Compound serving as MRGPRX2 antagonist as well as preparation method and application thereof

Abstract

The invention provides a compound as shown in a formula I, and a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof. The compound disclosed by the invention has a relatively good MRGPRX2 antagonism effect. # imgabs0 #

Description

[0001] This application requires:

[0002] The priority of the earlier application with patent number 202311089453.1 filed with the State Intellectual Property Office of China on August 25, 2023;

[0003] The priority of the earlier application with patent number 202311282832.2 filed with the State Intellectual Property Office of China on September 28, 2023;

[0004] Priority of the prior application with patent number 202410169529.X filed with the State Intellectual Property Office of China on February 5, 2024;

[0005] Priority of the prior application with patent number 202410166360.2 filed with the State Intellectual Property Office of China on February 5, 2024;

[0006] The entirety of said prior application is incorporated into the present application by reference. Technical Field

[0007] The present invention belongs to the field of medicine, and specifically relates to a compound as a 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 in a variety of connective tissues and vascularized organs. Their numbers are largest and their density is highest at the interface between the internal and external environments. They respond to foreign organisms and antigens and play a sentinel role. These sites include the dermis, skeletal muscle, oral mucosa, gastrointestinal mucosa and submucosa, conjunctiva, alveoli and airways, and auricles. MCs in the dermis are often very close to blood vessels, nerves, and lymphatic vessels. After activation by human high-affinity immunoglobulin E (IgE) receptor (FcεRI) and Mas-related G protein-coupled receptor X2 (MRGPRX2), MCs degranulate, release a variety of bioactive substances (such as histamine and proteases) or synthesize new prostaglandins, leukotrienes, and some cytokines from scratch, and play a central role in host defense, inflammation, and allergic reactions.

[0009] Mas-related G protein-coupled receptors (MRGPRs) are divided into nine subfamilies according to the different receptor members: MRGPRA, B, C, D, E, F, G, H and MRGPRX, which is unique to primates. 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 mainly expressed in skin MCs, and its expression rate is even higher than Fcε-RI. MRGPRX2 can sense a variety of endogenous or exogenous agonists including polycationic compounds and peptides to trigger mast cell degranulation reactions.

[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. At present, the IND application of MRGPRX2 antagonist EP262 has been approved by 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 various MRGPRX2 agonists, and block the release of trypsin and inflammatory factors in human mast cells. Oral administration of EP262 can effectively inhibit mast cell degranulation and increased vascular permeability in MRGPRX2-KI mice induced by agonists, showing significant potential for the treatment of mast cell-related diseases. All these indicate that the development of new MRGPRX2 antagonists for the treatment of various mast cell-related diseases is a potential 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. Summary of the invention

[0012] The object of the present invention is to provide novel compounds useful as MRGPRX2 antagonists.

[0013] In the first aspect of the present invention, there is provided a compound of formula I, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof:

[0014]

[0015] in,

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

[0017] X 1 , X 2 , X3 , 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 (e.g., 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, an 8-12-membered cycloheterocycloalkenyl or a 5-10-membered heteroaryl;

[0024] 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 3-8Halogenated 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 (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 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 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 Haloalkyl, C 3-8 Halogenated cycloalkyl, C 1-6Alkyl 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 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;

[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 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;

[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- 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;

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

[0038] In some embodiments, X 3 By 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, 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.

[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 The cycloalkyl radicals are each independently optionally substituted with 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 The cycloalkyl radicals are each independently optionally substituted with 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, where C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl and C 2-6The 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.

[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, s are 0, 1, 2 or 3, respectively.

[0047] In the present invention, the definitions of certain substituents in the compound as shown in Formula I can be as described below, 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 as 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 as shown in formula I is selected from the following structures:

[0052]

[0053] Among them, ring A, ring D, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , R 1 , R2 , R 3 , R a , R k , m and s are as defined above.

[0054] In some embodiments, Ring D is a 5-10 membered heteroaryl; 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;.

[0055] In a preferred embodiment of the present invention, the compound as shown in formula I is selected from the following structures:

[0056] 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 above;

[0057] C is a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, or a 3- to 10-membered heterocycloalkyl group;

[0058] In some embodiments, ring D is a 5-10 membered heteroaryl;

[0059] Further, in a preferred embodiment of the present invention, the compound as shown in Formula I has a structure as shown in Formula II-1, 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, a 5- to 8-membered heteroaryl or a 5- to 8-membered heterocycloalkyl; the ring D is a 5- to 8-membered heteroaryl; 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 1-6Haloalkoxy; 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; X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , m is as defined above; n is 0, 1, 2 or 3.

[0060] 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.

[0061] In a preferred embodiment of the present invention, the R 1 , R 2 , R 3 Each independently represents H, methyl, -CH2CF3, -CF3,

[0062] 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.

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

[0064] In a preferred embodiment of the present invention, C is pyrazolyl, pyridinyl or pyrimidinyl.

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

[0066] In a preferred embodiment of the present invention, C is

[0067] In a preferred embodiment of the present invention, ring D is a 5- to 10-membered heteroaryl group.

[0068] 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 atom or oxygen atom is 1, 2 or 3.

[0069] In a preferred embodiment of the present invention, ring D is pyridyl, oxadiazole, isoxazole or pyrazinyl.

[0070] In a preferred embodiment of the present invention, ring D is

[0071] In a preferred embodiment of the present invention, the compound as shown in formula I is selected from the following structures:

[0072]

[0073] 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.

[0074] In some embodiments, in Formula Ia,

[0075] is a single bond or a double bond;

[0076] X 1 is N or C; when X 1 When it is C, the C atom is R a replace;

[0077] 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;

[0078] Ring A is phenyl or 5-6 membered heteroaryl (i.e. when A exists);

[0079] 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 3-6Cycloalkyl 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;

[0080] 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 The cycloalkyl radicals are each independently optionally substituted with 1, 2, 3 or 4 R d Replace, when R d When there are multiple R d Same or different;

[0081] Ring B is C 3-12 Cycloalkyl;

[0082] Ring D is an 8-12-membered cycloheteroaryl group or an 8-12-membered cycloheterocycloalkenyl group;

[0083] 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;

[0084] Each R d1 are independently H, F, Cl, Br or I;

[0085] 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 3-6Cycloalkyl 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;

[0086] R 2 and R 3 Each independently is H or C 1-3 Alkyl; wherein R 2 and R 3 Same or different;

[0087] s is 0, 1, 2, 3, 4, 5, 6.

[0088] In a preferred embodiment of the present invention, the compound represented by formula I has a structure of formula Ib:

[0089]

[0090] 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.

[0091] X7 is N or CR a ;

[0092] 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;

[0093] R4, R5, and R6 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 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;

[0094] n' is 0, 1, 2, 3 or 4.

[0095] In some embodiments, in Formula Ib,

[0096] is a single bond or a double bond;

[0097] X 1 is N or C; when X 1 When it is C, the C atom is R a replace;

[0098] 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;

[0099] X7 is N or CR a ;

[0100] Ring A is phenyl or 5-6 membered heteroaryl (i.e. when A exists);

[0101] 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;

[0102] 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 The cycloalkyl radicals are each independently optionally substituted with 1, 2, 3 or 4 R d Replace, when R dWhen there are multiple R d Same or different;

[0103] Ring B is C 3-12 Cycloalkyl;

[0104] Ring C is a 5-6 membered heteroaryl or a 5-6 membered heterocycloalkenyl;

[0105] 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 For multiple times,

[0106] Each R d1 Same or different;

[0107] R 2 and R 3 Each independently is H or C 1-3 Alkyl; wherein R 2 and R 3 Same or different.

[0108] 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;

[0109] 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 Rb When there are multiple R b Same or different;

[0110] 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;

[0111] Each R d1 are independently H, F, Cl, Br or I;

[0112] n' is 0, 1, 2, 3 or 4.

[0113] In an optional embodiment of the present invention, each R d are H, F, Cl, Br and I, respectively and independently.

[0114] 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.

[0115] 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.

[0116] In an optional embodiment of the present invention, each R c Each is independently F, Cl, Br, I, CH3, CH2F, CHF2 or CF3.

[0117] In an optional embodiment of the present invention, R 1 and R aare independently H or optionally substituted by 1, 2, 3 or 4 R d Replaced CH3.

[0118] 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.

[0119] In an optional embodiment of the present invention, R a and R 1 Each is independently H, CH3 or CF3.

[0120] In an optional embodiment of the present invention, R a , R 1 , R4 and R5 are independently H, CH3 or CF3.

[0121] In an optional embodiment of the present invention, R 2 and R 3 are independently H or CH3.

[0122] In an optional embodiment of the present invention, ring B is C 3-6 Monocyclic cycloalkyl, C 6-10 Spirocycloalkyl, C 6-10 Cycloalkyl or C 4-10 Bridged ring cycloalkyl.

[0123] In an optional embodiment of the present invention, ring B is C 3-6 Monocyclic cycloalkyl, C 6-8 Spirocycloalkyl, C 6-9 Cycloalkyl or C 5-9 Bridged ring cycloalkyl.

[0124] In an optional embodiment of the present invention, Ring B is

[0125] In an optional embodiment of the present invention, ring A is phenyl, imidazolyl, pyrazolyl or pyrrolyl.

[0126] In an optional embodiment of the present invention, the structural unit for

[0127] In an optional embodiment of the present invention, the structural unit for

[0128] In an optional embodiment of the present invention, ring D is

[0129] is a single bond or a double bond;

[0130] T3 is N or CR t3 ;

[0131] T4 is N or CR4;

[0132] T5 is N or CR5;

[0133] T6 and T7 are independently N or C; when T6 and T7 are independently C, the connected is a double bond;

[0134] T8 is N or CR8;

[0135] 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 5-6 membered nitrogen-containing heteroaryl.

[0136] 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 bA 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;

[0137] 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;

[0138] 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;

[0139] n is 0, 1, 2, 3 or 4.

[0140] In an optional embodiment of the present invention, ring D is

[0141] is a single bond or a double bond;

[0142] T3 is NR t3 , CR t3 , C(R t3 )2;

[0143] T4 is NR4, CR4, C(R4)2;

[0144] T5 is NR5, CR5, C(R5)2;

[0145] T6 and T7 are independently N or C; when T6 and T7 are independently C, the bond is a double bond;

[0146] T8 is NR8, CR8, C(R8)2;

[0147] 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 5-6 membered nitrogen-containing heteroaryl.

[0148] 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 1-6Alkyl 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 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;

[0149] 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;

[0150] 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, C1-6 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;

[0151] n is 0, 1, 2, 3 or 4.

