the de novo synthesis of prostaglandins, leukotrienes, and several cytokines, playing a central role in host defense, inflammation, and allergic responses.

[0010] Mas-related G protein-coupled receptors (MRGPRs) are divided into nine subfamilies based on the receptor members: MRGPRA, B, C, D, E, F, G, H, and the primate-specific MRGPRX. Each subfamily includes different subtypes, such as MRGPRX1, MRGPRX2, MRGPRX3, and MRGPRX4. Transcriptome analysis shows that most MRGPR family members are expressed in peripheral neurons, but MRGPRX2 is primarily expressed in skin MCs, with an expression rate even higher than that of Fcε-RI. MRGPRX2 can sense a variety of endogenous or exogenous agonists, including polycationic compounds and peptides, to trigger mast cell degranulation.

[0011] Studies have shown that inappropriate activation of MRGPRX2 may lead to mast cell-related diseases such as drug pseudoallergy, rosacea, atopic dermatitis, allergic contact dermatitis, urticaria, pruritus, mastocytosis, interstitial cystitis, pain, rheumatoid arthritis, asthma, and ulcerative colitis. Currently, the IND application for the MRGPRX2 antagonist EP262 has been approved by the FDA for the treatment of mast cell-related diseases (such as chronic urticaria). Preclinical studies have shown that EP262 can effectively inhibit mast cell activation and degranulation induced by multiple MRGPRX2 agonists and block the release of trypsin and inflammatory factors in human mast cells. Oral administration of EP262 can effectively inhibit agonist-induced mast cell degranulation and increased vascular permeability in MRGPRX2-KI mice, showing significant potential for the treatment of mast cell-related diseases. All of this indicates that the development of new MRGPRX2 antagonists for the treatment of various mast cell-related diseases is a promising direction.

[0012] Currently, there are no drugs on the market that act as MRGPRX2 antagonists. Therefore, the development of new compounds that can antagonize MRGPRX2 activity has positive significance for the treatment of diseases. Summary of the Invention

[0013] The purpose of the present invention is to provide a novel compound for use as an MRGPRX2 antagonist.

[0014] In a first aspect of the present invention, there is provided a compound of formula IA, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof:

[0015] in,

[0016] X 1 、X 2 、X 3 、X 4 、X 5 and X 6 Each independently represents a ring atom;

[0017] X 1 、X 2 、X 3 、X 5 and X 6 are each independently N, CH2, CH or C;

[0018] X 4 is C;

[0019] X 1 With X 2 Between, X 5 With X 6 The bond between them is a single bond or a double bond;

[0020] X 5 and X 6 The linked group fragment In the example, A does not exist, X 5 and X 6 Each is independently R 4 or R 5 or when A exists, A and X 5 、X 6 The ring atoms together form a 6-10 membered aryl, a 3-11 membered heterocycloalkyl or a 5-10 membered heteroaryl; and the A is further R c Replaced by; said R c Substitution is one or more substitutions, when the substituent R c When there are multiple substituents, the substituents are the same or different; the heteroatoms in the heterocycloalkyl and heteroaryl groups are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3;

[0021] And when A and X 5 、X 6When the ring atoms together form a 6-membered aromatic group, R a For oxygen;

[0022] Or, when A and X 5 、X 6 The ring atoms together form a 5-membered heteroaryl group and R c When it is not H, R 1 C 1-6 Haloalkyl; the heteroatom in the heteroaryl group is selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3;

[0023] Ring B is C 3-12 Cycloalkyl;

[0024] Ring C is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; the heteroatom in the heteroaryl group is selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3;

[0025] R a 、R c 、R 1 、R 2 、R 3 、R 4 and R 5 are independently H, halogen, cyano, amino, oxo, C 1-6 Alkyl, C substituted by hydroxy 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl, halogenated C 3-8 Cycloalkyl, -OR f 、-C(O)OR f 、-OC(O)R f 、-N(R f )2、-N(R f )C(O)R f 、-N(R f )S(O)2R f or -S(O)2R f ; the R f Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylamino, -(CH2)rR g , 6-10 membered aromatic group, C 3-8 Cycloalkyl, 5-10 membered heteroaryl or 5-10 membered heterocycloalkyl, or two R f The group and the atoms to which it is attached together form a 5- to 11-membered heterocycloalkyl group; the R gH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl or 5-10 membered heterocycloalkyl; the heteroatoms in the heterocycloalkyl and heteroaryl groups are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0026] R b H, halogen, hydroxy, amino, cyano, carbonyl, oxo, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or 3-10 membered heterocycloalkyl, -(CHR j ) 0-3 -S(=O)(=NR j )-R k 、-(CHR j ) 1-3 -S(O)2-R k 、-(CHR j ) 1-3 -OC(O)-N(R k )2、-(CHR j ) 0-3 -(N=)S(=O)(R k )2、-(CHR j ) 0-3 -P(=O)(R k )2; said C 1-6 Alkyl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 The haloalkoxy group is optionally substituted with one or more R d Substituted; said R d A substituent selected from the group consisting of halogen, hydroxy, amino, nitro, cyano, carbonyl, oxo, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy; when the substituent R d When there are multiple R d the same or different; the heteroatoms in the heterocycloalkyl group are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3;

[0027] R j and R k are independently H, cyano, amino, C 1-6 Alkyl, C 1-6 Alkylamino, -(CH2) 0-3 C 3-8 Cycloalkyl, -COC 1-6 Alkyl, C 1-6 Haloalkyl, C substituted by hydroxy 1-6 Alkyl, a single 5- to 10-membered heterocycloalkyl; the heteroatom in the heterocycloalkyl is selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3;

[0028] m, n, and r are 0, 1, 2, or 3 respectively.

[0029] According to an embodiment of the present invention, the R b H, F, Cl, -CN, methyl, amino, methoxy, oxo, -CH2CF3, -CF3, -CHF2, -CH2CHF2, -CH2-SO2-CH3, -CH(CH3)SO2CH3, -CH2S(=O)(=NCH3)-CH3,

[0030] According to an embodiment of the present invention, the R a 、R c 、R 1 、R 2 、R 3 Each independently represents H, F, Cl, methyl, ethyl, amino, oxo, -CHF2, -CH2CF3, -CF3,

[0031] According to an embodiment of the present invention, the X 5 and X 6 The linked group fragment In the example, A does not exist, X 5 and X 6 Each is independently R 4 or R 5If replaced by Selected from In some embodiments, the R 4 、R 5 Each is independently H, F, Cl, methyl, -CF3, or -CHF2.

[0032] In some embodiments, the X 5 and X 6 The linked group fragment In the example, A does not exist, X 5 and X 6 Each is independently R 4 or R 5 If replaced by Selected from

[0033] According to an embodiment of the present invention, the X 5 and X 6 The linked group fragment In the case of A, A and X 5 、X 6 The ring atoms together form And the A is further R c replaced.

[0034] In some embodiments, when A is present, the structural fragment Selected from

[0035] In some embodiments, when A is present, the structural fragment Selected from

[0036] In some embodiments, the structural fragment Selected from the following structures:

[0037] According to an embodiment of the present invention, the ring C is a 6-8 membered aryl group or a 5-10 membered heteroaryl group; the heteroatoms in the heteroaryl group are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3.

[0038] According to an embodiment of the present invention, the ring C is a 5- to 6-membered nitrogen-containing heteroaryl group, and the number of the nitrogen atoms is 1, 2 or 3.

[0039] According to an embodiment of the present invention, the ring C is phenyl, pyrazolyl or pyridyl.

[0040] According to an embodiment of the present invention, the ring B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

[0041] According to an embodiment of the present invention, the structural fragment Selected from

[0042] In some embodiments, the structural fragment Selected from

[0043] In some embodiments, the formula IA can be selected from the following IA-1:

[0044] Among them, A, ring B, ring C, X 2 、X 3 、X 4 、X 5 、X 6 、R 1 、R 2 、R 3 、R b , m and n are as defined in Formula IA.

[0045] In a second aspect of the present invention, there is provided a compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof:

[0046] According to an embodiment of the present invention, the first aspect of the formula IA is selected from formula I, and the groups in the formula I have the definitions as described in formula IA;

[0047] According to an embodiment of the present invention,

[0048] In the formula I,

[0049] X 1 、X 2 、X 3 、X 4 、X 5 and X 6 Each independently represents a ring atom;

[0050] X 1 、X 2 、X 3 、X 5 and X 6 are each independently N, CH2, CH or C;

[0051] X 4 is C;

[0052] X 1 With X 2 Between, X 5 With X 6 The bond between them is a single bond or a double bond;

[0053] X 5 and X 6 The linked group fragment In the example, A does not exist, X 5 and X 6 Each is independently R 4 or R 5 or when A exists, A and X 5 、X 6 The ring atoms together form a 6-10 membered aryl, a 3-11 membered heterocycloalkyl or a 5-10 membered heteroaryl; the heteroatoms are independently selected from one or more of N, O and S; and the A is further replaced by R c Replaced by; said R c Substitution is one or more substitutions, when the substituent R c When there are multiple substituents, the substituents are the same or different; the heteroatoms in the heterocycloalkyl and heteroaryl groups are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3;

[0054] And when A and X 5 、X 6 When the ring atoms together form a 6-membered aromatic group, R a For oxygen;

[0055] Or, when A and X 5 、X 6 The ring atoms together form a 5-membered heteroaryl group and R c When it is not H, R 1 C 1-6 Haloalkyl; the heteroatom in the heteroaryl group is selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3;

[0056] Ring B is C 3-12 Cycloalkyl;

[0057] Ring C is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; the heteroatom in the heteroaryl group is selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3;

[0058] R a 、R c 、R 1 、R 2 、R 3、R 4 and R 5 are independently H, halogen, cyano, amino, oxo, C 1-6 Alkyl, C substituted by hydroxy 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl, halogenated C 3-8 Cycloalkyl, -OR f 、-C(O)OR f 、-OC(O)R f 、-N(R f )2、-N(R f )C(O)R f 、-N(R f )S(O)2R f or -S(O)2R f ; the R f Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylamino, -(CH2)rR g , 6-10 membered aromatic group, C 3-8 Cycloalkyl, 5-10 membered heteroaryl or 5-10 membered heterocycloalkyl, or two R f The group and the atoms to which it is attached together form a 5- to 11-membered heterocycloalkyl group; the R g H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl or 5-10 membered heterocycloalkyl; the heteroatoms in the heterocycloalkyl and heteroaryl groups are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0059] R b H, halogen, hydroxy, amino, cyano, carbonyl, oxo, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or 3-10 membered heterocycloalkyl; the C 1-6 Alkyl, C 3-8Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 The haloalkoxy group is optionally substituted with one or more R d Substituted; said R d A substituent selected from the group consisting of halogen, hydroxy, amino, nitro, cyano, carbonyl, oxo, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy; when the substituent R d When there are multiple R d the same or different; the heteroatoms in the heterocycloalkyl group are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3;

[0060] m, n, and r are 0, 1, 2, or 3 respectively.

[0061] In the present invention, the definitions of certain substituents in the compounds of Formula IA or Formula I may be as described below, and the definitions of substituents not mentioned are as described in any of the above schemes.

[0062] In a preferred embodiment of the present invention, the compound represented by Formula IA or Formula I is selected from the following structures:

[0063] Among them, X 5 and X 6 The linked group fragment wherein A is as defined in the first aspect of the present invention; ring C is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; the heteroatom in the heteroaryl group is selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; and X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、R 1 、R 2 、R 3 、R a 、R b , m and n are as defined in the first aspect of the present invention.

[0064] In a preferred embodiment of the present invention, the compound shown in Formula IA is selected from the following structures: Among them, X 5 and X 6 The linked group fragment wherein A is as defined in the first aspect of the present invention; ring C is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; the heteroatom in the heteroaryl group is selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; and X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、R 1 、R 2 、R 3 、R a 、R b , m and n are as defined in the first aspect of the present invention.

[0065] In a preferred embodiment of the present invention, the compound shown in Formula I is selected from the following structures: Among them, X 5 and X 6 The linked group fragment wherein A is as defined in the first aspect of the present invention; ring C is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; the heteroatom in the heteroaryl group is selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; and X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、R 1 、R 2 、R 3 、R a 、R b , m and n are as defined in the first aspect of the present invention.

[0066] In a preferred embodiment of the present invention, the compound shown in Formula IA is selected from the following structures:

[0067] Among them, A and X 5 、X 6 The ring atoms together form a 6-8 membered aryl, a 3-8 membered heterocycloalkyl, a 5-membered heteroaryl or a 6-membered heteroaryl; the heteroatoms are independently selected from one or more of N, O and S; the A is further replaced by R c Replaced by; said Rc Substitution is one or more substitutions, when the substituent R c When there are multiple substituents, the substituents are the same or different; and when A and X 5 、X 6 When the ring atoms together form a 6-membered aromatic group, R a is oxo; or, when A and X 5 、X 6 The ring atoms together form a 5-membered heteroaryl group and R c When it is not H, R 1 C 1-6 haloalkyl; the heteroatoms in the heterocycloalkyl and heteroaryl groups are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; ring C is a 6-10 membered aryl group or a 5-8 membered heteroaryl group; the heteroatoms in the heteroaryl group are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; R b H, halogen, hydroxy, amino, cyano, carbonyl, oxo, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or 3-8 membered heterocycloalkyl, -(CHR j ) 0-3 -S(=O)(=NR j )-R k 、-(CHR j ) 1-3 -S(O)2-R k 、-(CHR j ) 1-3 -OC(O)-N(R k )2、-(CHR j ) 0-3 -(N=)S(=O)(R k )2、-(CHR j ) 0-3 -P(=O)(R k )2; said C 1-6 Alkyl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Alkyl hydroxyl, C 1-6Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 The haloalkoxy group is optionally substituted with one or more R d Substituted; said R d A substituent selected from the group consisting of halogen, hydroxy, amino, nitro, cyano, carbonyl, oxo, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 The heteroatoms in the heterocycloalkyl group are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; R j and R k are independently H, cyano, amino, C 1-6 Alkyl, C 1-6 Alkylamino, -(CH2) 0-3 C 3-8 Cycloalkyl, -COC 1-6 Alkyl, C 1-6 Haloalkyl, C substituted by hydroxy 1-6 Alkyl, single 5- to 10-membered heterocycloalkyl; R a 、R c 、R 1 、R 2 、R 3 are independently H, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl, halogenated C 3-8 Cycloalkyl; X 1 、X 2 、X 3 、X 4 、X 5 、X 6 , m and n are as defined in the first aspect of the present invention. In a preferred embodiment of the present invention, the R b H, F, Cl, -CN, methyl, amino, oxo, -CH2CF3, -CF3, -CHF2, -CH2CHF2, -CH2-SO2-CH3, -CH(CH3)SO2CH3, -CH2S(=O)(=NCH3)-CH3, In a preferred embodiment of the present invention, the R a 、R c 、R 1 、R2 、R 3 Each independently represents H, F, Cl, methyl, amino, oxo, -CHF2, -CH2CF3, -CF3,

[0068] In a preferred embodiment of the present invention, the compound shown in Formula IA is selected from the following structures:

[0069] Among them, A and X 5 、X 6 The ring atoms together form a 6-8 membered aryl, a 3-8 membered heterocycloalkyl, a 5-membered heteroaryl or a 6-membered heteroaryl; the heteroatoms are independently selected from one or more of N, O and S; the A is further replaced by R c Replaced by; said R c Substitution is one or more substitutions, when the substituent R c When there are multiple substituents, the substituents are the same or different; and when A and X 5 、X 6 When the ring atoms together form a 6-membered aromatic group, R a is oxo; or, when A and X 5 、X 6 The ring atoms together form a 5-membered heteroaryl group and R c When it is not H, R 1 C 1- 6 haloalkyl; the heteroatoms in the heterocycloalkyl and heteroaryl groups are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; Ring C is a 6-10 membered aryl group or a 5-8 membered heteroaryl group; the heteroatoms in the heteroaryl group are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; R b H, halogen, hydroxy, amino, cyano, carbonyl, oxo, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or 3-8 membered heterocycloalkyl, -(CHR j ) 0-3 -S(=O)(=NR j )-R k 、-(CHR j ) 1-3 -S(O)2-R k 、-(CHR j) 1-3 -OC(O)-N(R k )2、-(CHR j ) 0-3 -(N=)S(=O)(R k )2、-(CHR j ) 0-3 -P(=O)(R k )2; said C 1-6 Alkyl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 The haloalkoxy group is optionally substituted with one or more R d Substituted; said R d A substituent selected from the group consisting of halogen, hydroxy, amino, nitro, cyano, carbonyl, oxo, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 The heteroatoms in the heterocycloalkyl group are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; R j and R k are independently H, cyano, amino, C 1-6 Alkyl, C 1-6 Alkylamino, -(CH2) 0-3 C 3-8 Cycloalkyl, -COC 1-6 Alkyl, C 1-6 Haloalkyl, C substituted by hydroxy 1-6 Alkyl, single 5- to 10-membered heterocycloalkyl; R a 、R c 、R 1 、R 2 、R 3 are independently H, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl, halogenated C 3-8 Cycloalkyl; X 1、X 2 、X 3 、X 4 、X 5 、X 6 , m and n are as defined in the first aspect of the present invention. In a preferred embodiment of the present invention, the R b H, F, Cl, -CN, methyl, methoxy, amino, oxo, -CH2CF3, -CF3, -CHF2, -CH2CHF2, -CH2-SO2-CH3, -CH(CH3)SO2CH3, -CH2S(=O)(=NCH3)-CH3, In a preferred embodiment of the present invention, the R a 、R c 、R 1 、R 2 、R 3 Each independently represents H, F, Cl, methyl, ethyl, amino, oxo, -CHF2, -CH2CF3, -CF3,

[0070] In a preferred embodiment of the present invention, the compound shown in Formula I is selected from the following structures:

[0071] Among them, A and X 5 、X 6 The ring atoms together form a 6-8 membered aryl, a 3-8 membered heterocycloalkyl, a 5-membered heteroaryl or a 6-membered heteroaryl; the heteroatoms are independently selected from one or more of N, O and S; the A is further replaced by R c Replaced by; said R c Substitution is one or more substitutions, when the substituent R c When there are multiple substituents, the substituents are the same or different; and when A and X 5 、X 6 When the ring atoms together form a 6-membered aromatic group, R a is oxo; or, when A and X 5 、X 6 The ring atoms together form a 5-membered heteroaryl group and R c When it is not H, R 1 C 1-6 haloalkyl; the heteroatoms in the heterocycloalkyl and heteroaryl groups are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; ring C is a 6-10 membered aryl group or a 5-8 membered heteroaryl group; the heteroatoms in the heteroaryl group are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; R b H, halogen, hydroxy, amino, cyano, carbonyl, oxo, C 1-6 Alkyl, C3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 a haloalkoxy group or a 3- to 8-membered heterocycloalkyl group; the heteroatoms in the heterocycloalkyl group are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; R a 、R c 、R 1 、R 2 、R 3 are independently H, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl, halogenated C 3-8 Cycloalkyl; X 1 、X 2 、X 3 、X 4 、X 5 、X 6 , m and n are as defined in the first aspect of the present invention. In a preferred embodiment of the present invention, the R b is H, F, Cl, methyl, amino, oxo, -CH2CF3, -CF3. In a preferred embodiment of the present invention, the R a 、R c 、R 1 、R 2 、R 3 Each independently represents H, F, Cl, methyl, amino, oxo, -CH2CF3, -CF3,

[0072] In a preferred embodiment of the present invention, the compound shown in Formula IA is selected from the following structures:

[0073] Among them, A and X 5 、X 6 The ring atoms together form a 6-8 membered aryl, a 3-8 membered heterocycloalkyl, a 5-membered heteroaryl or a 6-membered heteroaryl; the heteroatoms are independently selected from one or more of N, O and S; the A is further replaced by R c Replaced by; said R c Substitution is one or more substitutions, when the substituent R c When there are multiple substituents, the substituents are the same or different; and when A and X5 、X 6 When the ring atoms together form a 6-membered aromatic group, R a is oxo; or, when A and X 5 、X 6 The ring atoms together form a 5-membered heteroaryl group and R c When it is not H, R 1 C 1-6 haloalkyl; the heteroatoms in the heterocycloalkyl and heteroaryl groups are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; ring C is a 6-10 membered aryl group or a 5-8 membered heteroaryl group; the heteroatoms in the heteroaryl group are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; R b H, halogen, hydroxy, amino, cyano, carbonyl, oxo, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1- 6-halogenated alkoxy or 3-8 membered heterocycloalkyl, -(CHR j ) 0-3 -S(=O)(=NR j )-R k 、-(CHR j ) 1-3 -S(O)2-R k 、-(CHR j ) 1-3 -OC(O)-N(R k )2、-(CHR j ) 0-3 -(N=)S(=O)(R k )2、-(CHR j ) 0-3 -P(=O)(R k )2; said C 1-6 Alkyl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 The haloalkoxy group is optionally substituted with one or more R dSubstituted; said R d A substituent selected from the group consisting of halogen, hydroxy, amino, nitro, cyano, carbonyl, oxo, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 The heteroatoms in the heterocycloalkyl group are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; R j and R k are independently H, cyano, amino, C 1-6 Alkyl, C 1-6 Alkylamino, -(CH2) 0-3 C 3-8 Cycloalkyl, -COC 1-6 Alkyl, C 1-6 Haloalkyl, C substituted by hydroxy 1-6 Alkyl, single 5- to 10-membered heterocycloalkyl; R a 、R c 、R 1 、R 2 、R 3 are independently H, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl, halogenated C 3-8 Cycloalkyl; X 1 、X 2 、X 3 、X 4 、X 5 、X 6 , m and n are as defined in the first aspect of the present invention. In a preferred embodiment of the present invention, the R b H, F, Cl, -CN, methyl, methoxy, amino, oxo, -CH2CF3, -CF3, -CHF2, -CH2CHF2, -CH2-SO2-CH3, -CH(CH3)SO2CH3, -CH2S(=O)(=NCH3)-CH3, In a preferred embodiment of the present invention, the R a 、R c 、R 1 、R 2 、R 3Each independently represents H, F, Cl, methyl, ethyl, amino, oxo, -CHF2, -CH2CF3, -CF3,

