A fused heteroaryl compound, pharmaceutical compositions thereof and uses thereof

Abstract

This invention belongs to the pharmaceutical field and relates to a fused heteroaryl compound, pharmaceutical compositions thereof, and uses. Specifically, it relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in a medicament for treating and / or preventing MRGPRX2-related diseases.

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field and relates to a fused heteroaryl compound, its pharmaceutical composition, and its uses. Background Technology

[0002] Mast cells are important participants and regulators of the innate immune response to pathogens. They induce inflammation through direct exposure to pathogens and by sensing danger signals from surrounding tissues, including epithelial cells, endothelial cells, and tissue-resident immune cells. Mas-related G protein-coupled receptor X2 (MRGPRX2) is highly expressed in mast cells. MRGPRX2 on mast cells can be activated by various basic secretagogues, neurokinins, host defense antimicrobial peptides, and small molecule compounds such as neuromuscular blocking agents, causing mast cell degranulation and the release of histamine and other mediators, thereby inducing inflammation (Hiroyuki Ogasawara et al., Cells, 2021, 10(11)). MRGPRX2 is closely associated with various diseases, such as neurogenic inflammation, type 2 inflammation, nonhistamine pruritus, and drug-induced pseudohypersensitivity induced by mast cell activation.

[0003] Currently, there are no approved MRGPRX2 modulators on the market. Clinically, EP262 is an MRGPRX2 antagonist, and clinical trials have been initiated for chronic spontaneous urticaria that is not well controlled by antihistamines. Therefore, there is a need to develop more small-molecule MRGPRX2 modulators. Summary of the Invention

[0004] The first aspect of the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0005]

[0006] in,

[0007] A is

[0008] Each R x It is independently selected from halogen, cyano, hydroxy, carboxyl, amino, nitro, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, hydroxy-C1-C6 alkyl, amino-C1-C6 alkyl, carboxyl-C1-C6 alkyl, C1-C6 alkylamino, C2-C6 alkenyl or C2-C6 alkynyl;

[0009] Each R yIt is independently selected from halogen, cyano, hydroxy, carboxyl, amino, nitro, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, hydroxy-C1-C6 alkyl, amino-C1-C6 alkyl, carboxyl-C1-C6 alkyl, C1-C6 alkylamino, C2-C6 alkenyl or C2-C6 alkynyl;

[0010] n is 0, 1, 2, 3 or 4;

[0011] m can be 0, 1, 2, 3, or 4;

[0012] L 1 Selected from chemical bonds, -N(R) a )-、-S-、-O-、 The above Optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxyl, carboxyl, amino, or nitro; wherein L represents 1 It is attached to the position of A by a chemical bond; L represents 1 It is attached to the position of B by a chemical bond;

[0013] Each R a They may be the same or different, and each is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-12 membered heterocyclic, C3-C8 cycloalkyl, C6-C 10 aryl or 5-14 membered heteroaryl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, 3-12 membered heterocyclic, C3-C8 cycloalkyl, C6-C 10 Each of the aryl or 5-14 heteroaryl groups is independently and optionally substituted by one or more groups selected from the group consisting of: halogen, cyano, hydroxyl, carboxyl, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, C2-C6 alkenyl or C2-C6 alkynyl.

[0014] B represents cyclopropyl, cyclohexyl, and cycloheptyl. C 6- C 10 aryl or 5-20-membered heteroaryl; wherein the B is optionally surrounded by one or more R c replace;

[0015] Each R c They may be the same or different, and each is independently selected from halogen, cyano, nitro, hydroxy, carboxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6- C 10 aryl, 3-12 membered heterocyclic or 5-14 membered heteroaryl; wherein the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C 6- C 10 Each of the aryl, 3-12-membered heterocyclic or 5-14-membered heteroaryl groups is independently and optionally substituted by one or more groups selected from the group consisting of: halogen, cyano, hydroxyl, carboxyl, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, C2-C6 alkenyl or C2-C6 alkynyl;

[0016] p is 0, 1, or 2;

[0017] L 2 for Or -C(O)-; where L represents 2 Linked to (CH2) via chemical bonds p Location; L represents 2 Linked to the W site via chemical bonds;

[0018] Each R b They may be the same or different, and each is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-12 membered heterocyclic, C3-C8 cycloalkyl, C6-C 10 aryl or 5-14 membered heteroaryl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, 3-12 membered heterocyclic, C3-C8 cycloalkyl, C6-C 10 Each of the aryl or 5-14 heteroaryl groups is independently and optionally substituted by one or more groups selected from the group consisting of: halogen, cyano, hydroxyl, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl or C2-C6 alkynyl.

[0019] W is selected from C3-C 20 Cycloalkyl, 3-20 membered heterocyclic groups, C6-C 10 aryl or 5-20 heteroaryl; the W is optionally surrounded by one or more R d replace;

[0020] Each R d They may be the same or different, and each is independently selected from halogen, cyano, nitro, -OR e -SR e -S(=O)R e -S(=O)2R e -C(O)R e-C(O)-OR e -N(R) e (R) f C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, 3-12 membered heterocyclic, C6-C 10 aryl or 5-14 membered heteroaryl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, 3-12 membered heterocyclic, C6-C 10 The aryl or 5-14 heteroaryl groups are each independently and optionally bound by one or more R groups. g replace;

[0021] R e R f They may be the same or different, and each is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocyclic groups, C3-C8 cycloalkyl, C6-C 10 aryl or 5-14 membered heteroaryl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, 3-10 membered heterocyclic, C3-C8 cycloalkyl, C6-C 10 The aryl or 5-14 heteroaryl groups are each independently and optionally selected from one or more R groups of the group below. g replace;

[0022] Each R g They may be the same or different, and each is independently selected from halogen, cyano, hydroxy, amino, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, hydroxylated C1-C6 alkyl, amino C1-C6 alkyl, C3-C8 cycloalkyl, 3-12 membered heterocyclic groups, C6-C 10 Aryl or 5-14 heteroaryl groups;

[0023] The condition is that when L 1 -N(R) a When )-, B is not a cyclohexyl group.

[0024] In some implementations, A is

[0025] In some implementation schemes, R x It is selected from halogen, cyano, hydroxy, carboxyl, amino, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy or halogenated C1-C6 alkoxy.

[0026] In some implementation schemes, R xIt is selected from halogen, cyano, hydroxy, carboxyl, amino, nitro, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy or halogenated C1-C4 alkoxy.

[0027] In some implementation schemes, R x It is selected from halogen, cyano, hydroxy, carboxyl, amino, nitro, C1-C3 alkyl, halogenated C1-C3 alkyl, C1-C3 alkoxy or halogenated C1-C3 alkoxy.

[0028] In some implementation schemes, R x It is selected from fluorine, chlorine, bromine, cyano, hydroxyl, carboxyl, amino, nitro, methyl, ethyl, methoxy, difluoromethyl, or trifluoromethyl.

[0029] In some implementations, n is 0, 1, 2, or 3.

[0030] In some implementations, n is 0, 1, or 2.

[0031] In some implementations, n is 0 or 1.

[0032] In some implementations, A is Wherein R 1a R 2a R 3a R 4a They may be the same or different, and each is independently selected from hydrogen, halogen, cyano, hydroxy, carboxyl, amino, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, amino C1-C6 alkyl, carboxyl C1-C6 alkyl, C1-C6 alkylamino, C2-C6 alkenyl, or C2-C6 alkynyl.

[0033] In some implementations, the R 1a R 2a R 3a R 4a They may be the same or different, and each is independently selected from hydrogen, halogen, cyano, hydroxy, carboxyl, amino, nitro, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkoxy, hydroxy C1-C4 alkyl, amino C1-C4 alkyl, carboxyl C1-C4 alkyl, C1-C4 alkylamino, C2-C4 alkenyl, or C2-C4 alkynyl.

[0034] In some implementations, the R 1a R 2a R 3a R 4aThey may be the same or different, and each is independently selected from hydrogen, halogen, cyano, hydroxy, carboxyl, amino, nitro, C1-C3 alkyl, halogenated C1-C3 alkyl, C1-C3 alkoxy or halogenated C1-C3 alkoxy.

[0035] In some implementations, the R 1a R 2a R 3a R 4a Each is independently hydrogen.

[0036] In some implementations, A is

[0037] In some implementation schemes, R y It is selected from halogen, cyano, hydroxy, carboxyl, amino, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy or halogenated C1-C6 alkoxy.

[0038] In some implementation schemes, R y It is selected from halogen, cyano, hydroxy, carboxyl, amino, nitro, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy or halogenated C1-C4 alkoxy.

[0039] In some implementation schemes, R y It is selected from halogen, cyano, hydroxy, carboxyl, amino, nitro, C1-C3 alkyl, halogenated C1-C3 alkyl, C1-C3 alkoxy or halogenated C1-C3 alkoxy.

[0040] In some implementation schemes, R y It is selected from fluorine, chlorine, bromine, cyano, hydroxyl, carboxyl, amino, nitro, methyl, ethyl, methoxy, difluoromethyl, or trifluoromethyl.

[0041] In some implementations, m is 0, 1, 2, or 3.

[0042] In some implementations, m is 0, 1, or 2.

[0043] In some implementations, m is 0 or 1.

[0044] In some implementations, A is Wherein R 1c R 2c R 3c R 4cThey may be the same or different, and each is independently selected from hydrogen, halogen, cyano, hydroxy, carboxyl, amino, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, amino C1-C6 alkyl, carboxyl C1-C6 alkyl, C1-C6 alkylamino, C2-C6 alkenyl, or C2-C6 alkynyl.

[0045] In some implementations, the R 1c R 2c R 3c R 4c They may be the same or different, and each is independently selected from hydrogen, halogen, cyano, hydroxy, carboxyl, amino, nitro, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkoxy, hydroxy C1-C4 alkyl, amino C1-C4 alkyl, carboxyl C1-C4 alkyl, C1-C4 alkylamino, C2-C4 alkenyl, or C2-C4 alkynyl.

[0046] In some implementations, the R 1c R 2c R 3c R 4c They may be the same or different, and each is independently selected from hydrogen, halogen, cyano, hydroxy, carboxyl, amino, nitro, C1-C3 alkyl, halogenated C1-C3 alkyl, C1-C3 alkoxy or halogenated C1-C3 alkoxy.

[0047] In some implementations, the R 1c R 2c R 3c R 4c Each is independently hydrogen.

[0048] In some implementations, A is

[0049] In some implementations, the L 1 Selected from chemical bonds, -N(R) a -, -S-, -O- or

[0050] In some implementations, the L 1 Selected from -N(R) a )-、-S- or -O-.

[0051] In some implementations, the L 1 -N(R) a )-.

[0052] In some implementations, the R aSelected from hydrogen, C1-C6 alkyl, 3-10 membered heterocyclic, C3-C8 cycloalkyl, C6-C 10 aryl or 5-14 membered heteroaryl; wherein the C1-C6 alkyl, 3-10 membered heterocyclic, C3-C8 cycloalkyl, C6-C 10 Each of the aryl or 5-14 heteroaryl groups is independently and optionally substituted by one or more groups selected from the group consisting of: halogen, cyano, hydroxyl, carboxyl, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, C2-C6 alkenyl or C2-C6 alkynyl.

[0053] In some implementations, the R a Selected from hydrogen, C1-C6 alkyl, 3-8 membered heterocyclic, C3-C8 cycloalkyl, C6-C 10 aryl or 5-9 membered heteroaryl; wherein the C1-C6 alkyl, 3-8 membered heterocyclic, C3-C8 cycloalkyl, C6-C 10 Each of the aryl or 5-9 heteroaryl groups is independently and optionally substituted by one or more groups selected from the group consisting of: halogen, cyano, hydroxyl, carboxyl, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, C2-C6 alkenyl or C2-C6 alkynyl.

[0054] In some implementations, the R a Selected from hydrogen, C1-C4 alkyl, 3-6 membered heterocyclic, C3-C6 cycloalkyl, C6-C 10 aryl or 5-7 membered heteroaryl; wherein the C1-C4 alkyl, 3-6 membered heterocyclic, C3-C6 cycloalkyl, C6-C 10 Each of the aryl or 5-7 heteroaryl groups is independently and optionally substituted by one or more groups selected from the group consisting of: halogen, cyano, hydroxyl, carboxyl, amino, nitro, C1-C3 alkyl, C1-C3 alkoxy, halo-C1-C3 alkyl, halo-C1-C3 alkoxy, C2-C3 alkenyl or C2-C3 alkynyl.

[0055] In some implementations, the R a The group is selected from hydrogen, C1-C4 alkyl, 3-6 membered heterocyclic or C3-C6 cycloalkyl; wherein each of the C1-C4 alkyl, 3-6 membered heterocyclic or C3-C6 cycloalkyl groups is independently and optionally substituted by one or more groups selected from the group consisting of: halogen, cyano, hydroxy, carboxyl, amino, nitro, C1-C3 alkyl, C1-C3 alkoxy, halo-C1-C3 alkyl or halo-C1-C3 alkoxy.

[0056] In some implementations, the R aIt is selected from hydrogen or C1-C3 alkyl; wherein the C1-C3 alkyl is optionally substituted by one or more groups selected from the group consisting of: halogen, cyano, hydroxy, carboxyl, amino, nitro, C1-C3 alkyl, C1-C3 alkoxy, halo-C1-C3 alkyl or halo-C1-C3 alkoxy.

[0057] In some implementations, the R a It is selected from hydrogen or C1-C3 alkyl; wherein the C1-C3 alkyl is optionally substituted by one or more groups selected from the group consisting of fluorine, chlorine, bromine, cyano, hydroxyl, carboxyl, amino or nitro.

[0058] In some implementations, the R a It is hydrogen.

[0059] In some implementations, the L 1 Selected from chemical bonds, -NH-, -O- or in L represents 1 It is attached to the position of A by a chemical bond; L represents 1 It is attached to the position of B by a chemical bond.

[0060] In some implementations, the L 1 It is -NH-.

[0061] In some embodiments, B is cyclopropyl, cyclohexyl, cycloheptyl, or cyclopropyl. C6-C 10 aryl or 5-14 heteroaryl; wherein the B is optionally surrounded by one or more R c Replacement; the condition is when L 1 -N(R) a When )-, B is not a cyclohexyl group.

[0062] In some embodiments, B is cyclopropyl, cyclohexyl, cycloheptyl, or cyclopropyl. C6-C 10 aryl or 5-10 heteroaryl; wherein the B is optionally surrounded by one or more R c Replacement; the condition is when L 1 -N(R) a When )-, B is not a cyclohexyl group.

[0063] In some embodiments, B is cyclopropyl, cyclohexyl, cycloheptyl, or cyclopropyl. C6-C 10 aryl, 5-8 membered monocyclic heteroaryl, or 6-10 membered fused heteroaryl; wherein the B is optionally separated by one or more R cReplacement; the condition is when L 1 -N(R) a When )-, B is not a cyclohexyl group.

[0064] In some embodiments, B is cyclopropyl, cyclohexyl, phenyl or pyridyl; the B is optionally surrounded by one or more R c Replacement; the condition is when L 1 -N(R) a When )-, B is not a cyclohexyl group.

[0065] In some embodiments, B is selected from the group consisting of: phenyl or The B is optionally defined by one or more R. c Replace; among them This indicates that B is chemically bonded to L. 1 Location; This indicates that B is chemically bonded to -(CH2). p - position; condition is when L 1 -N(R) a When )-, B is not

[0066] In some embodiments, B is selected from the group consisting of: The B is optionally defined by one or more R. c Replacement; the condition is when L 1 -N(R) a When )-, B is not

[0067] In some implementations, the B is optionally represented by one, two, or three Rs. c replace.

[0068] In some implementations, the B is optionally represented by one or two Rs. c replace.

[0069] In some implementation schemes, R c Selected from halogen, cyano, nitro, hydroxy, carboxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10 aryl, 3-9 membered heterocyclic or 5-9 membered heteroaryl; wherein the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10The aryl, 3-9 membered heterocyclic or 5-9 membered heteroaryl groups are each optionally substituted independently by one or more groups selected from the group consisting of: halogen, cyano, hydroxyl, carboxyl, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, C2-C6 alkenyl or C2-C6 alkynyl.

[0070] In some implementation schemes, R c The group is selected from halogen, cyano, nitro, hydroxy, carboxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl or C3-C6 cycloalkyl; wherein each of the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl or C3-C6 cycloalkyl is independently and optionally substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxy, carboxyl, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, C2-C6 alkenyl or C2-C6 alkynyl.

[0071] In some implementation schemes, R c The group is selected from halogen, cyano, nitro, hydroxy, carboxyl, amino, C1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl, C2-C4 alkynyl or C3-C6 cycloalkyl; wherein each of the C1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl, C2-C4 alkynyl or C3-C6 cycloalkyl is independently and optionally substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxy, carboxyl, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, C2-C6 alkenyl or C2-C6 alkynyl.

[0072] In some implementation schemes, R c The group is selected from halogen, cyano, nitro, hydroxy, carboxyl, amino, C1-C3 alkyl or C1-C3 alkoxy; wherein each of the C1-C3 alkyl or C1-C3 alkoxy groups is independently and optionally substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxy, carboxyl, amino or nitro.

[0073] In some implementations, B is selected from... phenyl or in This indicates that B is chemically bonded to L. 1 Location; This indicates that B is chemically bonded to -(CH2). p - position; condition is when L 1 -N(R) a When )-, B is not

[0074] In some implementations, p is 1.

[0075] In some implementations, p is 0.

[0076] In some implementations, L 2 for in L represents 2 Linked to (CH2) via chemical bonds p Location; L represents 2 It is attached to the W site via a chemical bond.

[0077] In some implementations, the R b Selected from hydrogen, C1-C6 alkyl, 3-10 membered heterocyclic, C3-C8 cycloalkyl, C6-C 10 aryl or 5-14 membered heteroaryl; wherein the C1-C6 alkyl, 3-10 membered heterocyclic, C3-C8 cycloalkyl, C6-C 10 Each of the aryl or 5-14 heteroaryl groups is independently and optionally substituted by one or more groups selected from the group consisting of: halogen, cyano, hydroxyl, carboxyl, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, C2-C6 alkenyl or C2-C6 alkynyl.

