Quinolone compounds and use thereof

Abstract

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Description

Quinolone compounds and uses thereof Technical Field

[0001] The present disclosure relates to the field of medicine, and in particular to quinolone compounds or pharmaceutically acceptable salts thereof, and their use as immunomodulators in treating or preventing diseases or disorders such as autoimmune diseases, allergic diseases, inflammatory diseases and pain. Background Art

[0002] Mast cells (MCs) are myeloid cells found in connective tissues throughout our bodies. They are widely distributed around blood vessels and nerve endings in various tissues. They are a type of immune cell crucial for initiating inflammatory responses and are primarily associated with the innate immune response, a nonspecific branch of the immune system. They are particularly important in allergic reactions but are also involved in many other immune functions. Mast cells have long been implicated in the pathogenesis of allergic reactions, autoimmune diseases, and inflammatory diseases (particularly inflammatory skin diseases and chronic inflammatory diseases). Mast cell-associated G protein-coupled receptors (MRGPRs) are involved in signaling related to itch, inflammation, and pain in the body. Among them, MRGPRX2 is a target, widely distributed in barrier tissues, and is involved in regulating mast cell-related allergic reactions. Activation of MRGPRX2 induces mast cell degranulation; inhibition of MRGPRX2 significantly suppresses mast cell degranulation. MRGPRX2-mediated MC activation is independent of immunoglobulin E (IgE). Numerous essential secretagogues, such as SP, vasoactive intestinal peptide, cationic antimicrobial peptides, and the classic activator compound 48 / 80, can act as ligands for MRGPRX2. In recent years, with the deepening of research on MRGPRX2, the functions of MRGPRX2 have become increasingly important. MRGPRX2 is primarily involved in allergic and inflammatory responses related to non-IgE-mediated mast cell activation, neuroinflammation, pain, and pruritus. It also promotes innate immune responses in the skin and intestine to noxious stimuli or pathogen invasion, such as atopic dermatitis, urticaria, alopecia areata, inflammatory bowel disease, and asthma. Therefore, MRGPRX2 antagonists could be used to treat or prevent autoimmune diseases, allergic disorders, inflammatory diseases, pruritus, and pain. Recent studies have also found that mast cell degranulation, induced by MRGPRX2 activation, promotes IgE-mediated allergic reactions. Researchers observed that MRGPRX2 antagonists can significantly inhibit IgE-mediated anaphylactic shock in vivo (doi.org / 10.1016 / j.jaci.2024.11.021), further demonstrating the application value of MRGPRX2 antagonists in diseases related to mast cell activation.

[0003] Autoimmune diseases are a complex group of diseases, including psoriasis, atopic dermatitis, inflammatory bowel disease (IBD), urticaria, allergic rhinitis, asthma, and alopecia areata. The cause of the disease is usually due to an abnormal or overreaction of the body's immune system, which usually attacks its own tissues or organs, causing inflammation, damage, or dysfunction. The occurrence of this disease may be related to genetic, environmental, and infectious factors. Autoimmune diseases affect about one-tenth of the population, and the incidence of various autoimmune diseases is increasing over time worldwide. A study published in The Lancet investigated the incidence of autoimmune diseases in more than 22 million people between 2000 and 2019. During the survey, more than 970,000 people were diagnosed with at least one autoimmune disease (doi.org / 10.1016 / S0140-6736(23)00457-9). Autoimmune diseases cause great suffering to patients.

[0004] Psoriasis is a chronic, systemic, immune-mediated inflammatory skin disease with widespread prevalence. Its typical skin manifestation is erythema covered with silvery-white scales.

[0005] Atopic dermatitis is a disease caused by immune system disorders. Its symptoms are relatively severe in adolescents and adults, and the incidence is higher in infants and children. Peeling and thickening of the affected area is a significant manifestation of atopic dermatitis.

[0006] Inflammatory bowel disease (IBD) is an idiopathic intestinal inflammatory disease affecting the ileum, rectum, and colon. Clinical manifestations include diarrhea, abdominal pain, and even bloody stools. Inflammatory reactions caused by abnormal responses of the intestinal mucosal immune system are known to play a key role in the pathogenesis of IBD.

[0007] Allergic rhinitis (AR) is a non-infectious chronic inflammatory disease mediated primarily by immunoglobulin E (Ig E) after atopic individuals are exposed to allergens. Clinical manifestations include nasal itching, sneezing, runny nose, and nasal congestion. The global average prevalence of AR is as high as 20%, which not only seriously affects the quality of life of patients, but is also an independent risk factor for asthma. For the construction of AR models, the most commonly used allergen is ovalbumin (OVA), which has the advantages of low toxicity and the production of persistent antibodies after sensitization. Mice mainly produce Ig E during immune response, which is similar to humans, and their genetic data is more complete.

[0008] Bronchial asthma (abbreviated as asthma) is a chronic, nonspecific airway disease characterized by airway inflammation, airway mucus hypersecretion, airway hyperresponsiveness, and airway remodeling. With the deterioration of climate and environment, its incidence has increased annually and has become a serious risk factor for human life and health. Given the limitations of human experiments, asthma-related research is currently primarily conducted using animal models. An ideal animal model should closely reflect the pathophysiological mechanisms of human asthma, including allergic inflammation, eosinophilia, and high levels of mucus secretion in the airways. BALB / c and C57BL / 6 mice, commonly used experimental animals for asthma models, have the following key characteristics: a well-defined genetic background, a wide variety of strains, low cost, and the ability to easily induce characteristic asthma symptoms.

[0009] Rosacea is a chronic inflammatory skin disease affecting the cheeks, nose, chin and forehead, with clinical manifestations of recurrent flushing, telangiectasia, persistent facial erythema and papules and pustules.

[0010] Urticaria is a common immune-related skin disease characterized by wheals and itching. Mast cells are key effector cells in the pathogenesis of urticaria. Clinical symptoms primarily include localized edema (wheals) caused by temporary increased vascular permeability in the skin and mucous membranes. These wheals may be accompanied by significant and intense itching and scratching.

[0011] Overview of the Disclosure

[0012] This summary is provided to introduce some concepts in a simplified form that are further described in the detailed description below. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used to limit the scope of the claimed subject matter.

[0013] The compounds of the present disclosure can be used to treat or prevent autoimmune diseases, allergic diseases, inflammatory diseases, pruritus and pain, such as psoriasis, atopic dermatitis, inflammatory bowel disease (IBD), chronic urticaria, allergic rhinitis, asthma, alopecia areata, urticaria, allergic urticaria, rosacea, radiation dermatitis, eczema, pseudoallergic reaction, anaphylactic shock, systemic pruritus, neuropathic pruritus, prurigo nodularis, neuroinflammatory disease, ulcerative colitis, Crohn's disease, irritable bowel syndrome, respiratory inflammation, postoperative pain and vitiligo, etc., through the mechanism of immunomodulation. They have low toxicity and can be taken orally.

[0014] Specifically, the present disclosure provides compounds of formula (IA):

[0015] or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein each variable is as defined herein, for antagonizing MRGPRX2.

[0016] The present disclosure also provides compounds of formula (IB):

[0017] or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein each variable is as defined herein.

[0018] The compounds described above and the general formulae and specific compounds disclosed herein, as well as pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates and solvates thereof, are referred to herein as "compounds of the disclosure."

[0019] The compounds disclosed herein are antagonists of MRGPRX2 and can be used to treat or prevent diseases or disorders mediated by MRGPRX2, especially diseases or disorders caused by mast cell degranulation, and can especially be used to treat or prevent autoimmune diseases, allergic diseases, inflammatory diseases, itching and pain, such as psoriasis, atopic dermatitis, inflammatory bowel disease (IBD), chronic urticaria, allergic rhinitis, asthma, alopecia areata, urticaria, allergic urticaria, rosacea, radiation dermatitis, eczema, pseudoallergic reaction, anaphylactic shock, systemic pruritus, neuropathic pruritus, nodular prurigo, neuroinflammatory disease, ulcerative colitis, Crohn's disease, irritable bowel syndrome, respiratory inflammation, postoperative pain and vitiligo, etc.

[0020] Provided herein are compounds of the present disclosure that act as MRGPRX2 antagonists.

[0021] Provided herein are compounds of the present disclosure for use in treating or preventing MRGPRX2-mediated diseases or disorders.

[0022] Provided herein are compounds of the present disclosure for use in treating or preventing diseases or disorders resulting from mast cell degranulation.

[0023] Provided herein are compounds of the present disclosure for use in treating or preventing autoimmune diseases, allergic diseases, inflammatory diseases, pruritus, and pain, such as psoriasis, atopic dermatitis, inflammatory bowel disease (IBD), chronic urticaria, allergic rhinitis, asthma, alopecia areata, urticaria, allergic urticaria, rosacea, radiation dermatitis, eczema, pseudoallergic reaction, anaphylactic shock, generalized pruritus, neuropathic pruritus, prurigo nodularis, neuroinflammatory diseases, ulcerative colitis, Crohn's disease, irritable bowel syndrome, respiratory inflammation, postoperative pain, and vitiligo.

[0024] Provided herein are uses of the compounds of the present disclosure for the preparation of medicaments for the treatment or prophylaxis of autoimmune diseases, allergic diseases, inflammatory diseases, pruritus, and pain, such as psoriasis, atopic dermatitis, inflammatory bowel disease (IBD), chronic urticaria, allergic rhinitis, asthma, alopecia areata, urticaria, allergic urticaria, rosacea, radiation dermatitis, eczema, pseudoallergic reaction, anaphylactic shock, generalized pruritus, neuropathic pruritus, prurigo nodularis, neuroinflammatory diseases, ulcerative colitis, Crohn's disease, irritable bowel syndrome, respiratory inflammation, postoperative pain, and vitiligo.

[0025] Provided herein are methods for treating or preventing a disease or disorder mediated by MRGPRX2, wherein the method comprises administering to a subject in need thereof an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0026] Provided herein are methods for treating or preventing a disease or disorder in a subject comprising administering to a subject in need thereof an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is an autoimmune disease, allergic disease, inflammatory disease, pruritus, and pain, such as psoriasis, atopic dermatitis, inflammatory bowel disease (IBD), chronic urticaria, allergic rhinitis, asthma, alopecia areata, urticaria, allergic urticaria, rosacea, radiation dermatitis, eczema, pseudoallergic reaction, anaphylactic shock, generalized pruritus, neuropathic pruritus, prurigo nodularis, neuroinflammatory disease, ulcerative colitis, Crohn's disease, irritable bowel syndrome, respiratory inflammation, postoperative pain, and vitiligo.

[0027] Provided herein are methods for antagonizing MRGPRX2 in vitro, wherein the method comprises using a compound of the present disclosure or a pharmaceutically acceptable salt thereof in an in vitro assay for MRGPRX2.

[0028] Also provided herein are pharmaceutical compositions comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0029] In addition, provided herein are pharmaceutical combinations (combination products) or kits comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof (or a pharmaceutical composition thereof) as defined above and one or more other therapeutic agents (or a pharmaceutical composition thereof) for simultaneous, separate or sequential use in the treatment or prevention of MRGPRX2-mediated diseases or disorders.

[0030] Detailed description of this disclosure

[0031] EMBODIMENTS OF THE DISCLOSURE—SECTION A

[0032] Embodiment 1. A compound of formula (IA), a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for use in treating or preventing a disease or disorder mediated by MRGPRX2,

[0033] in:

[0034] R1 is -C 3-6 Cycloalkyl or -C 1-6 Straight-chain or branched alkyl group;

[0035] R2 is -COOH, -COOC 1-6 Straight or branched alkyl, -C(O)NH2, -C(O)-NH-C 1-6 Straight or branched alkyl, -C(O)-N(C 1-6 linear or branched alkyl)2 or -C(O)-NH-OH;

[0036] R3 is halogen;

[0037] B1 is -CR6 or N, wherein R6 is H, halogen or -OC 1-6 Straight-chain or branched alkyl group;

[0038] A is C 6-10 Aryl or 5-6 membered heteroaryl;

[0039] R4 is selected from -S(O)2-NH2, -S(O)2-NHR a 、-S(O)2-NR b R c 、-S(O)-NH2、-S(O)-NH-R a 、-S(O)-NR b R c 、-S-NH2、-S-NH-R a 、-S-NR b R c 、-S(O)2-R a 、-S(O)-R a 、-NH-S(O)2-R a 、-C(O)-NH2、-C(O)-NH-R a 、-C(O)-NR b R c 、-NH-C(O)-R a 、-C(O)-R a 、-NHR c 、-SR d and NO2;

[0040] R a and R dEach independently selected from C 1-20 Straight-chain or branched alkyl, C 2-20 Straight-chain or branched alkenyl, C 2-20 Straight-chain or branched alkynyl, C 3-10 wherein the heterocycloalkyl group contains one or more heteroatoms selected from N, O and S, and the alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl group is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halogen, -OH, -NH2, -CN, -NO2, -SC 1-6 Straight chain or branched alkyl, -OC 1-6 Straight chain or branched alkyl, -NHC 1-6 Straight or branched alkyl and -N(C 1-6 linear or branched alkyl)2;

[0041] R b and R c Together with the nitrogen atom to which they are attached, they form a 4-10 membered heterocycloalkyl group containing one or more heteroatoms selected from N, O and S, which is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of halogen, -OH, -NH2, -CN, -NO2, -SC 1-6 Straight chain or branched alkyl, -OC 1-6 Straight chain or branched alkyl, -NHC 1-6 Straight or branched alkyl and -N(C 1-6 linear or branched alkyl)2;

[0042] R5 is selected from halogen, -CN, -NH2, -OH, -NH-C 1-6 Straight or branched alkyl, -N(C 1-6 Straight chain or branched chain alkyl)2, C 1-6 Straight-chain or branched alkyl, C 1-6 Straight or branched alkoxy, -C(O)-NH2, -C(O)-NH-C 1-6 Straight or branched alkyl, -C(O)-N(C 1-6 Straight or branched alkyl)2 and -NH-C(O)-C 1-6 a halogenated straight or branched chain alkyl group; and

[0043] n is 0, 1, 2 or 3.

[0044] Embodiment 2. The compound for use according to any one of the preceding embodiments, its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate, wherein R1 is -C 3-4 Cycloalkyl or -C 1-3 Straight-chain or branched-chain alkyl.

[0045] Embodiment 3. The compound for use according to any one of the preceding embodiments, its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate, wherein R1 is or -C 1-3 Straight-chain or branched-chain alkyl.

[0046] Embodiment 4. The compound for use according to any one of the preceding embodiments, its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate, wherein R1 is

[0047] Embodiment 5. The compound for use according to any one of the preceding embodiments, its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate, wherein R1 is

[0048] Embodiment 6. The compound for use according to any one of the preceding embodiments, its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate, wherein R2 is -COOH, -COOC 1-3 Straight or branched alkyl, -C(O)NH2, -C(O)-NH-C 1-3 Straight or branched alkyl, -C(O)-N(C 1-3 linear or branched alkyl)2 or -C(O)-NH-OH.

[0049] Embodiment 7. The compound for use according to any one of the preceding embodiments, its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate, wherein R2 is -COOH, -COOC 1-3 Straight-chain or branched alkyl or -C(O)NH2.

[0050] Embodiment 8. The compound for use according to any one of the preceding embodiments, its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate, wherein R2 is -COOH or -COOC 1-3 Straight-chain or branched-chain alkyl.

[0051] Embodiment 9. The compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R2 is -COOH or -COOCH3.

[0052] Embodiment 10. The compound for use according to any one of the preceding embodiments, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R2 is -COOCH3 or -COOCH2CH3.

[0053] Embodiment 11. The compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R2 is -COOH.

[0054] Embodiment 12. The compound for use according to any one of the preceding embodiments, wherein R3 is F, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof.

[0055] Embodiment 13. The compound for use according to any one of the preceding embodiments, its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate, wherein B1 is -CR6 or N, wherein R6 is H, halogen or -OC 1-3 Straight-chain or branched-chain alkyl.

[0056] Embodiment 14. A compound for use according to any one of the preceding embodiments, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein B1 is -CR6 or N, wherein R6 is H, F, Cl or -OCH3.

[0057] Embodiment 15. The compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein B1 is -CR6, wherein R6 is H or -OCH3.

[0058] Embodiment 16. The compound for use according to any one of the preceding embodiments, wherein B1 is -CR6, wherein R6 is H, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof.

[0059] Embodiment 17. The compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein B1 is -CR6, wherein R6 is -OCH3.

[0060] Embodiment 18. The compound for use according to any one of the preceding embodiments, wherein B1 is N, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof.

[0061] Embodiment 19. The compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein A is phenyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl.

[0062] Embodiment 20. The compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein A is phenyl or pyridyl.

[0063] Embodiment 21. The compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein A is phenyl.

[0064] Embodiment 22. The compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein A is pyridyl.

[0065] Embodiment 23. A compound for use according to any one of the preceding embodiments, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R4 is selected from -S(O)2-NH2, -S(O)2-NHR a 、-S(O)2-NR b R c 、-S(O)-NH2、-S(O)-NH-R a 、-S(O)-NR b R c 、-S-NH2、-S-NH-R a 、-S-NR b R c 、-S(O)2-R a 、-S(O)-R a 、-NH-S(O)2-R a 、-C(O)-NH2、-C(O)-NH-R a 、-C(O)-NR b R c 、-NH-C(O)-R a 、-C(O)-R a 、-NHR d and-SR d .

[0066] Embodiment 24. A compound for use according to any one of the preceding embodiments, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R4 is selected from -S(O)2-NH2, -S(O)2-NHR a 、-S(O)2-NR b R c 、-S(O)-NH2、-S(O)-NH-R a 、-S(O)-NR b R c 、-S-NH-R a 、-S-NR b R c 、-S(O)2-R a 、-S(O)-R a 、-NH-S(O)2-R a 、-C(O)-NH2、-C(O)-NH-R a 、-C(O)-NR b R c 、-NH-C(O)-R a 、-NHR d and-SR d .

[0067] Embodiment 25. A compound for use according to any one of the preceding embodiments, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R4 is selected from -S(O)2-NH2, -S(O)2-NHR a 、-S(O)2-NR b R c 、-S(O)-NH-R a 、-S-NH-R a 、-S(O)-R a 、-NH-S(O)2-R a 、-C(O)-NH2、-C(O)-NH-R a 、-C(O)-NR b R c 、-NH-C(O)-R a 、-NHR d and-SR d .

[0068] Embodiment 26. A compound for use according to any one of the preceding embodiments, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R4 is selected from -S(O)2-NH2, -S(O)2-NHR a 、-S(O)2-NR bR c 、-S(O)-NH-R a 、-S-NH-R a 、-S(O)-R a 、-NH-S(O)2-R a 、-C(O)-NH2、-C(O)-NH-R a 、-NH-C(O)-R a 、-NHR d and-SR d .

[0069] Embodiment 27. A compound for use according to any one of the preceding embodiments, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R4 is selected from -S(O)2-NH2, -S(O)2-NHR a 、-S(O)2-NR b R c 、-NH-S(O)2-R a 、-C(O)-NH2、-C(O)-NH-R a 、-NH-C(O)-R a 、-NHR d and-SR d .

[0070] Embodiment 28. A compound for use according to any one of the preceding embodiments, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R4 is selected from -S(O)2-NH2, -S(O)2-NHR a 、-S(O)2-NR b R c 、-S(O)-NH-R a 、-S-NH-R a 、-NH-S(O)2-R a 、-C(O)-NH2、-C(O)-NH-R a and -NHR a .

[0071] Embodiment 29. A compound for use according to any one of the preceding embodiments, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R4 is selected from -S(O)2-NH2, -S(O)2-NHR a 、-S(O)2-NR b R c 、-NH-S(O)2-R a 、-C(O)-NH2、-C(O)-NH-R a、-C(O)-NR b R c and -NH-C(O)-R a .

[0072] Embodiment 30. A compound for use according to any one of the preceding embodiments, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R4 is selected from -S(O)2-NH2, -S(O)2-NHR a and -S(O)2-NR b R c .

[0073] Embodiment 31. A compound for use according to any one of the preceding embodiments, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R4 is -S(O)2-NHR a .

[0074] Embodiment 32. The compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R a and R d Each independently selected from C 1-15 Straight-chain or branched alkyl, C 2-15 Straight-chain or branched alkenyl, C 2-15 Straight-chain or branched alkynyl, C 3-10 wherein the heterocycloalkyl group contains one or more heteroatoms selected from N, O and S, and the alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl group is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halogen, -OH, -NH2, -CN, -NO2, -SC 1-6 Straight chain or branched alkyl, -OC 1-6 Straight chain or branched alkyl, -NHC 1-6 Straight or branched alkyl and -N(C 1-6 linear or branched alkyl)2.

[0075] Embodiment 33. The compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R a Selected from C 1-15 Straight-chain or branched alkyl, C 2-15 Straight-chain or branched alkenyl, C 2-15 Straight-chain or branched alkynyl, C 3-10cycloalkyl and 4-10 membered heterocycloalkyl, wherein the heterocycloalkyl contains one or more heteroatoms selected from N, O and S, and the alkyl is optionally substituted with 1, 2 or 3 substituents selected from the following: halogen, -OH, -NH2, -CN, -SC 1-6 Straight chain or branched alkyl, -OC 1-3 Straight or branched alkyl and -NHC 1-3 Straight or branched chain alkyl; for example, R a It is C 1-15 Straight-chain or branched alkyl, said alkyl being optionally substituted by 1, 2 or 3 halogens.

[0076] Embodiment 34. The compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R a Selected from C 1-15 Straight-chain or branched alkyl, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl, wherein the heterocycloalkyl contains 1, 2 or 3 heteroatoms selected from N, O and S, and the alkyl is optionally substituted with 1, 2 or 3 substituents selected from the following: halogen, -OH, -NH2, -CN, -SC 1-3 Straight chain or branched alkyl, -OC 1-3 Straight or branched alkyl and -NHC 1-3 Straight or branched chain alkyl; for example, R a It is C 1-15 Straight chain alkyl, said alkyl being optionally substituted with 1, 2 or 3 halogens.