[0152] In an optional embodiment of the present invention, ring D is

[0153] is a single bond or a double bond;

[0154] T3 is N or CR t3 ;

[0155] T4 is N or CR4;

[0156] T5 is N or CR5;

[0157] T6 and T7 are independently N or C;

[0158] T8 is N or CR8;

[0159] Ring C is C 6-10 Aryl, C 4-6 Cycloalkenyl, 5-6 membered heteroaryl or 4-9 membered heterocycloalkenyl;

[0160] 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;

[0161] 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 3-6Cycloalkyl 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;

[0162] n is 0, 1, 2, 3 or 4.

[0163] In an optional embodiment of the present invention, R b are independently H, F, Cl, Br or I.

[0164] 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.

[0165] 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.

[0166] 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.

[0167] 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.

[0168] 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 bReplace, when R b When there are multiple R b Same or different.

[0169] 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.

[0170] In an optional embodiment of the present invention, R6 is H, F, Cl, Br, I, CH3 or -CH2CH3, wherein said CH3 and -CH2CH3 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.

[0171] In an optional embodiment of the present invention, R6 is H, =O, CH3, CF3 or -O-CH3.

[0172] In an optional embodiment of the present invention, R6 is H or CH3.

[0173] 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.

[0174] 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 substituted by 1, 2, 3 or 4 R b Substituted CH3;

[0175] In an optional embodiment of the present invention, R t3 , R4, R5 and R8 are independently H, CH3 or CF3.

[0176] In an optional embodiment of the present invention, ring C is phenyl or a 5-membered nitrogen-containing heteroaryl.

[0177] In an optional embodiment of the present invention, ring C is phenyl, 5-6 membered nitrogen-containing heteroaryl or 5-6 membered heterocycloalkenyl.

[0178] 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.

[0179] In an optional embodiment of the present invention, Ring C is phenyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, thienyl, pyrrolyl or pyrrolidinyl.

[0180] In an optional embodiment of the present invention, Ring C is imidazolyl, pyrazolyl, thiazolyl, thienyl or pyrrolyl.

[0181] In an optional embodiment of the present invention, ring D is

[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 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 The same or different; the R b As defined above.

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

[0186]

[0187] In an optional embodiment of the present invention, ring D is

[0188]

[0189] In an optional embodiment of the present invention, ring D is

[0190]

[0191] 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

[0192]

[0193] In an optional embodiment of the present invention, ring D is

[0194] In an optional embodiment of the present invention, the compound of formula I has the structural formula Ic:

[0195]

[0196] 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.

[0197] 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):

[0198]

[0199] Among them, ring D, X 1 , R 1 , R 2 , R 3 , R a , R k , s are as defined above.

[0200] In a preferred embodiment of the present invention, the compound as shown in formula I is selected from any of the following compounds:

[0201]

[0202]

[0203] In a preferred embodiment of the present invention, the compound as shown in formula I is selected from any of the following compounds:

[0204]

[0205]

[0206]

[0207] In a preferred embodiment of the present invention, the pharmaceutically acceptable salt of the compound as shown in formula I is trifluoroacetate. In a preferred embodiment of the present invention, the compound as shown in formula I is selected from any of the following compounds:

[0208]

[0209]

[0210] In a preferred embodiment of the present invention, the compound as shown in formula I is selected from any of the following compounds:

[0211]

[0212]

[0213]

[0214]

[0215] In a preferred embodiment of the present invention, the pharmaceutically acceptable salt of the compound of Formula I is trifluoroacetate or formate.

[0216] The second aspect of the present invention provides a pharmaceutical composition, which includes: a compound as shown in 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 tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug; in some embodiments, the pharmaceutical composition further includes a pharmaceutically acceptable carrier.

[0217] 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.

[0218] Preferably, the MRGPRX2-related diseases include: mast cell-related diseases.

[0219] Preferably, the MRGPRX2-related diseases include: skin diseases, autoimmune diseases, and nervous system diseases.

[0220] Preferably, the skin disease is selected from atopic dermatitis, contact dermatitis, urticaria, and pruritus.

[0221] Preferably, the urticaria is selected from chronic spontaneous urticaria and induced urticaria.

[0222] Preferably, the autoimmune disease is selected from the group consisting of allergy, mastocytosis, rheumatoid arthritis, asthma, ulcerative colitis and interstitial cystitis.

[0223] Preferably, the neurological disease is selected from pain.

[0224] In the fourth aspect of the present invention, a method for antagonizing MRGPRX2, or preventing and / or treating a disease associated with MRGPRX2 is provided, comprising the steps of administering the compound of formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug as described in the first aspect of the present invention to a subject in need thereof. The disease associated with MRGPRX2 is as described above.

[0225] Additional aspects and advantages of the present invention will be given in part in the following description and in part will be obvious from the following description, or will be learned through practice of the present invention.

[0226] Terms and Definitions

[0227] Unless otherwise specified, the terms and definitions used in the present application, including the description and claims of this application, 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 at which a moiety or substituent is attached to a core or backbone structure.

[0228] Unless otherwise specified, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, 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.

[0229] Unless otherwise specified, the term "pharmaceutically acceptable salt" refers to salts of pharmaceutically acceptable non-toxic acids or bases including salts of inorganic acids and bases, and organic acids and bases.

[0230] 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 the administration of a compound to an organism.

[0231] Unless otherwise specified, the term "prodrug" refers to a compound of the present invention that can be converted into a biologically active compound under physiological conditions or by solvolysis. The prodrug of the present invention is prepared by modifying the functional groups in the compound, and the modification can be removed by conventional operations or in vivo to obtain the parent compound. The prodrug includes a compound formed by connecting a hydroxyl or amino group in the compound of the present invention to any group. When the prodrug of the compound of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free hydroxyl group and a free amino group, respectively.

[0232] Unless otherwise specified, the term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, and includes cis-trans isomers, enantiomers, diastereomers and conformational isomers.

[0233] 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 a pure optical isomer, or as a mixture of isomers, such as a racemic and diastereomeric mixture, depending on the number of asymmetric carbon atoms. When describing optically active compounds, prefixes D and L or R and S are used to represent 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 symbols for the rotation of plane polarized light caused by the specified compound, where (–) or L indicates that the compound is left-handed. Compounds prefixed with (+) or D are right-handed. For 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 generally referred to as mixtures of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. Many geometric isomers of olefins, C=N double bonds, etc. may also exist in the compounds described herein, and all such stable isomers are contemplated in 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 the cis- or trans- configuration.

[0234] When the bonds to the chiral carbon in the formula of the present invention are depicted as straight lines, it should be understood that both the (R) and (S) configurations of the chiral carbon and the enantiomerically pure compounds and mixtures thereof produced therefrom are included within the scope of the general formula. The graphic representation of racemates or enantiomerically pure compounds herein is from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, the absolute configuration of a stereocenter is indicated by a wedge-shaped bond and a dashed bond.

[0235] 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. Exemplary methods include fractional recrystallization using a chiral resolution 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 diastereomeric 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, the selection of chromatographic columns can be selected by those skilled in the art according to the structure of the compound and the test results. Further, optically pure starting materials or reagents of known configurations can also be used to obtain any enantiomer or diastereomer of the compounds described in the present invention through stereo organic synthesis.

[0236] Unless otherwise specified, the term "tautomer" refers to a functional group isomer resulting from the rapid movement of an atom in a molecule between two positions. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds may exist in 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 separate 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 characteristics within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form is predominant; while in phenols, the enol form is predominant. The present invention includes all tautomeric forms of the compounds.

[0237] Unless otherwise specified, the key is a solid wedge. 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.

[0238] Unless otherwise indicated, the term "solvate" means that the compound of the present invention or a salt thereof includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent forces between molecules, and when the solvent is water, it is a hydrate.

[0239] With respect to a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect. For oral dosage forms of the present invention, an "effective amount" of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance. The appropriate effective amount in each case can be determined by a person skilled in the art based on routine experiments.

[0240] 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.

[0241] 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., =O), 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 2, such as 2, 3, 4, 5, etc.

[0242] In the present application, "optional" or "optionally" means that the event or situation described later may or may not occur, and the description includes both the occurrence and non-occurrence of the event or situation. For example, "optionally substituted aryl" means that aryl is substituted or unsubstituted, and the description includes both substituted aryl and unsubstituted aryl.

[0243] In the present application, those skilled in the art can understand from the context that in Formula Ib, the variable name "Ring C" is different from the variable name "C" in Formula I-1, and both of them obviously have their own independent definitions and values.

[0244] Unless otherwise specified, the term “C 1-6"Alkyl" is used to refer to 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.; it 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.

[0245] Unless otherwise specified, the term “C 1-3 "Alkyl" is used to refer to 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 may 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.

[0246] Unless otherwise specified, the term “C 0-6 "Alkyl" includes C0 alkyl (i.e., a bond) and C 1-6 alkyl.

[0247] The term "halo" by itself or as part of another substituent is used interchangeably with the term "halogen-substituted."

[0248] Unless otherwise specified, "haloalkyl" or "halogen-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.

[0249] Unless otherwise specified, “C 2-6 "Alkenyl" is used to refer to a straight 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 includes 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.

[0250] Unless otherwise specified, “C 2-6 "Alkynyl" is used to refer to a straight 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.

[0251] Unless otherwise specified, the term “C 1-6 "Alkoxy" refers to those alkyl groups containing 1 to 6 carbon atoms which are attached to the rest of the molecule via an oxygen atom. 1-6 Alkoxy includes 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.

[0252] 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. 1-3 Alkoxy includes 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.

[0253] Unless otherwise specified, the term “C 1-6 "Alkylamino" refers to those alkyl groups containing 1 to 6 carbon atoms which are attached to the rest of the molecule through 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. 1-6Examples 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.

[0254] 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 spiro, fused and bridged rings. The cycloalkyl 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.; it 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.

[0255] 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 system. 3-6 Cycloalkyl includes C 3-5 , C 4-5 and C 5-6 Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 3-6 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0256] 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 , C3-12 , C 6-9 , C 6-12 , and C 9-12 Etc.; similarly, n-membered to n+m-membered means that the number of atoms in the ring is n to n+m, for example, 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, and 12-membered ring, and also includes any range from n to n+m, for example, 3-12-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring, 5-7-membered ring, 6-7-membered ring, 6-8-membered ring, and 6-10-membered ring, etc.

[0257] 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, wherein at least one ring is an aromatic ring. When one of the rings is a non-aromatic ring, the group may be connected through an aromatic ring or a non-aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, 2,3-dihydroindanyl, 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, wherein at least one ring is an aromatic ring.

[0258] 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, respectively. 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 may be 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 may occupy the position where 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.