[0074] In a preferred embodiment of the present invention, the compound shown in Formula IA is selected from the following structures:

[0075] Among them, A and X 5 、X 6 The ring atoms together form a 6-8 membered aryl, a 3-8 membered heterocycloalkyl, a 5-membered heteroaryl or a 6-membered heteroaryl; the heteroatoms are independently selected from one or more of N, O and S; the A is further replaced by R c Replaced by; said R c Substitution is one or more substitutions, when the substituent R c When there are multiple substituents, the substituents are the same or different; and when A and X 5 、X 6 When the ring atoms together form a 6-membered aromatic group, R a is oxo; or, when A and X 5 、X 6 The ring atoms together form a 5-membered heteroaryl group and R c When it is not H, R 1 C 1-6 haloalkyl; the heteroatoms in the heterocycloalkyl and heteroaryl groups are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; ring C is a 6-10 membered aryl group or a 5-8 membered heteroaryl group; the heteroatoms in the heteroaryl group are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; R b H, halogen, hydroxy, amino, cyano, carbonyl, oxo, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or 3-8 membered heterocycloalkyl, -(CHR j ) 0-3 -S(=O)(=NR j )-R k 、-(CHR j ) 1-3 -S(O)2-R k 、-(CHR j ) 1-3 -OC(O)-N(Rk )2、-(CHR j ) 0-3 -(N=)S(=O)(R k )2、-(CHR j ) 0-3 -P(=O)(R k )2; said C 1-6 Alkyl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 The haloalkoxy group is optionally substituted with one or more R d Substituted; said R d A substituent selected from the group consisting of halogen, hydroxy, amino, nitro, cyano, carbonyl, oxo, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 The heteroatoms in the heterocycloalkyl group are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; R j and R k are independently H, cyano, amino, C 1-6 Alkyl, C 1-6 Alkylamino, -(CH2) 0-3 C 3-8 Cycloalkyl, -COC 1-6 Alkyl, C 1-6 Haloalkyl, C substituted by hydroxy 1-6 Alkyl, single 5- to 10-membered heterocycloalkyl; R a 、R c 、R 1 、R 2 、R 3 are independently H, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl, halogenated C 3-8 Cycloalkyl; X 1 、X 2 、X3 、X 4 、X 5 、X 6 , m and n are as defined in the first aspect of the present invention. In a preferred embodiment of the present invention, the R b H, F, Cl, -CN, methyl, methoxy, amino, oxo, -CH2CF3, -CF3, -CHF2, -CH2CHF2, -CH2-SO2-CH3, -CH(CH3)SO2CH3, -CH2S(=O)(=NCH3)-CH3, In a preferred embodiment of the present invention, the R a 、R c 、R 1 、R 2 、R 3 Each independently represents H, F, Cl, methyl, ethyl, amino, oxo, -CHF2, -CH2CF3, -CF3,

[0076] In a preferred embodiment of the present invention, the compound shown in Formula IA is selected from the following structures:

[0077] Among them, A and X 5 、X 6 The ring atoms together form a 6-8 membered aryl, a 3-8 membered heterocycloalkyl, a 5-membered heteroaryl or a 6-membered heteroaryl; the heteroatoms are independently selected from one or more of N, O and S; the A is further replaced by R c Replaced by; said R c Substitution is one or more substitutions, when the substituent R c When there are multiple substituents, the substituents are the same or different; and when A and X 5 、X 6 When the ring atoms together form a 6-membered aromatic group, R a is oxo; or, when A and X 5 、X 6 The ring atoms together form a 5-membered heteroaryl group and R c When it is not H, R 1 C 1-6 haloalkyl; the heteroatoms in the heterocycloalkyl and heteroaryl groups are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; ring C is a 6-10 membered aryl group or a 5-8 membered heteroaryl group; the heteroatoms in the heteroaryl group are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; R b H, halogen, hydroxy, amino, cyano, carbonyl, oxo, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or 3-8 membered heterocycloalkyl, -(CHR j ) 0-3 -S(=O)(=NR j )-R k 、-(CHR j ) 1-3 -S(O)2-R k 、-(CHR j ) 1-3 -OC(O)-N(R k )2、-(CHR j ) 0-3 -(N=)S(=O)(R k )2、-(CHR j ) 0-3 -P(=O)(R k )2; said C 1-6 Alkyl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 The haloalkoxy group is optionally substituted with one or more R d Substituted; said R d A substituent selected from the group consisting of halogen, hydroxy, amino, nitro, cyano, carbonyl, oxo, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 The heteroatoms in the heterocycloalkyl group are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; R j and R k are independently H, cyano, amino, C 1-6 Alkyl, C 1-6 Alkylamino, -(CH2) 0-3 C 3-8Cycloalkyl, -COC 1-6 Alkyl, C 1-6 Haloalkyl, C substituted by hydroxy 1-6 Alkyl, single 5- to 10-membered heterocycloalkyl; R a 、R c 、R 1 、R 2 、R 3 are independently H, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl, halogenated C 3-8 Cycloalkyl; X 1 、X 2 、X 3 、X 4 、X 5 、X 6 , m and n are as defined in the first aspect of the present invention. In a preferred embodiment of the present invention, the R b H, F, Cl, -CN, methyl, methoxy, amino, oxo, -CH2CF3, -CF3, -CHF2, -CH2CHF2, -CH2-SO2-CH3, -CH(CH3)SO2CH3, -CH2S(=O)(=NCH3)-CH3, In a preferred embodiment of the present invention, the R a 、R c 、R 1 、R 2 、R 3 Each independently represents H, F, Cl, methyl, ethyl, amino, oxo, -CHF2, -CH2CF3, -CF3,

[0078] In some embodiments of the present invention, the compound represented by formula I is selected from the following structures:

[0079] Among them, ring C, X 3 、R 1 、R 4 、R 5 、R b and n are defined as above.

[0080] In a preferred embodiment of the present invention, the compound shown in Formula I is selected from the following structures:

[0081] Wherein, ring C is a 6-10 membered aryl group or a 5-8 membered heteroaryl group; the heteroatom in the heteroaryl group is selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; R b H, halogen, hydroxy, amino, cyano, carbonyl, oxo, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 a haloalkoxy group or a 3- to 8-membered heterocycloalkyl group; the heteroatoms in the heterocycloalkyl group are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; R a 、R 1 、R 2 、R 3 、R 4 、R 5 are independently H, halogen, cyano, amino, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl, halogenated C 3-8 Cycloalkyl; X 1 、X 2 、X 3 、X 4 、X 5 、X 6 , m and n are as defined in the first aspect of the present invention. In a preferred embodiment of the present invention, the R b is H, F, Cl, methyl, amino, oxo, -CH2CF3, -CF3. In a preferred embodiment of the present invention, the R a 、R 1 、R 2 、R 3 、R 4 、R 5 Each independently represents H, F, Cl, methyl, amino, oxo, -CH2CF3, -CF3,

[0082] In a preferred embodiment of the present invention, ring C is a 6- to 8-membered aryl group or a 5- to 10-membered heteroaryl group. The heteroatoms in the heteroaryl group are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3.

[0083] In a preferred embodiment of the present invention, ring C is a 5- to 6-membered nitrogen-containing heteroaryl group, and the number of the nitrogen atoms is 1, 2 or 3.

[0084] In a preferred embodiment of the present invention, ring C is phenyl, pyrazolyl or pyridinyl.

[0085] In a preferred embodiment of the present invention, the compound represented by formula IA is selected from any one of the following compounds:

[0086] In a preferred embodiment of the present invention, the pharmaceutically acceptable salt of the compound of Formula IA is trifluoroacetate.

[0087] In a preferred embodiment of the present invention, the compound represented by formula IA is selected from any one of the following compounds:

[0088] In a preferred embodiment of the present invention, the pharmaceutically acceptable salt of the compound of Formula IA or Formula I is trifluoroacetate.

[0089] In a third aspect, the present invention provides a pharmaceutical composition comprising: a compound of Formula IA or Formula I as described in the first or second aspect of the present invention, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs; and a pharmaceutically acceptable carrier.

[0090] In the fourth aspect, the present invention provides the use of the compound represented by Formula IA or Formula I as described in the first or second aspect of the present invention, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the use of the pharmaceutical composition described in the third aspect of the present invention, the uses including: antagonizing MRGPRX2; and / or, preventing and / or treating MRGPRX2-related diseases; and / or, preparing drugs, pharmaceutical compositions or preparations for antagonizing MRGPRX2, and / or preventing and / or treating MRGPRX2-related diseases.

[0091] Preferably, the MRGPRX2-related diseases include mast cell-related diseases.

[0092] Preferably, the MRGPRX2-related diseases include: skin diseases, autoimmune diseases, and nervous system diseases.

[0093] Preferably, the skin disease is selected from atopic dermatitis, contact dermatitis, urticaria, and pruritus.

[0094] Preferably, the urticaria is selected from chronic spontaneous urticaria and induced urticaria.

[0095] Preferably, the autoimmune disease is selected from the group consisting of allergy, mastocytosis, rheumatoid arthritis, asthma, ulcerative colitis and interstitial cystitis.

[0096] Preferably, the neurological disease is selected from pain.

[0097] In the fifth aspect of the present invention, a method for antagonizing MRGPRX2, or preventing and / or treating MRGPRX2-related diseases is provided, comprising the steps of administering to a subject in need thereof a compound of formula IA or formula I, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, according to the first or second aspect of the present invention.

[0098] Additional aspects and advantages of the present invention will be set forth in part in the description which follows and, in part, will be obvious from the description which follows, or may be learned by practice of the present invention.

[0099] Terms and Definitions

[0100] Unless otherwise specified, the terms and definitions used in this application, including the description and claims, are as follows. It will be understood by those skilled in the art that, according to the conventions used in the art, in the structural formula of this application, Used to depict chemical bonds, which are the points where a moiety or substituent is attached to a core or backbone structure.

[0101] Unless otherwise specified, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0102] Unless otherwise specified, the term "pharmaceutically acceptable salts" refers to salts of pharmaceutically acceptable non-toxic acids or bases including salts of inorganic acids and bases, and organic acids and bases.

[0103] Unless otherwise specified, the term "pharmaceutical composition" means a mixture of one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compound to an organism.

[0104] Unless otherwise specified, the term "prodrug" refers to a compound of the present invention that can be converted to a biologically active compound under physiological conditions or by solvolysis. Prodrugs of the present invention are prepared by modifying functional groups within the compound. These modifications can be removed by conventional procedures or in vivo to yield the parent compound. Prodrugs include compounds in which a hydroxyl or amino group within a compound of the present invention is attached to any group. When a prodrug of a compound of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free hydroxyl group or free amino group, respectively.

[0105] Unless otherwise specified, the term "stereoisomer" refers to isomers resulting from different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers, diastereomers, and conformational isomers.

[0106] Depending on the choice of raw materials and methods, the compounds of the present invention may exist in the form of one of the possible isomers or a mixture thereof, for example as pure optical isomers, or as a mixture of isomers, such as a racemic and diastereomeric mixture, depending on the number of asymmetric carbon atoms. When describing an optically active compound, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to the chiral center (or multiple chiral centers) in the molecule. The prefixes D and L or (+) and (–) are the symbols used to specify the rotation of plane polarized light caused by the compound, where (–) or L indicates that the compound is left-handed. Compounds prefixed with (+) or D are right-handed. With respect to a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be referred to as enantiomers, and mixtures of the isomers are often referred to as mixtures of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. Many geometric isomers of alkenes, C=N double bonds, etc. can also exist in the compounds described herein, and all such stable isomers are contemplated by the present invention. When the compounds described herein contain olefinic double bonds, unless otherwise specified, such double bonds include both E and Z geometric isomers. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be in either the cis- or trans- configuration.

[0107] When bonds to chiral carbon atoms in formulae of the present invention are depicted as straight lines, it is understood that both the (R) and (S) configurations of the chiral carbon atoms and the enantiomerically pure compounds and mixtures thereof are encompassed within the scope of the formulae. The diagrammatic representations of racemates and enantiomerically pure compounds herein are adapted from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, wedge-shaped bonds and dashed bonds are used to represent the absolute configuration of a stereocenter.

[0108] Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques. Compounds of the invention containing asymmetrically substituted carbon atoms can be separated in optically active form or racemic form. Resolution of a racemic mixture of a compound can be carried out by any of a number of methods known in the art. An exemplary method includes fractional recrystallization using a chiral resolving acid that is an optically active, salified organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or various optically active camphorsulfonic acids such as the D and L forms of β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include α-methyl-benzylamine (e.g., S and R forms or diastereoisomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc. The resolution of the racemic mixture can also be carried out by eluting on a chromatographic column filled with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). High performance liquid chromatography (HPLC) can also be used to carry out supercritical fluid chromatography (SFC). The selection of specific methods and elution conditions, chromatographic column selection can be selected by those skilled in the art according to the structure of the compound and test results. Further, optically pure starting materials or reagents of known configuration can also be used to obtain any enantiomer or diastereomer of the compound described in the present invention through stereoorganic synthesis.

[0109] Unless otherwise specified, the term "tautomer" refers to functional group isomers resulting from the rapid shift of an atom in a molecule between two positions. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds may exist as two or more interconvertible species. Prototropic tautomers arise from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer usually produce a mixture whose physical and chemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.

[0110] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed key Indicates the relative configuration of a stereocenter.

[0111] Unless otherwise indicated, the term "solvate" means that the compound of the present invention or its salt includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. When the solvent is water, it is a hydrate.

[0112] With respect to a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a non-toxic amount of the drug or agent sufficient to achieve the intended effect. For the oral dosage forms of the present invention, an "effective amount" of an active substance in the composition means the amount required to achieve the intended effect when used in combination with another active substance in the composition. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, as well as the specific active substance. The appropriate effective amount in each individual case can be determined by those skilled in the art through routine experimentation.

[0113] Unless otherwise specified, the terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.

[0114] Unless otherwise specified, the term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, including deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is a keto group (i.e., =0), it means that two hydrogen atoms are replaced. Keto substitution does not occur on aromatic groups.

[0115] In this application, "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes both instances where the event or circumstance occurs and instances where it does not occur. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both substituted aryl groups and unsubstituted aryl groups.

[0116] Unless otherwise specified, the term “C 1-6 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms. 1-6 Alkyl groups include C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 , C6 and C5 alkyl, etc.; which can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-6 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, and the like.

[0117] Unless otherwise specified, the term “C 1-3 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. 1-3 Alkyl groups include C 1-2 and C 2-3 Alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.

[0118] The term "halo" by itself or as part of another substituent is used interchangeably with the term "halogen-substituted."

[0119] Unless otherwise specified, "haloalkyl" or "halo-substituted alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with one or more halogens.

[0120] Unless otherwise specified, “C 2-6 "Alkenyl" is used to refer to a linear or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon double bond, which may be located at any position of the group. 2-6 Alkenyl groups include C 2-4 、C 2-3 , C4, C3 and C2 alkenyl, etc.; which may be monovalent, divalent or polyvalent. 2-6 Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, piperyl, hexadienyl, and the like.

[0121] Unless otherwise specified, “C 2-6 "Alkynyl" is used to represent a linear or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon triple bond, which may be located at any position of the group. 2-6 Alkynyl groups include C 2-4 、C 2-3 , C4, C3 and C2 alkynyl, etc. It can be monovalent, divalent or polyvalent. 2-6 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and the like.

[0122] Unless otherwise specified, the term “C 1-6 "Alkoxy" refers to an alkyl group containing 1 to 6 carbon atoms which is attached to the rest of the molecule via an oxygen atom. 1-6 Alkoxy groups include C 1-4 、C 1-3 、C 1-2 、C 2-6 、C2-4 , C6, C5, C4 and C3 alkoxy, etc. 1-6 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexyloxy, and the like.

[0123] Unless otherwise specified, the term “C 1-3 "Alkoxy" refers to those alkyl groups containing 1 to 3 carbon atoms which are attached to the rest of the molecule via an oxygen atom. The C 1-3 Alkoxy groups include C 1-2 、C 2-3 , C3 and C2 alkoxy, etc. 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

[0124] Unless otherwise specified, the term “C 1-6 "Alkylamino" means an alkyl group containing 1 to 6 carbon atoms which is attached to the rest of the molecule via an amino group. 1-6 Alkylamino groups include C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 , C6, C5, C4, C3 and C2 alkylamino, etc. 1-6 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH2CH3)(CH2CH3), -NHCH2CH2CH3, -NHCH2(CH3)2, -NHCH2CH2CH2CH3, and the like.

[0125] Unless otherwise specified, the term “C 3-8 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 8 carbon atoms, including monocyclic and bicyclic systems, wherein the bicyclic system includes spirocyclic, fused and bridged rings. 3-8 Cycloalkyl groups include C 3-6 、C 3-5 、C 4-8 、C 4-6 、C 4-5 、C 5-8 or C 5-6 Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2]bicyclooctane, and the like.

[0126] Unless otherwise specified, the term “C 3-6 "Cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic or bicyclic ring system. 3-6 Cycloalkyl groups include C 3-5 、C 4-5 and C 5-6 Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0127] Unless otherwise specified, C n-n+m or C n -C n+m Any specific case including n to n+m carbons, such as C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 , and C 12 , also includes any range from n to n+m, such as C 1-12 Including C 1- 3. C 1-6 、C 1-9 、C 3-6 、C 3-9 、C 3-12 、C 6-9 、C 6-12 , and C 9-12 Similarly, n-membered to n+m-membered means that the number of atoms in the ring is n to n+m, for example, a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, and a 12-membered ring, and also includes any range from n to n+m, for example, a 3-12-membered ring includes a 3-6-membered ring, a 3-9-membered ring, a 5-6-membered ring, a 5-7-membered ring, a 6-7-membered ring, a 6-8-membered ring, and a 6-10-membered ring, etc.

[0128] Unless otherwise specified, the term "aryl" refers to a monocyclic or polycyclic carbocyclic ring having 6 to 20 carbon atoms, at least one of which is aromatic. When one of the rings is non-aromatic, the group may be attached through either the aromatic ring or the non-aromatic ring. "Aryl" can be a 6- to 8-membered or a 6- to 10-membered aryl group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthrenyl, anthracenyl, and acenaphthenyl. The term "6- to 10-membered aryl" refers to a monocyclic or polycyclic carbocyclic ring having 6 to 10 carbon atoms, at least one of which is aromatic.

[0129] Unless otherwise specified, the term "heterocycloalkyl" refers to a cycloalkyl group in which one or more (e.g., 1, 2, 3, or 4, in some embodiments, 1 to 3) carbon atoms are replaced by heteroatoms, such as, but not limited to, N, O, S, and P. The term "mn-membered heterocycloalkyl" is understood to mean a saturated, unsaturated, or partially saturated ring having m to n atoms, wherein the heteroatoms are selected from N, O, S, P, preferably N, O, or S. The term "heterocycloalkyl" may be 3 to 8 members, 3 to 11 members, or 6 to 8 members. The term "3-11 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 3 to 11 ring atoms. The term "6-8 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 6 to 8 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)p, p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spirocyclic, cyclic and bridged rings. In addition, with respect to the "6-8 membered heterocycloalkyl", heteroatoms can occupy the position at which the heterocycloalkyl is connected to the rest of the molecule. For example, 6-8 membered heterocycloalkyl includes but is not limited to 6-membered, 7-membered, and 8-membered. Examples of 6-8 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, and hexahydropyridazinyl.

[0130] Unless otherwise specified, the term "heteroaromatic ring" or "heteroaryl" refers to a monocyclic or polycyclic carbon ring in which at least one ring atom (e.g., 1, 2, or 3) is a heteroatom independently selected from oxygen, sulfur, and nitrogen, and the remaining ring atoms are C, wherein at least one ring is aromatic. The group can be a carbon group or a heteroatom group (i.e., it can be C-linked or N-linked, as long as it is possible). When one of the rings is a non-aromatic ring, the group can be connected through the aromatic ring or through the non-aromatic ring. "Heteroaryl" can be a 5-10 membered (e.g., 5-, 6-, 7-, 8-, 9-, or 10-membered) heteroaryl, or a 5-8 membered heteroaryl. Examples of heteroaryl groups include, but are not limited to, imidazolyl, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, N-methylpyrrolyl, and tetrahydroquinoline. The term "heteroaromatic ring" may be used interchangeably with the terms "heteroaromatic ring," "heteroaryl," or "heteroaromatic ring group."

[0131] Unless otherwise specified, the term "oxo" refers to the replacement of two hydrogen atoms on a methylene group by oxygen atoms, ie, the methylene group is replaced by a carbonyl group, representing =0.