[0077] Embodiment 35. The compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R a Selected from C 1-15 Straight-chain or branched alkyl, C 3-6 4-6 membered cycloalkyl and 4-6 membered heterocycloalkyl, wherein the heterocycloalkyl contains 1, 2 or 3 heteroatoms selected from N, O and S, and the alkyl is optionally substituted with 1, 2 or 3 substituents selected from the following: halogen, -OH, -NH2 and -CN; for example, R a It is C 1-15 Straight chain alkyl, said alkyl being optionally substituted with 1, 2 or 3 halogens (eg 3 F).

[0078] Embodiment 36. The compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R a Selected from C 1-12 Straight-chain or branched alkyl, C 3-64-6 membered cycloalkyl and 4-6 membered heterocycloalkyl, wherein the heterocycloalkyl contains 1 or 2 heteroatoms selected from N, O and S, and the alkyl is optionally substituted with 1, 2 or 3 substituents selected from the following: halogen, -OH and -NH2; for example, R a It is C 1-12 Straight-chain or branched alkyl, which is optionally substituted by 1, 2 or 3 halogens (eg 3 F).

[0079] Embodiment 37. The compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R a Selected from C 1-9 Straight-chain or branched alkyl, C 5-6 5-6 membered cycloalkyl and 5-6 membered heterocycloalkyl, wherein the heterocycloalkyl contains 1 or 2 heteroatoms selected from N or O, and the alkyl is optionally substituted with 1, 2 or 3 substituents selected from the following: halogen, -OH and --NH2; for example, R a It is C 1-9 Straight-chain or branched alkyl, which is optionally substituted by 1, 2 or 3 halogens (eg 3 F).

[0080] Embodiment 38. The compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R a Selected from C 1-9 Straight-chain or branched alkyl, C 1-9 Straight chain or branched alkyl-OH, C 1-9 Straight chain or branched alkyl -NH2, C 1-9 Halogenated straight or branched alkyl (e.g. C 1-9 Chloro-substituted straight-chain or branched-chain alkyl, C 1-9 Fluorinated straight or branched alkyl or C 1-8 Straight or branched alkyl -CF3), cyclohexyl and tetrahydropyranyl; for example C 1-9 Straight chain alkyl or C 1-8 Straight chain alkyl -CF3.

[0081] Embodiment 39. The compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R a Selected from C 1-9 Straight or branched chain alkyl, such as C 1-9 Straight chain alkyl.

[0082] Embodiment 40. The compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein Ra Selected from C 1-9 Straight-chain or branched alkyl -OH.

[0083] Embodiment 41. The compound for use according to any one of the preceding embodiments, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R a Selected from C 1-9 Straight-chain or branched alkyl -NH2.

[0084] Embodiment 42. The compound for use according to any one of the preceding embodiments, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R a Selected from C 1-9 Halogenated straight or branched alkyl groups, such as C 1-9 Chloro-substituted straight-chain or branched-chain alkyl, C 1-9 Fluorinated straight or branched alkyl or C 1-8 Straight chain or branched alkyl -CF3, such as C 1-8 Straight chain alkyl -CF3.

[0085] Embodiment 43. The compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R a Selected from cyclohexyl and tetrahydropyranyl.

[0086] Embodiment 44. The compound for use according to any one of the preceding embodiments, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R d Selected from C 1-15 Straight-chain or branched alkyl, C 2-15 Straight chain or branched alkenyl and C 2-15 Straight or branched chain alkynyl, wherein the alkyl, alkenyl or alkynyl group is optionally substituted with 1, 2 or 3 substituents selected from halogen, -OH, -NH2, -CN and -NO2.

[0087] Embodiment 45. The compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R d Selected from C 1-12 Straight-chain or branched alkyl, C 2-12 Straight chain or branched alkenyl and C 2-12 Straight or branched chain alkynyl, wherein the alkyl, alkenyl or alkynyl group is optionally substituted with 1, 2 or 3 substituents selected from halogen, -OH and -CN.

[0088] Embodiment 46. The compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R d Selected from C 1-6 Straight-chain or branched alkyl, C 2-6 Straight chain or branched alkenyl and C 2-6 Straight or branched chain alkynyl, wherein the alkyl, alkenyl or alkynyl group is optionally substituted with 1, 2 or 3 substituents selected from halogen, -OH and -CN.

[0089] Embodiment 47. The compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R d Selected from C 1-6 Straight-chain or branched alkyl, C 2-6 Straight chain or branched alkenyl and C 2-6 Straight or branched chain alkynyl, wherein the alkyl group is optionally substituted with 1, 2 or 3 substituents selected from halogen, -OH and -CN.

[0090] Embodiment 48. The compound for use according to any one of the preceding embodiments, its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate, wherein R d Selected from C 1-3 Straight-chain or branched alkyl, C 2-3 Straight chain or branched alkenyl and C 2-3 Straight or branched chain alkynyl, wherein the alkyl group is optionally substituted with 1, 2 or 3 substituents selected from halogen, -OH and -CN.

[0091] Embodiment 49. The compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R d Selected from C 1-3 Straight-chain or branched alkyl (e.g., n-propyl), C 2-3 Straight-chain or branched alkenyl (eg, allyl) and C 2-3 Straight or branched alkynyl (eg, propargyl), wherein the alkyl group is optionally substituted with one -OH group (eg, -C 1-3 straight chain alkyl -OH, such as hydroxyethyl).

[0092] Embodiment 50. The compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R b and R cTogether with the nitrogen atom to which they are attached, they form a 4-10 membered heterocycloalkyl group containing one or more heteroatoms selected from N, O and S, which is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of halogen, -OH, -NH2, -CN, -NO2, -SC 1-6 Straight chain or branched alkyl, -OC 1-6 Straight chain or branched alkyl, -NHC 1-6 Straight or branched alkyl and -N(C 1-6 linear or branched alkyl)2.

[0093] Embodiment 51. The compound for use according to any one of the preceding embodiments, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R b and R c Together with the nitrogen atom to which they are attached, they form a 4-7 membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms selected from N, O and S, which is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halogen, -OH, -NH2, -CN, -SC 1-3 Straight chain or branched alkyl, -OC 1-3 Straight or branched alkyl and -NHC 1-3 Straight-chain or branched-chain alkyl.

[0094] Embodiment 52. The compound for use according to any one of the preceding embodiments, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R b and R c Together with the nitrogen atom to which they are attached, they form a 4-6 membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms selected from N, O and S, which is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halogen, -OH, -NH2, -CN, -SC 1-3 Straight chain or branched alkyl, -OC 1-3 Straight or branched alkyl and -NHC 1-3 Straight-chain or branched-chain alkyl.

[0095] Embodiment 53. The compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R b and R c Together with the nitrogen atom to which they are attached they form a 4-6 membered heterocycloalkyl group containing 1 or 2 heteroatoms selected from N, O and S, said heterocycloalkyl group being optionally substituted with 1, 2 or 3 substituents selected from halogen, -OH, -NH2 and -CN.

[0096] Embodiment 54. The compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R b and R c Together with the nitrogen atom to which they are attached, they form a 4-6 membered heterocycloalkyl group containing 1 or 2 heteroatoms selected from N, O and S, and optionally substituted by 1, 2 or 3 halogens.

[0097] Embodiment 55. The compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R b and R c Together with the N atom to which they are attached they form a 4-6 membered heterocycloalkyl group containing 1 or 2 heteroatoms selected from N or O, said heterocycloalkyl group being optionally substituted with 2 F atoms; for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, difluoroazetidinyl or 3,3-difluoroazetidinyl.

[0098] Embodiment 56. The compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R b and R c Together with the N atom to which they are attached they form a 4-6 membered heterocycloalkyl group containing 1 heteroatom selected from N, said heterocycloalkyl group being optionally substituted by 2 F atoms; for example, azetidinyl, pyrrolidinyl, piperidinyl, difluoroazetidinyl or 3,3-difluoroazetidinyl.

[0099] Embodiment 57. The compound for use according to any one of the preceding embodiments, its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate, wherein R5 is selected from halogen, -CN, -NH2, -OH, -NH-C 1-6 Straight-chain or branched alkyl, C 1-6 Straight-chain or branched alkyl, C 1-6 Straight or branched alkoxy, -C(O)-NH2, -C(O)-NH-C 1-6 Straight or branched alkyl and -NH-C(O)-C 1-6 Halogenated straight-chain or branched alkyl.

[0100] Embodiment 58. The compound for use according to any one of the preceding embodiments, its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate, wherein R5 is selected from halogen, -CN, -NH2, -OH, -NH-C 1-6Straight-chain or branched alkyl, C 1-6 Straight-chain or branched alkyl, C 1-6 Straight or branched alkoxy, -C(O)-NH2, -C(O)-NH-C 1-6 Straight or branched alkyl and -NH-C(O)-C 1-6 Halogenated straight-chain or branched alkyl.

[0101] Embodiment 59. The compound for use according to any one of the preceding embodiments, its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate, wherein R5 is selected from halogen, -CN, -NH2, -OH, -NH-C 1-6 Straight-chain or branched alkyl, C 1-6 Straight or branched alkyl and C 1-6 Straight-chain or branched alkoxy.

[0102] Embodiment 60. The compound for use according to any one of the preceding embodiments, its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate, wherein R5 is selected from halogen, -CN, -NH2, -OH, -NH-C 1-3 Straight-chain or branched alkyl, C 1-3 Straight chain alkyl and C 1-3 Straight-chain or branched alkoxy.

[0103] Embodiment 61. A compound for use according to any one of the preceding embodiments, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R5 is selected from halogen (e.g., F), -CN, -NH2 and C 1-3 Straight-chain alkoxy (eg, methoxy).

[0104] Embodiment 62. The compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein n is 0, 1 or 2.

[0105] Embodiment 63. The compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein n is 0.

[0106] Embodiment 64. The compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein n is 1.

[0107] Embodiment 65. The compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein n is 1 or 2.

[0108] Embodiment 66. The compound for use according to embodiment 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein:

[0109] A is phenyl or pyridyl;

[0110] R4 is -S(O)2-NHR a or -S(O)2-NR b R c ;

[0111] R a Selected from C 1-9 Straight chain alkyl, cyclohexyl and tetrahydropyran, the alkyl group is optionally substituted by 1, 2 or 3 groups selected from halogen, -OH, -NH2 and -SCH3 (for example, the alkyl group is optionally substituted by 1 group selected from halogen, -OH, -NH2 and -SCH3, or is optionally substituted by 3 halogens), for example -CF3 or C 1-8 Linear alkyl -CF3;

[0112] R b and R c Together with the N atom to which they are attached, they form a 4-6 membered heterocycloalkyl group containing 1 or 2 heteroatoms selected from N or O, which is optionally substituted with 2 F atoms (e.g., azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, difluoroazetidinyl, 3,3-difluoroazetidinyl);

[0113] R5 is selected from halogen, -CN, -NH2, C 1-3 Straight chain alkyl, C 1-3 Straight chain alkoxy, -C(O)-NH2 and -NH-C(O)-C 1-3 a halogenated straight or branched chain alkyl group; and

[0114] n is 0 or 1.

[0115] Embodiment 67. The compound for use according to embodiment 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein:

[0116] A is phenyl or pyridyl;

[0117] R4 is -S(O)-NH-R a or -S-NH-R a ;

[0118] R a It is C 1-9 Straight chain alkyl, which is optionally substituted with 1, 2 or 3 halogens (e.g. -CF3 or C 1-8 linear alkyl -CF3); and

[0119] n is 0.

[0120] Embodiment 68. The compound for use according to embodiment 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein:

[0121] A is phenyl or pyridyl;

[0122] R4 is -S(O)-R a , R a It is C 1-6 Halogenated straight or branched alkyl (e.g. R4 is -S(O)-C 1-6 chlorinated straight-chain or branched-chain alkyl); and

[0123] n is 0.

[0124] Embodiment 69. The compound for use according to embodiment 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein:

[0125] A is phenyl or pyridyl;

[0126] R4 is -NH-S(O)2-R a ;

[0127] R a Is a straight chain or branched C 1-6 a straight or branched chain alkyl group; and

[0128] n is 0.

[0129] Embodiment 70. The compound for use according to embodiment 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein:

[0130] A is phenyl or pyridyl;

[0131] R4 is -C(O)-NH-R a or -NH-C(O)-R a ;

[0132] R a Is a straight chain or branched C 1-6Straight or branched alkyl, the alkyl is optionally substituted by 1, 2 or 3 groups selected from halogen and -OH (for example, the alkyl is optionally substituted by 1 group selected from halogen and OH, or is optionally substituted by 2 or 3 halogens, such as -CF2, -CF3 or C 1-5 Linear alkyl -CF3);

[0133] R5 is selected from halogen, -CN, -NH2, C 1-3 Straight chain alkyl, C 1-3 Straight chain alkoxy, -C(O)-NH2 and -NH-C(O)-C 1-3 a halogenated straight or branched chain alkyl group; and

[0134] n is 0 or 1.

[0135] Embodiment 71. The compound for use according to any one of the preceding embodiments 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein:

[0136] R1 is For example

[0137] R2 is -COOH or -COOC 1-3 Straight-chain or branched alkyl; for example -COOH or -COOCH3;

[0138] R3 is F;

[0139] B1 is -CR6 or N, wherein R6 is H, halogen or -OC 1-3 Straight-chain or branched alkyl groups, such as H, F or -O-CH3;

[0140] A phenyl or pyridyl;

[0141] R4 is selected from -S(O)2-NH2, -S(O)2-NHR a 、-S(O)2-NR b R c 、-NH-S(O)2-R a 、-C(O)-NH2、-C(O)-NH-R a 、-C(O)-NR b R c and -NH-C(O)-R a ;

[0142] R a Selected from C 1-12 Straight-chain or branched alkyl, C 3-64-6 membered cycloalkyl and 4-6 membered heterocycloalkyl, wherein the heterocycloalkyl contains 1 or 2 heteroatoms selected from N, O and S, and the alkyl is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halogen and -OH;

[0143] R b and R c Together with the nitrogen atom to which they are attached, they form a 4-6 membered heterocycloalkyl group containing 1 or 2 heteroatoms selected from N, O and S, which is optionally substituted with 1, 2 or 3 halogens; and

[0144] n is 0.

[0145] Embodiment 72. The compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R4 is -S(O)2-NH2.

[0146] Embodiment 73. A compound for use according to any one of the preceding embodiments, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R4 is -S(O)2-NHR a .

[0147] Embodiment 74. A compound for use according to any one of the preceding embodiments, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R4 is -S(O)2-NR b R c .

[0148] Embodiment 75. The compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R a Selected from C 1-10 Straight-chain or branched alkyl, C 3-6 4-6 membered cycloalkyl and 4-6 membered heterocycloalkyl, wherein the heterocycloalkyl contains 1 or 2 heteroatoms selected from N or O, and the alkyl is optionally substituted with 1, 2 or 3 substituents selected from halogen and -OH;

[0149] Embodiment 76. The compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R a is C optionally substituted by 1, 2 or 3 hydroxyl groups or halogen 1-9 Straight or branched chain alkyl (e.g. C 1-8 linear or branched alkyl-CF3), or tetrahydropyranyl.

[0150] Embodiment 77. The compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R b and R c Together with the N atom to which they are attached, they form a 4-6 membered heterocycloalkyl group containing 1 or 2 heteroatoms selected from N and O, which is optionally substituted by 1 or 2 halogens (e.g., 2 F atoms); for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, difluoroazetidinyl or 3,3-difluoroazetidinyl.

[0151] Embodiment 78. The compound for use according to any one of the preceding embodiments, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein the compound is selected from Example Compounds 1-173.

[0152] Embodiment 79. The compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein the disease or disorder is a disease or disorder caused by mast cell degranulation.

[0153] Embodiment 80. The compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein the disease or disorder is selected from autoimmune diseases, allergic diseases, inflammatory diseases, pruritus and pain, such as inflammatory skin diseases.

[0154] Embodiment 81. A compound for use according to any one of the preceding embodiments, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein the disease or disorder is selected from psoriasis, atopic dermatitis, inflammatory bowel disease (IBD), chronic urticaria, allergic rhinitis, asthma, alopecia areata, urticaria, allergic urticaria, rosacea, radiation dermatitis, eczema, pseudoallergic reaction, anaphylactic shock, generalized pruritus, neuropathic pruritus, prurigo nodularis, neuroinflammatory disease, ulcerative colitis, Crohn's disease, irritable bowel syndrome, respiratory inflammation, postoperative pain and vitiligo.

[0155] Embodiment 82. The compound for use according to any one of the preceding embodiments, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein the disease or disorder is selected from rosacea, psoriasis, urticaria, atopic dermatitis, inflammatory bowel disease, allergic rhinitis and asthma.

[0156] Embodiment 83. Use of a compound as defined in any one of the preceding embodiments 1-78, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, in the preparation of a medicament for treating or preventing a disease or disorder mediated by MRGPRX2.

[0157] Embodiment 84. Use of a compound as defined in any one of the preceding embodiments 1-78, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, in the preparation of a medicament for treating or preventing a disease or disorder caused by mast cell degranulation.

[0158] Embodiment 85. Use of a compound as defined in any one of the preceding embodiments 1-78, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, in the preparation of a medicament for treating or preventing autoimmune diseases, allergic diseases, inflammatory diseases, itching and pain, such as inflammatory skin diseases.

[0159] Embodiment 86. Use of a compound as defined in any one of the preceding embodiments 1-78, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, in the preparation of a medicament for treating or preventing psoriasis, atopic dermatitis, inflammatory bowel disease (IBD), chronic urticaria, allergic rhinitis, asthma, alopecia areata, urticaria, allergic urticaria, rosacea, radiation dermatitis, eczema, pseudoallergic reaction, anaphylactic shock, generalized pruritus, neuropathic prurigo, nodular prurigo, neuroinflammatory disease, ulcerative colitis, Crohn's disease, irritable bowel syndrome, respiratory inflammation, postoperative pain and vitiligo.

[0160] Embodiment 87. Use of a compound as defined in any one of the preceding embodiments 1-78, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, in the preparation of a medicament for treating or preventing rosacea, psoriasis, urticaria, atopic dermatitis, inflammatory bowel disease, allergic rhinitis and asthma.

[0161] Embodiment 88. A method for treating or preventing a disease or disorder in an individual, the method comprising administering to an individual in need thereof an effective amount of a compound as defined in any one of the preceding embodiments 1-78, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein the disease or disorder is a MRGPRX2-mediated disease or disorder.

[0162] Embodiment 89. A method for treating or preventing a disease or disorder in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound as defined in any one of the preceding embodiments 1-78, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein the disease or disorder is a disease or disorder caused by mast cell degranulation.

[0163] Embodiment 90. A method for treating or preventing a disease or disorder in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound as defined in any one of the preceding embodiments 1-78, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein the disease or disorder is selected from autoimmune diseases, allergic diseases, inflammatory diseases, pruritus and pain, such as inflammatory skin diseases.

[0164] Embodiment 91. A method for treating or preventing a disease or disorder in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound as defined in any one of the preceding embodiments 1-78, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein the disease or disorder is selected from psoriasis, atopic dermatitis, inflammatory bowel disease (IBD), chronic urticaria, allergic rhinitis, asthma, alopecia areata, urticaria, allergic urticaria, rosacea, radiation dermatitis, eczema, pseudoallergic reaction, anaphylactic shock, generalized pruritus, neuropathic pruritus, prurigo nodularis, neuroinflammatory disease, ulcerative colitis, Crohn's disease, irritable bowel syndrome, respiratory inflammation, postoperative pain and vitiligo.

[0165] Embodiment 92. A method of treating or preventing a disease or disorder in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound as defined in any one of the preceding embodiments 1-78, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein the disease or disorder is selected from rosacea, psoriasis, urticaria, atopic dermatitis, inflammatory bowel disease, allergic rhinitis and asthma.

[0166] Embodiment 93. Use of a compound as defined in any one of the preceding embodiments 1-78, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for treating or preventing a disease or disorder mediated by MRGPRX2.

[0167] Embodiment 94. Use of a compound as defined in any one of the preceding embodiments 1-78, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for treating or preventing a disease or disorder caused by mast cell degranulation.

[0168] Embodiment 95. Use of a compound as defined in any one of the preceding embodiments 1-78, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for treating or preventing autoimmune diseases, allergic diseases, inflammatory diseases, itching and pain, such as inflammatory skin diseases.

[0169] Embodiment 96. Use of a compound as defined in any one of the preceding embodiments 1-78, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, for the treatment or prevention of psoriasis, atopic dermatitis, inflammatory bowel disease (IBD), chronic urticaria, allergic rhinitis, asthma, alopecia areata, urticaria, allergic urticaria, rosacea, radiation dermatitis, eczema, pseudoallergic reaction, anaphylactic shock, generalized pruritus, neuropathic pruritus, prurigo nodularis, neuroinflammatory disease, ulcerative colitis, Crohn's disease, irritable bowel syndrome, respiratory inflammation, postoperative pain and vitiligo.

[0170] Embodiment 97. Use of a compound as defined in any one of the preceding embodiments 1-78, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for treating or preventing rosacea, psoriasis, urticaria, atopic dermatitis, inflammatory bowel disease, allergic rhinitis and asthma.

[0171] Embodiment 98. A pharmaceutical composition for treating or preventing a disease or disorder mediated by MRGPRX2, comprising a compound as defined in any one of the preceding embodiments 1-78, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof.

[0172] Embodiment 99. A pharmaceutical composition for treating or preventing a disease or disorder caused by mast cell degranulation, comprising a compound as defined in any one of the preceding embodiments 1-78, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof.

[0173] Embodiment 100. A method for antagonizing MRGPRX2 in vitro, the method comprising using an effective amount of a compound defined in any one of the preceding embodiments 1-78, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for in vitro testing of MRGPRX2.

