Compound acting as mrgprx2 antagonist, and preparation method therefor and use thereof

Abstract

Provided in the present invention is a compound as represented by formula (I), or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof. The compound has a good antagonistic effect against MRGPRX2.

Description

Compounds as MRGPRX2 antagonists and their preparation methods and uses

[0001] This application requires the following:

[0002] Priority of the prior application No. 202311089453.1 filed with the State Intellectual Property Office of China on August 25, 2023;

[0003] Priority of the prior application No. 202311282832.2 filed with the State Intellectual Property Office of China on September 28, 2023;

[0004] Priority of the prior application No. 202410169529.X filed with the State Intellectual Property Office of China on February 5, 2024;

[0005] Priority of the earlier application No. 202410166360.2 filed with the State Intellectual Property Office of China on February 5, 2024;

[0006] The entire contents of said prior application are incorporated into the present application by reference. Technical Field

[0007] The present invention belongs to the field of medicine. Specifically, the present invention relates to a compound as an MRGPRX2 antagonist, and a preparation method and application thereof. Background Art

[0008] 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.

[0009] 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.

[0010] 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.

[0011] 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.

[0012] Summary of the Invention

[0013] The object of the present invention is to provide novel compounds for use as MRGPRX2 antagonists.

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

[0015] in,

[0016] is a single bond or a double bond;

[0017] X 1 、X 2 、X 3、X 4 、X 5 and X 6 Each independently represents a ring atom;

[0018] X 1 、X 2 、X 3 、X 5 and X 6 are each independently N, CH2, CH or C;

[0019] X 4 is C;

[0020] X 1 With X 2 Between, X 5 With X 6 The bond between them is a single bond or a double bond;

[0021] 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 (eg 2, 3, 4) substitutions, when the substituent R c When there are multiple substituents, the substituents are the same or different;

[0022] Ring B is C 3-12 Cycloalkyl;

[0023] Ring D is an 8-12-membered cycloheteroaryl group, an 8-12-membered cycloheterocycloalkenyl group, or a 5-10-membered heteroaryl group;

[0024] R a 、R c 、R 4 and R 5 Each is independently 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, C1-6 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 3-8 Cycloalkyl, 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 replaced by one or more (eg, 2, 3, 4) R d replace;

[0025] The R d A substituent selected from the group consisting of: H, 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 Halogenated alkoxy, C 3-6 Cycloalkyl; when the substituent R d When there are multiple R d Same or different; wherein, when R d Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl and C 2-6 alkynyl, each independently further optionally substituted by 1, 2, 3 or 4 R d1 Replace, when R d1 When there are multiple R d1 Same or different;

[0026] R d1 are independently H, F, Cl, Br or I;

[0027] R k are independently 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, C1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, 3-10 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, -C 0-6 Alkyl-NR d -C 0-6 Alkyl, C 1-6 Alkylamino, -C 0-6 Alkyl-NR d SO2-C 0- 6-alkyl or -C 0-6 Alkyl-P(=O)(R d )2; said C 1-6 Alkyl, C 3-8 Cycloalkyl, 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, 3-10 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl are optionally substituted by n R b Substituted; said R b A substituent selected from the group consisting of hydrogen, 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 Halogenated alkoxy, C 3-6 Cycloalkyl; when the substituent R b When n is the number, the R b Same or different; wherein, when R b Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl and C 2-6 alkynyl, each independently further optionally substituted by 1, 2, 3 or 4 R d1 Replace, when R d1 When there are multiple R d1 Same or different;

[0028] R 1 、R 2 and R 3 are independently H, halogen, cyano, C 1-6 Alkyl, C2-6 Alkenyl, C 1-6 Alkoxy, 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 ; Among them, when R 1 、R 2 and R 3 Selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-8 When cycloalkyl, each independently further optionally 1, 2, 3 or 4 R d Replace, when R d When there are multiple R d Same or different;

[0029] 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- to 10-membered aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered heterocycloalkyl;

[0030] m is 0, 1, 2, or 3;

[0031] n is 0, 1, 2, 3 or 4;

[0032] r is 0, 1, 2 or 3; s is 0, 1, 2, 3, 4, 5, 6.

[0033] In some embodiments, the halogen is selected from F, Cl, Br, I.

[0034] In some embodiments,

[0035] X 2 、X 3 、X 4 、X 6 is C;

[0036] X 1 is N or C; when X 1 When it is C, the C atom is R a replace;

[0037] X 5 is N or C; when X 5 When it is N, the connected is a single bond, when X 5 When it is C, the connected For double bonds.

[0038] In some embodiments, X 3 R a replace.

[0039] In some embodiments, each R c are independently H, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2, 3 or 4 R d Replace, when R d When there are multiple R d Same or different.

[0040] In some embodiments, each R d are independently H, F, Cl, Br, I, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl or C 2- 6 alkynyl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl and C 2-6 Alkynyl is optionally substituted by 1, 2, 3 or 4 R d1 Replace, when R d1 When there are multiple R d1 Same or different.

[0041] In some embodiments, R 1 H, C 1-3 Alkyl, C 1-3 Alkoxy or C 3-6 Cycloalkyl, wherein C 1-3 Alkyl, C 1-3 Alkoxy and C 3- 6 cycloalkyl groups are each independently optionally substituted by 1, 2, 3 or 4 R d Replace, when R d When there are multiple R d Same or different.

[0042] In some embodiments, R a H, C 1-3 Alkyl, C 1-3 Alkoxy or C 3-6 Cycloalkyl, wherein C 1-3 Alkyl, C 1-3 Alkoxy and C 3- 6 cycloalkyl groups are each independently optionally substituted by 1, 2, 3 or 4 R d Replace, when R d When there are multiple R d Same or different.

[0043] In some embodiments, Ring A is phenyl or a 5-6 membered heteroaryl.

[0044] In some embodiments, each R k are independently H, halogen, NH2, CN, =O, OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2, 3 or 4 R b Replace, when R b When there are multiple R b The same or different; the R b are independently H, F, Cl, Br, I, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl and C2-6 Alkynyl is optionally substituted by 1, 2, 3 or 4 R d1 Replace, when R d1 When there are multiple R d1 Same or different.

[0045] In some embodiments, R 2 and R 3 Each independently is H or C 1-3 Alkyl; wherein R 2 and R 3 Same or different.

[0046] In some embodiments, m, n, r, and s are 0, 1, 2, or 3, respectively.

[0047] In the present invention, the definitions of certain substituents in the compound represented by Formula I are as follows, and the definitions of substituents not mentioned are as described in any of the above schemes.

[0048] In a preferred embodiment of the present invention, the compound shown in Formula I is selected from the following structures:

[0049] Among them, ring A, ring B, ring D, 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 above; C is a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, or a 3- to 10-membered heterocycloalkyl group;

[0050] In some embodiments, Ring B is 1,4 substituted C 4-12 Cycloalkyl or 1,3 substituted C 3-12 Cycloalkyl; Ring D is a 5- to 10-membered heteroaryl.

[0051] In a preferred embodiment of the present invention, the compound shown in Formula I is selected from the following structures:

[0052] Among them, ring A, ring D, X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、R 1 、R 2 、R 3、R a 、R k , m and s are as defined above.

[0053] In some embodiments, ring D is a 5- to 10-membered heteroaryl group; R k are independently 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, -C 0-6 Alkyl-NR d -C 0-6 Alkyl, -C 0-6 Alkyl-NR d SO2-C 0-6 Alkyl or -C 0-6 Alkyl-P(=O)(R d )2; said C 1-6 Alkyl, C 3-8 Cycloalkyl, 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 by n R b Substituted; said R b A substituent selected from the group consisting of hydrogen, halogen, hydroxy, amino, nitro, cyano, carbonyl, oxo, carboxyl, C 1-6 Alkyl, 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 b When n is the number, the R b Same or different;.

[0054] In a preferred embodiment of the present invention, the compound shown in Formula I is selected from the following structures:

[0055] Among them, ring A, ring D, X 1 、X2 、X 3 、X 4 、X 5 、X 6 、R 1 、R 2 、R 3 、R a 、R b , m and n are as defined above;

[0056] C is a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, or a 3- to 10-membered heterocycloalkyl group;

[0057] In some embodiments, ring D is a 5-10 membered heteroaryl;

[0058] Furthermore, in a preferred embodiment of the present invention, the compound as shown in Formula I has the structure shown in Formula II-1, A and X 5 、X 6 The ring atoms together form a 6-8 membered aryl group, a 3-8 membered heterocycloalkyl group, a 5-membered heteroaromatic ring or a 6-membered heteroaromatic ring; 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; the C is a 6-8 membered aryl, a 5-8 membered heteroaryl or a 5-8 membered heterocycloalkyl; the ring D is a 5-8 membered heteroaryl; R a 、R c Each is independently 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 Haloalkoxy or 3-8 membered heterocycloalkyl; R b are independently H, halogen, hydroxy, amino, nitro, cyano, carbonyl, oxo, carboxyl, C 1-6 Alkyl, 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; R 1 、R 2 、R3 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 is defined as above; n is 0, 1, 2 or 3.

[0059] In a preferred embodiment of the present invention, the R a 、R b 、R c Each is independently H, F, Cl, methyl, amino, oxo, -CH2CF3, or -CF3.

[0060] In a preferred embodiment of the present invention, the R 1 、R 2 、R 3 Each independently represents H, methyl, -CH2CF3, -CF3,

[0061] In a preferred embodiment of the present invention, C is a 5- to 6-membered nitrogen-containing heteroaryl group or a 5- to 6-membered nitrogen-containing heterocycloalkyl group, and the number of the nitrogen atoms is 1, 2 or 3.

[0062] In a preferred embodiment of the present invention, C is pyrrolidinyl, imidazolyl, pyrazolyl, pyridinyl, or pyrimidinyl.

[0063] In a preferred embodiment of the present invention, C is pyrazolyl, pyridinyl or pyrimidinyl.

[0064] In a preferred embodiment of the present invention, C is

[0065] In a preferred embodiment of the present invention, C is

[0066] In a preferred embodiment of the present invention, ring D is a 5- to 10-membered heteroaryl group.

[0067] In a preferred embodiment of the present invention, ring D is a 5- to 6-membered nitrogen- or oxygen-containing heteroaryl group, and the number of the nitrogen atoms or oxygen atoms is 1, 2 or 3.

[0068] In a preferred embodiment of the present invention, ring D is pyridyl, oxadiazole, isoxazole, or pyrazinyl.

[0069] In a preferred embodiment of the present invention, ring D is

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

[0071] Among them, ring A, ring B, ring D, X 1 、X 5 、R 1 、R 2 、R 3 、R a 、R k , s are as defined above.

[0072] In some embodiments, in Formula Ia,

[0073] is a single bond or a double bond;

[0074] X 1 is N or C; when X 1 When it is C, the C atom is R a replace;

[0075] X 5 is N or C; when X 5 When it is N, the connected is a single bond, when X 5 When it is C, the connected is a double bond;

[0076] Ring A is phenyl or 5-6 membered heteroaryl (i.e. when A is present);

[0077] The A is further R c Replaced by; said R c Substitution is one or more (eg 2, 3, 4) substitutions, when the substituent R c When there are multiple substituents, the substituents are the same or different; each R c are independently H, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2, 3 or 4 R d Replace, when R dWhen there are multiple R d Same or different;

[0078] Each R 1 、R a are independently H, C 1-3 Alkyl, C 1-3 Alkoxy or C 3-6 Cycloalkyl, wherein C 1-3 Alkyl, C 1-3 Alkoxy and C 3- 6 cycloalkyl groups are each independently optionally substituted by 1, 2, 3 or 4 R d Replace, when R d When there are multiple R d Same or different;

[0079] Ring B is C 3-12 Cycloalkyl;

[0080] Ring D is an 8-12-membered cyclic heteroaryl group or an 8-12-membered cyclic heterocycloalkenyl group;

[0081] Each R d are independently H, F, Cl, Br, I, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl and C 2-6 Alkynyl is optionally substituted by 1, 2, 3 or 4 R d1 Replace, when R d1 When there are multiple R d1 Same or different;

[0082] Each R d1 are independently H, F, Cl, Br or I;

[0083] Each R k are independently H, halogen, NH2, CN, =O, OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2, 3 or 4 R b Replace, when R b When there are multiple Rb The same or different; the R b are independently H, F, Cl, Br, I, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl and C 2-6 Alkynyl is optionally substituted by 1, 2, 3 or 4 R d1 Replace, when R d1 When there are multiple R d1 Same or different;

[0084] R 2 and R 3 Each independently is H or C 1-3 Alkyl; wherein R 2 and R 3 Same or different;

[0085] s is 0, 1, 2, 3, 4, 5, 6.

[0086] In a preferred embodiment of the present invention, the compound represented by formula I has the structure of formula Ib:

[0087] Among them, ring A, ring B, X 1 、X 5 、R 1 、R 2 、R 3 、R a 、R k , s are as defined above.

[0088] X7 is N or CR a ;

[0089] Ring C is C 6-10 Aryl, C 4-8 cycloalkenyl, 5-8 membered heteroaryl or 4-9 membered heterocycloalkenyl; in some embodiments, ring C is C 6-10 Aryl, C 4-6 cycloalkenyl, 5-6 membered heteroaryl or 4-8 membered heterocycloalkenyl; in some embodiments, ring C is phenyl; in some embodiments, ring C is 5-6 membered heteroaryl or 5-6 membered heterocycloalkenyl; in some embodiments, ring C is 5-6 membered nitrogen-containing heteroaryl;

[0090] R4, R5, and R6 are independently H, halogen, hydroxy, amino, cyano, carbonyl, oxo, C 1-6 Alkyl, C 3-8 Cycloalkyl, C2-6 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, 3-10 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, C 1-6 Alkylamino; the C 1-6 Alkyl, C 3-8 Cycloalkyl, 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, 3-10 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl are optionally substituted by n R b Substituted; said R b A substituent selected from the group consisting of hydrogen, 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 Halogenated alkoxy, C 3-6 Cycloalkyl; when the substituent R b When n is the number, the R b Same or different; wherein, when R b Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl and C 2-6 alkynyl, each independently further optionally substituted by 1, 2, 3 or 4 R d1 Replace, when R d1 When there are multiple R d1 Same or different; R d1 are independently H, F, Cl, Br or I;

[0091] n' is 0, 1, 2, 3 or 4.

[0092] In some embodiments, in Formula Ib,

[0093] is a single bond or a double bond;

[0094] X 1 is N or C; when X 1 When it is C, the C atom is R a replace;

[0095] X 5 is N or C; when X 5 When it is N, the connected is a single bond, when X 5 When it is C, the connected is a double bond;

[0096] X7 is N or CR a ;

[0097] Ring A is phenyl or 5-6 membered heteroaryl (i.e. when A is present);

[0098] The A is further R c Replaced by; said R c Substitution is one or more (eg 2, 3, 4) substitutions, when the substituent R c When there are multiple substituents, the substituents are the same or different; each R c are independently H, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2, 3 or 4 R d Replace, when R d When there are multiple R d Same or different;

[0099] Each R 1 、R a are independently H, C 1-3 Alkyl, C 1-3 Alkoxy or C 3-6 Cycloalkyl, wherein C 1-3 Alkyl, C 1-3 Alkoxy and C 3- 6 cycloalkyl groups are each independently optionally substituted by 1, 2, 3 or 4 R d Replace, when R d When there are multiple R d Same or different;

[0100] Ring B is C 3-12 Cycloalkyl;

[0101] Ring C is a 5-6 membered heteroaryl or a 5-6 membered heterocycloalkenyl;

[0102] Each R d are independently H, F, Cl, Br, I, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl and C 2-6 Alkynyl is optionally substituted by 1, 2, 3 or 4 R d1 Replace, when R d1 For multiple times,

[0103] Each R d1 Same or different;

[0104] R 2 and R 3 Each independently is H or C 1-3 Alkyl; wherein R 2 and R 3 Same or different.

[0105] R4 and R5 are independently H, C 1-3 Alkyl, C 1-3 Alkoxy or C 3-6 Cycloalkyl, wherein C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Cycloalkyl is optionally substituted by 1, 2, 3 or 4 R b Replace, when R b When there are multiple R b Same or different;

[0106] R6 are independently H, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2, 3 or 4 R b Replace, when R b When there are multiple R b Same or different;

[0107] The R b are independently H, F, Cl, Br, I, C1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl and C 2-6 Alkynyl is optionally substituted by 1, 2, 3 or 4 R d1 Replace, when R d1 When there are multiple R d1 Same or different;

[0108] Each R d1 are independently H, F, Cl, Br or I;

[0109] n' is 0, 1, 2, 3 or 4.

[0110] In an optional embodiment of the present invention, each R d are independently H, F, Cl, Br, and I.

[0111] In an optional embodiment of the present invention, each R c are independently F, Cl, Br, I or C 1-3 Alkyl, wherein the C 1-3 The alkyl group is optionally substituted with 1, 2, 3 or 4 R d Replace, when R d When there are multiple R d Same or different.

[0112] In an optional embodiment of the present invention, each R c are independently F, Cl, Br, I, CH3 or -CH2CH3, wherein said CH3 and -CH2CH3 are independently optionally replaced by 1, 2, 3 or 4 R d Replace, when R d When there are multiple R d Same or different.

[0113] In an optional embodiment of the present invention, each R c are independently F, Cl, Br, I, CH3, CH2F, CHF2 or CF3.

[0114] In an optional embodiment of the present invention, R 1 and R a are independently H or optionally substituted by 1, 2, 3 or 4 R d Replaced CH3.

[0115] In an optional embodiment of the present invention, R a 、R 1, R4 and R5 are each independently H or optionally substituted by 1, 2, 3 or 4 R d Replaced CH3.

[0116] In an optional embodiment of the present invention, R a and R 1 are independently H, CH3 or CF3.

[0117] In an optional embodiment of the present invention, R a 、R 1 , R4 and R5 are each independently H, CH3 or CF3.

[0118] In an optional embodiment of the present invention, R 2 and R 3 are independently H or CH3.

[0119] In an optional embodiment of the present invention, Ring B is C 3-6 Monocyclic cycloalkyl, C 6-10 Spiroalkyl, C 6-10 Cycloalkyl or C 4-10 Bridged cycloalkyl.

[0120] In an optional embodiment of the present invention, ring B is C 3-6 Monocyclic cycloalkyl, C 6-8 Spiroalkyl, C 6-9 Cycloalkyl or C 5-9 Bridged cycloalkyl.

[0121] In an optional embodiment of the present invention, Ring B is

[0122] In an optional embodiment of the present invention, ring A is phenyl, imidazolyl, pyrazolyl or pyrrolyl.

[0123] In an optional embodiment of the present invention, the structural unit for

[0124] In an optional embodiment of the present invention, the structural unit for

[0125] In an optional embodiment of the present invention, ring D is

[0126] is a single bond or a double bond;

[0127] T3 is N or CR t3 ;

[0128] T4 is N or CR4;

[0129] T5 is N or CR5;

[0130] T6 and T7 are independently N or C; when T6 and T7 are independently C, the connected is a double bond;

[0131] T8 is N or CR8;

[0132] Ring C is C 6-10 Aryl, C 4-8 cycloalkenyl, 5-8 membered heteroaryl or 4-9 membered heterocycloalkenyl; in some embodiments, ring C is C 6-10 Aryl, C 4-6 In some embodiments, ring C is phenyl; in some embodiments, ring C is a 5-6 membered nitrogen-containing heteroaryl.

[0133] R t3 R4, R5, R6 and R8 are independently 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, 3-10 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, C 1-6 Alkylamino; the C 1-6 Alkyl, C 3-8 Cycloalkyl, 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, 3-10 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl are optionally substituted by n R b Substituted; said R b A substituent selected from the group consisting of hydrogen, 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, C1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl; when the substituent R b When n is the number, the R b Same or different; wherein, when R b Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl and C 2-6 alkynyl, each independently further optionally substituted by 1, 2, 3 or 4 R d1 Replace, when R d1 When there are multiple R d1 Same or different; R d1 are independently H, F, Cl, Br or I;

[0134] R t3 , R4, R5 and R8 are independently H, halogen, NH2, CN, OH, C 1-3 Alkyl, C 1-3 Alkoxy or C 3-6 Cycloalkyl, wherein C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Cycloalkyl is optionally substituted by 1, 2, 3 or 4 R b Replace, when R b When there are multiple R b Same or different;

[0135] Each R6 is independently H, halogen, NH2, CN, =O, OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2, 3 or 4 R b Replace, when R b When there are multiple R b Same or different;

[0136] n is 0, 1, 2, 3 or 4.

[0137] In an optional embodiment of the present invention, ring D is

[0138] is a single bond or a double bond;

[0139] T3 is NR t3 , CR t3 、C(R t3 )2;

[0140] T4 is NR4, CR4, C(R4)2;

[0141] T5 is NR5, CR5, C(R5)2;

[0142] T6 and T7 are independently N or C; when T6 and T7 are independently C, the connected is a double bond;

[0143] T8 is NR8, CR8, C(R8)2;

[0144] Ring C is C 6-10 Aryl, C 4-8 cycloalkenyl, 5-8 membered heteroaryl or 4-9 membered heterocycloalkenyl; in some embodiments, ring C is C 6-10 Aryl, C 4-6 In some embodiments, ring C is phenyl; in some embodiments, ring C is a 5-6 membered nitrogen-containing heteroaryl.

[0145] R t3 R4, R5, R6 and R8 are independently 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, 3-10 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, C 1-6 Alkylamino; the C 1-6 Alkyl, C 3-8 Cycloalkyl, 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, 3-10 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl are optionally substituted by n R bSubstituted; said R b A substituent selected from the group consisting of hydrogen, 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 Halogenated alkoxy, C 3-6 Cycloalkyl; when the substituent R b When n is the number, the R b Same or different; wherein, when R b Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl and C 2-6 alkynyl, each independently further optionally substituted by 1, 2, 3 or 4 R d1 Replace, when R d1 When there are multiple R d1 Same or different; R d1 are independently H, F, Cl, Br or I;

[0146] R t3 , R4, R5 and R8 are independently H, halogen, NH2, CN, OH, C 1-3 Alkyl, C 1-3 Alkoxy or C 3-6 Cycloalkyl, wherein C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Cycloalkyl is optionally substituted by 1, 2, 3 or 4 R b Replace, when R b When there are multiple R b Same or different;

[0147] Each R6 is independently H, halogen, NH2, CN, =O, OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2, 3 or 4 R b Replace, when R b When there are multiple R bSame or different;

[0148] n is 0, 1, 2, 3 or 4.