[0259] 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, 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 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, paracyclic and bridged rings, such as 8-12-membered paracyclic heterocycloalkenyl. For example, in the case of "5-6-membered heterocycloalkenyl", heteroatoms can occupy the position where 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.

[0260] 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. The cycloalkenyl group may include 4-12 (4, 5, 6, 7, 8, 9, 10, 11, 12) ring atoms, such as 4-9, 4-8, 5-6 yuan cycloalkenyl. The cycloalkenyl group includes monocyclic and bicyclic systems, wherein the bicyclic system includes spirocyclic, cyclic and bridged rings.

[0261] 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 an aromatic ring or through a 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 yuan (e.g., 5, 6, 7, 8, 9, 10 yuan), more preferably 5-6 yuan. 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 may be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2). The 5-6 membered heteroaryl may be connected to the rest of the molecule via 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, etc.), thiazole The term "heteroaromatic ring" may be used interchangeably with the term "heteroaromatic ring", "heteroaryl" or "heteroaromatic ring group".

[0262] Unless otherwise specified, the term "oxo" means that two hydrogen atoms on a methylene group are replaced by oxygen atoms, that is, a methylene group is replaced by a carbonyl group, representing =0.

[0263] Unless otherwise specified, the term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0264] In addition, it should be noted that, unless otherwise clearly indicated, the description method "...independently" used in the present invention should be understood in a broad sense, meaning that the individuals described are independent of each other and can be independently the same or different specific groups. In more detail, the description method "...independently" can mean that in different groups, the specific options expressed by the same symbols do not affect each other, and can also mean that in the same group, the specific options expressed by the same symbols do not affect each other.

[0265] In this application, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, 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.

[0266] The term "treat" refers to therapeutic treatment. When referring to a specific condition, treatment means: (1) ameliorating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade leading to or causing 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.

[0267] The term "prevent" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0268] The term "patient" refers to any animal, preferably a mammal, that is about to or has been administered the 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.

[0269] The term "therapeutically effective amount" refers to an amount of a compound that is effective in treating a disease or condition described herein when administered to a patient."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.

[0270] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0271] Beneficial Effects

[0272] After extensive and in-depth research, the inventors unexpectedly developed a compound or a pharmaceutically acceptable salt thereof, a preparation method and use. The present invention provides a compound shown in formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, wherein the compound of formula I has a significant inhibitory effect on MRGPRX2, can be used as an antagonist of MRGPRX2, and has high safety and drug properties (such as excellent pharmacokinetic properties, etc.). DETAILED DESCRIPTION

[0273] The present invention is 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. On the basis of a full understanding of the present invention, the experimental methods in the following examples that do not specify specific conditions are usually 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 solution of the present invention, and such changes should be deemed to be included in the scope of protection of the present invention.

[0274] This application has the following definitions:

[0275] Symbol or unit:

[0276] IC 50 : Half inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved

[0277] 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

[0278] N: equivalent concentration, for example, 2N hydrochloric acid means 2 mol / L hydrochloric acid solution

[0279] Reagents:

[0280] PPA: Polyphosphoric acid NMP: N-methylpyrrolidone

[0281] DMF: N,N-dimethylformamide

[0282] DCE: 1,2-dichloroethane

[0283] Preparation of Intermediate-1 (int-1)

[0284]

[0285] Under room temperature, 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) and stirred at 130°C for 12 h. After the reaction of the raw materials was complete as monitored by thin layer chromatography, stirring was stopped, the reaction solution was cooled to room temperature, and then water (200 mL) was added to dilute it, extracted with ethyl acetate (100 mL×5), the organic phase was collected and dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain the residue, which was separated and purified by silica gel column chromatography (DCM: MeOH (V / V) = 100:5) to obtain compound 5-chloro-2-(trifluoromethyl)imidazo[1,2-a]pyridine (int-1) (6.2 g, yield 72%).

[0286] LC-MS, M / Z (ESI): 221.99 [M+H] +

[0287] Preparation of Intermediate-2 (int-2)

[0288]

[0289] 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 monitoring by thin layer chromatography showed that the raw materials had reacted, stirring was stopped, the reaction solution was cooled to room temperature, and then water (200 mL) was added to dilute it, and it was extracted with ethyl acetate (100 mL×5). The organic phase was collected and dried over anhydrous sodium sulfate, and the organic phase was concentrated by distillation under reduced pressure. The residue was separated and purified by silica gel column chromatography (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%).

[0290] LC-MS, M / Z (ESI): 263.90 [M+H] +

[0291] Preparation of Intermediate-3 (int-3)

[0292]

[0293] Step 1: Synthesis of 6-chloro-2-(trifluoromethyl)quinolin-4-ol (C-3).

[0294]

[0295] At room temperature, p-chloroaniline (C-1) (5 g, 39.37 mmol) was added to PPA (200 mmol, 75 ml, 5.0 eq), and then ethyl trifluoroacetoacetate (C-2) (7.2 g, 39.37 mmol) was added, and the reaction solution was heated to 140°C for 12 hours. After the reaction was completed, the reaction solution was poured into ice water and extracted with ethyl acetate (4*50 mL). The obtained organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude compound 6-chloro-2-(trifluoromethyl)quinoline-4-ol (C-3) (8.5 g, yield 87.6%), which was directly used for the next step reaction.

[0296] LC-MS, M / Z(ESI):248.0[M+H] +

[0297] Step 2: Synthesis of 4,6-dichloro-2-(trifluoromethyl)quinoline (C-4).

[0298]

[0299] 6-Chloro-2-(trifluoromethyl)quinoline-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 was then heated to 80°C for 12 hours. After the reaction was completed, the crude product was dried and purified by silica gel column (PE: EA (V / V) = 100:2) to obtain compound 4,6-dichloro-2-(trifluoromethyl)quinoline (C-4) (8.3 g, yield 91.6%).

[0300] LC-MS, M / Z(ESI):265.9[M+H] +

[0301] Step 3: Synthesis of tert-butyl ((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)-amino)cyclohexane)carbamate (C-6).

[0302]

[0303] 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), and N,N-diisopropylethylamine (1.9 g, 15 mmol) was added, and the reaction solution was heated to 130°C for 12 hours. After the reaction was completed, the reaction solution was poured into ice water and extracted with ethyl acetate (4*50 mL), and the obtained organic phase was dried over anhydrous sodium sulfate, filtered and dried, and the obtained crude product was purified by silica gel column (PE: EA (V / V) = 2:1) to obtain tert-butyl ((1R, 3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)-amino)cyclohexane)carbamate (C-6) (1.9 g, yield 96.3%).

[0304] LC-MS, M / Z(ESI):444.1[M+H] +

[0305] Step 4: (1S, 3R)-N 1 Synthesis of -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine (int-3)

[0306]

[0307] 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 then 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 adjust it to alkalinity, and it 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, yield 91.3%).

[0308] LC / MS(ESI)(m / z):344[M+H] +

[0309] Preparation of intermediate-4 (int-4)

[0310]

[0311] Step 1: Synthesis of cis-tert-butyl 4-(2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)amino)cyclohexyl)carbamate (D-2)

[0312]

[0313] 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 g, 7.55 mmol) were added. 0 mg, 0.37 mmol), stirred in an oil bath at 100 ° C for 12 h under nitrogen protection. After monitoring by thin layer chromatography 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, extracted with ethyl acetate (30 mL×5), the organic phase was collected and dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure. 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 was 12.64%).

[0314] LC-MS, M / Z(ESI):398.80[M+H] +

[0315] Step 2: cis-N 1 Synthesis of (2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)cyclohexane-1,4-diamine (int-4)

[0316]

[0317] At room temperature, cis-tert-butyl 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), stirred for 10 min, and then HCl / Dioxane (4M) (0.48 ml, 1.91 mmol) was slowly added dropwise. Stirring was continued for 30 min at room temperature. After the reaction was completed by thin layer chromatography, saturated sodium bicarbonate aqueous solution was added to the reaction solution to adjust it to alkalinity, and 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,4S)-N 1 -(2-(Trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)cyclohexane-1,4-diamine (int-4) (150.26 mg, yield 94.12%).

[0318] LC-MS, M / Z(ESI):298.70[M+H] +

[0319] Example 1: Preparation of target compound 1

[0320] 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)

[0321]

[0322] The synthetic route of target compound 1 is as follows:

[0323]

[0324] Step 1: Synthesis of 4-chloro-2-methyl-2H-pyrazolo[4,3-c]pyridine (1-B)

[0325]

[0326] At room temperature, 4-chloro-1H-pyrazolo[4,3-c]pyridine (5 g, 32.56 mmol) was dissolved in anhydrous dimethyl sulfoxide (50 mL), stirred in an ice bath under nitrogen protection for 10 min, and then NaHMDS (24.42 mL, 2 M tetrahydrofuran solution) was slowly added dropwise. After the addition was completed, 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 completed, the reaction solution was slowly warmed to room temperature and stirred for 2 h. After monitoring by thin layer chromatography 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 (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%).

[0327] LC-MS, M / Z (ESI): 167.90 [M+H] +

[0328] 4-Chloro-2-methyl-2H-pyrazolo[4,3-c]pyridine (1-B): 1 H 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).

[0329] 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).

[0330] Step 2: Synthesis of tert-butyl (cis-4-((2-methyl-2H-pyrazolo[4,3-c]pyridin-4-yl)amino)cyclohexyl)carbamate (1-C)

[0331]

[0332] At room temperature, 4-chloro-2-methyl-2H-pyrazolo[4,3-c]pyridine (1-B) (560 mg, 3.34 mmol), 1N-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 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 (30 mL), extracted with ethyl acetate (20 mL×5), 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-tert-butyl 4-((2-methyl-2H-pyrazolo[4,3-c]pyridin-4-yl)amino)cyclohexyl)carbamate (1-C) (240 mg, yield 20.79%).

[0333] LC-MS, M / Z (ESI): 346.10 [M+H] +

[0334] Step 3: cis-N 1 Synthesis of -(2-methyl-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclohexane-1,4-diamine hydrochloride (1-D)

[0335]

[0336] 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 completed, stirring was continued at room temperature for 30 min. After the reaction of the raw material was completed as monitored by thin layer chromatography, stirring was stopped, the solvent was concentrated under reduced pressure to remove, ethyl acetate (5 mL) was added, and the mixture was stirred for 1 h at room temperature, 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).

[0337] LC-MS, M / Z(ESI):245.98[M+H] +

[0338] 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)

[0339]

[0340] 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'-bis(diphenylphosphine) (75 mg, 0.12 mmol) were dissolved in anhydrous 1,4-dioxane (2 mL), stirred at 100 ° C for 4 h under nitrogen protection, and after the reaction of the raw materials was completed by thin layer chromatography, stirring was stopped, the reaction solution was cooled to room temperature, and then water (10 mL) was added to dilute, 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, and the obtained 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).