[0174] Embodiments of the present disclosure—Part B

[0175] Embodiment 1. A compound of formula (IB), a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof,

[0176] in:

[0177] R1 is -C 3-6 Cycloalkyl or -C 1-6 Straight-chain or branched alkyl group;

[0178] R2 is -COOH or -COOC 1-6 Straight-chain or branched alkyl group;

[0179] R3 is halogen;

[0180] B1 is -CR6 or N, wherein R6 is H, halogen or -OC 1-6 a straight or branched chain alkyl group; and

[0181] A is phenyl; and R4 is selected from -S(O)2-NH-C 8-12 Straight or branched alkyl, -S(O)2-NH-C 1-6 Straight chain or branched alkyl -CF3, -S(O)2-NH-cyclohexyl, -S(O)2-NR b R c 、-S(O)-NH-C 1-6 Straight chain or branched alkyl -CF3, -S-NH-C 1-6 Straight chain or branched alkyl -CF3, -NH-S(O)2-C 1-6 Straight or branched alkyl, -C(O)-NH2, -C(O)-NH-C 2-6 Straight-chain or branched alkyl, -C(O)-NR b R c , -NH-C(O)-CF3, -NH-C(O)-CH2Cl, -NH-C 1-6 Straight or branched alkyl, -NH-C 1-6 Straight or branched alkenyl and -NH-C 1-6 Straight-chain or branched alkynyl; wherein R b and R c Together with the nitrogen atom to which they are attached, they form an azetidinyl or difluoroazetidinyl group;

[0182] Alternatively, A is pyridyl; and R4 is selected from -S(O)2-NH2, -S(O)2-NH-CH2CH2OH, -S(O)2-NH-CH2CH2Cl, -S(O)2-NH-C 4-6 Straight or branched alkyl, -S(O)2-NH-C 8-12 Straight or branched alkyl, -S(O)2-NH-cyclohexyl, -S(O)2-NH-tetrahydropyranyl, -S(O)2-NR b R c 、-S(O)-NH-C 1-6 Straight or branched alkyl, -S-NH-C 1-6Straight chain or branched alkyl -CF3, -NH-S(O)2-C 2-6 Straight or branched alkyl, -C(O)-NH-C 3-6 Branched alkyl, -C(O)-NR b R c , -NH-C(O)-CF2, -NH-C(O)-CH2CF3, -NH-C 1-6 Straight chain or branched alkyl and -SC 1-6 Hydroxyl linear or branched alkyl; wherein R b and R c Together with the nitrogen atom to which they are attached they form azetidinyl, difluoroazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.

[0183] Embodiment 2. A compound according to any one of the preceding embodiments, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R1 is -C 3-4 Cycloalkyl or -C 1-3 Straight-chain or branched-chain alkyl.

[0184] Embodiment 3. A compound according to any one of the preceding embodiments, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R1 is or -C 1-3 Straight-chain or branched-chain alkyl.

[0185] Embodiment 4. A compound according to any one of the preceding embodiments, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R1 is

[0186] Embodiment 5. A compound according to any one of the preceding embodiments, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R1 is

[0187] Embodiment 6. A compound according to any one of the preceding embodiments, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R2 is -COOH or -COOC 1-3 Straight-chain or branched-chain alkyl.

[0188] Embodiment 7. The compound according to any one of the preceding embodiments 1-7, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R2 is -COOH or -COOCH3.

[0189] Embodiment 8. The compound according to any one of the preceding embodiments 1-7, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R2 is -COOCH3 or -COOCH2CH3.

[0190] Embodiment 9. The compound according to any one of the preceding embodiments 1-7, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R2 is -COOH.

[0191] Embodiment 10. The compound according to any one of the preceding embodiments 1-7, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R2 is -COOCH3.

[0192] Embodiment 11. A compound according to any one of the preceding embodiments, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein R3 is F.

[0193] Embodiment 12. A compound according to any one of the preceding embodiments, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein B1 is -CR6 or N, wherein R6 is H, halogen or -OC 1-3 Straight-chain or branched-chain alkyl.

[0194] Embodiment 13. A compound according to any one of the preceding embodiments, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein B1 is -CR6 or N, wherein R6 is H, F, Cl or -OCH3.

[0195] Embodiment 14. A compound according to any one of the preceding embodiments, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein B1 is -CR6, wherein R6 is H or -OCH3.

[0196] Embodiment 15. A compound according to any one of the preceding embodiments, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein B1 is -CR6, wherein R6 is H.

[0197] Embodiment 16. A compound according to any one of the preceding embodiments, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein B1 is -CR6, wherein R6 is -OCH3.

[0198] Embodiment 17. A compound according to any one of the preceding embodiments, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein B1 is N.

[0199] Embodiment 18. A compound according to any one of the preceding embodiments, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein A is phenyl; and R4 is selected from -S(O)2-NH-C 8-12 Straight or branched alkyl, -S(O)2-NH-C 1-6 Straight chain or branched alkyl -CF3, -S(O)2-NH-cyclohexyl, -S(O)2-NR b R c 、-S(O)-NH-C 1-6 Straight chain or branched alkyl -CF3, -S-NH-C 1-6 Straight chain or branched alkyl -CF3, -NH-S(O)2-C 1-6 Straight or branched alkyl, -C(O)-NH2, -C(O)-NH-C 2-6 Straight or branched alkyl, -NH-C(O)-CF3, -NH-C(O)-CH2Cl, -NH-C 1-6 Straight or branched alkenyl and -NH-C 1-6 Straight-chain or branched alkynyl; wherein R b and R c Together with the nitrogen atom to which they are attached they form an azetidinyl or difluoroazetidinyl group.

[0200] Embodiment 19. A compound according to any one of the preceding embodiments, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein A is phenyl; and R4 is selected from -S(O)2-NH-C 8-12 Straight or branched alkyl, -S(O)2-NH-C 1-6 Straight chain or branched alkyl -CF3, -S(O)2-NH-cyclohexyl, -S(O)2-NR b R c 、-NH-S(O)2-C 1-6 Straight or branched alkyl, -C(O)-NH2, -C(O)-NH-C 2-6 Straight or branched alkyl, -NH-C(O)-CF3, -NH-C 1-6 Straight or branched alkyl and -NH-C 1-6 Straight-chain or branched alkenyl; wherein R b and R c Together with the nitrogen atom to which they are attached they form an azetidinyl or difluoroazetidinyl group.

[0201] Embodiment 20. A compound according to any one of the preceding embodiments, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein A is phenyl; and R4 is selected from -S(O)2-NH-C 8-10 Straight chain alkyl, -S(O)2-NH-C 2-4 Straight chain alkyl -CF3, -S(O)2-NH-cyclohexyl, -S(O)2-NR b R c 、-NH-S(O)2-C 2-4 Straight chain alkyl, -C(O)-NH2, -C(O)-NH-C 2-6 Straight or branched alkyl, -NH-C(O)-CF3, -NH-C 2-4 Straight chain alkyl and -NH-C 2-4 Straight-chain alkenyl; wherein R b and R c Together with the nitrogen atom to which they are attached they form an azetidinyl or difluoroazetidinyl group.

[0202] Embodiment 21. A compound according to any one of the preceding embodiments 1-18, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein A is phenyl; and R4 is selected from -S(O)2-NH-C 8-12 Straight or branched alkyl, -S(O)2-NH-C 1-6 Straight chain or branched alkyl -CF3, -S(O)2-NH-cyclohexyl, -S(O)2-NR b R c 、-C(O)-NH2、-C(O)-NH-C 2-6 Straight or branched alkyl, -NH-C(O)-CF3 and -NH-C 1-6 Straight-chain or branched alkenyl; wherein R b and R c Together with the nitrogen atom to which they are attached they form a difluoroazetidinyl group.

[0203] Embodiment 22. A compound according to any one of the preceding embodiments 1-18, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein A is phenyl; and R4 is selected from -S(O)2-NH-C 8-12 Straight chain alkyl, -S(O)2-NH-C 1-6 Straight chain alkyl -CF3, -S(O)2-NR b R c 、-C(O)-NH-C 2-6 Straight or branched alkyl, -NH-C(O)-CF3 and -NH-C 1-6 Straight-chain alkenyl; wherein Rb and R c Together with the nitrogen atom to which they are attached, they form a difluoroazetidinyl group;

[0204] Embodiment 23. A compound according to any one of the preceding embodiments 1-18, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein A is phenyl; and R4 is selected from -S(O)2-NH-C 8-10 Straight chain alkyl, -S(O)2-NH-C 2-4 Straight chain alkyl -CF3, -S(O)2-NR b R c 、-C(O)-NH-C 2-6 Straight or branched alkyl, -NH-C(O)-CF3 and -NH-C 2-4 Straight-chain alkenyl; wherein R b and R c Together with the nitrogen atom to which they are attached they form a difluoroazetidinyl group.

[0205] Embodiment 24. A compound according to any one of the preceding embodiments 1-18, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein A is phenyl; and R4 is selected from -S(O)2-NH-n-nonyl, -S(O)2-NH-n-propyl-CF3, -S(O)2-NR b R c , -C(O)-NH-n-propyl, -C(O)-NH-2,2-dimethylpropyl, -NH-C(O)-CF3 and -NH-allyl; wherein R b and R c Together with the nitrogen atom to which they are attached they form a difluoroazetidinyl group.

[0206] Embodiment 25. A compound according to any one of the preceding embodiments 1-18, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein A is phenyl; and R4 is -S(O)2-NH-C 8-12 Straight or branched alkyl, or -S(O)2-NH-C 1-6 Straight chain or branched alkyl -CF3.

[0207] Embodiment 26. A compound according to any one of the preceding embodiments, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein A is pyridyl; and R4 is selected from -S(O)2-NH2, -S(O)2-NH-CH2CH2OH, -S(O)2-NH-CH2CH2Cl, -S(O)2-NH-C 4-6 Straight or branched alkyl, -S(O)2-NH-C8-12 Straight or branched alkyl, -S(O)2-NH-cyclohexyl, -S(O)2-NH-tetrahydropyranyl, -S(O)2-NR b R c 、-NH-S(O)2-C 2-6 Straight or branched alkyl, -C(O)-NH-C 3-6 Branched alkyl, -NH-C(O)-CF2, -NH-C(O)-CH2CF3, -NH-C 1-6 Straight chain or branched alkyl and -SC 1-6 Hydroxyl linear or branched alkyl; wherein R b and R c Together with the nitrogen atom to which they are attached they form azetidinyl, difluoroazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.

[0208] Embodiment 27. A compound according to any one of the preceding embodiments, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein A is pyridyl; and R4 is selected from -S(O)2-NH2, -S(O)2-NH-CH2CH2OH, -S(O)2-NH-CH2CH2Cl, -S(O)2-NH-C 4-6 Straight or branched alkyl, -S(O)2-NH-C 8-12 Straight or branched alkyl, -S(O)2-NH-cyclohexyl, -S(O)2-NH-tetrahydropyranyl, -S(O)2-NR b R c 、-NH-S(O)2-C 2-6 Straight or branched alkyl, -C(O)-NH-C 3-6 Branched alkyl, -NH-C(O)-CF2, -NH-C(O)-CH2CF3 and -SC 1-6 Hydroxyl linear or branched alkyl; wherein R b and R c Together with the nitrogen atom to which they are attached they form azetidinyl, difluoroazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.

[0209] Embodiment 28. A compound according to any one of the preceding embodiments, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein A is pyridyl; and R4 is selected from -S(O)2-NH2, -S(O)2-NH-CH2CH2OH, -S(O)2-NH-CH2CH2Cl, -S(O)2-NH-C 4-6 Straight chain alkyl, -S(O)2-NH-C 8-10Straight chain alkyl, -S(O)2-NH-cyclohexyl, -S(O)2-NH-tetrahydropyranyl, -S(O)2-NR b R c 、-NH-S(O)2-C 2-4 Straight chain alkyl, -C(O)-NH-C 3-6 Branched alkyl, -NH-C(O)-CF2, -NH-C(O)-CH2CF3 and -SC 2-4 Hydroxyl linear alkyl; wherein R b and R c Together with the nitrogen atom to which they are attached they form azetidinyl, difluoroazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.

[0210] Embodiment 29. A compound according to any one of the preceding embodiments 1-26, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein A is pyridyl; and R4 is selected from -S(O)2-NH2, -S(O)2-NH-C 4-6 Straight or branched alkyl, -S(O)2-NH-C 8-12 Straight or branched alkyl, -S(O)2-NH-cyclohexyl, -S(O)2-NH-tetrahydropyranyl, -S(O)2-NR b R c 、-C(O)-NH-C 3-6 Branched alkyl, -NH-C(O)-CF2 and -NH-C(O)-CH2CF3; wherein R b and R c Together with the nitrogen atom to which they are attached they form azetidinyl, difluoroazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.

[0211] Embodiment 30. A compound according to any one of the preceding embodiments 1-26, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein A is pyridyl; and R4 is selected from -S(O)2-NH2, -S(O)2-NH-cyclohexyl, -S(O)2-NH-tetrahydropyranyl, -S(O)2-NR b R c , -NH-C(O)-CF2 and -NH-C(O)-CH2CF3; among which, R b and R c Together with the nitrogen atom to which they are attached they form azetidinyl, difluoroazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.

[0212] Embodiment 31. A compound according to any one of the preceding embodiments 1-26, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein A is pyridyl; and R4 is selected from -S(O)2-NH2, -S(O)2-NH-cyclohexyl, -S(O)2-NH-tetrahydropyranyl, -S(O)2-NR b R c and -NH-C(O)-CF2; wherein R b and R c Together with the nitrogen atom to which they are attached they form azetidinyl, difluoroazetidinyl, pyrrolidinyl or piperidinyl.

[0213] Embodiment 32. A compound according to any one of the preceding embodiments, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein

[0214] R1 is For example

[0215] R2 is -COOH or -COOC 1-3 Straight-chain or branched alkyl; for example -COOH or -COOCH3;

[0216] R3 is F;

[0217] B1 is -CR6 or N, wherein R6 is H, halogen or -OC 1-3 a linear or branched alkyl group, such as H, F, Cl, or -O-CH3; and

[0218] A is phenyl; and R4 is selected from -S(O)2-NH-C 8-10 Straight chain alkyl, -S(O)2-NH-C 2-4 Straight chain alkyl -CF3, -S(O)2-NR b R c 、-C(O)-NH-C 2-6 Straight or branched alkyl, -NH-C(O)-CF3 and -NH-C 2-4 Straight-chain alkenyl; wherein R b and R c Together with the nitrogen atom to which they are attached, they form a difluoroazetidinyl group;

[0219] Alternatively, A is pyridyl; and R4 is selected from -S(O)2-NH2, -S(O)2-NH-cyclohexyl, -S(O)2-NH-tetrahydropyranyl, -S(O)2-NR b R c , -NH-C(O)-CF2 and -NH-C(O)-CH2CF3; among which, R b and Rc Together with the nitrogen atom to which they are attached they form azetidinyl, difluoroazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.

[0220] Embodiment 33. A compound according to any one of the preceding embodiments, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein the compound is selected from Examples 9, 10, 13, 14, 38, 39, 40, 41, 46, 47, 51, 52, 60, 61, 62, 68, 69, 73, 95, 96, 98, 99, 100, 159 and 160.

[0221] Embodiment 34. A compound according to any one of the preceding embodiments, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein the compound is selected from Examples 12, 48, 49, 50, 79, 80, 81, 82, 87, 88, 89, 101, 102, 103, 104, 105, 106, 107, 108, 110, 113, 114, 119, 120, 121, 122, 123, 124, 126, 130, 167 and 168.

[0222] Embodiment 35. A compound according to any one of the preceding embodiments, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein the compound is selected from Examples 136, 137, 138, 139, 140, 141, 142, 143, 145, 146, 147, 148, 149, 150, 151, 152, 170, 171, 172 and 173.

[0223] Embodiment 36. A compound selected from:

[0224] or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof.

[0225] Embodiment 37. A pharmaceutical composition comprising a compound according to any one of Embodiments 1-36 or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, and a pharmaceutically acceptable excipient.

[0226] Embodiment 38. A compound according to any one of Embodiments 1-36, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, for use as a medicament.

[0227] Embodiment 39. A compound according to any one of Embodiments 1-36, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, for use in treating or preventing a disease or disorder mediated by MRGPRX2.

[0228] Embodiment 40. A compound according to any one of Embodiments 1-36, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, for use in treating or preventing a disease or disorder caused by mast cell degranulation.

[0229] Embodiment 41. A compound according to any one of Embodiments 1-36, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, for use in treating or preventing autoimmune diseases, allergic diseases, inflammatory diseases, pruritus and pain, such as inflammatory skin diseases.

[0230] Embodiment 42. A compound according to any one of Embodiments 1-36, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, for use in the treatment or prevention of psoriasis, atopic dermatitis, inflammatory bowel disease (IBD), chronic urticaria, allergic rhinitis, asthma, alopecia areata, urticaria, allergic urticaria, rosacea, radiation dermatitis, eczema, pseudoallergic reaction, anaphylactic shock, generalized pruritus, neuropathic pruritus, prurigo nodularis, neuropathic inflammation, ulcerative colitis, Crohn's disease, irritable bowel syndrome, respiratory inflammation, postoperative pain, and vitiligo. A compound according to any one of Embodiments 1-36, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, for use in the treatment or prevention of rosacea, psoriasis, urticaria, atopic dermatitis, inflammatory bowel disease, allergic rhinitis and asthma.

[0231] Embodiment 43. Use of a compound according to any one of Embodiments 1-36, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, or solvate thereof, in the preparation of a medicament for treating or preventing a disease or disorder mediated by MRGPRX2.

[0232] Embodiment 44. Use of a compound according to any one of Embodiments 1-36 or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof in the preparation of a medicament for treating or preventing a disease or disorder caused by mast cell degranulation.

[0233] Embodiment 45. Use of a compound according to any one of Embodiments 1-36, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, or solvate thereof, in the preparation of a medicament for treating or preventing autoimmune diseases, allergic diseases, inflammatory diseases, itching, and pain, such as inflammatory skin diseases.

[0234] Embodiment 46. Use of a compound according to any one of Embodiments 1 to 36, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, in the preparation of a medicament for treating or preventing psoriasis, atopic dermatitis, inflammatory bowel disease (IBD), chronic urticaria, allergic rhinitis, asthma, alopecia areata, urticaria, allergic urticaria, rosacea, radiation dermatitis, eczema, pseudoallergic reaction, anaphylactic shock, generalized pruritus, neuropathic prurigo, nodular prurigo, neuroinflammatory disease, ulcerative colitis, Crohn's disease, irritable bowel syndrome, respiratory inflammation, postoperative pain and vitiligo.

[0235] Embodiment 47. Use of a compound as defined in any one of Embodiments 1 to 36, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, in the preparation of a medicament for treating or preventing rosacea, psoriasis, urticaria, atopic dermatitis, inflammatory bowel disease, allergic rhinitis and asthma.

[0236] Embodiment 48. A method of treating or preventing a disease or disorder in an individual, the method comprising administering to an individual in need thereof an effective amount of a compound of any one of Embodiments 1-36, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, or solvate thereof, wherein the disease or disorder is an MRGPRX2-mediated disease or disorder.

[0237] Embodiment 49. A method of treating or preventing a disease or disorder in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound of any one of Embodiments 1-36, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, or solvate thereof, wherein the disease or disorder is a disease or disorder caused by mast cell degranulation.

[0238] Embodiment 50. A method of treating or preventing a disease or disorder in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound of any one of Embodiments 1-36, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, or solvate thereof, wherein the disease or disorder is selected from autoimmune diseases, allergic diseases, inflammatory diseases, pruritus, and pain, such as inflammatory skin diseases.

[0239] Embodiment 51. A method of treating or preventing a disease or disorder in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound of any one of Embodiments 1-36, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, or solvate thereof, wherein the disease or disorder is selected from psoriasis, atopic dermatitis, inflammatory bowel disease (IBD), chronic urticaria, allergic rhinitis, asthma, alopecia areata, urticaria, allergic urticaria, rosacea, radiation dermatitis, eczema, pseudoallergic reaction, anaphylactic shock, generalized pruritus, neuropathic pruritus, prurigo nodularis, neuroinflammatory disease, ulcerative colitis, Crohn's disease, irritable bowel syndrome, respiratory inflammation, postoperative pain, and vitiligo.

[0240] Embodiment 52. A method of treating or preventing a disease or disorder in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound as defined in any one of the preceding embodiments 1-36, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein the disease or disorder is selected from rosacea, psoriasis, urticaria, atopic dermatitis, inflammatory bowel disease, allergic rhinitis and asthma.

[0241] Embodiment 53. Use of a compound of any one of Embodiments 1-36, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, or solvate thereof, for treating or preventing a disease or disorder mediated by MRGPRX2.

[0242] Embodiment 54. Use of a compound according to any one of Embodiments 1-36 or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for treating or preventing a disease or disorder caused by mast cell degranulation.

[0243] Embodiment 55. Use of a compound of any one of Embodiments 1-36 or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for treating or preventing autoimmune diseases, allergic diseases, inflammatory diseases, itching and pain, such as inflammatory skin diseases.

[0244] Embodiment 56. Use of a compound according to any one of Embodiments 1 to 36, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, for treating or preventing psoriasis, atopic dermatitis, inflammatory bowel disease (IBD), chronic urticaria, allergic rhinitis, asthma, alopecia areata, urticaria, allergic urticaria, rosacea, radiation dermatitis, eczema, pseudoallergic reaction, anaphylactic shock, generalized pruritus, neuropathic prurigo, nodular prurigo, neuroinflammatory disease, ulcerative colitis, Crohn's disease, irritable bowel syndrome, respiratory inflammation, postoperative pain and vitiligo.

[0245] Embodiment 57. Use of a compound as defined in any one of Embodiments 1 to 36, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for treating or preventing rosacea, psoriasis, urticaria, atopic dermatitis, inflammatory bowel disease, allergic rhinitis and asthma.

[0246] Embodiment 58. A method for antagonizing MRGPRX2 in vitro, the method comprising using an effective amount of a compound according to any one of embodiments 1-36 or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for in vitro testing of MRGPRX2.

[0247] Embodiment 59. A pharmaceutical composition for treating or preventing a disease or disorder mediated by MRGPRX2, comprising a compound according to any one of embodiments 1-36 or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof.

[0248] Embodiment 60. A pharmaceutical composition for treating or preventing a disease or disorder caused by mast cell degranulation, comprising a compound according to any one of Embodiments 1-36 or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof.

[0249] Embodiment 61. A pharmaceutical combination comprising a compound according to any one of Embodiments 1-36, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, or solvate thereof, and one or more additional therapeutic agents.

[0250] Embodiments of the present disclosure—Part C

[0251] The present invention specifically provides a class of compounds represented by formula (I) and pharmaceutically acceptable salts, prodrugs or solvent compounds thereof for use in preparing drugs that are MRGPRX2 antagonists.