[0149] In an optional embodiment of the present invention, ring D is

[0150] is a single bond or a double bond;

[0151] T3 is N or CR t3 ;

[0152] T4 is N or CR4;

[0153] T5 is N or CR5;

[0154] T6 and T7 are each independently N or C;

[0155] T8 is N or CR8;

[0156] Ring C is C 6-10 Aryl, C 4-6 Cycloalkenyl, 5-6 membered heteroaryl or 4-9 membered heterocycloalkenyl;

[0157] R t3 , R4, R5 and R8 are independently H, halogen, NH2, OH, C 1-3 Alkyl, C 1-3 Alkoxy or C 3-6 Cycloalkyl, wherein C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Cycloalkyl is optionally substituted by 1, 2, 3 or 4 R b Replace, when R b When there are multiple R b Same or different;

[0158] R6 are independently H, halogen, NH2, CN, =O, OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2, 3 or 4 R b Replace, when R b When there are multiple R b Same or different;

[0159] n is 0, 1, 2, 3 or 4.

[0160] In an optional embodiment of the present invention, R b are independently H, F, Cl, Br or I.

[0161] In an optional embodiment of the present invention, each R6 is independently H, F, Cl, Br, I, NH2, CN, =O, C 1-3 Alkyl or C 1-3 Alkoxy, wherein the C 1-3 Alkyl and C 1-3 The alkoxy group is optionally substituted with 1, 2, 3 or 4 R b Replace, when R b When there are multiple R b Same or different.

[0162] In an optional embodiment of the present invention, each R6 is independently H, F, Cl, Br, I, NH2, CN, =O, CH3, -CH2CH3 or -O-CH3, wherein said CH3, -CH2CH3 and -O-CH3 are independently optionally replaced by 1, 2, 3 or 4 R b Replace, when R b When there are multiple R b Same or different.

[0163] In an optional embodiment of the present invention, each R6 is independently H, F, Cl, Br, CN, ═O, CH3, CF3, —CH2—CF3 or —O—CH3.

[0164] In an optional embodiment of the present invention, R6 is H, F, Cl, Br, I, ═O, C 1-3 Alkyl or C 1-3 Alkoxy, wherein the C 1-3 Alkyl and C 1-3 The alkoxy group is optionally substituted with 1, 2, 3 or 4 R b Replace, when R b When there are multiple R b Same or different.

[0165] In an optional embodiment of the present invention, R6 is H, F, Cl, Br, I or C 1-3 Alkyl, wherein the C 1-3 The alkyl group is optionally substituted with 1, 2, 3 or 4 R b Replace, when R b When there are multiple R b Same or different.

[0166] In an optional embodiment of the present invention, R6 is H, F, Cl, Br, I, =O, CH3, -CH2CH3 or -O-CH3, wherein said CH3, -CH2CH3 and -O-CH3 are independently optionally replaced by 1, 2, 3 or 4 R b Replace, when R b When there are multiple R b Same or different.

[0167] In an optional embodiment of the present invention, R6 is H, F, Cl, Br, I, CH3 or -CH2CH3, wherein said CH3 and -CH2CH3 are each independently optionally replaced by 1, 2, 3 or 4 R b Replace, when R b When there are multiple R b Same or different.

[0168] In an optional embodiment of the present invention, R6 is H, =O, CH3, CF3 or -O-CH3.

[0169] In an optional embodiment of the present invention, R6 is H or CH3.

[0170] In an optional embodiment of the present invention, R t3 R4, R5 and R8 are each independently H or optionally substituted by 1, 2, 3 or 4 R b Replaced CH3.

[0171] In an optional embodiment of the present invention, R t3 , R4, R5 and R8 are independently H, F, Cl, Br, I, NH2, CN, or optionally 1, 2, 3 or 4 R b substituted CH3;

[0172] In an optional embodiment of the present invention, R t3 , R4, R5 and R8 are each independently H, CH3 or CF3.

[0173] In an optional embodiment of the present invention, ring C is phenyl or a 5-membered nitrogen-containing heteroaryl group.

[0174] In an optional embodiment of the present invention, ring C is phenyl, 5-6 membered nitrogen-containing heteroaryl or 5-6 membered heterocycloalkenyl.

[0175] In an optional embodiment of the present invention, ring C is phenyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, thienyl, pyrrolyl or pyrrolidinyl, pyridazine, pyrimidine, dihydropyrrole, dihydroimidazole.

[0176] In an optional embodiment of the present invention, Ring C is phenyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, thienyl, pyrrolyl or pyrrolidinyl.

[0177] In an optional embodiment of the present invention, Ring C is imidazolyl, pyrazolyl, thiazolyl, thienyl or pyrrolyl.

[0178] In an optional embodiment of the present invention, ring D is

[0179] In an optional embodiment of the present invention, ring D is

[0180] In an optional embodiment of the present invention, ring D is

[0181] In an optional embodiment of the present invention, ring D is R t3 H, halogen, NH2, OH, C 1-3 Alkyl, C 1-3 Alkoxy or C 3-6 Cycloalkyl, wherein C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Cycloalkyl is optionally substituted by 1, 2, 3 or 4 R b Replace, when R b When there are multiple R b The same or different; the R b As defined above.

[0182] In an optional embodiment of the present invention, ring D is

[0183] In an optional embodiment of the present invention, ring D is

[0184] In an optional embodiment of the present invention, ring D is

[0185] In an optional embodiment of the present invention, the structural unit for In an optional embodiment of the present invention, the structural unit for In an optional embodiment of the present invention, ring D is

[0186] In an optional embodiment of the present invention, ring D is

[0187] In an optional embodiment of the present invention, the compound of formula I has the structural formula Ic:

[0188] Among them, ring A, ring D, X 1 、X 5 、R 1 、R 2 、R 3 、R a 、R k , s are as defined above.

[0189] In an optional embodiment of the present invention, the compound of formula (Ic) has the structural formula (Ic-1), (Ic-2), (Ic-3) or (Ic-4):

[0190] Among them, ring D, X 1 、R 1 、R 2 、R 3 、R a 、R k , s are as defined above.

[0191] In a preferred embodiment of the present invention, the compound represented by formula I is selected from any one of the following compounds:

[0192] In a preferred embodiment of the present invention, the compound represented by formula I is selected from any one of the following compounds:

[0193] In a preferred embodiment of the present invention, the pharmaceutically acceptable salt of the compound of Formula I is trifluoroacetate.

[0194] In a preferred embodiment of the present invention, the compound represented by formula I is selected from any one of the following compounds:

[0195] In a preferred embodiment of the present invention, the compound represented by formula I is selected from any one of the following compounds:

[0196] In a preferred embodiment of the present invention, the pharmaceutically acceptable salt of the compound of Formula I is trifluoroacetate or formate.

[0197] In a second aspect, the present invention provides a pharmaceutical composition comprising: a compound of formula I (including formula I-1, formula I-2, formula II-1, formula Ia, Ib, Ic, etc.) as described in the first aspect of the present invention, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs; in some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0198] The third aspect of the present invention provides the use of the compound of formula I as described in the first 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 second 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.

[0199] Preferably, the MRGPRX2-related diseases include mast cell-related diseases.

[0200] Preferably, the MRGPRX2-related diseases include: skin diseases, autoimmune diseases, and nervous system diseases.

[0201] Preferably, the skin disease is selected from atopic dermatitis, contact dermatitis, urticaria, and pruritus.

[0202] Preferably, the urticaria is selected from chronic spontaneous urticaria and induced urticaria.

[0203] Preferably, the autoimmune disease is selected from the group consisting of allergy, mastocytosis, rheumatoid arthritis, asthma, ulcerative colitis and interstitial cystitis.

[0204] Preferably, the neurological disease is selected from pain.

[0205] In a fourth aspect, the present invention provides a method for antagonizing MRGPRX2, or preventing and / or treating MRGPRX2-related diseases, comprising the steps of administering to a subject in need thereof the compound of Formula I, or its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs, as described in the first aspect of the present invention. The MRGPRX2-related diseases are as described above.

[0206] 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.

[0207] Terms and Definitions

[0208] 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.

[0209] 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.

[0210] 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.

[0211] 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.

[0212] 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.

[0213] 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.

[0214] 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.

[0215] 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.

[0216] 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.

[0217] 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.

[0218] 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.

[0219] 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.

[0220] 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.

[0221] 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.

[0222] 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. In the term "one or more" substitution, multiple refers to more than two, for example, 2, 3, 4, 5, etc.

[0223] 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.

[0224] In the present application, those skilled in the art can understand from the context that the variable name "ring C" in the general formula Ib is different from the variable name "C" in the general formula I-1, and the two obviously have their own independent definitions and values.

[0225] 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.

[0226] 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.

[0227] Unless otherwise specified, the term “C 0-6 "Alkyl" includes C0 alkyl (i.e., a bond) and C 1-6 alkyl.

[0228] The term "halo" by itself or as part of another substituent is used interchangeably with the term "halogen-substituted."

[0229] 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.

[0230] 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.

[0231] 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.

[0232] 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 、C 2-4 , 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.

[0233] 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.

[0234] 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.

[0235] Unless otherwise specified, the term “C 3-12"Cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 12 (3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, including monocyclic and bicyclic systems, wherein the bicyclic system includes spirocyclic, fused and bridged rings. The cycloalkyl group includes C 3-6 、C 3-5 、C 3-8 、C 6-10 、C 4-10 、C 4-12 、C 4-8 、C 4-6 、C 4-5 、C 5-8 or C 5-6 Cycloalkyl, etc.; which can be monovalent, divalent or polyvalent. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2]bicyclooctane, etc.

[0236] 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.

[0237] 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 9-12Similarly, 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.

[0238] Unless otherwise specified, the term "aryl" refers to a monocyclic or polycyclic carbocyclic ring having 6 to 20 (6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 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. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthrenyl, anthracenyl, and acenaphthenyl. The term "6-10 membered aryl" refers to a monocyclic or polycyclic carbocyclic ring having 6 to 10 carbon atoms, at least one of which is aromatic.

[0239] Unless otherwise specified, the term "heterocycloalkyl" refers to a cycloalkyl group in which one or more (in some embodiments, 1 to 3, such as 1, 2, 3) carbon atoms are replaced by heteroatoms, such as, but not limited to, N, O, S, and P. The term "mn-membered heterocycloalkyl" or "Cm-Cn 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 "3-11 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 3 to 11 (3, 4, 5, 6, 7, 8, 9, 10, 11) ring atoms. The term "heterocycloalkyl" may contain 3 to 11 ring atoms, 3 to 10 ring atoms, 5-10 ring atoms, 3-6 ring atoms, etc. 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.

[0240] Unless otherwise specified, the term "heterocycloalkenyl" by itself or in combination with other terms refers to a partially unsaturated cyclic group consisting of 5 to 12 ring atoms containing at least one carbon-carbon double bond, of which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., C(=O), NO and S(O)p, p is 1 or 2). Heterocycloalkenyl includes 4-12 (4, 5, 6, 7, 8, 9, 10, 11, 12) ring atoms, for example, 4-8 membered, 8-12 membered, 5-6 membered heterocycloalkenyl. Heterocycloalkenyl includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spirocyclic, fused rings and bridged rings, such as 8-12 membered fused heterocycloalkenyl. For example, in the case of "5-6 membered heterocycloalkenyl", the heteroatom can occupy the position at which the heterocycloalkenyl is attached to the rest of the molecule. The 5-6 membered heterocycloalkenyl group includes 5-membered and 6-membered heterocycloalkenyl groups and the like.

[0241] Unless otherwise specified, the term "cycloalkenyl" by itself or in combination with other terms refers to a partially unsaturated cyclic group consisting of 5 to 12 ring carbon atoms containing at least one carbon-carbon double bond. Cycloalkenyl groups can include 4-12 (4, 5, 6, 7, 8, 9, 10, 11, 12) ring atoms, for example, 4-9-membered, 4-8-membered, 5-6-membered cycloalkenyl groups. Cycloalkenyl groups include monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spirocyclic, fused rings and bridged rings.

[0242] Unless otherwise specified, the term "heteroaromatic ring" refers to a monocyclic or polycyclic carbocyclic ring in which at least one ring atom is a heteroatom independently selected from oxygen, sulfur and nitrogen, and the remaining ring atoms are C, wherein at least one ring is an aromatic ring. The group may be a carbon group or a heteroatom group (i.e., it may be C-connected or N-connected, as long as it is possible). When one of the rings is a non-aromatic ring, the group may be connected through the aromatic ring or through the non-aromatic ring. The heteroaromatic ring may include monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spirocyclic, paracyclic and bridged rings, for example, including 8-12 membered paracyclic heteroaromatic rings; the heteroaromatic ring may contain 1-4 (1, 2, 3, 4) heteroatoms selected from N, O, S, preferably 5-10 members (e.g., 5, 6, 7, 8, 9, 10 members), more preferably 5-6 members. Specifically, 5-6 membered heteroaryl represents a monocyclic group with a conjugated π electron system consisting of 5 to 6 ring atoms, wherein 1, 2, 3 or 4 ring atoms 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 can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2). The 5-6 membered heteroaryl can be connected to the rest of the molecule through a heteroatom or a carbon atom. The 5-6 membered heteroaryl includes 5-membered and 6-membered heteroaryl. Examples of heteroaryl groups include, but are not limited to, imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl, etc.), tetrazolyl, indolyl, benzotriazolyl, furyl (including 2-furyl and 3-furyl, etc.), Thienyl (including 2-thienyl and 3-thienyl), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl), benzothienyl, benzofuranyl, quinolyl, isoquinolyl, oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl), isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl), indolyl, pyrazinyl, pyridazinyl, pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl), pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl), pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl), N-methylpyrrolyl and tetrahydroquinoline. The term "heteroaromatic ring" can be used interchangeably with the terms "heteroaromatic ring", "heteroaryl" or "heteroaromatic ring group".

[0243] 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.

[0244] Unless otherwise specified, the term "halo" or "halogen" refers to fluoro, chloro, bromo and iodo.

[0245] 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.

[0246] 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.

[0247] 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.

[0248] The term "prevent" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0249] 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.

[0250] 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.

[0251] 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

[0252] After extensive and in-depth research, the inventors unexpectedly developed a compound or a pharmaceutically acceptable salt thereof, as well as a preparation method and use. The present invention provides a compound represented by Formula I, and its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs. The compound of Formula I has a significant inhibitory effect on MRGPRX2 and can be used as an antagonist of MRGPRX2, with high safety and drug-like properties (such as excellent pharmacokinetic properties). DETAILED DESCRIPTION

[0253] 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.

[0254] This application has the following definitions:

[0255] Symbol or unit:

[0256] IC 50 : Half-maximal inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved

[0257] M: mol / L, for example, n-butyllithium (14.56 mL, 29.1 mmol, 2.5 M n-hexane solution) means a n-butyllithium n-hexane solution with a molar concentration of 2.5 mol / L

[0258] N: equivalent concentration, for example, 2N hydrochloric acid means 2 mol / L hydrochloric acid solution

[0259] Reagents:

[0260] PPA: Polyphosphoric acid NMP: N-methylpyrrolidone

[0261] DMF: N,N-dimethylformamide

[0262] DCE: 1,2-dichloroethane

[0263] Preparation of intermediate-1 (int-1)

[0264] 2-Amino-6-chloropyridine (5 g, 39.1 mmol) and 3-bromo-1,1,1-trifluoroacetone (7.4 g, 39.1 mmol) were dissolved in ethylene glycol (100 mL) at room temperature and stirred at 130°C for 12 h. After TLC monitoring indicated complete reaction, stirring was stopped and the reaction solution was cooled to room temperature. Water (200 mL) was then added for dilution and extraction with ethyl acetate (100 mL x 5). The organic phase was collected and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography (DCM:MeOH (v / v) = 100:5) to afford 5-chloro-2-(trifluoromethyl)imidazo[1,2-a]pyridine (int-1) (6.2 g, 72% yield).

[0265] LC-MS, M / Z (ESI): 221.99 [M+H] +

[0266] Preparation of Intermediate-2 (int-2)

[0267] At room temperature, the compound 2-amino-6-bromopyridine (5 g, 28.9 mmol) and 3-bromo-1,1,1-trifluoroacetone (5.5 g, 28.9 mmol) were dissolved in ethylene glycol (50 mL) and stirred at 130°C for 12 h. After thin-layer chromatography monitoring showed that the raw materials had reacted completely, stirring was stopped, the reaction solution was cooled to room temperature, and then diluted with water (200 mL), extracted with ethyl acetate (100 mL×5), and 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 (DCM:MeOH (V / V)=100:5) to obtain compound 5-bromo-2-(trifluoromethyl)imidazo[1,2-a]pyridine (int-2) (4.9 g, yield 65%).

[0268] LC-MS, M / Z (ESI): 263.90 [M+H] +

[0269] Preparation of intermediate-3 (int-3)

[0270] Step 1: Synthesis of 6-chloro-2-(trifluoromethyl)quinolin-4-ol (C-3).

[0271] At room temperature, p-chloroaniline (C-1) (5 g, 39.37 mmol) was added to PPA (200 mmol, 75 ml, 5.0 eq), followed by the addition of ethyl trifluoroacetoacetate (C-2) (7.2 g, 39.37 mmol). The reaction mixture was heated to 140°C for 12 hours. After completion, the reaction mixture was poured into ice water and extracted with ethyl acetate (4 x 50 mL). The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude compound 6-chloro-2-(trifluoromethyl)quinolin-4-ol (C-3) (8.5 g, 87.6% yield), which was used directly in the next reaction.

[0272] LC-MS, M / Z(ESI):248.0[M+H] +

[0273] Step 2: Synthesis of 4,6-dichloro-2-(trifluoromethyl)quinoline (C-4).

[0274] 6-Chloro-2-(trifluoromethyl)quinolin-4-ol (C-3) (8.5 g, 34.5 mmol) was dissolved in DCE (100 ml) and phosphorus oxychloride (13.2 g, 86.25 mmol) was added at 0°C. The reaction temperature was then raised to 80°C for 12 hours. After completion of the reaction, the crude product was dried and purified on a silica gel column (PE:EA (V / V) = 100:2) to afford compound 4,6-dichloro-2-(trifluoromethyl)quinoline (C-4) (8.3 g, 91.6% yield).

[0275] LC-MS, M / Z(ESI):265.9[M+H] +

[0276] Step 3: Synthesis of tert-butyl ((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexane)carbamate (C-6).

[0277] At room temperature, 4,6-dichloro-2-(trifluoromethyl)quinoline (C-4) (1.32 g, 5 mmol) and tert-butyl ((1R,3S)-3-aminocyclohexyl)carbamate (C-5) (1 g, 4.67 mmol) were added to N-methylpyrrolidone (10 mL), followed by N,N-diisopropylethylamine (1.9 g, 15 mmol). The reaction solution was heated to 130°C and reacted for 12 hours. After completion of the reaction, the reaction solution was poured into ice water and extracted with ethyl acetate (4*50 mL). The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and dried. The crude product was purified on a silica gel column (PE:EA (V / V) = 2:1) to give tert-butyl ((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)-amino)cyclohexane)carbamate (C-6) (1.9 g, 96.3% yield).

[0278] LC-MS, M / Z(ESI):444.1[M+H] +

[0279] Step 4: (1S, 3R)-N 1 Synthesis of -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine (int-3)

[0280] At room temperature, tert-butyl ((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)-amino)cyclohexane)carbamate (C-6) (1 g, 2.3 mmol) was dissolved in 1,4-dioxane (20 mL), and concentrated hydrochloric acid (0.5 mL) was added. The reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, saturated sodium bicarbonate aqueous solution was added to the reaction solution to make it alkaline, and the mixture was extracted with dichloromethane / methanol (4*50 mL). The obtained organic phase was dried over anhydrous sodium sulfate, filtered and dried, and the crude product was purified by silica gel column (DCM:MeOH (V / V) = 100:2) to obtain compound (1S,3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine (int-3) (720 mg, 91.3% yield).

[0281] LC / MS(ESI)(m / z):344[M+H] +

[0282] Preparation of intermediate-4 (int-4)

[0283] Step 1: Synthesis of cis-tert-butyl 4-(2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)amino)cyclohexyl)carbamate (D-2)

[0284] At room temperature, 5-bromo-2-(trifluoromethyl)imidazo[1,2-a]pyridine (1.00 g, 3.77 mmol) and tert-butyl-((1s,4s)-4-amino)cyclohexane)carbamate (D-1) (1.62 g, 7.55 mmol) were dissolved in anhydrous 1,4-dioxane solution (10 mL), and then sodium tert-butoxide (725 mg, 7.55 mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (342.0 0 mg, 0.37 mmol), stirred in an oil bath at 100 ° C for 12 h under nitrogen protection. After thin-layer chromatography monitoring showed that the raw materials had reacted, stirring was stopped, the reaction solution was cooled to room temperature, and then water (50 mL) was added to dilute it, and 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 crude product was purified by silica gel column (PE: EA (V / V) = 2:1) to obtain compound cis-4-(2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)amino)cyclohexyl)carbamic acid tert-butyl ester (D-2) (190.00 mg, yield 12.64%).

[0285] LC-MS, M / Z(ESI):398.80[M+H] +

[0286] Step 2: cis-N 1 Synthesis of -(2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)cyclohexane-1,4-diamine (int-4)

[0287] At room temperature, tert-butyl cis-4-(2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)amino)cyclohexyl)carbamate (D-2) (190.00 mg, 0.48 mmol) was dissolved in anhydrous dichloromethane (2 mL) and stirred for 10 min. HCl / Dioxane (4 M) (0.48 ml, 1.91 mmol) was then slowly added dropwise. Stirring was continued at room temperature for 30 min. After the reaction was completed as monitored by thin-layer chromatography, saturated aqueous sodium bicarbonate was added to the reaction solution to make it alkaline. The mixture was extracted with dichloromethane / methanol (4×50 mL). The obtained organic phase was dried over anhydrous sodium sulfate, filtered and dried. The crude product was purified by silica gel column chromatography (DCM:MeOH (V / V) = 100:2) to obtain compound (1S,4S)-N 1-(2-(Trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)cyclohexane-1,4-diamine (int-4) (150.26 mg, 94.12% yield).

[0288] LC-MS, M / Z(ESI):298.70[M+H] +

[0289] Example 1: Preparation of target compound 1

[0290] cis-N 1 -(2-methyl-2H-pyrazolo[4,3-c]pyridin-4-yl)-N 4 -(2-(Trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)cyclohexane-1,4-diamine (Compound 1)

[0291] The synthetic route of target compound 1 is as follows:

[0292] Step 1: Synthesis of 4-chloro-2-methyl-2H-pyrazolo[4,3-c]pyridine (1-B)

[0293] At room temperature, 4-chloro-1H-pyrazolo[4,3-c]pyridine (5 g, 32.56 mmol) was dissolved in anhydrous dimethyl sulfoxide (50 mL) and stirred in an ice bath under nitrogen for 10 min. Then, NaHMDS (24.42 mL, 2 M tetrahydrofuran solution) was slowly added dropwise. After the addition was complete, the reaction solution was stirred in an ice bath for 10 min, and then iodomethane (6.08 mL) was slowly added dropwise. After the addition was complete, the reaction solution was slowly warmed to room temperature and stirred for 2 h. After thin layer chromatography monitoring showed that the raw materials had reacted completely, water (200 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (100 mL×5). The organic phase was collected and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM:MeOH (V / V)=100:10) to obtain compound 4-chloro-1-methyl-1H-pyrazolo[4,3-c]pyridine (2-B) (2.03 g, yield 37.20%) and compound 4-chloro-2-methyl-2H-pyrazolo[4,3-c]pyridine (1-B) (1.18 g, yield 21.62%).