[0132] Unless otherwise specified, the term "halo" or "halogen" refers to fluoro, chloro, bromo and iodo.

[0133] Additionally, it should be noted that, unless otherwise expressly stated, the term "independently" used in the present invention should be broadly construed to mean that the individual entities described are independent of one another and may independently represent the same or different specific groups. More specifically, the term "independently" can mean that specific options expressed by identical symbols in different groups do not affect each other, or that specific options expressed by identical symbols in the same group do not affect each other.

[0134] In this application, "pharmaceutically acceptable carrier" includes but is not limited to any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavoring, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the relevant governmental regulatory authorities as acceptable for human or livestock use.

[0135] The term "treat" refers to therapeutic treatment. When referring to a specific condition, treatment means: (1) alleviating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade that leads to or causes the condition or (b) one or more biological manifestations of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more biological manifestations of the condition.

[0136] The term "prevent" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0137] The term "patient" refers to any animal, preferably a mammal, that is about to be or has been administered a compound or composition according to embodiments of the present invention. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., preferably humans.

[0138] The term "therapeutically effective amount" refers to an amount of a compound that, when administered to a patient, is sufficient to effectively treat a disease or condition described herein. The "therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, and can be adjusted as needed by those skilled in the art.

[0139] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention. Beneficial effects

[0140] After extensive and in-depth research, the inventors unexpectedly developed a compound or pharmaceutically acceptable salt thereof, as well as a preparation method and use thereof. The present invention provides a compound represented by Formula IA, and its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs. The compound of Formula IA has a significant inhibitory effect on MRGPRX2 and can be used as an antagonist of MRGPRX2. It exhibits excellent pharmacokinetic properties and good drugability, and has no significant inhibitory effect on the BSEP bile efflux transporter, resulting in no risk of cholestatic toxicity. These compounds demonstrate, in multiple respects, a high safety profile and drugability. DETAILED DESCRIPTION

[0141] The present invention will be further described below in conjunction with specific examples. It should be understood that the following description is only the most preferred embodiment of the present invention and should not be considered as limiting the scope of protection of the present invention. Based on a full understanding of the present invention, the experimental methods in the following examples that do not specify specific conditions are generally carried out under conventional conditions or under conditions recommended by the manufacturer. Those skilled in the art may make non-essential changes to the technical solutions of the present invention, and such changes should be considered as included in the scope of protection of the present invention.

[0142] EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

[0143] HOBt: 1-hydroxybenzotriazole

[0144] DIEA: N,N-diisopropylethylamine

[0145] Ruphos Pd G4: methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II)

[0146] Intermediate A1: Preparation of N-((1R,3S)-3-aminocyclohexyl)-1-methyl-1H-pyrazole-4-carboxamide

[0147] The synthetic route of target intermediate A1 is as follows:

[0148] Step 1: Synthesis of tert-butyl ((1S,3R))-3-(1-methyl-1H-pyrazole-4-carboxamide)cyclohexyl)carbamate

[0149] At room temperature, 1-methyl-1H-pyrazole-4-carboxylic acid (500 mg, 4 mmol) was dissolved in N,N-dimethylformamide (10 mL), and then tert-butyl ((1S, 3R)-3-aminocyclohexane (428 mg, 4 mmol), N,N-diisopropylethylamine (408 mg, 12 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.38 g, 6 mmol) were added in sequence, and then the mixture was stirred at room temperature. The reaction was allowed to proceed for 12 hours. After completion of the reaction, the reaction solution was poured into ice water and extracted with ethyl acetate (3×50 mL). The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and spun down to dryness. The crude product was purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 10:1) to obtain the compound ((1S,3R))-3-(1-methyl-1H-pyrazole-4-carboxamido)cyclohexyl)carbamic acid tert-butyl ester (A1-3) (830 mg, 2.58 mmol, 64.5% yield).

[0150] LC-MS, M / Z(ESI):323.20[M+H] +

[0151] Step 2: Synthesis of N-((1R,3S)-3-aminocyclohexyl)-1-methyl-1H-pyrazole-4-carboxamide

[0152] At room temperature, tert-butyl ((1S,3R))-3-(1-methyl-1H-pyrazole-4-carboxamide)cyclohexyl)carbamate (830 mg, 2.58 mmol) was dissolved in anhydrous 1,4-dioxane (10 mL) and stirred at room temperature. Then, a solution of hydrogen chloride in 1,4-dioxane (4 mol / L, 1.76 mL, 4 mmol) was slowly added dropwise, and the reaction solution was stirred at room temperature for 30 min. After thin-layer chromatography monitoring showed that the raw materials had reacted completely, stirring was stopped, and a saturated sodium bicarbonate solution was added to the reaction system to adjust the pH to 7-8. The mixture was extracted with ethyl acetate (30 mL × 3), and the organic phase was collected and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column (dichloromethane:methanol (V / V) = 10:1) to obtain compound N-((1R,3S)-3-aminocyclohexyl)-1-methyl-1H-pyrazole-4-carboxamide (intermediate A1) (213 mg, yield 36.8%).

[0153] LC-MS, M / Z(ESI):223.13[M+H] +

[0154] Intermediate A2: Preparation of compound 3-chloro-1-(1-(methylsulfonyl)ethyl)-1H-pyrazole-4-carboxylic acid

[0155] The synthetic route of target intermediate A2 is as follows:

[0156] Step 1: Synthesis of ethyl 3-chloro-1-((methylthio)methyl)-1H-pyrazole-4-carboxylate

[0157] At room temperature, ethyl 3-chloro-1H-pyrazole-4-carboxylate (2.00 g, 11.46 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) and stirred in an ice bath at 0°C for 10 min. Sodium hydride (504 mg, 12.60 mmol) was then added portionwise, followed by the slow addition of chloromethyl methyl sulfide (1.33 g, 13.75 mmol). The reaction solution was slowly warmed to room temperature and stirred for 30 min. After the reaction was complete, stirring was stopped and the reaction solution was poured into water (30 mL), followed by extraction with ethyl acetate (30 mL × 3). The organic phase was collected and dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 10:1) to obtain ethyl 3-chloro-1-((methylthio)methyl)-1H-pyrazole-4-carboxylate (930 mg, 34.59% yield).

[0158] LC-MS, M / Z(ESI):235.3[M+H] +

[0159] 1 H NMR (400MHz, DMSO-d6) δ8.50(s,1H),5.26(s,2H),4.23(q,2H),2.14(s,3H),1.27(t,3H).

[0160] Step 2: Synthesis of ethyl 3-chloro-1-((methylsulfonyl)methyl)-1H-pyrazole-4-carboxylate

[0161] Ethyl 3-chloro-1-((methylthio)methyl)-1H-pyrazole-4-carboxylate (550 mg, 2.34 mmol) was dissolved in anhydrous dichloromethane (11 mL) at room temperature and stirred at 0°C for 10 min. m-Chloroperbenzoic acid (1.21 g, 7.03 mmol) was then added. The reaction mixture was slowly warmed to room temperature and stirred for 2 h. After thin-layer chromatography indicated complete reaction, stirring was stopped and the reaction mixture was poured into a saturated aqueous sodium thiosulfate solution (30 mL). The mixture was then extracted with ethyl acetate (30 mL × 3). The organic phase was collected and washed with a saturated aqueous sodium carbonate solution (40 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to afford ethyl 3-chloro-1-((methylsulfonyl)methyl)-1H-pyrazole-4-carboxylate (615 mg, 98.4% yield). The crude product was used directly in the next reaction.

[0162] LC-MS, M / Z(ESI):267.0[M+H] +

[0163] Step 3: Synthesis of ethyl 3-chloro-1-(1-(methylsulfonyl)ethyl)-1H-pyrazole-4-carboxylate

[0164] Ethyl 3-chloro-1-((methylsulfonyl)methyl)-1H-pyrazole-4-carboxylate (200 mg, 0.75 mmol) was dissolved in anhydrous DMF (2 mL) at room temperature, followed by the addition of cesium carbonate (488.67 mg, 1.50 mmol). The reaction mixture was stirred for 10 minutes, and then iodomethane (212.88 mg, 1.50 mmol) was slowly added dropwise. Stirring was continued at room temperature for 12 hours. After TLC monitoring indicated complete reaction, stirring was stopped and the reaction was quenched with water (5 mL). The reaction was then extracted with ethyl acetate (15 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM:MeOH (v / v) = 100:2) to afford ethyl 3-chloro-1-(1-(methylsulfonyl)ethyl)-1H-pyrazole-4-carboxylate (139 mg, 66.03% yield).

[0165] LC-MS, M / Z(ESI):281.0[M+H] +

[0166] Step 4: Synthesis of compound 3-chloro-1-(1-(methylsulfonyl)ethyl)-1H-pyrazole-4-carboxylic acid

[0167] At room temperature, ethyl 3-chloro-1-(1-(methylsulfonyl)ethyl)-1H-pyrazole-4-carboxylate (130 mg, 0.46 mmol) was dissolved in a mixture of methanol (2 mL) and water (0.8 mL). Sodium hydroxide (148 mg, 3.70 mmol) was then added, and the reaction mixture was stirred at room temperature for 2 h. After TLC monitoring indicated complete reaction, stirring was stopped, and the methanol was removed by distillation under reduced pressure. The residue was diluted with water (5 mL), and the pH was adjusted to 2 with dilute hydrochloric acid (2 mol / L). The mixture was then extracted with ethyl acetate (15 mL x 3). The organic phase was collected and dried over anhydrous sodium sulfate. The organic phase was then concentrated by distillation under reduced pressure to yield 3-chloro-1-(1-(methylsulfonyl)ethyl)-1H-pyrazole-4-carboxylic acid (110 mg, 94.01% yield).

[0168] LC-MS, M / Z(ESI):252.8[M+H] +

[0169] Intermediate A3: Preparation of 3-chloro-1-(2-hydroxy-2-methylpropyl)-1H-pyrazole-4-carboxylic acid

[0170] The synthetic route of target intermediate A3 is as follows:

[0171] Step 1: Synthesis of ethyl 3-chloro-1-(2-hydroxy-2-methylpropyl)-1H-pyrazole-4-carboxylate

[0172] To a solution of ethyl 3-chloro-1H-pyrazole-4-carboxylate (200 mg, 1.15 mmol) in N,N-dimethylformamide (3 mL) was added 1-bromo-2-methyl-2-propanol (351 mg, 2.29 mmol), cesium carbonate (1.12 g, 3.44 mmol) and potassium iodide (190 mg, 1.15 mmol), and the mixture was stirred at 70 ° C for 3 hours. LCMS detection showed that the reaction was complete. The reaction solution was diluted with water (100 mL), then extracted with ethyl acetate (200 mL × 3), and the organic phases were combined and concentrated to give a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 100: 0-0: 100) to give compound ethyl 3-chloro-1- (2-hydroxy-2-methylpropyl) -1H-pyrazole-4-carboxylate (181 mg, 64.1% yield).

[0173] LC-MS, M / Z(ESI):247.2[M+H] + .

[0174] Step 2: Synthesis of 3-chloro-1-(2-hydroxy-2-methylpropyl)-1H-pyrazole-4-carboxylic acid

[0175] To a solution of ethyl 3-chloro-1-(2-hydroxy-2-methylpropyl)-1H-pyrazole-4-carboxylate (181 mg, 0.73 mmol) in methanol (3 mL) and water (3 mL) was added lithium hydroxide (308 mg, 7.34 mmol), and the resulting mixture was stirred at 25 ° C for 2 hours. LCMS detection showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to give a crude product, which was purified by column chromatography (water: acetonitrile (V / V) = 100: 0 to 80: 20) to give compound 3-chloro-1-(2-hydroxy-2-methylpropyl)-1H-pyrazole-4-carboxylic acid (150 mg, 93.5% yield).

[0176] LC-MS, M / Z(ESI):219.0[M+H] + .

[0177] Example 1: Preparation of N-((1S,4S)-4-((2,7-bis(trifluoromethyl))imidazo[1,2-a](pyridin-5-yl)amino)cyclohexyl)-3-chloro-1-methyl-1H-pyrazole-4-carboxamide (Compound 20A)

[0178] The synthetic route of target compound 20A is as follows:

[0179] Step 1: Synthesis of 6-chloro-4-(trifluoromethyl)pyridin-2-amine

[0180] At room temperature, 2,6-dichloro-4-trifluoromethylpyridine (20A-1) (2.00 g, 9.26 mmol) was dissolved in 10 mL of 25% aqueous ammonia and stirred at 120°C for 12 h in a sealed metal reactor. After the reaction was complete, heating was stopped, the mixture was cooled to room temperature, and the solvent was removed by rotary evaporation under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 100:5) to afford 6-chloro-4-(trifluoromethyl)pyridin-2-amine (20A-2) (1.30 g, 71.43% yield).

[0181] LC-MS, M / Z(ESI):196.80[M+H] + .

[0182] Step 2: Synthesis of 5-chloro-2,7-bis(trifluoromethyl)imidazo[1,2-a]pyridine

[0183] At room temperature, 6-chloro-4-(trifluoromethyl)pyridin-2-amine (20A-2) (1.30 g, 6.61 mmol) and 3-bromo-1,1,1-trifluoroacetone (1.89 g, 9.92 mmol) were dissolved in ethylene glycol (15 mL). The reaction mixture was stirred at 120°C for 12 h. After TLC monitoring indicated complete reaction, stirring was stopped and the reaction mixture was cooled to room temperature. Water (80 mL) was then added for dilution and extraction with ethyl acetate (40 mL x 5). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified on a silica gel column (petroleum ether:ethyl acetate (v / v) = 100:5) to afford 5-chloro-2,7-bis(trifluoromethyl)imidazo[1,2-a]pyridine (20A-3) (1.29 g, 67.59% yield).

[0184] LC-MS, M / Z(ESI):289.22[M+H] +

[0185] Step 3: Synthesis of tert-butyl ((1S,4S)-4-((2,7-bis(trifluoromethyl))imidazo[1,2-a]pyridin-5-yl)amino)cyclohexyl)carbamate (20A-5)

[0186] At room temperature, compound 5-chloro-2,7-bis(trifluoromethyl)imidazo[1,2-a]pyridine (20A-3) (1.00 g, 3.47 mmol) and compound 1-N-Boc-cis-1,4-cyclohexanediamine (20A-4) (1.48 g, 6.93 mmol) were dissolved in anhydrous DMSO (10 mL), and then N,N-diisopropylethylamine (1.79 g, 13.96 mmol) was added dropwise. The reaction solution was stirred at 100°C for 4 h. After TLC monitoring showed that the raw materials had reacted, 50 mL of water was added to dilute the mixture, and the mixture was extracted with ethyl acetate (30 mL×5). The organic phase was collected and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 100:20) to obtain compound ((1S,4S)-4-((2,7-bis(trifluoromethyl))imidazo[1,2-a]pyridin-5-yl)amino)cyclohexyl)carbamic acid tert-butyl ester (20A-5) (1.60 g, yield 73.52%).

[0187] LC-MS, M / Z(ESI):467.01[M+H] +

[0188] Step 4: (1S, 4S)-N 1 Synthesis of -(2,7-bis(trifluoromethyl))imidazo[1,2-a]pyridin-5-yl)cyclohexane-1,4-diamine hydrochloride

[0189] At room temperature, the compound ((1S,4S)-4-((2,7-bis(trifluoromethyl))imidazo[1,2-a]pyridin-5-yl)amino)cyclohexyl)carbamic acid tert-butyl ester (20A-5) (1.60 g, 3.43 mmol) was dissolved in dichloromethane (20 mL), and then a solution of hydrogen chloride in 1,4-dioxane (4 mol / L, 4.0 mL, 16.0 mmol) was slowly added dropwise. The reaction solution was stirred at room temperature for 1 hour. After TLC monitoring, the solvent was removed by distillation under reduced pressure, ethyl acetate (40 mL) was added, and the mixture was stirred at room temperature for 2 hours. The suspension was filtered and dried under vacuum to obtain compound (1S,4S)-N 1 -(2,7-bis(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)cyclohexane-1,4-diamine hydrochloride (20A-6) (1.25 g, yield 90.47%).

[0190] LC-MS, M / Z(ESI):367.30[M+H] +

[0191] Step 5: Synthesis of N-((1S,4S)-4-((2,7-bis(trifluoromethyl))imidazo[1,2-a](pyridin-5-yl)amino)cyclohexyl)-3-chloro-1-methyl-1H-pyrazole-4-carboxamide

[0192] At room temperature, compound 3-chloro-1-methyl-1H-pyrazole-4-carboxylic acid (200 mg, 1.25 mmol) was dissolved in anhydrous DMF (5 mL) and stirred at 0°C for 10 min. Then, N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl)uronium hexafluorophosphate (HATU) (947.28 mg, 2.49 mmol) and N,N-diisopropylethylamine (397.85 mg, 4.98 mmol) were added. The reaction solution was stirred at 0°C for 30 min, and then compound (1S,4S)-N 1 -(2,7-bis(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)cyclohexane-1,4-diamine hydrochloride (20A-6) (501.71 mg, 1.25 mmol), and the reaction solution was heated to room temperature and stirred for 12 h. After TLC monitoring showed that the reaction of the raw materials was complete, stirring was stopped, water (50 mL) was added to the reaction solution to dilute it, and the mixture was extracted with ethyl acetate (30 mL×5). The organic phase was collected and dried over anhydrous sodium sulfate. The organic phase was concentrated by distillation under reduced pressure, and the resulting residue was separated and purified by column chromatography (dichloromethane:methanol (V / V)=100:5) to give compound N-((1S,4S)-4-((2,7-bis(trifluoromethyl))imidazo[1,2-a](pyridin-5-yl)amino)cyclohexyl)-3-chloro-1-methyl-1H-pyrazole-4-carboxamide (Compound 20A) (220 mg, 34.72%).

[0193] LC-MS, M / Z(ESI):509.20[M+H] +

[0194] 1 H NMR(400MHz, CDCl3)δ7.92(s,1H),7.86(t,1H),7.46(d,1H),6.68(d,1H),6.13(d, 1H),4.36(d,1H),4.21(dd,1H),3.88(s,3H),3.78–3.72(m,1H),2.13–1.79(m,8H).

[0195] Example 2: Preparation of 1-methyl-N-((1R,3S)-3-((6-methyl-2-(trifluoromethyl)-1,5-naphthyridin-4-yl)amino)cyclohexyl)-1H-pyrazole-4-carboxamide (Compound 21A)

[0196] The synthetic route of target compound 21A is as follows:

[0197] Step 1: Synthesis of 6-methyl-2-(trifluoromethyl)-1,5-naphthyridin-4(1H)-one

[0198] To a 100 mL single-necked flask, 5-amino-2-methylpyridine (2 g, 18.49 mmol), diphenyl ether-biphenyl cocrystal (20 mL), and ethyl 4,4,4-trifluoroacetoacetate (4.43 g, 24.04 mmol) were added sequentially. The mixture was heated to 250°C and stirred for 7 h. After completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0 to 1:4) to obtain compound 6-methyl-2-(trifluoromethyl)-1,5-naphthyridin-4(1H)-one (21A-3) (0.3 g, 7.11% yield).

[0199] LC-MS, M / Z(ESI):229.10[M+H] +

[0200] Step 2: Synthesis of 4-chloro-6-methyl-2-(trifluoromethyl)-1,5-naphthyridine

[0201] To a 100 mL two-necked flask, 6-methyl-2-(trifluoromethyl)-1,5-naphthyridin-4(1H)-one (0.2 g, 0.88 mmol) and dichloroethane (5 mL) were added sequentially. Under nitrogen, the reaction solution was cooled to 0°C, and then phosphorus oxychloride (1.34 g, 8.77 mmol) was slowly added. After 10 minutes, the reaction solution was heated to 80°C and stirred for 5 hours. After completion of the reaction, ice water was added to quench the reaction. The organic phase was separated and concentrated to obtain the crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0 to 20:1) to obtain compound 4-chloro-6-methyl-2-(trifluoromethyl)-1,5-naphthyridine (21A-4) (120 mg, 55.51% yield).

[0202] LC-MS, M / Z(ESI):247.15[M+H] +

[0203] Step 3: Synthesis of 1-methyl-N-((1R,3S)-3-((6-methyl-2-(trifluoromethyl)-1,5-naphthyridin-4-yl)amino)cyclohexyl)-1H-pyrazole-4-carboxamide

[0204] To a 100 mL single-necked flask were added 4-chloro-6-methyl-2-(trifluoromethyl)-1,5-naphthyridine (80 mg, 0.32 mmol), N-((1R,3S)-3-aminocyclohexyl)-1-methyl-1H-pyrazole-4-carboxamide (Intermediate A1) (108.16 mg, 0.49 mmol), BrettPhosPdG3 (14.70 mg, 0.16 mmol) and sodium tert-butoxide (77.94 mg, 0.81 mmol), and then 1,4-dioxane (8 mL) was added. The reaction solution was heated to 100 °C and stirred for 16 h. After the reaction, the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by reverse-phase preparative liquid chromatography (column: YMC-Triart Prep C18 (30 mm × 40 cm, 7 um); solvent: A = water + 0.1% ammonia water, B = acetonitrile; gradient: 20%-70%) to obtain 1-methyl-N-((1R,3S)-3-((6-methyl-2-(trifluoromethyl)-1,5-naphthyridin-4-yl)amino)cyclohexyl)-1H-pyrazole-4-carboxamide (Compound 21A) (14 mg, 9.98% yield).