[0252] Where:

[0253] B1 is selected from -CR4 or N atom; wherein R4 is selected from hydrogen atom, C1-C3 alkyl, halogen, C1-C3 alkoxy or nitro;

[0254] R1 is selected from a hydrogen atom, a C1-C3 alkyl group, a C1-C3 alkyl group substituted by 1-3 halogens, a C3-C6 cycloalkyl group, a C3-C6 cycloalkyl group substituted by 1-3 halogens, or R1 and B1 are bonded to form a 6-membered heterocyclic ring which is optionally substituted by a short-chain alkyl group;

[0255] B2 is selected from -NH, oxygen atom, -CH=CH- or is empty; when B2 is empty, for in, For the connection point;

[0256] R2 is selected from hydrogen atom, -C(=O)OR5 or -C(=O)NHR5'; wherein R5 is selected from hydrogen atom, C1-C4 alkyl; R5' is selected from hydrogen atom or hydroxyl group;

[0257] B3 is selected from -CR6, wherein R6 is selected from a hydrogen atom or a sulfur atom; wherein, when R6 is a sulfur atom, R2 is selected from -C(=O)NH2 and bonds with B3 to form an isothiazolinone;

[0258] R3 is selected from halogen, nitro or hydrogen atom;

[0259] Ring A is selected from unsubstituted or substituted aryl groups, wherein the substitution includes mono-, di-, tri- or tetra-substitution, and the substituents are independently selected from halogen, hydroxyl, nitro, cyano, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkyl substituted by 1-3 halogens, C1-C3 alkyl substituted by hydroxyl, C1-C3 alkyl substituted by phenolic hydroxyl, C1-C3 alkyl substituted by amino, C1-C3 alkyl substituted by anilino, unsubstituted or substituted amino, aminosulfonyl, aminosulfinyl, carbamoyl, sulfenyl, or alkylimidesulfoxide.

[0260] In one embodiment of the present invention, the aryl group is phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 5-pyrimidyl, triazine,

[0261] In one embodiment of the present invention:

[0262] The unsubstituted or substituted amino group -NR a R a ', substitution is divided into single substitution and double substitution, where the substituent R a 、R a'are independently selected from H, C1-C9 alkyl, C1-C9 alkyl substituted by 1-3 halogens, C3-C25 straight or branched alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, C1-C9 alkyl substituted by hydroxy, C1-C9 acyl, C2-C9 acyl substituted by 1-3 halogens, C2-C9 acyl substituted by hydroxy, C2-C5 alkoxycarbonyl, C1-C25 alkylsulfonyl;

[0263] Unsubstituted or substituted aminosulfonyl-SO2-NR b R b ', substitution is divided into single substitution and double substitution, the substituent R b 、R b 'are independently selected from H, C1-C9 alkyl, C1-C9 alkyl substituted by 1-3 halogen, C1-C9 alkyl substituted by hydroxy, C1-C9 alkyl substituted by amino, C1-C9 alkyl substituted by C1-3 alkylthiol (C1-3 alkyl-S-), C1-C25 alkylsulfonyl, C3-C25 straight or branched alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, 3-6 membered cyclic group containing 1-3 heteroatoms, C2-C25 alkenyl, C2-C9 alkynyl, C1-C5 acyl, C2-C5 acyl substituted by 1-3 halogen or C2-C5 alkoxycarbonyl;

[0264] Unsubstituted or substituted aminosulfinyl-SO-NR c R c ', substitution is divided into single substitution and double substitution, the substituent R c 、R c 'are independently selected from H, C1-C9 alkyl, C1-C9 alkyl substituted by 1-3 halogens, C1-C9 alkyl substituted by hydroxy, C1-C9 alkyl substituted by amino, C3-C25 straight or branched alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, C2-C25 alkenyl, C2-C9 alkynyl, C1-C5 acyl, C2-C5 acyl substituted by 1-3 halogens, or C2-C5 alkoxycarbonyl;

[0265] Unsubstituted or substituted carbamoyl-CO-NR d R d ', substitution is divided into single substitution and double substitution, the substituent R d 、R d'are independently selected from H, C1-C9 alkyl, C1-C9 alkyl substituted by 1-3 halogens, C1-C9 alkyl substituted by hydroxy, C1-C9 alkyl substituted by amino, C3-C25 straight or branched alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, C2-C25 alkenyl, C2-C9 alkynyl, C1-C5 acyl, C2-C5 acyl substituted by 1-3 halogens, or C2-C5 alkoxycarbonyl;

[0266] Unsubstituted or substituted sulfenyl-SR e , substituent R e Selected from C1-C9 straight or branched alkyl, C3-C6 cycloalkyl, halogenated C1-C9 alkyl, hydroxy-substituted C1-C9 alkyl, C1-C5 acyl, halogenated C2-C5 acyl;

[0267] Unsubstituted or substituted alkylimidesulfoxide-S(=O)(=NR f )-R f '(Right now ), substituent R f R is selected from H, C1-C9 straight or branched alkyl, C3-C25 straight or branched alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, halogenated C1-C9 alkyl, C1-C5 acyl, C2-C5 acyl substituted by 1-3 halogens, or C2-C5 alkoxycarbonyl; f ' is selected from C1-3 alkyl.

[0268] In one embodiment of the present invention, the above R a 、R a ' can be H at the same time, or not H at the same time, or not H at the same time.

[0269] In one embodiment of the present invention, the above R b 、R b 'Not H at the same time, or not H at the same time, or not H at the same time.

[0270] In one embodiment of the present invention, the above R c 、R c 'Not H at the same time, or not H at the same time, or not H at the same time.

[0271] In one embodiment of the present invention, the above R d 、R d 'Not H at the same time, or not H at the same time, or not H at the same time.

[0272] In one embodiment of the present invention, A group selected from the following formulae:

[0273] (1) O- to tetra-substituted phenyl, the substituents being selected from:

[0274] (a) C1-C3 alkyl;

[0275] (b) C1-C3 alkoxy;

[0276] (c) C1-C3 alkyl substituted by 1-3 halogens;

[0277] (d) a C1-C3 alkyl group substituted with a hydroxy group;

[0278] (e) a C1-C3 alkyl group substituted with a phenolic hydroxyl group;

[0279] (f) a C1-C3 alkyl group substituted with an amino group;

[0280] (g) a C1-C3 alkyl group substituted with an anilino group;

[0281] (h) halogen;

[0282] (i) hydroxyl groups;

[0283] (j) nitro;

[0284] (k) cyano;

[0285] (1) unsubstituted or substituted amino groups, wherein the substitution is divided into mono- and di-substituted, wherein the substituents are independently selected from C1-C9 alkyl, C1-C9 alkyl substituted by 1-3 halogens, C3-C25 straight or branched alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, C1-C9 alkyl substituted by hydroxy, C1-C9 acyl, C2-C9 acyl substituted by 1-3 halogens, C2-C9 acyl substituted by hydroxy, C2-C5 alkoxycarbonyl, and C1-C25 alkylsulfonyl;

[0286] (m) unsubstituted or substituted aminosulfonyl, the substitution being divided into mono- and di-substitution, and the substituents are independently selected from C1-C9 alkyl, C1-C9 alkyl substituted by 1-3 halogens, C1-C9 alkyl substituted by hydroxy, C1-C9 alkyl substituted by amino, C1-C9 alkyl substituted by C1-3 alkylthiol (C1-3 alkyl-S-), C1-C25 alkylsulfonyl, C3-C25 straight or branched chain alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, 3-6 membered cyclic group containing 1-3 heteroatoms, C2-C25 alkenyl, C2-C9 alkynyl, C1-C5 acyl, C2-C5 acyl substituted by 1-3 halogens, or C2-C5 alkoxycarbonyl;

[0287] (n) unsubstituted or substituted aminosulfinyl, wherein the substitution is divided into mono- and di-substituted, and the substituents are independently selected from C1-C9 alkyl, C1-C9 alkyl substituted by 1-3 halogens, C1-C9 alkyl substituted by hydroxy, C1-C9 alkyl substituted by amino, C3-C25 straight or branched chain alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, C2-C25 alkenyl, C2-C9 alkynyl, C1-C5 acyl, C2-C5 acyl substituted by 1-3 halogens, or C2-C5 alkoxycarbonyl;

[0288] (o) unsubstituted or substituted carbamoyl, the substitution being divided into mono- and di-substitution, and the substituents are independently selected from C1-C9 alkyl, C1-C9 alkyl substituted by 1-3 halogens, C1-C9 alkyl substituted by hydroxy, C1-C9 alkyl substituted by amino, C3-C25 straight or branched chain alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, C2-C25 alkenyl, C2-C9 alkynyl, C1-C5 acyl, C2-C5 acyl substituted by 1-3 halogens, or C2-C5 alkoxycarbonyl;

[0289] (p) unsubstituted or substituted sulfenyl, the substituent being selected from C1-C9 straight or branched chain alkyl, C3-C6 cycloalkyl, halogenated C1-C9 alkyl, hydroxy-substituted C1-C9 alkyl, C1-C5 acyl, halogenated C2-C5 acyl;

[0290] (q) unsubstituted or substituted alkylimidesulfoxide -S(=O)(=NR f )-R f '(Right now ), substitution is divided into mono- and di-substitution, and the substituent is selected from C1-C9 straight or branched chain alkyl, C3-C25 straight or branched chain alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, halogenated C1-C9 alkyl, C1-C5 acyl, C2-C5 acyl substituted with 1-3 halogens, or C2-C5 alkoxycarbonyl; R f 'Selected from C1-3 alkyl;

[0291] (2) Oxy- to tri-substituted 2-pyridyl, the substituents being selected from:

[0292] (a) C1-C3 alkyl;

[0293] (b) C1-C3 alkoxy;

[0294] (c) C1-C3 alkyl substituted by 1-3 halogens;

[0295] (d) a C1-C3 alkyl group substituted with a hydroxy group;

[0296] (e) a C1-C3 alkyl group substituted with a phenolic hydroxyl group;

[0297] (f) a C1-C3 alkyl group substituted with an amino group;

[0298] (g) a C1-C3 alkyl group substituted with an anilino group;

[0299] (h) halogen;

[0300] (i) hydroxyl groups;

[0301] (j) nitro;

[0302] (k) cyano;

[0303] (1) unsubstituted or substituted amino groups, wherein the substitution is divided into mono- and di-substituted, wherein the substituents are independently selected from C1-C9 alkyl, C1-C9 alkyl substituted by 1-3 halogens, C3-C25 straight or branched alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, C1-C9 alkyl substituted by hydroxy, C1-C9 acyl, C2-C9 acyl substituted by 1-3 halogens, C2-C9 acyl substituted by hydroxy, C2-C5 alkoxycarbonyl, and C1-C25 alkylsulfonyl;

[0304] (m) unsubstituted or substituted aminosulfonyl, the substitution being divided into mono- and di-substitution, and the substituents are independently selected from C1-C9 alkyl, C1-C9 alkyl substituted by 1-3 halogens, C1-C9 alkyl substituted by hydroxy, C1-C9 alkyl substituted by amino, C1-C9 alkyl substituted by C1-3 alkylthiol (C1-3 alkyl-S-), C1-C25 alkylsulfonyl, C3-C25 straight or branched chain alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, 3-6 membered cyclic group containing 1-3 heteroatoms, C2-C25 alkenyl, C2-C9 alkynyl, C1-C5 acyl, C2-C5 acyl substituted by 1-3 halogens, or C2-C5 alkoxycarbonyl;

[0305] (n) unsubstituted or substituted aminosulfinyl, wherein the substitution is divided into mono- and di-substituted, and the substituents are independently selected from C1-C9 alkyl, C1-C9 alkyl substituted by 1-3 halogens, C1-C9 alkyl substituted by hydroxy, C1-C9 alkyl substituted by amino, C3-C25 straight or branched chain alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, C2-C25 alkenyl, C2-C9 alkynyl, C1-C5 acyl, C2-C5 acyl substituted by 1-3 halogens, or C2-C5 alkoxycarbonyl;

[0306] (o) unsubstituted or substituted carbamoyl, the substitution being divided into mono- and di-substitution, and the substituents are independently selected from C1-C9 alkyl, C1-C9 alkyl substituted by 1-3 halogens, C1-C9 alkyl substituted by hydroxy, C1-C9 alkyl substituted by amino, C3-C25 straight or branched chain alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, C2-C25 alkenyl, C2-C9 alkynyl, C1-C5 acyl, C2-C5 acyl substituted by 1-3 halogens, or C2-C5 alkoxycarbonyl;

[0307] (p) unsubstituted or substituted sulfenyl, the substituent being selected from C1-C9 straight or branched chain alkyl, C3-C6 cycloalkyl, halogenated C1-C9 alkyl, hydroxy-substituted C1-C9 alkyl, C1-C5 acyl, halogenated C2-C5 acyl;

[0308] (q) unsubstituted or substituted alkylimidesulfoxide -S(=O)(=NR f )-R f '(Right now ), substitution is divided into mono- and di-substitution, and the substituent is selected from C1-C9 straight or branched chain alkyl, C3-C25 straight or branched chain alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, halogenated C1-C9 alkyl, C1-C5 acyl, C2-C5 acyl substituted with 1-3 halogens, or C2-C5 alkoxycarbonyl; R f 'Selected from C1-3 alkyl;

[0309] (3) O- to tri-substituted 3-pyridyl, the substituents being selected from:

[0310] (a) C1-C3 alkyl;

[0311] (b) C1-C3 alkoxy;

[0312] (c) C1-C3 alkyl substituted by 1-3 halogens;

[0313] (d) a C1-C3 alkyl group substituted with a hydroxy group;

[0314] (e) a C1-C3 alkyl group substituted with a phenolic hydroxyl group;

[0315] (f) a C1-C3 alkyl group substituted with an amino group;

[0316] (g) a C1-C3 alkyl group substituted with an anilino group;

[0317] (h) halogen;

[0318] (i) hydroxyl groups;

[0319] (j) nitro;

[0320] (k) cyano;

[0321] (1) unsubstituted or substituted amino groups, wherein the substitution is divided into mono- and di-substituted, wherein the substituents are independently selected from C1-C9 alkyl, C1-C9 alkyl substituted by 1-3 halogens, C3-C25 straight or branched alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, C1-C9 alkyl substituted by hydroxy, C1-C9 acyl, C2-C9 acyl substituted by 1-3 halogens, C2-C9 acyl substituted by hydroxy, C2-C5 alkoxycarbonyl, and C1-C25 alkylsulfonyl;

[0322] (m) unsubstituted or substituted aminosulfonyl, the substitution being divided into mono- and di-substitution, and the substituents are independently selected from C1-C9 alkyl, C1-C9 alkyl substituted by 1-3 halogens, C1-C9 alkyl substituted by hydroxy, C1-C9 alkyl substituted by amino, C1-C9 alkyl substituted by C1-3 alkylthiol (C1-3 alkyl-S-), C1-C25 alkylsulfonyl, C3-C25 straight or branched chain alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, 3-6 membered cyclic group containing 1-3 heteroatoms, C2-C25 alkenyl, C2-C9 alkynyl, C1-C5 acyl, C2-C5 acyl substituted by 1-3 halogens, or C2-C5 alkoxycarbonyl;

[0323] (n) unsubstituted or substituted aminosulfinyl, wherein the substitution is divided into mono- and di-substituted, and the substituents are independently selected from C1-C9 alkyl, C1-C9 alkyl substituted by 1-3 halogens, C1-C9 alkyl substituted by hydroxy, C1-C9 alkyl substituted by amino, C3-C25 straight or branched chain alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, C2-C25 alkenyl, C2-C9 alkynyl, C1-C5 acyl, C2-C5 acyl substituted by 1-3 halogens, or C2-C5 alkoxycarbonyl;

[0324] (o) unsubstituted or substituted carbamoyl, the substitution being divided into mono- and di-substitution, and the substituents are independently selected from C1-C9 alkyl, C1-C9 alkyl substituted by 1-3 halogens, C1-C9 alkyl substituted by hydroxy, C1-C9 alkyl substituted by amino, C3-C25 straight or branched chain alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, C2-C25 alkenyl, C2-C9 alkynyl, C1-C5 acyl, C2-C5 acyl substituted by 1-3 halogens, or C2-C5 alkoxycarbonyl;

[0325] (p) unsubstituted or substituted sulfenyl, the substituent being selected from C1-C9 straight or branched chain alkyl, C3-C6 cycloalkyl, halogenated C1-C9 alkyl, hydroxy-substituted C1-C9 alkyl, C1-C5 acyl, halogenated C2-C5 acyl;

[0326] (q) unsubstituted or substituted alkylimidesulfoxide -S(=O)(=NR f )-R f '(Right now ), substitution is divided into mono- and di-substitution, and the substituent is selected from C1-C9 straight or branched chain alkyl, C3-C25 straight or branched chain alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, halogenated C1-C9 alkyl, C1-C5 acyl, C2-C5 acyl substituted with 1-3 halogens, or C2-C5 alkoxycarbonyl; R f 'Selected from C1-3 alkyl;

[0327] (4) Oxy- to tri-substituted 4-pyridyl, the substituents being selected from:

[0328] (a) C1-C3 alkyl;

[0329] (b) C1-C3 alkoxy;

[0330] (c) C1-C3 alkyl substituted by 1-3 halogens;

[0331] (d) a C1-C3 alkyl group substituted with a hydroxy group;

[0332] (e) a C1-C3 alkyl group substituted with a phenolic hydroxyl group;

[0333] (f) a C1-C3 alkyl group substituted with an amino group;

[0334] (g) a C1-C3 alkyl group substituted with an anilino group;

[0335] (h) halogen;

[0336] (i) hydroxyl groups;

[0337] (j) nitro;

[0338] (k) cyano;

[0339] (1) unsubstituted or substituted amino groups, wherein the substitution is divided into mono- and di-substituted, wherein the substituents are independently selected from C1-C9 alkyl, C1-C9 alkyl substituted by 1-3 halogens, C3-C25 straight or branched alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, C1-C9 alkyl substituted by hydroxy, C1-C9 acyl, C2-C9 acyl substituted by 1-3 halogens, C2-C9 acyl substituted by hydroxy, C2-C5 alkoxycarbonyl, and C1-C25 alkylsulfonyl;

[0340] (m) unsubstituted or substituted aminosulfonyl, the substitution being divided into mono- and di-substitution, and the substituents are independently selected from C1-C9 alkyl, C1-C9 alkyl substituted by 1-3 halogens, C1-C9 alkyl substituted by hydroxy, C1-C9 alkyl substituted by amino, C1-C9 alkyl substituted by C1-3 alkylthiol (C1-3 alkyl-S-), C1-C25 alkylsulfonyl, C3-C25 straight or branched chain alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, 3-6 membered cyclic group containing 1-3 heteroatoms, C2-C25 alkenyl, C2-C9 alkynyl, C1-C5 acyl, C2-C5 acyl substituted by 1-3 halogens, or C2-C5 alkoxycarbonyl;

[0341] (n) unsubstituted or substituted aminosulfinyl, wherein the substitution is divided into mono- and di-substituted, and the substituents are independently selected from C1-C9 alkyl, C1-C9 alkyl substituted by 1-3 halogens, C1-C9 alkyl substituted by hydroxy, C1-C9 alkyl substituted by amino, C3-C25 straight or branched chain alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, C2-C25 alkenyl, C2-C9 alkynyl, C1-C5 acyl, C2-C5 acyl substituted by 1-3 halogens, or C2-C5 alkoxycarbonyl;

[0342] (o) unsubstituted or substituted carbamoyl, the substitution being divided into mono- and di-substitution, and the substituents are independently selected from C1-C9 alkyl, C1-C9 alkyl substituted by 1-3 halogens, C1-C9 alkyl substituted by hydroxy, C1-C9 alkyl substituted by amino, C3-C25 straight or branched chain alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, C2-C25 alkenyl, C2-C9 alkynyl, C1-C5 acyl, C2-C5 acyl substituted by 1-3 halogens, or C2-C5 alkoxycarbonyl;

[0343] (p) unsubstituted or substituted sulfenyl, the substituent being selected from C1-C9 straight or branched chain alkyl, C3-C6 cycloalkyl, halogenated C1-C9 alkyl, hydroxy-substituted C1-C9 alkyl, C1-C5 acyl, halogenated C2-C5 acyl;

[0344] (q) unsubstituted or substituted alkylimidesulfoxide -S(=O)(=NR f )-R f '(Right now ), substitution is divided into mono- and di-substitution, and the substituent is selected from C1-C9 straight or branched chain alkyl, C3-C25 straight or branched chain alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, halogenated C1-C9 alkyl, C1-C5 acyl, C2-C5 acyl substituted with 1-3 halogens, or C2-C5 alkoxycarbonyl; R f'Selected from C1-3 alkyl;

[0345] (5) O- to di-substituted 2-pyrimidinyl, the substituents being selected from:

[0346] (a) C1-C3 alkyl;

[0347] (b) C1-C3 alkoxy;

[0348] (c) C1-C3 alkyl substituted by 1-3 halogens;

[0349] (d) a C1-C3 alkyl group substituted with a hydroxy group;

[0350] (e) a C1-C3 alkyl group substituted with a phenolic hydroxyl group;

[0351] (f) a C1-C3 alkyl group substituted with an amino group;

[0352] (g) a C1-C3 alkyl group substituted with an anilino group;

[0353] (h) halogen;

[0354] (i) hydroxyl groups;

[0355] (j) nitro;

[0356] (k) cyano;

[0357] (1) unsubstituted or substituted amino groups, wherein the substitution is divided into mono- and di-substituted, wherein the substituents are independently selected from C1-C9 alkyl, C1-C9 alkyl substituted by 1-3 halogens, C3-C25 straight or branched alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, C1-C9 alkyl substituted by hydroxy, C1-C9 acyl, C2-C9 acyl substituted by 1-3 halogens, C2-C9 acyl substituted by hydroxy, C2-C5 alkoxycarbonyl, and C1-C25 alkylsulfonyl;

[0358] (m) unsubstituted or substituted aminosulfonyl, the substitution being divided into mono- and di-substitution, and the substituents are independently selected from C1-C9 alkyl, C1-C9 alkyl substituted by 1-3 halogens, C1-C9 alkyl substituted by hydroxy, C1-C9 alkyl substituted by amino, C1-C9 alkyl substituted by C1-3 alkylthiol (C1-3 alkyl-S-), C1-C25 alkylsulfonyl, C3-C25 straight or branched chain alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, 3-6 membered cyclic group containing 1-3 heteroatoms, C2-C25 alkenyl, C2-C9 alkynyl, C1-C5 acyl, C2-C5 acyl substituted by 1-3 halogens, or C2-C5 alkoxycarbonyl;