[0294] LC-MS, M / Z (ESI): 167.90 [M+H] +

[0295] 4-Chloro-2-methyl-2H-pyrazolo[4,3-c]pyridine (1-B): 1H NMR (400MHz, Chloroform-d) δ 8.09 (d, J = 0.9 Hz, 1H), 8.02 (d, J = 6.2 Hz, 1H), 7.43 (dd, J = 6.3, 1.0 Hz, 1H), 4.25 (s, 3H).

[0296] 4-Chloro-1-methyl-1H-pyrazolo[4,3-c]pyridine (2-B): 1 H NMR (400MHz, CDCl3) δ8.17 (d, J = 6.0 Hz, 1H), 8.12 (d, J = 1.0 Hz, 1H), 7.23 (dd, J = 6.0, 1.0 Hz, 1H), 4.08 (s, 3H).

[0297] Step 2: Synthesis of tert-butyl (cis-4-((2-methyl-2H-pyrazolo[4,3-c]pyridin-4-yl)amino)cyclohexyl)carbamate (1-C)

[0298] At room temperature, 4-chloro-2-methyl-2H-pyrazolo[4,3-c]pyridine (1-B) (560 mg, 3.34 mmol), 1 N-Boc-cis-1,4-cyclohexanediamine (1.43 g, 6.68 mmol) and potassium carbonate (1.39 g, 10.02 mmol) were dissolved in anhydrous dimethyl sulfoxide (6 mL), and the reaction solution was stirred at 120°C for 24 h. After TLC monitoring indicated complete reaction of the starting materials, stirring was stopped, the reaction solution was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (20 mL x 5). The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH (v / v) = 100:5) to obtain the compound (cis-tert-butyl 4-((2-methyl-2H-pyrazolo[4,3-c]pyridin-4-yl)amino)cyclohexyl)carbamate (1-C) (240 mg, 20.79% yield).

[0299] LC-MS, M / Z (ESI): 346.10 [M+H] +

[0300] Step 3: cis-N 1 Synthesis of -(2-methyl-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclohexane-1,4-diamine hydrochloride (1-D)

[0301] At room temperature, tert-butyl (cis-4-((2-methyl-2H-pyrazolo[4,3-c]pyridin-4-yl)amino)cyclohexyl)carbamate (1-C) (240 mg, 0.70 mmol) was dissolved in anhydrous dichloromethane (5 mL), and a solution of hydrogen chloride in 1,4-dioxane (0.88 mL, 4 mol / L) was slowly added dropwise at room temperature. After the addition was complete, stirring was continued at room temperature for 30 minutes. After monitoring the reaction of the raw materials by thin-layer chromatography, stirring was stopped, the solvent was removed by concentration under reduced pressure, ethyl acetate (5 mL) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was filtered, the filter cake was collected, and dried to obtain compound cis-N 1 -(2-Methyl-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclohexane-1,4-diamine hydrochloride (1-D).

[0302] LC-MS, M / Z(ESI):245.98[M+H] +

[0303] Step 4: cis-N 1 -(2-methyl-2H-pyrazolo[4,3-c]pyridin-4-yl)-N 4 Synthesis of -(2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)cyclohexane-1,4-diamine (Compound 1)

[0304] At room temperature, 5-chloro-2-(trifluoromethyl)imidazo[1,2-a]pyridine (int-1) (133 mg, 0.60 mmol), cis-N 1 -(2-Methyl-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclohexane-1,4-diamine hydrochloride (1-D) (170 mg, 0.60 mmol), cesium carbonate (785 mg, 2.40 mmol), tris(dibenzylideneacetone)dipalladium (55 mg, 0.06 mmol) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (75 mg, 0.12 mmol) were dissolved in anhydrous 1,4-dioxane (2 mL) and stirred at 100 ° C for 4 h under nitrogen protection. After the reaction of the raw materials was completed, the stirring was stopped, the reaction solution was cooled to room temperature, and then water (10 mL) was added to dilute it and extracted with ethyl acetate (10 mL×5). The organic phase was collected and dried over anhydrous sodium sulfate. The organic phase was concentrated and dried. The crude product was separated and purified by preparative liquid chromatography (column: C18 150×30mm; solvent: A = water + 0.05 volume formic acid (99%), B = acetonitrile; gradient: 25%-55%, 7 minutes) to obtain compound cis-N 1 -(2-methyl-2H-pyrazolo[4,3-c]pyridin-4-yl)-N 4-(2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)cyclohexane-1,4-diamine (Compound 1).

[0305] LC-MS, M / Z(ESI):429.85[M+H] +

[0306] 1 H NMR(400MHz,DMSO-d6)δ8.72(s,1H),8.49(s,1H),7.52(dd,1H),7.38–7.30(m,1H),7.15(s,1H),6.93(d,1H),6 .61(d,1H),6.48(d,1H),6.10(d,1H),4.12(s,1H),4.06(d,3H),3.69(s,1H),1.93(dd,4H),1.84–1.73(m,4H).

[0307] Example 2: Preparation of target compound 2

[0308] cis-N 1 -(1-methyl-1H-pyrazolo[4,3-c]pyridin-4-yl)-N 4 -(2-(Trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)cyclohexane-1,4-diamine (Compound 2)

[0309] The synthetic route of target compound 2 is as follows:

[0310] Step 1: Synthesis of tert-butyl (cis-4-((1-methyl-1H-pyrazolo[4,3-c]pyridin-4-yl)amino)cyclohexyl)carbamate (2-C)

[0311] At room temperature, 4-chloro-1-methyl-1H-pyrazolo[4,3-c]pyridine (2-B) (1.00 g, 5.97 mmol), 1-N-Boc-cis-1,4-cyclohexanediamine (2.56 g, 11.93 mmol) and potassium carbonate (2.47 g, 17.90 mmol) were dissolved in anhydrous dimethyl sulfoxide (10 mL), and then stirred at 120 ° C for 24 h. After the reaction of the raw materials was completed by thin layer chromatography monitoring, stirring was stopped and the temperature was lowered. The mixture was cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (30 mL×5), and the organic phase was collected and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (DCM:MeOH (V / V)=100:5) to obtain the compound cis-4-((1-methyl-1H-pyrazolo[4,3-c]pyridin-4-yl)amino)cyclohexyl)carbamic acid tert-butyl ester (2-C) (290 mg, yield 14.26%).

[0312] LC-MS, M / Z(ESI):346.06[M+H] +

[0313] Step 2: cis-N 1 -(1-Methyl-1H-pyrazolo[4,3-c]pyridin-4-yl)cyclohexane-1,4-diamine hydrochloride (2-D)

[0314] At room temperature, tert-butyl (cis-4-((1-methyl-1H-pyrazolo[4,3-c]pyridin-4-yl)amino)cyclohexyl)carbamate (2-C) (290 mg, 0.84 mmol) was dissolved in anhydrous dichloromethane (5 mL), and then a 4M hydrochloric acid solution in 1,4-dioxane (1.05 mL, 4.20 mmol) was slowly added dropwise and stirred for 30 min. After the reaction of the raw materials was completed as monitored by thin layer chromatography, stirring was stopped, the mixture was concentrated under reduced pressure, ethyl acetate (5 mL) was added, and the mixture was stirred at room temperature for 1 h. The mixture was filtered, the filter cake was collected, and dried to obtain compound cis-N 1 -(1-Methyl-1H-pyrazolo[4,3-c]pyridin-4-yl)cyclohexane-1,4-diamine hydrochloride (2-D) (165 mg, yield 65.51%).

[0315] LC-MS, M / Z(ESI):245.98[M+H] +

[0316] Step 3: cis-N 1 -(1-methyl-1H-pyrazolo[4,3-c]pyridin-4-yl)-N 4Synthesis of -(2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)cyclohexane-1,4-diamine (Compound 2)

[0317] At room temperature, 5-chloro-2-(trifluoromethyl)imidazo[1,2-a]pyridine (int-1) (100 mg, 0.45 mmol), cis-N 1 -(1-Methyl-1H-pyrazolo[4,3-c]pyridin-4-yl)cyclohexane-1,4-diamine hydrochloride (2-D) (128 mg, 0.45 mmol), cesium carbonate (591 mg, 1.81 mmol), tris(dibenzylideneacetone)dipalladium (42 mg, 0.04 mmol) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (56 mg, 0.09 mmol) were dissolved in anhydrous 1,4-dioxane (2 mL) and stirred in an oil bath at 100°C for 4 h under nitrogen protection. After the reaction of the raw materials was completed as monitored by thin-layer chromatography, stirring was stopped, the reaction solution was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (10 mL×5). The organic phase was collected and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by preparative liquid chromatography (column: C18 150×30 mm; solvent: A = water + 0.05 volume formic acid (99%), B = acetonitrile; gradient: 25%-55%, 7 minutes) to obtain compound cis-N 1 -(1-methyl-1H-pyrazolo[4,3-c]pyridin-4-yl)-N 4 -(2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)cyclohexane-1,4-diamine (Compound 2).

[0318] LC-MS, M / Z(ESI):429.98[M+H] +

[0319] 1 H NMR(400MHz,DMSO-d6)δ8.71(s,1H),8.24(s,1H),7.72(d,1H),7.34(t,1H),7.01(d,1H),6.92(d,1H),6.70(d ,1H),6.50(d,1H),6.10(d,1H),4.15(s,1H),3.89(s,3H),3.70(d,1H),1.98–1.91(m,4H),1.82–1.74(m,4H).

[0320] Example 3: Preparation of target compound 3

[0321] cis-N 1 -(1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N4 -(2-(Trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)cyclohexane-1,4-diamine (Compound 3)

[0322] The synthetic route of target compound 3 is as follows:

[0323] Step 1: cis-N 1 Synthesis of -(2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)cyclohexane-1,4-diamine (3)

[0324] At room temperature, 5-bromo-2-(trifluoromethyl)imidazo[1,2-a]pyridine (int-2) (500 mg, 1.89 mmol), cis-cyclohexane-1,4-diamine (215 mg, 1.89 mmol) and cesium carbonate (1.85 g, 5.67 mmol) were dissolved in dioxane (10 mL), and then (SP-4-1)-[1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(3-chloropyridine-KN)palladium (183 mg, 0.189 mmol) was added. The reaction solution was heated to 100 ° C under nitrogen protection and reacted for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the crude product was purified by silica gel column (DCM: MeOH (V / V) = 100:2) to obtain compound cis-N 1 -(2-(Trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)cyclohexane-1,4-diamine (3) (150 mg, 0.503 mmol, 26% yield).

[0325] LC / MS(ESI)(m / z):299[M+H] +

[0326] Step 2: cis-N 1 -(1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N 4 Synthesis of -(2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)cyclohexane-1,4-diamine (Compound 3)

[0327] At room temperature, cis-N 1-(2-(Trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)cyclohexane-1,4-diamine (50 mg, 0.168 mmol) was dissolved in tetrahydrofuran (1 mL), and then 4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (28 mg, 0.168 mmol) and N,N-diisopropylethylamine (43 mg, 0.336 mmol) were added. The temperature was raised to 60°C and the reaction was allowed to proceed for 12 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The crude product was separated and purified by preparative liquid chromatography (column: C18 150×30 mm; solvent: A = water + 0.05 volume formic acid (99%), B = acetonitrile; gradient: 25%-55%, 7 minutes) to obtain compound cis-N 1 -(1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N 4 -(2-(Trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)cyclohexane-1,4-diamine (Compound 3) (19 mg, 0.044 mmol, 26% yield).

[0328] LC / MS(ESI)(m / z):431[M+H] + ;

[0329] 1 H NMR (400MHz, CDCl3) δ8.40(s,1H),7.88(s,1H),7.72(s,1H),7.35–7.29(m,1H),7.20(d,1H),6.08(d,1H),5.56–5. 43(m,1H),4.37(s,1H),4.04(s,3H),3.98(d,1H),3.80(s,1H),2.26–2.18(m,1H),2.06–1.91(m,6H),1.63(s,1H).

[0330] Example 4: Preparation of target compound 4

[0331] cis-N 1 -(1-methyl-1H-pyrazolo[3,4-d]pyridazin-4-yl)-N 4 -(2-(Trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)cyclohexane-1,4-diamine (Compound 4)

[0332] The synthetic route of target compound 4 is as follows:

[0333] Step 1: Synthesis of 1-methyl-1H-pyrazolo[3,4-d]pyridazin-4-ol (2)

[0334] At room temperature, ethyl 5-formyl-1-methyl-1H-pyrazole-4-carboxylate (500 mg, 2.74 mmol) was dissolved in anhydrous ethanol (10 mL) and acetic acid (1 mL). 80% hydrazine hydrate (515 mg, 8.23 ​​mmol) was then added. The reaction mixture was then heated to 100°C and reacted for 12 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered, and washed with ethanol to yield the compound 1-methyl-1H-pyrazolo[3,4-d]pyridazin-4-ol.

[0335] LC / MS(ESI)(m / z):151[M+H] +

[0336] Step 2: Synthesis of 4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyridazine (4-3)

[0337] 1-Methyl-1H-pyrazolo[3,4-d]pyridazin-4-ol (100 mg, 0.593 mmol) was dissolved in phosphorus oxychloride (1 mL) at room temperature and stirred at 80°C for 1 hour. After completion of the reaction, the reaction solution was cooled to room temperature and added dropwise to a dilute sodium bicarbonate solution in an ice bath. After extraction with ethyl acetate, the organic phase was dried and concentrated. The crude product was purified on a silica gel column (PE:EA (v / v) = 1:1) to afford 4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyridazine.

[0338] LC / MS(ESI)(m / z):169[M+H] +

[0339] Step 3: cis-N 1 -(1-methyl-1H-pyrazolo[3,4-d]pyridazin-4-yl)-N 4 Synthesis of -(2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)cyclohexane-1,4-diamine (Compound 4)

[0340] At room temperature, cis-N 1-(2-(Trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)cyclohexane-1,4-diamine (int-4) (40 mg, 0.134 mmol), 4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyridazine (4-3) (22.6 mg, 0.134 mmol) and sodium trimethylsilanol (18.0 mg, 0.161 mmol) were dissolved in dioxane (1 mL), and then (SP-4-1)-[1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(3-chloropyridine-κN)-palladium (6.52 mg, 0.007 mmol) was added. Under nitrogen protection, the reaction solution was heated to 90 ° C and reacted for 12 hours. After the reaction was completed, the crude product was diluted with dichloromethane, filtered, dried, and concentrated, and then separated and purified by preparative liquid chromatography (chromatographic column: C18 150×30 mm; solvent: A = water + 0.05 volume formic acid (99%), B = acetonitrile; gradient: 25%-55%, 7 minutes) to obtain compound cis-N 1 -(1-methyl-1H-pyrazolo[3,4-d]pyridazin-4-yl)-N 4 -(2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)cyclohexane-1,4-diamine (Compound 4).

[0341] LC / MS(ESI)(m / z):431[M+H] + ;

[0342] 1 H NMR(400MHz,DMSO-d6)δ8.97(s,1H),8.71(s,1H),8.31(s,1H),7.36–7.32(m,1H),7.18(d,1H),6.93(d,1H),6.51(d ,1H),6.12(d,1H),4.27(s,1H),4.05(s,3H),3.71(s,1H),2.02–1.93(m,4H),1.82(s,2H),1.43(s,1H),1.27(s,1H).

[0343] Example 5: Preparation of target compound 5

[0344] (1R,3S)-N 1 -(1-methyl-1H-pyrazolo[4,3-c]pyridin-4-yl)-N 3 -(2-(Trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)cyclohexane-1,3-diamine (Compound 5)

[0345] The synthetic route of target compound 5 is as follows:

[0346] Step 1: Synthesis of tert-butyl ((1S,3R)-3-((1-methyl-1H-pyrazolo[4,3-c]pyridin-4-yl)amino)cyclohexyl)carbamate (5-3)

[0347] At room temperature, 4-chloro-1-methyl-1H-pyrazolo[4,3-c]pyridine (200 mg, 1.19 mmol) and tert-butyl ((1S,3R)-3-aminocyclohexyl)carbamate (255 mg, 1.19 mmol) were dissolved in dimethyl sulfoxide (2 mL). Diisopropylethylamine (461 mg, 3.57 mmol) was then added, and the mixture was heated to 150°C for 24 hours. After completion of the reaction, the mixture was directly purified on a silica gel column (PE:EA (V / V) = 1:1) to obtain tert-butyl ((1S,3R)-3-((1-methyl-1H-pyrazolo[4,3-c]pyridin-4-yl)amino)cyclohexyl)carbamate (5-3).

[0348] LC / MS (ESI) (m / z): 346 [M+H] +

[0349] Step 2: (1R, 3S)-N 1 Synthesis of -(1-methyl-1H-pyrazolo[4,3-c]pyridin-4-yl)cyclohexane-1,3-diamine (5-4)

[0350] At room temperature, tert-butyl ((1S,3R)-3-((1-methyl-1H-pyrazolo[4,3-c]pyridin-4-yl)amino)cyclohexyl)carbamate (5-3) (100 mg, 0.290 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added. The reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated to dryness. The crude product was purified by silica gel column (DCM:MeOH (V / V) = 100:2) to obtain compound (1R,3S)-N 1 -(1-methyl-1H-pyrazolo[4,3-c]pyridin-4-yl)cyclohexane-1,3-diamine (5-4).

[0351] LC / MS (ESI) (m / z): 246 [M+H] +

[0352] Step 3: (1R, 3S)-N 1 -(1-methyl-1H-pyrazolo[4,3-c]pyridin-4-yl)-N 3Synthesis of -(2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)cyclohexane-1,3-diamine (Compound 5)

[0353] At room temperature, (1R,3S)-N 1 -(1-methyl-1H-pyrazolo[4,3-c]pyridin-4-yl)cyclohexane-1,3-diamine (5-4) (71 mg, 0.290 mmol), 5-bromo-2-(trifluoromethyl)imidazo[1,2-a]pyridine (76.8 mg, 0.290 mmol) and cesium carbonate (283 mg, 0.870 mmol) were dissolved in dioxane (2 mL), and then (SP-4-1)-[1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(3-chloropyridine-κN)-palladium (28.0 mg, 0.029 mmol) was added, and the reaction temperature was also raised to 100 ° C under nitrogen protection for 12 hours. After the reaction was completed, the mixture was diluted with dichloromethane, filtered, concentrated and dried, and the resulting crude product was separated and purified by preparative liquid chromatography (column: C18 150×30 mm; solvent: A = water + 0.05 volume formic acid (99%), B = acetonitrile; gradient: 25%-55%, 7 minutes) to obtain compound (1R,3S)-N 1 -(1-methyl-1H-pyrazolo[4,3-c]pyridin-4-yl)-N 3 -(2-(Trifluoromethyl)imidazo[1,2-A]pyridin-5-yl)cyclohexane-1,3-diamine (Compound 5).

[0354] LC / MS (ESI) (m / z): 429.7 [M+H] + ;

[0355] 1 H NMR (400MHz, DMSO-d6) δ12.77–12.48(m,1H),8.60(s,1H),8.30(s,1H),7.71(d,1H),7.36–7.29(m,1H),6.90(d,2H),6.65( d,1H),6.21(d,1H),4.11(s,1H),3.94(s,3H),3.64(d,1H),2.41(d,1H),2.12–2.00(m,2H),1.86(d,1H),1.57–1.30(m,4H).

[0356] Example 6: Preparation of target compound 6

[0357] cis-N 1 -(1-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-N4 -(2-(Trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)cyclohexane-1,4-diamine (Compound 6)

[0358] The synthetic route of target compound 6 is as follows:

[0359] Step 1: cis-N 1 -(1-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-N 4 Synthesis of -(2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)cyclohexane-1,4-diamine (Compound 6)

[0360] At room temperature, cis-N 1 -(2-(Trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)cyclohexane-1,4-diamine (int-4) (40 mg, 0.134 mmol), 6-chloro-1-methyl-1H-pyrazolo[4,3-c]pyridine (6-1) (22.6 mg, 0.134 mmol) and sodium trimethylsilanol (18.0 mg, 0.161 mmol) were dissolved in dioxane (1 mL), and then (SP-4-1)-[1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(3-chloropyridine-κN)-palladium (6.52 mg, 0.007 mmol) was added. The reaction solution was heated to 90 degrees under nitrogen protection and reacted for 12 hours. After the reaction was completed, the mixture was diluted with dichloromethane and filtered, and the crude product was concentrated and dried. The crude product was separated and purified by preparative liquid chromatography (column: C18 150×30 mm; solvent: A = water + 0.05 volume formic acid (99%), B = acetonitrile; gradient: 25%-55%, 9 minutes) to obtain compound cis-N 1 -(1-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-N 4 -(2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)cyclohexane-1,4-diamine (Compound 6).

[0361] LC / MS (ESI) (m / z): 430.45 [M+H] + ;

[0362] 1H NMR(400MHz,DMSO-d6)δ8.68(s,1H),8.54(s,1H),7.90(s,1H),7.38–7.28(m,1H),6.91(d,1H),6 .48(d,1H),6.31(s,1H),6.16(d,1H),6.11(d,1H),3.82(s,1H),3.66(s,1H),2.05–1.63(m,1H).

[0363] Example 7: Preparation of target compound 7

[0364] (1S,3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 -(1-methyl-1H-pyrazolo[4,3-c]pyridin-4-yl)cyclohexane-1,3-diamine (Compound 7)

[0365] The synthetic route of target compound 7 is as follows:

[0366] Step 1: Synthesis of (1S,3R)-N1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N3-(1-methyl-1H-pyrazolo[4,3-c]pyridin-4-yl)cyclohexane-1,3-diamine (Compound 7)

[0367] At room temperature, (1S,3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine (int-3) (71 mg, 0.290 mmol), 4-chloro-1-methyl-1H-pyrazolo[4,5-C]pyridine (76.8 mg, 0.290 mmol) and cesium carbonate (283 mg, 0.870 mmol) were dissolved in dioxane (2 mL), and then (SP-4-1)-[1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(3-chloropyridine-κN)-palladium (28.0 mg, 0.029 mmol) was added. The reaction solution was heated to 100 degrees under nitrogen protection and reacted for 12 hours. After the reaction was completed, the mixture was diluted with dichloromethane and filtered, and the crude product was concentrated and dried. The crude product was separated and purified by preparative liquid chromatography (column: C18 150×30 mm; solvent: A = water + 0.05 volume formic acid (99%), B = acetonitrile; gradient: 25%-55%, 7 minutes) to obtain compound (1S,3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3-(1-methyl-1H-pyrazolo[4,3-c]pyridin-4-yl)cyclohexane-1,3-diamine (Compound 7).