[0205] LC-MS, M / Z(ESI):433.40[M+H] +

[0206] 1 H NMR(400MHz,DMSO-d6)δ8.16(d,1H),8.09(s,1H),7.85(d,1H),7.81(s,1H),7.66(d,1H),7.24(d,1H),7.05(s,1H),3.99–3.91(m,1 H),3.87-3.83(m,1H),3.81(s,3H),2.69(s,3H),2.14(d,1H),1.94(d,1H),1.86-1.76(m,2H),1.53-1.38(m,3H),1.29-1.22(m,1H).

[0207] Example 3: Preparation of N-((1R,3S)-3-((2-chloro-6-(trifluoromethyl)thieno[2,3-b]pyridin-4-yl)amino)cyclohexyl)-1-methyl-1H-pyrazole-4-carboxamide (Compound 22A)

[0208] The synthetic route of compound 22A is as follows:

[0209] Step 1: Synthesis of Thiophene-2-amine

[0210] Tert-butyl thiophen-2-ylcarbamate (2.00 g, 10.0 mmol) was dissolved in a solution of hydrogen chloride in 1,4-dioxane (20 mL, 4 mol / L). The reaction mixture was stirred at 25°C under nitrogen for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, then dissolved in dichloromethane (10 mL), and concentrated under reduced pressure three times to afford the crude product thiophene-2-amine (22A-2) (1.35 g, 98.4% yield), which was used directly in the next reaction.

[0211] LC-MS, M / Z(ESI):100.2[M+H] + .

[0212] Step 2: Synthesis of 6-(trifluoromethyl)thieno[3,2-b]pyridin-4-ol

[0213] Thiophene-2-amine (4.80 g, 35.0 mmol) was dissolved in polyphosphoric acid (50 mL), and ethyl 4,4,4-trifluoroacetoacetate (6.45 g, 35.0 mmol) was added under nitrogen. The reaction mixture was stirred at 140°C for 18 hours under N2 protection. The reaction mixture was cooled to room temperature and diluted with saturated sodium bicarbonate solution (500 mL). The mixture was then extracted with ethyl acetate (500 mL x 3). The organic layers were combined, washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was separated and purified on a silica gel column (petroleum ether:ethyl acetate (v / v) = 100:0 to 80:20, gradient elution) to obtain compound 6-(trifluoromethyl)thieno[3,2-b]pyridin-4-ol (22A-4) (750 mg, 9.3% yield).

[0214] 1 H NMR (400MHz, CDCl3): δ7.55 (d, J = 6.0 Hz, 1H), 7.46 (d, J = 6.0 Hz, 1H), 7.09 (s, 1H).

[0215] LC-MS, M / Z(ESI):220.2[M+H] + .

[0216] Step 3: Synthesis of 4-chloro-6-(trifluoromethyl)thieno[2,3-b]pyridine

[0217] 6-(Trifluoromethyl)thieno[3,2-b]pyridin-4-ol (683 mg, 3.12 mmol) was dissolved in toluene (7 mL), and N,N-dimethylformamide (0.1 mL) and thionyl chloride (1.85 g, 15.6 mmol) were added sequentially. The reaction mixture was stirred at 25°C for 4 hours. LC-MS analysis confirmed the formation of the desired product. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 100:0 to 80:20, gradient elution) to afford 4-chloro-6-(trifluoromethyl)thieno[2,3-b]pyridine (22A-5) (490 mg, 62.91% yield).

[0218] LC-MS, M / Z(ESI):238.0[M+H] + .

[0219] Step 4: Synthesis of 2,4-dichloro-6-(trifluoromethyl)thieno[2,3-b]pyridine

[0220] 2,2,6,6-Tetramethylpiperidine (0.46 mL, 2.73 mmol) was dissolved in tetrahydrofuran (10 mL) and the atmosphere was replaced with nitrogen. n-Butyl lithium (2.18 mL, 5.45 mmol, 2.5 mol / L in n-hexane) was added dropwise at -78°C. The reaction mixture was stirred at -78°C for 1 hour. A solution of 4-chloro-6-(trifluoromethyl)thieno[2,3-b]pyridine (648 mg, 2.73 mmol) in tetrahydrofuran (2 mL) was slowly added dropwise to the reaction system. The reaction mixture was stirred at -78°C for 1 hour. Then, a solution of hexachloroethane (775 mg, 3.27 mmol) in tetrahydrofuran (1 mL) was slowly added dropwise to the reaction system. The resulting reaction mixture was stirred at -78°C for 1 hour, then gradually warmed to 25°C and stirred for 14 hours. LC-MS detection showed that the starting material disappeared. Water (50 mL) was added to the reaction mixture to quench the reaction mixture, which was then extracted with ethyl acetate (50 mL×3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was separated and purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 100:0 to 80:20, gradient elution) to give compound 2,4-dichloro-6-(trifluoromethyl)thieno[2,3-b]pyridine (22A-6) (377 mg, 48.4% yield).

[0221] 1 H NMR (400MHz, CDCl3): δ7.67(s,1H),7.35(s,1H).

[0222] LC-MS, M / Z(ESI):272.0[M+H] + .

[0223] Step 5: Synthesis of tert-butyl ((1R,3S))-3-((2-chloro-6-trifluoromethyl))thieno[2,3-b]pyridin-4-yl)amino)cyclohexyl)carbamate

[0224] 2,4-Dichloro-6-(trifluoromethyl)thieno[2,3-b]pyridine (250 mg, 0.92 mmol) and tert-butyl (((1R,3S)-3-aminocyclohexyl)amino)formate (207 mg, 0.97 mmol) were dissolved in N-methylpyrrolidone (5 mL), and N,N-diisopropylethylamine (166 mg, 1.29 mmol) was added. The reaction solution was stirred at 130 ° C for 2 hours. The reaction solution was cooled to room temperature, water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL×3). The organic layers were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 100:0 to 80:20, gradient elution) to obtain compound ((1R,3S))-3-((2-chloro-6-trifluoromethyl))thieno[2,3-b]pyridin-4-yl)amino)cyclohexyl)carbamic acid tert-butyl ester (22A-7) (270 mg, yield 64.00%).

[0225] LC-MS, M / Z(ESI):450.2[M+H] + .

[0226] Step 6: (1R, 3S)-N 1 Synthesis of 2-((2-chloro-6-(trifluoromethyl)thieno[2,3-b]pyridin-4-yl)cyclohexane-1,3-diamine

[0227] Tert-butyl ((1R,3S))-3-((2-chloro-6-trifluoromethyl))thieno[2,3-b]pyridin-4-yl)amino)cyclohexyl)carbamate (150 mg, 0.33 mmol) was dissolved in anhydrous dichloromethane (5 mL) and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at 25°C for 1 hour. LC-MS analysis showed the formation of the target product. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane (10 mL). The residue was further concentrated under reduced pressure to obtain the crude product compound (1R,3S)-N 1 -((2-chloro-6-(trifluoromethyl)thieno[2,3-b]pyridin-4-yl)cyclohexane-1,3-diamine (22A-8) (110 mg, yield 92.4%), the crude product was used directly in the next reaction.

[0228] LC-MS, M / Z(ESI):350.2[M+H] + .

[0229] Step 7: Synthesis of N-((1R,3S)-3-((2-chloro-6-(trifluoromethyl)thieno[2,3-b]pyridin-4-yl)amino)cyclohexyl)-1-methyl-1H-pyrazole-4-carboxamide

[0230] (1R,3S)-N 1 -((2-chloro-6-(trifluoromethyl)thieno[2,3-b]pyridin-4-yl)cyclohexane-1,3-diamine (100 mg, 0.29 mmol) and 1-methylpyrazole-4-carboxylic acid (43.3 mg, 0.34 mmol) were dissolved in anhydrous dimethyl sulfoxide (2 mL), and N,N-diisopropylethylamine (185 mg, 1.43 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (164 mg, 0.86 mmol), and 1-hydroxybenzotriazole (116 mg, 0.86 mmol) were added in sequence. The reaction solution was stirred at 25 ° C under nitrogen protection. The mixture was stirred for 18 hours. LC-MS confirmed the formation of the target product. The reaction solution was dissolved in saturated brine (20 mL), then extracted with ethyl acetate (10 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was then separated and purified using a reverse-phase silica gel C18 column (water:acetonitrile (V / V) = 100:0 to 70:30, gradient elution) to obtain N-((1R,3S)-3-((2-chloro-6-(trifluoromethyl)thieno[2,3-b]pyridin-4-yl)amino)cyclohexyl)-1-methyl-1H-pyrazole-4-carboxamide (Compound 22A) (88.3 mg, 66.6% yield).

[0231] LC-MS, M / Z(ESI):458.2[M+H] + .

[0232] 1 H NMR (400MHz, DMSO-d6): δ8.10(s,1H),7.89(s,1H),7.87(d,1H),7.82(s,1H),7.23(d,1H),6.98(s,1H),4.02–3.90(m,1H),3. 83(s,4H),2.13–2.07(m,1H),1.96–1.90(m,1H),1.87–1.76(m,2H),1.55–1.46(m,1H),1.41–1.31(m,1H),1.25–1.21(m,2H).

[0233] Example 4: Preparation of N-((1R,3S)-3-((2-chloro-5-(trifluoromethyl)thieno[3,2-b]pyridin-7-yl)amino)cyclohexyl)-1-methyl-1H-pyrazole-4-carboxamide (Compound 23A) trifluoroacetate

[0234] The synthetic route of compound 23A trifluoroacetate is as follows:

[0235] Step 1: Synthesis of 5-(trifluoromethyl)thieno[3,2-b]pyridin-7-ol

[0236] To a solution of 3-aminothiophene (1.00 g, 5.43 mmol) in polyphosphoric acid (10 mL) was added ethyl trifluoroacetoacetate (0.54 g, 5.43 mmol). The reaction mixture was stirred at 140°C under nitrogen for 16 hours. The reaction mixture was cooled to room temperature, diluted with saturated aqueous sodium bicarbonate (100 mL), and extracted with ethyl acetate (100 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product, which was separated and purified on a silica gel column (petroleum ether:ethyl acetate (v / v) = 100:1 to 10:1, gradient elution) to obtain compound 5-(trifluoromethyl)thieno[3,2-b]pyridin-7-ol (720 mg, 55.3% yield).

[0237] 1 H NMR (400MHz, DMSO-d6): δ8.17(d,J=5.2Hz,1H),7.57(d,J=5.6Hz,1H),7.02(s,1H),3.87(s,1H).

[0238] LC-MS, M / Z(ESI):220.2[M+H] + .

[0239] Step 2: Synthesis of 7-chloro-5-(trifluoromethyl)thieno[3,2-b]pyridine

[0240] 5-(Trifluoromethyl)thieno[3,2-b]pyridin-7-ol (360 mg, 1.64 mmol) was dissolved in phosphorus oxychloride (3 mL), and the reaction mixture was stirred at 60°C for 2 hours. The phosphorus oxychloride was removed by concentration under reduced pressure, and water (10 mL) was added to the residue. The mixture was extracted with ethyl acetate (10 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product, which was separated and purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 100:1 to 5:1, gradient elution) to obtain 7-chloro-5-(trifluoromethyl)thieno[3,2-b]pyridine (292 mg, 71.1% yield).

[0241] LC-MS, M / Z(ESI):238.2[M+H] + .

[0242] Step 3: Synthesis of 2,7-dichloro-5-(trifluoromethyl)thieno[3,2-b]pyridine

[0243] 2,2,6,6-Tetramethylpiperidine (256 mg, 1.81 mmol) was dissolved in tetrahydrofuran (5 mL). The atmosphere was replaced with nitrogen, and n-butyllithium (0.66 mL, 1.65 mmol, 2.5 M) was added dropwise at -78°C. The reaction mixture was allowed to react at -78°C for 1 hour, followed by the dropwise addition of a solution of 7-chloro-5-(trifluoromethyl)thieno(3,2-b)pyridine (200 mg, 0.82 mmol) in tetrahydrofuran (1 mL). After stirring at -78°C for 1 hour, a solution of hexachloroethane (234 mg, 0.99 mmol) in tetrahydrofuran (1 mL) was slowly added dropwise. The resulting reaction mixture was stirred at -78°C for 1 hour, then gradually warmed to 25°C and stirred for 14 hours. Water (10 mL) was added to the reaction mixture to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to yield the crude product. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 100:1 to 10:1, gradient elution) to give 2,7-dichloro-5-(trifluoromethyl)thieno[3,2-b]pyridine (130 mg, 52.1% yield).

[0244] LC-MS, M / Z(ESI):272.0[M+H] + .

[0245] 1 H NMR (400MHz, DMSO-d6): δ8.21(s,1H),8.04(s,1H).

[0246] Step 4: Synthesis of tert-butyl (1R,3S)-3-((2-chloro-5-(trifluoromethyl)thieno[3,2-b]pyridin-7-yl)amino)cyclohexyl)carbamate

[0247] 2,7-Dichloro-5-(trifluoromethyl)thieno[3,2-b]pyridine (100 mg, 0.37 mmol) and tert-butyl (((1R,3S)-3-aminocyclohexyl)amino)formate (82.7 mg, 0.39 mmol) were dissolved in N-methylpyrrolidone (2 mL), and N,N-diisopropylethylamine (0.06 mL, 0.37 mmol) was added. The reaction solution was stirred at 130 ° C for 3 hours. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic layers were combined, washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, and concentrated to give a crude product, which was separated and purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 100:1 to 5:1, gradient elution) to give tert-butyl (1R,3S)-3-((2-chloro-5-(trifluoromethyl)thieno[3,2-b]pyridin-7-yl)amino)cyclohexyl)carbamate (100 mg, yield 54.4%).

[0248] LC-MS, M / Z(ESI):450.2[M+H] + .

[0249] Step 5: (1S, 3R)-N 1 Synthesis of 2-(2-chloro-5-(trifluoromethyl)thieno[3,2-b]pyridin-7-yl)cyclohexane-1,3-diamine

[0250] Tert-butyl (1R,3S)-3-((2-chloro-5-(trifluoromethyl)thieno[3,2-b]pyridin-7-yl)amino)cyclohexyl)carbamate (200 mg, 0.45 mmol) was dissolved in anhydrous dichloromethane (4 mL), trifluoroacetic acid (2 mL) was added, and the reaction solution was stirred at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product which was separated and purified on a silica gel column (dichloromethane:methanol (V / V) = 10:1 to 1:1, gradient elution) to obtain (1S,3R)-N 1 -(2-chloro-5-(trifluoromethyl)thieno[3,2-b]pyridin-7-yl)cyclohexane-1,3-diamine (20 mg, 11.6% yield).

[0251] LC-MS, M / Z(ESI):350.2[M+H] + .

[0252] Step 6: Synthesis of N-((1R,3S)-3-((2-chloro-5-(trifluoromethyl)thieno[3,2-b]pyridin-7-yl)amino)cyclohexyl)-1-methyl-1H-pyrazole-4-carboxamide

[0253] (1S,3R)-N 1 -(2-Chloro-5-(trifluoromethyl)thieno[3,2-b]pyridin-7-yl)cyclohexane-1,3-diamine (10.0 mg, 0.03 mmol) and 1-methylpyrazole-4-carboxylic acid (4.33 mg, 0.03 mmol) were dissolved in anhydrous dimethyl sulfoxide (1 mL), and N,N-diisopropylethylamine (2 drops), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (16.7 mg, 0.09 mmol), and 1-hydroxybenzotriazole (11.76 mg, 0.09 mmol) were added sequentially. The reaction solution was stirred at 25 ° C for 18 hours under nitrogen protection. The reaction solution was added to saturated brine (10 mL), then extracted with ethyl acetate (10 mL×3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give a crude product, which was purified by high performance preparative liquid chromatography (Xtimate C18, 21.2*250 mm, 5 μm; 0.1% TFA-ACN; 40-70; 20 mL / min) to give compound N-((1R,3S)-3-((2-chloro-5-(trifluoromethyl)thieno[3,2-b]pyridin-7-yl)amino)cyclohexyl)-1-methyl-1H-pyrazole-4-carboxamide trifluoroacetate (3.50 mg, yield 21.4%).

[0254] LC-MS, M / Z(ESI):458.0[M+H] + .

[0255] 1 H NMR (400MHz, MeOD): δ8.03(s,1H),7.88(s,1H),7.37(s,1H),7.04(s,1H),4.10–3.98(m,1H),3.90(s,3H),3.8 9–3.77(m,1H),2.40–2.29(m,1H),2.12–2.05(m,1H),2.01–1.91(m,2H),1.66–1.57(m,1H),1.51–1.35(m,3H).

[0256] Example 5: Preparation of 1-methyl-N-((1R,3S)-3-((1-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)-1H-pyrazole-4-carboxamide (Compound 26A)

[0257] The synthetic route of compound 26A is as follows:

[0258] Step 1: Synthesis of 6-chloro-2-methyl-4-(trifluoromethyl)pyridazin-3(2H)-one

[0259] 4-Bromo-6-chloro-2-methylpyridazin-3(2H)-one (500 mg, 2.24 mmol) was dissolved in N-methylpyrrolidone (5 mL) and methyl fluorosulfonyldifluoroacetate (12.9 g, 6.71 mmol) and cuprous iodide (85.3 g, 0.448 mmol) were added. The reaction mixture was stirred at 80°C for 18 hours. LC-MS analysis indicated that the reaction was complete. Water (30 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (50 mL × 3). The organic layers were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate (V / V) = 100:0 to 95:5) to obtain 6-chloro-2-methyl-4-(trifluoromethyl)pyridazin-3(2H)-one (300 mg, 63.1% yield).

[0260] LC-MS, M / Z(ESI):213.0[M+H] + .

[0261] Step 2: Synthesis of tert-butyl ((1R,3S)-3-((1-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)carbamate

[0262] 6-Chloro-2-methyl-4-(trifluoromethyl)pyridazin-3(2H)-one (500 mg, 2.35 mmol) was dissolved in toluene (10 mL). Tert-butyl (1R,3S)-3-aminocyclohexyl)carbamate (504 mg, 2.35 mmol), (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (200 mg, 0.235 mmol), and cesium carbonate (1.53 g, 4.71 mmol) were added. The reaction mixture was stirred at 80°C for 14 hours. LC-MS confirmed the reaction was complete. Water (50 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layers were combined, washed with saturated brine (30 mL × 3), and then dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 100:0-90:10) to give tert-butyl ((1R,3S)-3-((1-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)carbamate (600 mg, yield 65.3%).

[0263] LC-MS, M / Z(ESI):391.4[M+H]+ .

[0264] Step 3: Synthesis of 6-(((1S,3R)-3-aminocyclohexyl)amino)-2-methyl-4-(trifluoromethyl)pyridazin-3(2H)-one trifluoroacetate

[0265] Tert-butyl ((1R, 3S)-3-((1-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)carbamate (600 mg, 1.54 mmol) was dissolved in dichloromethane (5 mL) solvent, and trifluoroacetic acid (2 mL) was added. The reaction solution was reacted at 25 ° C. for 2 hours. LC-MS detection showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude compound 6-(((1S, 3R)-3-aminocyclohexyl)amino)-2-methyl-4-(trifluoromethyl)pyridazin-3(2H)-one trifluoroacetate (600 mg, yield 80.7%).

[0266] LC-MS, M / Z(ESI):291.4[M+H] + .

[0267] Step 4: 1-methyl-N-((1R,3S)-3-((1-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)-1H-pyrazole-4-carboxamide

[0268] 6-(((1S,3R)-3-aminocyclohexyl)amino)-2-methyl-4-(trifluoromethyl)pyridazin-3(2H)-one trifluoroacetate (300 mg, 0.620 mmol) and 1-methylpyrazole-4-carboxylic acid (78.2 mg, 0.620 mmol) were dissolved in dimethyl sulfoxide (5 mL). 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (178 mg, 0.930 mmol), 1-hydroxybenzotriazole (126 mg, 0.930 mmol), and N,N-diisopropylethylamine (401 mg, 3.10 mmol) were added. The reaction mixture was stirred at 25°C under N2 protection for 2 hours. LC-MS confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (Xtimate C18 21.2*250mm 5um; 0.1% NH3.H2O-ACN; 40-52; 20 mL / min) to give 1-methyl-N-((1R,3S)-3-((1-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)-1H-pyrazole-4-carboxamide (160 mg, 64.9% yield).

[0269] LC-MS, M / Z(ESI):399.4[M+H] + .

[0270] 1 H NMR (400MHz, DMSO-d6): δ8.09(s,1H),7.84(d,1H),7.81(d,1H),7.41(s,1H),6.59(d,1H),3.83(s,3H),3.82–3.74(m,1H),3.53 –3.46(m,4H),2.20–2.14(m,1H),2.03–1.96(m,1H),1.83–1.73(m,2H),1.43–1.31(m,1H),1.25–1.11(m,2H),1.08–0.98(m,1H).