[0359] (n) unsubstituted or substituted aminosulfinyl, wherein the substitution is divided into mono- and di-substituted, and the substituents are independently selected from C1-C9 alkyl, C1-C9 alkyl substituted by 1-3 halogens, C1-C9 alkyl substituted by hydroxy, C1-C9 alkyl substituted by amino, C3-C25 straight or branched chain alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, C2-C25 alkenyl, C2-C9 alkynyl, C1-C5 acyl, C2-C5 acyl substituted by 1-3 halogens, or C2-C5 alkoxycarbonyl;

[0360] (o) unsubstituted or substituted carbamoyl, the substitution being divided into mono- and di-substitution, and the substituents are independently selected from C1-C9 alkyl, C1-C9 alkyl substituted by 1-3 halogens, C1-C9 alkyl substituted by hydroxy, C1-C9 alkyl substituted by amino, C3-C25 straight or branched chain alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, C2-C25 alkenyl, C2-C9 alkynyl, C1-C5 acyl, C2-C5 acyl substituted by 1-3 halogens, or C2-C5 alkoxycarbonyl;

[0361] (p) unsubstituted or substituted sulfenyl, the substituent being selected from C1-C9 straight or branched chain alkyl, C3-C6 cycloalkyl, halogenated C1-C9 alkyl, hydroxy-substituted C1-C9 alkyl, C1-C5 acyl, halogenated C2-C5 acyl;

[0362] (q) unsubstituted or substituted alkylimidesulfoxide -S(=O)(=NR f )-R f '(Right now ), substitution is divided into mono- and di-substitution, and the substituent is selected from C1-C9 straight or branched chain alkyl, C3-C25 straight or branched chain alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, halogenated C1-C9 alkyl, C1-C5 acyl, C2-C5 acyl substituted with 1-3 halogens, or C2-C5 alkoxycarbonyl; R f 'Selected from C1-3 alkyl;

[0363] (6) O- to di-substituted 5-pyrimidinyl, the substituents being selected from:

[0364] (a) C1-C3 alkyl;

[0365] (b) C1-C3 alkoxy;

[0366] (c) C1-C3 alkyl substituted by 1-3 halogens;

[0367] (d) a C1-C3 alkyl group substituted with a hydroxy group;

[0368] (e) a C1-C3 alkyl group substituted with a phenolic hydroxyl group;

[0369] (f) a C1-C3 alkyl group substituted with an amino group;

[0370] (g) a C1-C3 alkyl group substituted with an anilino group;

[0371] (h) halogen;

[0372] (i) hydroxyl groups;

[0373] (j) nitro;

[0374] (k) cyano;

[0375] (1) unsubstituted or substituted amino groups, wherein the substitution is divided into mono- and di-substituted, wherein the substituents are independently selected from C1-C9 alkyl, C1-C9 alkyl substituted by 1-3 halogens, C3-C25 straight or branched alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, C1-C9 alkyl substituted by hydroxy, C1-C9 acyl, C2-C9 acyl substituted by 1-3 halogens, C2-C9 acyl substituted by hydroxy, C2-C5 alkoxycarbonyl, and C1-C25 alkylsulfonyl;

[0376] (m) unsubstituted or substituted aminosulfonyl, the substitution being divided into mono- and di-substitution, and the substituents are independently selected from C1-C9 alkyl, C1-C9 alkyl substituted by 1-3 halogens, C1-C9 alkyl substituted by hydroxy, C1-C9 alkyl substituted by amino, C1-C9 alkyl substituted by C1-3 alkylthiol (C1-3 alkyl-S-), C1-C25 alkylsulfonyl, C3-C25 straight or branched chain alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, 3-6 membered cyclic group containing 1-3 heteroatoms, C2-C25 alkenyl, C2-C9 alkynyl, C1-C5 acyl, C2-C5 acyl substituted by 1-3 halogens, or C2-C5 alkoxycarbonyl;

[0377] (n) unsubstituted or substituted aminosulfinyl, wherein the substitution is divided into mono- and di-substituted, and the substituents are independently selected from C1-C9 alkyl, C1-C9 alkyl substituted by 1-3 halogens, C1-C9 alkyl substituted by hydroxy, C1-C9 alkyl substituted by amino, C3-C25 straight or branched chain alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, C2-C25 alkenyl, C2-C9 alkynyl, C1-C5 acyl, C2-C5 acyl substituted by 1-3 halogens, or C2-C5 alkoxycarbonyl;

[0378] (o) unsubstituted or substituted carbamoyl, the substitution being divided into mono- and di-substitution, and the substituents are independently selected from C1-C9 alkyl, C1-C9 alkyl substituted by 1-3 halogens, C1-C9 alkyl substituted by hydroxy, C1-C9 alkyl substituted by amino, C3-C25 straight or branched chain alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, C2-C25 alkenyl, C2-C9 alkynyl, C1-C5 acyl, C2-C5 acyl substituted by 1-3 halogens, or C2-C5 alkoxycarbonyl;

[0379] (p) unsubstituted or substituted sulfenyl, the substituent being selected from C1-C9 straight or branched chain alkyl, C3-C6 cycloalkyl, halogenated C1-C9 alkyl, hydroxy-substituted C1-C9 alkyl, C1-C5 acyl, halogenated C2-C5 acyl;

[0380] (q) unsubstituted or substituted alkylimidesulfoxide -S(=O)(=NR f )-R f '(Right now ), substitution is divided into mono- and di-substitution, and the substituent is selected from C1-C9 straight or branched chain alkyl, C3-C25 straight or branched chain alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, halogenated C1-C9 alkyl, C1-C5 acyl, C2-C5 acyl substituted with 1-3 halogens, or C2-C5 alkoxycarbonyl; R f 'Selected from C1-3 alkyl;

[0381] (7) triazine group;

[0382] (8) a group of the formula:

[0383] wherein R7 is selected from a hydrogen atom, a hydroxyl group or an amine group;

[0384] wherein R8 is selected from -(CH2) n -XR9; wherein n is selected from 0-3; X is selected from a heteroatom; R9 is selected from a benzene ring, a condensed ring or a condensed heterocycle;

[0385] (9) A group of the formula:

[0386] In one embodiment of the present invention, Selected from unsubstituted or substituted phenyl groups, wherein the substitution is monosubstituted to tetrasubstituted, and the substituents are as defined above, wherein at least one substituent is selected from (a) unsubstituted or substituted amino groups, and the substituents are selected from the same range as above; (b) aminosulfonyl groups, wherein the amino group may be substituted, and the substitution is divided into monosubstituted and disubstituted, and the substituents are selected from the same range as above; (c) aminosulfinyl groups, wherein the amino group may be substituted, and the substitution is divided into monosubstituted and disubstituted, and the substituents are selected from the same range as above; (d) aminoformyl groups, wherein the amino group may be substituted, and the substitution is divided into monosubstituted and disubstituted, and the substituents are selected from the same range as above; (e) alkyliminesulfoxide groups, wherein the amino group wherein the amino group may be substituted, and the substitution is divided into monosubstituted and disubstituted, and the substituents are selected from the same range as above.

[0387] In one embodiment of the present invention, Selected from unsubstituted or substituted 2-pyridyl, wherein the substitution is monosubstituted to trisubstituted, and the substituents are as defined above, wherein at least one substituent is selected from (a) unsubstituted or substituted amino, and the substituents are selected from the same range as above; (b) aminosulfonyl, wherein the amino group may be substituted, and the substitution is divided into monosubstituted and disubstituted, and the substituents are selected from the same range as above; (c) aminosulfinyl, wherein the amino group may be substituted, and the substitution is divided into monosubstituted and disubstituted, and the substituents are selected from the same range as above; (d) aminoformyl, wherein the amino group may be substituted, and the substitution is divided into monosubstituted and disubstituted, and the substituents are selected from the same range as above; (e) alkyliminesulfoxide, wherein the amino group wherein the amino group may be substituted, and the substitution is divided into monosubstituted and disubstituted, and the substituents are selected from the same range as above.

[0388] In one embodiment of the present invention, Selected from unsubstituted or substituted 3-pyridyl, wherein the substitution is monosubstituted to trisubstituted, and the substituents are as defined above, wherein at least one substituent is selected from (a) unsubstituted or substituted amino, and the substituents are selected from the same range as above; (b) aminosulfonyl, wherein the amino group may be substituted, and the substitution is divided into monosubstituted and disubstituted, and the substituents are selected from the same range as above; (c) aminosulfinyl, wherein the amino group may be substituted, and the substitution is divided into monosubstituted and disubstituted, and the substituents are selected from the same range as above; (d) aminoformyl, wherein the amino group may be substituted, and the substitution is divided into monosubstituted and disubstituted, and the substituents are selected from the same range as above; (e) alkyliminesulfoxide, wherein the amino group wherein the amino group may be substituted, and the substitution is divided into monosubstituted and disubstituted, and the substituents are selected from the same range as above.

[0389] In one embodiment of the present invention, Selected from unsubstituted or substituted 4-pyridyl, wherein the substitution is mono- to tri-substituted, and the substituents are as defined above, wherein at least one substituent is preferably selected from (a) C1-C3 alkyl; (b) C1-C3 alkoxy; (c) unsubstituted or substituted amino, and the substituents are selected from the same range as above; (d) aminosulfonyl, wherein the amino group may be substituted, and the substitution is divided into mono- and di-substituted, and the substituents are selected from the same range as above; (e) aminosulfinyl, wherein the amino group may be substituted, and the substitution is divided into mono- and di-substituted, and the substituents are selected from the same range as above; (f) aminoformyl, wherein the amino group may be substituted, and the substitution is divided into mono- and di-substituted, and the substituents are selected from the same range as above; (g) alkyliminesulfoxide, wherein the amino group wherein the amino group may be substituted, and the substitution is divided into mono- and di-substituted, and the substituents are selected from the same range as above.

[0390] In one embodiment of the present invention, the amine group can also be selected from

[0391] In one embodiment of the present invention, The carbon atoms in the alkyl carbon chain may be replaced by heteroatoms at any position permitted by normal valence.

[0392] In one embodiment of the present invention, the unsaturated bond comprises a carbon-carbon double bond and / or a carbon-carbon triple bond.

[0393] In one embodiment of the present invention, the C2-C25 alkenyl group refers to a C2-C25 alkenyl group containing 1-10 unsaturated double bonds, for example: (H or a C1-C23 alkyl group containing 0-9 unsaturated double bonds)-CH=CH-.

[0394] In one embodiment of the present invention, the C2-C9 alkynyl group refers to a C2-C9 alkynyl group containing 1-3 unsaturated bonds. For example, (H or a C1-C7 alkyl group containing 0-2 unsaturated bonds)-C≡C-. Unsaturated bonds include carbon-carbon double bonds and / or carbon-carbon triple bonds.

[0395] In one embodiment of the present invention, the C1-C5 acyl group refers to (H or C1-C4 alkyl)-C(=O)-. The C1-C9 acyl group refers to (H or C1-C8 alkyl)-C(=O)-.

[0396] In one embodiment of the present invention, the C2-C5 acyl group substituted with 1-3 halogens refers to (C1-C4 alkyl group substituted with 1-3 halogens)-C(=O)-. The C2-C9 acyl group substituted with 1-3 halogens refers to (C1-C8 alkyl group substituted with 1-3 halogens)-C(=O)-.

[0397] In one embodiment of the present invention, the C2-C5 alkoxycarbonyl group refers to (C2-C5 alkyl)-OC(=O)-.

[0398] In one embodiment of the present invention, the C1-C25 acyl group refers to (H or a C1-C24 alkyl group containing 0-10 unsaturated double bonds)-C(=O)-.

[0399] In one embodiment of the present invention, the C1-C25 alkylsulfonyl group refers to (C1-C25 alkyl group containing 0-10 unsaturated bonds)-SO2-.

[0400] The present invention also provides the use of the compound represented by the above formula (I) and its pharmaceutically acceptable salt, prodrug or solvent compound as an immunomodulator in the preparation of autoimmune disease drugs

[0401] The present invention also provides an immunomodulator, which contains the compound represented by the above formula (I) and a pharmaceutically acceptable salt, prodrug or solvent compound thereof.

[0402] The present invention also provides use of the compound represented by the above formula (I) and its pharmaceutically acceptable salt, prodrug or solvent compound in the preparation of a drug for treating or preventing rosacea.

[0403] The present invention also provides use of the compound represented by the above formula (I) and its pharmaceutically acceptable salt, prodrug or solvent compound in the preparation of a drug for treating or preventing urticaria.

[0404] The present invention also provides use of the compound represented by the above formula (I) and its pharmaceutically acceptable salt, prodrug or solvent compound in the preparation of a drug for treating or preventing atopic dermatitis.

[0405] The present invention also provides use of the compound represented by the above formula (I) and its pharmaceutically acceptable salt, prodrug or solvent compound in the preparation of a drug for treating or preventing psoriasis.

[0406] The present invention also provides the use of the compound represented by the above formula (I) and its pharmaceutically acceptable salt, prodrug or solvent compound in the preparation of a drug for treating or preventing radiation dermatitis.

[0407] The present invention also provides the use of the compound represented by the above formula (I) and its pharmaceutically acceptable salt, prodrug or solvent compound in the preparation of a drug for treating or preventing vitiligo.

[0408] The present invention also provides use of the compound represented by the above formula (I) and its pharmaceutically acceptable salt, prodrug or solvent compound in the preparation of a drug for treating or preventing alopecia areata.

[0409] The present invention also provides use of the compound represented by the above formula (I) and its pharmaceutically acceptable salt, prodrug or solvent compound in the preparation of a drug for treating or preventing inflammatory bowel disease.

[0410] The present invention also provides a pharmaceutical combination comprising the compound represented by the above formula (I) and a pharmaceutically acceptable salt, prodrug or solvent compound thereof as an active ingredient, and a pharmaceutically acceptable carrier.

[0411] The present invention also provides the compound represented by the above formula (I) and its pharmaceutically acceptable salt, prodrug or solvent compound, and the use of the above pharmaceutical composition in the preparation of MRGPRX2 receptor antagonist-related drugs.

[0412] The present invention also provides the above-mentioned MRGPRX2 receptor antagonist-related drugs suitable for treating autoimmune diseases.

[0413] The present invention also provides compounds represented by the above formula (I) and pharmaceutically acceptable salts, prodrugs or solvent compounds thereof, which can be used to treat or prevent MRGPRX2-mediated diseases or disorders.

[0414] In one embodiment of the present invention, the compound represented by the above formula (I) and its pharmaceutically acceptable salt, prodrug or solvate can be taken orally to treat or prevent MRGPRX2-mediated diseases or disorders;

[0415] Alternatively, MRGPRX2-mediated diseases or disorders can be treated or prevented by topical application.

[0416] In certain embodiments, the present invention includes compounds of formula (I), wherein B1 and R1 are bonded to form a 6-membered heterocyclic ring optionally substituted with an alkyl group. Examples of such compounds include, but are not limited to, compounds of formula (II)-formula (III).

[0417] Wherein, Z is O or S; R n Selected from C1-C4 alkyl, halogen.

[0418] In certain embodiments, the present invention includes compounds of formula (I), wherein B3 is selected from CR6, wherein R6 is selected from a hydrogen atom or a sulfur atom; wherein, when R6 is a sulfur atom, R2 is selected from (C=O)NH2 and bonds with B3 to form an isothiazolinone. Examples of such compounds include, but are not limited to, compounds of formula (IV)-formula (V).

[0419] More specifically, the present disclosure provides the following solutions:

[0420] 1. Use of a compound represented by formula (I) and pharmaceutically acceptable salts, prodrugs or solvent compounds thereof in the preparation of MRGPRX2 antagonist drugs.

[0421] Where:

[0422] B1 is selected from -CR4 or N atom; wherein R4 is selected from hydrogen atom, C1-C3 alkyl, halogen, C1-C3 alkoxy or nitro;

[0423] R1 is selected from a hydrogen atom, a C1-C3 alkyl group, a C1-C3 alkyl group substituted by 1-3 halogens, a C3-C6 cycloalkyl group, a C3-C6 cycloalkyl group substituted by 1-3 halogens, or R1 and B1 are bonded to form a 6-membered heterocyclic ring which is optionally substituted by a short-chain alkyl group;

[0424] B2 is selected from -NH, oxygen atom, -CH=CH- or is empty;

[0425] R2 is selected from hydrogen atom, -C(=O)OR5 or -C(=O)NHR5'; wherein R5 is selected from hydrogen atom, C1-C4 alkyl; R5' is selected from hydrogen atom or hydroxyl group;

[0426] B3 is selected from -CR6, wherein R6 is selected from a hydrogen atom or a sulfur atom; wherein, when R6 is a sulfur atom, R2 is selected from -C(=O)NH2 and bonds with B3 to form an isothiazolinone;

[0427] R3 is selected from halogen, nitro or hydrogen atom;

[0428] Ring A is selected from unsubstituted or substituted aryl groups, wherein the substitution includes mono-, di-, tri- or tetra-substitution, and the substituents are independently selected from halogen, hydroxyl, nitro, cyano, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkyl substituted by 1-3 halogens, C1-C3 alkyl substituted by hydroxyl, C1-C3 alkyl substituted by phenolic hydroxyl, C1-C3 alkyl substituted by amino, C1-C3 alkyl substituted by anilino, unsubstituted or substituted amino, aminosulfonyl, aminosulfinyl, carbamoyl, sulfenyl, or alkylimidesulfoxide.

[0429] 2. The compound according to Scheme 1 and its pharmaceutically acceptable salt, prodrug or solvate, characterized in that the aryl group is phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 5-pyrimidinyl, triazinyl,

[0430] 3. The compound according to Scheme 1 and its pharmaceutically acceptable salt, prodrug or solvate, characterized in that Ring A is selected from an unsubstituted or substituted aryl group, wherein the substitution includes mono-, di-, tri-, or tetra-substitution, and at least one substituent is selected from an unsubstituted or substituted amino group, an aminosulfonyl group, an aminosulfinyl group, a carbamoyl group, a sulfenyl group, or an alkylimidesulfoxide group.

[0431] 4. Use of the compound represented by formula (I) described in Scheme 1 and its pharmaceutically acceptable salt, prodrug or solvate as an immunomodulator in the preparation of a drug for autoimmune diseases.

[0432] 5. Use of the compound represented by formula (I) described in Scheme 1 and its pharmaceutically acceptable salt, prodrug or solvent compound in the preparation of an immunomodulator.

[0433] 6. Use of the compound of formula (I) described in Scheme 1 and its pharmaceutically acceptable salt, prodrug or solvate in the preparation of a medicament for treating or preventing rosacea.

[0434] 7. Use of the compound represented by formula (I) described in Scheme 1 and its pharmaceutically acceptable salt, prodrug or solvate in the preparation of a medicament for treating or preventing urticaria.

[0435] 8. Use of the compound represented by formula (I) described in Scheme 1 and its pharmaceutically acceptable salt, prodrug or solvate in the preparation of a medicament for treating or preventing atopic dermatitis.

[0436] 9. Use of the compound represented by formula (I) described in Scheme 1 and its pharmaceutically acceptable salt, prodrug or solvate in the preparation of a medicament for treating or preventing psoriasis.

[0437] 10. Use of the compound represented by formula (I) described in Scheme 1 and its pharmaceutically acceptable salt, prodrug or solvate in the preparation of a drug for treating or preventing radiation dermatitis.

[0438] 11. Use of the compound represented by formula (I) described in Scheme 1 and its pharmaceutically acceptable salt, prodrug or solvate in the preparation of a drug for treating or preventing vitiligo.

[0439] 12. Use of the compound represented by formula (I) described in Scheme 1 and its pharmaceutically acceptable salt, prodrug or solvate in the preparation of a medicament for treating or preventing alopecia areata.

[0440] 13. Use of the compound represented by formula (I) described in Scheme 1 and its pharmaceutically acceptable salt, prodrug or solvate in the preparation of a medicament for treating or preventing inflammatory bowel disease.

[0441] 14. Use of the compound represented by formula (I) described in Scheme 1 and its pharmaceutically acceptable salt, prodrug or solvent compound in the preparation of a drug for treating or preventing diseases related to the MRGPRX2 target.

[0442] 15. Use of the compound represented by formula (I) described in Scheme 1 and its pharmaceutically acceptable salt, prodrug or solvate in the preparation of a medicament for treating or preventing radiation stomatitis.

[0443] 16. Use of the compound represented by formula (I) described in Scheme 1 and its pharmaceutically acceptable salt, prodrug or solvate in the preparation of a drug for treating or preventing inflammatory reactions.

[0444] 17. Use of the compound of formula (I) described in Scheme 1 and its pharmaceutically acceptable salt, prodrug or solvate in the preparation of a medicament for treating or preventing Henoch-Schonlein purpura.

[0445] 18. Use of the compound represented by formula (I) described in Scheme 1 and its pharmaceutically acceptable salt, prodrug or solvate in the preparation of a medicament for treating or preventing irritable bowel syndrome.

[0446] 19. Use of the compound represented by formula (I) described in Scheme 1 and its pharmaceutically acceptable salt, prodrug or solvate in the preparation of a medicament for treating or preventing allergic rhinitis.

[0447] 20. Use of the compound represented by formula (I) as described in Scheme 1 and its pharmaceutically acceptable salt, prodrug or solvate in the preparation of a medicament for treating or preventing asthma.

[0448] 21. Use of the compound of formula (I) described in Scheme 1 and its pharmaceutically acceptable salt, prodrug or solvate in the preparation of a medicament for treating or preventing multiple sclerosis.

[0449] 22. Use of the compound represented by formula (I) described in Scheme 1 and its pharmaceutically acceptable salt, prodrug or solvate in the preparation of a medicament for treating or preventing systemic lupus erythematosus.

[0450] 23. Use of the compound represented by formula (I) described in Scheme 1 and its pharmaceutically acceptable salt, prodrug or solvate in the preparation of a medicament for treating or preventing rheumatoid arthritis.

[0451] 24. Use of the compound represented by formula (I) described in Scheme 1 and its pharmaceutically acceptable salt, prodrug or solvate in the preparation of a medicament for treating or preventing autoimmune liver disease.