[0368] LC / MS(ESI)(m / z):475[M+H] + ;

[0369] 1 H NMR(400MHz,DMSO-d6)δ(d,1H),8.14(d,1H),7.87(d,1H),7.71(dd,2H),7.48(d,1H),7.12(d,1H),6.92(s,1H),6.69 (d,1H),4.24(d,1H),3.88(s,4H),2.39(d,1H),2.02–1.95(m,2H),1.82(s,1H),1.62–1.53(m,1H),1.46–1.31(m,3H).

[0370] Example 8: Preparation of target compound 8

[0371] cis-N1,N4-bis(2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)cyclohexane-1,4-diamine (Compound 8)

[0372] The synthetic route of target compound 8 is as follows:

[0373] Step 1: cis-N 1 ,N 4 -Synthesis of Bis(2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)cyclohexane-1,4-diamine (Compound 8)

[0374] At room temperature, 5-bromo-2-(trifluoromethyl)imidazo[1,2-a]pyridine (Int-1) (50.0 mg, 0.189 mmol), cis-N 1-(2-(Trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)cyclohexane-1,4-diamine (Int-4) (56.3 mg, 0.189 mmol) and cesium carbonate (73.9 mg, 0.227 mmol) were dissolved in dioxane (1 mL), and then (SP-4-1)-[1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(3-chloropyridine-κN)-palladium (9.19 mg, 0.009 mmol) was added. Under nitrogen protection, the reaction solution was heated to 100 degrees and reacted for 12 hours. After the reaction was completed, the mixture was filtered and concentrated, and the crude product was separated and purified by preparative liquid chromatography (column: C18 150×30 mm; solvent: A = water + 0.05 volume formic acid (99%), B = acetonitrile; gradient: 25%-55%, 8 minutes) to obtain compound cis-N 1 ,N 4 -bis(2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)cyclohexane-1,4-diamine (Compound 8).

[0375] LC / MS(ESI)(m / z):483[M+H] + ;

[0376] 1 H NMR (400MHz, DMSO-d6) δ8.69(s,2H),7.39–7.29(m,2H),6.93(d,2H),6.52(d,2H),6.13(d,2H),3.72(s,2H),2.02–1.92(m,4H),1.84(d,4H).

[0377] Example 9: Preparation of target compound 9

[0378] cis-N 1 Synthesis of -(1-methylimidazo[4,5-c]pyridine)-N4-(2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]cyclohexyl-1,4-diamine (Compound 9)

[0379] The synthetic route of target compound 9 is as follows:

[0380] Step 1: cis-N 1 -(1-methylimidazo[4,5-c]pyridine)-N 4 Synthesis of -(2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]cyclohexyl-1,4-diamine (Compound 9)

[0381] At room temperature, 4-chloro-1-methylimidazo[4,5-c]pyridine (9-1) (100.00 mg, 0.60 mmol) and cis-N 1 -(2-(Trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)cyclohexane-1,4-diamine (int-4) (199.74 mg, 0.60 mmol) was dissolved in anhydrous 1,4-dioxane (1 mL) solution, molecular sieves 4A (100 mg) were added, followed by cesium carbonate (583.21 mg, 1.79 mmol) and (SP-4-1)-[1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-yl]dichloro (3-Chloropyridine-KN) palladium (29.02 mg, 0.03 mmol) was stirred in an oil bath at 100°C for 12 h under nitrogen protection. After the reaction of the raw materials was completed, the reaction solution was cooled to room temperature, diluted with water (5 mL), and extracted with ethyl acetate (5 mL×3). The organic phase was concentrated and dried, and the residue was separated and purified by preparative liquid chromatography (column: C18150×30 mm; solvent: A=water+0.05 volume formic acid (99%), B=acetonitrile; gradient: 25%-55%, 7 minutes) to obtain compound cis-N 1 -(1-methyl-1H-imidazo[4,5-c]pyridin-4-yl)-N 4 -(2-(Trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]cyclohexane-1,4-diamine (Compound 9).

[0382] LC-MS, M / Z(ESI):429.76[M+H] +

[0383] 1 H NMR (400MHz, DMSO-d6) δ8.65(s,1H),8.04(s,1H),7.77(d,J=5.8Hz,1H),7.35(dd,J=8.9,7.7Hz,1H) ,6.94(d,J=8.9Hz,1H),6.80(d,J=5.8Hz,1H),6.50(d,J=6.7Hz,1H),6.14(d,J=7.7Hz,1H),5.97(d,J =7.6Hz,1H),4.29(s,1H),3.77(s,3H),3.71(q,J=5.8Hz,1H),2.03–1.74(m,8H).

[0384] Example 10: Preparation of target compound 10

[0385] cis-N 1 -(6-methoxyisoquinolin-1-yl)-N 4-[2-(Trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]cyclohexane-1,4-diamine (target compound 10)

[0386] The synthetic route of target compound 10 is as follows:

[0387] Step 1: Synthesis of tert-butyl (cis-4-((6-methoxyisoquinolin-1-yl)amino)cyclohexyl)carbamate (10-2)

[0388] 1-Chloro-6-methoxyisoquinoline (10-1) (300 mg, 1.55 mmol) was dissolved in dioxane (10.0 mL), and tert-butyl-(cis-4-amino)cyclohexane)carbamate (664 mg, 3.10 mmol) was added. Cesium carbonate (1.51 g, 4.65 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (131 mg, 154 μmol) were added. The mixture was stirred at 90°C under nitrogen for 4 hours. After completion of the reaction, the reaction solution was poured into water (25.0 mL) and extracted with dichloromethane (50.0 mL). The organic phase was collected and concentrated to dryness. The crude product was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 10:1-3:1) to obtain compound (cis-4-((6-methoxyisoquinolin-1-yl)amino)cyclohexyl)carbamic acid tert-butyl ester (10-2) (500 mg, yield 86.7%).

[0389] LC-MS, M / Z(ESI):372.3[M+H] +

[0390] Step 2: cis-N 1 Synthesis of -(6-methoxyisoquinolin-1-yl)cyclohexane-1,4-diamine hydrochloride (10-3)

[0391] Dissolve tert-butyl (cis-4-((6-methoxyisoquinolin-1-yl)amino)cyclohexyl)carbamate (10-2) (500 mg, 1.35 mmol) in 2M hydrochloric acid ethyl ester (5.00 mL), and react at 25°C for 2 hours. The reaction solution was concentrated and dried to obtain compound cis-N 1 -(6-methoxyisoquinolin-1-yl)cyclohexane-1,4-diamine hydrochloride (10-3) (400 mg, yield 96.4%).

[0392] LC-MS, M / Z(ESI):308.1[M+H]+

[0393] Step 3: cis-N 1 -(6-methoxyisoquinolin-1-yl)-N 4 Synthesis of -[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]cyclohexane-1,4-diamine (target compound 10)

[0394] cis-N 1 -(6-Methoxyisoquinolin-1-yl)cyclohexane-1,4-diamine hydrochloride (10-3) (295 mg, 959 μmol) and 5-chloro-2-(trifluoromethyl)imidazo[1,2-a]pyridine (int-1) (120 mg, 544 μmol), cesium carbonate (709 mg, 2.18 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (92.5 mg, 108 μmol) were dissolved in dioxane (10.0 mL) and reacted at 90 ° C for 4 hours under nitrogen protection. The reaction solution was concentrated to dryness, and the crude product was separated and purified by preparative liquid chromatography (column: C18 150×30 mm; solvent: A = water + 0.05 volume formic acid (99%), B = acetonitrile; gradient: 25%-55%, 7 minutes) to obtain compound cis-N 1 -(6-methoxyisoquinolin-1-yl)-N 4 -(2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl])cyclohexane-1,4-diamine (target compound 10).

[0395] LC-MS, M / Z(ESI):456.2[M+H] +

[0396] 1 H NMR(400MHz,DMSO-d6)δ:8.73(s,1H),8.27(d,1H),,7.81(d,1H),7.36(m,1H),7.0 5-7.12(m,2H),6.95(d,1H),6.77-6.85(m,2H),6.50(d,1H),6.12(d,1H),4.22(br d,1H),3.86(s,3H),3.73(br s,1H),1.91-2.11(m,4H),1.71-1.90(m,4H).

[0397] Example 11: Preparation of target compound 11

[0398] cis-N 1-(3-methylimidazo[1,5-a]pyrazin-8-yl)-N 4 -(2-(Trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)cyclohexane-1,4-diamine (target compound 11)

[0399] The synthetic route of target compound 11 is as follows:

[0400] Step 1: cis-N 1 -(3-methylimidazo[1,5-a]pyrazin-8-yl)-N 4 Synthesis of -(2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)cyclohexane-1,4-diamine (target compound 11)

[0401] Cis-N1-(6-methoxyisoquinolin-1-yl)cyclohexane-1,4-diamine (int-4) (200 mg, 670 μmol) and 8-chloro-3-methylimidazo[1,5-a]pyrazine (11-1) (74.9 mg, 446 μmol), cesium carbonate (582 mg, 1.79 mmol), [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)dichloropalladium(II) (60.9 mg, 89.4 μmol) were dissolved in dioxane (5.00 mL) and stirred at 100 ° C under nitrogen protection for 4 hours. The reaction solution was concentrated and separated and purified by high performance liquid chromatography (column: C18 150×30 mm; solvent: A = water + 0.05 volume formic acid (99%), B = acetonitrile; gradient: 15%-45%, 7 minutes) to obtain compound cis-N 1 -(3-methylimidazo[1,5-a]pyrazin-8-yl)-N 4 -(2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)cyclohexane-1,4-diamine (target compound 11).

[0402] LC-MS, M / Z(ESI):430.2[M+H] +

[0403] 1H NMR(400MHz, DMSO-d6)δ:8.74(s,1H),7.84(br s,1H),7.43(d,1H),7.36(m,1H),7.02(d,1H),6.96(d,1H),6.50(d,1H),6.12(d,1H),4.12(br d,1H),3.73(d,1H),2.51(s,3H),1.91-2.03(m,4H),1.74-1.87(m,4H).

[0404] Example 12: Preparation of target compound 12

[0405] cis-N 1 -(2-(trifluoromethyl)imidazo[1,2-a]pyrazin-8-yl)-N 4 -(2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl}cyclohexane)-1,4-diamino

[0406] The synthetic route of target compound 12 is as follows:

[0407] Step 1: Synthesis of 2-(trifluoromethyl)imidazo[1,2-a]pyrazine-8-ol (12-2)

[0408] At room temperature, 2-chloro-3-aminopyrazine (12-1) (500.00 mg, 3.86 mmol) and 3-bromo-1,1,1-trifluoroacetone (736.97 mg, 3.86 mmol) were dissolved in ethylene glycol (5 mL) solution. The reaction solution was stirred in an oil bath at 120°C for 12 h. After the reaction of the raw materials was completed, the reaction solution was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (20 mL×5). The organic phase was collected, concentrated and dried, and the residue was separated and purified by silica gel column chromatography (PE:EA (V / V) = 100:10) to obtain compound 2-(trifluoromethyl)imidazo[1,2-a]pyrazine-8-ol (12-2) (170.00 mg, yield 31.96%).

[0409] LC-MS, M / Z(ESI):203.94[M+H] +

[0410] Step 2: cis-N 1 -(2-(trifluoromethyl)imidazo[1,2-a]pyrazin-8-yl)-N 4 Synthesis of -(2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl}cyclohexyl)-1,4-diamine (12)

[0411] At room temperature, 2-(trifluoromethyl)imidazo[1,2-a]pyrazine-8-ol (12-2) (100.00 mg, 0.49 mmol) and 1,8-diazobisspiro[5.4.0]undec-7-ene (112.24 mg, 0.74 mmol) were dissolved in N-methylpyrrolidone (1 mL), and Carter condensation agent (BOP) (283.07 mg, 0.64 mmol) was added. The mixture was stirred at room temperature for 10 min, and cis-N 1 -(1-methylimidazo[4,5-c]pyridine)-N 4 -[2-(Trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]cyclohexyl-1,4-diamine (int-4) (146.86 mg, 0.49 mmol), continued stirring for 12 h, after the reaction of the raw material was completed, it was monitored by thin layer chromatography, diluted with water (5 mL), extracted with ethyl acetate (5 mL×3), concentrated and dried, and the crude product was separated and purified by preparative liquid chromatography (column: C18 150×30 mm; solvent: A = water + 0.05 volume formic acid (99%), B = acetonitrile; gradient: 25%-55%, 7 minutes) to obtain compound cis-N 1 -(2-(trifluoromethyl)imidazo[1,2-a]pyrazin-8-yl)-N 4 -(2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)cyclohexane-1,4-diamine (Compound 12).

[0412] LC-MS, M / Z(ESI):484.12[M+H] +

[0413] 1 H NMR(400MHz,DMSO-d6)δ8.65(s,1H),8.51(s,1H),7.80(d,1H),7.42(d,1H),7.36(t,1H),7.22(d ,1H),6.96(d,1H),6.47(d,1H),6.14(d,1H),4.24(tq,1H),3.85–3.66(m,1H),2.17–1.62(m,8H).

[0414] Example 13: Preparation of target compound 13

[0415] (1S,3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 -(2-methyl-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclohexane-1,3-diamine (Compound 13)

[0416] The synthetic route of target compound 13 is as follows:

[0417] Step 1: (1S, 3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 Synthesis of -(1-methyl-1H-pyrazolo[4,3-c]pyridin-4-yl)cyclohexane-1,3-diamine (Compound 13)

[0418] At room temperature, (1S,3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine (int-3) (50.0 mg, 0.145 mmol), 4-chloro-2-methyl-2H-pyrazolo[4,3-c]pyridine (1-B) (24.3 mg, 0.145 mmol) and cesium carbonate (56.7 mg, 0.174 mmol) were dissolved in dioxane (1 mL), and then (SP-4-1)-[1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(3-chloropyridine-κN)-palladium (7.05 mg, 0.007 mmol) was added. The reaction solution was heated to 100 degrees under nitrogen protection and reacted for 12 hours. After the reaction was completed, the mixture was filtered, concentrated and dried, and then separated and purified by preparative liquid chromatography (column: C18 150×30 mm; solvent: A = water + 0.05 volume formic acid (99%), B = acetonitrile; gradient: 25%-55%, 9 minutes) to obtain compound (1S,3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 -(2-methyl-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclohexane-1,3-diamine (Compound 13).

[0419] LC / MS(ESI)(m / z):475[M+H] + ;

[0420] 1H NMR(400MHz,DMSO-d6)δ8.57(d,1H),8.35(s,1H),7.87(d,1H),7.71(dd,1H),7.52(d,1H),7.48(d,1H),7.05(d,1H),6.92(s,1H),6.56( d,1H),4.21(d,1H),4.05(s,3H),3.86(d,1H),2.40(d,1H),2.04–1.95(m,2H),1.83(d,1H),1.58(d,1H),1.45–1.37(m,2H),1.28(s,1H).

[0421] Example 14: Preparation of target compound 14

[0422] (1S,3R)-N 1 -(6-2-(trifluoromethyl)quinolin-4-yl)-N 3 -(2-methyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)cyclohexane-1,3-diamine

[0423] The synthetic route of target compound 14 is as follows:

[0424] Step 1: (1S, 3R)-N 1 -(6-2-(trifluoromethyl)quinolin-4-yl)-N 3 Synthesis of -(2-methyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)cyclohexane-1,3-diamine (Compound 14).

[0425] At room temperature, (1S,3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine (int-3) (100 mg, 0.292 mmol), 4-chloro-2-methylpyrazolo[3,4-d]pyrimidine (14-1) (49.1 mg, 0.292 mmol) and potassium carbonate (120 mg, 0.876 mmol) were dissolved in dimethyl sulfoxide (1 mL) and then reacted at 80 degrees for 12 hours. After the reaction was completed, the mixture was filtered, concentrated and dried. The crude product was separated and purified by preparative liquid chromatography (chromatographic column: YMC-Triart Prep C18 7μm×30mm×40cm; solvent: A=0.1% ammonia water, B=acetonitrile; gradient: 20%-70%, 9 minutes) to obtain compound (1S,3R)-N 1 -(6-2-(trifluoromethyl)quinolin-4-yl)-N 3-(2-methyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)cyclohexane-1,3-diamine (Compound 14).

[0426] LC / MS (ESI) (m / z): 238.8 [M / 2+H] + ;

[0427] 1 H NMR(400MHz,DMSO-d6)δ8.58(d,1H),8.28(s,1H),8.19(s,1H),8.08(d,1H),7.89(d,1H),7.73(dd,1H),7.51(d,1H),6.97(s,1H),4.35– 4.30(m,1H),4.06(s,3H),3.94–3.90(m,1H),2.36(d,1H),2.02(dd,2H),1.85(d,1H),1.60(d,1H),1.48–1.41(m,2H),1.33–1.27(m,1H).

[0428] Example 15: Preparation of target compound 15

[0429] (1S,3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 -(1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclohexane-1,3-diamine (target compound 15).

[0430] The synthetic route of target compound 15 is as follows:

[0431] Step 1: Synthesis of 5-chloro-1-methyl-pyrazolo[3,4-c]pyridine (15-2B)

[0432] 5-Chloro-2-methyl-pyrazolo[3,4-c]pyridine (15-2A)

[0433] 5-Chloro-2H-pyrazolo[3,4-c]pyridine (15-1) (1.00 g, 6.51 mmol) was dissolved in acetone (55.0 mL). Potassium hydroxide (548 mg, 9.77 mmol) was added under nitrogen protection. The mixture was reacted at 0°C for 30 minutes. Subsequently, iodomethane (924 mg, 6.51 mmol) was added under nitrogen protection. The reaction solution was heated to 25°C and reacted for 1 hour. After the reaction, the reaction solution was poured into water (50.0 mL) and extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine (80.0 mL) and concentrated to dryness. The crude product was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 10:1-1:1) to give compound 5-chloro-1-methyl-pyrazolo[3,4-c]pyridine (15-2B) (400 mg, 36.6% yield), and compound 5-chloro-2-methyl-pyrazolo[3,4-c]pyridine (15-2A).

[0434] Step 2: (1S, 3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 -(1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclohexane-1,3-diamine (target compound 15).

[0435] (1S,3R)-N 1 6-Chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine (int-3) (300 mg, 788 umol) and 5-chloro-1-methyl-pyrazolo[3,4-c]pyridine (2B) (132 mg, 788 umol) were dissolved in dioxane (10.0 mL). Cesium carbonate (771 mg, 2.37 mmol) and methanesulfonic acid (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (71.5 mg, 78.9 mmol) were added under nitrogen protection. The mixture was stirred at 100°C for 6 hours. After completion of the reaction, the reaction solution was concentrated to dryness. The crude product was separated and purified by preparative liquid chromatography (column: Phenomenex Luna C18 150*25mm*10μm; solvent: A = water + trifluoroacetic acid, B = acetonitrile; gradient: 26%-56%, 11 minutes) to obtain compound (1S,3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 -(1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclohexane-1,3-diamine (target compound 15). LC-MS, M / Z (ESI): 475.1 [M+H] +

[0436] 1 H NMR(CDCl3,400MHz)δ:8.51(s,1H),7.92(d,1H),7.74(d,1H),7.63(d,1H),7.54(m,1H),6.68(s,1H),6.58( d,1H),5.55-5.83(m,1H),4.03(s,3H),3.67-3.78(m,2H),2.49(d,1H),1.91-2.15(m,4H),1.66-1.70(m,2H)

[0437] Example 16: Preparation of target compound 16

[0438] (1S, 3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 -(Imidazolo[1,5-b]pyridazin-5-yl)cyclohexane-1,3-diamine

[0439] The synthetic route of compound 16 is as follows:

[0440] Step 1: Synthesis of 1,2-diazine-3-ylmethylamine (Compound 16-2)

[0441] To a solution of 3-cyanopyridazine (4.00 g, 38.1 mmol) in methanol (60 mL) were added hydrochloric acid (12.7 mL, 6 M) and palladium on carbon (400 mg, 10% wt, 55% water). The reaction mixture was stirred at 30°C for 12 hours under a hydrogen atmosphere (40 psi). The resulting mixture was filtered, and the filtrate was concentrated to obtain the crude product, which was separated and purified on a C18 column (water:acetonitrile (V / V) = 100:0-90:10, gradient elution) to afford 1,2-diazin-3-ylmethylamine (Compound 16-2).

[0442] LC-MS, M / Z (ESI): 110.2 (M+H) +

[0443] Step 2: Synthesis of N-(pyridazin-3-ylmethyl)formamide (Compound 16-3)

[0444] 1,2-Diazin-3-ylmethylamine (Compound 16-2) (3.00 g, 27.5 mmol) was added to formic acid (20 mL), and the reaction was stirred at 120° C. for 2 days. The resulting mixture was concentrated to give N-(pyridazin-3-ylmethyl)formamide (Compound 16-3), which was used directly in the next reaction.

[0445] LC-MS, M / Z (ESI): 138.2 (M+H) +

[0446] Step 3: Synthesis of imidazo(1,5-b)pyridazine (Compound 16-4)

[0447] N-(pyridazin-3-ylmethyl)formamide (Compound 16-3) (3.00 g, 21.9 mmol) was dissolved in phosphorus oxychloride (20 mL), and the reaction solution was stirred at 110°C for 1 hour. The mixture was spin-dried, and saturated aqueous sodium bicarbonate solution (100 mL) was slowly added. The mixture was extracted with dichloromethane (100 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was separated and purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 100:0-50:50, gradient elution) to obtain imidazo(1,5-b)pyridazine (Compound 16-4).

[0448] LC-MS, M / Z (ESI): 120.2 (M+H) +

[0449] Step 4: Synthesis of 5-iodo(1,5-b)pyridazine (Compound 16-5)

[0450] To an imidazo(1,5-b)pyridazine (compound 16-4) (100 mg, 0.84 mmol) in acetonitrile (10 mL) was added N-iodosuccinimide (179 mg, 0.80 mmol). The reaction mixture was stirred at 25°C for 20 minutes. LCMS confirmed the formation of the desired product. The reaction mixture was diluted with saturated brine (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was separated and purified on a silica gel column (petroleum ether:ethyl acetate (v / v) = 100:0-65:35, gradient elution) to obtain compound 5-iodo(1,5-b)pyridazine (compound 16-5).

[0451] LC-MS, M / Z (ESI): 246.0 (M+H) +

[0452] Step 5: (1S, 3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 Synthesis of -(imidazo[1,5-b]pyridazin-5-yl)cyclohexane-1,3-diamine (Compound 16)

[0453] To a solution of 5-iodo(1,5-b)pyridazine (Compound 16-5) (100 mg, 0.41 mmol) in tert-butanol (5 mL) was added (1S,3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine (int-3) (210.mg, 0.61mmol), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (32.4mg, 0.04mmol), sodium tert-butoxide (118mg, 1.22mmol). The reaction solution was stirred at 50°C for 4 hours. The reaction mixture was cooled to room temperature, diluted with water (20mL), and then extracted with ethyl acetate (10mL×3). The organic layers were combined and concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 100:0-60:40, gradient elution) to obtain compound (1S,3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 -(imidazo(1,5-b)pyridazin-5-yl)cyclohexane-1,3-diamine (Compound 16).