[0078] In some implementations, the R b Selected from hydrogen, C1-C6 alkyl, 3-8 membered heterocyclic, C3-C8 cycloalkyl, C6-C 10 aryl or 5-9 membered heteroaryl; wherein the C1-C6 alkyl, 3-8 membered heterocyclic, C3-C8 cycloalkyl, C6-C 10 Each of the aryl or 5-9 heteroaryl groups is independently and optionally substituted by one or more groups selected from the group consisting of: halogen, cyano, hydroxyl, carboxyl, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, C2-C6 alkenyl or C2-C6 alkynyl.

[0079] In some implementations, the R b Selected from hydrogen, C1-C4 alkyl, 3-6 membered heterocyclic, C3-C6 cycloalkyl, C6-C 10 aryl or 5-7 membered heteroaryl; wherein the C1-C4 alkyl, 3-6 membered heterocyclic, C3-C6 cycloalkyl, C6-C 10Each of the aryl or 5-7 heteroaryl groups is independently and optionally substituted by one or more groups selected from the group consisting of: halogen, cyano, hydroxyl, carboxyl, amino, nitro, C1-C3 alkyl, C1-C3 alkoxy, halo-C1-C3 alkyl, halo-C1-C3 alkoxy, C2-C4 alkenyl or C2-C4 alkynyl.

[0080] In some implementations, the R b The group is selected from hydrogen, C1-C4 alkyl, 3-6 membered heterocyclic or C3-C6 cycloalkyl; wherein each of the C1-C4 alkyl, 3-6 membered heterocyclic or C3-C6 cycloalkyl groups is independently and optionally substituted by one or more groups selected from the group consisting of: halogen, cyano, hydroxy, carboxyl, amino, nitro, C1-C3 alkyl, C1-C3 alkoxy, halo-C1-C3 alkyl or halo-C1-C3 alkoxy.

[0081] In some implementations, the R b It is selected from hydrogen or C1-C3 alkyl; wherein the C1-C3 alkyl is optionally substituted by one or more groups selected from the group consisting of: halogen, cyano, hydroxy, carboxyl, amino, nitro, C1-C3 alkyl, C1-C3 alkoxy, halo-C1-C3 alkyl or halo-C1-C3 alkoxy.

[0082] In some implementations, the R b It is selected from hydrogen or C1-C3 alkyl; wherein the C1-C3 alkyl is optionally substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxy, carboxyl, amino or nitro.

[0083] In some implementation schemes, R b Selected from hydrogen or methyl.

[0084] In some implementation schemes, R b Selected from hydrogen.

[0085] In some implementations, L 2 for Or -C(O)-; where L represents 2 Linked to (CH2) via chemical bonds p Location; L represents 2 It is attached to the W site via a chemical bond.

[0086] In some implementations, L 2 for in L represents 2 Linked to (CH2) via chemical bonds p Location; L represents 2It is attached to the W site via a chemical bond.

[0087] In some implementations, W is selected from C3-C 14 Cycloalkyl, 3-14 membered heterocyclic, C6-C 10 aryl or 5-14 heteroaryl; the W is optionally surrounded by one or more R d replace.

[0088] In some implementations, W is selected from C3-C 12 Cycloalkyl, 3-12 membered heterocyclic, C6-C 10 aryl or 5-12 heteroaryl; the W is optionally surrounded by one or more R d replace.

[0089] In some implementations, W is selected from C3-C 11 Cycloalkyl, 3-11 membered heterocyclic, C6-C 10 aryl or 5-10 heteroaryl; the W is optionally surrounded by one or more R d replace.

[0090] In some embodiments, W is selected from C3-C8 monocyclic cycloalkyl groups, C5-C6 cycloalkyl groups, and C7-C8 cycloalkyl groups. 11 Polycyclic alkyl, C5-C 11 Spirocycloalkyl, C5-C 11 Bridged cycloalkyl, 3-8 membered monocyclic heterocyclic group, 5-11 membered fused heterocyclic group, 5-11 membered spirocyclic group, 5-11 membered bridged heterocyclic group, C6-C 10 aryl, 5-8 membered monocyclic heteroaryl, or 6-10 membered fused heteroaryl; wherein W is optionally coated with one or more R d replace.

[0091] In some embodiments, W is selected from C3-C7 monocyclic cycloalkyl groups, C5-C6 cycloalkyl groups, and C7-C6 cycloalkyl groups. 11 Polycyclic alkyl, C5-C 11 Spirocycloalkyl, C5-C 11 Bridged cycloalkyl, 3-7 membered monocyclic heterocyclic group, 7-11 membered fused heterocyclic group, 5-11 membered spirocyclic group, 5-11 membered bridged heterocyclic group, C6-C 10 aryl, 5-8 membered monocyclic heteroaryl, or 8-10 membered fused heteroaryl; wherein W is optionally coated with one or more R d replace.

[0092] In some embodiments, W is selected from C3-C7 monocyclic cycloalkyl groups, C5-C6 cycloalkyl groups, and C7-C6 cycloalkyl groups. 11 Polycyclic alkyl, C7-C 11 Spirocycloalkyl, C6-C 10Bridged cycloalkyl, 5-8 membered monocyclic heterocyclic, 5-6 membered heterocyclic phenyl, 5-6 membered heterocyclic 5-6 membered heteroaryl, 5-6 membered heterocyclic 5-6 membered heterocyclic, 5-6 membered heterocyclic C3-C6 cycloalkyl, 8-11 membered spirocyclic, 6-10 membered bridged heterocyclic, C6-C 10 aryl, 5-6 membered monocyclic heteroaryl, 5-6 membered heteroaryl-5-6 membered heteroaryl or 5-6 membered heteroaryl-phenyl; wherein W is optionally coated with one or more R d replace.

[0093] In some embodiments, W is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, C5-C 11 Polycyclic alkyl, C7-C 11 Spirocycloalkyl, C6-C 10 Bridged cycloalkyl, 3-7 membered monocyclic heterocyclic, phenyl, 5-6 membered monocyclic heteroaryl, 5-membered heteroaryl-6-membered heteroaryl, 6-membered heteroaryl-6-membered heteroaryl, or 5-6-membered heteroaryl-phenyl; wherein W is optionally separated by one or more R d replace.

[0094] In some embodiments, the W is selected from the group consisting of: pyrazolyl, pyrazolopyridyl, pyrrolopyridyl, pyrazolopyrimidinyl, pyrazolophenyl, 1-methylbicyclo[2.2.2]octane, pyridyl, pyrimidinyl, imidazopyrimidinyl, pyridopyrazolyl, isoxazolyl, oxazolyl, pyrazolopyrimidinyl, pyrazolopyridazinyl, benzoisooxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, pyridopyrimidinyl, pyrazolofuranyl, pyrazoloisooxazolyl, pyridazinyl, pyrimidinylpiperidinoneyl, triazolopyrimidinyl, imidazopyridazinyl, oxazolopyrimidinyl or isoxazolopyrimidinyl; the W is optionally separated by one or more R d replace.

[0095] In some embodiments, the W is selected from the group consisting of: The W is optionally defined by one or more R. d replace.

[0096] In some embodiments, the W is selected from the group consisting of: The W is optionally defined by one or more R. d replace.

[0097] In some implementations, the R d Selected from halogen, cyano, nitro, -OR e -SR e -S(=O)R e -S(=O)2R e -C(O)R e-C(O)-OR e -N(R) e (R) f ), C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, 3-8 membered heterocyclic, C6-C 10 aryl or 5-10 membered heteroaryl; wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 ynyl, C3-C6 cycloalkyl, 3-8 membered heterocyclic, C6-C 10 Aryl or 5-10 heteroaryl groups are each independently and optionally bound by one or more R groups. g replace.

[0098] In some implementations, the R d Selected from halogen, cyano, nitro, -OR e -SR e -S(=O)R e -S(=O)2R e -C(O)R e -C(O)-OR e -N(R) e (R) f C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic, C6-C 10 aryl or 5-6 membered heteroaryl; wherein the C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic, C6-C 10 Each of the aryl or 5-6 heteroaryl groups is independently and optionally bounded by one or more R groups. g replace.

[0099] In some implementations, the R d Selected from fluorine, chlorine, bromine, cyano, nitro, -OR e -N(R) e (R) f ), C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic, C6-C 10 aryl or 5-6 membered heteroaryl; wherein the C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic, C6-C 10 Each of the aryl or 5-6 heteroaryl groups is independently and optionally bounded by one or more R groups. g replace.

[0100] In some implementations, the R d Selected from fluorine, chlorine, bromine, cyano, nitro, -OR e -N(R)e (R) f ), C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 heterocyclic, phenyl, or 5-6 heteroaryl; wherein the C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 heterocyclic, phenyl, or 5-6 heteroaryl are each optionally and independently formed by one or more R g replace.

[0101] In some implementation schemes, R e R f They may be the same or different, and each is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-8 membered heterocyclic, C3-C6 cycloalkyl, C6-C 10 aryl or 5-10 membered heteroaryl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-8 membered heterocyclic, C3-C6 cycloalkyl, C6-C 10 The aryl or 5-10 heteroaryl groups are each independently and optionally selected from one or more R groups of the group below. g replace.

[0102] In some implementation schemes, R e R f They may be the same or different, and each is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-6 membered heterocyclic, C3-C6 cycloalkyl, C6-C 10 aryl or 5-6 membered heteroaryl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, 3-6 membered heterocyclic, C3-C6 cycloalkyl, C6-C 10 The aryl or 5-6 heteroaryl groups are each independently and optionally selected from one or more R groups of the group below. g replace.

[0103] In some implementation schemes, R e R f They may be the same or different, and each is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 4-6 membered heterocyclic, C3-C6 cycloalkyl, C6-C 10 aryl or 4-6-membered heteroaryl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, 4-6-membered heterocyclic, C3-C6 cycloalkyl, C6-C 10 The aryl or 4-6 heteroaryl groups are each independently and optionally selected from one or more R groups of the group below. g replace.

[0104] In some implementation schemes, R e R fThey may be the same or different, and each independently selected from hydrogen, C1-C3 alkyl, or phenyl; wherein the C1-C3 alkyl or phenyl is each independently and optionally selected from one or more of the following groups. g replace.

[0105] In some implementations, the R g Selected from halogen, cyano, hydroxy, amino, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, hydroxylated C1-C6 alkyl, amino C1-C6 alkyl, C3-C8 cycloalkyl, 3-12 membered heterocyclic groups, C6-C 10 Aryl or 5-14 heteroaryl compounds.

[0106] In some implementations, the R g Selected from halogen, cyano, hydroxy, amino, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, hydroxylated C1-C6 alkyl, amino C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclic, C6-C 10 Aryl or 5-10 heteroaryl compounds.

[0107] In some implementations, the R g Selected from halogen, cyano, hydroxy, amino, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, hydroxylated C1-C6 alkyl, amino C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic groups, C6-C 10 Aryl or 5-7 heteroaryl compounds.

[0108] In some implementations, the R g It is selected from halogen, cyano, hydroxy, amino, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated C1-C6 alkyl, C1-C6 alkoxy or halogenated C1-C6 alkoxy.

[0109] In some implementations, the R g It is selected from fluorine, chlorine, bromine, cyano, hydroxyl, amino, nitro, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, halogenated C1-C3 alkyl, C1-C3 alkoxy or halogenated C1-C3 alkoxy.

[0110] In some embodiments, the W is selected from the group consisting of:

[0111]

[0112] In some embodiments, the W is selected from the group consisting of: On the other hand, the present invention provides the following compounds or pharmaceutically acceptable salts thereof:

[0113]

[0114]

[0115] In some embodiments, the present invention provides the following compounds or pharmaceutically acceptable salts thereof:

[0116]

[0117] A second aspect of the present invention provides a pharmaceutical composition comprising the compound described in the first aspect above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0118] Another aspect of the present invention provides the use of the first aspect described above or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in the second aspect above, in the preparation of a medicament for treating and / or preventing MRGPRX2-related diseases.

[0119] Another aspect of the present invention provides a method for treating MRGPRX2-related diseases, comprising the steps of administering a therapeutically effective amount of the first aspect described above or a pharmaceutically acceptable salt thereof to a patient in need, or administering a therapeutically effective amount of the pharmaceutical composition described in the second aspect described above to a patient in need.

[0120] In some implementations, the diseases associated with MRGPRX2 include: skin diseases, autoimmune diseases, and neurological diseases.

[0121] Another aspect of the present invention provides an intermediate compound selected from:

[0122]

[0123]

[0124] definition

[0125] Unless otherwise stated, the following terms as used in this application shall have the following meanings. A particular term should not be considered uncertain or unclear unless specifically defined, but should be understood in accordance with its ordinary meaning in the art.

[0126] The term “substituted” or “replaced by” refers to the substitution of one or more hydrogen atoms on a specific atom by a substituent, provided that the valence state of the specific atom is normal and the substituted compound is stable.

[0127] The term "optional" or "optionally" means that the event or situation subsequently described may or may not occur, including both the occurrence and non-occurrence of the event or situation. The phrase "optionally replaced by..." as used in this invention includes both "replaced" and "not replaced".

[0128] In this article, "one or more" refers to an integer from one to ten. For example, "one or more" means one, two, three, four, five, six, seven, eight, nine, or ten; further, it can be one, two, three, four, or five; and even further, it can be one, two, or three; but the chemical valence bond requirement must be met.

[0129] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Therefore, for example, if a group is substituted by two Rs, each R has an independent option.

[0130] The numerical ranges mentioned in this article refer to the integers within a given range. For example, "C1-C6" means that the group can have 1, 2, 3, 4, 5, or 6 carbon atoms; "C3-C6" means that the group can have 3, 4, 5, or 6 carbon atoms.

[0131] The term "membered ring" refers to the number of skeletal atoms or groups of atoms that make up the ring. For example, groups like C=O, S(=O)2, or S(=O) have skeletal atoms C, S, and S respectively, and are represented as unary. "5-7 membered rings" indicates that the number of skeletal atoms or groups of atoms in the ring is 5, 6, or 7. For example, pyridine and piperidine are six-membered rings, while thiazoles and pyrroles are five-membered rings.

[0132] The term "chemical bond" refers to the strong force that binds two or more adjacent atoms (or ions) together within a pure molecule or crystal, mainly including covalent bonds, ionic bonds, metallic bonds, and coordinate bonds. Unless otherwise stated, the chemical bonds in the compounds of this invention existing in free form are mostly covalent bonds.

[0133] In This indicates the point where the group is chemically bonded to the rest of the molecule.

[0134] The term "effective dose" or "therapeutic effective dose" refers to a sufficient amount of a drug or agent that is non-toxic but achieves the desired effect.

[0135] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological potency of a particular compound as a free acid or base without any adverse biological effects. Examples include acid (including organic and inorganic acids) addition salts or base addition salts (including organic and inorganic bases).

[0136] The term "pharmaceutically acceptable carrier" refers to carriers that do not cause significant irritation to the body and do not impair the biological activity and properties of the active compound. This includes, but is not limited to, diluents, disintegrants, binders, flow aids, and wetting agents.

[0137] The compounds of this invention contain asymmetric centers that may lead to stereoisomerism, as well as other chemical structures; therefore, this invention also includes these stereoisomers and mixtures thereof. Since the compounds of this invention (or pharmaceutically acceptable salts thereof) can exist in diastereomer or enantiomeric forms, or mixtures thereof, all optical isomers (e.g., enantiomers and diastereomers), racemic mixtures of said isomers, diastereomer mixtures, and other mixtures are within the scope of this invention. The compounds of this invention can be prepared using diastereomers, enantiomers, or racemic mixtures as starting materials. Optically active pure forms can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0138] Solid lines may be used in this article. solid wedge Or virtual wedge The carbon-carbon bonds of the compounds of the present invention are indicated. Bonds to asymmetric carbon atoms are described by solid lines, indicating the presence of all possible stereoisomers at that carbon atom, such as cis isomers, trans isomers, enantiomers, diastereomers, or racemates and mixtures thereof. Bonds to asymmetric carbon atoms are described by solid or imaginary wedges, indicating the presence of the indicated stereoisomers, such as (R)- or (S)- enantiomers.

[0139] The terms "tautomer" or "tautomer form" refer to isomers of different functional groups in dynamic equilibrium that can rapidly interconvert. All tautomer forms of the compounds of this invention are within the scope of this invention, i.e., existing as a single isomer or as a mixture of said tautomers in any proportion. Non-limiting examples include: keto-enols, imine-enamines, lactam-lactamimides, etc.

[0140] This application also includes compounds of this application that are identical to those described herein, but with one or more atoms replaced by isotopes of different atomic weights or mass numbers than those commonly found in nature. Examples of isotopes that can be incorporated into the compounds of this application include isotopes of hydrogen, carbon, oxygen, nitrogen, and sulfur, such as 2H, 3H, 11C, 13C, 14C, 15O, 17O, 18O, 35S, etc., respectively. Certain isotopically labeled compounds of this application (e.g., those labeled with 3H and 14C) can be used in the analysis of compound and / or substrate tissue distribution. Deuterated (i.e., 2H) and carbon-14 (i.e., 14C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emission isotopes, such as 15O and 11C, can be used in positron emission tomography (PET) studies to determine substrate occupancy. The isotopically labeled compounds of this application can typically be prepared by replacing the unlabeled reagent with an isotopically labeled reagent using a procedure similar to those disclosed in the schemes and / or examples below. Furthermore, substitution with a heavier isotope (such as deuterium (2H)) can provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirement), and is therefore preferred in certain cases, where deuterium substitution can be partial or complete, with partial deuterium substitution referring to at least one hydrogen atom being replaced by at least one deuterium atom.

[0141] The present invention middle This indicates that any position within the ring, such as a benzene ring or a pyridine ring, is optionally occupied by one or more R... x replace. middle This indicates that any position within the ring, such as the pyridine ring or the imidazole ring, is optionally occupied by one or more R... y replace.

[0142] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which can be straight-chain or branched. For example, the term "C1-C6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms, and non-limiting examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl, etc. The term "C1-C6 alkyl" can further be "C1-C4 alkyl", "C1-C3 alkyl", C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, or C6 alkyl.