[0271] Example 6: Preparation of N-((1S,4S)-4-((1-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide (Compound 27A)

[0272] The synthetic route of compound 27A is as follows:

[0273] Step 1: Synthesis of tert-butyl (1S,4S)-4-((1-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)carbamate

[0274] To a solution of 6-chloro-2-methyl-4-(trifluoromethyl)pyridazin-3(2H)-one (1.00 g, 4.70 mmol) in 1,4-dioxane (15 mL) was added cis-tert-butyl (4-aminocyclohexyl)carbamate (1.00 g, 21.2 mmol), cesium carbonate (3.06 g, 9.41 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (200 mg, 0.240 mmol). The reaction was stirred at 80°C under nitrogen for 18 hours. LCMS confirmed the reaction was complete. The reaction solution was filtered, the filtrate was diluted with water (100 mL), extracted with ethyl acetate (100 mL×3), the organic layers were combined, washed with saturated brine (100 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 100:0 to 80:20) to obtain compound (1S,4S)-4-((1-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)carbamic acid tert-butyl ester (27A-2) (700 mg, yield 38.1%).

[0275] LC-MS, M / Z(ESI):391.2[M+H] +

[0276] Step 2: Synthesis of 6-(((1S,4S)-4-aminocyclohexyl)amino)-2-methyl-4-(trifluoromethyl)pyridazin-3(2H)-one (27A-3)

[0277] To a solution of tert-butyl cis-4-((1-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)carbamate (27A-2) (300 mg, 0.760 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (3.00 mL), and the reaction mixture was stirred at 25°C for 1 hour. LCMS confirmed the reaction was complete. The reaction mixture was poured into saturated aqueous sodium bicarbonate (50 mL) and extracted with dichloromethane (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to afford compound 6-(((1S,4S)-4-aminocyclohexyl)amino)-2-methyl-4-(trifluoromethyl)pyridazin-3(2H)-one (27A-3) (300 mg, 80.5% yield), which was used directly in the next reaction.

[0278] LC-MS, M / Z(ESI):291.2[M+H] +

[0279] Step 3: Synthesis of N-((1S,4S)-4-((1-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide (Compound 27A)

[0280] To a solution of 6-(((1S,4S)-4-aminocyclohexyl)amino)-2-methyl-4-(trifluoromethyl)pyridazin-3(2H)-one (27A-3) (250 mg, 0.860 mmol) in dimethyl sulfoxide (2.0 mL) were added 1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxylic acid (193 mg, 0.990 mmol), EDCI (237 mg, 1.28 mmol), HOBt (174 mg, 224 mmol) and DIEA (0.64 mL). The reaction solution was reacted at 25 ° C for 1 hour. LCMS detection showed that the reaction was complete. The reaction solution was filtered and added with water (50 mL), extracted with ethyl acetate (50 mL × 3), washed with saturated brine (50 mL × 3), and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was prepared (Xtimate C 18 21.2*250mm 5um; 0.1% NH3.H2O-ACN; 30-62; 40mL / min) was purified to give N-((1S,4S)-4-((1-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide (Compound 27A) (151 mg, yield 62.7%).

[0281] LC-MS, M / Z(ESI):467.4[M+H] +

[0282] 1 H NMR (400MHz, DMSO-d6): δ8.31(s,1H),8.00(s,1H),7.94(d,1H),7.56(s,1H),6.59(d,1H),5.18( q,2H),3.85–3.74(m,1H),3.67–3.60(m,1H),3.50(s,3H),1.91–1.80(m,2H),1.69–1.56(m,6H).

[0283] Example 7: Preparation of 3-chloro-N-((1S,4S)-4-((1-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide (Compound 28A)

[0284] The synthetic route of compound 28A is as follows:

[0285] Step 1: Synthesis of ethyl 3-chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxylate

[0286] To a solution of ethyl 3-chloro-1H-pyrazole-4-carboxylate (1.00 g, 5.72 mmol) in N,N-dimethylformamide (10 mL) were added 2,2,2-trifluoroethyl trifluoromethanesulfonate (3.90 g, 17.2 mmol) and cesium carbonate (5.60 g, 17.2 mmol), and the reaction mixture was stirred at 25 ° C for 18 hours. LCMS detection showed that the reaction was complete. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic layers were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 100:0 to 75:25) to obtain the compound ethyl 3-chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxylate (1.20 g, yield 81.6%).

[0287] LC-MS, M / Z(ESI):257.4[M+H] +

[0288] Step 2: Synthesis of 3-chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxylic acid (Compound 28A-4)

[0289] To a solution of ethyl 3-chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxylate (1.20 g, 4.67 mmol) in tetrahydrofuran (10 mL) were added methanol (3.0 mL), water (2.0 mL), and lithium hydroxide (0.590 g, 14.0 mmol), and the reaction solution was stirred at 25°C for 2 hours. LCMS confirmed the completion of the reaction. The reaction solution was added with water (100 mL), and the pH was adjusted to 4 with 1 M dilute hydrochloric acid. The mixture was then extracted with dichloromethane (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 3-chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxylic acid (600 mg, 56.1% yield), which was used directly in the next reaction.

[0290] LC-MS, M / Z(ESI):229.0[M+H] +

[0291] Step 3: Synthesis of 3-chloro-N-((1S,4S)-4-((1-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide

[0292] To a solution of 3-chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxylic acid (100 mg, 0.430 mmol) in dimethyl sulfoxide (2.0 mL) were added 6-(((1S,4S)-4-aminocyclohexyl)amino)-2-methyl-4-(trifluoromethyl)pyridazin-3(2H)-one (152 mg, 0.520 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (126 mg, 0.650 mmol), 1-hydroxybenzotriazole (88.7 mg, 0.650 mmol) and N,N-diisopropylethylamine (0.36 mL), and the reaction solution was stirred at 25°C for 1 hour. LCMS detected that the reaction was complete, the reaction solution was filtered, the filtrate was diluted with water (50 mL), extracted with ethyl acetate (50 mL×3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product which was purified by preparative liquid chromatography (Xtimate C18 21.2*250mm 5um; 0.1% FA.H2O-ACN; 35-60; 20 mL / min) to give compound 3-chloro-N-((1S,4S)-4-((1-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide (16.4 mg, yield 7.5%).

[0293] LC-MS, M / Z(ESI):501.0[M+H] +

[0294] 1 H NMR (400MHz, CD3OD): δ8.22(s,1H),7.43(s,1H),4.97(q,2H),4.03–3.95(m,1H),3.81–3.74(m,1H),3.63(s,3H),1.86–1.76(m,8H).

[0295] Example 8: Preparation of N-((1S,3S)-3-((1-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclobutyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide (Compound 29A)

[0296] The synthetic route of compound 29A is as follows:

[0297] Step 1: Synthesis of tert-butyl (1S,3S)-3-((1-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclobutyl)carbamate

[0298] 6-Chloro-2-methyl-4-(trifluoromethyl)pyridazin-3(2H)-one (100 mg, 0.470 mmol) was dissolved in toluene (2 mL), and tert-butyl ((1S,3S)-3-aminocyclobutyl)carbamate (105 mg, 0.565 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (II) (40.0 mg, 0.0470 mmol) and cesium carbonate (306 mg, 0.941 mmol) were added, and the reaction solution was stirred at 80 ° C for 14 hours. LC-MS detection showed that the reaction was complete. Water (50 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (50 mL×3). The organic layers were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product which was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 100:0 to 80:20) to give compound (1S,3S)-3-((1-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclobutyl)carbamic acid tert-butyl ester (100 mg, yield 58.6%).

[0299] LC-MS, M / Z(ESI):363.4[M+H] + .

[0300] Step 2: Synthesis of 6-(((1S,3S)-3-aminocyclobutyl)amino)-2-methyl-4-(trifluoromethyl)pyridazin-3(2H)-one trifluoroacetate

[0301] Tert-butyl (1S,3S)-3-((1-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclobutyl)carbamate (100 mg, 0.276 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (2 mL) was added. The reaction mixture was allowed to react at 25°C for 1.5 hours. LC-MS analysis confirmed the completion of the reaction, and the reaction mixture was concentrated under reduced pressure to afford the crude product, 6-(((1S,3S)-3-aminocyclobutyl)amino)-2-methyl-4-(trifluoromethyl)pyridazin-3(2H)-one trifluoroacetate (100 mg, 96.7% yield), which was used directly in the next step.

[0302] LC-MS, M / Z(ESI):263.4[M+H] + .

[0303] Step 3: Synthesis of N-((1S,3S)-3-((1-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclobutyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide

[0304] 6-(((1S,3S)-3-Aminocyclobutyl)amino)-2-methyl-4-(trifluoromethyl)pyridazin-3(2H)-one trifluoroacetate (70.0 mg, 0.240 mmol) and 1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxylic acid (46.6 mg, 0.240 mmol) were dissolved in dimethyl sulfoxide (3 mL), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (92.1 mg, 0.480 mmol), 1-hydroxybenzotriazole (64.9 mg, 0.480 mmol) and N,N-diisopropylethylamine (155 mg, 1.20 mmol) were added. The reaction solution was stirred at 25 ° C. under N2 protection for 2 hours. The reaction was completed by LC-MS, and the reaction solution was purified by preparative liquid chromatography (Xtimate C18 21.2*250mm 5um; 0.05% NH3.H2O-ACN; 20-45; 20 mL / min) to give compound N-((1S,3S)-3-((1-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclobutyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide (Compound 29A) (74.0 mg, 70.3% yield).

[0305] LC-MS, M / Z(ESI):439.2[M+H] + .

[0306] 1 H NMR (400MHz, DMSO-d6): δ8.38(d,1H),8.28(s,1H),7.97(s,1H),7.41(s,1H),6.97(d,1H),5.19( q,2H),4.14–4.04(m,1H),3.76–3.67(m,1H),3.51(s,3H),2.72–2.65(m,2H),1.91–1.83(m,2H).

[0307] Example 9: Preparation of 3-chloro-N-((1S,4S)-4-((6-oxo-1-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide (Compound 30A)

[0308] The synthetic route of compound 30A is as follows:

[0309] Step 1: Synthesis of 4-bromo-6-chloro-2-(2,2,2-trifluoroethyl)pyridazin-3(2H)-one

[0310] To a solution of 4-bromo-6-chloropyridazin-3(2H)-one (500 mg, 2.39 mmol) in N,N-dimethylformamide (10 mL) were added 2,2,2-trifluoroethyl trifluoromethanesulfonate (831 mg, 3.58 mmol) and potassium carbonate (989 mg, 7.16 mmol). The resulting mixture was stirred at 25°C for 18 hours. LCMS confirmed the reaction was complete. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (40 mL) and concentrated to yield the crude product. This crude product was purified on a silica gel column (petroleum ether:ethyl acetate (v / v) = 100:0 to 80:20) to afford 4-bromo-6-chloro-2-(2,2,2-trifluoroethyl)pyridazin-3(2H)-one (500 mg, 71.9% yield).

[0311] LC-MS, M / Z(ESI):293.2[M+H] + .

[0312] Step 2: Synthesis of 6-chloro-2-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0313] To a solution of 4-bromo-6-chloro-2-(2,2,2-trifluoroethyl)pyridazin-3(2H)-one (2.00 g, 6.862 mmol) in N-methylpyrrolidone (40 mL) was added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (3.95 g, 20.6 mmol) and cuprous iodide (261 mg, 1.37 mmol). The resulting mixture was reacted at 25°C for 14 hours. LCMS confirmed the reaction was complete. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated brine (100 mL) and concentrated to yield the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 100:0 to 90:10) to give 6-chloro-2-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (1.00 g, 51.9% yield).

[0314] LC-MS, M / Z(ESI):281.0[M+H] + .

[0315] Step 3: Synthesis of tert-butyl (1S,4S)-4-((6-oxo-1-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)carbamate

[0316] To a solution of tert-butyl ((1S,4S)-4-aminocyclohexyl)carbamate (382 mg, 1.78 mmol) in 1,4-dioxane (10 mL) was added 6-chloro-2-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (500 mg, 1.78 mmol), Ruphos Pd G4 (1.55 g, 1.82 mmol), and cesium carbonate (1.74 g, 5.35 mmol). The resulting mixture was stirred at 80°C for 18 hours. LCMS confirmed the reaction was complete. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), and concentrated to yield the crude product. The crude product was purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 100:0 to 75:25) to give compound tert-butyl (1S,4S)-4-((6-oxo-1-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)carbamate (200 mg, yield 24.5%).

[0317] LC-MS, M / Z(ESI):459.2[M+H] + .

[0318] Step 4: Synthesis of 6-(((1S,4S)-4-aminocyclohexyl)amino)-2-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)pyridazin-3(2H)-one trifluoroacetate

[0319] To a solution of tert-butyl (1S,4S)-4-((6-oxo-1-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)carbamate (100 mg, 0.218 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (2 mL, 0.218 mmol), and the resulting mixture was stirred at 25°C for 3 hours. LCMS analysis confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure to afford 6-(((1S,4S)-4-aminocyclohexyl)amino)-2-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)pyridazin-3(2H)-one trifluoroacetate (100 mg, crude), which was used directly in the next reaction.

[0320] LC-MS, M / Z(ESI):359.0[M+H] + .

[0321] Step 5: Synthesis of 3-chloro-N-((1S,4S)-4-((6-oxo-1-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide (Compound 30A)

[0322] To a solution of 6-(((1S,4S)-4-aminocyclohexyl)amino)-2-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)pyridazin-3(2H)-one trifluoroacetate (80.0 mg, 0.167 mmol) and 3-chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxylic acid (38.3 mg, 0.167 mmol) in dimethyl sulfoxide (2 mL) was added N,N-diisopropylethylamine (0.138 mL, 0.835 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (48.2 mg, 0.251 mmol), and 1-hydroxybenzotriazole (33.9 mg, 0.251 mmol), and the resulting mixture was stirred at 25° C. for 14 hours. The reaction was complete by LCMS. The reaction solution was purified by preparative liquid chromatography (Xtimate C18 21.2*250mm 5um; 0.05% NH3.H2O-ACN; 20-45; 20 mL / min) to give compound 3-chloro-N-((1S,4S)-4-((6-oxo-1-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide (Compound 30A) (37.0 mg, yield 38.8%).

[0323] LC-MS, M / Z(ESI):569.2[M+H] + .

[0324] 1 H NMR (400MHz, DMSO-d6): δ8.37(s,1H),7.87(d,1H),7.65(s,1H),6.82(d,1H),5.20(q,2H) ,4.75(q,2H),3.85–3.74(m,1H),3.64–3.55(m,1H),1.85–1.75(m,2H),1.72–1.60(m,6H).

[0325] Example 10: Preparation of 3-chloro-1-(2,2-difluoroethyl)-N-((1S,4S)-4-((1-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)-1H-pyrazole-4-carboxamide (Compound 34A)

[0326] The synthetic route of compound 34A is as follows:

[0327] Step 1: Synthesis of ethyl 3-chloro-1-(2,2-difluoroethyl)-1H-pyrazole-4-carboxylate

[0328] To a solution of ethyl 3-chloro-1H-pyrazole-4-carboxylate (1.00 g, 5.30 mmol) in N,N-dimethylformamide (10 mL) were added 2,2-difluoroethyl trifluoromethanesulfonate (2.45 g, 11.5 mmol) and cesium carbonate (3.73 g, 11.5 mmol), and the resulting mixture was stirred at 25° C. for 18 hours. LCMS indicated the reaction was complete, and the reaction solution was diluted with water (100 mL), then extracted with ethyl acetate (100 mL × 3). The organic layers were combined and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 100:0 to 80:20) to give ethyl 3-chloro-1-(2,2-difluoroethyl)-1H-pyrazole-4-carboxylate (500 mg, 36.6% yield).

[0329] LC-MS, M / Z(ESI):239.0[M+H] +

[0330] Step 2: Synthesis of 3-chloro-1-(2,2-difluoroethyl)-1H-pyrazole-4-carboxylic acid

[0331] To a solution of ethyl 3-chloro-1-(2,2-difluoroethyl)-1H-pyrazole-4-carboxylate (500 mg, 2.09 mmol) in tetrahydrofuran (5 mL), methanol (2 mL), and water (1 mL) was added lithium hydroxide (264 mg, 6.29 mmol). The resulting mixture was stirred at 25°C for 2 h. LCMS confirmed the reaction was complete. The reaction solution was diluted with water (100 mL), adjusted to pH 4 with 1 M hydrochloric acid, and extracted with dichloromethane (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to afford 3-chloro-1-(2,2-difluoroethyl)-1H-pyrazole-4-carboxylic acid (420 mg, 95.2% yield), which was used directly in the next step.

[0332] LC-MS, M / Z(ESI):211.0[M+H] +

[0333] Step 3: Synthesis of 3-chloro-1-(2,2-difluoroethyl)-N-(cis-4-((1-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)-1H-pyrazole-4-carboxamide

[0334] To a solution of 3-chloro-1-(2,2-difluoroethyl)-1H-pyrazole-4-carboxylic acid (150 mg, 0.712 mmol) in dimethyl sulfoxide (2 mL) were added 6-(((1S,4S)-4-aminocyclohexyl)amino)-2-methyl-4-(trifluoromethyl)pyridazin-3(2H)-one (207 mg, 0.712 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (205 mg, 1.069 mmol), 1-hydroxybenzotriazole (144 mg, 1.07 mmol) and N,N-diisopropylethylamine (0.588 mL, 3.56 mmol), and the reaction solution was reacted at 25°C for 1 hour. LCMS detection showed that the reaction was complete. The reaction solution was diluted with saturated brine (50 mL), then extracted with ethyl acetate (50 mL×3). The organic phases were combined and concentrated to give a crude product, which was purified by preparative liquid chromatography (Xtimate C18 21.2*550mm 5um; 0.1% FA.H2O-ACN; 30-55; 20 mL / min) to give compound 3-chloro-1-(2,2-difluoroethyl)-N-((1S,4S)-4-((1-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)-1H-pyrazole-4-carboxamide (59.8 mg, yield 17.2%).

[0335] LC-MS, M / Z(ESI):483.4[M+H] +

[0336] 1 H NMR (400MHz, CD3OD): δ8.15(s,1H),7.42(s,1H),6.20(tt,1H),4.60–4.58(m ,2H),4.01–3.94(m,1H),3.80–3.74(m,1H),3.62(s,3H),1.87–1.74(m,8H).

[0337] Example 11: Preparation of 3-chloro-N-((1S,4S)-4-((1-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)amino)cyclohexyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide (Compound 39A)

[0338] The synthetic route of compound 39A is as follows:

[0339] Step 1: Synthesis of 5-bromo-1-methyl-3-(trifluoromethyl)pyridin-2(1H)-one

[0340] To a solution of 5-bromo-3-(trifluoromethyl)pyridin-2(1H)-one (5.00 g, 20.7 mmol) in N,N-dimethylformamide (50 mL) were added potassium carbonate (14.3 g, 103 mmol) and iodomethane (3.52 g, 24.8 mmol), and the resulting mixture was stirred at 25°C for 2 hours. LCMS indicated the reaction was complete, and the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (40 mL), and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 100:0 to 90:10) to give 5-bromo-1-methyl-3-(trifluoromethyl)pyridin-2(1H)-one (4.00 g, 75.6% yield).

[0341] LC-MS, M / Z(ESI):256.0[M+H] + .

[0342] Step 2: Synthesis of tert-butyl (1S,4S)4-((1-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)amino)cyclohexyl)carbamate

[0343] To a solution of 5-bromo-1-methyl-3-(trifluoromethyl)pyridin-2(1H)-one (200 mg, 0.781 mmol) and tert-butyl ((1S,4S)-4-aminocyclohexyl)carbamate (251 mg, 1.17 mmol) in N,N-dimethylformamide (10 mL) were added sodium tert-butoxide (225 mg, 2.34 mmol) and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (62.1 mg, 0.078 mmol), and the resulting mixture was stirred at 120° C. for 18 hours. LCMS detected that the reaction was complete. Water (10 mL) was added to the reaction mixture to dilute it, followed by extraction with ethyl acetate (10 mL×3). The organic layers were combined, washed with saturated brine (10 mL), and concentrated under reduced pressure to give a crude product which was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 100:0 to 95:5) to give compound (1S,4S)-tert-butyl 4-((1-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)amino)cyclohexyl)carbamate (50.0 mg, 16.4% yield).

[0344] LC-MS, M / Z(ESI):390.2[M+H] + .

[0345] Step 3: Synthesis of 5-(((1S,4S)-4-aminocyclohexyl)amino)-1-methyl-3-(trifluoromethyl)pyridin-2(1H)-one trifluoroacetate

[0346] To a solution of tert-butyl (1S,4S)-4-((1-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)amino)cyclohexyl)carbamate (20.0 mg, 0.051 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.5 mL, 0.051 mmol), and the resulting mixture was stirred at 25°C for 1 hour. LCMS analysis indicated that the reaction was complete, and the reaction solution was concentrated under reduced pressure to afford 5-(((1S,4S)-4-aminocyclohexyl)amino)-1-methyl-3-(trifluoromethyl)pyridin-2(1H)-one trifluoroacetate (20.0 mg, crude), which was used directly in the next step.

[0347] LC-MS, M / Z(ESI):290.2[M+H] + .