[0454] LC-MS, M / Z (ESI): 461.0 (M+H) +

[0455] 1 H NMR (400MHz, DMSO-d6): δ8.60(d,1H),8.17(s,1H),7.96–7.87(m,3H),7.74(dd,1H),7.50(d,1H),6.91(s,1H),6.09(dd,1H),5.69(d,1H) ),3.94–3.66(m,2H),2.39–2.33(m,1H),2.12–1.97(m,2H),1.89–1.79(m,1H),1.62–1.50(m,1H),1.44–1.34(m,2H),1.26–1.22(m,1H).

[0456] Example 17: Preparation of target compound 17

[0457] (1R,3S)-N 1 -((1,2,4)triazolo(4,3-a)pyridin-3-yl)-N 3 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine (Compound 17)

[0458] The synthetic route of compound 17 is as follows:

[0459] Step 1: (1R, 3S)-N 1 -((1,2,4)triazolo(4,3-a)pyridin-3-yl)-N 3 Synthesis of -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine (Compound 17)

[0460] To a solution of 3-bromo-(1,2,4)triazolo(4,3-a)pyridine (Compound 17-1) (69.1 mg, 0.35 mmol) in N,N-dimethylformamide (2 mL) were added (1S,3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine (int-3) (120 mg, 0.35 mmol), sodium tert-butoxide (101 mg, 1.05 mmol), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (27.8 mg, 0.04 mmol). The reaction solution was stirred at 120°C under nitrogen for 18 hours. The reaction solution was diluted with saturated brine (20 mL) and then extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by preparative liquid chromatography (Xtimate C18, 21.2×250 mm, 5 μm; 0.1% FA-ACN; 20-50; 20 mL / min) to give compound (1R, 3S)-N 1 -((1,2,4)triazolo(4,3-a)pyridin-3-yl)-N 3 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine (Compound 17).

[0461] LC-MS, M / Z(ESI):461.2[M+H] +

[0462] 1H NMR (400MHz, DMSO-d6): δ8.59(d,1H),8.09(d,1H),7.89(d,1H),7.73(dd,1H),7.51(d,1H),7.43(d,1H),7.07(dd,1H),6.95(s,1H),6.7 3(t,1H),6.55(d,1H),3.98–3.81(m,2H),2.48–2.40(m,1H),2.26–2.15(m,1H),2.08–1.99(m,1H),1.91–1.80(m,1H),1.63–1.29(m,4H).

[0463] Example 18: Preparation of target compound 18

[0464] (1S, 3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 -(Oxazolo(4,5-b)pyridin-2-yl)cyclohexane-1,3-diamine (target compound 18)

[0465] The synthetic route of compound 18 is as follows:

[0466] Step 1: (1S, 3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 Synthesis of -(oxazolo(4,5-b)pyridin-2-yl)cyclohexane-1,3-diamine (Compound 18)

[0467] To a solution of oxazolo(4,5-b)pyridine-2(3H)-thione (18-1) (66.4 mg, 0.44 mmol) in DMF (2 mL) and ACN (2 mL) were added (1S,3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine (int-3) (150 mg, 0.44 mmol), triethylamine (0.61 mL, 4.40 mmol). The reaction solution was stirred at 80 ° C for 48 hours under nitrogen protection. The reaction solution was cooled to room temperature, diluted with saturated brine (20 mL), and 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. The crude product was purified by preparative liquid chromatography (Xtimate C18, 50*250 mm, 10 μm; 0.05% NH3·H2O-ACN; 50-80; 60 mL / min) to obtain compound (1S, 3R)-N 1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 -(Oxazolo(4,5-b)pyridin-2-yl)cyclohexane-1,3-diamine (Compound 18).

[0468] LC-MS, M / Z(ESI):462.2[M+H] +

[0469] 1 H NMR (400MHz, CD3OD): δ8.38(d,1H),8.08(dd,1H),7.91(d,1H),7.69(dd,1H),7.61(dd,1H),7.03(dd,1H),6 .94(s,1H),4.01–3.80(m,2H),2.57–2.43(m,1H),2.21–2.11(m,2H),2.01–1.95(m,1H),1.71–1.40(m,4H).

[0470] Example 19: Preparation of target compound 19

[0471] (1S, 3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 -(2-(2,2,2-trifluoroethyl)-2H-pyrazolo(3,4-d)pyrimidin-4-yl)cyclohexane-1,3-diamine (Compound 19)

[0472] The synthetic route of compound 19 is as follows:

[0473] Step 1: Synthesis of 4-chloro-2-(2,2,2-trifluoroethyl)-2H-pyrazolo(3,4-d)pyrimidine (Compound 19-3)

[0474] To a solution of 4-chloro-2H-pyrazolo(3,4-d)pyrimidine (19-1) (500 mg, 3.24 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydroxide (155 mg, 3.88 mmol, 60% Wt) under ice-cooling. The mixture was stirred at 0°C for 30 minutes. 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.13 g, 4.85 mmol) was then added to the reaction solution, and stirring was continued at 0°C for 1 hour. LCMS confirmed the reaction was complete. Saturated brine (20 mL) was slowly added dropwise to the reaction solution, and 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. The crude product was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 100:0-50:50, gradient elution) to obtain compound 4-chloro-2-(2,2,2-trifluoroethyl)-2H-pyrazolo(3,4-d)pyrimidine (compound 19-3) (200 mg, yield 26.1%).

[0475] LC-MS, M / Z(ESI):237.0[M+H] +

[0476] Step 2: Synthesis of (1S,3R)-N1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N3-(2-(2,2,2-trifluoroethyl)-2H-pyrazolo(3,4-d)pyrimidin-4-yl)cyclohexane-1,3-diamine (Compound 19)

[0477] To 4-chloro-2-(2,2,2-trifluoroethyl)-2H-pyrazolo(3,4-d)pyrimidine (Compound 19-3) (50.0 mg, 0.15 mmol), (1S,3R)-N 1To a solution of -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine (int-3) (34.4 mg, 0.15 mmol) in N,N-dimethylformamide (3 mL) was added methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (11.6 mg, 0.02 mmol) and sodium tert-butoxide (41.9 mg, 0.44 mmol). The mixture was stirred at 80°C under nitrogen for 12 hours. After LCMS detection, saturated brine (50 mL) was added for dilution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by preparative liquid chromatography (Xtimate C18, 21.2*250mm, 5μm; 0.05% NH3.H2O-ACN; 48.68; 60mL / min) to give compound (1S,3R)-N1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N3-(2-(2,2,2-trifluoroethyl)-2H-pyrazolo(3,4-d)pyrimidin-4-yl)cyclohexane-1,3-diamine (Compound 19).

[0478] LC-MS, M / Z(ESI):544.0[M+H] +

[0479] 1 H NMR (400MHz, DMSO-d6): δ8.58(d,1H),8.52(s,1H),8.34(d,1H),8.24(s,1 H),7.90(d,1H),7.74(dd,1H),7.51(d,1H),6.98(s,1H),5.47(q,2H),4.4 2–4.27(m,1H),4.01–3.86(m,1H),2.40–2.34(m,1H),2.05–1.96(m,2H),1 .92–1.82(m,1H),1.65–1.56(m,1H),1.52–1.40(m,2H),1.34–1.28(m,1H).

[0480] Example 20: Preparation of target compound 20

[0481] (1S, 3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 -(2-methylimidazo(1,2-c)pyrimidin-5-yl)cyclohexane-1,3-diamine (target compound 20)

[0482] The synthetic route of compound 20 is as follows:

[0483] Step 1: Synthesis of 5-chloro-2-methylimidazo(1,2-c)pyrimidine (Compound 20-3)

[0484] 2-Chloropyrimidin-4-amine (Compound 20-1) (2.00 g, 15.4 mmol) and 1-bromopropan-2-one (500 mg, 15.4 mmol) were added to N,N-dimethylformamide (10 mL), and the mixture was stirred at 80°C for 5 hours under microwave conditions. The reaction solution was cooled to room temperature, diluted with water (100 mL), and then extracted with ethyl acetate (100 mL × 3). The organic layer was separated and concentrated under reduced pressure to obtain compound 5-chloro-2-methylimidazo (1,2-c) pyrimidine (Compound 20-3), which was used directly in the next reaction.

[0485] LC-MS, M / Z(ESI):168.2[M+H] +

[0486] Step 2: (1S, 3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 Synthesis of -(2-methylimidazo(1,2-c)pyrimidin-5-yl)cyclohexane-1,3-diamine (Compound 20)

[0487] To a solution of 5-chloro-2-methylimidazo(1,2-c)pyrimidine (Compound 20-3) (300 mg, 1.79 mmol) in N-methylpyrrolidone (10 mL) was added (1S,3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine (int-3) (615 mg, 1.79 mmol) and N,N-diisopropylethylamine (231 mg, 1.79 mmol) were added, and the mixture was stirred at 130°C for 1 hour. LC-MS detected that the reaction was complete, and the reaction solution was purified by preparative liquid chromatography (chromatographic column: Xtimate C18 21.2*250mm 5μm, mobile phase: A = 0.05% ammonia water, B = acetonitrile; gradient: 48%-68%, 2h) to obtain compound (1S, 3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 -(2-Methylimidazo(1,2-c)pyrimidin-5-yl)cyclohexane-1,3-diamine (Compound 20) (2.40 mg, yield 0.4%)

[0488] LC-MS, M / Z(ESI):475.0[M+H] +

[0489] 1 H NMR (400MHz, DMSO-d6): δ8.60(d,1H),7.90(d,1H),7.82–7.63(m,2H),7.60–7.45(m,2H),7.35(d,1H),6.97(s,1H),6. 69(d,1H),4.36–4.14(m,1H),3.96–3.87(m,1H),2.42–2.37(m,1H),2.30(s,3H),2.08–1.84(m,3H),1.64–1.37(m,4H).

[0490] Example 21: Preparation of target compound 21

[0491] (1S, 3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 -(7-Fluoro-2-methyl-2H-pyrazolo(4,3-c)pyridin-4-yl)cyclohexane-1,3-diamine (Compound 21)

[0492] The synthetic route of compound 21 is as follows:

[0493] Step 1: Synthesis of 2,4-dichloro-5-fluoronicotinaldehyde (Compound 21-2)

[0494] To a solution of 2,4-dichloro-5-fluoropyridine (Compound 21-1) (1.50 g, 9.26 mmol) in tetrahydrofuran (20 mL) was added lithium diisopropylamide (4.63 ml, 9.26 mmol, 2 M) dropwise at -78°C. After stirring at -78°C for 1 hour, N,N-dimethylformamide (1.35 g, 18.5 mmol) was added, and the resulting mixture was stirred at -78°C for 1 hour. LCMS analysis indicated that the reaction was complete. The reaction solution was quenched with saturated aqueous ammonium chloride (50 mL), then extracted with ethyl acetate (50 mL × 3). The organic layers were combined and concentrated under reduced pressure. The product was separated and purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 100:0 to 90:10, gradient elution) to obtain 2,4-dichloro-5-fluoronicotinaldehyde (Compound 21-2).

[0495] 1H NMR (400MHz, CDCl3): δ10.41(d,1H),8.45(s,1H).

[0496] Step 2: Synthesis of 4-chloro-7-fluoro-2H-pyrazolo(4,3-c)pyridine (Compound 21-3)

[0497] To a flask containing 2,4-dichloro-5-fluoronicotinaldehyde (Compound 21-2) (700 mg, 3.61 mmol) was added tetrahydrofuran (10 mL), hydrazine hydrate (347 mg, 10.8 mmol), and triethylamine (962 mg, 7.22 mmol), and the resulting mixture was stirred at 25°C for 18 hours. LCMS confirmed the reaction was complete. The reaction mixture was quenched by adding water (50 mL) and extracted with ethyl acetate (30 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 4-chloro-7-fluoro-2H-pyrazolo(4,3-c)pyridine (Compound 21-3), which was used directly in the next reaction.

[0498] LC-MS, M / Z(ESI):172.2[M+H] +

[0499] Step 3: Synthesis of 4-chloro-7-fluoro-2-methyl-2H-pyrazolo(4,3-c)pyridine (Compound 21-4)

[0500] 4-Chloro-7-fluoro-2H-pyrazolo(4,3-c)pyridine (Compound 21-3) (400 mg, 2.33 mmol) was dissolved in dichloromethane (5 mL), and trimethyloxonium tetrafluoroboric acid (517 mg, 3.50 mmol) was added. The resulting mixture was stirred at 35°C for 14 hours. LC-MS confirmed the reaction was complete. The reaction solution was diluted with water (10 mL) and extracted with dichloromethane (30 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. The crude product was separated and purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 100:0 to 60:40, gradient elution) to obtain compound 4-chloro-7-fluoro-2-methyl-2H-pyrazolo(4,3-c)pyridine (Compound 21-4).

[0501] LC-MS, M / Z(ESI):186.2[M+H] + .

[0502] Step 4: (1S, 3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 Synthesis of -(7-fluoro-2-methyl-2H-pyrazolo(4,3-c)pyridin-4-yl)cyclohexane-1,3-diamine (Compound 21)

[0503] To a 50 mL three-necked flask, add (1S, 3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine (int-3) (96.3 mg, 0.28 mmol), sodium tert-butoxide (62.3 mg, 0.65 mmol) and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (34.3 mg, 0.04 mmol). After nitrogen substitution, a solution of 4-chloro-7-fluoro-2-methyl-2H-pyrazolo(4,3-c)pyridine (compound 21-4) (40.0 mg, 0.22 mmol) in N,N-dimethylformamide (2.5 mL) was added, and the mixture was stirred at 120° C. for 3 hours. LCMS detected the reaction to be complete. The reaction solution was diluted with water (10 mL), then extracted with ethyl acetate (5 mL×3), the organic layers were combined, washed with saturated brine, and concentrated under reduced pressure to obtain a crude product, which was purified by preparative liquid chromatography (Bonnasil-Bs C18, 20*250 mm, 8 μm; 0.1% TFA-ACN; 22-52%; 20 mL / min) to obtain compound (1S, 3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 -(7-fluoro-2-methyl-2H-pyrazolo(4,3-c)pyridin-4-yl)cyclohexane-1,3-diamine (Compound 21), trifluoroacetate salt.

[0504] LC-MS, M / Z(ESI):493.4[M+H] + .

[0505] 1 H NMR (400MHz, CD3OD): δ8.83(s,1H),8.44(d,1H),7.96(d,1H),7.78(dd,1H),7.52(d,1H),7.00(s,1H),4.27(s,3H) ,4.03–3.92(m,2H),2.55–2.49(m,1H),2.26–2.19(m,2H),2.12–2.06(m,1H),1.80–1.69(m,2H),1.65–1.54(m,2H).

[0506] Example 22: Preparation of target compound 22

[0507] (1S, 3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3-(2,3-Dimethyl-3H-imidazo[4,5-c]pyridin-4-yl)cyclohexane-1,3-diamine (Compound 22)

[0508] The synthetic route of compound 22 is as follows:

[0509] Step 1: Synthesis of 2-chloro-N-methyl-4-nitropyridin-3-amine

[0510] 2-Chloro-3-fluoro-4-nitropyridine (5.00 g, 28.3 mmol) was dissolved in methylamine (50 mL, 1 M THF solution), and the resulting mixture was stirred at 40 ° C for 3 hours. LCMS detected the reaction completion. The reaction solution was diluted with water (50 mL), extracted with ethyl acetate (25 mL × 3), and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. It was separated and purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 100:0 to 75:25, gradient elution) to obtain 2-chloro-N-methyl-4-nitropyridine-3-amine (compound 22-2).

[0511] LC-MS, M / Z(ESI):188.0[M+H] +

[0512] Step 2: 2-Chloro-N 3 -Synthesis of methylpyridine-3,4-diamine

[0513] To a solution of 2-chloro-N-methyl-4-nitropyridin-3-amine (compound 22-2) (1.00 g, 5.33 mmol) in methanol (20 mL) and water (2 mL) were added zinc powder (1.74 g, 26.7 mmol) and ammonium chloride (2.85 g, 53.3 mmol) in sequence, and the resulting mixture was stirred at 25 ° C for 1 hour. LCMS detection showed that the reaction was complete. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product which was separated and purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 100:0 to 50:50, gradient elution) to obtain 2-chloro-N-methyl-4-nitropyridin-3-amine. 3 -methylpyridine-3,4-diamine (Compound 22-3).

[0514] LC-MS, M / Z(ESI):158.0[M+H] +

[0515] Step 3: 4-chloro-2,3-dimethyl-3H-imidazo(4,5-c)pyridine

[0516] To 2-chloro-N 3To a solution of methylpyridine-3,4-diamine (compound 22-3) (130 mg, 0.83 mmol) in ethanol (3 mL) were added trimethyl orthoacetate (495 mg, 4.12 mmol) and 4-methylbenzenesulfonic acid (41.5 mg, 0.17 mmol) in sequence, and the resulting mixture was stirred at 90°C for 1 hour. LCMS detected that the reaction was complete. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (150 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product that was separated and purified on a silica gel column (petroleum ether: ethyl acetate (V / V) = 100:0 to 50:50, gradient elution) to obtain compound 4-chloro-2,3-dimethyl-3H-imidazo (4,5-c) pyridine (compound 22-4).

[0517] LC-MS, M / Z(ESI):181.9[M+H] +

[0518] Step 4: (1S, 3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 Synthesis of -(2,3-dimethyl-3H-imidazo[4,5-c]pyridin-4-yl)cyclohexane-1,3-diamine (Compound 22)

[0519] To a solution of 4-chloro-2,3-dimethyl-3H-imidazo(4,5-c)pyridine (Compound 22-4) (114 mg, 0.63 mmol) in N,N-dimethylformamide (3 mL) were added (1S,3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine (int-3) (324 mg, 0.94 mmol), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (100 mg, 0.13 mmol), sodium tert-butoxide (120 mg, 1.26 mmol), the resulting mixture was stirred at 120 ° C for 5 hours. 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 layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by high performance liquid chromatography (Xtimate C18, 21.2*250mm, 5μm; 0.05% NH3.H2O-ACN; 30-60; 60mL / min) to obtain compound (1S, 3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3-(2,3-dimethyl-3H-imidazo[4,5-c]pyridin-4-yl)cyclohexane-1,3-diamine (Compound 22).

[0520] LC-MS, M / Z (ESI): 489.2 (M+H) +

[0521] 1 H NMR (400MHz, CD3OD): δ8.39(d,1H),7.93(d,1H),7.76(d,1H),7.70(dd,1H),7.00(s,1H),6.89(d,1H),4.20–4.14(m,1H),4.04(s,3 H),3.94–3.84(m,1H),2.71–2.63(m,1H),2.57(s,3H),2.24–2.13(m,2H),2.05–1.96(m,1H),1.79–1.65(m,1H),1.60–1.43(m,3H).

[0522] Example 23: Preparation of target compound 23

[0523] (1S, 3R)-N 1 -(6-chloro-2-trifluoromethylquinolin-4-yl)-N 3 -(6-Fluoro-(1,2,4)triazolo(4,3-a)pyridin-3-yl)cyclohexane-1,3-diamine (Compound 23)

[0524] The synthetic route of compound 23 is as follows:

[0525] Step 1: Synthesis of 5-fluoro-2-hydrazinopyridine

[0526] Under nitrogen, 2,5-difluoropyridine (10.0 g, 86.9 mmol) and hydrazine (20 mL, 80% wt aqueous solution) were added to ethanol (20 mL), and the resulting mixture was stirred at 120°C for 18 hours. LCMS confirmed the reaction was complete, and the reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting solid was slurried with petroleum ether, collected by filtration, and dried under vacuum to obtain compound 5-fluoro-2-hydrazinopyridine (Compound 23-2), which was used directly in the next step.

[0527] LC-MS, M / Z(ESI):128.2[M+H] +

[0528] Step 2: Synthesis of 6-fluoro-(1,2,4)triazolo(4,3-a)pyridine (Compound 23-3)

[0529] 5-Fluoro-2-hydrazinylpyridine (Compound 23-2) (200 mg, 1.57 mmol) was dissolved in diethoxymethyl acetate (1 mL), and the resulting mixture was stirred at 25°C for 1.5 hours. LCMS confirmed the reaction was complete. The reaction solution was slurried with petroleum ether, and the solid was collected by filtration and dried under vacuum to yield compound 6-fluoro-(1,2,4)triazolo(4,3-a)pyridine (Compound 23-3).

[0530] LCMS, M / Z(ESI):138.0[M+H] +

[0531] Step 3: Synthesis of 3-bromo-6-fluoro-(1,2,4)triazolo(4,3-a)pyridine (Compound 23-4)

[0532] To a solution of 6-fluoro(1,2,4)triazolo(4,3-a)pyridine (compound 23-3) (200 mg, 1.46 mmol) in dichloromethane (11 mL) was added N-bromosuccinimide (286 mg, 1.60 mmol), and the reaction mixture was stirred at 45°C for 18 hours. LCMS confirmed the reaction was complete. The reaction solution was diluted with saturated aqueous sodium bicarbonate (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were combined and concentrated under reduced pressure to give a crude product, which was then separated and purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 100:0-60:40, gradient elution) to give compound 3-bromo-6-fluoro-(1,2,4)triazolo(4,3-a)pyridine (compound 23-4).

[0533] LC-MS, M / Z(ESI):216.0[M+H] +

[0534] Step 4: (1S, 3R)-N 1 -(6-chloro-2-trifluoromethylquinolin-4-yl)-N 3 Synthesis of (6-fluoro-(1,2,4)triazolo(4,3-a)pyridin-3-yl)cyclohexane-1,3-diamine (Compound 23)

[0535] Under nitrogen protection, 3-bromo-6-fluoro(1,2,4)triazolo(4,3-a)pyridine (Compound 23-4) (200 mg, 0.93 mmol) and (1S,3R)-N 1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine (int-3) (318 mg, 0.93 mmol) was dissolved in N,N-dimethylacetamide (8 mL), and sodium tert-butoxide (445 mg, 4.63 mmol) and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (221 mg, 0.28 mmol) were added. The resulting mixture was stirred at 80°C for 18 hours. LCMS confirmed the reaction was complete. The reaction solution was purified by preparative liquid chromatography (Xtimate C18×21.2 250mm 5um; 0.05% NH3.H2O-ACN; 52-82; 20 mL / min) to obtain compound (1S,3R)-N 1 -(6-chloro-2-trifluoromethylquinolin-4-yl)-N 3 -(6-Fluoro-(1,2,4)triazolo(4,3-a)pyridin-3-yl)cyclohexane-1,3-diamine (Compound 23).