[0143] The term "alkylene" refers to a saturated straight-chain or branched aliphatic hydrocarbon group, which is a residue derived by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane. The term "C1-C6 alkylene" refers to an alkylene containing 1 to 6 carbon atoms. Further preferred are "C1-C3 alkylene". Non-limiting examples include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), etc.

[0144] The term "C1-C6 alkoxy" refers to "C1-C6 alkyl-O-", where "C1-C6 alkyl" is as defined above. Non-limiting examples of C1-C6 alkoxy compounds include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, 2-methyl-2-propoxy, 1-pentoxy, 2-pentoxy, 3-pentoxy, 2-methyl-2-butoxy, 3-methyl-2-butoxy, 3-methyl-1-butoxy, 2-methyl-1-butoxy, etc. The "C1-C6 alkoxy" of this invention can further be "C1-C4 alkoxy" or "C1-C3 alkoxy".

[0145] The term "halogen" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0146] The term "hydroxyl group" refers to the -OH group.

[0147] The term "amino" refers to the -NH2 group.

[0148] The term "cyano" refers to the -CN group.

[0149] The term "nitro" refers to the -NO2 group.

[0150] The term "carboxyl group" refers to -C(O)OH.

[0151] In this invention, "halogenated C1-C6 alkyl" or "halogenated C1-C6 alkoxy" means that the alkyl or alkoxy group is replaced by one or more halogen atoms, wherein "halogen," "C1-C6 alkyl," or "C1-C6 alkoxy" are as defined above. Specific examples include, but are not limited to, difluoroethyl (-CH2CHF2, -CF2CH3, -CHFCH2F), trifluoroethyl (-CH2CF3, -CF2CH2F, -CFHCHF2), trifluoromethyl (-CF3), trifluoromethoxy (-OCF3), etc. The term "halogenated C1-C6 alkyl" can further be "halogenated C1-C4 alkyl" or "halogenated C1-C3 alkyl"; the term "halogenated C1-C6 alkoxy" can further be "halogenated C1-C4 alkoxy" or "halogenated C1-C3 alkoxy."

[0152] The term "hydroxy C1-C6 alkyl" indicates that an alkyl group is substituted with one or more hydroxyl groups. "Hydroxy" or "C1-C6 alkyl" is as defined above. Specific examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, etc. The term "hydroxy C1-C6 alkyl" can further be "hydroxy C1-C4 alkyl" or "hydroxy C1-C3 alkyl".

[0153] The term "amino C1-C6 alkyl" indicates that the alkyl group is replaced by one or more amino groups. "Amino" and "C1-C6 alkyl" are as defined above. Specific examples include, but are not limited to, -CH2NH2, -(CH2)2NH2, -CH(NH2)CH3, -CH(NH2)CH2NH2, -(CH2)3NH2, etc. The term "amino C1-C6 alkyl" can further be "amino C1-C4 alkyl" or "amino C1-C3 alkyl".

[0154] The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond, wherein the definition of alkyl is as described above. The "C2-C6 alkenyl" used in this invention refers to an alkenyl group having 2 to 6 carbon atoms. It can be a mono-olefin, diene, or tri-olefin, and non-limiting examples include, but are not limited to, vinyl, propenyl, isopropenyl, butenyl, etc.

[0155] The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond, wherein the definition of an alkyl group is as described above. The "C2-C6 alkynyl" used in this invention refers to an alkynyl group having 2 to 6 carbon atoms. Non-limiting examples include, but are not limited to, ethynyl, propynyl, butynyl, pentyynyl, and hexynyl.

[0156] The term "cycloalkyl" refers to a saturated monocyclic or polycyclic cyclic hydrocarbon group, including monocyclic cycloalkyl, spirocyclic alkyl, fused cycloalkyl, and bridged cycloalkyl. For example, the term "C3-C..." 20"Cycloalkyl" refers to a cycloalkyl group containing 3-20 carbon atoms in a ring, and it can further be C3-C4. 14 cycloalkyl, C3-C 12 cycloalkyl, C3-C 11 cycloalkyl, C3-C 10 Cycloalkyl, C3-C8 cycloalkyl, C3-C6 cycloalkyl, and non-limiting examples of which include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.

[0157] The term "C3-C8 monocyclic cycloalkyl" refers to a saturated monocyclic cyclic hydrocarbon group having 3 to 8 ring carbon atoms, preferably a C3-C7 monocyclic cycloalkyl (i.e., a 3- to 7-membered monocyclic cycloalkyl) or a C3-C6 monocyclic cycloalkyl (i.e., a 3- to 6-membered monocyclic cycloalkyl), more preferably a C3, C4, C5, or C6 monocyclic cycloalkyl. Specific examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0158] The term "fused cyclic alkyl" refers to a polycyclic hydrocarbon group formed by two or more monocyclic rings sharing a pair of adjacent carbon atoms. Based on the number of rings formed, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused cyclic alkyl groups. The term "C5-C..." 11 "Fused cycloalkyl" refers to a polycyclic cyclic hydrocarbon group having 5 to 11 ring carbon atoms, wherein the monocyclic ring sharing adjacent carbon atom pairs is a 3- to 8-membered monocyclic cycloalkyl ring. Preferably, it is C7-C6. 10 Fused cycloalkyl groups, more preferably 6-membered fused cycloalkyl groups consisting of 5-membered monocyclic cycloalkyl rings and 3-membered monocyclic cycloalkyl rings, 7-membered fused cycloalkyl groups consisting of 5-membered monocyclic cycloalkyl rings and 4-membered monocyclic cycloalkyl rings, 8-membered fused cycloalkyl groups consisting of 5-membered monocyclic cycloalkyl rings and 5-membered monocyclic cycloalkyl rings, 7-membered fused cycloalkyl groups consisting of 6-membered monocyclic cycloalkyl rings and 3-membered monocyclic cycloalkyl rings, 8-membered fused cycloalkyl groups consisting of 6-membered monocyclic cycloalkyl rings and 4-membered monocyclic cycloalkyl rings, 9-membered fused cycloalkyl groups consisting of 6-membered monocyclic cycloalkyl rings and 5-membered monocyclic cycloalkyl rings, and 10-membered fused cycloalkyl groups consisting of 6-membered monocyclic cycloalkyl rings and 6-membered monocyclic cycloalkyl rings. Specific examples of fused cycloalkyl groups include, but are not limited to: These fused alkyl groups can be connected to the rest of the molecule via any one of the ring atoms.

[0159] The term "spirocycloalkyl" refers to a polycyclic hydrocarbon group formed by two or more monocyclic rings sharing a single carbon atom (called a spiro atom). Based on the number of shared spiro atoms between the rings, spirocycloalkyl groups are classified into monospirocycloalkyl, bispirocycloalkyl, and polyspirocycloalkyl groups. The term "C5-C" is also used. 11 "Spirocycloalkyl" refers to a polycyclic cyclic hydrocarbon group having 5 to 11 ring carbon atoms, wherein the monocyclic ring sharing the spiro atom is a 3- to 8-membered monocyclic cycloalkyl ring. Preferably, it is C7-C6. 11Spirocycloalkyl; most preferably 7-membered (4-membered monocyclic cycloalkyl ring / 4-membered monocyclic cycloalkyl ring), 8-membered (4-membered monocyclic cycloalkyl ring / 5-membered monocyclic cycloalkyl ring), 9-membered (4-membered monocyclic cycloalkyl ring / 6-membered monocyclic cycloalkyl ring, 5-membered monocyclic cycloalkyl ring / 5-membered monocyclic cycloalkyl ring), 10-membered (5-membered monocyclic cycloalkyl ring / 6-membered monocyclic cycloalkyl ring), or 11-membered (6-membered monocyclic cycloalkyl ring / 6-membered monocyclic cycloalkyl ring) monospirocycloalkyl. Specific examples of spirocycloalkyl include, but are not limited to: These spirocycloalkyl groups can be attached to the rest of the molecule via any one of the ring atoms.

[0160] The term "bridged cycloalkyl" refers to a polycyclic cyclic hydrocarbon group formed by two or more monocyclic rings sharing two non-directly connected carbon atoms. Based on the number of rings formed, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl. The term "C5-C..." 11 "Bridged cycloalkyl" refers to a polycyclic cyclic hydrocarbon group having 5 to 11 ring carbon atoms, wherein any two rings share two non-directly connected carbon atoms. Preferably, it is C7-C6. 11 Bridged cycloalkyl; more preferably C6-C 10 Bridged cycloalkyl groups. Specific examples of bridged cycloalkyl groups include, but are not limited to: These bridged cycloalkyl groups can be connected to the rest of the molecule through any one of the ring atoms.

[0161] The term "aryl" refers to an aromatic ring group consisting of an all-carbon monocyclic or fused polycyclic aromatic ring with a conjugated π-electron system. The "C6-C" group described in this invention... 10 "Aryl" can include, but is not limited to, phenyl, naphthyl, anthracene, etc.

[0162] The term "heterocyclic group" refers to a saturated or partially saturated non-aromatic ring, in which at least one ring system contains one or more heteroatoms. It can be a monocyclic, bicyclic, polycyclic, spirocyclic, or bridged ring, i.e., containing a monocyclic heterocyclic group, a fused heterocyclic group, a spirocyclic group, or a bridged heterocyclic group. The "3-20 membered heterocyclic group" described in this invention refers to a cyclic group containing heteroatoms and 3-20 ring atoms, wherein the heteroatoms are selected from nitrogen, oxygen, and sulfur. The nitrogen, carbon, or sulfur atoms in the heterocyclic group can optionally be oxidized, such as the "-CH2-" group of the heterocyclic group, which can optionally be oxidized to form -C(=O)-; or the sulfur can optionally be oxidized to form a sulfone or sulfoxide. The term "3-20 membered heterocyclic group" can be further defined as "3-14 membered heterocyclic group", "3-12 membered heterocyclic group", "3-11 membered heterocyclic group", "3-10 membered heterocyclic group", "3-9 membered heterocyclic group", "3-8 membered heterocyclic group", "3-6 membered heterocyclic group", and "4-6 membered heterocyclic group". The heterocyclic group described in this invention can further be a monocyclic heterocyclic group (such as a 3-8 member monocyclic heterocyclic group, a 3-7 member monocyclic heterocyclic group, a 5-8 member monocyclic heterocyclic group, a 5-6 member monocyclic heterocyclic group), a spirocyclic heterocyclic group (such as a 5-12 member spirocyclic heterocyclic group, a 5-11 member spirocyclic heterocyclic group, an 8-11 member spirocyclic heterocyclic group), a fused heterocyclic group (such as a 5-12 member fused heterocyclic group, a 5-11 member fused heterocyclic group, an 8-11 member fused heterocyclic group), and a bridged heterocyclic group (such as a 5-12 member bridged heterocyclic group, a 5-11 member bridged heterocyclic group, a 6-10 member bridged heterocyclic group). The number of heteroatoms in the heterocyclic group described in this invention can be 1, 2, 3, 4, 5, or 6; more specifically, the number of heteroatoms can be 1, 2, or 3.

[0163] The term "monocyclic heterocyclic group" refers to a monocyclic group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. The heterocycle can be saturated or partially saturated. The "3-8 membered monocyclic heterocyclic group" described in this invention can further be a "3-8 membered saturated monocyclic heterocyclic group" and a "3-8 membered partially saturated monocyclic heterocyclic group." The "3-8 membered monocyclic heterocyclic group" is preferably a "3-7 membered monocyclic heterocyclic group," "3-6 membered monocyclic heterocyclic group," "4-7 membered monocyclic heterocyclic group," "4-6 membered monocyclic heterocyclic group," "6-8 membered monocyclic heterocyclic group," "5-8 membered monocyclic heterocyclic group," "5-6 membered monocyclic heterocyclic group," etc. Non-limiting examples of the "3-8 membered monocyclic heterocyclic group" include, but are not limited to: aziridine, 2H-aziridine, diaziridine, 3H-diazacyclopropenyl, aziridine, oxacyclobutyl, thiocyclobutyl, aziridine-heptyl, thiocycloheptyl, 1,4-dioxane, 1,3-dioxane, 1,3-dioxanepentyl, 1,4-dioxanediadienyl, tetrahydrofuranyl, dihydropyrrolyl, pyrrolylyl (pyrrolidine-1-yl, pyrrolidine-2-yl, pyrrolidine-3-yl), imidazoalkyl, 4,5-dihydroimidazoyl. Pyrazolyl (pyrazolidine-2-yl, pyrazolidine-3-yl), 4,5-dihydropyrazolyl, 2,5-dihydrothiophenyl, tetrahydrothiophenyl, 4,5-dihydrothiazolyl, thiazolyl, piperidinyl (piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl), tetrahydropyridinyl, piperidinoneyl, tetrahydropyridinoneyl, dihydropiperidinoneyl, piperazinyl (2,5-piperazinyl), morpholinyl, 4,5-dihydrooxazolyl, 4,5-dihydroisooxazolyl, 2,3-dihydroisooxazolyl, oxazolyl, 2H-1,2-oxazinyl, 4H-1,2-oxazinyl, etc.

[0164] The term "spiroheterocyclic group" refers to a saturated or partially saturated cyclic structure formed by two or more cyclic structures sharing a single ring atom, which contains at least one heteroatom selected from nitrogen, oxygen, or sulfur. The "5-11 member spiroheterocyclic group" described in this invention can further be an "8-11 member spiroheterocyclic group" or an "8-10 member spiroheterocyclic group," more preferably a 7-membered (4-membered monocyclic heterocyclic group / 4-membered monocyclic heterocyclic group or 4-membered monocyclic heterocyclic group / 4-membered monocyclic cycloalkyl group or 4-membered monocyclic cycloalkyl group / 4-membered monocyclic heterocyclic group), an 8-membered (4-membered monocyclic heterocyclic group / 5-membered monocyclic heterocyclic group), a 9-membered (4-membered monocyclic heterocyclic group / 6-membered monocyclic heterocyclic group, 5-membered monocyclic heterocyclic group / 5-membered monocyclic heterocyclic group), a 10-membered (5-membered monocyclic heterocyclic group / 6-membered monocyclic heterocyclic group), or an 11-membered (6-membered monocyclic heterocyclic group / 6-membered monocyclic heterocyclic group) monospiroheterocyclic group. Non-limiting examples of spiroheterocyclic groups include, but are not limited to: wait.

[0165] The term "fused heterocyclic group" refers to a saturated or partially saturated cyclic structure formed by two or more ring structures sharing two adjacent atoms, containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. One of the rings in the fused ring may be an aromatic ring, but the fused ring as a whole does not possess aromaticity. Based on the number of constituent rings, fused heterocyclic groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic. The "5-11 fused heterocyclic group" described in this invention can further be an "8-11 fused heterocyclic group", "7-11 fused heterocyclic group", "6-10 fused heterocyclic group", "8-10 fused heterocyclic group", "6-10 nitrogen-containing fused heterocyclic group", or "8-10 nitrogen-containing fused heterocyclic group"; even further, it can be a 6-membered (5-membered monocyclic heterocyclic group fused with a 3-membered monocyclic heterocyclic group), a 7-membered (5-membered monocyclic heterocyclic group fused with a 4-membered monocyclic heterocyclic group), an 8-membered (5-membered monocyclic heterocyclic group fused with another 5-membered monocyclic heterocyclic group), a 9-membered (5-membered monocyclic heterocyclic group fused with a 6-membered monocyclic heterocyclic group), or a 10-membered (6-membered monocyclic heterocyclic group fused with another 6-membered monocyclic heterocyclic group) bicyclic fused heterocyclic group. The "8-10 fused heterocyclic group" described in this invention includes "8-10 saturated fused heterocyclic group" and "8-10 partially saturated fused heterocyclic group". Non-limiting examples of fused heterocyclic groups include, but are not limited to: These fused heterocyclic groups can be connected to the rest of the molecule by any suitable ring atom.

[0166] The term "bridged heterocyclic group" refers to a saturated or partially saturated cyclic structure formed by any two rings sharing two non-directly connected atoms, containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. Based on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. The "5-11 member bridged heterocyclic group" described in this invention can further be a "7-10 member bridged heterocyclic group," "6-10 member bridged heterocyclic group," "7 member bridged heterocyclic group," "8 member bridged heterocyclic group," etc., and even more further, it can be a 5-membered nitrogen-containing ring bridged to a 4-membered ring, a 5-membered nitrogen-containing ring bridged to a 5-membered ring, a 6-membered nitrogen-containing ring bridged to a 4-membered ring, or a 5-membered nitrogen-containing ring bridged to a 5-membered ring. Non-limiting examples of bridged heterocyclic groups include, but are not limited to: wait.

[0167] The term "heteroaryl" refers to an aromatic monocyclic or fused polycyclic group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. The "5-20 membered heteroaryl" described in this invention can further be "5-14 membered heteroaryl," "5-12 membered heteroaryl," "5-10 membered heteroaryl," "5-9 membered heteroaryl," "5-7 membered heteroaryl," "5-6 membered heteroaryl," and even further, can be 5-8 membered monocyclic heteroaryl (e.g., 4-, 5-, 6-, 7-, or 8-membered rings), 5-6 membered monocyclic heteroaryl, 6-14 membered fused heteroaryl, 6-10 membered fused heteroaryl, 8-10 membered fused heteroaryl, or 6-9 membered fused heteroaryl. The number of heteroatoms in the heteroaryl group described in this invention can be 1, 2, 3, 4, 5, or 6; more specifically, the number of heteroatoms can be 1, 2, or 3. Non-limiting examples of heteroaryl groups include, but are not limited to: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, and tetrazolyl (also known as tetrazolyl, such as 5H-tetrazolyl, 2H-tetrazolyl). Triazolyl (e.g., 2-triazolyl, 5-triazolyl, 4H-1,2,4-triazolyl, 1H-1,2,4-triazolyl, 1,2,3-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl and 3-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl, pyridinoneyl, oxadiazoloneyl, indoloneyl, etc. The term "fused heteroaryl" can also include, but is not limited to, polycyclic aromatic groups formed by the fusion of benzene rings and heteroaryl rings. The “8-10 fused heteroaryl” mentioned in this invention refers to a fused heteroaryl ring system having 8 to 10 ring atoms, including 5-membered heteroaryl and 6-membered heteroaryl, 6-membered heteroaryl and 6-membered heteroaryl, or 5-6-membered heteroaryl and phenyl, etc.Non-limiting examples include, but are not limited to: imidazopyridyl, pyrazolopyridyl, pyrrolopyridyl, pyridinopyrimidyl, pyrazolophenyl, imidazopyrimidyl, pyridinopyrazolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, benzopyrazolyl, benzimidazolone, benzothiophenyl, indoleyl (e.g., 2-indoleyl), purineyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl), pyrazolopyrimidyl, pyrazolopyridazinyl, benzisoxazolyl, quinazolinyl, pyrazolofuranyl, pyrazolosoxazolyl, triazolopyrimidyl, imidazopyridazinyl, oxazolopyrimidyl or isoxazolopyrimidyl, etc.