[0452] 25. Use of the compound represented by formula (I) described in Scheme 1 and its pharmaceutically acceptable salt, prodrug or solvate in the preparation of a medicament for treating or preventing autoimmune nephropathy.

[0453] definition

[0454] The following words, phrases and symbols used in this disclosure have the meanings described below unless the context in which they are used indicates otherwise.

[0455] As used herein, the singular forms “the” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0456] As used herein, "includes," "comprising," "having," and variations thereof are intended to indicate the presence of the stated features, components, or steps, but they do not preclude the presence or addition of one or more other features, components, or steps. Unless otherwise indicated, "includes," "comprising," or "having" as used herein encompasses the situation consisting of the stated features, components, or steps.

[0457] According to the convention in this technical field, the structural formula herein uses Used to delineate the bond at the point of attachment of a radical moiety or substituent to the core or backbone structure.

[0458] The term "halogen atom" used herein means a F atom, a Cl atom, a Br atom and an I atom, preferably F or Cl.

[0459] The term "heteroatom" used herein means an N atom, an O atom, and an S atom.

[0460] The term "alkyl" as used herein refers to a straight-chain or branched saturated hydrocarbon group containing, for example, 1 to 20 carbon atoms (C 1-20 ), 1 to 15 carbon atoms (C 1-15 ), 1 to 12 carbon atoms (C 1-12 ), 1 to 10 carbon atoms (C 1-10 ), 1 to 9 carbon atoms (C 1-9 ), 3 to 9 carbon atoms (C 3-9 ), 1 to 6 carbon atoms (C 1-6 ) or 1 to 3 carbon atoms (C 1-3 ) is a straight or branched saturated hydrocarbon chain group. x～y "Alkyl" refers to a straight or branched chain saturated hydrocarbon group containing x to y carbon atoms. For example, "C 1-12 Alkyl" or "C 1-12 "Straight-chain or branched-chain alkyl" refers to a straight-chain or branched-chain saturated hydrocarbon group containing 1 to 12 carbon atoms. 1-6 Alkyl" or "C 1-6The term "straight or branched alkyl" refers to a straight or branched saturated hydrocarbon containing 1 to 6 (1, 2, 3, 4, 5 or 6) carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl and n-decyl.

[0461] The term "alkenyl" as used herein refers to a straight or branched unsaturated hydrocarbon group containing one or more carbon-carbon double bonds, such as an alkenyl group having 2 to 25 carbon atoms, 2 to 20 carbon atoms (C 2-20 ), 2 to 15 carbon atoms (C 2-15 ), 2 to 12 carbon atoms (C 2-12 ), 2 to 10 carbon atoms (C 2-10 ), 2 to 9 carbon atoms (C 2-9 ), 3 to 9 carbon atoms (C 3-9 ), 2 to 6 carbon atoms (C 2-6 ) or 2 to 3 carbon atoms (C 2-3 ) are straight-chain or branched unsaturated hydrocarbon groups. In these groups, there may be, for example, 1, 2, 3 or 4 C=C double bonds. For example, "C 2-7 Alkenyl" or "C 2-7 "Straight chain or branched chain alkenyl" refers to a straight chain or branched chain alkenyl containing 2 to 7 carbon atoms, "C 2-6 Alkenyl" or "C 2-6 The term "straight-chain or branched alkenyl" refers to a straight-chain or branched alkenyl group containing 2 to 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, hexenyl, and the like.

[0462] The term "alkynyl" as used herein refers to a straight or branched chain unsaturated hydrocarbon group containing one or more carbon-carbon triple bonds, for example, a straight or branched chain hydrocarbon group having 2 to 20 carbon atoms (C 2-20 ), 2 to 15 carbon atoms (C 2-15 ), 2 to 12 carbon atoms (C 2-12 ), 2 to 10 carbon atoms (C 2-10 ), 2 to 9 carbon atoms (C 2-9 ), 3 to 9 carbon atoms (C 3-9 ), 2 to 6 carbon atoms (C 2-6 ) or 2 to 3 carbon atoms (C 2-3 ) are straight-chain or branched unsaturated hydrocarbon groups. In these groups, there may be, for example, 1, 2, 3 or 4 C=C double bonds. For example, "C 2-6 Alkynyl" or "C 2-6The term "straight-chain or branched-chain alkynyl" refers to a straight-chain or branched-chain alkynyl group having 2 to 6 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, 2-propargyl, and 2-butynyl.

[0463] The term "alkoxy" as used herein refers to an -O-alkyl group, wherein alkyl is as defined above, for example, C 1-6 Alkoxy, C 1-3 Alkoxy. For example, C2 alkoxy is -OCH2CH3. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, s-pentoxy, n-heptoxy, and n-octoxy.

[0464] The term "haloalkyl" as used herein refers to a straight or branched chain alkyl group as defined herein, wherein one or more hydrogen atoms, for example 1, 2, 3, 4 or 5 hydrogen atoms, are replaced by halogen atoms, and when more than one hydrogen atom is replaced by a halogen atom, the halogen atoms may be the same or different from each other. Examples of haloalkyl groups include, but are not limited to -(CH2) 0-8 CF3, -CF3, -CHF2, -CH2F, -CH2CF3, -(CH2)2CF3, -(CH2)3CF3 and -(CH2)4CF3, -(CH2)2CH2Cl. Preferred haloalkyl groups are C 1-6 trifluoroalkyl, more preferably -CF3.

[0465] The term "cycloalkyl" as used herein refers to a saturated cyclic hydrocarbon group having 3-10 ring atoms (3-10 members), such as 3-9 ring atoms (3-9 members), 3-7 ring atoms (3-7 members), 3-6 ring atoms (3-6 members) or 5-6 ring atoms (5-6 members), which may have one or more rings, for example, 1 or 2 rings. For example, the cycloalkyl group is a monocyclic cycloalkyl group, preferably a monocyclic C 3-7 Cycloalkyl, monocyclic C 3-6 Cycloalkyl or monocyclic C 5-6 Cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. For example, the cycloalkyl is a bicyclic cycloalkyl, such as a bicyclic C6-C 10Cycloalkyl. Bicyclic cycloalkyl groups include fused, bridged, or spirocyclic rings. Examples of bridged cycloalkyl groups include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, bicyclo[4.2.1]nonane, tricyclo[3.3.1.0 3,7]nonane (octahydro-2,5-methylenepentalene or noradamantane), and tricyclo[3.3.1.1 3,7]decane (adamantane). The term "heterocycloalkyl" as used herein refers to a saturated ring having 4-10 ring atoms (4-10 members), such as 4-9 ring atoms (4-9 members), 4-7 ring atoms (4-7 members), 4-6 ring atoms (4-6 members), 5-7 ring atoms (5-7 members), 5-6 ring atoms (5-6 members) or 7-9 ring atoms (7-9 members), wherein one or more, such as 1, 2 or 3, preferably 1 or 2, of the ring atoms are heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon atoms; it may have one or more rings, such as 1, 2 or 3, or 1 or 2 rings, wherein the N and S heteroatoms may be optionally oxidized to various oxidation states. The point of attachment of the heterocyclyl group may be on the N heteroatom or on the C atom. Heterocyclyl groups also include fused rings, bridged rings or spiro rings. Examples of "heterocycloalkyl" include, but are not limited to, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, tetrahydrofuranyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, tetrahydropyranyl, morpholinyl, and thiomorpholinyl. For example, a 4-6 membered heterocycloalkyl group contains 1, 2, or 3, such as 1 or 2, heteroatoms selected from N, O, or S (e.g., selected from N or O; or, selected from N), which is optionally substituted with one or more halogens, such as 2 F atoms on the same C atom; examples thereof include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, difluoroazetidinyl, or 3,3-difluoroazetidinyl. For example, 5-6 membered heterocycloalkyl contains 1, 2 or 3, for example 1 or 2, heteroatoms selected from N, O or S (for example selected from N or O; or, selected from O); an example is tetrahydropyranyl (for example tetrahydrofuran-4-yl).

[0466] As used herein, the term "aryl" refers to a monocyclic or polycyclic fused aromatic carbocyclic group, such as phenyl or naphthyl.

[0467] As used herein, the term "heteroaryl" refers to an aromatic ring group having 5-6 ring atoms (5-6 members), 5 ring atoms (5 members) or 6 ring atoms (6 members), wherein one or more, e.g., 1, 2 or 3, preferably 1 or 2, ring atoms are heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon, wherein the N or S heteroatom is optionally oxidized to various oxidation states. Examples of heteroaryl groups include, but are not limited to, furanyl (including, but not limited to, furan-2-yl), imidazolyl (including, but not limited to, 1H-imidazol-1-yl), isoxazolyl, isothiazolyl, oxadiazolyl, 1,3-oxazolyl, pyridinyl (e.g., pyridin-4-yl, pyridin-2-yl, and pyridin-3-yl), pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, 1,3-thiazolyl, thienyl (including, but not limited to, thien-2-yl and thien-3-yl), triazolyl, and triazinyl, for example:

[0468] As used herein, the terms "optional," "optionally," or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted with" includes "unsubstituted" and "substituted with 1, 2, 3, or more." It is understood by those skilled in the art that, for any group containing one or more substituents, the group does not include any substitution or substitution pattern that is sterically impractical, chemically incorrect, synthetically infeasible, and / or inherently unstable.

[0469] As used herein, the term "substituted" or "substituted by" means that one or more hydrogen atoms on a given atom or group are replaced by one or more substituents independently selected from the specified group of substituents, provided that the normal valence of the given atom is not exceeded. The term "substituted by 1, 2 or 3" means that 1, 2 or 3 hydrogens on a given atom or group are replaced by 1, 2 or 3 substituents independently selected from the specified group of substituents, provided that the normal valence of the specified atom is not exceeded. Combinations of substituents and / or variables are permissible only if such combinations result in chemically correct and stable compounds. A chemically correct and stable compound means a compound that is sufficiently robust to be isolated from a reaction mixture.

[0470] The compounds of the present disclosure may exist in isotopically traced or enriched forms, which contain one or more atoms having an atomic mass or mass number that is different from the atomic mass or mass number of the atom found in the largest amount in nature. Isotopes may be radioactive or non-radioactive. Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine, and iodine include, but are not limited to: 2 H. 3H. 13 C. 14 C. 15 N. 18 O. 32 P. 35 S. 18 F. 36 Cl and 125 I. Compounds containing other isotopes of these and / or other atoms are within the scope of this invention.

[0471] It will be appreciated by those skilled in the art that some compounds disclosed herein may include one or more chiral centers or rings, and therefore may include two or more stereoisomers. Racemic mixtures of these isomers, single isomers, and a mixture enriched in enantiomers, as well as diastereomers and specific diastereomer partially enriched mixtures when there are two chiral centers, are within the scope of the present disclosure. It will also be appreciated by those skilled in the art that the present disclosure includes all single stereoisomers (e.g., enantiomers, diastereomers, cis- or trans-isomers (e.g., substituent configurations on divalent cyclic saturated or partially saturated groups) or atropisomers, as long as chemically possible) of compounds of formula (I), racemates of the disclosed compounds, mixtures thereof, and, if appropriate, their individual tautomeric forms.

[0472] As used herein, the term "pharmaceutically acceptable salt" includes, but is not limited to, acid addition salts of the compounds disclosed herein formed with inorganic acids, such as hydrochlorides, hydrobromides, carbonates, bicarbonates, phosphates, sulfates, sulfites, nitrates, and the like; and acid addition salts of the compounds disclosed herein formed with organic acids, such as formate, acetate, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethanesulfonate, benzoate, salicylate, stearate, and salts of the formula HOOC-(CH2) n "Pharmaceutically acceptable salts" also include base addition salts of the compounds of the present disclosure with acidic groups and pharmaceutically acceptable cations such as sodium, potassium, calcium, aluminum, lithium and ammonium.

[0473] As used herein, the term "subject" refers to both mammals and non-mammals. Mammals refer to any member of the class mammals, including, but not limited to, humans; non-human primates such as chimpanzees and other apes and monkeys; farm animals such as cattle, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents such as rats, mice, and guinea pigs; and the like. In some embodiments, the subject is a human.

[0474] All numerical ranges herein are understood to disclose each and all values ​​within the range and each and all value subsets within the range, regardless of whether they are specifically disclosed otherwise. For example, when any numerical range is mentioned, it should be considered to refer to each value in the numerical range, for example, each integer in the numerical range. The present disclosure includes all values ​​falling within these ranges, all smaller ranges, and the upper or lower limit of the range.

[0475] Technical and scientific terms used herein without specific definition have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0476] The various embodiments and features in the various embodiments described in the present disclosure should be understood to be capable of being combined with each other in any manner, and the various schemes obtained by these combinations are included in the scope of the present disclosure, just as the schemes obtained by these combinations are specifically and individually listed in this document, unless the context clearly indicates otherwise.

[0477] To the extent permitted by law, all patents, patent applications, and other documents cited or referred to herein are incorporated by reference in their entirety. The discussion of these references is intended only to summarize the claims made therein. No admission is made that any of the cited patents, patent applications, or documents, or any portion thereof, is relevant material or prior art. The right to challenge the accuracy and pertinence of any assertion that the cited patents, patent applications, and other documents are relevant material or prior art is specifically reserved.

[0478] Administration and therapy

[0479] The compounds of the present disclosure (e.g., any of the compounds described in the Examples herein) alone or in combination with one or more additional therapeutic agents can be formulated into pharmaceutical compositions. Pharmaceutical compositions include: (a) a compound of the present disclosure; (b) a pharmaceutically acceptable carrier (e.g., one or more pharmaceutically acceptable carriers); and optionally (c) at least one additional therapeutic agent.

[0480] A pharmaceutically acceptable carrier refers to an excipient or adjuvant that is compatible with the active ingredient in the composition (in some embodiments, can stabilize the active ingredient) and is not harmful to the individual being treated. Suitable pharmaceutically acceptable carriers are disclosed in standard reference books in the field (e.g., Remington's Pharmaceutical Sciences, Remington: The Science and Practice of Pharmacy) and include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, fragrances, flavorings, diluents, and other known additives to provide a good appearance of the drug (i.e., a compound of the present disclosure or its pharmaceutical composition) or to facilitate the manufacture of the drug product (i.e., medicament).

[0481] The compounds of the present disclosure can be administered in various known ways, such as orally, topically, parenterally, by inhalation or by implantation. As used herein, the term "parenteral" includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intraspinal, intralesional, and intracranial injection or infusion. Oral or topical administration, such as topical administration to the skin or mucous membranes, such as topical application, is preferred.

[0482] The compounds of the present disclosure may be administered in any convenient formulation, such as tablets, capsules, ointments, creams, gels, pastes, emulsions, powders, patches, solutions, dispersions, suspensions, syrups, sprays, suppositories, and the like.

[0483] The precise dose of the disclosed compounds capable of treating or preventing a MRGPRX2-mediated disease or disorder will depend on a number of factors, including the host, the nature and severity of the condition being treated, and the mode of administration.

[0484] The beneficial technical effects achieved by the present invention include at least:

[0485] (1) Currently available fluoroquinolones, such as ciprofloxacin, are generally considered agonists of MRGPRX2, and some patients experience side effects such as itching and rash after using fluoroquinolone compounds. However, the present inventors surprisingly discovered that the compounds provided herein can be used as MRGPRX2 antagonists to treat or prevent autoimmune diseases, allergic diseases, inflammatory diseases, itching, and pain, etc.

[0486] (2) MRGPRX2 targets are mainly concentrated in barrier tissues. Local administration, such as local administration to the skin, can produce more targeted treatment for local lesions, reduce the side effects caused by systemic absorption of drugs, and improve the patient's treatment experience.

[0487] General synthetic method

[0488] Different synthetic routes were used in the preparation of the compounds of the present invention. The compounds of formula (IA), (IB) and (I) can be synthesized using the following synthetic methods.

[0489] wherein the variables are as defined in formula (IA), (IB) or (I), for example, for formula (IA), R9 is C 1-6 Straight or branched alkyl or hydrogen atom, preferably C 1-3 A straight chain or branched alkyl group, R3 is a halogen; Ring A is further represented by R4 and (R5) n substituted (not shown), B2 is absent; for example, for formula (IB), R9 is C 1-6 Straight or branched alkyl or hydrogen atom, preferably C 1-3 Straight or branched alkyl, R3 is halogen; Ring A is further substituted by R4 (not shown in the figure), and B2 does not exist.

[0490] Reaction 1:

[0491] The intermediate 1 and the intermediate 2 are synthesized by reacting them by Suzuki reaction in the presence of a base such as K2CO3, Na2CO3, Cs2CO3, etc., in the presence of a palladium catalyst such as 1,1-bis(diphenylphosphino)ferrocenedichloropalladium(II), palladium(II) chloride, and palladium(II) acetate in a solvent such as DMF, DMSO, THF, dichloromethane, acetonitrile, etc. The reaction can be carried out at normal pressure under an inert gas environment (including nitrogen, argon, etc.). The reaction is usually carried out at room temperature to about 150°C for about 16 to 24 hours.

[0492] Reaction formula 1 also corresponds to the case where B2 in the compound of formula (I) is empty (ie, does not exist) and B3 is CH.

[0493] Reaction 2:

[0494] The compound of general formula (B) can be prepared by hydrolyzing compound (A). The hydrolysis of compound (A) can be carried out under conventional hydrolysis reaction conditions, for example, in the presence of a basic compound such as LiOH, NaOH, KOH, etc., in a solvent including dichloromethane, an alcohol such as methanol, DMF, DMSO, THF, etc. The reaction is usually carried out at a temperature of room temperature to about 60°C for about 0.1 to 24 hours.

[0495] Reaction formula 2 also corresponds to the case where B2 in the compound of formula (I) is empty (ie, does not exist) and B3 is CH.

[0496] Reaction 3:

[0497] The compound of formula (C) can be synthesized from the compound of formula (B) by a condensation reaction. The compound of formula (B) can be reacted with a relevant amine in the presence of a condensing agent (e.g., DMAP, HATU, etc.) and in a solvent including dichloromethane, DMF, THF, etc. The reaction is usually carried out at room temperature for about 3 to 12 hours.

[0498] Reaction formula 3 corresponds to the case where B2 in the compound of formula (I) is empty (ie, does not exist) and B3 is CH.

[0499] Reaction 4:

[0500] Intermediate 2 can be prepared by reacting compound (D) with a bis(pinacolato)diboron compound (E) in a typical inert solvent in the presence of a palladium catalyst and a base. The reaction is carried out at normal pressure under an inert gas environment including nitrogen, argon, etc. The reaction can usually be carried out at a temperature of room temperature to about 150° C. for about 16 to 24 hours.

[0501] Reaction 5:

[0502] wherein R7 is a hydrogen atom or a halogen atom.

[0503] The compound of formula (F) is synthesized by reacting intermediate 3 with intermediate 1 in the presence of a base such as K2CO3, Na2CO3, Cs2CO3, LDA, NaH, etc., in the presence of a copper catalyst such as CuI, Cu(I), or a palladium catalyst such as 1,1-bis(diphenylphosphino)ferrocenedichloropalladium(II), palladium chloride(II) and palladium acetate(II), in a solvent such as DMF, DMSO, THF, toluene, etc., by Buchwald reaction, Kumada reaction, Negishi reaction or Ullmann reaction. The reaction can be carried out under an inert gas environment including nitrogen, argon, etc. at normal pressure. The reaction is usually carried out at room temperature to about 80-150°C for about 16-24 hours.

[0504] Reaction formula 5 corresponds to the case where B2 in the compound of formula (I) is empty (ie, does not exist) and B3 is CH. Example

[0505] In this application, when a chemical name and a structural formula are inconsistent, the structural formula shall prevail unless the context indicates that the chemical name rather than the structural formula is correct.

[0506] All non-aqueous reactions were performed under dry argon using oven-dried glassware. Reaction progress was monitored by thin layer chromatography on glass plates coated with General Reagent Silica Gel 60. Flash column chromatography was performed on General Reagent Silica Gel. Mass spectra of the compounds were recorded using an Agilent G7115A LC-MS / MS instrument. NMR spectra were recorded at ambient temperature using a Bruker Avance 400 spectrometer. Relative to external tetramethylsilane, 1 Chemical shifts for H are reported in parts per million (δ) and are referenced to the signal of residual protons in the deuterated solvent.

[0507] Unless otherwise specified, the experimental materials and reagents used in the following examples can be obtained from commercial channels.

[0508] Preparation of intermediate compound 7:

[0509] Preparation of 2,4,5-trifluoro-3-methoxybenzoyl chloride (2)

[0510] To 2,4,5-trifluoro-3-methoxybenzoic acid (1) (30.0 g, 145.5 mmol) was added SOCl2 (180 mL) solution and stirred at 85°C for 3 hours. After cooling to room temperature, the solvent was evaporated and the mixture was dried under vacuum to obtain a light yellow oil (32.0 g, 142.5 mmol, 97.9% yield), which was used directly in the next reaction without further purification.

[0511] Preparation of ethyl 3-oxo-3-(2,4,5-trifluoro-3-methoxyphenyl)propionate (3)

[0512] To a solution of potassium 3-ethoxy-3-oxopropanoate (2) (48.5 g, 284.9 mmol) in EA (300 mL) was added MgCl2 (33.9 g, 356.1 mmol). The mixture was stirred at room temperature for 30 minutes under nitrogen. Trimethylamine (28.8 g, 284.6 mmol) was then added to the mixture, and the mixture was stirred for another 30 minutes at room temperature. 2,4,5-trifluoro-3-methoxybenzoyl chloride (32.0 g, 142.5 mmol) was added dropwise to the mixture, and the mixture was stirred at 85°C for 2 hours. After the mixture was cooled to room temperature, water (150 ml) was added and the mixture was acidified with HCl (2 M) (pH = 1-2). The mixture was extracted with EA (200 mL), the organic phase was dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to obtain a brown oily crude product (58.0 g).