[0341] LC-MS, M / Z(ESI):429.85[M+H] +

[0342] 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).

[0343] Example 2: Preparation of target compound 2

[0344] 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)

[0345]

[0346] The synthetic route of target compound 2 is as follows:

[0347]

[0348] Step 1: Synthesis of tert-butyl (cis-4-((1-methyl-1H-pyrazolo[4,3-c]pyridin-4-yl)amino)cyclohexyl)carbamate (2-C)

[0349]

[0350] 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, the stirring was stopped and the temperature was lowered. To room temperature, water (50 mL) was added to dilute, and the mixture was extracted with ethyl acetate (30 mL×5). The organic phase was collected and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 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 was 14.26%).

[0351] LC-MS, M / Z(ESI):346.06[M+H] +

[0352] Step 2: cis-N 1 -(1-Methyl-1H-pyrazolo[4,3-c]pyridin-4-yl)cyclohexane-1,4-diamine hydrochloride (2-D)

[0353]

[0354] 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 material was completed 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 for 1 h at room temperature. 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%).

[0355] LC-MS, M / Z(ESI):245.98[M+H] +

[0356] Step 3: cis-N 1 -(1-methyl-1H-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 2)

[0357]

[0358] 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'-bis(diphenylphosphine) (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, water (10 mL) was added to dilute, 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 150×30mm; 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)-N4 -(2-(Trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)cyclohexane-1,4-diamine (Compound 2).

[0359] LC-MS, M / Z(ESI):429.98[M+H] +

[0360] 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).

[0361] Example 3: Preparation of target compound 3

[0362] 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)

[0363]

[0364] The synthetic route of target compound 3 is as follows:

[0365]

[0366] Step 1: cis-N 1 Synthesis of -(2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)cyclohexane-1,4-diamine (3)

[0367]

[0368] 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-yl]dichloro(3-chloropyridine-KN)palladium (183 mg, 0.189 mmol) was added, and the reaction solution was heated to 100 ° C under nitrogen protection 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, yield 26%).

[0369] LC / MS(ESI)(m / z):299[M+H] +

[0370] 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)

[0371]

[0372] 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, and the temperature was raised to 60°C for 12 hours. After the reaction was completed, it was concentrated under reduced pressure, 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 -(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, yield 26%).

[0373] LC / MS(ESI)(m / z):431[M+H] + ;

[0374] 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).

[0375] Example 4: Preparation of target compound 4

[0376] 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)

[0377]

[0378] The synthetic route of target compound 4 is as follows:

[0379]

[0380] Step 1: Synthesis of 1-methyl-1H-pyrazolo[3,4-d]pyridazin-4-ol (2)

[0381]

[0382] At room temperature, 5-formyl-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (500 mg, 2.74 mmol) was dissolved in anhydrous ethanol (10 mL) and acetic acid (1 mL), and then 80% hydrazine hydrate (515 mg, 8.23 ​​mmol) was added, and then the reaction solution was heated to 100°C for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature and filtered, and washed with ethanol to obtain the compound 1-methyl-1H-pyrazolo[3,4-d]pyridazin-4-ol.

[0383] LC / MS(ESI)(m / z):151[M+H]+

[0384] Step 2: Synthesis of 4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyridazine (4-3)

[0385]

[0386] At room temperature, 1-methyl-1H-pyrazolo[3,4-d]pyridazine-4-ol (100 mg, 0.593 mmol) was dissolved in phosphorus oxychloride (1 mL), and then stirred at 80°C for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature and added dropwise to a diluted sodium bicarbonate solution under an ice bath. After extraction with ethyl acetate, the organic phase was dried and concentrated. The crude product was purified by silica gel column (PE: EA (V / V) = 1:1) to obtain the compound 4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyridazine.

[0387] LC / MS(ESI)(m / z):169[M+H] +

[0388] 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)

[0389]

[0390] 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, and the reaction solution was heated to 90 ° C under nitrogen protection for 12 hours. After the reaction was completed, the crude product was diluted and filtered with dichloromethane, dried and concentrated, and 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).

[0391] LC / MS(ESI)(m / z):431[M+H] + ;

[0392] 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).

[0393] Example 5: Preparation of target compound 5

[0394] (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)

[0395]

[0396] The synthetic route of target compound 5 is as follows:

[0397]

[0398] Step 1: Synthesis of tert-butyl ((1S,3R)-3-((1-methyl-1H-pyrazolo[4,3-c]pyridin-4-yl)amino)cyclohexyl)carbamate (5-3)

[0399]

[0400] 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), and then diisopropylethylamine (461 mg, 3.57 mmol) was added, and the temperature was raised to 150°C for 24 hours. After the reaction was completed, it was directly purified by silica gel column (PE:EA (V / V) = 1:1) to obtain compound ((1S,3R)-3-((1-methyl-1H-pyrazolo[4,3-c]pyridin-4-yl)amino)cyclohexyl)carbamate tert-butyl ester (5-3).

[0401] LC / MS(ESI)(m / z):346[M+H] +

[0402] Step 2: (1R,3S)-N 1 Synthesis of -(1-methyl-1H-pyrazolo[4,3-c]pyridin-4-yl)cyclohexane-1,3-diamine (5-4)

[0403]

[0404] 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 then 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 and dried. 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).

[0405] LC / MS(ESI)(m / z):246[M+H] +

[0406] Step 3: (1R, 3S)-N 1 -(1-methyl-1H-pyrazolo[4,3-c]pyridin-4-yl)-N 3 Synthesis of -(2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)cyclohexane-1,3-diamine (Compound 5)

[0407]

[0408] 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 and filtered, concentrated and dried, and the obtained 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).

[0409] LC / MS(ESI)(m / z):429.7[M+H] + ;

[0410] 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).

[0411] Example 6: Preparation of target compound 6

[0412] 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)

[0413]

[0414] The synthetic route of target compound 6 is as follows:

[0415]

[0416] 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)

[0417]

[0418] 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, and the reaction solution was heated to 90 degrees under nitrogen protection 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).

[0419] LC / MS (ESI) (m / z): 430.45 [M+H] + ;

[0420] 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).

[0421] Example 7: Preparation of target compound 7

[0422] (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)

[0423]

[0424] The synthetic route of target compound 7 is as follows:

[0425]

[0426] 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)

[0427]

[0428] 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-imidazole-2-ylidene]dichloro(3-chloropyridine-κN)-palladium (28.0 mg, 0.029 mmol) was added, and 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).

[0429] LC / MS(ESI)(m / z):475[M+H] + ;

[0430] 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).

[0431] Example 8: Preparation of target compound 8

[0432] cis-N1,N4-bis(2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)cyclohexane-1,4-diamine (Compound 8)

[0433]

[0434] The synthetic route of target compound 8 is as follows:

[0435]

[0436] 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)

[0437]

[0438] 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-imidazole-2-ylidene]dichloro(3-chloropyridine-κN)-palladium (9.19 mg, 0.009 mmol) was added, and 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 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).

[0439] LC / MS(ESI)(m / z):483[M+H] + ;

[0440] 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).

[0441] Example 9: Preparation of target compound 9

[0442] cis-N 1Synthesis of -(1-methylimidazo[4,5-c]pyridine)-N4-(2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]cyclohexyl-1,4-diamine (Compound 9)

[0443]

[0444] The synthetic route of target compound 9 is as follows:

[0445]

[0446] 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)

[0447]

[0448] 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), extracted with ethyl acetate (5 mL×3), and the organic phase was concentrated and dried. 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).

[0449] LC-MS, M / Z(ESI):429.76[M+H] +

[0450] 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).

[0451] Example 10: Preparation of target compound 10

[0452] 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)

[0453]

[0454] The synthetic route of target compound 10 is as follows:

[0455]

[0456] Step 1: Synthesis of tert-butyl (cis-4-((6-methoxyisoquinolin-1-yl)amino)cyclohexyl)carbamate (10-2)

[0457]

[0458] 1-Chloro-6-methoxyisoquinoline (10-1) (300 mg, 1.55 mmol) was dissolved in dioxane (10.0 mL), tert-butyl-(cis-4-amino)cyclohexane)carbamate (664 mg, 3.10 mmol) was added, and then 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, and the mixture was stirred at 90°C for 4 hours under nitrogen protection. After the reaction was completed, the reaction solution was poured into water (25.0 mL), extracted with dichloromethane (50.0 mL), and 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%).

[0459] LC-MS, M / Z(ESI):372.3[M+H] +

[0460] Step 2: cis-N 1 Synthesis of -(6-methoxyisoquinolin-1-yl)cyclohexane-1,4-diamine hydrochloride (10-3)

[0461]

[0462] Dissolve tert-butyl (cis-4-((6-methoxyisoquinolin-1-yl)amino)cyclohexyl)carbamate (10-2) (500 mg, 1.35 mmol) in 2M hydrochloric acid ethyl acetate (5.00 mL), and react at 25°C for 2 hours. Concentrate and dry the reaction solution to obtain compound cis-N 1 -(6-Methoxyisoquinolin-1-yl)cyclohexane-1,4-diamine hydrochloride (10-3) (400 mg, yield 96.4%).

[0463] LC-MS, M / Z(ESI):308.1[M+H] +

[0464] 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)

[0465]

[0466] The cis-N1 -(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).

[0467] LC-MS, M / Z(ESI):456.2[M+H] +

[0468] 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).

[0469] Example 11: Preparation of target compound 11

[0470] 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)

[0471]

[0472] The synthetic route of target compound 11 is as follows:

[0473]

[0474] 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)

[0475]

[0476] Dissolve 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)palladium(II) dichloride (60.9 mg, 89.4 μmol) in dioxane (5.00 mL) and stir at 100 °C for 4 hours under nitrogen protection. 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).

[0477] LC-MS, M / Z(ESI):430.2[M+H] +

[0478] 1 H 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).

[0479] Example 12: Preparation of target compound 12

[0480] 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

[0481]

[0482] The synthetic route of target compound 12 is as follows:

[0483]

[0484] Step 1: Synthesis of 2-(trifluoromethyl)imidazo[1,2-a]pyrazine-8-ol (12-2)

[0485]

[0486] 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, and 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, and then diluted with water (30 mL), 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 (PE: EA (V / V) = 100:10) to obtain compound 2-(trifluoromethyl)imidazo[1,2-a]pyrazine-8-phenol (12-2) (170.00 mg, yield 31.96%).