[0536] LC-MS, M / Z(ESI):479.0[M+H] +

[0537] 1 H NMR (400MHz, CD3OD): δ8.27(d,1H),8.07–7.93(m,1H),7.81(d,1H),7.59(dd,1H),7.39(dd,1H),7.19–7.05(m,1H),6.85( s,1H),3.93–3.65(m,2H),2.59–2.47(m,1H),2.22–2.12(m,1H),2.11–2.01(m,1H),1.94–1.83(m,1H),1.68–1.30(m,4H).

[0538] Example 24: Synthesis of Compound 24

[0539] (1S,3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 -(2-methyl-2H-pyrazolo[3,4-d]pyridazin-4-yl)cyclohexane-1,3-diamine

[0540] The synthetic route of compound 24 is as follows:

[0541] Step 1: Synthesis of methyl 3-formyl-1-methylpyrazole-4-carboxylate (Compound 24-2)

[0542] At room temperature, 4-bromo-1-methylpyrazole-3-carboxaldehyde (24-1) (5.50 g, 0.029 mol), triethylamine (8.86 g, 0.088 mol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (705 mg, 0.870 mmol) were dissolved in methanol (55.0 mL). The atmosphere was then replaced with carbon monoxide (15 psi) three times, and the reaction mixture was allowed to react at 60°C for 12 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered, and dried. The crude product was purified by column chromatography (PE:EA (V / V) = 1:1) to obtain methyl 3-formyl-1-methylpyrazole-4-carboxylate (compound 24-2).

[0543] LC / MS (ESI) (m / z): 169.0 (M+H) + .

[0544] Step 2: Synthesis of 2-methylpyrazolo[4,3-d][1,2]diazine-4-ol (Compound 24-3)

[0545] At room temperature, methyl 3-formyl-1-methylpyrazole-4-carboxylate (Compound 24-2) (4.00 g, 0.024 mol) and hydrazine hydrate (2.34 g, 0.072 mmol) were dissolved in ethanol / acetic acid (40 mL / 4.0 mL) and then reacted at 100°C for 12 hours. After the reaction was completed, the reaction solution was cooled and filtered, and the filter cake was washed with ethanol. The filter cake was collected and dried to obtain the compound 2-methylpyrazolo[4,3-d][1,2]diazine-4-ol (Compound 24-3). LC / MS (ESI) (m / z): 151.0 (M+H) + .

[0546] Step 3: (1S, 3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 Synthesis of -(2-methyl-2H-pyrazolo[3,4-d]pyridazin-4-yl)cyclohexane-1,3-diamine (Compound 24)

[0547] At room temperature, 2-methylpyrazolo[4,3-d][1,2]diazine-4-ol (compound 24-3) (175 mg, 1.17 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (776 mg, 1.76 mmol) were dissolved in dimethyl sulfoxide (4.0 mL), and then 1,8-diazacyclo[5,4,0]undecene-7 (445 mg, 2.93 mmol) was slowly added. The reaction solution was stirred at room temperature for 10 min, and then (1S, 3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine (int-3) (400 mg, 1.17 mmol), the reaction solution continued to react at room temperature for 1 hour, and then the temperature was raised to 100°C for 24 hours. After the reaction was completed, the reaction solution was cooled and filtered, and the filtrate was concentrated to obtain a crude product which was purified by preparative liquid chromatography (chromatographic column: YMC-Triart Prep C18 7μm 30mm×40cm; solvent: A = 0.1% ammonia water, B = acetonitrile; gradient: 20%-65%, 9 minutes) to obtain (1S,3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 -(2-methyl-2H-pyrazolo[3,4-d]pyridazin-4-yl)cyclohexane-1,3-diamine (Compound 24).

[0548] LC / MS (ESI) (m / z): 476.2 (M+H) + ;

[0549] 1 H NMR(400MHz,DMSO-d6)δ8.76(s,1H),8.58(d,1H),8.44(s,1H),7.88(d,1H),7.72(dd,1H),7.48(d,1H),7.21(d,1H),6.95(s,1H),4.33(s ,1H),4.16(s,3H),3.91(s,1H),2.39(d,1H),2.12(d,1H),1.99(s,1H),1.84(d,1H),1.60(d,1H),1.49(d,1H),1.41(d,1H),1.29(s,1H).

[0550] Example 25: Synthesis of Compound 25

[0551] (1S,3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 -(1-methyl-1H-pyrazolo[3,4-c]pyridin-7-yl)cyclohexane-1,3-diamine

[0552] The synthetic route of compound 25 is as follows:

[0553] Step 1: (1S, 3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 Synthesis of -(1-methyl-1H-pyrazolo[3,4-c]pyridin-7-yl)cyclohexane-1,3-diamine (Compound 25)

[0554] At room temperature, (1S, 3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine (int-3) (30.0 mg, 0.080 mmol), 7-chloro-1-methylpyrazolo[3,4-c]pyridine (10.0 mg, 0.060 mmol) and sodium tert-butoxide (8.00 mg, 0.080 mmol) were dissolved in 1,4-dioxane (0.5 mL), and [2-(dicyclohexylphosphino)-3-tert-butoxy-6-methoxy-2',6'-diisopropyl-1,1'-biphenyl](4-((2-(trimethylsilyl)ethoxy)carbonyl)phenyl-1-yl)palladium bromide (6.00 mg, 0.006 mmol) was added under nitrogen protection. After the addition was complete, the mixture was stirred at 25 ° C for 12 hours under nitrogen protection. After the reaction was completed, the reaction solution was filtered and the filtrate was dried by rotary evaporation. The crude product was purified by preparative liquid chromatography (chromatographic column: YMC-Triart Prep C18 7μm 30mm×40cm; solvent: A = 0.1% ammonia water, B = acetonitrile; gradient: 30%-90%, 9 minutes) to obtain compound (1S,3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 -(1-methyl-1H-pyrazolo[3,4-c]pyridin-7-yl)cyclohexane-1,3-diamine (Compound 25).

[0555] LC / MS (ESI) (m / z): 475.2 (M+H) + ;

[0556] 1H NMR(400MHz,DMSO-d6)δ8.60(d,1H),7.92–7.80(m,2H),7.71(dd,1H),7.57(d,1H),7.51(d,1H),6.92(s,1H),6.85(d,1H),5.99(d,1 H),4.27(s,3H),4.23–4.14(m,1H),3.85(d,1H),2.49(s,1H),2.12(d,1H),2.01(d,1H),1.84(d,1H),1.59(d,1H),1.51–1.36(m,3H).

[0557] Example 26: Preparation of target compound 26

[0558] (1S,3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 -(2-methylpyrazolo[1,5-a]pyrazin-4-yl)cyclohexane-1,3-diamine (Compound 26)

[0559] The synthetic route of target compound 26 is as follows:

[0560] Step 1: (1S, 3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 Synthesis of -(2-methylpyrazolo[1,5-a]pyrazin-4-yl)cyclohexane-1,3-diamine (Compound 26)

[0561] At room temperature, (1S,3R)-N1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine (int-3) (100 mg, 0.290 mmol), 4-chloro-2-methylpyrazolo[1,5-a]pyrazine (58.9 mg, 0.350 mmol) and sodium tert-butoxide (283 mg, 0.870 mmol) were dissolved in tert-butanol (5 mL), and then methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (28.0 mg, 0.029 mmol) was added. After the addition, the reaction solution was replaced with nitrogen three times and the temperature was raised to 100°C and stirred for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, saturated aqueous ammonium chloride solution (30 mL) was added to quench the reaction, and then extracted with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative liquid chromatography (column: C18 150 × 30 mm; solvent: A = water + 0.05 volume formic acid (99%), B = acetonitrile; gradient: 15%-45%, 7 minutes) to obtain compound (1S, 3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 -(2-methylpyrazolo[1,5-a]pyrazin-4-yl)cyclohexane-1,3-diamine formate (Compound 26).

[0562] LC / MS (ESI) (m / z): 475.3 (M+H) + ;

[0563] 1 H NMR(400MHz,DMSO-d6)δ8.59(d,1H),7.87(d,1H),7.74(dd,2H),7.51(d,1H),7.25(d,1H),7.17(d,1H),6.94(s,1H) ,6.75(s,1H),4.24–4.20(m,1H),3.90–3.85(m,1H),2.35(s,3H),2.05–2.02(m,3H),1.83(m,1H),1.49–1.35(m,4H).

[0564] Example 27: Synthesis of Compound 27

[0565] (1S,3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 -(6-chloro-2-methyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)cyclohexane-1,3-diamine (Compound 27)

[0566] The synthetic route of compound 27 is as follows:

[0567] Step 1: (1S, 3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 -(6-chloro-2-methyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)cyclohexane-1,3-diamine

[0568] Synthesis of (Compound 27)

[0569] At room temperature, (1S,3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine (int-3) (68.0 mg, 0.200 mmol), 4,6-dichloro-2-methylpyrazolo[3,4-d]pyrimidine (40.0 mg, 0.200 mmol) and potassium carbonate (54.0 mg, 0.390 mmol) were placed in N,N-dimethylformamide (1.0 mL), and the reaction solution was heated to 60°C and stirred for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the crude product was purified by preparative liquid chromatography (chromatographic column: YMC-Triart Prep C18 7μm 30mm×40cm; solvent: A = 0.1% ammonia water, B = acetonitrile; gradient: 30%-80%, 9 minutes) to obtain compound (1S,3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 -(6-chloro-2-methyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)cyclohexane-1,3-diamine (Compound 27).

[0570] LC / MS (ESI) (m / z): 510.0 (M+H) + ;

[0571] 1 H NMR(400MHz,DMSO-d6)δ8.52(dd,2H),8.27(s,1H),7.85(d,1H),7.69(dd,1H),7.45(d,1H),6.95(s,1H) ,4.28–4.15(m,1H),4.03(d,3H),3.96–3.85(m,1H),2.30(d,1H),1.98(t,2H),1.81(d,1H),1.58(d,1H), 1.49–1.41(m,1H),1.40–1.32(m,1H),1.26(dd,1H).

[0572] Example 28: Synthesis of Compound 28

[0573] (1S,3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 -(2,6-dimethyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)1,3-cyclohexanediamine (Compound 28)

[0574] The synthetic route of compound 28 is as follows:

[0575] first step:

[0576] (1S,3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 Synthesis of -(2,6-dimethyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)1,3-cyclohexanediamine (Compound 28)

[0577] At room temperature, (1S,3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 -(6-chloro-2-methyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)cyclohexane-1,3-diamine (Compound 27) (40.0 mg, 0.080 mmol), methylboronic acid (47.0 mg, 0.780 mmol) and potassium phosphate (50.0 mg, 0.240 mmol) were dissolved in 1,4-dioxane (0.5 mL) and water (20 μL). [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (6.00 mg, 0.010 mmol) was added under nitrogen protection. After the addition, the reaction solution was stirred at 40°C under nitrogen protection for 48 hours. After the reaction was completed, the reaction solution was filtered and the filtrate was dried. The crude product was purified by preparative thin layer chromatography (dichloromethane: methanol (V / V) = 20:1) to obtain compound (1S,3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 -(2,6-dimethyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)1,3-cyclohexanediamine (Compound 28).

[0578] LC / MS (ESI) (m / z): 490.2 (M+H) + ;

[0579] 1H NMR(400MHz, CDCl3)δ8.00(d,2H),7.72(s,1H),7.62(dd,1H),6.78(s,1H),5.10(s,1H),4.36–4.27(m,1H),4.07(s, 3H),3.75(s,1H),3.55–3.45(m,1H),2.72(s,1H),2.58(s,3H),2.24(s,2H),2.04(d,1H),1.64(s,2H),1.41(s,2H).

[0580] Example 29: Synthesis of Compound 29

[0581] (1S,3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 -(6-chloro-2-methyl-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclohexane-1,3-diamine (Compound 29)

[0582] The synthetic route of compound 29 is as follows:

[0583] Step 1: Synthesis of 4,6-dichloro-2-methylpyrazolo[4,3-c]pyridine (Compound 29-2)

[0584] At room temperature, 4,6-dichloro-2H-pyrazolo[4,3-c]pyridine (Compound 29-1) (200 mg, 1.06 mmol) was dissolved in ethyl acetate (2 mL), and trimethyloxonium tetrafluoroborate (157 mg, 1.06 mmol) was added. After the addition, the reaction solution was stirred at 25°C for 12 hours. After the reaction was completed, a saturated sodium bicarbonate solution (2 mL) was added for washing, followed by saturated brine (2 mL), drying, filtering, and spin drying. The crude product was purified by column chromatography (petroleum ether:ethyl acetate (V / V) = 10:1 to 1:1) to obtain compound 4,6-dichloro-2-methylpyrazolo[4,3-c]pyridine (Compound 29-2).

[0585] LC / MS (ESI) (m / z): 202.0 (M+H) + .

[0586] Step 2: (1S, 3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 Synthesis of 6-chloro-2-methyl-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclohexane-1,3-diamine (Compound 29)

[0587] At room temperature, 4,6-dichloro-2-methylpyrazolo[4,3-c]pyridine (Compound 29-2) (50.0 mg, 0.248 mmol) was dissolved in N,N-dimethylacetamide (0.5 mL), and then N,N-diisopropylethylamine (96.2 mg, 0.744 mmol) and (1S,3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine (int-3) (85.3 mg, 0.248 mmol) was added, and the reaction solution was stirred at 125°C for 12 hours. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated. The crude product was purified by preparative liquid chromatography (chromatographic column: YMC-Triart Prep C18 7μm 30mm×40cm; solvent: A = 0.1% ammonia water, B = acetonitrile; gradient: 40%-100%, 9 minutes) to obtain compound (1S,3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 -(6-chloro-2-methyl-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclohexane-1,3-diamine (Compound 29).

[0588] LC / MS (ESI) (m / z): 509.0 (M+H) + ;

[0589] 1 H NMR(400MHz,DMSO-d6)δ(d,1H),8.39(s,1H),7.87(d,1H),7.71(dd,1H),7.54(d,1H),7.47(d,1H),6.95(s,1H),6.58(s,1H), 4.14(d,1H),4.03(s,3H),3.90(d,1H),2.35(d,1H),2.00(dd,2H),1.83(d,1H),1.59(d,1H),1.45–1.37(m,2H),1.27(s,1H).

[0590] Example 30: Synthesis of Compound 30

[0591] cis-N 1 -(6-Fluoro-(1,2,4)triazolo(4,3-a)pyridin-3-yl)-N 4 -(2-(Trifluoromethyl)imidazo(1,2-a)pyridin-5-yl)cyclohexane-1,4-diamine (Compound 30)

[0592] The synthetic route of compound 30 is as follows:

[0593] cis-N 1 -(2-(Trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)cyclohexane-1,4-diamine (int-4) (500 mg, 1.67 mmol) and 3-bromo-6-fluoro-(1,2,4)triazolo(4,3-a)pyridine (432 mg, 1.99 mmol) were dissolved in anhydrous N,N-dimethylformamide (10 mL), and methanesulfonate (2-di-tert-butylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (265 mg, 0.333 mmol) and sodium tert-butoxide (320 mg, 3.33 mmol) were added. The reaction solution was stirred at 120 ° C for 18 hours under nitrogen protection. The reaction was complete after LC-MS detection. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by preparative liquid chromatography (Xtimate C18, 21.2*250mm, 5μm; 0.05% NH3.H2O-ACN; 45-75; 60mL / min) to obtain compound (cis-N 1 -(6-Fluoro-(1,2,4)triazolo(4,3-a)pyridin-3-yl)-N 4 -(2-(trifluoromethyl)imidazo(1,2-a)pyridin-5-yl)cyclohexane-1,4-diamine (45.0 mg, 6.2% yield).

[0594] 1 H NMR (400MHz, DMSO-d6): δ8.69(s,1H),8.47–8.43(m,1H),7.57(dd,1H),7.33(dd,1H),7.28–7.21(m,1H),6. 92(d,1H),6.55–6.47(m,2H),6.11(d,1H),3.87(s,1H),3.67(s,1H),2.05–1.96(m,2H),1.93–1.78(m,6H).

[0595] LC-MS, M / Z(ESI):434.2[M+H] + .

[0596] Example 31: Synthesis of Compound 31

[0597] cis-N 1 -(7-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro-(1,2,4)triazolo(4,3-a)pyrazin-3-yl)-N 4-(2-(Trifluoromethyl)imidazo(1,2-a)pyridin-5-yl)cyclohexane-1,4-diamine (Compound 31)

[0598] The synthetic route of compound 31 is as follows:

[0599] Step 1: Synthesis of 3-bromo-7-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro-(1,2,4)triazolo(4,3-a)pyrazine

[0600] To a solution of 3-bromo-5,6,7,8-tetrahydro-(1,2,4)triazolo(4,3-a)pyrazine (500 mg, 2.09 mmol) in acetonitrile (5 mL) were added potassium carbonate (865 mg, 6.27 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (969 mg, 4.18 mmol), and the reaction mixture was stirred at 80°C for 16 hours. LCMS confirmed the reaction was complete, and the reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by a C18 column (water:acetonitrile (V / V) = 100:0 to 40:60) and lyophilized to afford 3-bromo-7-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro-(1,2,4)triazolo(4,3-a)pyrazine (200 mg, 33.6% yield).

[0601] LC-MS, M / Z(ESI):285.2[M+H] +

[0602] Step 2: (cis-N 1 -(7-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-N 4 Synthesis of -(2-(trifluoromethyl)imidazo(1,2-a)pyridin-5-yl)cyclohexane-1,4-diamine

[0603] To a solution of 3-bromo-7-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro-(1,2,4)triazolo(4,3-a)pyrazine (100 mg, 0.35 mmol) in N,N-dimethylformamide (3 mL) was added cis-N 1-(2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)cyclohexane-1,4-diamine (int-4) (86.4 mg, 0.29 mmol), sodium tert-butoxide (83.0 mg, 0.87 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (279 mg, 0.058 mmol). The reaction mixture was stirred at 120°C for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude product, which was purified by preparative high-performance liquid chromatography (Xtimate C18, 21.2*250 mm, 5 μm; 10 mM NH 3. H2O; 18-47; 60 mL / min), and lyophilized to obtain compound cis-N 1 -(7-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro-(1,2,4)triazolo(4,3-a)pyrazin-3-yl)-N 4 -(2-(trifluoromethyl)imidazo(1,2-a)pyridin-5-yl)cyclohexane-1,4-diamine (10.0 mg, 5.7% yield).

[0604] LC-MS, M / Z(ESI):503.2[M+H] +

[0605] 1 H NMR (400MHz, DMSO-d6): δ8.72(s,1H),7.36(t,1H),6.94(d,1H),6.52(d,1H),6.12(d,1H),5.72 (d,1H),3.82(s,2H),3.73–3.65(m,4H),3.47–3.43(m,2H),3.07(t,2H),1.99–1.85(m,4H),1.82 -1.75(m,4H).

[0606] Example 32: Synthesis of Compound 32

[0607] (3-(((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl)amino)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(cyclopropyl)methanone

[0608] The synthetic route of compound 32 is as follows:

[0609] Step 1: 3-Bromo-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine hydrochloride

[0610] At room temperature, tert-butyl 3-bromo-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (500 mg, 1.65 mmol) was dissolved in dichloromethane (2 mL) and a solution of hydrogen chloride in 1,4-dioxane (4 mol / L, 4 mL). The reaction mixture was stirred at 25°C for 12 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain 3-bromo-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (500 mg, 100% yield). LC / MS (ESI) (m / z): 203.0 (M+H) + .

[0611] Step 2: (3-bromo-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(cyclopropyl)methanone

[0612] 3-Bromo-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (0.5 g, 2.46 mmol) was dissolved in dichloromethane (10 mL) at room temperature, and then diisopropylethylamine (955 mg, 7.39 mmol), dimethylaminopyridine (30.0 mg, 0.246 mmol) and cyclopropylcarbonyl chloride (309 mg, 2.96 mmol) were added at 0°C, and the reaction solution was stirred at 25°C for 12 hours. After the reaction is completed, the reaction solution is diluted with saturated sodium bicarbonate solution, and then extracted with dichloromethane (10 mL*3). The organic phases are combined, washed with saturated brine (5 mL), and then dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product which is purified by column chromatography (DCM:MeOH (V / V) = 1 / 0 to 10 / 1) to give compound (3-bromo-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(cyclopropyl)methanone (200 mg, 0.738 mmol, yield 30%).

[0613] LC / MS (ESI) (m / z): 271.0 (M+H) +

[0614] Step 3:

[0615] (3-(((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl)amino)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(cyclopropyl)methanone

[0616] At room temperature, (1S,3R)-N 1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine (int-3) (100.0 mg, 0.290 mmol), (3-bromo-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(cyclopropyl)methanone (118 mg, 0.440 mmol) and sodium tert-butoxide (56.0 mg, 0.58 mmol) were dissolved in N,N-dimethylformamide (1.0 mL), and then methanesulfonic acid (2-di-tert-butylphosphino-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (23.0 mg, 0.029 mmol) was added, and the reaction solution was stirred at 120 ° C for 24 hours under nitrogen protection. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated. The crude product was purified by preparative high performance liquid chromatography (chromatographic column: YMC-Triart Prep C18 7μm 30mm×40cm; solvent: A=0.1% ammonia water, B=acetonitrile; gradient: 20%-70%, 9 minutes) to give compound (3-(((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl)amino)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(cyclopropyl)methanone (4.40 mg, yield 2.8%).

[0617] LC / MS (ESI) (m / z): 534.1 (M+H) + ;

[0618] 1 H NMR(400MHz,DMSO-d6)δ8.56(d,1H),7.86(d,1H),7.70(dd,1H),7.45(d,1H),6.88(s,1H),5.89(d,1H),4.88(s,1H),4.57(s,1H),4. 05(s,1H),3.92–3.54(m,5H),2.34(d,1H),2.07(d,2H),1.97–1.93(m,1H),1.78(d,1H),1.58–1.26(m,4H),1.20(s,2H),0.72(d,2H).

[0619] Example 33: Synthesis of Compound 33

[0620] (1S,3R)-N 1 -[6-chloro-2-(trifluoromethyl)quinolin-4-yl]-N 3 -(5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-3-yl)cyclohexane-1,3-diamine

[0621] The synthetic route of compound 33 is as follows:

[0622] first step:

[0623] tert-Butyl 3-(((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)amino)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate

[0624] At room temperature, tert-butyl 3-bromo-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (100 mg, 0.330 mmol) was dissolved in N,N-dimethylformamide (1 mL), and then (1S,3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine (int-3) (113 mg, 0.330 mmol), sodium tert-butoxide (44.0 mg, 0.46 mmol) and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (26.0 mg, 0.033 mmol). After the addition, the reaction solution was stirred at 120 ° C for 12 hours under nitrogen protection. After completion of the reaction, the reaction solution was added to a saturated ammonium chloride solution (10 mL), followed by extraction with ethyl acetate (3×15 mL). The organic phases were combined, washed with saturated brine (15 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (dichloromethane:methanol (V / V) = 100:1 to 20:1) to give compound 3-(((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)amino)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester (50.0 mg, yield 26.8%).