[0168] The term "alkylamino" refers to a -NHR group, where R is an alkyl group as defined above. Non-limiting examples of the term "C1-C6 alkylamino" include, but are not limited to, methylamino, ethylamino, propylamino, or 2-propylamino.

[0169] The term "oxo" means "=O". Detailed Implementation

[0170] The following examples and test cases illustrate the present invention in detail, but they do not limit the scope of the invention, and variations can be made without departing from the scope of the invention.

[0171] The compounds of the present invention can also be conveniently prepared by combining various synthetic methods described in this specification or known in the art, such combinations being readily performed by those skilled in the art.

[0172] M: mol / L; nM refers to nmol / L; 1 1H NMR: Proton nuclear magnetic resonance spectrum; MS (ESI): Mass spectrometry; DMSO-d6: Deuterated dimethyl sulfoxide; Methanol-d4: Deuterated methanol; Boc: tert-butyloxycarbonyl; Cbz: benzyloxycarbonyl. "v / v" refers to the volume ratio.

[0173] Example 1: 1-Methyl-N-(5-((2-(trifluoromethyl)quinolin-4-yl)amino)bicyclo[3.2.1]octane-1-yl)-1H-pyrazole-4-carboxamide

[0174]

[0175] a) Benzyl (5-((2-(trifluoromethyl)quinolin-4-yl)amino)bicyclo[3.2.1]octane-1-yl)carbamate

[0176] Benzyl (5-aminobicyclo[3.2.1]octane-1-yl)carbamate (200 mg) was dissolved in N-methylpyrrolidone (10 mL), and 4-chloro-2-(trifluoromethyl)quinoline (247 mg) and N,N-diisopropylethylamine (293 mg) were added. The mixture was stirred at 180 °C for 3 hours under microwave conditions. The reaction solution was concentrated to dryness under reduced pressure, extracted with ethyl acetate and water, and separated. The organic phase was concentrated to dryness under reduced pressure and subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 (v / v)) to give the title product (200 mg). MS (ESI, m / z): 470.2 [M+H] + .

[0177] b)N 1 -(2-(trifluoromethyl)quinolin-4-yl)bicyclo[3.2.1]octane-1,5-diamine

[0178] Benzyl (5-((2-(trifluoromethyl)quinolin-4-yl)amino)bicyclo[3.2.1]octane-1-yl)carbamate (200 mg) was dissolved in ethanol (10 mL), and palladium on carbon (200 mg, 10%) was added. The mixture was stirred at 20 °C for 3 hours under hydrogen atmosphere at 1 atm. The reaction solution was filtered and concentrated to dryness under reduced pressure to give the title product (100 mg). MS (ESI, m / z): 336.2 [M+H] + .

[0179] c) 1-Methyl-N-(5-((2-(trifluoromethyl)quinolin-4-yl)amino)bicyclo[3.2.1]octane-1-yl)-1H-pyrazole-4-carboxamide

[0180] Dissolve 1-methyl-1H-pyrazole-4-carboxylic acid (45 mg) in N,N-dimethylformamide (10 mL), add N,N-diisopropylethylamine (116 mg) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (136 mg), stir at 20 °C for 10 minutes, then add N 1 -(2-(trifluoromethyl)quinoline-4-yl)bicyclo[3.2.1]octane-1,5-diamine (100 mg) was stirred at 20 °C for 3 hours. The reaction solution was concentrated to dryness under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol = 20:1 (v / v)) to give 25.5 mg of the title product. 1H NMR(400MHz, DMSO-d6)δ8.46(d,J=8.5Hz,1H),8.12(s,1H),7.90–7.83(m,3H),7.74(t, J=7.7Hz,1H),7.56(t,J=7.6Hz,1H),7.45–7.41(m,1H),6.80(s,1H),3.84(s,3H),2.48 –2.42(m,1H),2.32–2.23(m,2H),2.20–2.13(m,1H),2.13–2.04(m,2H),2.04–1.94(m,1 H),1.93–1.84(m,1H),1.84–1.68(m,3H),1.61–1.50(m,1H).MS(ESI,m / z):444.2[M+H] + .

[0181] Example 2: N-(4-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)morpholin-2-yl)methyl)-1-methyl- 1 H-pyrazole-4-formamide

[0182]

[0183] a)(4-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)morpholin-2-yl)methyl)tert-butyl carbamate

[0184] 100 mg of 4,6-dichloro-2-(trifluoromethyl)quinoline was dissolved in 6 mL of N-methylpyrrolidone, and 107 mg of tert-butyl (morpholino-2-ylmethyl)carbamate and 146 mg of N,N-diisopropylethylamine were added. The mixture was stirred at 130 °C for 5 hours. The reaction solution was extracted with water and ethyl acetate, and the liquid was separated. The organic phase was concentrated to dryness under reduced pressure and subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 (v / v)) to give the title product (130 mg). MS (ESI, m / z): 446.1 [M+H] + .

[0185] b)(4-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)morpholin-2-yl)methylamine

[0186] 170 mg of (4-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)morpholin-2-yl)methyl)carbamate tert-butyl ester was dissolved in 5 mL of 1,4-dioxane, and a 1,4-dioxane solution of hydrogen chloride (5 mL, 4 M) was added. The mixture was stirred at 20 °C for 2 hours. The reaction solution was concentrated to dryness under reduced pressure, extracted with saturated sodium bicarbonate and ethyl acetate, and separated. The organic phase was concentrated to dryness under reduced pressure to give the title product (120 mg). MS (ESI, m / z): 346.1 [M+H] +.

[0187] c)N-(4-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)morpholin-2-yl)methyl)-1-methyl-1H-pyrazole-4-carboxamide

[0188] (60 mg) of (4-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)morpholin-2-yl)methylamine was dissolved in acetonitrile (6 mL), followed by the addition of 1-methyl-1H-pyrazole-4-carboxylic acid (26 mg), N-methylimidazolium (65 mg), and finally tetramethylchlorourea hexafluorophosphate (63 mg). The mixture was purged with nitrogen and stirred at 20 °C for 2 hours. The reaction mixture was extracted with water and ethyl acetate, separated, and the organic phase was concentrated to dryness under reduced pressure. Silica gel column chromatography (dichloromethane:methanol = 20:1 (v / v)) yielded the title product (37 mg). 1 H NMR(400MHz, DMSO-d6)δ8.22(t,J=6.0Hz,1H),8.14–8.10(m,2H),8.02(d,J= 2.4Hz,1H),7.90–7.82(m,2H),7.34(s,1H),4.06–3.99(m,1H),3.98–3.87(m, 2H),3.84(s,3H),3.61(d,J=12.4Hz,1H),3.41(t,J=6.0Hz,2H),3.31(s,1H) ,3.17–3.07(m,1H),2.84(dd,J=12.4,10.1Hz,1H).MS(ESI,m / z):454.1[M+H] + .

[0189] Example 3: (S)-2-(3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)piperidin-1-yl)-1-(1-methyl-1H-pyrazol-4-yl)ethane-1-one

[0190]

[0191] a) tert-butyl(S)-(1-(2-(1-methyl-1H-pyrazol-4-yl)-2-oxoethyl)piperidin-3-yl)carbamate

[0192] 1.0 g of tert-butyl(S)-piperidin-3-ylcarbamate and 1.0 g of 2-bromo-1-(1-methyl-1H-pyrazol-4-yl)ethyl-1-one were dissolved in acetonitrile (10 mL), and 1.38 g of potassium carbonate were added. The mixture was stirred at 25 °C for 2 hours. The reaction solution was poured into water, extracted with ethyl acetate, and separated. The organic phase was concentrated to dryness under reduced pressure. The product was purified by column chromatography to the title product. Silica gel column chromatography (dichloromethane:methanol = 20:1 (v / v)) yielded the title product (1.1 g). MS (ESI, m / z): 323.2 [M+H]+.

[0193] b)(S)-2-(3-aminopiperidin-1-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl-1-one

[0194] 1.1 g of tert-butyl (S)-(1-(2-(1-methyl-1H-pyrazol-4-yl)-2-oxoethyl)piperidin-3-yl)carbamate was dissolved in ethyl acetate (0.5 mL), and 5 mL (4 M) of a 1,4-dioxane solution of hydrogen chloride was added. The mixture was stirred at 25 °C for 3 hours. The reaction solution was concentrated to dryness under reduced pressure, and extracted with saturated sodium bicarbonate solution and ethyl acetate. The extract was separated, and the organic phase was concentrated to dryness under reduced pressure to give the title product (700 mg). MS (ESI, m / z): 223.2 [M+H] + .

[0195] c)(S)-2-(3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)piperidin-1-yl)-1-(1-methyl-1H-pyrazol-4-yl)ethane-1-one

[0196] (S)-2-(3-aminopiperidin-1-yl)-1-(1-methyl-1H-pyrazol-4-yl)ethyl-1-one (100 mg) and 4,6-dichloro-2-(trifluoromethyl)quinoline (130 mg) were dissolved in N,N-dimethylformamide solution (5 mL), and then N,N-diisopropylethylamine (260 mg) was added. After the addition was complete, the mixture was stirred at 90 °C for 3 hours. The reaction solution was concentrated to dryness under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol = 20:1 (v / v)) to give the title product (6 mg). 1H NMR(400MHz,DMSO-d6)δ8.58(d,J=2.3Hz,1H),8.49(s,1H),8.00(s,1H),7.95–7.84(m,1H), 7.75(dd,J=9.0,2.2Hz,1H),7.43(d,J=7.8Hz,1H),6.79(s,1H),3.88(s,5H),3.04(dd,J=10 .8,3.7Hz,1H),2.83(d,J=10.7Hz,1H),2.20(t,J=10.1Hz,2H),1.98(dt,J=12.7,6.5Hz,2H) ,1.73(dh,J=10.8,6.4,5.7Hz,2H),1.50(dt,J=10.6,5.2Hz,1H).MS(ESI,m / z):452.1[M+H] + .

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

[0198]

[0199] a)(4-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)benzyl)tert-butyl carbamate

[0200] 200 mg of tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzyl)carbamate was dissolved in 10 mL of 1,4-dioxane. 300 mg of 4,6-dichloro-2-(trifluoromethyl)quinoline, 55 mg of 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride, and 734 mg of cesium carbonate were added, and the mixture was stirred at 100 °C for 3 hours. The reaction solution was concentrated to dryness under reduced pressure, extracted with ethyl acetate and water, and separated. The organic phase was concentrated to dryness under reduced pressure, and the solution was subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 (v / v)) to give the title product (200 mg). MS (ESI, m / z): 437.1 [M+H] + .

[0201] b)(4-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)phenyl)methylamine

[0202] 200 mg of tert-butyl (4-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)benzyl)carbamate was dissolved in 1 mL of methanol, and 5 mL of a 1,4-dioxane solution of hydrogen chloride (4 M) was added. The mixture was stirred at 20 °C for 3 hours. The reaction solution was concentrated to dryness under reduced pressure, extracted with saturated sodium bicarbonate solution and ethyl acetate, and separated. The organic phase was concentrated to dryness under reduced pressure to give the title product (100 mg). MS (ESI, m / z): 337.1 [M+H] + .

[0203] c)N-(4-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)benzyl)-1-methyl-1H-pyrazole-4-carboxamide

[0204] 1-Methyl-1H-pyrazole-4-carboxylic acid (45 mg) was dissolved in N,N-dimethylformamide (10 mL), and N,N-diisopropylethylamine (116 mg) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (136 mg) were added. The mixture was stirred at 20 °C for 10 minutes, and then 4-(6-chloro-2-(trifluoromethyl)quinoline-4-yl)phenyl)methylamine (100 mg) was added and stirred at 20 °C for 3 hours. The reaction solution was concentrated to dryness under reduced pressure, and silica gel column chromatography (dichloromethane:methanol = 20:1 (v / v)) was performed to give the title product (68 mg). 1 H NMR (400MHz, DMSO-d6) δ8.73(t,J=6.0Hz,1H),8.31(d,J=9.0Hz,1H),8.18(s,1H),8.00(dd,J=9.0,2.4Hz,1H),7.92(d,J =7.1Hz,3H),7.62(d,J=8.0Hz,2H),7.55(d,J=8.0Hz,2H),4.56(d,J=6.0Hz,2H),3.87(s,3H).MS(ESI,m / z):445.1[M+H] + .

[0205] Example 5: N-((1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)piperidin-3-yl)methyl)-1-methyl-1H-pyrazole-4-carboxamide

[0206]

[0207] a) tert-butyl((1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)piperidin-3-yl)methyl)carbamate

[0208] 200 mg of tert-butyl(piperidin-3-ylmethyl)carbamate was dissolved in 10 mL of N-methylpyrrolidone, and 193 mg of 4,6-dichloro-2-(trifluoromethyl)quinoline and 293 mg of N,N-diisopropylethylamine were added. The mixture was stirred at 180 °C for 3 hours under microwave conditions. The reaction solution was extracted with ethyl acetate and water, and the liquid was separated. The organic phase was washed with saturated sodium chloride solution and concentrated to dryness under reduced pressure. The solution was then subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 (v / v)) to give the title product (200 mg). MS (ESI, m / z): 444.2 [M+H] + .

[0209] b) 1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)piperidin-3-yl)methylamine

[0210] 200 mg of tert-butyl ((1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)piperidin-3-yl)methyl)carbamate was dissolved in 1 mL of methanol, and 4 mL (4 M) of a 1,4-dioxane solution of hydrogen chloride was added. The mixture was stirred at 20 °C for 3 hours. The reaction solution was concentrated to dryness under reduced pressure, extracted with saturated sodium bicarbonate solution and ethyl acetate, and separated. The organic phase was concentrated to dryness under reduced pressure to give the title product (100 mg). MS (ESI, m / z): 344.1 [M+H] + .

[0211] c)N-((1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)piperidin-3-yl)methyl)-1-methyl-1H-pyrazole-4-carboxamide

[0212] 1-Methyl-1H-pyrazole-4-carboxylic acid (45 mg) was dissolved in N,N-dimethylformamide (10 mL), and N,N-diisopropylethylamine (116 mg) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (136 mg) were added. The mixture was stirred at 20 °C for 10 minutes, and then (1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)piperidin-3-yl)methylamine (100 mg) was added. The mixture was stirred at 20 °C for 3 hours. The reaction solution was concentrated to dryness under reduced pressure, and silica gel column chromatography (dichloromethane:methanol = 20:1 (v / v)) was performed to give the title product (68 mg). 1H NMR(400MHz, DMSO-d6)δ8.15(t,J=5.9Hz,1H),8.10–8.05(m,2H),7.92(d,J=2.3Hz ,1H),7.85–7.78(m,2H),7.27(s,1H),3.83(s,3H),3.64(d,J=11.9Hz,2H),3.53(d, J=12.5Hz,2H),3.15–3.07(m,1H),2.99(t,J=11.5Hz,1H),2.72(t,J=11.2Hz,1H), 1.93–1.84(m,2H),1.84–1.73(m,1H),1.29–1.21(m,1H).MS(ESI,m / z):452.1[M+H] + .

[0213] Example 6: (2-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)morpholino)(1-methyl-1H-pyrazol-4-yl)methyl ketone

[0214]

[0215] a)((4-(1-methyl-1H-pyrazole-4-carbonyl)morpholin-2-yl)methyl)tert-butyl carbamate

[0216] 100 mg of (morpholino-2-ylmethyl)carbamate tert-butyl ester was dissolved in acetonitrile (6 mL), followed by the addition of 70 mg of 1-methyl-1H-pyrazole-4-carboxylic acid and 190 mg of N-methylimidazolium. Finally, 156 mg of tetramethylchlorourea hexafluorophosphate was added. The mixture was purged with nitrogen and stirred at 20 °C for 2 hours. The reaction solution was quenched with water, extracted with ethyl acetate, separated, and the organic phase was concentrated to dryness under reduced pressure to obtain the title product (300 mg). MS (ESI, m / z): 325.2 [M+H] + .

[0217] b)(2-(aminomethyl)morpholino)(1-methyl-1H-pyrazol-4-yl)methyl ketone

[0218] 170 mg of tert-butyl ((4-(1-methyl-1H-pyrazole-4-carbonyl)morpholin-2-yl)methyl)carbamate was dissolved in 5 mL of 1,4-dioxane, and a 4 M solution of 1,4-dioxane in hydrogen chloride was added. The mixture was stirred at 20 °C for 2 hours. The reaction solution was concentrated to dryness under reduced pressure, extracted with saturated sodium bicarbonate solution and ethyl acetate, separated, and the organic phase was concentrated to dryness under reduced pressure to give the title product (100 mg).