[0487] LC-MS, M / Z(ESI):203.94[M+H] +

[0488] 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)

[0489]

[0490] At room temperature, 2-(trifluoromethyl)imidazo[1,2-a]pyrazine-8-ol (12-2) (100.00 mg, 0.49 mmol) and 1,8-diazobispiro[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 by thin layer chromatography, water (5 mL) was added for dilution, 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).

[0491] LC-MS, M / Z(ESI):484.12[M+H] +

[0492] 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).

[0493] Example 13: Preparation of target compound 13

[0494] (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)

[0495]

[0496] The synthetic route of target compound 13 is as follows:

[0497]

[0498] 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)

[0499]

[0500] 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-imidazole-2-ylidene]dichloro(3-chloropyridine-κN)-palladium (7.05 mg, 0.007 mmol) was added, and 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 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).

[0501] LC / MS(ESI)(m / z):475[M+H] + ;

[0502] 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).

[0503] Example 14: Preparation of target compound 14

[0504] (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

[0505]

[0506] The synthetic route of target compound 14 is as follows:

[0507]

[0508] 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).

[0509]

[0510] 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, and the crude product was separated and 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: 20%-70%, 9 minutes) to obtain compound (1S,3R)-N1 -(6-2-(trifluoromethyl)quinolin-4-yl)-N 3 -(2-methyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)cyclohexane-1,3-diamine (Compound 14).

[0511] LC / MS(ESI)(m / z):238.8[M / 2+H] + ;

[0512] 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).

[0513] Example 15: Preparation of target compound 15

[0514] (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).

[0515]

[0516] The synthetic route of target compound 15 is as follows:

[0517]

[0518] Step 1: Synthesis of 5-chloro-1-methyl-pyrazolo[3,4-c]pyridine (15-2B)

[0519]

[0520] 5-Chloro-2-methyl-pyrazolo[3,4-c]pyridine(15-2A)

[0521] 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, and the mixture was reacted at 0°C for 30 minutes, followed by addition of iodomethane (924 mg, 6.51 mmol) under nitrogen protection, and the reaction mixture was heated to 25°C for 1 hour. After the reaction, the reaction mixture was poured into water (50.0 mL), extracted with ethyl acetate (100 mL), and 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 obtain 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).

[0522] 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).

[0523]

[0524] (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), and cesium carbonate (771 mg, 2.37 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) (71.5 mg, 78.9 mmol) were added under nitrogen protection, and stirred at 100°C for 6 hours. After the reaction was completed, 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] +

[0525] 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)

[0526] Example 16: Preparation of target compound 16

[0527] (1S, 3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 -(Imidazolo[1,5-b]pyridazin-5-yl)cyclohexane-1,3-diamine

[0528]

[0529] The synthetic route of compound 16 is as follows:

[0530]

[0531] Step 1: Synthesis of 1,2-diazine-3-ylmethylamine (Compound 16-2)

[0532]

[0533] 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 carbon (400 mg, 10% wt, 55% water), and the reaction solution was stirred at 30 ° C for 12 hours under a hydrogen (40 psi) atmosphere. The resulting mixture was filtered, and the filtrate was concentrated to obtain a crude product, which was separated and purified by a C18 column (water: acetonitrile (V / V) = 100:0-90:10, gradient elution) to obtain 1,2-diazine-3-ylmethylamine (compound 16-2).

[0534] LC-MS, M / Z (ESI): 110.2 (M+H) +

[0535] Step 2: Synthesis of N-(pyridazin-3-ylmethyl)formamide (Compound 16-3)

[0536]

[0537] 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 step.

[0538] LC-MS, M / Z (ESI): 138.2 (M+H) +

[0539] Step 3: Synthesis of imidazo(1,5-b)pyridazine (Compound 16-4)

[0540]

[0541] 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 a saturated sodium bicarbonate aqueous solution (100 mL) was slowly added, and extracted with dichloromethane (100 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a 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 imidazo (1,5-b) pyridazine (compound 16-4).

[0542] LC-MS, M / Z (ESI): 120.2 (M+H) +

[0543] Step 4: Synthesis of 5-iodo(1,5-b)pyridazine (Compound 16-5)

[0544]

[0545] N-iodosuccinimide (179 mg, 0.80 mmol) was added to acetonitrile (10 mL) of imidazo (1,5-b) pyridazine (compound 16-4) (100 mg, 0.84 mmol), and the reaction solution was stirred at 25 ° C for 20 minutes. LCMS detected the formation of the target product, the reaction solution was diluted with saturated brine (20 mL), extracted with ethyl acetate (20 mL × 3), the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was separated and purified by 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).

[0546] LC-MS, M / Z (ESI): 246.0 (M+H) +

[0547] 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)

[0548]

[0549] 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 (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 -(Imidazolo(1,5-b)pyridazin-5-yl)cyclohexane-1,3-diamine (Compound 16).

[0550] LC-MS, M / Z(ESI):461.0(M+H) +

[0551] 1H 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).

[0552] Example 17: Preparation of target compound 17

[0553] (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)

[0554]

[0555] The synthetic route of compound 17 is as follows:

[0556]

[0557] 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)

[0558]

[0559] 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 for 18 hours under nitrogen protection. The reaction solution was diluted with saturated brine (20 mL), then extracted with ethyl acetate (10 mL×3), the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. 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 obtain 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).

[0560] LC-MS, M / Z(ESI):461.2[M+H] +

[0561] 1 H 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).

[0562] Example 18: Preparation of target compound 18

[0563] (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)

[0564]

[0565] The synthetic route of compound 18 is as follows:

[0566]

[0567] 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)

[0568]

[0569] 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*250mm, 10μm; 0.05% NH3·H2O-ACN; 50-80; 60mL / 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).

[0570] LC-MS, M / Z(ESI):462.2[M+H] +

[0571] 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).

[0572] Example 19: Preparation of target compound 19

[0573] (1S, 3R)-N1 -(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)

[0574]

[0575] The synthetic route of compound 19 is as follows:

[0576]

[0577] Step 1: Synthesis of 4-chloro-2-(2,2,2-trifluoroethyl)-2H-pyrazolo(3,4-d)pyrimidine (Compound 19-3)

[0578]

[0579] Under ice bath, sodium hydrogen (155 mg, 3.88 mmol, 60% Wt) was added 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), and the mixture was stirred at 0°C for 30 minutes, and then 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.13 g, 4.85 mmol) was added to the reaction solution, and stirring was continued at 0°C for 1 hour. LCMS detected that the reaction was complete, and saturated brine (20 mL) was slowly added dropwise to the reaction solution, and extracted with ethyl acetate (10 mL×3), and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a 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%).

[0580] LC-MS, M / Z(ESI):237.0[M+H] +

[0581] 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)

[0582]

[0583] 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 1 -(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) solution was added with 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), and the mixture was stirred at 80°C for 12 hours under nitrogen protection. After LCMS detection, saturated brine (50 mL) was added for dilution, and ethyl acetate (50 mL×3) was extracted, and 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).

[0584] LC-MS, M / Z(ESI):544.0[M+H] +

[0585] 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).

[0586] Example 20: Preparation of target compound 20

[0587] (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)

[0588]

[0589] The synthetic route of compound 20 is as follows:

[0590]

[0591] Step 1: Synthesis of 5-chloro-2-methylimidazo(1,2-c)pyrimidine (Compound 20-3)

[0592]

[0593] 2-Chloropyrimidine-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), and the crude product was directly used for the next reaction

[0594] LC-MS, M / Z(ESI):168.2[M+H] +

[0595] 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)

[0596]

[0597] 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), 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*250mm5μm, mobile phase: A=0.05% ammonia water, B=acetonitrile; slope: 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%)

[0598] LC-MS, M / Z(ESI):475.0[M+H] +

[0599] 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).

[0600] Example 21: Preparation of target compound 21

[0601] (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)

[0602]

[0603] The synthetic route of compound 21 is as follows:

[0604]

[0605] Step 1: Synthesis of 2,4-dichloro-5-fluoronicotinaldehyde (Compound 21-2)

[0606]

[0607] At -78 ° C, lithium diisopropylamide (4.63 ml, 9.26 mmol, 2 M) was added dropwise to a solution of 2,4-dichloro-5-fluoropyridine (compound 21-1) (1.50 g, 9.26 mmol) in tetrahydrofuran (20 mL), and N,N-dimethylformamide (1.35 g, 18.5 mmol) was added after stirring at -78 ° C for 1 hour, and the resulting mixture was stirred at -78 ° C for 1 hour. LCMS detected that the reaction was complete. The reaction solution was quenched with saturated aqueous ammonium chloride solution (50 mL), then extracted with ethyl acetate (50 mL × 3), the organic layers were combined, and concentrated under reduced pressure, separated and purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 100:0 to 90:10, gradient elution), and 2,4-dichloro-5-fluoronicotinaldehyde (compound 21-2) was obtained.

[0608] 1H NMR (400MHz, CDCl3): δ10.41(d,1H),8.45(s,1H).

[0609] Step 2: Synthesis of 4-chloro-7-fluoro-2H-pyrazolo(4,3-c)pyridine (Compound 21-3)

[0610]

[0611] Tetrahydrofuran (10 mL), hydrazine hydrate (347 mg, 10.8 mmol) and triethylamine (962 mg, 7.22 mmol) were added to a flask containing 2,4-dichloro-5-fluoronicotinaldehyde (compound 21-2) (700 mg, 3.61 mmol), and the resulting mixture was stirred at 25 ° C for 18 hours. LCMS detected that the reaction was complete. The reaction solution was quenched by adding water (50 mL), extracted with ethyl acetate (30 mL × 3), and 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 directly used in the next step reaction.

[0612] LC-MS, M / Z(ESI):172.2[M+H] +

[0613] Step 3: Synthesis of 4-chloro-7-fluoro-2-methyl-2H-pyrazolo(4,3-c)pyridine (Compound 21-4)

[0614]

[0615] 4-Chloro-7-fluoro-2H-pyrazolo (4,3-c) pyridine (compound 21-3) (400 mg, 2.33 mmol) was dissolved in dichloromethane (5 mL), trimethyloxonium tetrafluoroboric acid (517 mg, 3.50 mmol) was added, and the resulting mixture was stirred at 35 ° C for 14 hours. LC-MS detected that the reaction was complete. The reaction solution was diluted with water (10 mL), 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 by 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).

[0616] LC-MS, M / Z(ESI):186.2[M+H] + .

[0617] 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)

[0618]

[0619] 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 replacement, 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) solution was added, and the mixture was stirred at 120 ° C for 3 hours. LCMS detected that the reaction was 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.