[0625] LC / MS (ESI) (m / z): 566.2 (M+H) + .

[0626] Step 2: (1S, 3R)-N 1 -[6-chloro-2-(trifluoromethyl)quinolin-4-yl]-N 3 -(5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-3-yl)cyclohexane-1,3-diamine

[0627] At room temperature, tert-butyl 3-(((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)amino)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (50.0 mg, 0.088 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added. After the addition, the reaction solution was stirred at 25°C for 1 hour. After completion of the reaction, the reaction solution was concentrated, and the crude product was purified by preparative liquid chromatography (column: YMC-Triart Prep C18 7μm 30mm×40cm; solvent: A = 0.1% ammonia water, B = acetonitrile; gradient: 25%-75%, 9 minutes) to obtain compound (1S,3R)-N 1 -[6-chloro-2-(trifluoromethyl)quinolin-4-yl]-N 3 -(5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-3-yl)cyclohexane-1,3-diamine

[0628] (7.90 mg, 19.5% yield).

[0629] LC / MS (ESI) (m / z): 466.1 (M+H) + ;

[0630] 1 H NMR (400 MHz, DMSO-d 6 )δ8.56(d,1H),7.85(d,1H),7.70(dd,1H),7.45(d,1H),6.88(s,1H),5.72(d,1H),3.79(d,1H),3.72(s,2H), 3.61(dd,1H),3.49(t,2H),2.93(t,2H),2.33(d,1H),2.06(d,1H),1.94(d,1H),1.77(d,1H),1.41(ddd,4H).

[0631] Intermediate A1: (1S,3R)-N 1 Synthesis of 6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine

[0632] The synthetic route of intermediate A1 is as follows:

[0633] Step 1: Synthesis of 6-chloro-2-(trifluoromethyl)quinolin-4-ol (A1-2)

[0634] At room temperature, p-chloroaniline (5 g, 39.37 mmol) was added to PPA (200 mmol, 75 ml), followed by ethyl trifluoroacetate (7.2 g, 39.37 mmol). The reaction mixture was heated to 140°C and stirred for 12 h. After completion of the reaction, the reaction mixture was poured into ice water and extracted with ethyl acetate (50 mL x 4). The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and spun down to dryness to yield 6-chloro-2-(trifluoromethyl)quinolin-4-ol (A1-2) (crude product, 8.5 g, 87.6% yield).

[0635] LC-MS, M / Z(ESI):248.0[M+H] + .

[0636] Step 2: Synthesis of 4,6-dichloro-2-(trifluoromethyl)quinoline (A1-3)

[0637] 6-Chloro-2-(trifluoromethyl)quinolin-4-ol (A1-2) (8.5 g, 34.5 mmol) was dissolved in 1,2-dichloroethane (100 mL), and phosphorus oxychloride (13.2 g, 86.25 mmol) was added at 0°C. The reaction solution was then heated to 80°C and stirred for 12 hours. After completion of the reaction, the reaction solution was spin-dried, and the resulting crude product was rapidly purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 20:1 to 10:1) to obtain compound 4,6-dichloro-2-(trifluoromethyl)quinoline (A1-3) (8.3 g, 91.6% yield).

[0638] LC-MS, M / Z(ESI):265.9[M+H] + .

[0639] Step 3: Synthesis of tert-butyl ((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)-amino)cyclohexyl)carbamate (A1-4)

[0640] At room temperature, 4,6-dichloro-2-(trifluoromethyl)quinoline (A1-3) (1.32 g, 5 mmol) and tert-butyl ((1R, 3S)-3-aminocyclohexyl)carbamate (1 g, 4.67 mmol) were added to NMP, and then diisopropylethylamine (1.9 g, 15 mmol) was added. The reaction solution was heated to 130 oC. Stir for 12 h. After completion of the reaction, the reaction solution was poured into ice water and extracted with ethyl acetate (50 mL x 4). The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and spun down to obtain tert-butyl ((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamate (A1-4) (crude product, 1.9 g, 96.3% yield).

[0641] LC-MS, M / Z(ESI):444.1[M+H] + .

[0642] Step 4: (1S, 3R)-N 1 Synthesis of -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine (Intermediate A1)

[0643] At room temperature, tert-butyl ((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)-amino)cyclohexyl)carbamate (A1-4) (1 g, 2.3 mmol) was dissolved in 1,4-dioxane (20 mL). Concentrated hydrochloric acid (0.5 mL) was then added, and the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the crude product was purified by column chromatography on silica gel (dichloromethane:methanol (v / v) = 10:1 to 20:1) to obtain (1S,3R)-N1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine (Intermediate A1) (720 mg, 91.3% yield).

[0644] LC / MS(ESI)(m / z):344[M+H] + .

[0645] Intermediate A2: Synthesis of 5-chloro-2-(trifluoromethyl)imidazo[1,2-a]pyridine

[0646] The synthetic route of intermediate A2 is as follows:

[0647] 2-Amino-6-chloropyridine (5 g, 38.89 mmol) and 3-bromo-1,1,1-trifluoroacetone (7.42 g, 38.89 mmol) were dissolved in ethylene glycol (50 mL) at room temperature and stirred at 130°C for 12 h. After completion of the reaction as monitored by thin-layer chromatography (TLC), stirring was stopped and the reaction solution was cooled to room temperature. Water (200 mL) was then added for dilution and extraction with ethyl acetate (100 mL x 5). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (DCM:MeOH = 100:0) to afford 5-chloro-2-(trifluoromethyl)imidazo[1,2-a]pyridine (Intermediate A2) (5.87 g, 68.42% yield).

[0648] LC-MS, M / Z (ESI): 220.90 [M+H] + .

[0649] Example 34: cis-N 1 -[4-(1H-pyrazol-1-yl)pyridin-2-yl]-N 4 Synthesis of 2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]cyclohexane-1,4-diamine (Compound 1A)

[0650] The synthetic route of compound 1A is as follows:

[0651] Step 1: Synthesis of 2-fluoro-4-(1H-pyrazol-1-yl)pyridine (1A-2)

[0652] 2,4-Difluoropyridine (1A-1) (1.69 g, 14.6 mmol) was dissolved in N,N-dimethylformamide (10 mL), and 1H-pyrazole (1.00 g, 14.6 mmol) was added, followed by potassium phosphate (6.24 g, 29.3 mmol). The reaction mixture was stirred at 25°C under nitrogen for 1 hour. The reaction mixture was poured into water (25 mL) and extracted with ethyl acetate (50 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by column chromatography on silica gel (petroleum ether:ethyl acetate (v / v) = 10:1 to 5:1) to obtain compound 2-fluoro-4-(1H-pyrazol-1-yl)pyridine (1A-2) (1.00 g, 41.7% yield).

[0653] LC-MS, M / Z(ESI):164.3[M+H] + .

[0654] Step 2: Synthesis of tert-butyl (cis-4-((4-(1H-pyrazol-1-yl)pyridin-2-yl)amino)cyclohexyl)carbamate (1A-4)

[0655] 2-Fluoro-4-(1H-pyrazol-1-yl)pyridine (1A-2) (700 mg, 4.29 mmol) and 1-N-Boc-cis-1,4-cyclohexanediamine (1A-3) (1.01 g, 4.72 mmol) were dissolved in N-methylpyrrolidone (10 mL), potassium carbonate (1.78 g, 12.8 mmol) was added, and the reaction solution was stirred at 140 ° C for 2 hours. The reaction solution was cooled to room temperature and then poured into water (25 mL), extracted with ethyl acetate (50 mL), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 10:1 to 3:1) to obtain compound (cis-4-((4-(1H-pyrazol-1-yl)pyridin-2-yl)amino)cyclohexyl)carbamic acid tert-butyl ester (1A-4) (500 mg, yield 32.6%).

[0656] LC-MS, M / Z(ESI):358.1[M+H] + .

[0657] Step 3: cis-N 1 Synthesis of -(4-(1H-pyrazol-1-yl)pyridin-2-yl)cyclohexane-1,4-diamine (1A-5)

[0658] Dissolve tert-butyl (cis-4-((4-(1H-pyrazol-1-yl)pyridin-2-yl)amino)cyclohexyl)carbamate (1A-4) (400 mg, 1.12 mmol) in a 1,4-dioxane solution of hydrogen chloride (2 M, 5 mL) and react at 25°C for 2 hours. The reaction solution was concentrated to obtain compound cis-N 1 -(4-(1H-pyrazol-1-yl)pyridin-2-yl)cyclohexane-1,4-diamine (1A-5) (250 mg, yield 86.4%).

[0659] LC-MS, M / Z(ESI):258.2[M+H] + .

[0660] Step 4: cis-N 1 -[4-(1H-pyrazol-1-yl)pyridin-2-yl]-N 4 Synthesis of 2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]cyclohexane-1,4-diamine (target compound 1A)

[0661] cis-N 1 -(4-(1H-pyrazol-1-yl)pyridin-2-yl)cyclohexane-1,4-diamine (1A-5) (250 mg, 971 μmol) and 5-chloro-2-(trifluoromethyl)imidazo[1,2-a]pyridine (Intermediate A2) (200 mg, 906 μmol), cesium carbonate (1.18 g, 3.63 mmol), SPhos Pd G3 (212 mg, 272 μmol) were dissolved in 1,4-dioxane (10 mL) and stirred at 100 ° C for 4 hours under nitrogen protection. The reaction solution was concentrated and separated and purified by high performance preparative liquid chromatography (column: C 18 150×30mm; solvent: A = water + 0.05 volume formic acid (99%), B = acetonitrile; gradient: 20%-50%, 7 minutes), to obtain compound cis-N 1 -[4-(1H-pyrazol-1-yl)pyridin-2-yl]-N 4 -[2-(Trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]cyclohexane-1,4-diamine (target compound 1A) (17.6 mg, yield 4.16%).

[0662] LC-MS, M / Z(ESI):442.2[M+H] + .

[0663] 1 H NMR(400MHz,DMSO-d6)δ:8.72(s,1H),8.47(d,1H),8.03(d,1H),7.78(d,1H),7.31-7.40(m,1H),7 .03(s,1H),6.91-6.98(m,2H),6.70(d,1H),6.55-6.59(m,1H),6.52(d,1H),6.12(d,1H),3.96(br s,1H),3.60-3.69(m,1H),1.68-1.97(m,8H).

[0664] Example 35: Synthesis of 1-(2-(((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)amino)pyridin-4-yl)pyrrolidin-2-one (Compound 2A) The synthetic route of Compound 2A is as follows:

[0665] Step 1: Synthesis of 1-(2-chloropyridin-4-yl)pyrrolidin-2-one

[0666] Dissolve 4-bromo-2-chloropyridine (2.00 g, 10.39 mmol) in 1,4-dioxane (20 mL), add pyrrolidin-2-one (884 mg, 10.4 mmol), potassium phosphate (4.41 g, 20.7 mmol), 1,1'-bis(diphenylphosphino)ferrocene (1.73 g, 3.12 mmol), and palladium acetate (233 mg, 1.04 mmol). Stir the reaction mixture at 90°C under nitrogen for 2 h. Pour the reaction mixture into water (50 mL) and extract with dichloromethane (100 mL). Collect the organic phase, dry over anhydrous sodium sulfate, filter, and concentrate. The crude product was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 50:1 to 2:1) to obtain compound 1-(2-chloropyridin-4-yl)pyrrolidin-2-one (2A-2) (1.20 g, yield 58.7%).

[0667] LC-MS, M / Z(ESI):197.3[M+H] + .

[0668] Step 2: Synthesis of 1-(2-(((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)amino)pyridin-4-yl)pyrrolidin-2-one

[0669] At room temperature, (1S,3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine (100 mg, 0.292 mmol), 1-(2-chloropyridin-4-yl)tetrahydropyrrol-2-one (57.2 mg, 0.292 mmol) and [(trimethylsilyl)oxy]sodium (131 mg, 1.17 mmol) were dissolved in 1,4-dioxane (3 mL), and then (SP-4-1)-[1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(3-chloropyridine-κN)-palladium (14.2 mg, 0.015 mmol) was added. After the addition was complete, the reaction solution was heated to 100 ° C and stirred for 12 hours. After the reaction was complete, the reaction solution was filtered, the filtrate was dried, and the crude product was purified by high performance preparative liquid chromatography (chromatographic column: YMC-Triart Prep C 18 7μm 30mm×40cm mobile phase A: 0.1% ammonia water; mobile phase B: acetonitrile; flow rate: 42mL / min, gradient: 30%-80%, 9 minutes) to give 1-(2-(((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)amino)pyridin-4-yl)pyrrolidin-2-one (17.0 mg, 11% yield).

[0670] LC / MS (ESI) (m / z): 504.4 (M+H) + .

[0671] 1 H NMR(400MHz,DMSO-d6)δ8.06(d,1H),7.77(d,1H),7.69(d,1H),7.36(dd,1H),6.79(s,1H),6.58– 6.41(m,3H),4.78(d,1H),3.73–3.57(m,3H),3.51–3.42(m,1H),2.38–2.34(m, 2H),1.94(dt,4H),1.74(d,1H),1.38(d,1H),1.20(dd,2H),1.10–1.02(m,2H).

[0672] Example 36: Synthesis of N-(2-(((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)amino)pyridin-4-yl)methanesulfonamide (Compound 3A)

[0673] The synthetic route of compound 3A is as follows:

[0674] Step 1: (1S, 3R)-N 1 Synthesis of 6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N3-(4-iodopyridin-2-yl)cyclohexane-1,3-diamine

[0675] 2-Fluoro-4-iodopyridine (3A-1) (250 mg, 1.12 mmol) was dissolved in N-methylpyrrolidone (10.0 mL) and (1S,3R)-N 1 -[6-chloro-2-(trifluoromethyl)quinolin-4-yl]cyclohexane-1,3-diamine (Intermediate A1) (426 mg, 1.12 mmol) and potassium phosphate (619 mg, 4.48 mmol) were added, and then stirred at 130°C for 2 hours under nitrogen protection. The reaction solution was cooled to room temperature, poured into water (50.0 mL), and extracted with dichloromethane (100 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative high performance liquid chromatography (column: Phenomenex luna C18 150*40mm*15μm; solvent: A = water + 0.05 volume formic acid (30%), B = acetonitrile; gradient: 32%-62%, 15 minutes) to obtain compound (1S,3R)-N 1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N3-(4-iodopyridin-2-yl)cyclohexane-1,3-diamine (100 mg, 16.2% yield).

[0676] LC-MS, M / Z(ESI):547.3[M+H] +

[0677] Step 2: Synthesis of N-(2-(((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)amino)pyridin-4-yl)methanesulfonamide

[0678] At room temperature, (1S,3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N3-(4-iodopyridin-2-yl)cyclohexane-1,3-diamine (80.0 mg, 0.233 mmol), methanesulfonamide (27.7 mg, 0.233 mmol), tris(dibenzylideneacetone)palladium (21.0 mg, 0.023 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (13.3 mg, 0.023 mmol) and cesium carbonate (228 mg, 0.699 mmol) were dissolved in 1,4-dioxane (2.0 mL), and the reaction solution was stirred at 80 ° C for 12 hours under nitrogen protection. After completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative liquid chromatography (chromatographic column: YMC-Triart Prep C18 7 μm 30 mm × 40 cm; solvent: A = 0.1% ammonia water, B = acetonitrile; gradient: 10%-55%, 9 minutes) to give compound N-(2-(((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)amino)pyridin-4-yl)methanesulfonamide (Compound 3A) (13.0 mg, 10.5% yield).

[0679] LC / MS (ESI) (m / z): 514.3 (M+H) + ;

[0680] 1H NMR(400MHz,DMSO-d6)δ10.11(s,1H),8.57(d,1H),7.86(d,1H),7.75–7.65(m,2H),7.46(d,1H),6.88(s,1H),6.46(d,1H),6.22 –6.14(m,2H),3.81(dd,2H),2.94(s,3H),2.27(d,1H),1.95(d,2H),1.78(d,1H),1.54–1.45(m,1H),1.30(dd,2H),1.12(d,1H).

[0681] Example 37: (1S,3R)-N 1 Synthesis of -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N3-(4-(pyrimidin-2-yl)pyridin-2-yl)cyclohexane-1,3-diamine (Compound 7A)

[0682] The synthetic route of compound 7A is as follows:

[0683] Step 1: Synthesis of 2-(2-chloropyridin-4-yl)pyrimidine

[0684] 2-Bromopyrimidine (0.25 g, 1.57 mmol) was dissolved in a mixture of 1,4-dioxane (10 mL) and water (2 mL). 2-Chloropyridine-4-boronic acid pinacol ester (0.37 g, 1.57 mmol) was added, followed by potassium carbonate (0.43 g, 3.11 mmol) and bistriphenylphosphine palladium dichloride (110 mg, 0.16 mmol). The mixture was stirred at 110°C overnight under nitrogen. After completion of the reaction, the reaction mixture was concentrated, water (10 mL) was added, and extraction with ethyl acetate (20 mL x 3) was performed. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 4:1) to obtain 2-(2-chloropyridin-4-yl)pyrimidine (0.37 g, yield: 83.0%).

[0685] LC-MS, M / Z(ESI):192.1[M+H] + .

[0686] Step 2: (1S, 3R)-N 1 -(6-chloro-2-(trifluoromethyl))-quinolin-4-yl)-N 3 Synthesis of -(4-(pyrimidin-2-yl))-pyridin-2-yl)cyclohexane-1,3-diamine

[0687] (1S,3R)-N1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine (Intermediate A1) (Intermediate A1) (100 mg, 0.29 mmol), 2-(2-chloropyridin-4-yl)pyrimidine (67 mg, 0.35 mmol), TMSNa (145 mg, 1.16 mmol), (SP-4-1)-[1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(3-chloropyridine-κN)-palladium (12 mg, 0.012 mmol) were placed in a reaction bottle, 1,4-dioxane (3 mL) was added under argon protection, and the reaction was carried out at 100°C for 4 h. After the reaction, saturated sodium chloride solution (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography on silica gel (dichloromethane: methanol (V / V) = 10:1) to obtain compound (1S,3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N3-(4-(pyrimidin-2-yl)pyridin-2-yl)cyclohexane-1,3-diamine (Compound 7A) (35 mg, 24% yield).

[0688] LC-MS, M / Z(ESI):499.3[M+H] + .

[0689] Example 38: (1R,3S)-N 1 -(6-chloro-2-(trifluoromethyl))-quinolin-4-yl)-N 3 Synthesis of trifluoroacetate of 3-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)cyclohexane-1,3-diamine (Compound 16A)

[0690] The synthetic route of compound 16A is as follows:

[0691] Step 1: Synthesis of 2-chloro-3-(1-methyl-1H-pyrazol-4-yl)pyrazine

[0692] To a solution of 2,3-dichloropyrazine (1.00 g, 6.71 mmol) in dimethyl sulfoxide (12 mL) and water (3 mL) were added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.68 g, 8.06 mmol), (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride (0.49 g, 0.67 mmol), and cesium carbonate (2.78 g, 20.1 mmol). The reaction mixture was stirred at 80°C under nitrogen for 18 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, washed with saturated brine (20 mL), 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) = 100:1 to 5:2, gradient elution) to give compound 2-chloro-3-(1-methyl-1H-pyrazol-4-yl)pyrazine (700 mg, yield 53.6%).

[0693] LC-MS, M / Z(ESI):195.0[M+H] +

[0694] Step 2: (1S, 3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 Synthesis of 3-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)cyclohexane-1,3-diamine trifluoroacetate

[0695] To a solution of 2-chloro-3-(1-methylpyrazol-4-yl)pyrazine (200 mg, 1.03 mmol) in N,N-dimethylformamide (5 mL) were added (1S,3R)-N1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine (Intermediate A1) (353 mg, 1.03 mmol), cesium carbonate (1.00 g, 3.08 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (119 mg, 0.21 mmol) and tris(dibenzylideneacetone)dipalladium (94.1 mg, 0.10 mmol). The resulting mixture was then stirred at 80° C. under nitrogen for 12 hours. The reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure to obtain a crude product which was purified by preparative liquid chromatography (Kinetex EVO C18, 21.2*250mm, 5um; 0.1% TFA-ACN; 40-70%; 20mL / min) to obtain compound (1S,3R)-N 1 -(6-chloro-2-trifluoromethyl)quinolin-4-yl)-N 3-(3-methylpyrazol-4-yl)pyrazin-2-yl)cyclohexane-1,3-diamine trifluoroacetate (13.3 mg, yield 2.1%).

[0696] LC-MS, M / Z(ESI):502.2[M+H] +

[0697] 1 H NMR (400MHz, MeOD): δ8.57(d,1H),8.11(s,1H),8.04–7.82(m,4H),7.75(d,1H),7.25(s,1H),4.25–4.11(m,1H) ),4.11–4.01(m,1H),3.98(s,3H),2.61–2.48(m,1H),2.23–2.09(m,2H),2.06–2.00(m,1H),1.76–1.42(m,4H).

[0698] Example 39: (1S,3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 Synthesis of -(3-chloropyridin-2-yl)cyclohexane-1,3-diamine (Compound 17A)

[0699] The synthetic route of compound 17A is as follows:

[0700] At room temperature, (1S,3R)-N 1 -(6-Chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine (Intermediate A1) (Intermediate A1) (200 mg, 0.581 mmol), 3-chloro-2-bromo-pyridine (165.7 mg, 0.872 mmol) and sodium tert-butoxide (566 mg, 1.74 mmol) were dissolved in tert-butanol (10 mL), and then methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (56.0 mg, 0.058 mmol) was added. After the addition, the atmosphere was replaced with nitrogen three times and the temperature was raised to 100°C and stirred for 12 hours. After the reaction was completed, saturated aqueous ammonium chloride solution (30 mL) was poured into the reaction mixture to quench the reaction, and then the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was separated and purified by high performance liquid chromatography (column: C18 150 × 30 mm; solvent: A = water + 0.05 volume formic acid (99%), B = acetonitrile; gradient: 15%-45%, 7 minutes) to obtain compound (1S, 3R)-N 1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 -(3-chloropyridin-2-yl)cyclohexane-1,3-diamine (13.0 mg, yield 4.9%).

[0701] LC / MS (ESI) (m / z): 454.09 (M+H) + ;

[0702] 1H NMR(400MHz,DMSO-d6)δ8.05–8.01(m,2H),7.67–7.65(m,2H),1 7.45(d,1H),6.83(s,1H),6.54(dd,1H),5.11–5.09(m,1H),4.89(d,1H),4.22–4.17(m,1H),3 .80–3.76(m,1H).2.75(d,1H),2.22(t,2H),2.00(d,1H),1.67–1.70(m,1H),1.42–1.33(m,3H)

[0703] The preparation methods of the following compounds are described in the above examples.