[0219] c)(2-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)morpholino)(1-methyl-1H-pyrazol-4-yl)methyl ketone

[0220] Dissolve 80 mg of (2-(aminomethyl)morpholino)(1-methyl-1H-pyrazol-4-yl) ketone in 6 mL of 1,4-dioxane, add 90 mg of 4,6-dichloro-2-(trifluoromethyl)quinoline, 30 mg of [2-(dicyclohexylphosphine)-3-tert-butoxy-6-methoxy-2',6'-diisopropyl-1,1'-biphenyl](4-((2-(trimethylsilyl)ethoxy)carbonyl)phenyl-1-yl)palladium bromide and 118 mg of sodium tert-butoxide, purge with nitrogen, stir at 100 °C for 12 hours, extract the reaction solution with water and ethyl acetate, separate the liquid, concentrate the organic phase to dryness under reduced pressure, and precipitate by silica gel column chromatography (dichloromethane:methanol = 20:1 (v / v)) to give the title product (4 mg). 1 HNMR(400MHz,DMSO-d6)δ8.54(d,J=2.4Hz,1H),8.06(s,1H),7.91(t,J=9.2H z,2H),7.77(dd,J=9.2,2.0Hz,1H),7.67(s,1H),6.94(s,1H),4.34(s,1H),4. 04(d,J=16.8Hz,1H),3.90(d,J=11.6Hz,1H),3.84(s,3H),3.74(s,1H),3.64 –3.57(m,1H),3.49(d,J=13.6Hz,3H),2.90(s,1H).MS(ESI,m / z):454.1[M+H] + .

[0221] Example 7: 3-Chloro-1-methyl-N-(4-(2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)benzyl)-1H-pyrazole-4-carboxamide

[0222]

[0223] a) 5-Bromo-2-(trifluoromethyl)imidazo[1,2-a]pyridine

[0224] 1 g of 6-bromopyridin-2-amine was dissolved in 16 mL of ethanol, and 2.2 g of 3-bromo-1,1,1-trifluoroprop-2-one was added. The mixture was purged with nitrogen and stirred at 90 °C for 12 hours. The reaction solution was concentrated to dryness under reduced pressure, extracted with ethyl acetate and saturated sodium bicarbonate solution, and separated. The organic phase was concentrated to dryness under reduced pressure and subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 4:1 (v / v)) to give the title product (1 g). MS (ESI, m / z): 265.0 [M+H] +

[0225] b)((4-(2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)benzyl)tert-butyl carbamate

[0226] 100 mg of 5-bromo-2-(trifluoromethyl)imidazo[1,2-a]pyridine was dissolved in 5 mL of 1,4-dioxane. Then, 150 mg of tert-butyl carbamate (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzyl)carbamate, 31 mg of [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex, and 250 mg of cesium carbonate were added. The mixture was purged with nitrogen and stirred at 100 °C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The filtrate was then subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 4:1 (v / v)) to give the title product (120 mg). MS (ESI, m / z): 392.1 [M+H] + .

[0227] c)(4-(2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)phenyl)methylamine

[0228] 120 mg of (4-(2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)benzyl)carbamate tert-butyl ester was dissolved in 5 mL of 1,4-dioxane, and a 1,4-dioxane solution of hydrogen chloride (5 mL, 4 M) was added. The mixture was stirred at 20 °C for 2 hours. The reaction solution was concentrated to dryness under reduced pressure, extracted with saturated sodium bicarbonate solution and ethyl acetate, and separated. The organic phase was concentrated to dryness under reduced pressure to give the title product (90 mg). MS (ESI, m / z): 292.1 [M+H] + .

[0229] d) 3-Chloro-1-methyl-N-(4-(2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)benzyl)-1H-pyrazole-4-carboxamide

[0230] (4-(2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)phenyl)methylamine (90 mg) was dissolved in acetonitrile (6 mL), followed by the addition of 3-chloro-1-methyl-1H-pyrazole-4-carboxylic acid (30 mg), N-methylimidazolium (63 mg), and finally tetramethylchlorourea hexafluorophosphate (56 mg). The mixture was purged with nitrogen, stirred at 20 °C for 2 hours, quenched with water, extracted with ethyl acetate, dried, concentrated, and then lyophilized to obtain the title product (30 mg). 1H NMR(400MHz, Methanol-d4)δ8.08(d,J=2.4Hz,2H),7.72–7.49(m,6H),7.04(dd, J=6.8,1.3Hz,1H),4.65(s,2H),3.87(d,J=1.2Hz,3H).MS(ESI,m / z):434.1[M+H] + .

[0231] Example 8: (R)-4-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N-(1-methyl-1H-pyrazol-4-yl)morpholin-2-carboxamide

[0232]

[0233] a) Tert-butyl(R)-2-((1-methyl-1H-pyrazol-4-yl)carbamoyl)morpholine-4-carboxylic acid tert-butyl ester

[0234] (R)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (0.5 g) and 1-methyl-1H-pyrazole-4-amine (0.2 g) were dissolved in dichloromethane (5 mL), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.76 g) and 4-dimethylaminopyridine (0.48 g) were added. The mixture was stirred at 25 °C for 2 hours. The reaction solution was extracted with water and ethyl acetate, separated, and the organic phase was concentrated to dryness under reduced pressure. Silica gel column chromatography (dichloromethane:methanol = 20:1 (v / v)) gave the title product (670 mg). MS (ESI, m / z): 311.2 [M+H] + .

[0235] b)(R)-N-(1-methyl-1H-pyrazol-4-yl)morpholin-2-carboxamide

[0236] 670 mg of tert-butyl(R)-2-((1-methyl-1H-pyrazol-4-yl)carbamoyl)morpholine-4-carboxylic acid tert-butyl ester was dissolved in ethyl acetate (0.5 mL), and 4 mL of 1,4-dioxane solution of hydrogen chloride (4 M) was added. The mixture was stirred at 25 °C for 3 hours. The reaction solution was concentrated to dryness under reduced pressure. The mixture was extracted with saturated sodium bicarbonate solution and ethyl acetate, and the liquid was separated. The organic phase was concentrated to dryness under reduced pressure to obtain the title product (400 mg).

[0237] c)(R)-4-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N-(1-methyl-1H-pyrazol-4-yl)morpholin-2-carboxamide

[0238] (R)-N-(1-methyl-1H-pyrazol-4-yl)morpholine-2-carboxamide (400 mg) and 4,6-dichloro-2-(trifluoromethyl)quinoline (400 mg) were dissolved in N,N-dimethylformamide solution (5 mL), and then N,N-diisopropylethylamine (0.98 g) was added. After the addition was complete, the mixture was stirred at 90 °C for 3 hours. The reaction solution was concentrated to dryness under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol = 20:1 (v / v)) to give the title product (16 mg). 1 HNMR(400MHz,DMSO)δ10.12(s,1H),8.30(d,J=2.4Hz,1H),8.14(d,J=9.0Hz,1H), 7.95–7.87(m,2H),7.59(s,1H),7.42(s,1H),4.57(dd,J=8.8,2.9Hz,1H),4.08(dd t,J=20.8,11.7,6.2Hz,2H),3.79(s,3H),3.66(d,J=12.3Hz,1H),3.52(d,J=12.6H z,1H),3.33(m,1H),3.21(ddd,J=12.5,9.1,3.4Hz,1H).MS(ESI,m / z):440.1[M+H] + .

[0239] Example 9: 1-Methyl-N-(trans-4-((2-(trifluoromethyl)imidazol[1,2-a]pyridin-5-yl)oxy)cyclohexyl)- 1 H-pyrazole-4-formamide

[0240]

[0241] a) tert-butyl(trans-4-((2-(trifluoromethyl)imidazol[1,2-a]pyridin-5-yl)oxy)cyclohexyl)carbamate

[0242] 5-Chloro-2-(trifluoromethyl)imidazolium[1,2-a]pyridine (0.2 g) and tert-butyl(trans-4-hydroxycyclohexyl)carbamate (0.25 g) were dissolved in 5 mL of toluene. Di(allyl)dichloropalladium (20 mg) and (R)-(-)-1-[(S)-2-diphenylphosphine]ferroceneethyldicyclohexylphosphine (40 mg) were added. The mixture was stirred at 90 °C for 3 hours. The reaction solution was concentrated to dryness under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol = 20:1 (v / v)) to give the title product (157 mg). MS (ESI, m / z): 400.2 [M+H] + .

[0243] b) trans-4-((2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)oxo)cyclohexane-1-amine

[0244] 157 mg of tert-butyl(trans-4-((2-(trifluoromethyl)imidazolium[1,2-a]pyridin-5-yl)oxy)cyclohexyl)carbamate was dissolved in a small amount of ethyl acetate (0.5 mL), and 4 mL (4 M) of 1,4-dioxane hydrochloride solution was added. The mixture was stirred at 25 °C for 3 hours. The reaction solution was concentrated to dryness under reduced pressure, and extracted with saturated sodium bicarbonate solution and ethyl acetate. The organic phase was concentrated to dryness under reduced pressure to give the title product (109 mg). MS (ESI, m / z): 300.1 [M+H] + .

[0245] c) 1-Methyl-N-(trans-4-((2-(trifluoromethyl)imidazol[1,2-a]pyridin-5-yl)oxy)cyclohexyl)-1H-pyrazole-4-carboxamide

[0246] Trans-4-((2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)oxo)cyclohexane-1-amine (100 mg) and 1-methyl-1H-pyrazole-4-carboxylic acid (57 mg) were dissolved in acetonitrile (5 mL), then N-methylimidazolium (74 mg) and N,N,N',N'-tetramethylchloromethanesulfonium hexafluorophosphate (252 mg) were added. After the addition was complete, the mixture was stirred at 25 °C for 3 hours. The reaction solution was concentrated to dryness under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol = 20:1 (v / v)) to give the title product (27 mg). 1 H NMR (400MHz, DMSO) δ8.31(s,1H),8.16(s,1H),7.95–7.84(m,2H),7.48(dd,J=9.1,7.5Hz,1H),7.30(d,J=9.0Hz,1H),6.69(d,J=7.6Hz,1H),4 .80–4.69(m,1H),3.86(m,4H),2.25(d,J=9.4Hz,2H),1.97(d,J=9.7Hz,2H),1.78–1.63(m,2H),1.61–1.45(m,2H).MS(ESI,m / z):408.2[M+H] + .

[0247] Example 10: N-((1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)pyrrolidine-3-yl)methyl)-1-methyl-1H-pyrazole-4-carboxamide

[0248]

[0249] a) tert-butyl((1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)pyrrolidine-3-yl)methyl)carbamate

[0250] 0.5 g of tert-butyl (pyrrolidone-3-ylmethyl)carbamate and 4,6-dichloro-2-(trifluoromethyl)quinoline (470 mg) were dissolved in 10 mL of N,N-dimethylformamide. N,N-diisopropylethylamine (700 mg) was added, and the mixture was stirred at 90 °C for 2 hours. The reaction solution was concentrated to dryness under reduced pressure, and silica gel column chromatography (dichloromethane:methanol = 20:1 (v / v)) was performed to give the title product (700 mg). MS (ESI, m / z): 430.1 [M+H] + .

[0251] b)(1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)pyrrolidine-3-yl)methylamine

[0252] 700 mg of tert-butyl ((1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)pyrrolidine-3-yl)methyl)carbamate was dissolved in 0.5 mL of ethyl acetate. A 4 mL, 4 M solution of 1,4-dioxane hydrogen chloride was added, and the mixture was stirred at 25 °C for 3 hours. The reaction solution was concentrated to dryness under reduced pressure. Extraction was performed with saturated sodium bicarbonate solution and ethyl acetate, followed by separation. The organic phase was concentrated to dryness under reduced pressure to give the title product (450 mg). MS (ESI, m / z): 330.1 [M+H] + .

[0253] c)N-((1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)pyrrolidine-3-yl)methyl)-1-methyl-1H-pyrazole-4-carboxamide

[0254] (1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)pyrrolidine-3-yl)methylamine (110 mg) and 1-methyl-1H-pyrazole-4-carboxylic acid (57 mg) were dissolved in acetonitrile solution (5 mL), then N-methylimidazolium (74 mg) and N,N,N',N'-tetramethylchloromethanesulfonium hexafluorophosphate (252 mg) were added. After the addition was complete, the mixture was stirred at 25 °C for 3 hours. The reaction solution was concentrated to dryness under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol = 20:1 (v / v)) to give the title product (27 mg). 1H NMR (400MHz, DMSO) δ8.37–8.26 (m, 2H), 8.13 (s, 1H), 7.93 (d, J = 8.9Hz, 1H), 7. 85(s,1H),7.74(dd,J=9.1,2.2Hz,1H),6.75(d,J=2.9Hz,1H),3.91–3.75(m,5 H),3.56(ddd,J=25.1,10.2,7.0Hz,2H),3.21(dtt,J=19.9,13.3,6.4Hz,1H), 2.52(p,J=1.9Hz,3H),2.12(dq,J=13.4,6.5Hz,1H).MS(ESI,m / z):438.1[M+H] + .

[0255] Example 11: (3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)piperidin-1-yl)(1-methyl-1H-pyrazol-4-yl)methyl ketone

[0256]

[0257] a)(1-(1-methyl-1H-pyrazole-4-carbonyl)piperidin-3-yl)methyl)tert-butyl carbamate

[0258] 1-Methyl-1H-pyrazole-4-carboxylic acid (141 mg) was dissolved in N,N-dimethylformamide (10 mL), followed by the addition of N,N-diisopropylethylamine (364 mg) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (425 mg). The mixture was stirred at 20 °C for 10 minutes, and then tert-butyl (piperidin-3-ylmethyl)carbamate (200 mg) was added and stirred at 20 °C for 3 hours. The reaction mixture was concentrated to dryness under reduced pressure and purified by silica gel column chromatography (ethyl acetate:methanol = 10:1 (v / v)) to give the title product (150 mg). MS (ESI, m / z): 323.2 [M+H] + .

[0259] b)(3-(aminomethyl)piperidin-1-yl)(1-methyl-1H-pyrazole-4-yl)methyl ketone

[0260] 150 mg of tert-butyl (1-(1-methyl-1H-pyrazole-4-carbonyl)piperidin-3-yl)methyl)carbamate was dissolved in 1 mL of methanol and 4 mL of 1,4-dioxane hydrochloride solution (4 M). The mixture was stirred at 25 °C for 3 hours. The reaction solution was concentrated to dryness under reduced pressure. Extraction was performed with saturated sodium bicarbonate solution and ethyl acetate. The organic phase was concentrated to dryness under reduced pressure to give the title product (100 mg). MS (ESI, m / z): 223.2 [M+H] +c)(3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)piperidin-1-yl)(1-methyl-1H-pyrazol-4-yl)methyl ketone

[0261] 100 mg of 4,6-dichloro-2-(trifluoromethyl)quinoline was dissolved in 10 mL of N-methylpyrrolidone, and 96.6 mg of 3-(aminomethyl)piperidin-1-yl)(1-methyl-1H-pyrazol-4-yl)methyl ketone and 147.3 mg of N,N-diisopropylethylamine were added. The mixture was stirred at 180 °C for 3 hours under microwave conditions. The reaction solution was extracted with ethyl acetate and water, separated, and the organic phase was concentrated to dryness under reduced pressure. The solution was then subjected to silica gel column chromatography (dichloromethane:methanol = 20:1 (v / v)) to give the title product (60 mg). 1 H NMR (400MHz, DMSO-d6) δ8.52(s,1H),7.92(d,J=9.0Hz,2H),7.76(m,J=9.0,2.2Hz,2H),7.57(s,1H),6.83(s,1H),4.41–3.98(m,2H),3 .76(s,3H),3.14–2.80(m,2H),2.74–2.52(m,2H),2.05–1.90(m,2H),1.80–1.67(m,1H),1.52–1.28(m,2H).MS(ESI,m / z):452.1[M+H] + .

[0262] Example 12: N-7-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-7-azabicyclo[2.2.1]heptane-2-yl)-1-methyl-1H-pyrazole-4-carboxamide

[0263]

[0264] a) tert-butyl(7-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-7-azabicyclo[2.2.1]heptane-2-yl)carbamate

[0265] 200 mg of tert-butyl(7-azabicyclo[2.2.1]heptane-2-yl)carbamate was dissolved in 10 mL of N-methylpyrrolidone, and 216 mg of 4,6-dichloro-2-(trifluoromethyl)quinoline and 293 mg of N,N-diisopropylethylamine were added. The mixture was stirred at 180 °C for 3 hours under microwave conditions. The reaction solution was extracted with ethyl acetate and water, separated, and the organic phase was concentrated to dryness under reduced pressure. Silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 (v / v)) yielded the title product (120 mg). MS (ESI, m / z): 442.1 [M+H] + .

[0266] b) 7-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-7-azabicyclo[2.2.1]heptane-2-amine

[0267] 120 mg of tert-butyl(7-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-7-azabicyclo[2.2.1]heptane-2-yl)carbamate was dissolved in 1 mL of methanol, and 4 mL (4 M) of a 1,4-dioxane solution of hydrogen chloride was added. The mixture was stirred at 20 °C for 3 hours. The reaction solution was concentrated to dryness under reduced pressure, and extracted with saturated sodium bicarbonate solution and ethyl acetate. The organic phase was concentrated to dryness under reduced pressure to give the title product (70 mg). MS (ESI, m / z): 342.1 [M+H] + .

[0268] c) N-(7-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-7-azabicyclo[2.2.1]heptane-2-yl)-1-methyl-1H-pyrazole-4-carboxamide

[0269] 1-Methyl-1H-pyrazole-4-carboxylic acid (45 mg) was dissolved in N,N-dimethylformamide (10 mL), and N,N-diisopropylethylamine (116 mg) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (136 mg) were added. The mixture was stirred at 20 °C for 10 minutes, and then 7-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-7-azabicyclo[2.2.1]heptane-2-amine (100 mg) was added. The mixture was stirred at 20 °C for 3 hours. The reaction solution was concentrated to dryness under reduced pressure, and silica gel column chromatography (dichloromethane:methanol = 20:1 (v / v)) was performed to give isomer A (13 mg) and isomer B (29 mg) of the title product.