[0620] LC-MS, M / Z(ESI):493.4[M+H] + .

[0621] 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).

[0622] Example 22: Preparation of target compound 22

[0623] (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)

[0624]

[0625] The synthetic route of compound 22 is as follows:

[0626]

[0627] Step 1: Synthesis of 2-chloro-N-methyl-4-nitropyridine-3-amine

[0628]

[0629] 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 that the reaction was complete. The reaction solution was diluted with water (50 mL), extracted with ethyl acetate (25 mL × 3), the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give a crude product. Separated and purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 100: 0 to 75: 25, gradient elution) to give 2-chloro-N-methyl-4-nitropyridine-3-amine (compound 22-2).

[0630] LC-MS, M / Z(ESI):188.0[M+H] +

[0631] Step 2: 2-Chloro-N 3 -Synthesis of methylpyridine-3,4-diamine

[0632]

[0633] Zinc powder (1.74 g, 26.7 mmol) and ammonium chloride (2.85 g, 53.3 mmol) were added to a solution of 2-chloro-N-methyl-4-nitropyridine-3-amine (compound 22-2) (1.00 g, 5.33 mmol) in methanol (20 mL) and water (2 mL) in sequence, and the resulting mixture was stirred at 25 ° C for 1 hour. LCMS detected 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 separated and purified by a silica gel column (petroleum ether: ethyl acetate (V / V) = 100:0 to 50:50, gradient elution) to obtain 2-chloro-N-methyl-4-nitropyridine-3-amine. 3 -methylpyridine-3,4-diamine (Compound 22-3).

[0634] LC-MS, M / Z(ESI):158.0[M+H] +

[0635] Step 3: 4-chloro-2,3-dimethyl-3H-imidazo(4,5-c)pyridine

[0636]

[0637] To 2-chloro-N 3 -Methylpyridine-3,4-diamine (compound 22-3) (130 mg, 0.83 mmol) was added to a solution of ethanol (3 mL) with trimethyl orthoacetate (495 mg, 4.12 mmol) and 4-methylbenzenesulfonic acid (41.5 mg, 0.17 mmol) in turn, 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), extracted with ethyl acetate (150 mL × 3), the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was separated and purified by 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).

[0638] LC-MS, M / Z(ESI):181.9[M+H] +

[0639] Step 4: (1S, 3R)-N1 -(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)

[0640]

[0641] 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 detected 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).

[0642] LC-MS, M / Z(ESI):489.2(M+H) +

[0643] 1H 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).

[0644] Example 23: Preparation of target compound 23

[0645] (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)

[0646]

[0647] The synthetic route of compound 23 is as follows:

[0648]

[0649] Step 1: Synthesis of 5-fluoro-2-hydrazinopyridine

[0650]

[0651] Under nitrogen protection, 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 detected that the reaction was complete, the reaction solution was cooled to room temperature, and concentrated under reduced pressure. The resulting solid was slurried with petroleum ether, and the solid was collected by filtration and dried in vacuo to obtain compound 5-fluoro-2-hydrazinopyridine (compound 23-2), which was used directly in the next step.

[0652] LC-MS, M / Z(ESI):128.2[M+H] +

[0653] Step 2: Synthesis of 6-fluoro-(1,2,4)triazolo(4,3-a)pyridine (Compound 23-3)

[0654]

[0655] 5-Fluoro-2-hydrazinopyridine (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 detected that the reaction was complete. The reaction solution was slurried with petroleum ether, and the solid was collected by filtration and dried in vacuo to obtain compound 6-fluoro-(1,2,4)triazolo(4,3-a)pyridine (Compound 23-3).

[0656] LCMS, M / Z(ESI):138.0[M+H] +

[0657] Step 3: Synthesis of 3-bromo-6-fluoro-(1,2,4)triazolo(4,3-a)pyridine (Compound 23-4)

[0658]

[0659] N-bromosuccinimide (286 mg, 1.60 mmol) was added to 6-fluoro (1,2,4) triazolo (4,3-a) pyridine (compound 23-3) (200 mg, 1.46 mmol) in dichloromethane (11 mL), and the reaction mixture was stirred at 45 ° C for 18 hours. LCMS detected that the reaction was complete. The reaction solution was diluted with saturated sodium bicarbonate aqueous solution (20 mL), extracted with ethyl acetate (20 mL × 3), and the organic phases were combined and 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: 0-60: 40, gradient elution) to obtain compound 3-bromo-6-fluoro-(1,2,4) triazolo (4,3-a) pyridine (compound 23-4).

[0660] LC-MS, M / Z(ESI):216.0[M+H] +

[0661] 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)

[0662]

[0663] 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), 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, and the resulting mixture was stirred at 80°C for 18 hours. LCMS detected that 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).

[0664] LC-MS, M / Z(ESI):479.0[M+H] +

[0665] 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).

[0666] Example 24: Synthesis of Compound 24

[0667] (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

[0668]

[0669] The synthetic route of compound 24 is as follows:

[0670]

[0671] Step 1: Synthesis of methyl 3-formyl-1-methylpyrazole-4-carboxylate (Compound 24-2)

[0672]

[0673] At room temperature, 4-bromo-1-methylpyrazole-3-carboxaldehyde (24-1) (5.50 g, 0.029 mol), triethylamine (8.86 g, 0.088 mol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (705 mg, 0.870 mmol) were dissolved in methanol (55.0 mL), and then replaced with carbon monoxide (15 Psi) gas three times, and the reaction solution was reacted at 60 ° C for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered and dried, and the obtained crude product was purified by column chromatography (PE: EA (V / V) = 1: 1) to obtain 3-formyl-1-methylpyrazole-4-carboxylic acid methyl ester (compound 24-2).

[0674] LC / MS (ESI) (m / z): 169.0 (M+H) + .

[0675] Step 2: Synthesis of 2-methylpyrazolo[4,3-d][1,2]diazine-4-ol (Compound 24-3)

[0676]

[0677] At room temperature, 3-formyl-1-methylpyrazole-4-carboxylic acid methyl ester (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, the filter cake was washed with ethanol, and the filter cake was collected and dried to obtain compound 2-methylpyrazolo[4,3-d][1,2]diazine-4-ol (compound 24-3). LC / MS (ESI) (m / z): 151.0 (M+H) + .

[0678] 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)

[0679]

[0680] 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 heated 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).

[0681] LC / MS (ESI) (m / z): 476.2 (M+H) + ;

[0682] 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).

[0683] Example 25: Synthesis of Compound 25

[0684] (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

[0685]

[0686] The synthetic route of compound 25 is as follows:

[0687]

[0688] 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)

[0689]

[0690] 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-(dicyclohexylphosphine)-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, the filtrate was dried, and the crude product was purified by preparative liquid chromatography (chromatographic column: YMC-Triart PrepC18 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).

[0691] LC / MS(ESI)(m / z):475.2(M+H) + ;

[0692] 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).

[0693] Example 26: Preparation of target compound 26

[0694] (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)

[0695]

[0696] The synthetic route of target compound 26 is as follows:

[0697]

[0698] 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)

[0699] 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 was complete, 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).

[0700] LC / MS(ESI)(m / z):475.3(M+H) + ;

[0701] 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).

[0702] Example 27: Synthesis of Compound 27

[0703] (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)

[0704]

[0705] The synthetic route of compound 27 is as follows:

[0706]

[0707] 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

[0708] Synthesis of (Compound 27)

[0709]

[0710] 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-TriartPrep 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).

[0711] LC / MS (ESI) (m / z): 510.0 (M+H) + ;

[0712] 1H 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).

[0713] Example 28: Synthesis of Compound 28

[0714] (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)

[0715]

[0716] The synthetic route of compound 28 is as follows:

[0717]

[0718] first step:

[0719] (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)

[0720]

[0721] 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), methylboric 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), and [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 for 48 hours under nitrogen protection. After the reaction was completed, the reaction solution was filtered, the filtrate was dried, and 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).

[0722] LC / MS (ESI) (m / z): 490.2 (M+H) + ;

[0723] 1 H 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).

[0724] Example 29: Synthesis of Compound 29

[0725] (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)

[0726]

[0727] The synthetic route of compound 29 is as follows:

[0728]

[0729] Step 1: Synthesis of 4,6-dichloro-2-methylpyrazolo[4,3-c]pyridine (Compound 29-2)

[0730]

[0731] 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 then 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, and then saturated brine (2 mL) was washed, dried, filtered, and spin-dried. 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).

[0732] LC / MS (ESI) (m / z): 202.0 (M+H) + .

[0733] 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)

[0734]

[0735] 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), after addition, the reaction solution was stirred at 125°C for 12 hours. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated, 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: 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).

[0736] LC / MS (ESI) (m / z): 509.0 (M+H) + ;

[0737] 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).

[0738] Example 30: Synthesis of Compound 30

[0739] 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)

[0740]

[0741] The synthetic route of compound 30 is as follows:

[0742]

[0743] The 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, and the reaction solution was stirred at 120°C for 18 hours under nitrogen protection. The reaction was completed 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 the 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, yield 6.2%).

[0744] 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).

[0745] LC-MS, M / Z(ESI):434.2[M+H] + .

[0746] Example 31: Synthesis of Compound 31

[0747] 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)

[0748]

[0749] The synthetic route of compound 31 is as follows:

[0750]

[0751] Step 1: Synthesis of 3-bromo-7-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro-(1,2,4)triazolo(4,3-a)pyrazine

[0752]

[0753] Potassium carbonate (865 mg, 6.27 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (969 mg, 4.18 mmol) were added 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), and the reaction solution was stirred at 80° C. for 16 hours. LCMS detected that the reaction was complete, and the reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by a C18 column (water:acetonitrile (V / V)=100:0-40:60) and lyophilized to obtain compound 3-bromo-7-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro-(1,2,4)triazolo(4,3-a)pyrazine (200 mg, yield 33.6%).

[0754] LC-MS, M / Z(ESI):285.2[M+H] +

[0755] 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

[0756]

[0757] 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 solution was stirred at 120°C for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain a crude product, which was purified by high performance liquid chromatography (Xtimate C18, 21.2*250mm, 5μm; 10mM NH3.H2O; 18-47; 60mL / 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, yield 5.7%).

[0758] LC-MS, M / Z(ESI):503.2[M+H] +

[0759] 1 H NMR (400 MHz, 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). Example 32: Synthesis of Compound 32

[0760] (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

[0761]

[0762] The synthetic route of compound 32 is as follows:

[0763]

[0764] Step 1: 3-Bromo-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine hydrochloride

[0765]

[0766] 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 1,4-dioxane solution of hydrogen chloride (4 mol / L, 4 mL), and the reaction solution was stirred at 25°C for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the compound 3-bromo-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (500 mg, yield 100%). LC / MS(ESI)(m / z):203.0(M+H) + .