[0348] Step 4: Synthesis of 3-chloro-N-((1S,4S)-4-((1-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)amino)cyclohexyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide (Compound 39A)

[0349] To a solution of 5-(((1S,4S)-4-aminocyclohexyl)amino)-1-methyl-3-(trifluoromethyl)pyridin-2(1H)-one trifluoroacetate (20.0 mg, 0.069 mmol) and 3-chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxylic acid (15.8 mg, 0.069 mmol) in dimethyl sulfoxide (3 mL) were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26.5 mg, 0.138 mmol), 1-hydroxybenzotriazole (18.7 mg, 0.138 mmol) and N,N-diisopropylethylamine (0.057 mL, 0.346 mmol), and the resulting mixture was reacted at 25° C. for 18 hours. The reaction was complete after LCMS analysis. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (Xtimate C18 21.2*250mm 5um; 0.05% NH3.H2O-ACN; 15-35; 25 mL / min) to give compound 3-chloro-N-((1S,4S)-4-((1-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)amino)cyclohexyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide (Compound 39A) (7.60 mg, 21.4% yield).

[0350] LC-MS, M / Z(ESI):500.2[M+H] + .

[0351] 1 H NMR (400MHz, DMSO-d6): δ8.39(s,1H),7.81(d,1H),7.68(d,1H),7.15(d,1H),5.20(q,2 H),4.93(d,1H),3.93–3.70(m,1H),3.44(s,3H),3.20–3.13(m,1H),1.75–1.56(m,8H).

[0352] Example 12: Preparation of 3-chloro-N-((1S,4S)-4-((1-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)-1-(1-(methylsulfonyl)ethyl)-1H-pyrazole-4-carboxamide (Compound 42A)

[0353] The synthetic route of compound 42A is as follows:

[0354] Step 1: Synthesis of 6-(((1S,4S)-4-aminocyclohexyl)amino)-2-methyl-4-(trifluoromethyl)pyridazin-3(2H)-one hydrochloride

[0355] At room temperature, tert-butyl (1S,4S)-4-((1-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)carbamate (100 mg, 0.26 mmol) was dissolved in dichloromethane (2 mL) and stirred in an ice bath at 0°C for 10 minutes. A solution of hydrogen chloride in 1,4-dioxane (0.13 mL, 0.13 mmol) was then slowly added dropwise. After the addition was complete, the reaction solution was allowed to warm to room temperature and stirred at room temperature for 1 hour. After TLC monitoring indicated complete reaction of the starting material, stirring was stopped and the reaction solution was concentrated under reduced pressure to yield 6-(((1S,4S)-4-aminocyclohexyl)amino)-2-methyl-4-(trifluoromethyl)pyridazin-3(2H)-one hydrochloride (100 mg, crude), which was used directly in the next reaction.

[0356] LC-MS, M / Z(ESI):291.1[M+H] +

[0357] Step 2: Synthesis of 3-chloro-N-((1S,4S)-4-((1-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)-1(1-(methylsulfonyl)ethyl)-1H-pyrazole-4-carboxamide

[0358] At room temperature, compound 3-chloro-1-(1-(methylsulfonyl)ethyl)-1H-pyrazole-4-carboxylic acid (32.00 mg, 0.13 mmol) was dissolved in anhydrous N,N-dimethylformamide (1 mL), and then N,N-diisopropylethylamine (65.47 mg, 0.50 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (96.98 mg, 0.25 mmol) were added. The mixture was stirred at room temperature for 30 minutes, and then 6-(((1S,4S)-4-aminocyclohexyl)amino)-2-methyl-4-(trifluoromethyl)pyridazin-3(2H)-one hydrochloride (50.00 mg, 0.15 mmol) was added, and stirring was continued at room temperature for 4 hours. After TLC monitoring showed that the reaction of the raw materials was complete, stirring was stopped, the reaction solution was cooled to room temperature, and then 10 mL of water was added to dilute it, extracted with ethyl acetate (5 mL×3), the organic phase was collected and dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V)=100:20) to obtain compound 3-chloro-N-((1S,4S)-4-((1-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)-1-(1-(methylsulfonyl)ethyl)-1H-pyrazole-4-carboxamide.

[0359] LC-MS, M / Z(ESI):525.0[M+H] +

[0360] 1 H NMR (400MHz, DMSO-d6): δ8.52(s,1H),7.87(d,1H),7.54(s,1H),6.62(d,1H),5.92(q,1H),3.85–3. 76(m,1H),3.62(s,1H),3.50(s,3H),2.99(s,3H),1.83(d,J=7.1Hz,3H),1.75(s,2H),1.65(d,6H).

[0361] Example 13: Preparation of 3-chloro-1-(2-hydroxy-2-methylpropyl)-N-((1S,4S)-4-((1-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)-1H-pyrazole-4-carboxamide (Compound 48A)

[0362] The synthetic route of compound 48A is as follows:

[0363] To a solution of 3-chloro-1-(2-hydroxy-2-methylpropyl)-1H-pyrazole-4-carboxylic acid (200 mg, 0.915 mmol) in dimethyl sulfoxide (2 mL) were added 6-(((1S,4S)-4-aminocyclohexyl)amino)-2-methyl-4-(trifluoromethyl)pyridazin-3(2H)-one (266 mg, 0.915 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (263 mg, 1.37 mmol), 1-hydroxybenzotriazole (185 mg, 1.37 mmol), and N,N-diisopropylethylamine (0.756 mL, 4.58 mmol), and the reaction solution was reacted at 25° C. for 1 hour. LCMS detection showed that the reaction was complete. The reaction solution was diluted with saturated brine (50 mL), then extracted with ethyl acetate (50 mL×3). The organic phases were combined and concentrated to give a crude product, which was purified by preparative liquid chromatography (Xtimate C18 21.2*250mm 5μm; 0.1% FA.H2O-ACN; 25-55; 20 mL / min) to give compound 3-chloro-1-(2-hydroxy-2-methylpropyl)-N-((1S,4S)-4-((1-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)-1H-pyrazole-4-carboxamide (115 mg, yield 25.6%).

[0364] LC-MS, M / Z(ESI):491.2[M+H] +

[0365] 1 H NMR (400MHz, CD3OD): δ8.08(s,1H),7.43(s,1H),4.06(s,2H),4.02–3.97(m ,1H),3.80–3.75(m,1H),3.63(s,3H),1.86–1.76(m,8H),1.19–1.17(m,6H).

[0366] Example 14: Preparation of 3-chloro-1-methyl-N-((1S,4S)-4-((1-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)-1H-pyrazole-4-carboxamide (Compound 49A)

[0367] The synthetic route of compound 49A is as follows:

[0368] To a solution of 6-(((1S,4S)-4-aminocyclohexyl)amino)-2-methyl-4-(trifluoromethyl)pyridazin-3(2H)-one (200 mg, 0.689 mmol) in dimethyl sulfoxide (2 mL) was added 3-chloro-1-methyl-1H-pyrazole-4-carboxylic acid (111 mg, 0.689 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (198 mg, 1.03 mmol), 1-hydroxybenzotriazole (140 mg, 1.03 mmol), and N,N-diisopropylethylamine (0.569 mL, 3.45 mmol), and the resulting mixture was stirred at 25° C. for 1 hour. The reaction was complete by LCMS. The reaction solution was diluted with saturated brine (50 mL), then extracted with ethyl acetate (50 mL×3). The organic phases were combined and concentrated to give a crude product, which was purified by preparative liquid chromatography (Xtimate C18 30*150mm 5um; 0.1% FA.H2O-ACN; 28-48; 25 mL / min) to give compound 3-chloro-1-methyl-N-((1S,4S)-4-((1-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)-1H-pyrazole-4-carboxamide (16.7 mg, yield 2.6%).

[0369] LC-MS, M / Z(ESI):433.2[M+H] +

[0370] 1 H NMR (400MHz, CD3OD): δ8.04(s,1H),7.43(s,1H),4.02–3.95(m,1H),3.87(s,3H),3.81–3.74(m,1H),3.63(s,3H),1.87–1.73(m,8H).

[0371] Example 15: Preparation of 4-fluoro-N-((1S,4S)-4-((1-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)benzamide (Compound 50A)

[0372] The synthetic route of compound 50A is as follows:

[0373] At room temperature, the compound p-fluorobenzoic acid (18.00 mg, 0.13 mmol) was dissolved in anhydrous N,N-dimethylformamide (1 mL), and then N,N-diisopropylethylamine (65.47 mg, 0.50 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl)uronium hexafluorophosphate (96.98 mg, 0.25 mmol) were added. The reaction solution was stirred at room temperature for 30 minutes, and then 6-(((1S,4S)-4-aminocyclohexyl)amino)-2-methyl-4-(trifluoromethyl)pyridazin-3(2H)-one hydrochloride (50.00 mg, 0.15 mmol) was added, and the reaction solution was continued to stir at room temperature for 4 hours. After TLC monitoring showed that the reaction of the raw materials was completed, stirring was stopped, the reaction solution was cooled to room temperature, and then 10 mL of water was added to dilute it, and then extracted with ethyl acetate (5 mL×3). The organic phase was collected and dried over anhydrous sodium sulfate, and the organic phase was concentrated by distillation under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 100:15) to obtain compound 4-fluoro-N-((1S,4S)-4-((1-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)benzamide.

[0374] LC-MS, M / Z(ESI):413.0[M+H] +

[0375] 1 H NMR (400MHz, DMSO-d6): δ8.26(d,1H),7.98–7.87(m,2H),7.57(s,1H),7.33-.23(m,2H),6 .62(d,1H),3.86-.80(m,1H),3.64(s,1H),3.51(s,3H),1.87(dd,2H),1.73-1.61(m,6H).

[0376] Example 16: Preparation of 3-chloro-N-((1S,4S)-4-((1-cyclopropyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide (Compound 31A)

[0377] The synthetic route of compound 31A is as follows:

[0378] Step 1: Synthesis of 4-bromo-6-chloro-2-cyclopropylpyridazin-3(2H)-one

[0379] To a solution of 4-bromo-6-chloropyridazin-3(2H)-one (7.50 g, 35.8 mmol) in dioxane (60 mL) were added pyridine (23.1 mL, 286 mmol), triethylamine (24.9 mL, 179 mmol), cyclopropylboronic acid (9.23 g, 107 mmol), and copper acetate (6.50 g, 35.8 mmol). The resulting reaction solution was stirred at 80°C under nitrogen for 30 minutes. LCMS analysis confirmed the reaction was complete. The reaction solution was cooled to room temperature, diluted with water (50 mL), and then extracted with ethyl acetate (50 mL x 3). The organic phases were combined and concentrated to give the crude product, which was purified on a silica gel column (petroleum ether:ethyl acetate (v / v) = 100:0 to 80:20) to afford 4-bromo-6-chloro-2-cyclopropylpyridazin-3(2H)-one (1.40 g, 15.7% yield).

[0380] LC-MS, M / Z(ESI):249.0[M+H] +

[0381] Step 2: Synthesis of 6-chloro-2-cyclopropyl-4-(trifluoromethyl)pyridazin-3(2H)-one

[0382] To a solution of 4-bromo-6-chloro-2-cyclopropylpyridazin-3(2H)-one (1.40 g, 5.61 mmol) in N-methylpyrrolidone (15 mL) was added cuprous iodide (534 mg, 2.81 mmol) and methyl fluorosulfonyldifluoroacetate (5.39 g, 28.1 mmol), and the resulting reaction solution was stirred at 100 ° C for 14 hours under a nitrogen atmosphere. LCMS detection showed that the reaction was complete. The reaction solution was cooled to room temperature, diluted with water (50 mL), and then extracted with ethyl acetate (50 mL × 3). The organic phases were combined and concentrated under reduced pressure to give a crude product, which was purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 100:0 to 90:10) to give compound 6-chloro-2-cyclopropyl-4-(trifluoromethyl)pyridazin-3(2H)-one (1.20 g, 89.6% yield).

[0383] LC-MS, M / Z(ESI):239.0[M+H] +

[0384] Step 3: Synthesis of tert-butyl (1S,4S)-4-((1-cyclopropyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)carbamate

[0385] To a solution of 6-chloro-2-cyclopropyl-4-(trifluoromethyl)pyridazin-3(2H)-one (1.20 g, 5.03 mmol) in 1,4-dioxane (15 mL) were added tert-butyl ((1S,4S)-4-aminocyclohexyl)carbamate (2.16 g, 10.1 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (428 mg, 0.503 mmol), and cesium carbonate (4.92 g, 15.1 mmol). The resulting reaction solution was stirred at 80°C under nitrogen for 18 hours. LCMS confirmed the reaction was complete. The reaction solution was cooled to room temperature, diluted with water (100 mL), and then extracted with ethyl acetate (50 mL×3). The organic layers were combined and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 100:0 to 80:20) to give compound (1S,4S)-4-((1-cyclopropyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)carbamic acid tert-butyl ester (1.50 g, yield 71.6%).

[0386] LC-MS, M / Z(ESI):417.4[M+H] +

[0387] Step 4: Synthesis of 6-(((1S,4S)-4-aminocyclohexyl)amino)-2-cyclopropyl-4-(trifluoromethyl)pyridazin-3(2H)-one trifluoroacetate

[0388] To a solution of tert-butyl (1S,4S)-4-((1-cyclopropyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)carbamate (500 mg, 1.20 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (2 mL), and the resulting mixture was stirred at 25 ° C. for 14 hours. LCMS detection showed that the reaction was complete. The reaction solution was directly concentrated under reduced pressure to give compound 6-(((1S,4S)-4-aminocyclohexyl)amino)-2-cyclopropyl-4-(trifluoromethyl)pyridazin-3(2H)-one trifluoroacetate (500 mg, crude product), which was used directly in the next step.

[0389] LC-MS, M / Z(ESI):317.2[M+H] +

[0390] Step 5: Synthesis of 3-chloro-N-((1S,4S)-4-((1-cyclopropyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide

[0391] To a solution of 6-(((1S,4S)-4-aminocyclohexyl)amino)-2-cyclopropyl-4-(trifluoromethyl)pyridazin-3(2H)-one trifluoroacetate (500 mg, 1.11 mmol) and 3-chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxylic acid (253 mg, 1.11 mmol) in dimethyl sulfoxide (10 mL) were added N,N-diisopropylethylamine (0.914 mL, 5.53 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (318 mg, 1.66 mmol), and 1-hydroxybenzotriazole (224 mg, 1.66 mmol), and the resulting mixture was stirred at 25° C. for 14 hours. The reaction was complete by LCMS. The reaction solution was purified by preparative liquid chromatography (Xtimate C18 21.2*550mm 5um; 0.1% FA.H2O-ACN; 30-60; 20 mL / min) to obtain compound 3-chloro-N-((1S,4S)-4-((1-cyclopropyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide (350 mg, yield 60.0%).

[0392] LC-MS, M / Z(ESI):527.2[M+H] +

[0393] 1 H NMR (400MHz, CD3OD): δ8.21(s,1H),7.38(s,1H),4.96(q,2H),4.13–4.04(m,1H),4.01–3 .93(m,1H),3.74–3.67(m,1H),1.84–1.71(m,8H),1.14–1.08(m,2H),0.97–0.90(m,2H).

[0394] Example 17: Preparation of 3-fluoro-N-((1S,4S)-4-((1-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide (Compound 45A)

[0395] The synthetic route of compound 45A is as follows:

[0396] Step 1: Synthesis of 4-bromo-3-fluoro-1-(2,2,2-trifluoroethyl)-1H-pyrazole

[0397] To a solution of 4-bromo-3-fluoro-1H-pyrazole (0.80 g, 4.85 mmol) in N,N-dimethylformamide (5 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.25 g, 9.70 mmol) and cesium carbonate (3.16 g, 9.70 mmol), and the resulting mixture was stirred at 25°C for 14 hours. LCMS analysis confirmed the reaction was complete. The reaction solution was diluted with water (50 mL) and then extracted with ethyl acetate (30 mL x 3). The organic layers were combined and concentrated under reduced pressure to afford the crude product, which was purified by silica gel column chromatography (PE:EA (V / V) = 100:0 to 90:10) to afford 4-bromo-3-fluoro-1-(2,2,2-trifluoroethyl)-1H-pyrazole (0.70 g, 58.4% yield).

[0398] 1 H NMR (400MHz, DMSO-d6): δ8.11(s,1H),5.06(q,2H).

[0399] Step 2: Synthesis of methyl 3-fluoro-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxylate

[0400] To a solution of 4-bromo-3-fluoro-1-(2,2,2-trifluoroethyl)-1H-pyrazole (300 mg, 1.22 mmol) in methanol (10 mL) were added (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride (88.9 mg, 0.121 mmol) and triethylamine (0.506 mL, 3.64 mmol). The resulting mixture was stirred at 80°C under a CO atmosphere for 18 hours. LCMS confirmed the reaction was complete. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and then extracted with dichloromethane (10 mL x 3). The organic phases were combined and concentrated under reduced pressure to afford the crude product, which was purified by silica gel column chromatography (PE:EA (V / V) = 100:0 to 80:20) to afford methyl 3-fluoro-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxylate (170 mg, 61.9% yield).

[0401] LC-MS, M / Z(ESI):227.0[M+H] +

[0402] Step 3: Synthesis of 3-fluoro-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxylic acid

[0403] To a mixture of methyl 3-fluoro-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxylate (40.0 mg, 0.177 mmol) in tetrahydrofuran (2 mL) and water (2 mL) was added lithium hydroxide (37.1 mg, 0.884 mmol), and the resulting mixture was stirred at 25°C for 14 hours. LCMS analysis confirmed the reaction was complete. The reaction solution was adjusted to pH 3 with 1M hydrochloric acid and then extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 3-fluoro-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxylic acid (30.0 mg, 79.9% yield). The crude product was used directly in the next step without purification.

[0404] LC-MS, M / Z(ESI):213.0[M+H] +

[0405] Step 4: Synthesis of 3-fluoro-N-((1S,4S)-4-((1-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide

[0406] To a solution of 6-(((1S,4S)-4-aminocyclohexyl)amino)-2-methyl-4-(trifluoromethyl)pyridazin-3(2H)-one (41.1 mg, 0.141 mmol) and 3-fluoro-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxylic acid (30.0 mg, 0.141 mmol) in dimethyl sulfoxide (0.117 mL, 0.707 mmol) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (54.2 mg, 0.283 mmol), 1-hydroxybenzotriazole (38.2 mg, 0.283 mmol), and N,N-diisopropylethylamine (91.4 mg, 0.707 mmol). The reaction was stirred at 25°C for 14 hours. LCMS indicated the reaction was complete. The reaction solution was directly purified by preparative liquid chromatography (Xtimate C18 21.2*550mm 5um; 0.1% FA.H2O-ACN; 30-60; 20 mL / min) to obtain compound 3-chloro-1-(2,2-difluoroethyl)-N-((1S,4S)-4-((1-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)-1H-pyrazole-4-carboxamide (30.1 mg, 32.1% yield).

[0407] LC-MS, M / Z(ESI):485.4[M+H] +

[0408] 1 H NMR (400MHz, CD3OD): δ8.10–8.07(m,1H),7.43(s,1H),4.91–4.87(m,2H),3.97–3 .90(m,1H),3.80–3.75(m,1H),3.62(s,3H),1.91–1.84(m,2H),1.82–1.68(m,6H).

[0409] Example 18: Preparation of 3-chloro-N-((1S,4S)-4-((5-(difluoromethyl)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide (Compound 51A)

[0410] The synthetic route of compound 51A is as follows:

[0411] Step 1: Synthesis of (E)-6-chloro-2-methyl-4-phenylvinylpyridazin-3(2H)-one

[0412] To a solution of 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (1.21 g, 5.41 mmol) in 1,4-dioxane (15 mL) were added (E)-phenylvinylboronic acid (1.00 g, 6.76 mmol), potassium phosphate (1.72 g, 8.11 mmol), and bis(triphenylphosphine)palladium dichloride (0.38 g, 0.541 mmol). The resulting mixture was stirred at 85° C. under nitrogen for 18 hours. LCMS analysis indicated that the reaction was complete. The reaction solution was cooled to room temperature, diluted with water (100 mL), and then extracted with ethyl acetate (100 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (PE:EA (V / V) = 100:0-85:15) to obtain compound (E)-6-chloro-2-methyl-4-phenylvinylpyridazin-3(2H)-one (1.20 g, yield 90.2%).

[0413] LC-MS, M / Z(ESI):247.0[M+H] +

[0414] Step 2: Synthesis of 6-chloro-2-methyl-3-oxo-2,3-dihydropyridazine-4-carbaldehyde

[0415] To a mixture of (E)-6-chloro-2-methyl-4-phenylvinylpyridazin-3(2H)-one (800 mg, 3.24 mmol) in acetonitrile (3 mL), ethyl acetate (2 mL), and water (3 mL) at 0°C were added ruthenium trichloride (84.8 mg, 0.324 mmol) and sodium periodate (2.08 mg, 9.73 mmol). The resulting mixture was stirred at 25°C for 18 hours. LCMS confirmed the reaction was complete. The resulting mixture was diluted with water (50 mL) and then extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to afford 6-chloro-2-methyl-3-oxo-2,3-dihydropyridazine-4-carbaldehyde (500 mg, crude product), which was used directly in the next reaction.

[0416] LC-MS, M / Z(ESI):173.4[M+H] +

[0417] Step 3: Synthesis of 6-chloro-4-(difluoromethyl)-2-methylpyridazin-3(2H)-one

[0418] To a solution of 6-chloro-2-methyl-3-oxo-2,3-dihydropyridazine-4-carbaldehyde (500 mg, 1.74 mmol) in dichloromethane (5 mL) at 0°C was added diethylaminosulfur trifluoride (841 mg, 5.22 mmol), and the resulting mixture was stirred at 20°C for 18 hours. LCMS confirmed the reaction was complete. The reaction solution was quenched with saturated aqueous sodium carbonate (30 mL) and then extracted with dichloromethane (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 100:0-90:10) to afford 6-chloro-4-(difluoromethyl)-2-methylpyridazin-3(2H)-one (160 mg, 33.1% yield).