[0704] Test Example 1: MRGPRX2 in vitro calcium flux assay

[0705] 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 The experimental results are shown in Table 1.

[0706] Table 1: MRGPRX2 calcium flux assay results

[0707] The results of the MRGPRX2 calcium flux test showed that the compound of the present invention has a good antagonistic effect on MRGPRX2.

[0708] Test Example 2: Compound toxicity test on hepatocytes

[0709] 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).

[0710] The results of the hepatotoxicity test showed that the compound of the present invention exhibited good safety and low hepatotoxicity.

[0711] Test Example 3: Pharmacokinetics test in mice

[0712] Mouse pharmacokinetic studies were conducted using male ICR mice weighing 20-25 g and fasted overnight. Three mice were orally gavaged and administered 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. Key pharmacokinetic parameters were analyzed using WinNonlin 7.0 software using a non-compartmental model. The experimental results are shown in Table 2.

[0713] Table 2: Pharmacokinetic test results in mice

[0714] The results of the mouse pharmacokinetic test showed that the compound of the present invention exhibited excellent pharmacokinetic properties and good drugability.

[0715] Test Example 4: Pharmacokinetics test in rats

[0716] 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.

[0717] The results of the rat pharmacokinetic test showed that the compound of the present invention exhibited excellent rat pharmacokinetic properties and good drugability.

[0718] Test Example 5: Thermodynamic Solubility Test

[0719] 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.

[0720] The results of the thermodynamic solubility test show that the compound of the present invention has good thermodynamic solubility and good drugability.

[0721] Test Example 6: Human liver microsome stability test

[0722] 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 with 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.

[0723] 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.

[0724] Test Example 7: Inhibition test of compounds on cytochrome P450

[0725] 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).

[0726] 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.

[0727] 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.

[0728] 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.

[0729] Test Example 8: Evans Blue Vascular Permeability Test

[0730] 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.

[0731] 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.

[0732] 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 I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug: in, is a single bond or a double bond; 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 Each independently is 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 6-10 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; Ring B is C 3-12 Cycloalkyl; Ring D is an 8-12-membered cycloheteroaryl, an 8-12-membered cycloheterocycloalkenyl or a 5-10-membered heteroaryl; R a , R c , R 4 and R 5 are each independently 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 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; 1-6 Alkyl, C 3-8 Cycloalkyl, 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 replace; The R d A substituent selected from the group consisting of: H, 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 Halogenated alkoxy, C 3-6 Cycloalkyl; when the substituent R d When it is multiple, the R d The same or different; where R d Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl and C 2-6 alkynyl, each independently optionally substituted by 1, 2, 3 or 4 R d1 Replace, when R d1 When there are multiple R d1 Same or different; R d1 are independently H, F, Cl, Br or I; R k are independently 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 Haloalkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 haloalkoxy, 3- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -C 0-6 Alkyl-NR d -C 0-6 Alkyl, C 1-6 Alkylamino, -C 0-6 Alkyl-NR d SO2-C 0- 6 alkyl or -C 0-6 Alkyl-P(=O)(R d )2; said C 1-6 Alkyl, C 3-8 Cycloalkyl, 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 Halogenated alkoxy, 3-10 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered hetero The aryl group is optionally substituted by n R b Substitution; said R b A substituent selected from the group consisting of hydrogen, 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 Halogenated alkoxy, C 3-6 Cycloalkyl; when the substituent R b When n is the number, the R b The same or different; where R b Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl and C 2-6 alkynyl, each independently optionally substituted by 1, 2, 3 or 4 R d1 Replace, when R d1 When there are multiple R d1 Same or different; R 1 , R 2 and R 3 are independently H, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, 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 ; Among them, when R 1 , R 2 and R 3 Selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, each independently optionally substituted by 1, 2, 3 or 4 R d Replace, when R d When there are multiple R d Same or different; 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- 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- to 10-membered aryl, 5- to 10-membered heteroaryl or 5- to 10-membered heterocycloalkyl; m is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; r is 0, 1, 2 or 3; s is 0, 1, 2, 3, 4, 5, 6.

2. The compound of formula (I) as claimed in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: The compound shown in formula I has the structure shown in formula I-1: Among them, ring A, ring B, ring D, 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; C is a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group or a 3- to 10-membered heterocycloalkyl group; Preferably, ring B is 1,4-substituted C 4-12 Cycloalkyl or 1,3 substituted C 3-12 Cycloalkyl; Ring D is a 5- to 10-membered heteroaryl.

3. The compound of formula (I) as claimed in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: The compound shown in formula I has the structure shown in formula I-2: Among them, ring A, ring D, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , R 1 , R 2 , R 3 , R a , R k , m and s as defined in claim 1; Preferably, ring D is a 5- to 10-membered heteroaryl group; R k are independently 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 Haloalkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C 0-6 Alkyl-NR d -C 0-6 Alkyl, -C 0-6 Alkyl-NR d SO2-C 0-6 Alkyl or -C 0-6 Alkyl-P(=O)(R d )2; said C 1-6 Alkyl, C 3-8 Cycloalkyl, 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 by n R b Substitution; said R b A substituent selected from the group consisting of hydrogen, halogen, hydroxy, amino, nitro, cyano, carbonyl, oxo, carboxyl, C 1-6 Alkyl, 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 b When n is the number, the R b Same or different.

4. The compound of formula I as claimed in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: The compound shown in formula I has the structure shown in formula II-1: Among them, ring A, ring D, 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; C is a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, or a 3- to 10-membered heterocycloalkyl group; Preferably, ring D is a 5- to 10-membered heteroaryl group; Preferably, 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 heteroaromatic ring or a 6-membered heteroaromatic ring; 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; The C is a 6- to 8-membered aryl group, a 5- to 8-membered heteroaryl group, or a 5- to 8-membered heterocycloalkyl group; Ring D is a 5- to 8-membered heteroaryl group; R a , R c are each independently 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 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; R b are independently H, halogen, hydroxy, amino, nitro, cyano, carbonyl, oxo, carboxyl, C 1-6 Alkyl, 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; 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 Haloalkyl, C 3-8 Cycloalkyl, halogenated C 3-8 Cycloalkyl; n is 0, 1, 2 or 3; Preferably, C is a 5- to 6-membered nitrogen-containing heteroaryl group or a 5- to 6-membered nitrogen-containing heterocycloalkyl group, and the number of nitrogen atoms is 1, 2 or 3; More preferably, C is pyrrolidinyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl; Still more preferably, C is 5. The compound according to any one of claims 1 to 4, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: The R a , R b , R c Each is independently H, F, Cl, methyl, amino, oxo, -CH2CF3, -CF3; and / or, the R 1 , R 2 , R 3 Each independently represents H, methyl, -CH2CF3, -CF3, 6. The compound according to any one of claims 1 to 5, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: Ring D is a 5- to 10-membered heteroaryl group; Preferably, ring D is a 5-6-membered nitrogen- or oxygen-containing heteroaryl group, and the number of the nitrogen atoms or oxygen atoms is 1, 2 or 3; Preferably, ring D is pyridyl, oxadiazole, isoxazole, pyrazinyl; Preferably, ring D is 7. The compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug according to any one of claims 1 to 6, characterized in that: The compound shown in Formula I has the structure shown in Formula Ia: Among them, ring A, ring B, ring D, X 1 , X 5 , R 1 , R 2 , R 3 , R a , R k s as defined in any one of claims 1 to 6; Preferably, in the formula Ia, is a single bond or a double bond; X 1 is N or C; when X 1 When it is C, the C atom is R a replace; X 5 is N or C; when X 5 When N is connected is a single bond, when X 5 When it is C, the connected is a double bond; Ring A is phenyl or a 5-6 membered heteroaryl group; The A is further R c Replaced by; said R c Substitution is one or more (e.g., 2, 3, 4) substitutions, when the substituent R c When there are multiple substituents, the substituents are the same or different; each R c are independently H, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2, 3 or 4 R d Replace, when R d When there are multiple R d Same or different; Each R 1 , R a H, C 1-3 Alkyl, C 1-3 Alkoxy or C 3-6 Cycloalkyl, wherein C 1-3 Alkyl, C 1-3 Alkoxy and C 3- 6 cycloalkyl groups are each independently optionally substituted by 1, 2, 3 or 4 R d Replace, when R d When there are multiple R d Same or different; Ring B is C 3-12 Cycloalkyl; Ring D is an 8-12-membered cycloheteroaryl group or an 8-12-membered cycloheterocycloalkenyl group; Each R d are independently H, F, Cl, Br, I, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, where C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl and C 2-6 The alkynyl groups are each independently optionally substituted with 1, 2, 3 or 4 R d1 Replace, when R d1 When there are multiple R d1 Same or different; Each R d1 are independently H, F, Cl, Br or I; Each R k are independently H, halogen, NH2, CN, =O, OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2, 3 or 4 R b Replace, when R b When there are multiple R b The same or different; the R b are independently H, F, Cl, Br, I, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, where C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl and C 2-6 The alkynyl groups are each independently optionally substituted with 1, 2, 3 or 4 R d1 Replace, when R d1 When there are multiple R d1 Same or different; R 2 and R 3 Each independently is H or C 1-3 Alkyl; wherein R 2 and R 3 Same or different; s is 0, 1, 2, 3, 4, 5, 6.

8. The compound of formula I according to any one of claims 1 to 7, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: The compound shown in Formula I has the structure shown in Formula Ib: Among them, ring A, ring B, X 1 , X 5 , R 1 , R 2 , R 3 , R a , R k , s as defined in any one of claims 1 to 7; X7 is N or CR a ; Ring C is C 6-10 Aryl, C 4-8 cycloalkenyl, 5-8 membered heteroaryl or 4-9 membered heterocycloalkenyl; for example, ring C is C 6-10 Aryl, C 4-6 Cycloalkenyl, 5-6 membered heteroaryl or 4-8 membered heterocycloalkenyl; for example, ring C is phenyl; for example, ring C is 5-6 membered heteroaryl or 5-6 membered heterocycloalkenyl; for example, ring C is 5-6 membered nitrogen-containing heteroaryl; Preferably, R4, R5, and R6 are independently 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-halogenated alkoxy, 3- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C 1-6 Alkylamino; the C 1-6 Alkyl, C 3-8 Cycloalkyl, 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 A haloalkoxy group, a 3- to 10-membered heterocycloalkyl group, a 6- to 10-membered aryl group, or a 5- to 10-membered heteroaryl group is optionally substituted by n R b Substitution; said R b A substituent selected from the group consisting of hydrogen, 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-alkylhydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl; when the substituent R b When n is the number, the R b The same or different; where R b Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl and C 2-6 alkynyl, each independently optionally substituted by 1, 2, 3 or 4 R d1 Replace, when R d1 When there are multiple R d1 Same or Different; R d1 are independently H, F, Cl, Br or I; n' is 0, 1, 2, 3 or 4; Preferably, in the formula Ib, is a single bond or a double bond; X 1 is N or C; when X 1 When it is C, the C atom is R a replace; X 5 is N or C; when X 5 When N is connected is a single bond, when X 5 When it is C, the connected is a double bond; X7 is N or CR a ; Ring A is phenyl or a 5-6 membered heteroaryl group; 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; each R c are independently H, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2, 3 or 4 R d Replace, when R d When there are multiple R d Same or different; Each R 1 , R a H, C 1-3 Alkyl, C 1-3 Alkoxy or C 3-6 Cycloalkyl, wherein C 1-3 Alkyl, C 1-3 Alkoxy and C 3- 6 cycloalkyl groups are each independently optionally substituted by 1, 2, 3 or 4 R d Replace, when R d When there are multiple R d Same or different; Ring B is C 3-12 Cycloalkyl; Ring C is a 5-6 membered heteroaryl or a 5-6 membered heterocycloalkenyl; Each R d are independently H, F, Cl, Br, I, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, where C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl and C 2-6 The alkynyl groups are each independently optionally substituted with 1, 2, 3 or 4 R d1 Replace, when R d1 When there are multiple R d1 Same or different; R 2 and R 3 Each independently is H or C 1-3 Alkyl; wherein R 2 and R 3 Same or different; R4 and R5 are independently H, C 1-3 Alkyl, C 1-3 Alkoxy or C 3-6 Cycloalkyl, wherein C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 The cycloalkyl radicals are each independently optionally substituted with 1, 2, 3 or 4 R b Replace, when R b When there are multiple R b Same or different; R6 are independently H, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein The C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2, 3 or 4 R b Replace, when R b When there are multiple R b Same or different; The R b are independently H, F, Cl, Br, I, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, where C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl and C 2-6 The alkynyl groups are each independently optionally substituted with 1, 2, 3 or 4 R d1 Replace, when R d1 When there are multiple R d1 Same or different; Each R d1 are independently H, F, Cl, Br or I; n' is 0, 1, 2, 3 or 4.

9. The compound of formula I according to any one of claims 1 to 8, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: Each R d are independently H, F, Cl, Br, and I; Preferably, each R c are independently F, Cl, Br, I or C 1-3 Alkyl, wherein the C 1-3 The alkyl group is optionally substituted with 1, 2, 3 or 4 R d Replace, when R d When there are multiple R d The same or different; preferably, each R c are independently F, Cl, Br, I, CH3 or -CH2CH3, wherein said CH3 and -CH2CH3 are independently optionally replaced by 1, 2, 3 or 4 R d Replace, when R d When there are multiple R d The same or different; preferably, each R c are independently F, Cl, Br, I, CH3, CH2F, CHF2 or CF3; Preferably, R 1 and R a are independently H or optionally substituted by 1, 2, 3 or 4 R d Substituted CH3; Preferably, R a , R 1 R4 and R5 are each independently H or optionally substituted by 1, 2, 3 or 4 R d Substituted CH3; Preferably, R a and R 1 are independently H, CH3 or CF3; Preferably, R a , R 1 , R4 and R5 are independently H, CH3 or CF3; Preferably, R 2 and R 3 are independently H or CH3; Preferably, ring B is C 3-6 Monocyclic cycloalkyl, C 6-10 Spirocycloalkyl, C 6-10 Cycloalkyl or C 4-10 bridged ring cycloalkyl; Preferably, ring B is C 3-6 Monocyclic cycloalkyl, C 6-8 Spirocycloalkyl, C 6-9 Cycloalkyl or C 5-9 bridged ring cycloalkyl; Preferably, ring B is Preferably, ring A is phenyl, imidazolyl, pyrazolyl or pyrrolyl; Preferably, the structural unit for Preferably, the structural unit for Preferably, Ring D is in, is a single bond or a double bond; T3 is N or CR t3 ; T4 is N or CR4; T5 is N or CR5; T6 and T7 are independently N or C; when T6 and T7 are independently C, the connected is a double bond; T8 is N or CR8; Ring C is C 6-10 Aryl, C 4-8 cycloalkenyl, 5-8 membered heteroaryl or 4-9 membered heterocycloalkenyl; in some embodiments, ring C is C 6-10 Aryl, C 4-6 cycloalkenyl, 5-6 membered heteroaryl or 4-8 membered heterocycloalkenyl; in some embodiments, ring C is phenyl; in some embodiments, ring C is 5-6 membered nitrogen-containing heteroaryl; R t3 R4, R5, R6 and R8 are independently 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 Haloalkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 haloalkoxy, 3- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C 1-6 Alkylamino; the C 1-6 Alkyl, C 3-8 Cycloalkyl, 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 A haloalkoxy group, a 3- to 10-membered heterocycloalkyl group, a 6- to 10-membered aryl group, or a 5- to 10-membered heteroaryl group is optionally substituted by n R b Substitution; said R b A substituent selected from the group consisting of hydrogen, 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 Halogenated alkoxy, C 3-6 Cycloalkyl; when the substituent R b When n is the number, the R b The same or different; where R b Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl and C 2-6 alkynyl, each independently optionally substituted by 1, 2, 3 or 4 R d1 Replace, when R d1 When there are multiple R d1 Same or Different; R d1 are independently H, F, Cl, Br or I; R t3 R4, R5 and R8 are independently H, halogen, NH2, CN, OH, C 1-3 Alkyl, C 1-3 Alkoxy or C 3-6 Cycloalkyl, wherein C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 The cycloalkyl radicals are each independently optionally substituted with 1, 2, 3 or 4 R b Replace, when R b When there are multiple R b Same or different; Each R6 is independently H, halogen, NH2, CN, =O, OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2, 3 or 4 R b Replace, when R b When there are multiple R b Same or different; n is 0, 1, 2, 3 or 4; Or, ring D is in, is a single bond or a double bond; T3 is NR t3 , CR t3 , C(R t3 )2; T4 is NR4, CR4, C(R4)2; T5 is NR5, CR5, C(R5)2; T6 and T7 are independently N or C; when T6 and T7 are independently C, the connected is a double bond; T8 is NR8, CR8, C(R8)2; Ring C is C 6-10 Aryl, C 4-8 cycloalkenyl, 5-8 membered heteroaryl or 4-9 membered heterocycloalkenyl; in some embodiments, ring C is C 6-10 Aryl, C 4-6 cycloalkenyl, 5-6 membered heteroaryl or 4-8 membered heterocycloalkenyl; in some embodiments, ring C is phenyl; in some embodiments, ring C is 5-6 membered nitrogen-containing heteroaryl; R t3 R4, R5, R6 and R8 are independently 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 Haloalkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 haloalkoxy, 3- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C 1-6 Alkylamino; the C 1-6 Alkyl, C 3-8 Cycloalkyl, 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 A haloalkoxy group, a 3- to 10-membered heterocycloalkyl group, a 6- to 10-membered aryl group, or a 5- to 10-membered heteroaryl group is optionally substituted by n R b Substitution; said R b A substituent selected from the group consisting of hydrogen, halogen, hydroxy, amino, nitro, cyano, carbonyl, oxo, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 halogen Alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl; when the substituent R b When n is the number, the R b The same or different; where R b Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl and C 2-6 alkynyl, each independently optionally substituted by 1, 2, 3 or 4 R d1 Replace, when R d1 When there are multiple R d1 Same or Different; R d1 are independently H, F, Cl, Br or I; R t3 R4, R5 and R8 are independently H, halogen, NH2, CN, OH, C 1-3 Alkyl, C 1-3 Alkoxy or C 3-6 Cycloalkyl, wherein C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 The cycloalkyl radicals are each independently optionally substituted with 1, 2, 3 or 4 R b Replace, when R b When there are multiple R b Same or different; Each R6 is independently H, halogen, NH2, CN, =O, OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2, 3 or 4 R b Replace, when R b When there are multiple R b Same or different; n is 0, 1, 2, 3 or 4; Or, ring D is in, is a single bond or a double bond; T3 is N or CR t3 ; T4 is N or CR4; T5 is N or CR5; T6 and T7 are independently N or C; T8 is N or CR8; Ring C is C 6-10 Aryl, C 4-6 Cycloalkenyl, 5-6 membered heteroaryl or 4-9 membered heterocycloalkenyl; R t3 R4, R5 and R8 are independently H, halogen, NH2, OH, C 1-3 Alkyl, C 1-3 Alkoxy or C 3-6 Cycloalkyl, wherein C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 The cycloalkyl radicals are each independently optionally substituted with 1, 2, 3 or 4 R b Replace, when R b When there are multiple R b Same or different; R6 are independently H, halogen, NH2, CN, =O, OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2, 3 or 4 R b Replace, when R b When there are multiple R b Same or different; n is 0, 1, 2, 3 or 4.

10. The compound of formula I according to any one of claims 1 to 9, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: R b are independently H, F, Cl, Br or I; Preferably, each R6 is independently H, F, Cl, Br, I, NH2, CN, =O, C 1-3 Alkyl or C 1-3 Alkoxy, wherein the C 1-3 Alkyl and C 1-3 The alkoxy group is optionally substituted with 1, 2, 3 or 4 R b Replace, when R b When there are multiple R b Same or different; Preferably, each R6 is independently H, F, Cl, Br, I, NH2, CN, =O, CH3, -CH2CH3 or -O-CH3, wherein said CH3, -CH2CH3 and -O-CH3 are independently optionally replaced by 1, 2, 3 or 4 R b Replace, when R b When there are multiple R b Same or different; Preferably, each R6 is independently H, F, Cl, Br, CN, =O, CH3, CF3, -CH2-CF3 or -O-CH3; Preferably, R t3 R4, R5 and R8 are independently H, F, Cl, Br, I, NH2, CN, or optionally substituted by 1, 2, 3 or 4 R b Substituted CH3; Preferably, R t3 , R4, R5 and R8 are independently H, CH3 or CF3; Preferably, ring C is phenyl or a 5-membered nitrogen-containing heteroaryl group; Preferably, ring C is phenyl, 5-6 membered nitrogen-containing heteroaryl or 5-6 membered heterocycloalkenyl; Preferably, ring C is phenyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, thienyl, pyrrolyl or pyrrolidinyl, pyridazine, pyrimidine, dihydropyrrole, dihydroimidazole; Preferably, ring D is Preferably, ring D is Preferably, ring D is R t3 H, halogen, NH2, OH, C 1-3 Alkyl, C 1-3 Alkoxy or C 3-6 Cycloalkyl, wherein C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 The cycloalkyl radicals are each independently optionally substituted with 1, 2, 3 or 4 R b Replace, when R b When there are multiple R b Same or different; Preferably, ring D is Preferably, the structural unit for Preferably, the structural unit for Preferably, ring D is 11. The compound of formula I according to any one of claims 1 to 10, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: The compound of formula I has the structural formula Ic: Among them, ring A, ring D, X 1 , X 5 , R 1 , R 2 , R 3 , R a , R k s as defined in any one of claims 1 to 11; Preferably, the compound of formula (Ic) has the structural formula (Ic-1), (Ic-2), (Ic-3) or (Ic-4): Among them, ring D, X 1 , R 1 , R 2 , R 3 , R a , R k , s as defined in any one of claims 1-10.

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

13. The compound of formula (I) as claimed in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: The compound represented by formula I includes: Optionally, the pharmaceutically acceptable salt is trifluoroacetate.

14. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises: a compound of formula I as described in any one of claims 1 to 13, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof; and a pharmaceutically acceptable carrier.

15. A use of the compound of formula I as claimed in any one of claims 1 to 13, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the use of the pharmaceutical composition according to claim 11, 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; Preferably, the MRGPRX2-related diseases include: mast cell-related diseases; Preferably, the MRGPRX2-related diseases include: skin diseases, autoimmune diseases, and nervous system diseases; Preferably, the skin disease is selected from atopic dermatitis, contact dermatitis, urticaria, and pruritus; Preferably, the urticaria is selected from chronic spontaneous urticaria and induced urticaria; Preferably, the autoimmune disease is selected from allergy, mastocytosis, rheumatoid arthritis, asthma, ulcerative colitis and interstitial cystitis; Preferably, the neurological disease is selected from pain.

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