[0767] Step 2: (3-bromo-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(cyclopropyl)methanone

[0768]

[0769] At room temperature, 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), 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 was completed, the reaction solution was diluted with saturated sodium bicarbonate solution, and then extracted with dichloromethane (10 mL*3). The organic phases were combined, washed with saturated brine (5 mL), and then dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was purified by column chromatography (DCM:MeOH (V / V) = 1 / 0 to 10 / 1) to obtain compound (3-bromo-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(cyclopropyl)methanone (200 mg, 0.738 mmol, yield 30%).

[0770] LC / MS (ESI) (m / z): 271.0 (M+H) +

[0771] Step 3:

[0772] (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

[0773]

[0774] 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]pyrazine-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 under nitrogen protection for 24 hours. 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-TriartPrep C18 7μm 30mm×40cm; solvent: A=0.1% ammonia water, B=acetonitrile; gradient: 20%-70%, 9 minutes) to obtain 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)-yl)(cyclopropyl)methanone (4.40 mg, yield 2.8%).

[0775] LC / MS (ESI) (m / z): 534.1 (M+H) + ;

[0776] 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).

[0777] Example 33: Synthesis of Compound 33

[0778] (1S,3R)-N 1 -[6-Chloro-2-(trifluoromethyl)quinolin-4-yl]-N3 -(5,6,7,8-Tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-3-yl)cyclohexane-1,3-diamine

[0779] The synthetic route of compound 33 is as follows:

[0780]

[0781] first step:

[0782] 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

[0783]

[0784] 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 the reaction was completed, the reaction solution was added to a saturated ammonium chloride solution (10 mL), and then extracted with ethyl acetate (3×15 mL). The organic phases were combined, washed with saturated brine (15 mL), and 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%).

[0785] LC / MS (ESI) (m / z): 566.2 (M+H) + .

[0786] 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

[0787]

[0788] 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 the reaction was completed, the reaction solution was concentrated, and the crude product was purified by preparative liquid chromatography (chromatographic column: YMC-Triart Prep C18 7μm30mm×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

[0789] (7.90 mg, 19.5% yield).

[0790] LC / MS (ESI) (m / z): 466.1 (M+H) + ;

[0791] 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).

[0792] Intermediate A1: (1S,3R)-N 1 Synthesis of -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine

[0793] The synthetic route of intermediate A1 is as follows:

[0794]

[0795] Step 1: Synthesis of 6-chloro-2-(trifluoromethyl)quinoline-4-ol (A1-2)

[0796]

[0797] At room temperature, p-chloroaniline (5 g, 39.37 mmol) was added to PPA (200 mmol, 75 ml), and then ethyl trifluoroacetate (7.2 g, 39.37 mmol) was added, and the reaction solution was heated to 140°C and stirred for 12 h. After the reaction was completed, the reaction solution was poured into ice water and extracted with ethyl acetate (50 mL × 4 times), and the obtained organic phase was dried over anhydrous sodium sulfate, filtered and spin-dried to obtain 6-chloro-2-(trifluoromethyl)quinoline-4-ol (A1-2) (crude product, 8.5 g, yield 87.6%).

[0798] LC-MS, M / Z(ESI):248.0[M+H] + .

[0799] Step 2: Synthesis of 4,6-dichloro-2-(trifluoromethyl)quinoline (A1-3)

[0800]

[0801] 6-Chloro-2-(trifluoromethyl)quinoline-4-ol (A1-2) (8.5 g, 34.5 mmol) was dissolved in 1,2-dichloroethane (100 mL), phosphorus oxychloride (13.2 g, 86.25 mmol) was added at 0°C, and then the reaction solution was heated to 80°C and stirred for 12 hours. After the reaction was completed, the reaction solution was spin-dried, and the obtained crude product was quickly purified by 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, yield 91.6%).

[0802] LC-MS, M / Z(ESI):265.9[M+H] + .

[0803] Step 3: Synthesis of tert-butyl ((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)-amino)cyclohexyl)carbamate (A1-4)

[0804]

[0805] 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 diisopropylethylamine (1.9 g, 15 mmol) was added, and the reaction solution was heated to 130 ° C and stirred for 12 h. After the reaction was completed, the reaction solution was poured into ice water and extracted with ethyl acetate (50 mL×4). The obtained organic phase was dried over anhydrous sodium sulfate, filtered and dried to obtain the compound (tert-butyl ((1R, 3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)-amino)cyclohexyl)carbamate (A1-4) (crude product, 1.9 g, yield 96.3%).

[0806] LC-MS, M / Z(ESI):444.1[M+H] + .

[0807] Step 4: (1S, 3R)-N 1 Synthesis of -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine (Intermediate A1)

[0808]

[0809] 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), and then concentrated hydrochloric acid (0.5 mL) was added, and the reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution 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 compound (1S, 3R)-N1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine (intermediate A1) (720 mg, yield 91.3%).

[0810] LC / MS(ESI)(m / z):344[M+H] + .

[0811] Intermediate A2: Synthesis of 5-chloro-2-(trifluoromethyl)imidazo[1,2-a]pyridine

[0812] The synthetic route of intermediate A2 is as follows:

[0813]

[0814] Under room temperature, compound 2-amino-6-chloropyridine (5 g, 38.89 mmol) and compound 3-bromo-1,1,1-trifluoroacetone (7.42 g, 38.89 mmol) were dissolved in ethylene glycol (50 mL) and stirred at 130°C for 12 h. After the reaction was complete as monitored by thin layer chromatography, stirring was stopped, the reaction solution was cooled to room temperature, and then water (200 mL) was added to dilute it, extracted with ethyl acetate (100 mL×5), the organic phase was collected and dried with anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (DCM: MeOH = 100:0) to obtain compound 5-chloro-2-(trifluoromethyl)imidazo[1,2-a]pyridine (intermediate A2) (5.87 g, yield 68.42%).

[0815] LC-MS, M / Z (ESI): 220.90 [M+H] + .

[0816] 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)

[0817] The synthetic route of compound 1A is as follows:

[0818]

[0819] Step 1: Synthesis of 2-fluoro-4-(1H-pyrazol-1-yl)pyridine (1A-2)

[0820]

[0821] 2,4-difluoropyridine (1A-1) (1.69 g, 14.6 mmol) was dissolved in N,N-dimethylformamide (10 mL), 1H-pyrazole (1.00 g, 14.6 mmol) was added, and potassium phosphate (6.24 g, 29.3 mmol) was added. The reaction solution was stirred at 25 ° C for 1 hour under nitrogen protection. The reaction solution was 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 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, yield 41.7%).

[0822] LC-MS, M / Z(ESI):164.3[M+H] + .

[0823] Step 2: Synthesis of tert-butyl (cis-4-((4-(1H-pyrazol-1-yl)pyridin-2-yl)amino)cyclohexyl)carbamate (1A-4)

[0824]

[0825] 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), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated, and the crude product was separated and purified by 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%).

[0826] LC-MS, M / Z(ESI):358.1[M+H] + .

[0827] Step 3: cis-N 1 Synthesis of -(4-(1H-pyrazol-1-yl)pyridin-2-yl)cyclohexane-1,4-diamine (1A-5)

[0828]

[0829] 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 solution of hydrogen chloride in 1,4-dioxane (2 M, 5 mL) and react at 25°C for 2 hours. Concentrate the reaction solution 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%).

[0830] LC-MS, M / Z(ESI):258.2[M+H] + .

[0831] Step 4: cis-N 1 -[4-(1H-pyrazol-1-yl)pyridin-2-yl]-N 4Synthesis of -[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]cyclohexane-1,4-diamine (target compound 1A)

[0832]

[0833] The 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%).

[0834] LC-MS, M / Z(ESI):442.2[M+H] + .

[0835] 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).

[0836] 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 shown below:

[0837]

[0838] Step 1: Synthesis of 1-(2-chloropyridin-4-yl)pyrrolidin-2-one

[0839]

[0840] 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), and stir the reaction solution at 90°C for 2 h under nitrogen protection. Pour the reaction solution into water (50 mL), 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%).

[0841] LC-MS, M / Z(ESI):197.3[M+H] + .

[0842] 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

[0843]

[0844] 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-imidazole-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 completed, the reaction solution was filtered, the filtrate was dried, and the obtained crude product was purified by high performance preparative liquid chromatography (chromatographic column: YMC-Triart Prep C 187μm 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, yield 11%).

[0845] LC / MS (ESI) (m / z): 504.4 (M+H) + .

[0846] 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),3.7 3–3.57(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).

[0847] 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)

[0848] The synthetic route of compound 3A is as follows:

[0849]

[0850] Step 1: (1S, 3R)-N 1 Synthesis of -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N3-(4-iodopyridin-2-yl)cyclohexane-1,3-diamine

[0851]

[0852] 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), 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), extracted with dichloromethane (100 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated, and 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, yield 16.2%).

[0853] LC-MS, M / Z(ESI):547.3[M+H] +

[0854] Step 2: Synthesis of N-(2-(((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)amino)pyridin-4-yl)methanesulfonamide

[0855]

[0856] 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(diphenylphosphine)-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 the reaction was completed, 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 7μm 30mm×40cm; solvent: A=0.1% ammonia water, B=acetonitrile; gradient: 10%-55%, 9 minutes) to obtain 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, yield 10.5%).

[0857] LC / MS (ESI) (m / z): 514.3 (M+H) + ;

[0858] 1 H 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).

[0859] 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)

[0860] The synthetic route of compound 7A is as follows:

[0861]

[0862] Step 1: Synthesis of 2-(2-chloropyridin-4-yl)pyrimidine

[0863]

[0864] 2-Bromopyrimidine (0.25 g, 1.57 mmol) was dissolved in a mixed solvent 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, potassium carbonate (0.43 g, 3.11 mmol) and bistriphenylphosphine palladium dichloride (110 mg, 0.16 mmol) were added, and the mixture was stirred at 110°C overnight under nitrogen protection. After the reaction was completed, the reaction solution was concentrated, water (10 mL) was added, and ethyl acetate was extracted (20 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 4:1) to obtain compound 2-(2-chloropyridin-4-yl)pyrimidine (0.37 g, yield: 83.0%).

[0865] LC-MS, M / Z(ESI):192.1[M+H] + .