[0419] LC-MS, M / Z(ESI):195.0[M+H] +

[0420] Step 4: Synthesis of tert-butyl (1S,4S)-4-((5-(difluoromethyl)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)carbamate

[0421] To a solution of 6-chloro-4-(difluoromethyl)-2-methylpyridazin-3(2H)-one (150 mg, 0.771 mmol) in 1,4-dioxane (2 mL) were added tert-butyl ((1S,4S)-4-aminocyclohexyl)carbamate (330 mg, 1.54 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (65.6 mg, 0.077 mmol), and cesium carbonate (754 mg, 2.31 mmol). The resulting mixture was stirred at 25° C. under nitrogen for 14 hours. The reaction was complete by LCMS. The reaction solution was diluted with water (30 mL), then extracted with ethyl acetate (50 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product which was purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 100:0-75:35) to obtain compound (1S,4S)-4-((5-(difluoromethyl)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)carbamic acid tert-butyl ester (100 mg, yield 34.8%).

[0422] LC-MS, M / Z(ESI):373.2[M+H] +

[0423] Step 5: Synthesis of 6-(((1S,4S)-4-aminocyclohexyl)amino)-4-(difluoromethyl)-2-methylpyridazin-3(2H)-one

[0424] To tert-butyl (1S,4S)-4-((5-(difluoromethyl)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)carbamate (30.0 mg, 0.073 mmol) was added hydrochloric acid (2 mL, 4 M dioxane solution), and the resulting mixture was stirred at 25 ° C for 1 hour. LCMS detection showed that the reaction was complete. The reaction solution was directly concentrated to give 6-(((1S,4S)-4-aminocyclohexyl)amino)-4-(difluoromethyl)-2-methylpyridazin-3(2H)-one hydrochloride (30.0 mg, crude product), which was used directly in the next reaction.

[0425] LC-MS, M / Z(ESI):273.4[M+H] +

[0426] Step 6: Synthesis of 3-chloro-N-((1S,4S)-4-((5-(difluoromethyl)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide

[0427] To a solution of 6-(((1S,4S)-4-aminocyclohexyl)amino)-4-(difluoromethyl)-2-methylpyridazin-3(2H)-one (60.0 mg, 0.220 mmol) and 3-chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxylic acid (50.4 mg, 0.220 mmol) in dimethyl sulfoxide (3 mL) was added N,N-diisopropylethylamine (142 mg, 1.10 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (84.6 mg, 0.440 mmol), and 1-hydroxybenzotriazole (59.5 mg, 0.440 mmol), and the resulting mixture was stirred at 25° C. for 18 hours. The reaction was complete by LCMS. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to yield a crude product. The crude product was purified by preparative liquid chromatography (Prime C18, 30*150 mm, 5 μm; 0.05% NH3.H2O-ACN; 35-56; 25 mL / min) to yield 3-chloro-N-((1S,4S)-4-((5-(difluoromethyl)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide (12.0 mg, 11.3% yield).

[0428] LC-MS, M / Z(ESI):483.2[M+H] +

[0429] 1 H NMR (400MHz, CD3OD): δ8.22(s,1H),7.27(s,1H),6.76(t,1H),4.97(q,2H),4.02–3.92(m,1H),3.82–3.73(m,1H),3.62(s,3H),1.86–1.73(m,8H).

[0430] Example 19: Preparation of 3-chloro-N-((1S,4S)-4-((1-ethyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide (Compound 52A)

[0431] The synthetic route of compound 52A is as follows:

[0432] Step 1: Synthesis of 4-bromo-6-chloro-2-ethylpyridazin-3(2H)-one

[0433] To a solution of 4-bromo-6-chloropyridazin-3(2H)-one (2.00 g, 9.55 mmol) in N,N-dimethylformamide (10 mL) at 0°C was added sodium hydride (955 mg, 23.9 mmol, 60% wt). The mixture was stirred at 0°C for 30 minutes, followed by the addition of iodoethane (2.98 g, 19.1 mmol). The resulting mixture was stirred at 25°C for 1 hour. LCMS confirmed the reaction was complete. The reaction solution was diluted with water (50 mL) and then extracted with ethyl acetate (20 mL x 3). The organic phases were combined and concentrated to afford the crude product, which was then purified on a silica gel column (petroleum ether:ethyl acetate (v / v) = 100:0 to 90:0) to afford 4-bromo-6-chloro-2-ethylpyridazin-3(2H)-one (1.00 g, 44.1% yield).

[0434] LC-MS, M / Z(ESI):237.0[M+H] +

[0435] Step 2: Synthesis of 6-chloro-2-ethyl-4-(trifluoromethyl)pyridazin-3(2H)-one

[0436] To a solution of 4-bromo-6-chloro-2-ethylpyridazin-3(2H)-one (1.00 g, 4.21 mmol) in N-methylpyrrolidone (10 mL) was added cuprous iodide (541 mg, 1.26 mmol) and methyl fluorosulfonyldifluoroacetate (2.63 g, 12.6 mmol). The resulting mixture was stirred at 90°C under nitrogen for 18 hours. LCMS analysis indicated the reaction was complete. The reaction solution was cooled to room temperature, diluted with water (50 mL), and then extracted with ethyl acetate (20 mL x 3). The organic phases were combined and concentrated to give the crude product. The crude product was purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 100:0 to 90:0) to give 6-chloro-2-ethyl-4-(trifluoromethyl)pyridazin-3(2H)-one (500 mg, 52.4% yield).

[0437] LC-MS, M / Z(ESI):227.0[M+H] +

[0438] Step 3: Synthesis of tert-butyl (1S,4S)-4-((1-ethyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)carbamate

[0439] To a solution of 6-chloro-2-ethyl-4-(trifluoromethyl)pyridazin-3(2H)-one (200 mg, 0.883 mmol) and tert-butyl ((1S,4S)-4-aminocyclohexyl)carbamate (378 mg, 1.77 mmol) in 1,4-dioxane (4 mL) was added methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (375 mg, 0.441 mmol) and cesium carbonate (719 mg, 2.21 mmol), and the resulting mixture was stirred at 80° C. for 18 hours. The reaction was complete by LCMS. The reaction solution was cooled to room temperature, diluted with water (20 mL), extracted with ethyl acetate (10 mL×3), and the organic phases were combined and concentrated to give a crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 100:0 to 80:20) to give compound (1S,4S)-4-((1-ethyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)carbamic acid tert-butyl ester (180 mg, yield 50.4%).

[0440] LC-MS, M / Z(ESI):405.4[M+H] +

[0441] Step 4: Synthesis of 6-(((1S,4S)-4-aminocyclohexyl)amino)-2-ethyl-4-(trifluoromethyl)pyridazin-3(2H)-one hydrochloride

[0442] To a solution of tert-butyl (1S,4S)-4-((1-ethyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)carbamate (180 mg, 0.445 mmol) in dichloromethane (2 mL) was added hydrogen chloride solution (2 mL, 4 M in 1,4-dioxane), and the resulting mixture was stirred at 25 ° C for 2 hours. LCMS detection showed that the reaction was complete. The reaction solution was directly spin-dried to give compound 6-(((1S,4S)-4-aminocyclohexyl)amino)-2-ethyl-4-(trifluoromethyl)pyridazin-3(2H)-one (120 mg, 88.6% yield), which was used directly in the next reaction.

[0443] LC-MS, M / Z(ESI):305.4[M+H] +

[0444] Step 5: Synthesis of 3-chloro-N-((1S,4S)-4-((1-ethyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide

[0445] To a solution of 6-(((1S,4S)-4-aminocyclohexyl)amino)-2-ethyl-4-(trifluoromethyl)pyridazin-3(2H)-one (60.0 mg, 0.197 mmol) and 3-chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxylic acid (54.1 mg, 0.237 mmol) in dimethyl sulfoxide (4 mL) were added N,N-diisopropylethylamine (76.5 mg, 0.591 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (56.7 mg, 0.296 mmol), and 1-hydroxybenzotriazole (39.9 mg, 0.296 mmol), and the resulting mixture was stirred at 25° C. for 18 hours. The reaction was complete by LCMS. The reaction solution was purified by preparative liquid chromatography (Xtimate C18 21.2*550mm 5um; 0.1% FA.H2O-ACN; 20-60; 20 mL / min) to obtain compound 3-chloro-N-((1S,4S)-4-((1-ethyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide (45.9 mg, 45.2% yield).

[0446] LC-MS, M / Z(ESI):515.4[M+H] +

[0447] 1 H NMR (400MHz, CD3OD): δ8.22(s,1H),7.41(s,1H),4.96(q,2H),4.06(q,2H),4.01–3.94(m,1H),3.81–3.73(m,1H),1.90–1.69(m,8H),1.31(t,3H).

[0448] Example 20: Preparation of 4-methoxy-N-((1S,4S)-4-((1-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)benzamide (Compound 53A)

[0449] The synthetic route of compound 53A is as follows:

[0450] At room temperature, the compound p-anisic acid (45.00 mg, 0.30 mmol) was dissolved in anhydrous N,N-dimethylformamide (1 mL), and then N,N-diisopropylethylamine (152.90 mg, 1.18 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (224.92 mg, 0.59 mmol) were added. The mixture was stirred at room temperature for 30 minutes, and then 6-(((1S,4S)-4-aminocyclohexyl)amino)-2-methyl-4-(trifluoromethyl)pyridazin-3(2H)-one hydrochloride (103.03 mg, 0.35 mmol) was added, and stirring was continued at room temperature for 4 hours. After TLC monitoring showed that the reaction of the raw materials was complete, stirring was stopped, water (10 mL) was added to the reaction solution to dilute it, and the mixture was extracted with ethyl acetate (4 mL×3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V)=50:50) to give compound 4-methoxy-N-((1S,4S)-4-((1-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)amino)cyclohexyl)benzamide (46.6 mg, yield 37.10%).

[0451] LC-MS, M / Z(ESI):425.1[M+H] +

[0452] 1 H NMR(400MHz, CDCl3)δ7.76–7.68(m,2H),7.08(s,1H),6.97–6.89(m,2H),5.99(d, 1H),4.17–4.08(m,2H),3.85(s,3H),3.79(s,1H),3.67(s,3H),1.97–1.62(m,8H).

[0453] Example 21: Preparation of N-((1R,3S)-3-((7-chloro-4-oxo-3-(2,2,2-trifluoroethyl)-3,4-dihydrophthalazin-1-yl)amino)cyclohexyl)-1-methyl-1H-pyrazole-4-carboxamide (Compound 24A)

[0454] The synthetic route of compound 24A is as follows:

[0455] Step 1: Synthesis of compound 4,6-dichlorophthalazin-1-ol

[0456] At room temperature, 1,4,6-trichlorophthalazine (5.00 g, 21.42 mmol) was dissolved in acetic acid (50 mL), and the reaction mixture was stirred at 120°C for 5 hours. After TLC monitoring indicated complete reaction, stirring was stopped and the mixture was cooled to room temperature. Water (300 mL) was then added to dilute the reaction mixture, followed by extraction with ethyl acetate (50 mL x 3). The organic phase was collected and dried over anhydrous sodium sulfate. The organic phase was concentrated by vacuum distillation, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 100:20) to obtain 4,6-dichlorophthalazin-1-ol (4.32 g, 93.81% yield).

[0457] LC-MS, M / Z(ESI):216.2[M+H] +

[0458] Step 2: Synthesis of compound 4,6-dichloro-2-(2,2,2-trifluoroethyl)phthalazin-1(2H)-one

[0459] At room temperature, compound 4,6-dichlorophthalazin-1-ol (3.00 g, 13.95 mmol) and potassium carbonate (1.93 g, 27.90 mmol) were dissolved in anhydrous N,N-dimethylformamide (30 mL), and then 2-iodo-1,1,1-trifluoroethane (4.39 g, 20.93 mmol) was added. After the addition was completed, the reaction solution was stirred in an oil bath at 80°C for 12 hours. After TLC monitoring showed that the raw material reaction was complete, stirring was stopped, the reaction solution was cooled to room temperature, and then water (200 mL) was added to dilute it, and extracted with ethyl acetate (40 mL×3). The organic phase was collected and dried over anhydrous sodium sulfate, and the organic phase was concentrated by distillation under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 100:10) to obtain compound 4,6-dichloro-2-(2,2,2-trifluoroethyl)phthalazin-1(2H)-one (580 mg, yield 14%).

[0460] LC-MS, M / Z(ESI):298.3[M+H] +

[0461] Step 3: Synthesis of tert-butyl ((1R,3S)-3-((7-chloro-4-oxo-3-(2,2,2-trifluoroethyl)-3,4-dihydrophthalazin-1-yl)amino)cyclohexyl)carbamate

[0462] At room temperature, the compound, 6-dichloro-2-(2,2,2-trifluoroethyl)phthalazin-1(2H)-one (400.00 mg, 1.35 mmol) and tert-butyl ((1R,3S)-3-aminocyclohexyl)carbamate (346.27 mg, 1.62 mmol) were dissolved in toluene (5 mL), and sodium tert-butoxide (258.80 mg, 2.70 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (125.07 mg, 0.27 mmol) and tris(dibenzylidene-BASE acetone)dipalladium (123.30 mg, 0.13 mmol) were added. The reaction solution was stirred at 80 ° C for 4 hours under nitrogen protection. After TLC monitoring showed that the reaction of the raw materials was complete, stirring was stopped and the mixture was cooled to room temperature. Water (20 mL) was then added to dilute the reaction solution, and the mixture was extracted with ethyl acetate (8 mL×5). The organic phase was collected and dried over anhydrous sodium sulfate. The organic phase was concentrated by distillation under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V)=100:40) to obtain the compound (tert-butyl ((1R,3S)-3-((7-chloro-4-oxo-3-(2,2,2-trifluoroethyl)-3,4-dihydrophthalazin-1-yl)amino)cyclohexyl)carbamate (100.00 mg, yield 15.64%).

[0463] LC-MS, M / Z(ESI):475.9[M+H] +

[0464] Step 4: Synthesis of compound 4-(((1S,3R)-3-aminocyclohexyl)amino)-6-chloro-2-(2,2,2-trifluoroethyl)phthalazin-1(2H)-one hydrochloride

[0465] At room temperature, tert-butyl ((1R,3S)-3-((7-chloro-4-oxo-3-(2,2,2-trifluoroethyl)-3,4-dihydrophthalazin-1-yl)amino)cyclohexyl)carbamate (100 mg, 0.21 mmol) was dissolved in dichloromethane (2 mL) and stirred at 0°C for 10 minutes. A solution of hydrogen chloride in 1,4-dioxane (0.11 mL, 0.11 mmol) was then slowly added dropwise. The reaction solution was allowed to warm to room temperature and stirred for 2 hours. After TLC monitoring indicated complete reaction of the starting materials, stirring was stopped and the solvent was removed by evaporation under reduced pressure to yield 4-(((1S,3R)-3-aminocyclohexyl)amino)-6-chloro-2-(2,2,2-trifluoroethyl)phthalazin-1(2H)-one hydrochloride (80 mg, crude product), which was used directly in the next reaction.

[0466] LC-MS, M / Z(ESI):375.3[M+H] +

[0467] Step 5: Synthesis of compound N-((1R,3S)-3-((7-chloro-4-oxo-3-(2,2,2-trifluoroethyl)-3,4-dihydrophthalazin-1-yl)amino)cyclohexyl)-1-methyl-1H-pyrazole-4-carboxamide

[0468] At room temperature, compound 1-methyl-1H-pyrazole-4-carboxylic acid (20 mg, 0.16 mmol) was dissolved in anhydrous N,N-dimethylformamide (2 mL), and then N,N-diisopropylethylamine (81.98 mg, 0.64 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (120.60 mg, 0.32 mmol) were added. The mixture was stirred at room temperature for 30 minutes, and then 4-(((1S,3R)-3-aminocyclohexyl)amino)-6-chloro-2-(2,2,2-trifluoroethyl)phthalazin-1(2H)-one hydrochloride (80 mg, 0.19 mmol) was added, and stirring was continued at room temperature for 4 hours. After TLC monitoring showed that the reaction of the raw materials was complete, stirring was stopped, the reaction solution was cooled to room temperature, and then water (10 mL) was added to dilute it, and it was extracted with ethyl acetate (5 mL×3). The organic phase was collected and dried over anhydrous sodium sulfate. The organic phase was concentrated by distillation under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V)=100:30) to obtain compound N-((1R,3S)-3-((7-chloro-4-oxo-3-(2,2,2-trifluoroethyl)-3,4-dihydrophthalazin-1-yl)amino)cyclohexyl)-1-methyl-1H-pyrazole-4-carboxamide (23.4 mg, yield 24.81%).

[0469] LC-MS, M / Z(ESI):483.1[M+H] +

[0470] 1 H NMR(400MHz,DMSO-d6)δ8.41(d,1H),8.26(d,1H),8.10(s,1H),7.90(dd,1H),7.86(d,1H),7.82(s,1H),6.73(d,1H) ,4.87–4.70(m,2H),3.83(s,3H),3.77–3.67(m,2H),2.23(d,1H),2.08(d,1H),1.87–1.76(m,2H),1.42–1.25(m,4H).

[0471] The preparation methods of the following compounds are described in the above examples.

[0472] Test Example 1: MRGPRX2 in vitro calcium flux assay

[0473] The determination of the antagonistic effect of the compounds on MRGPRX2 was carried out in a CHO stable cell line that highly expresses human MRGPRX2. 18 hours before the experiment, the cells were seeded at a certain density in a black-walled, transparent-bottomed plate containing DMEM / F12 (1:1) culture medium and incubated at 37°C, 5% CO2 for 18 hours. Then, the corresponding amount of dye solution was added to the cells in each well, and the cells were returned to the 37°C incubator for further incubation in the dark for 30 minutes, and then incubated at room temperature in the dark for 10 minutes. Then, different final concentrations of compounds were added to each well, and the cells were equilibrated for 20 minutes. Finally, a certain amount of C48 / 80 solution was added to the cells, and the fluorescence signal value was detected by FLIPR. The antagonistic effect (IC) of the compound was calculated using the software GraphPad Prism 8.0, with the compound concentration as the X-axis and the fluorescence signal value as the Y-axis. 50 value). Where A represents IC 50 Value ≤ 100nM, B means 100nM <IC 50 Value ≤ 500nM, C represents IC 50 The value is greater than 500nM.

[0474] The results of the MRGPRX2 calcium flux test showed that the compound of the present invention has a good antagonistic effect on MRGPRX2.

[0475] Table 1 MRGPRX2 calcium flux assay results

[0476] Test Example 2: MRGPRX2 in vitro IP-1 assay

[0477] The determination of the antagonistic effect of the compound on MRGPRX2 was carried out in a CHO stable cell line that highly expresses human MRGPRX2. The drug diluted in DMSO gradient was added to the microplate, the stable cells were digested with trypsin, the cells were collected, inoculated into the microplate after counting, and placed at 37°C for incubation for 10 minutes. A certain concentration of Cortistatin-14 solution was added, centrifuged and incubated at 37°C for 60 minutes. After the incubation was completed, diluted d2-IP1 and Anti-IP1-Cryptate were added to each test well, centrifuged and allowed to stand at room temperature for 1 hour. After the incubation was completed, the readings at 665nm and 620nm were detected. The antagonistic effect (IC) of the compound was calculated using the software Graphpad with the compound concentration as the X-axis and the fluorescence signal ratio as the Y-axis. 50 value).

[0478] Table 2: MRGPRX2 IP-1 trial results

[0479] The results of the IP-1 test of MRGPRX2 showed that the compound of the present invention has a good antagonistic effect on MRGPRX2.

[0480] Test Example 3: Hepatotoxicity test of compounds

[0481] The toxicity test of the compounds on hepatocellular carcinoma was conducted on HepG2 (ATCC, HB-8065) ​​cells. Cell viability was measured using the CellTiter-Glo Luminescent Cell Viability Assay kit (Promega, G7573). The toxicity of the compounds was characterized by inhibition of HepG2 cell viability. HepG2 cells in the logarithmic phase were collected, the cell suspension concentration was adjusted, and 5000 cells / well were plated in a 96-well cell culture plate. The cells were incubated overnight in a cell culture incubator with 5% CO2 and 37°C. The next day, the medium was changed and different concentrations of compound solutions were added. A negative control group (cells + DMSO) and a blank control group (medium + DMSO) were set up at the same time. The cells were incubated in a cell culture incubator with 5% CO2 and 37°C for 72 hours. After the treatment, the kit instructions were followed and the luminescence signal values ​​in different wells were detected on the EnVision plate reader (2104). The inhibition of HepG2 cell viability by different concentrations of compounds was calculated according to the following formula, with the compound concentration as the X-axis and the inhibition rate as the Y-axis. The toxicity of the compound on HepG2 (IC 50 value).

[0482] Table 3: HepG2 toxicity results

[0483] The results of the hepatotoxicity test showed that the compound of the present invention exhibited good safety and low hepatotoxicity.