[0270] Isomer A: 1 H NMR (400MHz, DMSO-d6) δ8.15–8.12(m,2H),8.04–7.97(m,2H),7.83(s,1H),7.77(dd,J=9.0,2.3Hz,1H),7.24(s,1H),4.62(d,J=4.5Hz,1H),4.50(d, J=4.2Hz,1H),4.04–3.98(m,1H),3.83(s,3H),2.13(d,J=12.9Hz,1H),2.0 6–1.95(m,1H),1.74(s,2H),1.58–1.46(m,2H).MS(ESI,m / z):450.1[M+H] +

[0271] Isomer B: 1H NMR (400MHz, DMSO-d6) δ8.18(d,J=7.2Hz,2H),8.13(d,J=2.4Hz,1H),8.06(d,J=9 .0Hz,1H),7.89–7.83(m,2H),7.27(s,1H),4.67(t,J=4.4Hz,1H),4.55(t,J=4.5H z,1H),4.27(dd,J=11.4,5.6Hz,1H),3.86(s,3H),1.94–1.82(m,2H),1.81–1.68( m,2H),1.68–1.62(m,1H),1.56(dd,J=12.5,5.0Hz,1H).MS(ESI,m / z):450.1[M+H] +

[0272] Example 13: N-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)adamantane-1-yl)-1-methyl-1H-pyrazole-4-carboxamide

[0273]

[0274] a)N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)adamantane-1,3-diamine

[0275] adamantane-1,3-diamine (200 mg) was dissolved in N-methylpyrrolidone (10 mL), and 4,6-dichloro-2-(trifluoromethyl)quinoline (216 mg) and N,N-diisopropylethylamine (293 mg) were added. The mixture was stirred at 180 °C for 3 hours under microwave conditions. The reaction solution was extracted with ethyl acetate and water, separated, and the organic phase was concentrated to dryness under reduced pressure. Silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 (v / v)) yielded the title product (200 mg). b) N-3-((6-chloro-2-(trifluoromethyl)quinoline-4-yl)amino)adamantane-1-yl)-1-methyl-1H-pyrazole-4-carboxamide

[0276] Dissolve 57 mg of 1-methyl-1H-pyrazole-4-carboxylic acid in 10 mL of N,N-dimethylformamide, add 166 mg of N,N-diisopropylethylamine and 176 mg of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, stir at 20 °C for 10 minutes, and then add N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)adamantane-1,3-diamine (150 mg), stirred at 20 °C for 3 hours, the reaction solution was concentrated to dryness under reduced pressure, and silica gel column chromatography (dichloromethane:methanol = 20:1 (v / v)) was performed to give the title product (70 mg). 1H NMR(400MHz, DMSO-d6)δ8.68(d,J=2.3Hz,1H),8.13(s,1H),7.90(d,J=9.0Hz, 1H),7.82(s,1H),7.75(dd,J=9.0,2.2Hz,1H),7.40(s,1H),7.02(s,1H),6.89 (s,1H),3.83(s,3H),2.31(s,2H),2.56–2.51(m,2H),2.16(d,J=11.8Hz,2H), 2.12–2.05(m,4H),1.99–1.91(m,2H),1.66(s,2H).MS(ESI,m / z):504.2[M+H] + .

[0277] Example 14: (2-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)-7-azabicyclo[2.2.1]heptane-7-yl)(1-methyl-1H-pyrazol-4-yl) methyl ketone

[0278]

[0279] a) tert-butyl (7-(1-methyl-1H-pyrazole-4-carbonyl)-7-azabicyclo[2.2.1]heptane-2-yl)carbamate

[0280] 1-Methyl-1H-pyrazole-4-carboxylic acid (141 mg) was dissolved in N,N-dimethylformamide (10 mL), followed by N,N-diisopropylethylamine (364 mg) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (425 mg). The mixture was stirred at 20 °C for 10 minutes, and then tert-butyl(7-azabicyclo[2.2.1]heptane-2-yl)carbamate (200 mg) was added. The mixture was stirred at 20 °C for 3 hours. The reaction solution was concentrated to dryness under reduced pressure. The crude product was purified by column chromatography (ethyl acetate:methanol = 10:1 (v / v)) to give the title product (150 mg). MS (ESI, m / z): 321.2 [M+H] + .

[0281] b)(2-amino-7-azabicyclo[2.2.1]heptane-7-yl)(1-methyl-1H-pyrazol-4-yl) methyl ketone

[0282] 150 mg of tert-butyl (7-(1-methyl-1H-pyrazole-4-carbonyl)-7-azabicyclo[2.2.1]heptane-2-yl)carbamate was dissolved in 1 mL of methanol, and 4 mL (4 M) of a 1,4-dioxane solution of hydrogen chloride was added. The mixture was stirred at 20 °C for 3 hours. The reaction solution was concentrated to dryness under reduced pressure, extracted with saturated sodium bicarbonate solution and ethyl acetate, and separated. The organic phase was concentrated to dryness under reduced pressure to give the title product (100 mg). MS (ESI, m / z): 221.1 [M+H] + .

[0283] c)(2-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)-7-azabicyclo[2.2.1]heptane-7-yl)(1-methyl-1H-pyrazol-4-yl)methyl ketone

[0284] 4,6-Dichloro-2-(trifluoromethyl)quinoline (100 mg) was dissolved in N-methylpyrrolidone (10 mL), and (2-amino-7-azabicyclo[2.2.1]heptane-7-yl)(1-methyl-1H-pyrazol-4-yl) methyl ketone (96.6 mg) and N,N-diisopropylethylamine (147.3 mg) were added. The mixture was stirred at 180 °C for 3 hours under microwave conditions. The reaction solution was extracted with ethyl acetate and water, separated, and the organic phase was concentrated to dryness under reduced pressure. The solution was then subjected to silica gel column chromatography (ethyl acetate:methanol = 10:1 (v / v)) to give the title product (58 mg). 1 H NMR(400MHz, DMSO-d6)δ8.70(d,J=2.3Hz,1H),8.17–8.10(m,1H),8.08–7.88(m,2H),7.83(d,J=3.3Hz,1H),7.78(ddd,J=9.2,7.0,2.3Hz,1H) ,7.24(s,1H),4.69–4.43(m,2H),4.21–3.98(m,1H),3.86(d,J=18.4Hz,3H),2.18–1.96(m,1H),1.90–1.46(m,5H).MS(ESI,m / z):450.1[M+H] + .

[0285] Example 15: tert-butyl (cis-4-((2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)oxy)cyclohexyl)carbamate

[0286]

[0287] a) tert-butyl(cis-4-((2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)oxy)cyclohexyl)carbamate

[0288] 200 mg of 5-fluoro-2-(trifluoromethyl)imidazolium[1,2-a]pyridine was dissolved in N,N-dimethylformamide, followed by the addition of sodium hydride (520 mg, 60% w / w) and stirring for 10 minutes. Then, 252 mg of tert-butyl (cis-4-hydroxycyclohexyl) carbamate was added, and the mixture was stirred at 90 °C for 3 hours. The reaction mixture was quenched with water, extracted with ethyl acetate, and separated. The organic phase was concentrated to dryness under reduced pressure and subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 2:1 (v / v)) to give the title product (219 mg). MS (ESI, m / z): 400.2 [M+H] + .

[0289] b) cis-4-((2-(trifluoromethyl)imidazol[1,2-a]pyridin-5-yl)oxy)cyclohexane-1-amine

[0290] 0.4 g of tert-butyl(cis-4-((2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)oxy)cyclohexyl)carbamate was dissolved in ethyl acetate (0.5 mL), and 4 mL (4 M) of 1,4-dioxane hydrochloride solution was added. The mixture was stirred at 25 °C for 3 hours. The reaction solution was concentrated to dryness under reduced pressure, and extracted with saturated sodium bicarbonate solution and ethyl acetate. The extract was separated, and the organic phase was concentrated to dryness under reduced pressure to give the title product (0.2 g). MS (ESI, m / z): 300.1 [M+H] + .

[0291] c) 1-Methyl-N-(cis-4-((2-(trifluoromethyl)imidazol[1,2-a]pyridin-5-yl)oxy)cyclohexyl)-1H-pyrazole-4-carboxamide

[0292] cis-4-((2-(trifluoromethyl)imidazol[1,2-a]pyridin-5-yl)oxy)cyclohexane-1-amine (100 mg) and 1-methyl-1H-pyrazole-4-carboxylic acid (57 mg) were dissolved in acetonitrile solution (5 mL), then N-methylimidazolium (74 mg) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (252 mg) were added. After the addition was complete, the mixture was stirred at 25 °C for 3 hours. The reaction solution was concentrated to dryness under reduced pressure and subjected to silica gel column chromatography (dichloromethane:methanol = 20:1 (v / v)) (39 mg). 1H NMR (400MHz, DMSO) δ8.26(s,1H),8.15(s,1H),7.91–7.82(m,2H),7.48(dd,J=9.1,7.6Hz,1H),7.30(d,J=9.0Hz,1H),6 .60(d,J=7.6Hz,1H),5.04–4.99(m,1H),3.85(m,4H),2.20–2.08(m,2H),1.87–1.69(m,6H).MS(ESI,m / z):408.2[M+H] + .

[0293] Example 16: N-((1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)azatidine-3-yl)methyl)-1-methyl-1H-pyrazole-4-carboxamide

[0294]

[0295] a) tert-butyl((1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)azatidine-3-yl)methyl)carbamate

[0296] 500 mg of tert-butyl(azatidine-3-ylmethyl)carbamate was dissolved in N,N-dimethylformamide, followed by the addition of 700 mg of N,N-diisopropylethylamine and stirring for ten minutes. Then, 4,6-dichloro-2-(trifluoromethyl)quinoline (410 mg) was added, and the mixture was stirred at 90 °C for 3 hours. The reaction mixture was quenched with water, extracted with ethyl acetate, and the liquid was separated. The organic phase was concentrated to dryness under reduced pressure and subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 (v / v)) to give the title product (0.61 g). MS (ESI, m / z): 416.1 [M+H] + .

[0297] b)(1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)azatidine-3-yl)methylamine

[0298] 0.61 g of tert-butyl((1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)azatidine-3-yl)methyl)carbamate was dissolved in ethyl acetate (0.5 mL), and 4 mL (4 M) of a 1,4-dioxane solution of hydrogen chloride was added. The mixture was stirred at 25 °C for 3 hours. The reaction solution was concentrated to dryness under reduced pressure. Extraction was performed with saturated sodium bicarbonate solution and ethyl acetate, followed by separation. The organic phase was concentrated to dryness under reduced pressure to give the title product (0.3 g). MS (ESI, m / z): 316.1 [M+H] + .

[0299] c)N-((1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)azatidine-3-yl)methyl)-1-methyl-1H-pyrazole-4-carboxamide

[0300] (1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)azatidine-3-yl)methylamine (300 mg) and 1-methyl-1H-pyrazole-4-carboxylic acid (189 mg) were dissolved in acetonitrile solution (5 mL), then N-methylimidazolium (246 mg) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (900 mg) were added. After the addition was complete, the mixture was stirred at 25 °C for 3 hours. The reaction solution was concentrated to dryness under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol = 20:1 (v / v)) to give the title product (26 mg). 1 H NMR (400MHz, DMSO) δ8.30(t,J=5.8Hz,1H),8.11(s,1H),8.00(d,J=2.3Hz,1H),7.93(d,J=9.0Hz,1H),7.82(s,1H),7.75(dd,J=9.0,2.3Hz,1H),6 .50(s,1H),4.57(t,J=8.5Hz,2H),4.24(dd,J=8.8,5.2Hz,2H),3.84(s,3H),3.54(t,J=6.4Hz,2H),3.07–2.94(m,1H).MS(ESI,m / z):424.1[M+H] + .

[0301] Example 17: N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)oxy)cyclohexyl)-1-methyl-1H-pyrazole-4-carboxamide

[0302]

[0303] a)((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)tert-butyl carbamate

[0304] (1R,3S)-3-hydroxycyclohexyl)carbamate tert-butyl ester (100 mg) was dissolved in N,N-dimethylformamide (6 mL), cooled to 0 °C, and sodium hydride (37 mg, 60% w / w) was added and stirred for 10 minutes. Then, 4-bromo-6-chloro-2-(trifluoromethyl)quinoline (190 mg) was added, and the mixture was stirred at 25 °C for 2 hours. The reaction solution was quenched with water, extracted with ethyl acetate, separated, and the organic phase was concentrated to dryness under reduced pressure. The solution was then subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 (v / v)) to give the title product (100 mg). MS (ESI, m / z): 445.1 [M+H] + .

[0305] b)(1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)oxy)cyclohexyl-1-amine

[0306] 100 mg of tert-butyl ((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamate was dissolved in 5 mL of 1,4-dioxane, and a 1,4-dioxane solution of hydrogen chloride (5 mL, 4 M) was added. The mixture was stirred at 20 °C for 2 hours. The reaction solution was concentrated to dryness under reduced pressure, extracted with saturated sodium bicarbonate solution and ethyl acetate, and separated. The organic phase was concentrated to dryness under reduced pressure to give the title product (70 mg). MS (ESI, m / z): 345.1 [M+H] + .

[0307] c)N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)oxy)cyclohexyl)-1-methyl-1H-pyrazole-4-carboxamide

[0308] 1-Methyl-1H-pyrazole-4-carboxylic acid (22 mg) was dissolved in N,N-dimethylformamide (6 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (80 mg) and N,N-diisopropylethylamine (90 mg) were added. The mixture was stirred for 10 minutes, and finally (1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)oxy)cyclohexyl-1-amine (60 mg) was added. The mixture was purged with nitrogen and stirred at 20 °C for 2 hours. The reaction mixture was extracted with water and ethyl acetate, separated, and the organic phase was concentrated to dryness under reduced pressure. The solution was then subjected to silica gel column chromatography (dichloromethane:methanol = 20:1 (v / v)) to give the title product (36 mg). 1 H NMR(400MHz, DMSO-d6)δ8.19(d,J=2.4Hz,1H),8.11(t,J=4.4Hz,2H),7.96–7.88 (m,2H),7.82(s,1H),7.64(s,1H),5.08(dt,J=10.4,5.8Hz,1H),4.10–3.97(m,1 H),3.83(s,3H),2.39–2.30(m,1H),2.17(d,J=10.4Hz,1H),1.87(t,J=12.8Hz,2 H),1.57(dq,J=46.4,11.6Hz,3H),1.35–1.20(m,1H).MS(ESI,m / z):453.1[M+H] + .

[0309] Example 18: N-(5-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)bicyclo[3.1.1]heptane-1-yl)-1-methyl-1H-pyrazole-4-carboxamide

[0310]

[0311] a) tert-butyl(5-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)bicyclo[3.1.1]heptane-1-yl)carbamate

[0312] 193 mg of tert-butyl(5-aminobicyclo[3.1.1]heptane-1-yl)carbamate was dissolved in 10 mL of N-methylpyrrolidone, and 200 mg of 4,6-dichloro-2-(trifluoromethyl)quinoline and 293 mg of potassium carbonate were added. The mixture was stirred at 160 °C for 1 hour under microwave conditions. The reaction solution was concentrated, extracted with ethyl acetate and water, and separated. The organic phase was washed with saturated sodium chloride solution and concentrated to dryness under reduced pressure. Silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 (v / v)) yielded 120 mg of the title product. MS (ESI, m / z): 456.2 [M+H] + .

[0313] b)N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)bicyclo[3.1.1]heptane-1,5-diamine

[0314] 120 mg of tert-butyl(5-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)bicyclo[3.1.1]heptane-1-yl)carbamate was dissolved in methanol (1 mL), and 4 mL (4 M) of a 1,4-dioxane solution of hydrogen chloride was added. The mixture was stirred at 20 °C for 3 hours. The reaction solution was concentrated to dryness under reduced pressure, extracted with saturated sodium bicarbonate solution and ethyl acetate, and separated. The organic phase was concentrated to dryness under reduced pressure to give the title product (80 mg). MS (ESI, m / z): 456.2 [M+H] + .

[0315] c)N-(5-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)bicyclo[3.1.1]heptane-1-yl)-1-methyl-1H-pyrazole-4-carboxamide

[0316] Dissolve 1-methyl-1H-pyrazole-4-carboxylic acid (45 mg) in N,N-dimethylformamide (10 mL), add N,N-diisopropylethylamine (116 mg) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (136 mg), stir at 20 °C for 10 minutes, then add N 1-(6-chloro-2-(trifluoromethyl)quinoline-4-yl)bicyclo[3.1.1]heptane-1,5-diamine (80 mg) was stirred at 20 °C for 3 hours. The reaction solution was concentrated to dryness under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol = 20:1 (v / v)) to give 27 mg of the title product. 1 H NMR (400MHz, DMSO-d6) δ8.56(d,J=2.3Hz,1H),8.20(s,1H),8.08(d,J=10.0Hz,2H),7.90(d,J=9.0Hz,1H),7.79(s,1H),7.75(dd,J =9.0,2.3Hz,1H),6.55(s,1H),3.83(s,3H),2.29(d,J=7.6Hz,3H),1.95(ddt,J=19.8,11.7,6.1Hz,7H).MS(ESI,m / z):464.1[M+H] + .

[0317] Example 19: 4-Amino-N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinoline-4-yl)amino)cyclohexyl)bicyclo[2.2.2]octane-1-carboxamide

[0318]

[0319] a)(4-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamoyl)bicyclo[2.2.2]oct-1-yl)tert-butyl carbamate

[0320] (1S, 3R)-N 1 100 mg of 6-chloro-2-(trifluoromethyl)quinoline-4-yl)cyclohexane-1,3-diamine was dissolved in 10 mL of N,N-dimethylformamide. 113 mg of NN-diisopropylethylamine and 94 mg of 4-((tert-butoxycarbonyl)amino)bicyclo[2.2.2]octane-1-carboxylic acid were added. The mixture was stirred at 20 °C for 10 minutes. Then, 132 mg of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate was added and stirred at 20 °C for 3 hours. The reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol = 10:1 (v / v)) to give the title product (80 mg).