[0866] Step 2: (1S, 3R)-N1 -(6-chloro-2-(trifluoromethyl))-quinolin-4-yl)-N 3 Synthesis of -(4-(pyrimidin-2-yl))-pyridin-2-yl)cyclohexane-1,3-diamine

[0867]

[0868] (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), TMSONa (145 mg, 1.16 mmol), (SP-4-1)-[1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazole-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 was completed, saturated sodium chloride solution (10 mL) was added to the reaction solution, and ethyl acetate was used for extraction (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, yield 24%).

[0869] LC-MS, M / Z(ESI):499.3[M+H] + .

[0870] 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)

[0871] The synthetic route of compound 16A is as follows:

[0872]

[0873] Step 1: Synthesis of 2-chloro-3-(1-methyl-1H-pyrazol-4-yl)pyrazine

[0874]

[0875] 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) were added to a solution of 2,3-dichloropyrazine (1.00 g, 6.71 mmol) in dimethyl sulfoxide (12 mL) and water (3 mL) in sequence. The reaction solution was stirred at 80°C for 18 hours under nitrogen protection. The reaction mixture was diluted with water (20 mL) and then extracted with ethyl acetate (10 mL×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 by 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%)

[0876] LC-MS, M / Z(ESI):195.0[M+H] +

[0877] 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

[0878]

[0879] To a solution of 2-chloro-3-(1-methylpyrazol-4-yl)pyrazine (200 mg, 1.03 mmol) in N,N-dimethylformamide (5 mL) was 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(diphenylphosphino)-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. for 12 hours under nitrogen protection. 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%).

[0880] LC-MS, M / Z(ESI):502.2[M+H] +

[0881] 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).

[0882] 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)

[0883] The synthetic route of compound 17A is as follows:

[0884]

[0885] 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 mixture 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)-N1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 -(3-chloropyridin-2-yl)cyclohexane-1,3-diamine (13.0 mg, yield 4.9%).

[0886] LC / MS (ESI) (m / z): 454.09 (M+H) + ;

[0887] 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) The preparation methods of the following compounds refer to the above examples.

[0888]

[0889]

[0890]

[0891] Test Example 1: MRGPRX2 in vitro calcium flow assay

[0892] 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 bottom plate containing DMEM / F12 (1:1) culture medium and kept at 37°C, 5% CO2 for 18 hours. Then, the corresponding amount of dye solution was added to each well of the cells, 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 balanced 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.

[0893] Table 1: MRGPRX2 calcium flux assay results

[0894]

[0895]

[0896] The results of the MRGPRX2 calcium flux test showed that the compounds of the present invention have a good antagonistic effect on MRGPRX2.

[0897] Test Example 2: Test of the toxicity of compounds to liver cells

[0898] The toxicity test of the compound on liver cells was conducted on HepG2 (ATCC, HB-8065) ​​cells, and the cell viability was measured using CellTiter-Glo Luminescent Cell Viability Assay kit (Promega, G7573) to characterize the toxicity of the compound by inhibiting the viability of HepG2 cells. HepG2 cells in the logarithmic phase were collected, the concentration of the cell suspension was adjusted, and 5000 cells / well were plated in a 96-well cell culture plate. The cells were placed in a cell culture incubator at 5% CO2 and 37°C and incubated overnight. The next day, the medium was changed and different concentrations of compound solutions were added. At the same time, a negative control group (cells + DMSO) and a blank control group (medium + DMSO) were set up and incubated in a cell culture incubator at 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).

[0899]

[0900] The results of the hepatocellular toxicity test showed that the compound of the present invention exhibited good safety and low hepatocellular toxicity.

[0901] Test Example 3: Pharmacokinetics test in mice

[0902] Mouse pharmacokinetic test, using male ICR mice, 20-25g, fasted overnight. Take 3 mice, oral gavage 10mg / kg. Blood was collected before administration and 15, 30 minutes and 1, 2, 4, 8, 24 hours after administration. The blood sample was centrifuged at 6800g, 2-8℃ for 6 minutes, and the plasma was collected and stored at -80℃. Take the plasma at each time point, add 3-5 times the amount of acetonitrile solution containing internal standard, mix, vortex mix for 1 minute, centrifuge at 13000 rpm and 4℃ for 10 minutes, take the supernatant and add 3 times the amount of water to mix, take an appropriate amount of the mixed solution for LC-MS / MS analysis. The main pharmacokinetic parameters were analyzed by non-compartmental model using WinNonlin 7.0 software. The experimental results are shown in Table 2.

[0903] Table 2: Results of pharmacokinetic studies in mice

[0904]

[0905] The results of the mouse pharmacokinetic test showed that the compound of the present invention exhibited excellent pharmacokinetic properties and good drugability.

[0906] Test Example 4: Pharmacokinetics test in rats

[0907] For the pharmacokinetic test in rats, male SD rats, 180-240g, fasted overnight were used. Three rats were taken and 10 mg / kg was orally administered by gavage. Blood was collected before administration and 15, 30 minutes, and 1, 2, 4, 8, and 24 hours after administration. The blood sample was centrifuged at 6800g, 2-8℃ for 6 minutes, and the plasma was collected and stored at -80℃. The plasma at each time point was taken, mixed with 3-5 times the amount of acetonitrile solution containing the internal standard, vortexed for 1 minute, centrifuged at 13000 rpm and 4℃ for 10 minutes, the supernatant was taken and mixed with 3 times the amount of water, and an appropriate amount of the mixed solution was taken for LC-MS / MS analysis. The main pharmacokinetic parameters were analyzed by non-compartmental model using WinNonlin 7.0 software.

[0908] The results of the rat pharmacokinetic test show that the compound of the present invention exhibits excellent rat pharmacokinetic properties and good drugability.

[0909] Test Example 5: Thermodynamic Solubility Test

[0910] Prepare phosphate buffered saline (PBS) at pH 7.4. Accurately weigh the compound, add the prepared phosphate buffer at pH 7.4 to a solution with a concentration of 4 mg / mL, shake at 1000 rpm for 1 hour, and then incubate at room temperature overnight. The incubated solution was centrifuged at 12000 rpm for 10 minutes to remove undissolved particles, and the supernatant was transferred to a new centrifuge tube. After the supernatant was appropriately diluted, an acetonitrile solution containing an internal standard was added, and the standard curve prepared with the same matrix was used for quantification.

[0911] The results of the thermodynamic solubility test show that the compound of the present invention has good thermodynamic solubility and good drugability.

[0912] Test Example 6: Human liver microsome stability test

[0913] The stability test of human liver microsomes was performed by incubating the compound with human liver microsomes in vitro. First, the compound to be tested was prepared into a 10mM stock solution in DMSO solvent, and then the compound was diluted to 0.5mM with acetonitrile. Human liver microsomes (Corning) were diluted with PBS to form a microsome / buffer solution, and the solution was used to dilute 0.5mM of the compound to form a working solution. The compound concentration in the working solution was 1.5μM and the human liver microsome concentration was 0.75mg / ml. Take a deep well plate, add 30μL of working solution to each well, and then add 15μL of preheated 6mM NADPH solution to start the reaction and incubate at 37°C. At 0, 5, 15, 30, and 45 minutes of incubation, add 135μL of acetonitrile to the corresponding wells to terminate the reaction. After terminating the reaction with acetonitrile at the last 45 minutes, the deep well plate was vortexed for 10 minutes (600rpm / min) and then centrifuged for 15 minutes. After centrifugation, the supernatant was collected and purified water was added in a 1:1 ratio for LC-MS / MS detection. The ratio of the peak area of ​​the compound to the peak area of ​​the internal standard at each time point was obtained. The peak area ratios of the compound at 5, 15, 30, and 45 minutes were compared with the peak area ratio at 0 minute, and the remaining percentage of the compound at each time point was calculated. T1 / 2 was calculated using Graphpad 5 software.

[0914] The results of the human liver microsome stability test show that the compounds of the present invention exhibit excellent human liver microsome stability and good drugability.

[0915] Test Example 7: Inhibition test of compounds on cytochrome P450

[0916] The inhibitory potential of the compounds on the cytochrome P450 (CYP450) subtype CYP3A4 (two substrates midazolam and testosterone) was tested. The test compound was first prepared into a 10mM stock solution in DMSO solvent, and the CYP3A4 inhibitor ketoconazole was prepared into 10mM, 2.5mM, and 2.5mM stock solutions in DMSO solvent. The test compound and ketoconazole were diluted to 400 times the final concentration (compound: 10μM, ketoconazole: 2.5μM) with acetonitrile.

[0917] 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.

[0918] Prepare human liver microsome solution with potassium phosphate buffer on ice at a concentration of 0.2 mg / mL. Prepare test compound and control inhibitor solution at 2 times the final concentration with human liver microsome solution on ice. Add 30 μL of test compound and control inhibitor solution to the test wells, respectively, and add 15 μL of substrate for duplicate well operation. Incubate the 96-well assay plate and NADPH solution at 37°C for 5 minutes, and add 15 μL of preheated 8mM NADPH solution to the assay plate to start the reaction. The CYP3A4 assay plate was preincubated at 37°C for 5 minutes. Add 120 μL of acetonitrile to terminate the reaction. 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 taken, purified water was added in a 1:1 ratio, and then LC-MS / MS detection was performed to obtain the ratio of the peak area of ​​the compound to the peak area of ​​the internal standard. The peak area ratio of the compound was compared with the peak area ratio of the control inhibitor to calculate the inhibition rate.

[0919] The results of the inhibition test of the compounds on cytochrome P450 show that the compounds of the present invention have no obvious inhibitory effect on CYP3A4 (two substrates, midazolam and testosterone) and have good drugability.

[0920] Test Example 8: Evans blue vascular permeability test

[0921] The Evans blue vascular permeability test used C57 mice, with the left hind toe of the mouse as the model group and the right hind toe as the negative control group. Different doses of drugs were given by gavage, and 0.4% Evans blue (Sigma-Aldrich, Lot#SHBP1253) solution was injected into the tail vein 2h after administration. 5-10min later, C48 / 80 (Sigma-Aldrich, Lot#C2313) solution was injected subcutaneously into the left hind toe, and saline was injected into the right hind toe. The mice were killed 15min later, and the thickness of the left and right hind toes of the mice was measured with a vernier caliper. The mouse feet were cut off, dried, and weighed. The toes were crushed, and the Evans blue in the toes was dissolved with acetone: saline (7:3), and the absorbance was measured at 620nm, and the absorbance per unit volume was calculated. The swelling rate of the mouse ears and the amount of Evans blue permeation per unit mass were calculated.

[0922] 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.

[0923] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary 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 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 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 The cycloalkyl radicals are each independently optionally substituted with 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 For multiple times, Each 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 as claimed in 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 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; 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 The cycloalkyl radicals are each independently optionally substituted with 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 For multiple times, Each 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 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 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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