[0513] Preparation of 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (4)

[0514] To a solution of ethyl 3-oxo-3-(2,4,5-trifluoro-3-methoxyphenyl)propanoate (3) (58.0 g, 210.0 mmol) in Ac2O (64.3 g, 630.0 mmol) was added triethoxymethane (46.6 g, 314.4 mmol) and stirred at 100°C for 2 hours. The solvent was removed under reduced pressure to obtain a residue. The residue was dissolved in DMSO (400 ml) and cyclopropaneamine (14.4 g, 252.2 mmol) was added and stirred at room temperature for 2 hours. K2CO3 (43.4 g, 314.8 mmol) was then added to the mixture and stirred at 100°C for another hour. After cooling to room temperature, water (500 mL) was added to the mixture and stirred for 10 minutes. The suspension was filtered to remove the filtrate, and the filtered solid was washed with water (50 mL) and dried in vacuo to give the desired product as a white solid (21.0 g, 65.0 mmol, 45.6% two-step yield).

[0515] Preparation of ethyl 7-azido-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (5)

[0516] To a solution of ethyl 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (4) (10.0 g, 30.9 mmol) in DMF (50 mL) was added NaN3 (4.02 g, 61.8 mmol) and stirred at 70°C for 36 hours. After the reaction was completed, the mixture was cooled to room temperature and filtered through celite. The filtrate was added to water (50 mL) and extracted with EA (70 mL x 3). The organic phase was washed with water (50 ml x 3) and brine (50 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product as a brown solid (5.6 g).

[0517] Preparation of ethyl 7-amino-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (6):

[0518] To a solution of ethyl 7-azido-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (5) (5.6 g, crude product) in THF / MeOH (50 mL / 10 mL) was added Pd / C (2.8 g, 10% by weight), the atmosphere was replaced with hydrogen three times, and the mixture was stirred at room temperature under hydrogen (balloon) for 4 hours. The mixture was filtered, the solvent was removed under reduced pressure, and the mixture was purified by silica gel column chromatography (DCM / MeOH = 50 / 1 to 20 / 1) to give a white solid (3.8 g, 11.86 mmol, 38.3% yield over two steps).

[0519] Preparation of ethyl 7-bromo-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (7):

[0520] To a solution of ethyl 7-amino-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (6) (3.80 g, 11.86 mmol) in ACN (50 mL) were added tert-butyl alcohol (1.84 g, 17.84 mmol) and CuBr2 (5.30 g, 23.73 mmol) and stirred at 70°C for 2 hours. The mixture was cooled to room temperature, diluted with saturated NH4Cl solution (25 mL) and extracted with EA (50 mL x 3). The organic phase was washed with brine (30 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was dissolved in DCM / MTBE (10 mL / 610 ml) and stirred at room temperature for 10 minutes. The suspension was filtered to remove the filtrate, and the filtered solid was dried under vacuum to obtain the desired product as a yellow solid (2.0 g, 5.21 mmol, 43.9%).

[0521] LCMS::386.1[M+H] + . 1 H NMR(400MHz,MeOD)δ8.77(s,1H),7.92(d,J=8.5Hz,1H),4.33(q,J=7.1Hz,2H),4.14-4 .10(m,1H),3.94(s,3H),1.37(t,J=7.1Hz,3H),1.26-1.16(m,2H),1.09-0.99(m,2H).

[0522] Preparation of intermediate compound 9:

[0523] Preparation of N-(2-hydroxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (9)

[0524] To a mixture of 4-bromo-N-(2-hydroxyethyl)benzenesulfonamide (8) (1 g, 3.57 mmol) in 1,4-dioxane (10 mL) were added B2Pin2 (1.2 g, 4.28 mmol), KOAc (1.05 g, 10.71 mmol) and Pd(dppf)Cl2 (259.04 mg, 356.97 mmol) at room temperature. The mixture was then heated to 90 degrees Celsius and stirred for 16 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH=20:1) to give the title product (582 mg, 312.24 mmol, 58.2%) as a brown solid. LCMS: 327.9 [M+H] + .

[0525] A series of derivatives can be obtained by replacing similar starting materials through the same preparation route as above.

[0526] Example 1 Ethyl 1-cyclopropyl-6-fluoro-7-(4-(N-(2-hydroxyethyl)aminosulfonyl)phenyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate

[0527] The synthetic route is as follows:

[0528] To a mixture of N-(2-hydroxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (9) (146 mg, 312.24 umol) in 1,4-dioxane (3 mL) and H2O (1 mL) at room temperature were added ethyl 7-bromo-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (7) (100 mg, 260.28 umol), K3PO4 (165.74 mg, 780.84 umol) and Pd(dtbpf)Cl2 (16.81 mg, 26.03 umol). The mixture was then heated to 90 degrees Celsius and stirred for 16 hours. The reaction solution was then cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using a gradient of DCM:MeOH from 1:0 to 20:1 to afford the product as a brown solid (66 mg, 130.81 umol, 35.18%).

[0529] LCMS: 505.1[M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.58(s,1H),7.96(d,J=8.3Hz,2H),7.86-7.68(m,3H),4.72(t,J=5.6Hz,1H),4.25(q,J=7.1Hz ,2H),4.05(dt,J=6.4,2.5Hz,1H),3.47-3.23(m,5H),2.88(t,J=6.1Hz,2H),1.29(t,J=7.1Hz,3H),1.36-1.03(m,7H).

[0530] Example 2 1-Cyclopropyl-6-fluoro-7-(4-(N-(2-hydroxyethyl)aminosulfonyl)phenyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

[0531] The synthetic route is shown in the figure below

[0532] To a solution of ethyl 1-cyclopropyl-6-fluoro-7-(4-(N-(2-hydroxyethyl)aminosulfonyl)phenyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (66 mg, 130.81 umol) in THF (3 mL) were added H2O (1 mL) and LiOH (12.53 mg, 523.26 umol). The reaction solution was stirred at room temperature for 2 h. After the reaction was completed, the pH was adjusted to neutral, the reaction solution was diluted with DCM (10 mL), and then washed with water (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a white solid product (22 mg, 46.17 umol, 35.30%).

[0533] LCMS: 477.2[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ14.61(s,1H),8.82(s,1H),7.98(dd,J=8.7,4.7Hz,3H),7.77(dd,J=13.3,6.9Hz,3 H),4.72(t,J=5.2Hz,1H),4.28-4.17(m,1H),3.44-3.36(m,5H),2.88(q,J=6.0Hz,2H),1.23-1.12(m,4H).

[0534] Example 3 7-(4-(N-(2-chloroethyl)aminosulfonyl)phenyl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

[0535] To a solution of 1-cyclopropyl-6-fluoro-7-(4-(N-(2-hydroxyethyl)aminosulfonyl)phenyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 2) (22 mg, 130.81 umol) in THF (3 mL) at room temperature were added H₂O (1 mL) and SOCl₂ (5 mL). After completion of the reaction as determined by MS, the reaction solution was concentrated under reduced pressure. The crude product was purified by preparative liquid chromatography (0.1% FA, H₂O) to give the product as a white solid (13.70 mg, 36.37 umol, 78.77%).

[0536] LCMS: 495.1[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ14.63(s,1H),8.82(s,1H),8.16(d,J=10.6Hz,1H),7.98(d,J=11.1Hz,3H),7.80(d,J =7.9Hz,2H),4.21(q,J=5.8Hz,1H),3.61(t,J=6.1Hz,2H),3.39(s,3H),3.21-3.17(m,2H),1.20-1.13(m,4H).

[0537] Example 4 7-(3-cyano-4-(2,2,2-trifluoroacetylamino)phenyl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

[0538] Preparation of ethyl 7-(4-amino-3-cyanophenyl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate

[0539] A mixture of ethyl 7-bromo-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (200 mg, 561.57 μmol), 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (205.62 mg, 842.35 μmol), Pd(dtbpf)Cl2 (36.26 mg, 56.16 μmol), K3PO4 (357.6 mg, 1.68 mmol) in 1,4-dioxane (5 mL) and H2O (1 mL) was stirred at 90 degrees Celsius under nitrogen for 16 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using DCM:MeOH = 20:1 as eluent to give a white solid product (130 mg, 561.57 ummol, 54.93%). LCMS: 422.0 [M+H] + .

[0540] Preparation of 7-(4-amino-3-cyanophenyl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

[0541] A mixture of ethyl 7-(4-amino-3-cyanophenyl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (130 mg, 308.47 umol), LiOH (29.55 mg, 1.23 umol) in THF (3 mL) and H2O (1 mL) was stirred at room temperature for 2 hours. After the reaction was completed, it was concentrated under reduced pressure. The crude product was purified by preparative liquid chromatography (0.1% NH3-H2O, H2O) to give a white solid product (22.73 mg, 308.47 umol, 18.73%). LCMS: 394.1 [M+H] + .

[0542] To a solution of 7-(4-amino-3-cyanophenyl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (35 mg, 88.97 umol) in DCM (3 mL) was added 2,2,2-trifluoroacetic anhydride (28.03 mg, 133.46 umol) and TEA (13.51 mg, 133.46 umol) at room temperature. The mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The crude product was purified by preparative HPLC (0.1% formic acid in water) to give a white solid product (17.35 mg, 88.97 umol, 39.85%).

[0543] LCMS: 489.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ14.60(s,1H),11.94(s,1H),8.82(s,1H),8.21(s,1H),8.06-7 .91(m,2H),7.81(d,J=8.4Hz,1H),4.33-4.10(m,1H),3.43(s,3H),1.27-1.09(m,4H).

[0544] Example 5 1-Cyclopropyl-6-fluoro-8-methoxy-4-oxo-7-(4-(N-(tetrahydro-2H-pyran-4-yl)aminosulfonyl)phenyl)-1,4-dihydroquinoline-3-carboxylic acid

[0545] Referring to the preparation process in Examples 1-4, similar raw materials were substituted to obtain the target compound with the following structure:

[0546] LCMS: 517.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ14.65(s,1H),8.51(s,1H),7.71(d,J=8.2Hz,1H),7 .69–7.62(m,2H),7.52–7.44(m,2H),6.88(d,J=11.7Hz,1H),4.25–4.15(m,1 H),3.84(s,3H),3.72(dt,J=12.1,7.2Hz,2H),3.57(dt,J=12.5,7.0Hz,2H), 3.22-3.16(m,1H),2.07–1.89(m,4H),1.27–1.19(m,2H),1.16–1.05(m,2H).

[0547] Example 6 7-(3-cyano-4-(N-cyclohexylaminosulfonyl)phenyl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

[0548] Referring to the preparation process in Examples 1-4, similar raw materials were substituted to obtain the target compound with the following structure:

[0549] LCMS: 540.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ14.85(s,1H),8.71(s,1H),8.12-7.85(m,4H),7.71(dt,J=7.4,1.7 Hz,1H),7.26(d,J=12.1Hz,1H),4.13-3.80(m,4H),3.36-3.15(m,1H),1.75-0.88(m,14H).

[0550] Example 7 1-Cyclopropyl-6-fluoro-8-methoxy-4-oxo-7-(4-(piperidin-1-ylsulfonyl)phenyl)-1,4-dihydroquinoline-3-carboxylic acid

[0551] Referring to the preparation process in Examples 1-4, similar raw materials were substituted to obtain the target compound with the following structure:

[0552] LCMS: 501.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ14.80(s,1H),8.61(s,1H),8.04(d,J=7.8Hz,1H),7.74–7.67(m,2H),7.47-7 .35(m,2H),4.20–4.10(m,1H),3.85(s,3H),2.96-2.80(m,4H),1.67–1.46(m,6H),1.29–1.05(m,4H).

[0553] Example 8 1-Cyclopropyl-6-fluoro-8-methoxy-4-oxo-7-(4-(pyrrolidin-1-ylsulfonyl)phenyl)-1,4-dihydroquinoline-3-carboxylic acid

[0554] Referring to the preparation process in Examples 1-4, similar raw materials were substituted to obtain the target compound with the following structure:

[0555] LCMS: 487.1[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ14.79(s,1H),8.56(s,1H),7.94(d,J=7.8Hz,1H),7.73–7.65(m,2H),7.51–7.43(m,2H ),4.21–4.11(m,1H),3.81(s,3H),3.21–3.11(m,4H),1.80–1.66(m,4H),1.39–1.24(m,2H),1.18–1.02(m,2H).

[0556] Example 9 7-(4-(azetidin-1-ylsulfonyl)phenyl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

[0557] Referring to the preparation process in Examples 1-4, similar raw materials were substituted to obtain the target compound with the following structure:

[0558] LCMS: 473.1[M+H] + . 1H NMR (400MHz, DMSO-d6) δ14.77(s,1H),8.62(s,1H),7.94(d,J=7.8Hz,1H),7.72–7.65(m,2H),7.51–7.43(m,2H ),4.26-4.10(m,1H),3.85(s,3H),3.39–3.24(m,4H),1.96-1.87(m,2H),1.29–1.14(m,2H),1.08–1.02(m,2H).

[0559] Example 10 1-Cyclopropyl-7-(4-((3,3-difluoroazetidin-1-yl)sulfonyl)phenyl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

[0560] Referring to the preparation process in Examples 1-4, similar raw materials were substituted to obtain the target compound with the following structure:

[0561] LCMS: 509.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ14.75(s,1H),8.61(s,1H),7.91(d,J=8.2Hz,1H),7.76–7.68 (m,2H),7.51–7.43(m,2H),4.23–4.13(m,1H),3.83–3.64(m,7H),1.29–1.02(m,4H).

[0562] According to a similar method, the present invention also synthesized a series of compounds with the following structures:

[0563] Biological activity test:

[0564] 1. In vitro target binding assay:

[0565] Bioluminescence resonance energy transfer (BRET) is an important biophysical technique for monitoring molecular interactions and has been widely used to study protein-protein interactions in living cells. This technique requires that the relevant protein be connected to an energy donor (such as luciferase) and an acceptor (such as fluorescent protein). When the relevant drug molecule interacts with the protein, the protein structure changes, the distance between the energy donor and the energy acceptor changes, and the luminescence energy induced by the chemical reaction is transferred to the corresponding acceptor, resulting in an increase in acceptor emission and the generation of a BRET signal. In this work, a DNA synthesis target human MRGPRX2 was used to bind to the donor luciferase Nluc ( Promega) (Source: Beijing Qingke, Batch No.: SZ0171228-1), as well as the receptor fluorescent protein Venus and the related test protein, human β-arrestin1 (ARRB1) (Source: Guangzhou Dahong Biology, Batch No. HY22694-4396). And inserted into the eukaryotic expression vector plasmid pcDNA3.1 (+) (Source: Qiyun Biology, Batch No.: QY2310) as a fusion gene through the Linker sequence (GGSG). The cell line used in the experiment was human embryonic kidney cell HEK-293T, which was routinely cultured in a 10cm cell culture dish using complete cell culture medium and a ratio of: high glucose DMEM medium plus 10% (V / V) fetal bovine serum. On the first day of culture, 2×10 6 Cells were plated on a 10 cm dish and the same number of cells was passaged every 72 h. The cells were resuspended and counted one day before transfection. 6 cells / 6 cm dish or 4 × 10 6 Cells / 10cm dish are plated, and transfection can be performed 16 to 24 hours after plating. The plasmid of the constructed fusion protein gene is transfected into the cell line for expression, and the transfected cells are cultured under appropriate conditions for a period of time to allow sufficient expression of the fusion protein. The transfection is carried out by encapsulating the plasmid DNA with PEI reagent. The encapsulation process needs to be carried out in Opti-MEM culture medium. The ratio of plasmid, PEI (source: Yisheng Biology, batch number: WP5430010), and Opti-MEM (source: Gibco, batch number: 2883564) is 1:4:14 (W:W:V). Add the encapsulated plasmid to an appropriate amount of complete cell culture medium and mix gently. Change the medium to the cells cultured previously. After 24 hours of transfection, collect the cells. Then use HBSS (source: White Shark, batch number: 24179687) to resuspend the cells and count them with a cell counter. Dilute the cells to a density of 3 to 5×10 5 Cells / mL were then plated at 100 μL / well into a flat-bottomed white 96-well microplate, with 3 to 5 × 10 cells per well. 4 First, add 10 μL of antagonist compounds diluted with HBSS at different concentrations into the wells, and then add the agonist compound at a specific concentration (EC80 ), after reacting for 2 minutes, add the substrate Furimazine (source: Taoshu, batch number: 362434) with a final concentration of 10 μM. After reacting for another 2 minutes, place the 96-well plate in a PHERAstar FSX microplate reader (source: BMG Labtech) and simultaneously detect the readings at 440 nm and 530 nm. Based on the fluorescence readings at 440 nm and 530 nm, calculate the Ratio value and net BRET value. Ratio = Em530nm / Em440nm, net BRET = Ratio co-transfer - Ratio single transfer. The calculated net BRET value was entered into Graphpad Prism 9, and the curve and IC were fitted using nonlinear regression (four-parameter equation). 50 calculate.

[0566] R-ZINC-3573 (Source: MCE, Catalog No.: HY-118069) has been reported to have an agonist effect on MRGPRX2 and was used as an agonist in this experiment. 50 See Table 1 for values.

[0567] Table 1 Note: 80μM>IC 50 >10μM is +, 10μM>IC 50 >1μM is ++, 1μM>IC 50 >0.1μM is +++.

[0568] 2. In vivo efficacy experiments:

[0569] 2.1 Rosacea

[0570] Experimental animals: BALB / c mice, Guangdong Weitonglihua Experimental Animal Technology Co., Ltd.

[0571] Model building:

[0572] The hair on the back of the mouse was shaved, and the modeling area was marked on the back skin, avoiding the area with rich subcutaneous blood vessels. LL-37 (an antimicrobial peptide used for rosacea modeling) (Source: Qiangyao Biology, Batch No.: 20240319) solution was drawn up with a microsyringe and injected into the skin along the intradermal route. The solution was slowly withdrawn after injection. The modeling lasted for 5 to 7 days, twice a day.

[0573] Animals were divided into groups and dosed:

[0574] The drug was administered on the day of grouping, defined as D1, and continued for 7 consecutive days, once a day. The normal control group and the model control group were only administered with the vehicle under the same conditions. The changes in the skin lesions at the injection site on the back of each group of mice were observed, and scores were given in the range of 0 to 4 according to the degree of erythema, where no erythema was scored as 0, vaguely visible erythema was scored as 1, pale erythema with blurred boundaries was scored as 2, erythema with clear boundaries was scored as 3, and erythema with dark color and clear boundaries was scored as 4. The dosing regimen of the mouse rosacea model is as follows:

[0575] The experimental results showed that the model group (solvent administration) developed typical rosacea-like skin lesions with obvious erythema, while the blank group (solvent administration) had no abnormal skin symptoms. The example group significantly improved erythema symptoms during the experimental period, which was statistically significant. The erythema scores of each group are shown in Table 2. The data are expressed as mean ± standard error (SEM).

[0576] Table 2 *Compared with the model control group, P<0.05; **Compared with the model control group, P<0.01.

[0577] 2.2 Psoriasis

[0578] Experimental animals: BALB / c mice, Guangdong Weitonglihua Experimental Animal Technology Co., Ltd.

[0579] The severity of psoriasis clinical disease was assessed using the Psoriasis Activity and Severity Index (PASI) score. The PASI scoring criteria for mice are as follows:

[0580] Model building:

[0581] The hair on the back of the mice was shaved, and the application area was marked with a marker. Imiquimod cream (source: Sichuan Mingxin Pharmaceutical, batch number: 24054002) was applied to the back of the mice for several consecutive days to establish a psoriasis mouse model. Pure water was used to remove the residual cream before application every day.

[0582] Animals were divided into groups and dosed:

[0583] Dosing began on the day of grouping, designated Day 1, and continued for 8 consecutive days, once daily. The normal control group and the model control group were administered only the vehicle under the same conditions. Mice were scored according to the PASI (Psoriasis Area and Severity Index). The dosing regimen for the mouse psoriasis model is as follows:

[0584] The experimental results showed that the model group developed typical psoriasis-like lesions: erythema, scaling, and skin thickening. The blank group had no abnormal skin symptoms. The example group significantly improved psoriasis-like lesions at the end of the experiment, which was statistically significant. The PASI scores of each group are shown in Table 3. The data are expressed as mean ± standard error (SEM).

[0585] Table 3 *Compared with the model control group, P<0.05; **Compared with the model control group, P<0.01.

[0586] 2.3 Urticaria

[0587] Experimental animals: BALB / c mice, Hangzhou Ziyuan Experimental Animal Technology Co., Ltd.

[0588] Model building:

[0589] Mice were randomly divided into groups and pre-haired on their backs, with the hair removed in an area of ​​approximately 2 cm x 2 cm. All mice, except the normal control group, were sensitized by tail vein injection of anti-dinitrobenzene monoclonal antibody (Source: Sigma-Aldrich, Lot No.: 0000241402) (0.2 ng / mL) at 0.5 mL per mouse. Twenty-four hours later, 50 μL of 0.15% dinitrofluorobenzene (Source: Shanghai MacLean, Lot No.: C14969320) was applied to the back of both ears of each sensitized group for challenge. The normal control group received both injections and smears of normal saline under the same conditions.

[0590] The dosing regimen for the mouse urticaria model is as follows (the normal control group and the model control group were administered only the vehicle under the same conditions) (once a day):

[0591] The experimental results showed that the model group had typical urticaria wheal symptoms, the blank group had no abnormal skin symptoms, the embodiment group significantly improved the number of wheals at the end of the experiment, which was statistically significant, and the serum IgE and histamine test results after the experiment were significantly improved, which was statistically significant. The number of wheals, serum IgE and histamine levels in each group are shown in Table 4, and the data are expressed as mean ± standard error (SEM).

[0592] Mouse IgE ELISA detection kit: purchased from Shanghai ELISA Biotechnology Co., Ltd., batch number: ml1037602.

[0593] Mouse histamine ELISA detection kit: purchased from Shanghai ELISA Biotechnology Co., Ltd., batch number: ml1001877.

[0594] ELISA detector, manufacturer: BioTeK, model: Epoch.

[0595] Table 4 *Compared with the model control group, P<0.05; **Compared with the model control group, P<0.01.

[0596] 2.4 Atopic dermatitis

[0597] Experimental animals: BALB / c mice, Guangdong Weitonglihua Experimental Animal Technology Co., Ltd.

[0598] Model building:

[0599] MC903 (calcipotriol) (source: Taoshu, batch number: 235760) was applied to the right ear of the mice once a day for 14 days.

[0600] Animal grouping and drug administration:

[0601] Animals were randomly divided into 6 groups before induction on day 1. The model control group was given only the vehicle under the same conditions. The groups were dosed as follows: Note: BID, twice a day; po, oral administration.