[0321] b) 4-Amino-N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinoline-4-yl)amino)cyclohexyl)bicyclo[2.2.2]octane-1-carboxamide

[0322] 80 mg of tert-butyl (4-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinoline-4-yl)amino)cyclohexyl)carbamoyl)bicyclo[2.2.2]oct-1-yl)carbamate was dissolved in 1 mL of methanol, and 4 mL of a 1,4-dioxane solution of hydrogen chloride (4 M) was added. The mixture was stirred at 20 °C for 3 hours. The reaction solution was filtered, the filter cake was dried, and silica gel column chromatography (ethyl acetate:methanol = 10:1 (v / v)) was performed to give 4 mg of the title product. 1 H NMR (400MHz, DMSO-d6) δ8.61(d,J=2.3Hz,1H),8.45(s,1H),7.89(d,J=9.0Hz,1H),7.74(dd,J=9.0,2.2Hz,1H),7.48(d,J=7.9Hz,1H),7.22(d,J=8 .0Hz,1H),6.89(s,1H),3.81–3.75(m,2H),2.03–1.90(m,2H),1.77–1.69 (m,7H),1.63–1.53(m,6H),1.49–1.14(m,5H).MS(ESI,m / z):495.2[M+H] + .

[0323] Example 20: N-(4-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)pyridin-2-yl)-1-methyl-1H-pyrazole-4-carboxamide

[0324]

[0325] a)(2-(1-methyl-1H-pyrazole-4-carboxamido)pyridine-4-yl)tert-butyl carbamate

[0326] 1-Methyl-1H-pyrazole-4-carboxamide (200 mg) was dissolved in N,N-dimethylformamide (6 mL), and tert-butyl (2-bromopyridin-4-yl)carbamate (870 mg), cuprous iodide (60 mg), potassium carbonate (440 mg), and N,N'-dimethylethylenediamine (56 mg) were added. The mixture was purged with nitrogen and stirred at 110 °C for 5 hours. The reaction solution was extracted with water and ethyl acetate, separated, and the organic phase was concentrated to dryness under reduced pressure. The residue was subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 (v / v)) to give the title product (170 mg). MS (ESI, m / z): 318.2 [M+H] + .

[0327] b) N-(4-aminopyridin-2-yl)-1-methyl-1H-pyrazole-4-carboxamide

[0328] 170 mg of (2-(1-methyl-1H-pyrazole-4-carboxamido)pyridin-4-yl)tert-butyl carbamate was dissolved in 5 mL of 1,4-dioxane, and a 4 mL, 4 M solution of 1,4-dioxane containing hydrogen chloride was added. The mixture was stirred at 20 °C for 2 hours. The reaction solution was concentrated to dryness under reduced pressure, extracted with saturated sodium bicarbonate solution and ethyl acetate, and separated. The organic phase was concentrated to dryness under reduced pressure to give the title product (80 mg). MS (ESI, m / z): 218.1 [M+H] + .

[0329] c)N-(4-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)pyridin-2-yl)-1-methyl-1H-pyrazole-4-carboxamide

[0330] N-(4-aminopyridin-2-yl)-1-methyl-1H-pyrazole-4-carboxamide (22 mg) was dissolved in xylene (6 mL), potassium tert-butoxide (22 mg) was added, the mixture was purged with nitrogen, and stirred for 20 minutes. Then, 4-bromo-6-chloro-2-(trifluoromethyl)quinoline (67 mg), tris(dibenzylacetone)palladium (18 mg), P,P'-(9,9-dimethyl-9H-oxanthracene-4,5-diyl)bis[N,N,N',N'-tetraethylphosphonic acid diamide (22 mg) and potassium phosphate (125 mg) were added. The mixture was purged with nitrogen, stirred at 100 °C for 4 hours, and the reaction mixture was extracted with water and ethyl acetate. The liquid was separated, and the organic phase was concentrated to dryness under reduced pressure. The solution was then subjected to silica gel column chromatography (dichloromethane:methanol = 20:1) to give the title product (15 mg). 1 H NMR (400MHz, DMSO-d6) δ10.51(s,1H),9.93(s,1H),8.66(d,J=2.4Hz,1H),8.45(s,1H),8.36–8.25(m,2H),8.20–8.05 (m,2H),7.92(dd,J=9.2,2.0Hz,1H),7.67(s,1H),7.16(dd,J=5.6,2.0Hz,1H),3.88(s,3H).MS(ESI,m / z):447.1[M+H] + .

[0331] Test Example 1

[0332] The FDSS high-throughput fluorescence detector, model FDSS / μCell, was used to acquire MRGPRX2-mediated calcium flow signals.

[0333] Main reagents: Substance P (from MedChemExpress); Fluo-4, AM detection kit (from Invitrogen), used as a fluorescent dye for calcium ions.

[0334] Solution preparation method:

[0335] (1) Extracellular calcium-free solution: sodium chloride 140mM, potassium chloride 5mM, magnesium chloride 1mM, probenecid 2mM, glucose 10mM and 4-hydroxyethylpiperazine ethanesulfonic acid 10mM, with the pH adjusted to 7.4 using sodium hydroxide.

[0336] (2) Extracellular calcium-containing solution: sodium chloride 140mM, potassium chloride 5mM, magnesium chloride 1mM, probenecid 2mM, glucose 10mM, 4-hydroxyethylpiperazine ethanesulfonic acid 10mM, calcium chloride 2mM, pH adjusted to 7.4 with sodium hydroxide.

[0337] (3) Loading buffer: 9890 μL of calcium-free extracellular fluid for cells, 10 μL of Fluo-4 AM (2 mM stock solution); 100 μL of probenecid (reconstituted with deionized water), total volume 10 mL;

[0338] (4) Substance P stimulation buffer: Prepare 150 μM Substance P solution with calcium-containing extracellular fluid, take 20 μL and add it to the detection well, and dilute 5 times to a final concentration of 30 μM.

[0339] Test methods: The antagonistic activity of the test samples was characterized in MRGPRX2-Flp-in-Trex293 cells (a cell line stably expressing the human MRGPRX2 receptor). The cell line was cultured in 90% DMEM + 10% FBS (fetal bovine serum) + 15 μg / mL cymoxanil S hydrochloride + 50 μg / mL hygromycin B at 37°C with 5% CO2. The target was endogenously expressed and verified by real-time quantitative PCR. The efficacy was determined using an FDSS high-throughput fluorescence detector (model FDSS / μCELL) to observe the change in fluorescence intensity before and after drug administration, thus providing a functional readout of intracellular calcium mobilization. The detection method is as follows:

[0340] 1. Compound preparation: Dissolve the compound sample in dimethyl sulfoxide (DMSO) to prepare a 20 mM stock solution. Take 10 μL of the stock solution and add it to 20 μL of DMSO. The solution is then serially diluted to 10 different DMSO concentrations. The test concentrations of the control compound are 10.00, 3.33, 1.11, 0.37, 0.12, 0.041, 0.0137, 0.0046, 0.0015, and 0.0005 μM.

[0341] 2. Coating of detection plates: Add 60 μL / well of 20 μg / mL poly-L-lysine to a 96-well black plate for coating, place in an incubator at 37°C for 30 minutes, then wash twice with phosphate buffer before use.

[0342] 3. Cell preparation: MRGPRX2 cells were cultured at 175 cm⁻¹. 2 In the culture flask, once the cell density reaches 80%, remove the culture medium, wash once with 7 mL of phosphate buffer, and then add 3 mL of 0.25% trypsin for digestion. After complete digestion, add 7 mL of culture medium to neutralize, centrifuge at 800 rpm for 3 minutes, aspirate the supernatant, and resuspend in 5 mL of culture medium. Count the cells.

[0343] 4. Cell plating: Adjust the density to 4 × 10⁻⁶ cells based on the cell count results. 4 Cells were cultured in wells at 1 μg / mL working concentration of doxycycline. After incubation at 25°C for 30 minutes, the cells were cultured overnight in a CO2 incubator at 37°C. After 18–24 hours of culture, the cell density reached approximately 90%.

[0344] 5. Fluorescent dye incubation: Discard the cell culture medium, add 100 μL / well of calcium-free external solution to wash once, then add 60 μL / well of loading buffer and incubate at 37°C in the dark for 60 minutes.

[0345] 6. Compound incubation: Discard the loading buffer, add 100 μL / well of calcium-containing external solution to wash twice, add 80 μL / well of the test compound prepared with external solution, and incubate at 25°C in the dark for 20 minutes.

[0346] 7. Fluorescence data acquisition: Real-time fluorescence signal recording was performed using an FDSS / μCELL instrument with an excitation wavelength of 480nm and an emission wavelength of 540nm. Recording was performed once per second. After recording the baseline for 10 seconds, 20μL of Substance P stimulation buffer per well was added, and recording continued until 180 seconds.

[0347] 8. Data Processing: Experimental data were analyzed and processed using Excel and GraphPad Prism software. The fluorescence signal of MRGPRX2 was the peak value of the signal-to-noise ratio (Ratio) after the addition of the stimulation buffer. The percentage of compound inhibition (%) was calculated as follows: [(Ratio...] 对照 –Ratio 空白 Ratio (test sample – Ratio blank) × 100%, where the Ratio control is the maximum peak value of Ratio after adding Substance P stimulation buffer to 0.5% dimethyl sulfoxide; Ratio 空白 The maximum peak value of Ratio without the addition of Substance P stimulation buffer. 供试品The peak value of the Ratio is the maximum value after adding Substance P stimulation buffer to the test compound. Concentration-dependent inhibition curves were fitted based on the percentage of inhibition at different compound concentrations to report the IC50 for each compound. 50 The results are shown in Table 1. The antagonistic activity of the compounds against MRGPRX2 is as follows: A represents <50 nM, B represents 50–1000 nM, and C represents >1000 nM.

[0348] Table 1

[0349] Example MRGPRX2 antagonist activity Example 1 B Example 3 B Example 12 Isomer A C Example 12 Isomer B C Example 19 A