[0484] Test Example 4: Pharmacokinetics test in mice

[0485] Mouse pharmacokinetic studies were conducted using male ICR mice weighing 20-25 g and fasted overnight. Three mice were orally gavaged at 10 mg / kg. Blood was collected before dosing and 15, 30 minutes, and 1, 2, 4, 8, and 24 hours after dosing. Blood samples were centrifuged at 6800 g for 6 minutes at 2-8°C, and plasma was collected and stored at -80°C. Plasma was collected at each time point and mixed with 3-5 times the volume of acetonitrile solution containing the internal standard. The mixture was vortexed for 1 minute and centrifuged at 13,000 rpm at 4°C for 10 minutes. The supernatant was mixed with 3 times the volume of water, and an appropriate amount of the mixture was analyzed by LC-MS / MS. The main pharmacokinetic parameters were analyzed using a non-compartmental model using WinNonlin 7.0 software.

[0486] Table 4 Pharmacokinetic test results in mice

[0487] The results of the mouse pharmacokinetic test showed that the compound of the present invention exhibited excellent pharmacokinetic properties and good drugability.

[0488] Test Example 5: Pharmacokinetics test in rats

[0489] For the pharmacokinetic study in rats, male SD rats weighing 180-240 g were fasted overnight. Three rats were orally gavaged at 10 mg / kg. Blood was collected before dosing and 15, 30 minutes, and 1, 2, 4, 8, and 24 hours after dosing. Blood samples were centrifuged at 6800 g for 6 minutes at 2-8°C, and plasma was collected and stored at -80°C. Plasma was collected at each time point and mixed with 3-5 times the volume of acetonitrile solution containing the internal standard. The mixture was vortexed for 1 minute and centrifuged at 13,000 rpm at 4°C for 10 minutes. The supernatant was mixed with 3 times the volume of water, and an appropriate amount of the mixture was analyzed by LC-MS / MS. The main pharmacokinetic parameters were analyzed using a non-compartmental model using WinNonlin 7.0 software.

[0490] Table 5 Pharmacokinetic test results in rats

[0491] The results of the rat pharmacokinetic test showed that the compound of the present invention exhibited excellent rat pharmacokinetic properties and good drugability.

[0492] Test Example 6: Determination of the inhibitory effect of compounds on BSEP bile efflux transporter

[0493] The inhibitory effect of compounds on the BSEP (Bile Salt Export Pump) bile efflux transporter was tested using vesicles expressing the human BSEP bile efflux transporter (GenoMembrane). The vesicles were preincubated with various concentrations of compound for 5 minutes. Negative control (NC) and positive control (PC) controls were also established: the NC control consisted of vesicles preincubated with blank buffer for 5 minutes at 37°C, while the PC control consisted of vesicles preincubated with a positive inhibitor for 5 minutes at 37°C. Subsequently, the cells were incubated with the probe substrate at 37°C for 5 minutes in the presence of ATP or AMP. The assay was terminated with pre-chilled Buffer B1 (10× Buffer B1 (Stopping and Washing Buffer): 100 mM Hepes-Tris, 1000 mM KNO3, 500 mM Sucrose). The test sample was transferred to a 96-well filter plate, filtered with a vacuum pump, and then washed repeatedly 5 times with 0.2 mL of pre-cooled Buffer B1. The vesicles on the filter plate were dissolved with 50 μL of 80% methanol. After collection, the filtrate was collected by centrifugation at 2000 rpm for 2 minutes. Repeat once, combine the two filtrates together, mix well, and obtain approximately 100 μL of filtrate. Pre-cooled methanol containing the internal standard was added and centrifuged at 12,000 rpm for 5 minutes. The supernatant was used for LC-MS / MS quantitative detection of the content of the transported substrate. The IC of the compound inhibiting the bile efflux transporter activity was calculated using the Prism software, with the compound concentration as the X-axis and the relative activity (% of NC) as the Y-axis. 50 values ​​and inhibition rates.

[0494] The transport rate (activity) and relative activity under different conditions were calculated according to the following formula:

[0495] Table 6 Inhibitory effects of test compounds on BSEP bile efflux transporter

[0496] The results of the BSEP bile efflux transporter inhibition test showed that the compound of the present invention had no obvious inhibitory effect on the BSEP bile efflux transporter and no risk of cholestatic toxicity.

[0497] The structure of reference compound 1 is: Test Example 7: Thermodynamic Solubility Test

[0498] Prepare phosphate buffered saline (PBS) at pH 7.4. Accurately weigh the compound and add it to the prepared PBS at pH 7.4 to a concentration of 4 mg / mL. Shake the solution at 1000 rpm for 1 hour, then incubate at room temperature overnight. Centrifuge the incubated solution at 12000 rpm for 10 minutes to remove undissolved particles, and transfer the supernatant to a fresh centrifuge tube. After appropriate dilution of the supernatant, add acetonitrile containing the internal standard and quantify using a standard curve prepared in the same matrix.

[0499] The results of the thermodynamic solubility test show that the compound of the present invention has good thermodynamic solubility and good drugability.

[0500] Test Example 8: Human liver microsome stability test

[0501] The stability test for human liver microsomes was performed by incubating the compound with human liver microsomes in vitro. The test compound was first prepared as a 10 mM stock solution in DMSO solvent, and then diluted to 0.5 mM using acetonitrile. Human liver microsomes (Corning) were diluted with PBS to form a microsome / buffer solution, and this solution was used to dilute 0.5 mM of the compound to form a working solution. The working solution contained 1.5 μM compound and 0.75 mg / mL human liver microsomes. A deep-well plate was prepared, and 30 μL of the working solution was added to each well. The reaction was then initiated by adding 15 μL of preheated 6 mM NADPH solution and incubated at 37°C. The reaction was terminated by adding 135 μL of acetonitrile to the corresponding wells at 0, 5, 15, 30, and 45 minutes of incubation. After terminating the reaction with acetonitrile at the final 45-minute time point, the deep-well plate was vortexed for 10 minutes (600 rpm / min) and then centrifuged for 15 minutes. After centrifugation, the supernatant was collected and purified water was added in a 1:1 ratio. LC-MS / MS analysis was then performed to obtain the ratio of the peak area of ​​the compound to the peak area of ​​the internal standard at each time point. The peak area ratios of the compound at 5, 15, 30, and 45 minutes were compared with the peak area ratio at 0 minute. The remaining percentage of the compound at each time point was calculated, and T1 / 2 was calculated using Graphpad 5 software.

[0502] Table 8 Human liver microsome stability data of compounds

[0503] The results of the human liver microsome stability test show that the compound of the present invention exhibits excellent human liver microsome stability and good drugability.

[0504] Test Example 9: Inhibition test of compounds on cytochrome P450

[0505] Compounds were tested for their inhibitory potential against the cytochrome P450 (CYP450) isoform CYP3A4 (two substrates, midazolam and testosterone). Test compounds were prepared in DMSO to a 10 mM stock solution. The CYP3A4 inhibitor ketoconazole was prepared in DMSO to 10 mM, 2.5 mM, and 2.5 mM stock solutions. Test compounds and ketoconazole were diluted in acetonitrile to a 400-fold final concentration (compound: 10 μM, ketoconazole: 2.5 μM).

[0506] Potassium phosphate buffer (0.1 M, pH 7.4) was used to prepare 4 times the final concentration of NADPH cofactor (66.7 mg NADPH was added to 10 mL potassium phosphate buffer) and substrate. The final concentration of CYP3A4 substrate midazolam was 320 μM, and the final concentration of CYP3A4 substrate testosterone was 20 μM.

[0507] Prepare a 0.2 mg / mL human liver microsomal solution in potassium phosphate buffer on ice. Prepare test compound and control inhibitor solutions at 2x the final concentration in the human liver microsomal solution on ice. Add 30 μL of test compound and control inhibitor solution to each test well, along with 15 μL of substrate, in duplicate. Incubate the 96-well assay plate and NADPH solution at 37°C for 5 minutes. Add 15 μL of preheated 8 mM NADPH solution to the assay plate to initiate the reaction. Preincubate the CYP3A4 assay plate at 37°C for 5 minutes. Terminate the reaction by adding 120 μL of acetonitrile. After quenching, shake the plate on a shaker (IKA, MTS2 / 4) for 10 minutes (600 rpm / min) and then centrifuge for 15 minutes. After centrifugation, the supernatant was collected and purified water was added in a 1:1 ratio. LC-MS / MS was then performed to obtain the ratio of the compound peak area to the internal standard peak area. The peak area ratio of the compound was compared with the peak area ratio of the control inhibitor to calculate the inhibition rate.

[0508] The results of the inhibition test of the compound on cytochrome P450 show that the compound of the present invention has no obvious inhibitory effect on CYP3A4 (two substrates, midazolam and testosterone) and has good drugability.

[0509] Test Example 10: Evans blue vascular permeability test

[0510] The Evans blue vascular permeability test was performed using C57 mice, with the left hind paw of the mouse as the model group and the right hind paw as the negative control group. Different doses of drugs were administered orally, and 2 hours after administration, a 0.4% Evans blue (Sigma-Aldrich, Lot#SHBP1253) solution was injected into the tail vein. 5-10 minutes later, a C48 / 80 (Sigma-Aldrich, Lot#C2313) solution was injected subcutaneously into the left hind paw, and a normal saline solution was injected into the right hind paw. The mice were killed 15 minutes later, and the thickness of the left and right hind paws of the mice was measured with a vernier caliper. The mouse feet were cut off, dried, and weighed. The paws were crushed, and the Evans blue in the paws was dissolved with acetone: normal saline (7:3). The absorbance was measured at 620 nm, and the absorbance per unit volume was calculated. The mouse ear swelling rate and the amount of Evans blue exuded per unit mass were calculated.

[0511] The results of the Evans blue vascular permeability test showed that the compound of the present invention exhibited good efficacy, could significantly inhibit C48 / 80-induced vascular leakage, and had good drugability.

[0512] Although the embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, replace and modify the above embodiments within the scope of the present invention.

Claims

1. The compound represented by formula IA, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug: in, X 1 , X 2 , X 3 , X 4 , X 5 and X 6 Each independently represents a ring atom; X 1 , X 2 , X 3 , X 5 and X 6 are each independently N, CH2, CH or C; X 4 is C; X 1 With X 2 Between, X 5 With X 6 The bond between them is a single bond or a double bond; X 5 and X 6 The linked group fragment In the example, A does not exist, X 5 and X 6 Each is independently R 4 or R 5 or when A exists, A and X 5 , X 6 The ring atoms together form a 6- to 10-membered aryl, a 3- to 11-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl; and the A is further R c Replaced by; said R c Substitution is one or more substitutions, when the substituent R c When there are multiple substituents, the substituents are the same or different; the heteroatoms in the heterocycloalkyl and heteroaryl groups are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2 or 3; And when A and X 5 , X 6 When the ring atoms are combined to form a 6-membered aromatic group, R a For oxygen generation; Or, when A and X 5 , X 6 The ring atoms together form a 5-membered heteroaryl group and R c When it is not H, R 1 C 1-6 Haloalkyl; the heteroatom in the heteroaryl is selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2 or 3; Ring B is C 3-12 Cycloalkyl; Ring C is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; the heteroatom in the heteroaryl group is selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; R a , R c , R 1 , R 2 , R 3 , R 4 and R 5 are independently H, halogen, cyano, amino, oxo, C 1-6 Alkyl, C substituted by hydroxy 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, halogenated C 3-8 Cycloalkyl, -OR f 、-C(O)OR f 、-OC(O)R f 、-N(R f )2、-N(R f )C(O)R f 、-N(R f )S(O)2R f or -S(O)2R f ; said R f Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylamino, -(CH2)rR g , 6-10 membered aromatic group, C 3-8 Cycloalkyl, 5- to 10-membered heteroaryl or 5- to 10-membered heterocycloalkyl, or two R f The group and the atoms to which it is attached together form a 5- to 11-membered heterocycloalkyl group; g H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl or 5-10 membered heterocycloalkyl; the heteroatoms in the heterocycloalkyl and heteroaryl are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; R b H, halogen, hydroxyl, amino, cyano, carbonyl, oxo, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or 3-10 membered heterocycloalkyl, -(CHR j ) 0-3 -S(=O)(=NR j )-R k 、-(CHR j ) 1-3 -S(O)2-R k 、-(CHR j ) 1-3 -OC(O)-N(R k )2、-(CHR j ) 0-3 -(N=)S(=O)(R k )2、-(CHR j ) 0-3 -P(=O)(R k )2; said C 1-6 Alkyl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 The haloalkoxy group is optionally substituted with one or more R d Substitution; said R d A substituent selected from the group consisting of halogen, hydroxy, amino, nitro, cyano, carbonyl, oxo, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy; when the substituent R d When it is multiple, the R d The same or different; the heteroatoms in the heterocycloalkyl group are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2 or 3; R j and R k are independently H, cyano, amino, C 1-6 Alkyl, C 1-6 Alkylamino, -(CH2) 0-3 C 3-8 Cycloalkyl, -COC 1-6 Alkyl, C 1-6 Haloalkyl, C substituted by hydroxy 1-6 Alkyl, single 5- to 10-membered heterocycloalkyl; m, n, and r are 0, 1, 2, or 3 respectively.

2. The compound of formula IA as claimed in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: The R b H, F, Cl, -CN, methyl, amino, methoxy, oxo, -CH2CF3, -CF3, -CHF2, -CH2CHF2, -CH2-SO2-CH3, -CH(CH3)SO2CH3, -CH2S(=O)(=NCH3)-CH3, and / or, the R a , R c , R 1 , R 2 , R 3 Each independently represents H, F, Cl, methyl, ethyl, amino, oxo, -CHF2, -CH2CF3, -CF3, and / or, the X 5 and X 6 The linked group fragment In the example, A does not exist, X 5 and X 6 Each is independently R 4 or R 5 If replaced by Selected from and / or, the R 4 , R 5 Each is independently H, F, Cl, methyl, -CF3, -CHF2; and / or, the X 5 and X 6 The linked group fragment In the example, A does not exist, X 5 and X 6 Each is independently R 4 or R 5 If replaced by Selected from and / or, the X 5 and X 6 The linked group fragment When A exists, A and X 5 , X 6 The ring atoms come together to form And the A is further R c replaced by; and / or, when A is present, the structural fragment Selected from and / or, when A is present, the structural fragment Selected from and / or, the ring B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; and / or, the structural fragment Selected from and / or, the structural fragment Selected from 3. The compound of formula IA as claimed in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: The formula IA can be selected from the following IA-1: Among them, A, ring B, ring C, X 2 , X 3 , X 4 , X 5 , X 6 , R 1 , R 2 , R 3 , R b , m and n are as defined in claim 1; Or the formula IA is selected from the structures shown in the following formulas I-1, I-2 or I-3, in, X 5 and X 6 The linked group fragment A is defined as in claim 1; Ring C is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; the heteroatom in the heteroaryl group is selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , R 1 , R 2 , R 3 , R a , R b , m and n are as defined in claim 1; Or the formula IA is selected from the structure shown in the following formula II-1 or II-3, Among them, A and X 5 , X 6 The ring atoms together form a 6- to 8-membered aryl group, a 3- to 8-membered heterocycloalkyl group, a 5-membered heteroaryl group or a 6-membered heteroaryl group; the heteroatoms are independently selected from one or more of N, O and S; the A is further replaced by R c Replaced by; said R c Substitution is one or more substitutions, when the substituent R c When there are multiple substituents, the substituents are the same or different; and when A and X 5 , X 6 When the ring atoms are combined to form a 6-membered aromatic group, R a is oxo; or, when A and X 5 , X 6 The ring atoms together form a 5-membered heteroaryl group and R c When it is not H, R 1 C 1-6 Haloalkyl; the heteroatoms in the heterocycloalkyl and heteroaryl are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2 or 3; Ring C is a 6- to 10-membered aryl group or a 5- to 8-membered heteroaryl group; the heteroatom in the heteroaryl group is selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; R b H, halogen, hydroxyl, amino, cyano, carbonyl, oxo, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or 3- to 8-membered heterocycloalkyl, -(CHR j ) 0-3 -S(=O)(=NR j )-R k 、-(CHR j ) 1-3 -S(O)2-R k 、-(CHR j ) 1-3 -OC(O)-N(R k )2、-(CHR j ) 0-3 -(N=)S(=O)(R k )2、-(CHR j ) 0-3 -P(=O)(R k )2; said C 1-6 Alkyl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 The haloalkoxy group is optionally substituted with one or more R d Substitution; said R d A substituent selected from the group consisting of halogen, hydroxy, amino, nitro, cyano, carbonyl, oxo, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy; the heteroatom in the heterocycloalkyl is selected from one or more of N, O, and S, and the number of the heteroatoms is 1, 2 or 3; R j and R k are independently H, cyano, amino, C 1-6 Alkyl, C 1-6 Alkylamino, -(CH2) 0-3 C 3-8 Cycloalkyl, -COC 1-6 Alkyl, C 1-6 Haloalkyl, C substituted by hydroxy 1-6 Alkyl, single 5- to 10-membered heterocycloalkyl; R a , R c , R 1 , R 2 , R 3 are independently H, halogen, cyano, amino, oxo, C 1-6 Alkyl, C substituted by hydroxy 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, halogenated C 3-8 Cycloalkyl; X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , m and n are as defined in claim 1; and / or, the R b H, F, Cl, -CN, methyl, amino, oxo, -CH2CF3, -CF3, -CHF2, -CH2CHF2, -CH2-SO2-CH3, -CH(CH3)SO2CH3, -CH2S(=O)(=NCH3)-CH3, and / or, the R a , R c , R 1 , R 2 , R 3 Each independently represents H, F, Cl, methyl, amino, oxo, -CHF2, -CH2CF3, -CF3, 4. The compound of formula IA as claimed in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: It has a structure shown in formula II-2, II-4 or II-5, in, Ring C is a 6- to 10-membered aryl group or a 5- to 8-membered heteroaryl group; the heteroatom in the heteroaryl group is selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; R b H, halogen, hydroxyl, amino, cyano, carbonyl, oxo, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or 3- to 8-membered heterocycloalkyl, -(CHR j ) 0-3 -S(=O)(=NR j )-R k 、-(CHR j ) 1-3 -S(O)2-R k 、-(CHR j ) 1-3 -OC(O)-N(R k )2、-(CHR j ) 0-3 -(N=)S(=O)(R k )2、-(CHR j ) 0-3 -P(=O)(R k )2; said C 1-6 Alkyl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 The haloalkoxy group is optionally substituted with one or more R d Substitution; said R d A substituent selected from the group consisting of halogen, hydroxy, amino, nitro, cyano, carbonyl, oxo, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy; the heteroatom in the heterocycloalkyl is selected from one or more of N, O, and S, and the number of the heteroatoms is 1, 2 or 3; R j and R k are independently H, cyano, amino, C 1-6 Alkyl, C 1-6 Alkylamino, -(CH2) 0-3 C 3-8 Cycloalkyl, -COC 1-6 Alkyl, C 1-6 Haloalkyl, C substituted by hydroxy 1-6 Alkyl, single 5- to 10-membered heterocycloalkyl; R a , R 1 , R 2 , R 3 , R 4 , R 5 are independently H, halogen, cyano, amino, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, halogenated C 3-8 Cycloalkyl; X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , m and n are as defined in claim 1; and / or, the R b H, F, Cl, -CN, methyl, methoxy, amino, oxo, -CH2CF3, -CF3, -CHF2, -CH2CHF2, -CH2-SO2-CH3, -CH(CH3)SO2CH3, -CH2S(=O)(=NCH3)-CH3, and / or, the R a , R 1 , R 2 , R 3 , R 4 , R 5 Each independently represents H, F, Cl, methyl, ethyl, amino, oxo, -CHF2, -CH2CF3, -CF3, 5. The compound of formula IA, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug according to any one of claims 1 to 4, characterized in that: Ring C is a 6- to 8-membered aryl group or a 5- to 10-membered heteroaryl group; the heteroatom in the heteroaryl group is selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; and / or, Ring C is a 5- to 6-membered nitrogen-containing heteroaryl group, and the number of the nitrogen atoms is 1, 2 or 3; and / or, Ring C is phenyl, pyrazolyl or pyridyl.

6. The compound of formula IA as claimed in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: The compounds include: Optionally, the pharmaceutically acceptable salt of the compound is trifluoroacetate.

7. The compound of formula IA as claimed in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: The compounds include: Optionally, the pharmaceutically acceptable salt of the compound is trifluoroacetate.

8. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises: a compound of formula IA as described in any one of claims 1 to 7, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof; and a pharmaceutically acceptable carrier.

9. A use of a compound of formula IA as claimed in any one of claims 1 to 7, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or a use of a pharmaceutical composition as claimed in claim 8, comprising: Antagonizes MRGPRX2; and / or, preventing and / or treating MRGPRX2-related diseases; And / or, preparing drugs, pharmaceutical compositions or preparations for antagonizing MRGPRX2, and / or preventing and / or treating MRGPRX2-related diseases.

10. The use according to claim 9, characterized in that The MRGPRX2-related diseases include: mast cell-related diseases; Or the MRGPRX2-related diseases include: skin diseases (such as atopic dermatitis, contact dermatitis, urticaria, chronic spontaneous urticaria, induced urticaria, pruritus), autoimmune diseases (such as allergies, mastocytosis, rheumatoid arthritis, asthma, ulcerative colitis and interstitial cystitis), and nervous system diseases (such as pain).