[0602] During the experiment, the thickness of the right ears of the mice was measured. The results showed that the thickness of the right ears of the mice decreased in all the example groups compared with the model group, which was statistically significant. The data are expressed as mean ± standard error (SEM). *Compared with the model control group, P<0.05; **Compared with the model control group, P<0.01.

[0603] 2.5 Inflammatory bowel disease (IBD)

[0604] Experimental animals: C57BL / 6 mice, Guangdong Weitonglihua Experimental Animal Technology Co., Ltd.

[0605] Model building and grouping:

[0606] C57BL / 6 mice were used, and a 3% DSS (dextran sulfate sodium) (source: MPBIO, batch number: YD11024) aqueous solution was prepared as drinking water for the mice. Note: QD, once a day; po, oral administration; the solvent is the dosing solvent of the preparation example.

[0607] During the experiment, the animals were weighed regularly every day, their status (including feces and death) was observed, and the efficacy was evaluated by DAI scoring. DAI scoring criteria: 0 points for normal feces, 1 point for soft but visible feces, 2 points for soft and loose feces, 3 points for soft and moist feces, 4 points for loose feces; 0-1 point for no occult blood, 2 points for positive occult blood, 3 points for visible blood in stool, 4 points for severe blood in stool; 0 point for no weight loss or increase, 1 point for a weight loss of 1%-5%, 2 points for a weight loss of 6%-10%, 3 points for a weight loss of 11%-15%, and 4 points for a weight loss of more than 15%. The sum of the three total scores is the total DAI score, and the animals are weighed and scored every other day. The experimental results showed that the drug-treated group showed significant efficacy and was statistically significant. The DAI scores are shown in Table 5, and the data are expressed as mean ± standard error (SEM):

[0608] Table 5 *Compared with the model control group, P<0.05; **Compared with the model control group, P<0.01; ***Compared with the model control group, P<0.001.

[0609] 2.6 Allergic rhinitis

[0610] Experimental animals: BALB / c mice, Guangdong Weitonglihua Experimental Animal Technology Co., Ltd.

[0611] Model building

[0612] Modeling began on the day of grouping, defined as M1. Except for the normal group, each mouse in all modeling groups received an intraperitoneal injection of 250 μg of OVA (ovalbumin) mixed with 5 mg aluminum hydroxide / mL (source: Shanghai McLean, batch number: C16255388), while the normal control group received an equal amount of sterile PBS solution. The injection time period was M1, M7, and M14. Starting from M21, the mice were challenged once a day with 50 mg / mL OVA solution, with a volume of 10 μl in each nostril each time. No nasal drops were performed on the normal control group.

[0613] Animal grouping and drug administration

[0614] Dosing began on the day of nasal provocation, defined as Day 1, and continued for 7 consecutive days, once daily. The normal control group and the model control group were administered only the vehicle under the same conditions. The dosing regimen for the mouse allergic rhinitis model was as follows:

[0615] Evaluation indicators

[0616] Rhinitis symptom score

[0617] During the drug administration period, the number of sneezes in each group was recorded 10 minutes after nasal drop stimulation every day.

[0618] During the experiment, allergic rhinitis model mice developed typical symptoms: shortness of breath, scratching of the ears and nose, and sneezing. Compared with the model group, the example group showed a significant reduction in the number of sneezes. The count results for each group are shown in Table 6, with the unit being (sneezes / mouse). Data are expressed as mean ± standard error (SEM).

[0619] Table 6 Note: The unit is the number of sneezes / sneezes.

[0620] IgE testing

[0621] Before dissection, blood was collected from the eyeballs. After collecting the mouse blood, it was centrifuged at 1800 rpm at 4°C for 15 min, and the upper serum was collected and aliquoted and stored at -80°C for testing. Nasal lavage fluid and tracheal tissue were also collected. The IgE content of the above three samples was detected by ELISA (Source: Shanghai ELISA Biotechnology Co., Ltd., Batch No.: ml1037602).

[0622] IgE detection (ELISA, BioTeK, Epoch): Compared with the model group, the embodiment group can significantly reduce the IgE content in peripheral blood, nasal lavage fluid and tracheal tissue. The results of peripheral blood, nasal lavage fluid and tracheal tissue of each group are shown in Table 7.

[0623] Table 7 *Compared with the model control group, P<0.05; **Compared with the model control group, P<0.01.

[0624] 2.7 Asthma

[0625] Experimental animals: BALB / c mice, Guangdong Weitonglihua Experimental Animal Technology Co., Ltd.

[0626] Model building

[0627] Modeling began on the day of grouping, which was defined as M1. Except for the normal group, each mouse in all modeling groups received an intraperitoneal injection of 500 μg of OVA (ovalbumin) mixed with 5 mg aluminum hydroxide / mL (source: Shanghai McLean, batch number: C16255388) to sensitize the mice. The normal control group received an equal amount of sterile PBS solution. The injection cycles were M1, M7, and M14. Starting from M21, continuous nebulization challenge was performed for 7 days with a 20 mg / mL OVA (ovalbumin) solution. Each nebulization challenge lasted 30 minutes. The normal control group did not undergo nebulization.

[0628] Animal grouping and drug administration

[0629] Dosing began on day M21, defined as D1, and continued for 7 consecutive days, once daily. The normal control group and the model control group were administered only the vehicle under the same conditions. The dosing regimen for the mouse asthma model is as follows:

[0630] Evaluation indicators

[0631] Bronchoalveolar lavage (BALF) cell differential count

[0632] The lungs were gently lavaged twice with normal saline, and BALF was collected. The recovered BALF was stored at 4°C and analyzed for cell differential counts using a fully automated hematology analyzer (source: SYSMEX, model XN-1000). During the experiment, the asthma model mice developed typical symptoms: shortness of breath and scratching of the ears and nose. Compared with the model group, the Example group significantly reduced the number of inflammatory cells in the BALF. The results of BALF cell differential counts in each group are shown in Table 8. Data are expressed as mean ± standard error (SEM).

[0633] Table 8 *Compared with the model control group, P<0.05; **Compared with the model control group, P<0.01; ***Compared with the model control group, P<0.001.

[0634] Serum IgE test

[0635] Before dissection, blood was collected from the eyeballs. After collecting the blood, the mice were centrifuged at 1800 rpm for 15 minutes at 4°C. The upper serum layer was aliquoted and stored at -80°C for testing. Simultaneously, bronchoalveolar lavage fluid and lung tissue were collected. The IgE content of these three samples was tested using ELISA (Source: Shanghai ELISA Biotechnology Co., Ltd., Lot No. ml1037602). Compared with the model group, the example group significantly reduced the IgE content in peripheral blood, bronchoalveolar lavage fluid, and lung tissue. The results of the IgE content in peripheral blood, lavage fluid, and lung tissue of each group are shown in Table 9. Data are expressed as mean ± standard error (SEM).

[0636] Table 9 Note: *: compared with the model control group, P < 0.05, **: compared with the model control group, P < 0.01, ***: compared with the model control group, P < 0.001.

[0637] ELISA detector, manufacturer: BioTeK, model: Epoch.

[0638] The embodiments provided above are not intended to limit the scope of the present invention, and the steps described are not intended to limit the order in which they are performed. Based on this disclosure, those skilled in the art can make obvious improvements to the present invention in combination with existing technologies, which also fall within the scope of protection defined by the claims of the present invention.

Claims

1. A compound of formula (IA), a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, which is used for treating or preventing an MRGPRX2-mediated disease or disorder, Wherein: R1 is -C 3-6 cycloalkyl or -C 1-6 linear or branched alkyl; R2 is -COOH, -COOC 1-6 a straight-chain or branched alkyl group, -C(O)NH2, -C(O)-NH-C 1-6 a straight-chain or branched alkyl group, -C(O)-N(C 1-6 a straight-chain or branched alkyl group)2 or -C(O)-NH-OH; R3 is a halogen; B1 is -CR6 or N, where R6 is H, halogen or -O-C 1-6 a straight-chain or branched alkyl group; A is C 6-10 aryl or 5- to 6-membered heteroaryl; R4 is selected from -S(O)2-NH2, -S(O)2-NHR a , -S(O)2-NR b R c , -S(O)-NH2, -S(O)-NH-R a , -S(O)-NR b R c , -S-NH2, -S-NH-R a , -S-NR b R c , -S(O)2-R a , -S(O)-R a , -NH-S(O)2-R a , -C(O)-NH2, -C(O)-NH-R a , -C(O)-NR b R c , -NH-C(O)-R a , -C(O)-R a , -NHR c , -S-R d and NO2; R a and R d are each independently selected from C 1-20 linear or branched alkyl, C 2-20 linear or branched alkenyl, C 2-20 linear or branched alkynyl, C 3-10 cycloalkyl having from 3 to 10 carbon atoms and 4-10 membered heterocycloalkyl, wherein said heterocycloalkyl contains one or more heteroatoms selected from N, O and S, and said alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally substituted by 1, 2 or 3 substituents selected from the following: halogen, -OH, -NH2, -CN, -NO2, -SC 1-6 linear or branched alkyl, -OC 1-6 linear or branched alkyl, -NHC 1-6 linear or branched alkyl and -N(C 1-6 linear or branched alkyl)2; R b and R c together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl group, said heterocycloalkyl group containing one or more heteroatoms selected from N, O and S, and said heterocycloalkyl group being optionally substituted by 1, 2 or 3 substituents selected from the following: halogen, -OH, -NH2, -CN, -NO2, -SC 1-6 straight-chain or branched-chain alkyl, -OC 1-6 straight-chain or branched-chain alkyl, -NHC 1-6 straight-chain or branched-chain alkyl and -N(C 1-6 straight-chain or branched-chain alkyl)2; R5 is selected from halogen, -CN, -NH2, -OH, -NH-C 1-6 a straight-chain or branched-chain alkyl group, -N(C 1-6 a straight-chain or branched-chain alkyl group)2, C 1-6 a straight-chain or branched-chain alkyl group, C 1-6 a straight-chain or branched-chain alkoxy group, -C(O)-NH2, -C(O)-NH-C 1-6 a straight-chain or branched-chain alkyl group, -C(O)-N(C 1-6 a straight-chain or branched-chain alkyl group)2 and -NH-C(O)-C 1-6 a halogenated straight-chain or branched-chain alkyl group; and n is 0, 1, 2 or 3.

2. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for use in the use according to any one of the preceding claims, wherein, R1 is 3. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for use in the use according to any one of the preceding claims, wherein, R2 is -COOH, -COOC 1-3 a straight or branched alkyl group or -C(O)NH2.

4. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for use in the use according to any one of the preceding claims, wherein, R3 is F.

5. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for use in the use according to any one of the preceding claims, wherein, B1 is -CR6 or N, where R6 is H, halogen or -O-C 1-3 a straight-chain or branched alkyl group.

6. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for use in the use according to any one of the preceding claims, wherein, A is phenyl or pyridyl.

7. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for use in the use according to any one of the preceding claims, wherein, R4 is selected from -S(O)2-NH2, -S(O)2-NHR a , -S(O)2-NR b R c , -S(O)-NH-R a , -S-NH-R a , -S(O)-R a , -NH-S(O)2-R a , -C(O)-NH2, -C(O)-NH-R a , -NH-C(O)-R a , -NHR d and -S-R d .

8. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for use in the use according to any one of the preceding claims, wherein, R4 is selected from -S(O)2-NH2, -S(O)2-NHR a and -S(O)2-NR b R c .

9. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for use in the use according to any one of the preceding claims, wherein, R a selected from C 1-15 linear or branched alkyl, C 3-6 cycloalkyl having 3 to 6 members and heterocycloalkyl having 4 to 6 members, wherein said heterocycloalkyl contains 1, 2 or 3 heteroatoms selected from N, O and S, and said alkyl is optionally substituted with 1, 2 or 3 substituents selected from the following: halogen, -OH, -NH2 and -CN; for example, R a is C 1-15 linear alkyl, and said alkyl is optionally substituted with 1, 2 or 3 halogens.

10. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for use in the use according to any one of the preceding claims, wherein, R d selected from C 1-6 a straight-chain or branched-chain alkyl group, C 2-6 a straight-chain or branched-chain alkenyl group, and C 2-6 a straight-chain or branched-chain alkynyl group, wherein the alkyl, alkenyl or alkynyl group is optionally substituted with 1, 2 or 3 substituents selected from: halogen, -OH, and -CN.

11. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for use in the use according to any one of the preceding claims, wherein, R b and R c together with the N atom to which they are attached form a 4-6 membered heterocycloalkyl group containing 1 or 2 heteroatoms selected from N, O and S, said heterocycloalkyl group being optionally substituted by 1, 2 or 3 substituents selected from: halogen, -OH, -NH2 and -CN.

12. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for use in the use according to any one of the preceding claims, wherein, R5 is selected from halogen, -CN, -NH2, -OH, -NH-C 1-6 a straight-chain or branched-chain alkyl group, C 1-6 a straight-chain or branched-chain alkyl group and C 1-6 a straight-chain or branched-chain alkoxy group.

13. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for use in the use according to any one of the preceding claims, wherein, n is 0 or 1.

14. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for the use according to any one of the preceding claims 1, wherein: R1 is R2 is -COOH or -COOC 1-3 a straight-chain or branched-chain alkyl group; for example, -COOH or -COOCH3; R3 is F; B1 is -CR6 or N, where R6 is H, halogen or -O-C 1-3 a straight-chain or branched alkyl group, such as H, F or -O-CH3; A is phenyl or pyridyl; R4 is selected from -S(O)2-NH2, -S(O)2-NHR a , -S(O)2-NR b R c , -NH-S(O)2-R a , -C(O)-NH2, -C(O)-NH-R a , -C(O)-NR b R c and -NH-C(O)-R a ; R a selected from C 1-12 a straight-chain or branched-chain alkyl group, a C 3-6 cycloalkyl group having 3 to 6 carbon atoms, and a 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms selected from N, O, and S, wherein the alkyl group is optionally substituted by 1, 2, or 3 substituents selected from the following: halogen and -OH; R b and R c together with the N atom to which they are attached form a 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms selected from N, O and S, said heterocycloalkyl group being optionally substituted by 1, 2 or 3 halogens; and n is 0.

15. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for use in the use according to any one of the preceding claims, wherein the compound is selected from:

16. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for use in the use according to any one of claims 1-15, wherein, The disease or disorder is especially a disease or disorder caused by mast cell degranulation, and the disease or disorder is preferably selected from autoimmune diseases, allergic diseases, inflammatory diseases, pruritus and pain, and the disease or disorder is preferably selected from psoriasis, atopic dermatitis, inflammatory bowel disease (IBD), chronic urticaria, allergic rhinitis, asthma, alopecia areata, urticaria, allergic urticaria, rosacea, radiodermatitis, eczema, pseudoallergic reaction, anaphylactic shock, generalized pruritus, neurogenic pruritus, nodular prurigo, neurogenic inflammation, ulcerative colitis, Crohn's disease, irritable bowel syndrome, respiratory inflammation, postoperative pain, and vitiligo.

17. A method for antagonizing MRGPRX2 in vitro, the method comprising using an effective amount of a compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof as defined in any one of the preceding claims 1-15 in an in vitro test of MRGPRX2.

18. A compound of formula (IB), a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, Wherein: R1 is -C 3-6 cycloalkyl or -C 1-6 a linear or branched alkyl group; R2 is -COOH or -COOC 1-6 a straight-chain or branched-chain alkyl group; R3 is a halogen; B1 is -CR6 or N, where R6 is H, halogen or -O-C 1-6 a straight-chain or branched alkyl; and A is phenyl; and R4 is selected from -S(O)2-NH-C 8-12 a straight-chain or branched alkyl group, -S(O)2-NH-C 1-6 a straight-chain or branched alkyl group-CF3, -S(O)2-NH-cyclohexyl, -S(O)2-NR b R c 、-S(O)-NH-C 1-6 a straight-chain or branched alkyl group-CF3, -S-NH-C 1-6 a straight-chain or branched alkyl group-CF3, -NH-S(O)2-C 1-6 a straight-chain or branched alkyl group, -C(O)-NH2, -C(O)-NH-C 2-6 a straight-chain or branched alkyl group, -C(O)-NR b R c 、-NH-C(O)-CF3, -NH-C(O)-CH2Cl, -NH-C 1-6 a straight-chain or branched alkyl group, -NH-C 1-6 a straight-chain or branched alkenyl group and -NH-C 1-6 a straight-chain or branched alkynyl group; wherein, R b and R c together with the N atom to which they are attached form azetidinyl or difluoroazetidinyl; Alternatively, A is a pyridyl group; and R4 is selected from -S(O)2-NH2, -S(O)2-NH-CH2CH2OH, -S(O)2-NH-CH2CH2Cl, -S(O)2-NH-C 4-6 a straight-chain or branched-chain alkyl group, -S(O)2-NH-C 8-12 a straight-chain or branched-chain alkyl group, -S(O)2-NH-cyclohexyl, -S(O)2-NH-tetrahydropyranyl, -S(O)2-NR b R c -, -S(O)-NH-C 1-6 a straight-chain or branched-chain alkyl group, -S-NH-C 1-6 a straight-chain or branched-chain alkyl group -CF3, -NH-S(O)2-C 2-6 a straight-chain or branched-chain alkyl group, -C(O)-NH-C 3-6 a branched-chain alkyl group, -C(O)-NR b R c -, -NH-C(O)-CF2, -NH-C(O)-CH2CF3, -NH-C 1-6 a straight-chain or branched-chain alkyl group and -S-C 1-6 a hydroxy straight-chain or branched-chain alkyl group; wherein, R b and R c together with the N atom to which they are attached form an azetidinyl, difluoroazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl group.

19. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof according to any one of the preceding claims, wherein, R1 is 20. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof according to any one of the preceding claims 1-7, wherein, R2 is -COOH or -COOCH3.

21. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof according to any one of the preceding claims, wherein, R3 is F.

22. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof according to any one of the preceding claims, wherein, B1 is -CR6 or N, wherein R6 is H, F, Cl or -OCH3.

23. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof according to any one of the preceding claims, wherein, A is phenyl; and R4 is selected from -S(O)2-NH-C 8-10 a straight-chain alkyl group, -S(O)2-NH-C 2-4 a straight-chain alkyl group-CF3, -S(O)2-NH-cyclohexyl, -S(O)2-NR b R c , -NH-S(O)2-C 2-4 a straight-chain alkyl group, -C(O)-NH2, -C(O)-NH-C 2-6 a straight-chain or branched-chain alkyl group, -NH-C(O)-CF3, -NH-C 2-4 a straight-chain alkyl group and -NH-C 2-4 a straight-chain alkenyl group; wherein, R b and R c together with the N atom to which they are attached form azetidinyl or difluoroazetidinyl.

24. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof according to any one of the preceding claims, wherein, A is a pyridyl group; and R4 is selected from -S(O)2-NH2, -S(O)2-NH-CH2CH2OH, -S(O)2-NH-CH2CH2Cl, -S(O)2-NH-C 4-6 a straight-chain alkyl group, -S(O)2-NH-C 8-10 a straight-chain alkyl group, -S(O)2-NH-cyclohexyl, -S(O)2-NH-tetrahydropyranyl, -S(O)2-NR b R c , -NH-S(O)2-C 2-4 a straight-chain alkyl group, -C(O)-NH-C 3-6 a branched-chain alkyl group, -NH-C(O)-CF2, -NH-C(O)-CH2CF3, and -S-C 2-4 a hydroxy straight-chain alkyl group; wherein, R b and R c together with the N atom to which they are attached form azetidinyl, difluoroazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; for example, A is pyridyl; and R4 is selected from -S(O)2-NH2, -S(O)2-NH-cyclohexyl, -S(O)2-NH-tetrahydropyranyl, -S(O)2-NR b R c , -NH-C(O)-CF2 and -NH-C(O)-CH2CF3; wherein, R b and R c together with the N atom to which they are attached form azetidinyl, difluoroazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.

25. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof according to any one of the preceding claims, wherein, R1 is For example R2 is -COOH or -COOC 1-3 a straight-chain or branched-chain alkyl group; for example, -COOH or -COOCH3; R3 is F; B1 is -CR6 or N, where R6 is H, halogen or -O-C 1-3 a straight-chain or branched alkyl group such as H, F, Cl or -O-CH3; and A is phenyl; and R4 is selected from -S(O)2-NH-C 8-10 a straight-chain alkyl group, -S(O)2-NH-C 2-4 a straight-chain alkyl group-CF3, -S(O)2-NR b R c -, -C(O)-NH-C 2-6 a straight-chain or branched-chain alkyl group, -NH-C(O)-CF3 and -NH-C 2-4 a straight-chain alkenyl group; wherein, R b and R c together with the N atom to which they are attached form a difluoroazetidinyl ring; Alternatively, A is a pyridyl group; and R4 is selected from -S(O)2-NH2, -S(O)2-NH-cyclohexyl, -S(O)2-NH-tetrahydropyranyl, -S(O)2-NR b R c , -NH-C(O)-CF2, and -NH-C(O)-CH2CF3; wherein R b and R c together with the N atom to which they are attached form an azetidinyl, difluoroazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl group.

26. Compounds selected from: or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof.

27. A pharmaceutical composition, which comprises the compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof according to any one of claims 18-26, and a pharmaceutically acceptable excipient.

28. The compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof according to any one of claims 18-26, which is used as a drug.

29. The compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof according to any one of claims 18-26, which is used for treating or preventing a disease or disorder mediated by MRGPRX2, especially a disease or disorder caused by mast cell degranulation, and the disease or disorder is preferably selected from autoimmune diseases, allergic diseases, inflammatory diseases, pruritus and pain, and the disease or disorder is more preferably selected from psoriasis, atopic dermatitis, inflammatory bowel disease (IBD), chronic urticaria, allergic rhinitis, asthma, alopecia areata, urticaria, allergic urticaria, rosacea, radiodermatitis, eczema, pseudoallergic reaction, anaphylactic shock, generalized pruritus, neurogenic pruritus, nodular prurigo, neurogenic inflammation, ulcerative colitis, Crohn's disease, irritable bowel syndrome, respiratory inflammation, postoperative pain, and vitiligo.

30. A pharmaceutical combination comprising the compound according to any one of claims 18 - 26 or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, and one or more other therapeutic agents.

31. A method for antagonizing MRGPRX2 in vitro, the method comprising using an effective amount of the compound according to any one of claims 18 - 26 or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof in an in vitro test for MRGPRX2.