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: in, A is Each R x It is independently selected from halogen, cyano, hydroxy, carboxyl, amino, nitro, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, hydroxy-C1-C6 alkyl, amino-C1-C6 alkyl, carboxyl-C1-C6 alkyl, C1-C6 alkylamino, C2-C6 alkenyl or C2-C6 alkynyl; Each R y It is independently selected from halogen, cyano, hydroxy, carboxyl, amino, nitro, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, hydroxy-C1-C6 alkyl, amino-C1-C6 alkyl, carboxyl-C1-C6 alkyl, C1-C6 alkylamino, C2-C6 alkenyl or C2-C6 alkynyl; n is 0, 1, 2, 3 or 4; m can be 0, 1, 2, 3, or 4; L 1 Selected from chemical bonds, -N(R) a )-、-S-、-O-、 The above Optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxyl, carboxyl, amino, or nitro; wherein L represents 1 It is attached to the position of A by a chemical bond; L represents 1 It is attached to the position of B by a chemical bond; Each R a They may be the same or different, and each is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-12 membered heterocyclic, C3-C8 cycloalkyl, C6-C 10 aryl or 5-14 membered heteroaryl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, 3-12 membered heterocyclic, C3-C8 cycloalkyl, C6-C 10 Each of the aryl or 5-14 heteroaryl groups is independently and optionally substituted by one or more groups selected from the group consisting of: halogen, cyano, hydroxyl, carboxyl, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, C2-C6 alkenyl or C2-C6 alkynyl. B represents cyclopropyl, cyclohexyl, and cycloheptyl. C 6- C 10 aryl or 5-20-membered heteroaryl; wherein the B is optionally surrounded by one or more R c replace; Each R c They may be the same or different, and each is independently selected from halogen, cyano, nitro, hydroxy, carboxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C 6- C 10 aryl, 3-12 membered heterocyclic or 5-14 membered heteroaryl; wherein the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C 6- C 10 Each of the aryl, 3-12-membered heterocyclic or 5-14-membered heteroaryl groups is independently and optionally substituted by one or more groups selected from the group consisting of: halogen, cyano, hydroxyl, carboxyl, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, C2-C6 alkenyl or C2-C6 alkynyl; p is 0, 1, or 2; L 2 for Or -C(O)-; where L represents 2 Linked to (CH2) via chemical bonds p Location; L represents 2 Linked to the W site via chemical bonds; Each R b They may be the same or different, and each is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-12 membered heterocyclic, C3-C8 cycloalkyl, C6-C 10 aryl or 5-14 membered heteroaryl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, 3-12 membered heterocyclic, C3-C8 cycloalkyl, C6-C 10 Each of the aryl or 5-14 heteroaryl groups is independently and optionally substituted by one or more groups selected from the group consisting of: halogen, cyano, hydroxyl, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl or C2-C6 alkynyl. W is selected from C3-C 20 Cycloalkyl, 3-20 membered heterocyclic groups, C6-C 10 aryl or 5-20 heteroaryl; the W is optionally surrounded by one or more R d replace; Each R d They may be the same or different, and each is independently selected from halogen, cyano, nitro, -OR e -SR e -S(=O)R e -S(=O)2R e -C(O)R e -C(O)-OR e -N(R) e (R) f C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, 3-12 membered heterocyclic, C6-C 10 aryl or 5-14 membered heteroaryl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, 3-12 membered heterocyclic, C6-C 10 The aryl or 5-14 heteroaryl groups are each independently and optionally bound by one or more R groups. g replace; R e R f They may be the same or different, and each is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocyclic groups, C3-C8 cycloalkyl, C6-C 10 aryl or 5-14 membered heteroaryl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, 3-10 membered heterocyclic, C3-C8 cycloalkyl, C6-C 10 The aryl or 5-14 heteroaryl groups are each independently and optionally selected from one or more R groups of the group below. g replace; Each R g They may be the same or different, and each is independently selected from halogen, cyano, hydroxy, amino, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, hydroxylated C1-C6 alkyl, amino C1-C6 alkyl, C3-C8 cycloalkyl, 3-12 membered heterocyclic groups, C6-C 10 Aryl or 5-14 heteroaryl groups; The condition is that when L 1 -N(R) a When )-, B is not a cyclohexyl group.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The A is The R x Selected from halogen, cyano, hydroxy, carboxyl, amino, nitro, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy or halo-C1-C6 alkoxy; Preferably, the R x Selected from halogen, cyano, hydroxy, carboxyl, amino, nitro, C1-C4 alkyl, halo-C1-C4 alkyl, C1-C4 alkoxy or halo-C1-C4 alkoxy; Preferably, the R x Selected from halogen, cyano, hydroxy, carboxyl, amino, nitro, C1-C3 alkyl, halo-C1-C3 alkyl, C1-C3 alkoxy or halo-C1-C3 alkoxy; More preferably, the R x Selected from fluorine, chlorine, bromine, cyano, hydroxyl, carboxyl, amino, nitro, methyl, ethyl, methoxy, difluoromethyl, or trifluoromethyl; And / or, n is 0, 1, 2 or 3; preferably, n is 0, 1 or 2; more preferably, n is 0 or 1; More preferably, A is Wherein R 1a R 2a R 3a R 4a They may be the same or different, and each is independently selected from hydrogen, halogen, cyano, hydroxy, carboxyl, amino, nitro, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, hydroxy-C1-C6 alkyl, amino-C1-C6 alkyl, carboxyl-C1-C6 alkyl, C1-C6 alkylamino, C2-C6 alkenyl, or C2-C6 alkynyl; More preferably, the R 1a R 2a R 3a R 4a They may be the same or different, and each is independently selected from hydrogen, halogen, cyano, hydroxy, carboxyl, amino, nitro, C1-C4 alkyl, halo-C1-C4 alkyl, C1-C4 alkoxy, halo-C1-C4 alkoxy, hydroxy-C1-C4 alkyl, amino-C1-C4 alkyl, carboxyl-C1-C4 alkyl, C1-C4 alkylamino, C2-C4 alkenyl, or C2-C4 alkynyl; More preferably, the R 1a R 2a R 3a R 4a They may be the same or different, and each is independently selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, amino, nitro, C1-C3 alkyl, halo-C1-C3 alkyl, C1-C3 alkoxy or halo-C1-C3 alkoxy; More preferably, the R 1a R 2a R 3a R 4a Each is independently hydrogen; Alternatively, A is The R y Selected from halogen, cyano, hydroxy, carboxyl, amino, nitro, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy or halo-C1-C6 alkoxy; Preferably, the R y Selected from halogen, cyano, hydroxy, carboxyl, amino, nitro, C1-C4 alkyl, halo-C1-C4 alkyl, C1-C4 alkoxy or halo-C1-C4 alkoxy; Preferably, the R y Selected from halogen, cyano, hydroxy, carboxyl, amino, nitro, C1-C3 alkyl, halo-C1-C3 alkyl, C1-C3 alkoxy or halo-C1-C3 alkoxy; More preferably, the R y Selected from fluorine, chlorine, bromine, cyano, hydroxyl, carboxyl, amino, nitro, methyl, ethyl, methoxy, difluoromethyl, or trifluoromethyl; And / or, m is 0, 1, 2 or 3; preferably, m is 0, 1 or 2; more preferably, m is 0 or 1; More preferably, A is Wherein R 1c R 2c R 3c R 4c They may be the same or different, and each is independently selected from hydrogen, halogen, cyano, hydroxy, carboxyl, amino, nitro, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, hydroxy-C1-C6 alkyl, amino-C1-C6 alkyl, carboxyl-C1-C6 alkyl, C1-C6 alkylamino, C2-C6 alkenyl, or C2-C6 alkynyl; Preferably, the R 1c R 2c R 3c R 4c They may be the same or different, and each is independently selected from hydrogen, halogen, cyano, hydroxy, carboxyl, amino, nitro, C1-C4 alkyl, halo-C1-C4 alkyl, C1-C4 alkoxy, halo-C1-C4 alkoxy, hydroxy-C1-C4 alkyl, amino-C1-C4 alkyl, carboxyl-C1-C4 alkyl, C1-C4 alkylamino, C2-C4 alkenyl, or C2-C4 alkynyl; Preferably, the R 1c R 2c R 3c R 4c They may be the same or different, and each is independently selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, amino, nitro, C1-C3 alkyl, halo-C1-C3 alkyl, C1-C3 alkoxy or halo-C1-C3 alkoxy; More preferably, the R 1c R 2c R 3c R 4c Each is independently hydrogen; More preferably, A is 3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The L 1 Selected from chemical bonds, -N(R) a -, -S-, -O- or Preferably, the L 1 Selected from -N(R) a -, -S-, or -O-; Preferably, the L 1 -N(R) a )-; More preferably, the R a Selected from hydrogen, C1-C6 alkyl, 3-10 membered heterocyclic, C3-C8 cycloalkyl, C6-C 10 aryl or 5-14 membered heteroaryl; wherein the C1-C6 alkyl, 3-10 membered heterocyclic, C3-C8 cycloalkyl, C6-C 10 Each of the aryl or 5-14 heteroaryl groups is independently and optionally substituted by one or more groups selected from the group consisting of: halogen, cyano, hydroxyl, carboxyl, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, C2-C6 alkenyl or C2-C6 alkynyl. More preferably, the R a Selected from hydrogen, C1-C6 alkyl, 3-8 membered heterocyclic, C3-C8 cycloalkyl, C6-C 10 aryl or 5-9 membered heteroaryl; wherein the C1-C6 alkyl, 3-8 membered heterocyclic, C3-C8 cycloalkyl, C6-C 10 Each of the aryl or 5-9 heteroaryl groups is independently and optionally substituted by one or more groups selected from the group consisting of: halogen, cyano, hydroxyl, carboxyl, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, C2-C6 alkenyl or C2-C6 alkynyl. More preferably, the R a Selected from hydrogen, C1-C4 alkyl, 3-6 membered heterocyclic, C3-C6 cycloalkyl, C6-C 10 aryl or 5-7 membered heteroaryl; wherein the C1-C4 alkyl, 3-6 membered heterocyclic, C3-C6 cycloalkyl, C6-C 10 Each of the aryl or 5-7 heteroaryl groups is independently and optionally substituted by one or more groups selected from the group consisting of: halogen, cyano, hydroxyl, carboxyl, amino, nitro, C1-C3 alkyl, C1-C3 alkoxy, halo-C1-C3 alkyl, halo-C1-C3 alkoxy, C2-C3 alkenyl or C2-C3 alkynyl. More preferably, the R a The group is selected from hydrogen, C1-C4 alkyl, 3-6 membered heterocyclic or C3-C6 cycloalkyl; wherein each of the C1-C4 alkyl, 3-6 membered heterocyclic or C3-C6 cycloalkyl groups is independently and optionally substituted by one or more groups selected from the group consisting of: halogen, cyano, hydroxy, carboxyl, amino, nitro, C1-C3 alkyl, C1-C3 alkoxy, halo-C1-C3 alkyl or halo-C1-C3 alkoxy; More preferably, the R a Selected from hydrogen or C1-C3 alkyl; wherein the C1-C3 alkyl is optionally substituted by one or more groups selected from the group consisting of: halogen, cyano, hydroxy, carboxyl, amino, nitro, C1-C3 alkyl, C1-C3 alkoxy, halo-C1-C3 alkyl or halo-C1-C3 alkoxy. More preferably, the R a Selected from hydrogen or C1-C3 alkyl; wherein the C1-C3 alkyl is optionally substituted by one or more groups selected from the group consisting of: fluorine, chlorine, bromine, cyano, hydroxyl, carboxyl, amino, or nitro; More preferably, the R a It is hydrogen; More preferably, the L 1 Selected from chemical bonds, -NH-, -O- or in L represents 1 It is attached to the position of A by a chemical bond; L represents 1 It is attached to the position of B by a chemical bond; More preferably, the L 1 It is -NH-.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, B is cyclopropyl, cyclohexyl, or cycloheptyl. C6-C 10 aryl or 5-14 heteroaryl; wherein the B is optionally surrounded by one or more R c Replacement; the condition is when L 1 -N(R) a When )-, B is not a cyclohexyl group; Preferably, B is cyclopropyl, cyclohexyl, cycloheptyl, or cyclopropyl. C6-C 10 aryl or 5-10 heteroaryl; wherein the B is optionally surrounded by one or more R c Replacement; the condition is when L 1 -N(R) a When )-, B is not a cyclohexyl group; Preferably, B is cyclopropyl, cyclohexyl, cycloheptyl, or cyclopropyl. C6-C 10 aryl, 5-8 membered monocyclic heteroaryl, or 6-10 membered fused heteroaryl; wherein the B is optionally separated by one or more R c Replacement; the condition is when L 1 -N(R) a When )-, B is not a cyclohexyl group; More preferably, B is cyclopropyl, cyclohexyl, or... phenyl or pyridyl; the B is optionally surrounded by one or more R c Replacement; the condition is when L 1 -N(R) a When )-, B is not a cyclohexyl group; More preferably, the B group is selected from the following group: phenyl or The B is optionally defined by one or more R. c Replace; among them This indicates that B is chemically bonded to L. 1 Location; This indicates that B is chemically bonded to -(CH2). p - position; condition is when L 1 -N(R) a When )-, B is not Preferably, B is selected from the group consisting of: The B is optionally defined by one or more R. c Replacement; the condition is when L 1 -N(R) a When )-, B is not More preferably, the B is optionally divided by one, two, or three Rs. c replace; More preferably, the B is optionally divided by one or two Rs. c replace; More preferably, R c Selected from halogen, cyano, nitro, hydroxy, carboxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10 aryl, 3-9 membered heterocyclic or 5-9 membered heteroaryl; wherein the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10 Each of the aryl, 3-9 membered heterocyclic or 5-9 membered heteroaryl groups is independently and optionally substituted by one or more groups selected from the group consisting of: halogen, cyano, hydroxyl, carboxyl, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, C2-C6 alkenyl or C2-C6 alkynyl. More preferably, R c The group is selected from halogen, cyano, nitro, hydroxy, carboxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 ynyl or C3-C6 cycloalkyl; wherein each of the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 ynyl or C3-C6 cycloalkyl is independently and optionally substituted by one or more groups selected from the group consisting of: halogen, cyano, hydroxy, carboxyl, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, C2-C6 alkenyl or C2-C6 ynyl; More preferably, R c The group is selected from halogen, cyano, nitro, hydroxy, carboxyl, amino, C1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl, C2-C4 ynyl or C3-C6 cycloalkyl; wherein each of the C1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl, C2-C4 ynyl or C3-C6 cycloalkyl is optionally substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxy, carboxyl, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, C2-C6 alkenyl or C2-C6 ynyl; More preferably, R c The group is selected from halogen, cyano, nitro, hydroxy, carboxyl, amino, C1-C3 alkyl or C1-C3 alkoxy; wherein each of the C1-C3 alkyl or C1-C3 alkoxy groups is independently and optionally substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxy, carboxyl, amino or nitro. More preferably, B is selected from... phenyl or in This indicates that B is chemically bonded to L. 1 Location; This indicates that B is chemically bonded to -(CH2). p - position; condition is when L 1 -N(R) a When )-, B is not 5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The value of p is 1; or the value of p is 0.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The L 2 for in L represents 2 Linked to (CH2) via chemical bonds p Location; L represents 2 Linked to the W site via chemical bonds; Preferably, the R b Selected from hydrogen, C1-C6 alkyl, 3-10 membered heterocyclic, C3-C8 cycloalkyl, C6-C 10 aryl or 5-14 membered heteroaryl; wherein the C1-C6 alkyl, 3-10 membered heterocyclic, C3-C8 cycloalkyl, C6-C 10 Each of the aryl or 5-14 heteroaryl groups is independently and optionally substituted by one or more groups selected from the group consisting of: halogen, cyano, hydroxyl, carboxyl, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, C2-C6 alkenyl or C2-C6 alkynyl. Preferably, the R b Selected from hydrogen, C1-C6 alkyl, 3-8 membered heterocyclic, C3-C8 cycloalkyl, C6-C 10 aryl or 5-9 membered heteroaryl; wherein the C1-C6 alkyl, 3-8 membered heterocyclic, C3-C8 cycloalkyl, C6-C 10 Each of the aryl or 5-9 heteroaryl groups is independently and optionally substituted by one or more groups selected from the group consisting of: halogen, cyano, hydroxyl, carboxyl, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, C2-C6 alkenyl or C2-C6 alkynyl. Preferably, the R b Selected from hydrogen, C1-C4 alkyl, 3-6 membered heterocyclic, C3-C6 cycloalkyl, C6-C 10 aryl or 5-7 membered heteroaryl; wherein the C1-C4 alkyl, 3-6 membered heterocyclic, C3-C6 cycloalkyl, C6-C 10 Each of the aryl or 5-7 heteroaryl groups is independently and optionally substituted by one or more groups selected from the group consisting of: halogen, cyano, hydroxyl, carboxyl, amino, nitro, C1-C3 alkyl, C1-C3 alkoxy, halo-C1-C3 alkyl, halo-C1-C3 alkoxy, C2-C4 alkenyl or C2-C4 alkynyl. Preferably, the R b The group is selected from hydrogen, C1-C4 alkyl, 3-6 membered heterocyclic or C3-C6 cycloalkyl; wherein each of the C1-C4 alkyl, 3-6 membered heterocyclic or C3-C6 cycloalkyl groups is independently and optionally substituted by one or more groups selected from the group consisting of: halogen, cyano, hydroxy, carboxyl, amino, nitro, C1-C3 alkyl, C1-C3 alkoxy, halo-C1-C3 alkyl or halo-C1-C3 alkoxy; Preferably, the R b Selected from hydrogen or C1-C3 alkyl; wherein the C1-C3 alkyl is optionally substituted by one or more groups selected from the group consisting of: halogen, cyano, hydroxy, carboxyl, amino, nitro, C1-C3 alkyl, C1-C3 alkoxy, halo-C1-C3 alkyl or halo-C1-C3 alkoxy. Preferably, the R b Selected from hydrogen or C1-C3 alkyl; wherein the C1-C3 alkyl is optionally substituted by one or more groups selected from the group consisting of: halogen, cyano, hydroxy, carboxyl, amino or nitro; More preferably, the R b Selected from hydrogen or methyl; More preferably, the R b Selected from hydrogen; More preferably, the L 2 for Or -C(O)-; where L represents 2 Linked to (CH2) via chemical bonds p Location; L represents 2 Linked to the W site via chemical bonds; More preferably, the L 2 for in L represents 2 Linked to (CH2) via chemical bonds p Location; L represents 2 It is attached to the W site via a chemical bond.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The W is selected from C3-C. 14 Cycloalkyl, 3-14 membered heterocyclic, C6-C 10 aryl or 5-14 heteroaryl; the W is optionally surrounded by one or more R d replace; Preferably, W is selected from C3-C. 12 Cycloalkyl, 3-12 membered heterocyclic, C6-C 10 aryl or 5-12 heteroaryl; the W is optionally surrounded by one or more R d replace; Preferably, W is selected from C3-C. 11 Cycloalkyl, 3-11 membered heterocyclic, C6-C 10 aryl or 5-10 heteroaryl; the W is optionally surrounded by one or more R d replace; Preferably, W is selected from C3-C8 monocyclic cycloalkyl groups and C5-C6 groups. 11 Polycyclic alkyl, C5-C 11 Spirocycloalkyl, C5-C 11 Bridged cycloalkyl, 3-8 membered monocyclic heterocyclic group, 5-11 membered fused heterocyclic group, 5-11 membered spirocyclic group, 5-11 membered bridged heterocyclic group, C6-C 10 aryl, 5-8 membered monocyclic heteroaryl, or 6-10 membered fused heteroaryl; wherein W is optionally coated with one or more R d replace; Preferably, W is selected from C3-C7 monocyclic cycloalkyl groups and C5-C6 monocyclic cycloalkyl groups. 11 Polycyclic alkyl, C5-C 11 Spirocycloalkyl, C5-C 11 Bridged cycloalkyl, 3-7 membered monocyclic heterocyclic group, 7-11 membered fused heterocyclic group, 5-11 membered spirocyclic group, 5-11 membered bridged heterocyclic group, C6-C 10 aryl, 5-8 membered monocyclic heteroaryl, or 8-10 membered fused heteroaryl; wherein W is optionally coated with one or more R d replace; Preferably, W is selected from C3-C7 monocyclic cycloalkyl groups and C5-C6 monocyclic cycloalkyl groups. 11 Polycyclic alkyl, C7-C 11 Spirocycloalkyl, C6-C 10 Bridged cycloalkyl, 5-8 membered monocyclic heterocyclic, 5-6 membered heterocyclic phenyl, 5-6 membered heterocyclic 5-6 membered heteroaryl, 5-6 membered heterocyclic 5-6 membered heterocyclic, 5-6 membered heterocyclic C3-C6 cycloalkyl, 8-11 membered spirocyclic, 6-10 membered bridged heterocyclic, C6-C 10 aryl, 5-6 membered monocyclic heteroaryl, 5-6 membered heteroaryl-5-6 membered heteroaryl or 5-6 membered heteroaryl-phenyl; wherein W is optionally coated with one or more R d replace; Preferably, W is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and C5-C. 11 Polycyclic alkyl, C7-C 11 Spirocycloalkyl, C6-C 10 Bridged cycloalkyl, 3-7 membered monocyclic heterocyclic, phenyl, 5-6 membered monocyclic heteroaryl, 5-membered heteroaryl-6-membered heteroaryl, 6-membered heteroaryl-6-membered heteroaryl, or 5-6-membered heteroaryl-phenyl; wherein W is optionally separated by one or more R d replace; More preferably, the W is selected from the group consisting of: pyrazolyl, pyrazolopyridyl, pyrrolopyridyl, pyrazolopyrimidinyl, pyrazolophenyl, 1-methylbicyclo[2.2.2]octane, pyridyl, pyrimidinyl, imidazopyrimidinyl, pyridopyrazolyl, isoxazolyl, oxazolyl, pyrazolopyrimidinyl, pyrazolopyridazinyl, benzoisooxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, pyridopyrimidinyl, pyrazolofuranyl, pyrazoloisooxazolyl, pyridazinyl, pyrimidinylpiperidinoneyl, triazolopyrimidinyl, imidazopyridazinyl, oxazolopyrimidinyl or isoxazolopyrimidinyl; the W is optionally separated by one or more R d replace; More preferably, the W is selected from the group consisting of: The W is optionally defined by one or more R. d replace; More preferably, the W is selected from the group consisting of: The W is optionally defined by one or more R. d replace; More preferably, the R d Selected from halogen, cyano, nitro, -OR e -SR e -S(=O)R e -S(=O)2R e -C(O)R e -C(O)-OR e -N(R) e (R) f ), C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, 3-8 membered heterocyclic, C6-C 10 aryl or 5-10 membered heteroaryl; wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 ynyl, C3-C6 cycloalkyl, 3-8 membered heterocyclic, C6-C 10 Aryl or 5-10 heteroaryl groups are each independently and optionally bound by one or more R groups. g replace; More preferably, the R d Selected from halogen, cyano, nitro, -OR e -SR e -S(=O)R e -S(=O)2R e -C(O)R e -C(O)-OR e -N(R) e (R) f C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic, C6-C 10 aryl or 5-6 membered heteroaryl; wherein the C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic, C6-C 10 Each of the aryl or 5-6 heteroaryl groups is independently and optionally bounded by one or more R groups. g replace; More preferably, the R d Selected from fluorine, chlorine, bromine, cyano, nitro, -OR e -N(R) e (R) f ), C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic, C6-C 10 aryl or 5-6 membered heteroaryl; wherein the C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic, C6-C 10 Each of the aryl or 5-6 heteroaryl groups is independently and optionally bounded by one or more R groups. g replace; More preferably, the R d Selected from fluorine, chlorine, bromine, cyano, nitro, -OR e -N(R) e (R) f ), C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 heterocyclic, phenyl, or 5-6 heteroaryl; wherein the C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 heterocyclic, phenyl, or 5-6 heteroaryl are each optionally and independently formed by one or more R g replace; More preferably, the R e R f They may be the same or different, and each is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-8 membered heterocyclic, C3-C6 cycloalkyl, C6-C 10 aryl or 5-10 membered heteroaryl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-8 membered heterocyclic, C3-C6 cycloalkyl, C6-C 10 The aryl or 5-10 heteroaryl groups are each independently and optionally selected from one or more R groups of the group below. g replace; More preferably, the R e R f They may be the same or different, and each is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-6 membered heterocyclic, C3-C6 cycloalkyl, C6-C 10 aryl or 5-6 membered heteroaryl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, 3-6 membered heterocyclic, C3-C6 cycloalkyl, C6-C 10 The aryl or 5-6 heteroaryl groups are each independently and optionally selected from one or more R groups of the group below. g replace; More preferably, the R e R f They may be the same or different, and each is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 4-6 membered heterocyclic, C3-C6 cycloalkyl, C6-C 10 aryl or 4-6-membered heteroaryl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, 4-6-membered heterocyclic, C3-C6 cycloalkyl, C6-C 10 The aryl or 4-6 heteroaryl groups are each independently and optionally selected from one or more R groups of the group below. g replace; More preferably, the R e R f They may be the same or different, and each independently selected from hydrogen, C1-C3 alkyl, or phenyl; wherein the C1-C3 alkyl or phenyl is each independently and optionally selected from one or more of the following groups. g replace; More preferably, the R g Selected from halogen, cyano, hydroxy, amino, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, hydroxylated C1-C6 alkyl, amino C1-C6 alkyl, C3-C8 cycloalkyl, 3-12 membered heterocyclic groups, C6-C 10 Aryl or 5-14 heteroaryl groups; More preferably, the R g Selected from halogen, cyano, hydroxy, amino, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, hydroxylated C1-C6 alkyl, amino C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclic, C6-C 10 Aryl or 5-10 heteroaryl groups; More preferably, the R g Selected from halogen, cyano, hydroxy, amino, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, hydroxylated C1-C6 alkyl, amino C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic groups, C6-C 10 Aryl or 5-7 heteroaryl; More preferably, the R g Selected from halogen, cyano, hydroxy, amino, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C1-C6 alkoxy or halo-C1-C6 alkoxy; More preferably, the R g Selected from fluorine, chlorine, bromine, cyano, hydroxyl, amino, nitro, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, halo-C1-C3 alkyl, C1-C3 alkoxy or halo-C1-C3 alkoxy; More preferably, the W is selected from the group consisting of: More preferably, the W is selected from the group consisting of:

8. A compound or a pharmaceutically acceptable salt thereof, characterized in that, The compound is selected from: Preferably, the compound is selected from:

9. A pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

10. Use of a compound of formula I or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 9 in the preparation of a medicament for the treatment and / or prevention of MRGPRX2-related diseases.

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